AVAHO

AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.

Neil Osterweil/MDedge News

The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.

Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.

“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.

In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.

Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.

The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.

At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.

Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).

The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.

Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.

The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.

SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.

AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.

Neil Osterweil/MDedge News

The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.

Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.

“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.

In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.

Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.

The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.

At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.

Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).

The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.

Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.

The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.

SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.

AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.

Neil Osterweil/MDedge News

The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.

Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.

“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.

In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.

Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.

The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.

At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.

Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).

The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.

Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.

The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.

SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.

LUGANO, Switzerland – Adding the immunomodulator lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone, investigators in the phase 3 ROBUST trial found.

Among 570 patients with activated B-cell (ABC) type DLBCL followed for a median of 27.1 months, median progression-free survival (PFS) – the primary endpoint – had not been reached either for patients randomized to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone) plus lenalidomide (R2-CHOP) or R-CHOP plus placebo.

The 1-year and 2-year PFS rate with R2-CHOP was 77%, compared with 75% for R-CHOP, and 2-year PFS rates were 67% and 64%, respectively, and neither comparison was statistically significant reported Umberto Vitolo, MD, from the Citta della Salute e della Scienzia Hospital and University in Turin, Italy.“The future direction is that promising preclinical data with next-generation immunomodulatory agents will be evaluated in future DLBCL clinical trials,” he said at the International Conference on Malignant Lymphoma.

The ROBUST trial is the latest in a long line of studies that failed to show improvement in outcomes with the addition of a novel agent to R-CHOP.

The rationale for adding lenalidomide to R-CHOP came from in-vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non–germinal center–like B (GCB) type DLBCL, Dr. Vitolo said.

In the ROBUST trial, investigators across 257 global sites enrolled 570 patients with ABC-type DLBCL, stratified them by International Prognostic Index (IPI) score (2 vs. 3 or greater), bulky disease (less than 7 cm vs. 7 cm or more), and age (younger than 65 years vs. 65 years and older) and randomly assigned them to receive R-CHOP with either oral lenalidomide 15 mg or placebo daily on days 1-14 of each 21-day cycle for six cycles.

All patients were required to have neutropenia prophylaxis according to local practice, with either a granulocyte- or granulocyte-macrophage colony-stimulating factor.

The efficacy analysis was by intention-to-treat and included 285 patients in each arm.

The investigators found no significant difference in the primary endpoint of PFS. Overall response rates (ORR) and complete response (CR) rates were high in both arms. The ORR was 91% in each arm, and the CR rate was 69% for R2-CHOP and 65% for R-CHOP.

Event-free survival (EFS) – a composite of first disease progression, death, or relapse after CR or start of second-line therapy – also did not differ significantly between the groups. The 1-year and 2-year EFS rates were 68% vs. 71% and 59% vs. 61%, respectively. The median EFS was not reached in either arm.

Similarly, overall survival did not differ between the groups. At 48 months of follow-up, 57 patients in the R2-CHOP arm and 62 patients in the R-CHOP arm had died. Respective 1- and 2-year overall survival rates were 91% vs. 90%, and 79% vs. 80%.

In the safety analysis, which included 283 patients in the R2-CHOP arm and 284 in the placebo/R-CHOP arm, there were no new safety signals observed. In all, 78% of patients in the lenalidomide arm and 71% in the placebo arm had at least one grade 3 or greater adverse events. The most common adverse events were hematologic, including neutropenia, febrile neutropenia, anemia, thrombocytopenia, and leukopenia.

The ROBUST study was funded by Celgene. Dr. Vitolo reported consulting and speaker’s bureau fees and research funding from the company.

SOURCE: Vitolo U et al. 15-ICML, Abstract 005.

LUGANO, Switzerland – Adding the immunomodulator lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone, investigators in the phase 3 ROBUST trial found.

Among 570 patients with activated B-cell (ABC) type DLBCL followed for a median of 27.1 months, median progression-free survival (PFS) – the primary endpoint – had not been reached either for patients randomized to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone) plus lenalidomide (R2-CHOP) or R-CHOP plus placebo.

The 1-year and 2-year PFS rate with R2-CHOP was 77%, compared with 75% for R-CHOP, and 2-year PFS rates were 67% and 64%, respectively, and neither comparison was statistically significant reported Umberto Vitolo, MD, from the Citta della Salute e della Scienzia Hospital and University in Turin, Italy.“The future direction is that promising preclinical data with next-generation immunomodulatory agents will be evaluated in future DLBCL clinical trials,” he said at the International Conference on Malignant Lymphoma.

The ROBUST trial is the latest in a long line of studies that failed to show improvement in outcomes with the addition of a novel agent to R-CHOP.

The rationale for adding lenalidomide to R-CHOP came from in-vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non–germinal center–like B (GCB) type DLBCL, Dr. Vitolo said.

In the ROBUST trial, investigators across 257 global sites enrolled 570 patients with ABC-type DLBCL, stratified them by International Prognostic Index (IPI) score (2 vs. 3 or greater), bulky disease (less than 7 cm vs. 7 cm or more), and age (younger than 65 years vs. 65 years and older) and randomly assigned them to receive R-CHOP with either oral lenalidomide 15 mg or placebo daily on days 1-14 of each 21-day cycle for six cycles.

All patients were required to have neutropenia prophylaxis according to local practice, with either a granulocyte- or granulocyte-macrophage colony-stimulating factor.

The efficacy analysis was by intention-to-treat and included 285 patients in each arm.

The investigators found no significant difference in the primary endpoint of PFS. Overall response rates (ORR) and complete response (CR) rates were high in both arms. The ORR was 91% in each arm, and the CR rate was 69% for R2-CHOP and 65% for R-CHOP.

Event-free survival (EFS) – a composite of first disease progression, death, or relapse after CR or start of second-line therapy – also did not differ significantly between the groups. The 1-year and 2-year EFS rates were 68% vs. 71% and 59% vs. 61%, respectively. The median EFS was not reached in either arm.

Similarly, overall survival did not differ between the groups. At 48 months of follow-up, 57 patients in the R2-CHOP arm and 62 patients in the R-CHOP arm had died. Respective 1- and 2-year overall survival rates were 91% vs. 90%, and 79% vs. 80%.

In the safety analysis, which included 283 patients in the R2-CHOP arm and 284 in the placebo/R-CHOP arm, there were no new safety signals observed. In all, 78% of patients in the lenalidomide arm and 71% in the placebo arm had at least one grade 3 or greater adverse events. The most common adverse events were hematologic, including neutropenia, febrile neutropenia, anemia, thrombocytopenia, and leukopenia.

The ROBUST study was funded by Celgene. Dr. Vitolo reported consulting and speaker’s bureau fees and research funding from the company.

SOURCE: Vitolo U et al. 15-ICML, Abstract 005.

LUGANO, Switzerland – Adding the immunomodulator lenalidomide (Revlimid) to standard chemotherapy for patients with newly diagnosed ABC-type diffuse large B-cell lymphoma (DLBCL) – the so-called R2-CHOP regimen – did not significantly improve either progression-free or overall survival, compared with R-CHOP alone, investigators in the phase 3 ROBUST trial found.

Among 570 patients with activated B-cell (ABC) type DLBCL followed for a median of 27.1 months, median progression-free survival (PFS) – the primary endpoint – had not been reached either for patients randomized to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone) plus lenalidomide (R2-CHOP) or R-CHOP plus placebo.

The 1-year and 2-year PFS rate with R2-CHOP was 77%, compared with 75% for R-CHOP, and 2-year PFS rates were 67% and 64%, respectively, and neither comparison was statistically significant reported Umberto Vitolo, MD, from the Citta della Salute e della Scienzia Hospital and University in Turin, Italy.“The future direction is that promising preclinical data with next-generation immunomodulatory agents will be evaluated in future DLBCL clinical trials,” he said at the International Conference on Malignant Lymphoma.

The ROBUST trial is the latest in a long line of studies that failed to show improvement in outcomes with the addition of a novel agent to R-CHOP.

The rationale for adding lenalidomide to R-CHOP came from in-vitro studies showing antiproliferative and immunomodulatory action of lenalidomide against DLBCL, as well as two proof-of-concept clinical studies (REAL07 and MC078E) indicating efficacy against non–germinal center–like B (GCB) type DLBCL, Dr. Vitolo said.

In the ROBUST trial, investigators across 257 global sites enrolled 570 patients with ABC-type DLBCL, stratified them by International Prognostic Index (IPI) score (2 vs. 3 or greater), bulky disease (less than 7 cm vs. 7 cm or more), and age (younger than 65 years vs. 65 years and older) and randomly assigned them to receive R-CHOP with either oral lenalidomide 15 mg or placebo daily on days 1-14 of each 21-day cycle for six cycles.

All patients were required to have neutropenia prophylaxis according to local practice, with either a granulocyte- or granulocyte-macrophage colony-stimulating factor.

The efficacy analysis was by intention-to-treat and included 285 patients in each arm.

The investigators found no significant difference in the primary endpoint of PFS. Overall response rates (ORR) and complete response (CR) rates were high in both arms. The ORR was 91% in each arm, and the CR rate was 69% for R2-CHOP and 65% for R-CHOP.

Event-free survival (EFS) – a composite of first disease progression, death, or relapse after CR or start of second-line therapy – also did not differ significantly between the groups. The 1-year and 2-year EFS rates were 68% vs. 71% and 59% vs. 61%, respectively. The median EFS was not reached in either arm.

Similarly, overall survival did not differ between the groups. At 48 months of follow-up, 57 patients in the R2-CHOP arm and 62 patients in the R-CHOP arm had died. Respective 1- and 2-year overall survival rates were 91% vs. 90%, and 79% vs. 80%.

In the safety analysis, which included 283 patients in the R2-CHOP arm and 284 in the placebo/R-CHOP arm, there were no new safety signals observed. In all, 78% of patients in the lenalidomide arm and 71% in the placebo arm had at least one grade 3 or greater adverse events. The most common adverse events were hematologic, including neutropenia, febrile neutropenia, anemia, thrombocytopenia, and leukopenia.

The ROBUST study was funded by Celgene. Dr. Vitolo reported consulting and speaker’s bureau fees and research funding from the company.

SOURCE: Vitolo U et al. 15-ICML, Abstract 005.

Controlling CNS disease is “paramount” in treating diffuse large B-cell lymphoma with synchronous CNS and systemic disease (synDLBCL), according to researchers.

Nephron/Wikimedia Commons/CC BY-SA 3.0

In a retrospective study, the CNS was the most common site of relapse in patients with synDLBCL, and patients had better outcomes when they received CNS-directed therapy.

The 2-year progression-free survival rate was 50% in patients who received CNS-intensive therapy and 31% in those who received CNS-conservative therapy. The 2-year overall survival rate was 54% and 44%, respectively.

Dr. Joel C. Wight, of Austin Health in Heidelberg, Australia, and colleagues conducted this study and recounted their findings in the British Journal of Haematology.

The researchers retrospectively analyzed 80 patients with synDLBCL treated at 10 centers in Australia and the United Kingdom. Patients had DLBCL not otherwise specified (n = 67); high-grade B-cell lymphoma, including double-hit lymphoma (n = 12); or T-cell histiocyte-rich DLBCL (n = 1).

At baseline, all patients were treatment-naive, they had a median age of 64 years (range, 18-87 years), and 68% were male. Seventy percent of patients had high-risk disease according to the CNS International Prognostic Index (IPI), and 96% had non-CNS extranodal disease. The median number of extranodal sites outside the CNS was 2 (range, 0 to more than 10).

Patients were divided into those who received CNS-intensive therapy (n = 38) and those given CNS-conservative therapy (n = 42). The CNS-conservative group was significantly older (P less than .001), significantly more likely to have high-risk disease according to the National Comprehensive Cancer Network IPI (P = .009) or CNS IPI (P = .01) and significantly more likely to have leptomeningeal disease only (P less than .001).
 

Treatment

CNS-intensive therapy was defined as any established multiagent IV chemotherapy regimen with two or more CNS-penetrating drugs and cytarabine, with or without intrathecal chemotherapy and/or radiotherapy.

CNS-conservative therapy was defined as one or fewer IV CNS-penetrating chemotherapy agents in induction, with or without intrathecal chemotherapy and/or radiotherapy.

Systemic induction in the CNS-intensive group consisted of R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with IV methotrexate and cytarabine) in 66% of patients and R-CODOX-M/IVAC (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, cytarabine) in 24% of patients.

The most common systemic induction regimens in the CNS-conservative group were R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimens, given to 83% of patients.

CNS-directed IV therapy was given to 100% of the CNS-intensive group and 60% of the CNS-conservative group. This consisted of IV methotrexate plus cytarabine (97%) or MATRix (methotrexate, cytarabine, and thiotepa; 3%) in the CNS-intensive group and high-dose methotrexate in the conservative group.

Intrathecal chemotherapy was given to 97% of the CNS-intensive group and 60% of the CNS-conservative group. CNS-directed radiation was given to 32% and 19%, respectively.

Thirteen patients in the CNS-intensive group and one in the CNS-conservative group underwent autologous transplant as consolidation.

Outcomes

Dose reductions were more frequent in the CNS-conservative group than in the CNS-intensive group, at 48% and 18% (P = .009), as was early cessation of chemotherapy, at 52% and 18% (P = .002). Rates of treatment-related mortality were similar, at 13% in the CNS-intensive group and 12% in the CNS-conservative group.

At the end of induction, the complete response rate was 69% in the CNS-intensive group and 51% in the CNS-conservative group (P = .16). Primary refractory disease was observed in 19% and 38% of patients, respectively (P = .07).

The CNS was the most common site of relapse or progression (n = 28). CNS progression or relapse occurred in 25% of the CNS-intensive group and 49% of the CNS-conservative group (P = .03).

The 2-year progression-free survival rate was 50% for the CNS-intensive group and 31% for the CNS-conservative group (P = .006). The 2-year overall survival rate was 54% and 44%, respectively (P = .037).

When patients were matched for induction outcomes, consolidative transplant did not improve survival.

“The most significant factor affecting survival was the ability to control the CNS disease, which was improved by the addition of IV cytarabine to [high-dose methotrexate],” the researchers wrote.

“Whilst the younger age and more intensive systemic treatment of the CNS-intensive group may have contributed to the improved survival, it is clear that CNS disease control was substantially improved by the addition of cytarabine with lower rates of CNS relapse/progression observed.”

The researchers noted that “adequate control of the CNS disease is paramount and is best achieved by intensive CNS-directed induction.”

There was no formal funding for this study, and the researchers did not provide financial disclosures.

jensmith@mdedge.com

SOURCE: Wight JC et al. Br J Haematol. 2019 Jun 24. doi: 10.1111/bjh.16064.

Controlling CNS disease is “paramount” in treating diffuse large B-cell lymphoma with synchronous CNS and systemic disease (synDLBCL), according to researchers.

Nephron/Wikimedia Commons/CC BY-SA 3.0

In a retrospective study, the CNS was the most common site of relapse in patients with synDLBCL, and patients had better outcomes when they received CNS-directed therapy.

The 2-year progression-free survival rate was 50% in patients who received CNS-intensive therapy and 31% in those who received CNS-conservative therapy. The 2-year overall survival rate was 54% and 44%, respectively.

Dr. Joel C. Wight, of Austin Health in Heidelberg, Australia, and colleagues conducted this study and recounted their findings in the British Journal of Haematology.

The researchers retrospectively analyzed 80 patients with synDLBCL treated at 10 centers in Australia and the United Kingdom. Patients had DLBCL not otherwise specified (n = 67); high-grade B-cell lymphoma, including double-hit lymphoma (n = 12); or T-cell histiocyte-rich DLBCL (n = 1).

At baseline, all patients were treatment-naive, they had a median age of 64 years (range, 18-87 years), and 68% were male. Seventy percent of patients had high-risk disease according to the CNS International Prognostic Index (IPI), and 96% had non-CNS extranodal disease. The median number of extranodal sites outside the CNS was 2 (range, 0 to more than 10).

Patients were divided into those who received CNS-intensive therapy (n = 38) and those given CNS-conservative therapy (n = 42). The CNS-conservative group was significantly older (P less than .001), significantly more likely to have high-risk disease according to the National Comprehensive Cancer Network IPI (P = .009) or CNS IPI (P = .01) and significantly more likely to have leptomeningeal disease only (P less than .001).
 

Treatment

CNS-intensive therapy was defined as any established multiagent IV chemotherapy regimen with two or more CNS-penetrating drugs and cytarabine, with or without intrathecal chemotherapy and/or radiotherapy.

CNS-conservative therapy was defined as one or fewer IV CNS-penetrating chemotherapy agents in induction, with or without intrathecal chemotherapy and/or radiotherapy.

Systemic induction in the CNS-intensive group consisted of R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with IV methotrexate and cytarabine) in 66% of patients and R-CODOX-M/IVAC (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, cytarabine) in 24% of patients.

The most common systemic induction regimens in the CNS-conservative group were R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimens, given to 83% of patients.

CNS-directed IV therapy was given to 100% of the CNS-intensive group and 60% of the CNS-conservative group. This consisted of IV methotrexate plus cytarabine (97%) or MATRix (methotrexate, cytarabine, and thiotepa; 3%) in the CNS-intensive group and high-dose methotrexate in the conservative group.

Intrathecal chemotherapy was given to 97% of the CNS-intensive group and 60% of the CNS-conservative group. CNS-directed radiation was given to 32% and 19%, respectively.

Thirteen patients in the CNS-intensive group and one in the CNS-conservative group underwent autologous transplant as consolidation.

Outcomes

Dose reductions were more frequent in the CNS-conservative group than in the CNS-intensive group, at 48% and 18% (P = .009), as was early cessation of chemotherapy, at 52% and 18% (P = .002). Rates of treatment-related mortality were similar, at 13% in the CNS-intensive group and 12% in the CNS-conservative group.

At the end of induction, the complete response rate was 69% in the CNS-intensive group and 51% in the CNS-conservative group (P = .16). Primary refractory disease was observed in 19% and 38% of patients, respectively (P = .07).

The CNS was the most common site of relapse or progression (n = 28). CNS progression or relapse occurred in 25% of the CNS-intensive group and 49% of the CNS-conservative group (P = .03).

The 2-year progression-free survival rate was 50% for the CNS-intensive group and 31% for the CNS-conservative group (P = .006). The 2-year overall survival rate was 54% and 44%, respectively (P = .037).

When patients were matched for induction outcomes, consolidative transplant did not improve survival.

“The most significant factor affecting survival was the ability to control the CNS disease, which was improved by the addition of IV cytarabine to [high-dose methotrexate],” the researchers wrote.

“Whilst the younger age and more intensive systemic treatment of the CNS-intensive group may have contributed to the improved survival, it is clear that CNS disease control was substantially improved by the addition of cytarabine with lower rates of CNS relapse/progression observed.”

The researchers noted that “adequate control of the CNS disease is paramount and is best achieved by intensive CNS-directed induction.”

There was no formal funding for this study, and the researchers did not provide financial disclosures.

jensmith@mdedge.com

SOURCE: Wight JC et al. Br J Haematol. 2019 Jun 24. doi: 10.1111/bjh.16064.

Controlling CNS disease is “paramount” in treating diffuse large B-cell lymphoma with synchronous CNS and systemic disease (synDLBCL), according to researchers.

Nephron/Wikimedia Commons/CC BY-SA 3.0

In a retrospective study, the CNS was the most common site of relapse in patients with synDLBCL, and patients had better outcomes when they received CNS-directed therapy.

The 2-year progression-free survival rate was 50% in patients who received CNS-intensive therapy and 31% in those who received CNS-conservative therapy. The 2-year overall survival rate was 54% and 44%, respectively.

Dr. Joel C. Wight, of Austin Health in Heidelberg, Australia, and colleagues conducted this study and recounted their findings in the British Journal of Haematology.

The researchers retrospectively analyzed 80 patients with synDLBCL treated at 10 centers in Australia and the United Kingdom. Patients had DLBCL not otherwise specified (n = 67); high-grade B-cell lymphoma, including double-hit lymphoma (n = 12); or T-cell histiocyte-rich DLBCL (n = 1).

At baseline, all patients were treatment-naive, they had a median age of 64 years (range, 18-87 years), and 68% were male. Seventy percent of patients had high-risk disease according to the CNS International Prognostic Index (IPI), and 96% had non-CNS extranodal disease. The median number of extranodal sites outside the CNS was 2 (range, 0 to more than 10).

Patients were divided into those who received CNS-intensive therapy (n = 38) and those given CNS-conservative therapy (n = 42). The CNS-conservative group was significantly older (P less than .001), significantly more likely to have high-risk disease according to the National Comprehensive Cancer Network IPI (P = .009) or CNS IPI (P = .01) and significantly more likely to have leptomeningeal disease only (P less than .001).
 

Treatment

CNS-intensive therapy was defined as any established multiagent IV chemotherapy regimen with two or more CNS-penetrating drugs and cytarabine, with or without intrathecal chemotherapy and/or radiotherapy.

CNS-conservative therapy was defined as one or fewer IV CNS-penetrating chemotherapy agents in induction, with or without intrathecal chemotherapy and/or radiotherapy.

Systemic induction in the CNS-intensive group consisted of R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with IV methotrexate and cytarabine) in 66% of patients and R-CODOX-M/IVAC (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, cytarabine) in 24% of patients.

The most common systemic induction regimens in the CNS-conservative group were R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimens, given to 83% of patients.

CNS-directed IV therapy was given to 100% of the CNS-intensive group and 60% of the CNS-conservative group. This consisted of IV methotrexate plus cytarabine (97%) or MATRix (methotrexate, cytarabine, and thiotepa; 3%) in the CNS-intensive group and high-dose methotrexate in the conservative group.

Intrathecal chemotherapy was given to 97% of the CNS-intensive group and 60% of the CNS-conservative group. CNS-directed radiation was given to 32% and 19%, respectively.

Thirteen patients in the CNS-intensive group and one in the CNS-conservative group underwent autologous transplant as consolidation.

Outcomes

Dose reductions were more frequent in the CNS-conservative group than in the CNS-intensive group, at 48% and 18% (P = .009), as was early cessation of chemotherapy, at 52% and 18% (P = .002). Rates of treatment-related mortality were similar, at 13% in the CNS-intensive group and 12% in the CNS-conservative group.

At the end of induction, the complete response rate was 69% in the CNS-intensive group and 51% in the CNS-conservative group (P = .16). Primary refractory disease was observed in 19% and 38% of patients, respectively (P = .07).

The CNS was the most common site of relapse or progression (n = 28). CNS progression or relapse occurred in 25% of the CNS-intensive group and 49% of the CNS-conservative group (P = .03).

The 2-year progression-free survival rate was 50% for the CNS-intensive group and 31% for the CNS-conservative group (P = .006). The 2-year overall survival rate was 54% and 44%, respectively (P = .037).

When patients were matched for induction outcomes, consolidative transplant did not improve survival.

“The most significant factor affecting survival was the ability to control the CNS disease, which was improved by the addition of IV cytarabine to [high-dose methotrexate],” the researchers wrote.

“Whilst the younger age and more intensive systemic treatment of the CNS-intensive group may have contributed to the improved survival, it is clear that CNS disease control was substantially improved by the addition of cytarabine with lower rates of CNS relapse/progression observed.”

The researchers noted that “adequate control of the CNS disease is paramount and is best achieved by intensive CNS-directed induction.”

There was no formal funding for this study, and the researchers did not provide financial disclosures.

jensmith@mdedge.com

SOURCE: Wight JC et al. Br J Haematol. 2019 Jun 24. doi: 10.1111/bjh.16064.

Malignant testicular neoplasms can arise from either the germ cells or sex-cord stromal cells, with the former comprising approximately 95% of all testicular cancers (Table 1). Germ cell tumors may contain a single histology or a mix of multiple histologies. For clinical decision making, testicular tumors are categorized as either pure seminoma (no nonseminomatous elements present) or nonseminomatous germ cell tumors (NSGCT). The prevalence of seminoma and NSGCT is roughly equal. If a testicular tumor contains both seminomatous and nonseminomatous components, it is called a mixed germ cell tumor. Because of similarities in biological behavior, the approach to treatment of mixed germ cell tumors is similar to that for NSGCT.

The key points to remember for testicular cancer are:

1. With early diagnosis and aggressive multidisciplinary therapy, the overwhelming majority of patients can be cured;
2. Specialized care is often critical and affects outcomes; and
3. Survivorship, or post-treatment care, is very important for these patients, as they often have lifespan of several decades and a unique set of short- and long-term treatment-related complications.

Developmental Biology and Genetics

The developmental biology of germ cells and germ cell neoplasms is beyond the scope of this review, and interested readers are recommended to refer to pertinent articles on the topic.^1,2 A characteristic genetic marker of all germ cell tumors is an isochromosome of the short arm of chromosome 12, i(12p). This is present in testicular tumors regardless of histologic subtype as well as in carcinoma-in-situ. In germ cell tumors without i(12p) karyotype, excess 12p genetic material consisting of repetitive segments has been found, suggesting that this is an early and potentially critical change in oncogenesis.³ Several recent studies have revealed a diverse genomic landscape in testicular cancers, including KIT, KRAS and NRAS mutations in addition to a hyperdiploid karyotype.^4,5

Evaluation and Diagnosis

Case Presentation

A 23-year-old Caucasian man presents to a primary care clinic for a pre-employment history and physical exam. He reports testicular pain on the sexually transmitted infections screening questionnaire. On examination, the physician finds a firm, mobile, minimally-tender, 1.5-cm mass in the inferior aspect of left testicle. No contralateral testicular mass or inguinal lymphadenopathy is noted, and a detailed physical exam is otherwise unremarkable. The physician immediately orders an ultrasound of the testicles, which shows a 1.5-cm hypoechoic mass in the inferior aspect of the left testicle, with an unremarkable contralateral testicle. After discussion of the results, the patient is referred a urologic oncologist with expertise in testicular cancer for further care.

The urologic oncologist orders a computed tomography (CT) abdomen and pelvis with and without contrast, which shows a 1.8-cm pathologic-appearing retroperitoneal lymph node at the level of the left renal vein. Chest radiograph with anteroposterior and lateral views is unremarkable. Tumor markers are as follows: beta human chorionic gonadotropin (beta-HCG) 8 mIU/mL (normal range, 0–4 mIU/mL), alpha-fetoprotein (AFP) 2 ng/mL (normal range, 0–8.5 ng/mL), and lactate dehydrogenase (LDH) 195 U/L (normal range, 119–213 U/L).

What is the approach to the initial workup and diagnosis of testicular cancer?

Clinical Presentation and Physical Exam

The majority of testicular cancers are diagnosed on work-up of a nodule or painless swelling of one testicle, usually noted incidentally by the patient. Approximately 30% to 40% of patients complain of a dull ache or heavy sensation in the lower abdomen, perianal area, or scrotum, while acute pain is the presenting symptom in 10%.³

In approximately 10% of patients, the presenting symptom is a result of distant metastatic involvement, such as cough and dyspnea on exertion (pulmonary or mediastinal metastasis), intractable bone pain (skeletal metastasis), intractable back/flank pain, presence of psoas sign or unexplained lower extremity deep vein thrombosis (bulky retroperitoneal metastasis), or central nervous system symptoms (vertebral, spinal or brain metastasis). Constitutional symptoms (unexplained weight loss, anorexia, fatigue) often accompany these symptoms.³

Rarely (5% or less), testicular cancer may present with systemic endocrine symptoms or paraneoplastic symptoms. Gynecomastia is the most common in this category, occurring in approximately 2% of germ cell tumors and more commonly (20%–30%) in Leydig cell tumors of testis.⁶ Classically, these patients are either 6- to 10-year-old boys with precocious puberty or young men (mid 20s-mid 30s) with a combination of testicular mass, gynecomastia, loss of libido, and impotence. Workup typically reveals increased beta-HCG levels in blood.

Anti-Ma2-antibody-associated limbic encephalitis is the most common (and still quite rare) paraneoplastic complication associated with testicular germ cell tumors. The Ma2 antigen is selectively expressed in the neuronal nucleoli of normal brain tissue and the testicular tumor of the patient. Importantly, in a subset of these patients, the treatment of testicular cancer may result in improvement of symptoms of encephalitis.⁷

The first step in the diagnosis of testicular neoplasm is a physical exam. This should include a bimanual examination of the scrotal contents, starting with the normal contralateral testis. Normal testicle has a homogeneous texture and consistency, is freely movable, and is separable from the epididymis. Any firm, hard, or fixed mass within the substance of the tunica albuginea should be considered suspicious until proven otherwise. Spread to the epididymis or spermatic cord occurs in 10% to 15% of patients and examination should include these structures as well.³ A comprehensive system-wise examination for features of metastatic spread as discussed above should then be performed. If the patient has cryptorchidism, ultrasound is a mandatory part of the diagnostic workup.

If clinical evaluation suggests a possibility of testicular cancer, the patient must be counseled to undergo an expedited diagnostic workup and specialist evaluation, as a prompt diagnosis and treatment is key to not only improving the likelihood of cure, but also minimizing the treatments needed to achieve it.

Role of Imaging

Scrotal Ultrasound

Scrotal ultrasound is the first imaging modality used in the diagnostic workup of patient with suspected testicular cancer. Bilateral scrotal ultrasound can detect lesions as small as 1 to 2 mm in diameter and help differentiate intratesticular lesions from extrinsic masses. A cystic mass on ultrasound is unlikely to be malignant. Seminomas appear as well-defined hypoechoic lesions without cystic areas, while NSGCTs are typically inhomogeneous with calcifications, cystic areas, and indistinct margins. However, this distinction is not always apparent or reliable. Ultrasound alone is also insufficient for tumor staging.⁸ For these reasons, a radical inguinal orchiectomy must be pursued for accurate determination of histology and local stage.

If testicular ultrasound shows a suspicious intratesticular mass, the following workup is typically done:

• Measurement of serum tumor markers (beta-HCG, AFP and LDH);
• CT abdomen and pelvis with and without contrast;
• Chest radiograph anteroposterior and lateral views, or CT chest with and without contrast if clinically indicated;
• Any additional focal imaging based on symptoms (eg, magnetic resonance imaging [MRI] scan with and without contrast to evaluate the brain if the patient has CNS symptoms).

CT Scan

CT scan is the preferred imaging modality for staging of testicular cancers, specifically for evaluation of the retroperitoneum, as it is the predominant site for metastases.⁹ CT scan should encompass the abdomen and pelvis, and contrast-enhanced sequences should be obtained unless medically contraindicated. CT scan of the chest (if not initially done) is compulsory should a CT of abdomen and pelvis and/or a chest radiograph show abnormal findings.

The sensitivity and specificity of CT scans for detection of nodal metastases can vary significantly based on the cutoff. For example, in a series of 70 patients using a cutoff of 10 mm, the sensitivity and specificity of CT scans for patients undergoing retroperitoneal lymph node dissection were 37% and 100%, respectively.¹⁰ In the same study, a cutoff of 4 mm increased the sensitivity to 93% and decreased the specificity to 58%. The current general consensus for this cutoff value is 8 to 10 mm measured in the short axis in the transverse (axial) plane.

Approximately 20% of men with clinical stage I testicular cancer (ie, those with non-enlarged retroperitoneal lymph nodes) who do not undergo any adjuvant therapy will have disease relapse in the retroperitoneum, suggesting that they had occult micrometastases that were missed on the initial CT scans.^11,12

MRI/Radionuclide Bone Scan/PET Scan

Abdominal or pelvic MRI, whole-body radionuclide bone scan, and positron emission tomography (PET) scans are almost never needed as part of the initial staging workup for testicular cancers due to several limitations, including a high false-negative rate, specifically for the PET scans, and lack of any additional value compared with CT and testicular ultrasound alone.^9,13,14 If necessary, these should only be ordered after a multidisciplinary oncology consultation to prevent unnecessary delays in treatment, inappropriate changes to treatment, and unnecessary increases in cost of care.

Tumor Markers, Biopsy, and Staging

What is the role of tumor markers in the management of testicular cancers?

Serum AFP, beta-hCG, and LDH have a well-established role as tumor markers in testicular cancer. The alpha subunit of hCG is shared between multiple pituitary hormones and hence does not serve as a specific marker for testicular cancer. Serum levels of AFP and/or beta-hCG are elevated in approximately 80% percent of men with NSGCTs, even in absence of metastatic spread. On the other hand, serum beta-hCG is elevated in less than 20% and AFP is not elevated in pure seminomas.³

Tumor markers by themselves are not sufficiently sensitive or specific for the diagnosis of testicular cancer, in general, or to differentiate among its subtypes. Despite this limitation, marked elevations in these markers are rarely due to causes other than germ cell tumor. For example, serum beta-hCG concentrations greater than 10,000 mIU/mL occur only in germ cell tumors, trophoblastic differentiation of a primary lung or gastric cancer, gestational trophoblastic disease, or pregnancy. Serum AFP concentrations greater than 10,000 ng/mL occur almost exclusively in germ cell tumors and hepatocellular carcinoma.¹⁵

The pattern of marker elevation may play an important role in management of testicular cancer patients. For example, in our practice, several patients have had discordant serum tumor markers and pathology results (eg, elevated AFP with pure seminoma on orchiectomy). One of these patients was treated with adjuvant retroperitoneal lymph node dissection, which confirmed that he had a NSGCT with a seminoma, choriocarcinoma, and teratoma on pathology evaluation of retroperitoneal lymph nodes.

Serum tumor markers have 2 additional critical roles—(1) in the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging¹⁶ and International Germ Cell Cancer Collaboration Group (IGCCCG) risk stratification of testicular cancer,¹⁷ and (2) in post-treatment disease monitoring.

Is a testicular biopsy necessary for diagnosis?

A testicular biopsy is almost never pursued to confirm the diagnosis of testicular cancer. There is a concern that percutaneous testicular biopsy, which is associated with scrotal skin violation, can adversely affect outcomes due to tumor seeding of scrotal sac or metastatic spread into the inguinal nodes via scrotal skin lymphatics.

Tissue diagnosis is made by radical orchiectomy in a majority of cases. Rarely in our practice, we obtain a biopsy of metastatic lesion for a tissue diagnosis. This is only done in cases where chemotherapy must be started urgently to prevent worsening of complications from metastatic spread. This decision should be made only after a multidisciplinary consultation with urologic and medical oncology teams.

How is testicular cancer staged?

Both seminomatous and nonseminomatous germ cell tumors of the testis are staged using the AJCC/UICC staging system, which incorporates assessments of the primary tumor (T), lymph nodes (N), and distant metastases (M) and serum tumor marker values (S). Details of this staging system are beyond the scope of this review and further information can be obtained through the AJCC website (www.cancerstaging.org). This TNMS staging enables a prognostic assessment and helps with the therapeutic approach.

For patients with advanced germ cell tumors, a risk group classification developed by the IGCCCG is used to classify patients into good-risk, intermediate-risk, and poor-risk category (Table 2). This classification has been extensively validated for the past 2 decades, provides important prognostic information, and helps inform therapy decisions.

 

 

Treatment

Case 1 Continued

Based on the patient’s imaging and biomarker results, the patient undergoes a left radical inguinal orchiectomy. The physician’s operative note mentions that the left testicle was delivered without violation of scrotal integrity. A pathology report shows pure spermatocytic seminoma (unifocal, 1.4 cm size) with negative margins and no evidence of lymphovascular invasion. No lymph nodes are identified in the resection specimen. Post-orchiectomy markers are “negative,” meaning within normal range. After discussions with medical and radiation oncology physicians, the patient opts to pursue active surveillance.

Surgery alone followed by active surveillance is an appropriate option for this patient, as the likelihood of recurrence is low and most recurrences can be subsequently salvaged using treatment options detailed below.

What are the therapeutic options for testicular cancer?

An overview of management for most testicular cancers is presented in Table 3. Note that the actual treatments are significantly more complex and need a comprehensive multidisciplinary consultation (urologic, medical and radiation oncology) at centers with specialized testicular cancer teams, if possible.

Fertility Preservation

All patients initiating treatment for testicular cancer must be offered options for fertility preservation and consultation with a reproductive health team, if available. At the time of diagnosis, approximately 50% patients have some degree of impairment in spermatogenesis, but with effective fertility preservation, successful pregnancy can occur for as many as 30% to 60% of patients.^18,19

Orchiectomy

Radical inguinal orchiectomy with high ligation of the spermatic cord at the level of the internal ring is the procedure of choice for suspected testicular cancer. The goal is to provide a definitive tissue diagnosis and local tumor control with minimal morbidity. It can be performed under general, regional, or local anesthesia. Depending on the complexity and surgical expertise, it can be done in an inpatient or outpatient setting. During the procedure, the testicle is delivered from the scrotum through an incision in the inguinal region and then resected. A testicular prosthesis is usually inserted, with resultant excellent cosmetic and patient satisfaction outcomes.²⁰

Testicular sparing surgery (TSS) has been explored as an alternative to radical orchiectomy but is not considered a standard-of-care option at this time. Small studies have shown evidence for comparable short-term oncologic outcomes in a very select group of patients, generally with solitary tumors < 2 cm in size and solitary testicle. If this is being considered as an option, we recommended obtaining a consultation from a urologist at a high-volume center. For a majority of patients, the value of a TSS is diminished due to excellent anatomic/cosmetic outcomes with a testicular prosthesis implanted during the radical orchiectomy, and resumption of sexual functions by the unaffected contralateral testicle.

Retroperitoneal Lymph Node Dissection

As discussed, conventional cross-sectional imaging has a high false-negative rate for detection of retroperitoneal involvement. General indications for RPLND in various stages and histologies of testicular cancer germ cell tumors are outlined in Table 3. Seminoma tends to most commonly metastasize to retroperitoneum, but RPLND for seminoma is generally reserved for a very small subset of these patients. Patterns of metastases of NSGCT (except choriocarcinoma) are considered to be well-defined. In a series of patients with stage II NSGCTs, left-sided tumors metastasized to the pre- and para-aortic nodes in 88% and 86% of cases, respectively (drainage basin of left testicular vein); and right-sided tumors involved the interaortocaval nodes in 93% of patients.³ Inguinal and pelvic nodal metastases may rarely be seen and should not be used to rule out the diagnosis of testicular cancer.

Choriocarcinoma is an exception to this pattern of retroperitoneal spread, as it tends to have a higher likelihood of hematogenous metastases to distant organs. Compared with NSGCTs, pure seminomas are either localized to the testis (80% of all cases) or limited to the retroperitoneum (an additional 15% of all cases) at presentation.³

Depending on the case and expertise of the surgical team, robotic or open RPLND can be performed.²¹ Regardless of the approach used, RPLND remains a technically challenging surgery. The retroperitoneal “landing zone” lymph nodes lie in close proximity to, and are often densely adherent to, the abdominal great vessels. Complication rates vary widely in the reported literature, but can be as high as 50%.^21-23 As detailed in Table 2, the number and size of involved retroperitoneal lymph nodes have prognostic importance.

In summary, RPLND is considered to be a viable option for a subset of early-stage NSGCT (T1-3, N0-2, M0) and for those with advanced seminoma, NSGCT, or mixed germ cell tumors with post-chemotherapy residual disease.

Systemic Chemotherapy

Except for the single-agent carboplatin, most chemotherapy regimens used to treat testicular cancer are combinations of 2 or more chemotherapy agents. For this review, we will focus on the 3 most commonly used regimens: bleomycin, etoposide, and cisplatin (BEP), etoposide and cisplatin (EP), and etoposide, ifosfamide, and cisplatin (VIP).

The core principles of testicular cancer chemotherapy are:

1. Minimize dose interruptions, delays, or reductions, as these adversely affect outcomes without clearly improving side effect profile;
2. Do not substitute carboplatin for cisplatin in combination regimens because carboplatin-containing combination regimens have been shown to result in significantly poorer outcomes in multiple trials of adults with germ cell tumors;^24-27 and
3. Give myeloid growth factor support, if necessary.

BEP

The standard BEP regimen comprises a 21-day cycle with bleomycin 30 units on days 1, 8, and 15; etoposide 100 mg/m² on days 1 to 5; and cisplatin 20 mg/m² on days 1 to 5. Number of cycles varies based on histology and stage (Table 3). A strong justification to maintain treatment intensity comes from the Australian and New Zealand Germ Cell Trial Group trial. In this study, 166 men were randomly assigned to treatment using 3 cycles of standard BEP or 4 cycles of a modified BEP regimen (bleomycin 30 units day 1; etoposide 120 mg/m² days 1 to 3; cisplatin 100 mg/m² day 1) every 21 days. This trial was stopped at interim analyses because the modified BEP arm was inferior to the standard BEP arm. With a median follow-up of 8.5 years, 8-year overall survival was 92% with standard BEP and 83% with modified BEP (P = 0.037).²⁸

Bleomycin used in the BEP regimen has been associated with uncommon but potentially fatal pulmonary toxicity that tends to present as interstitial pneumonitis, which may ultimately progress to fibrosis or bronchiolitis obliterans with organizing pneumonia.²⁹ This has led to evaluation of EP as an alternative to BEP.

EP

The standard EP regimen consists of a 21-day cycle with etoposide 100 mg/m² on days 1 to 5, and cisplatin 20 mg/m² on days 1 to 5. Due to conflicting data from multiple randomized trials, there is considerable debate in the field regarding whether 4 cycles of EP are equivalent to 3 cycles of BEP.^30,31 The benefit of the EP regimen is that it avoids the higher rates of pulmonary, cutaneous, and neurologic toxicities associated bleomycin, but it does result in the patient receiving an up to 33% higher cumulative dose of cisplatin and etoposide due to the extra cycle of treatment. This has important implications in terms of tolerability and side effects, including delayed toxicities such as second malignancies, which increase with a higher cumulative dose of these agents (etoposide in particular).

VIP

The standard VIP regimen consists of a 21-day cycle with etoposide 75 mg/m² on days 1 to 5; cisplatin 20 mg/m² on days 1 to 5; ifosfamide 1200 mg/m² on days 1 to 5; and mesna 120 mg/m² IV push on day 1 followed by 1200 mg/m² on days 1 to 5. For patients with intermediate- or poor-risk disease, 4 cycles of VIP has demonstrated comparable efficacy but higher rates of hematologic toxicities compared with 4 cycles of BEP.^32-34 It remains an option for upfront treatment of patients who are not good candidates for a bleomycin-based regimen, and for patients who need salvage chemotherapy.

Adverse Effects of Chemotherapy

Acute and late chemotherapy toxicities vary significantly between regimens depending on the chemotherapy drugs used. Bleomycin-induced pneumonitis may masquerade as a “pneumonia,” which can lead to a delay in diagnosis or institution of treatment, as well as institution of an incorrect treatment (for example, there is a concern that bleomycin toxicity can be precipitated or worsened by a high fraction of inspired oxygen). Chemotherapy-associated neutropenia tends to occur a few days (7–10 days) after initiation of chemotherapy, and neutrophil counts recover without intervention in most patients after an additional 7 to 10 days. Myeloid growth factor support (eg, filgrastim, pegfilgrastim) can be given to patients either prophylactically (if they had an episode of febrile or prolonged neutropenia with the preceding cycle) or secondarily if they present with neutropenia (an absolute neutrophil count ≤ 500 cells/µL) with fever or active infection. Such interventions tend to shorten the duration of neutropenia but does not affect overall survival. Patients with asymptomatic neutropenia do not benefit from growth factor use.³⁵

 

 

Stem Cell Transplant

Autologous stem cell transplant (SCT) is the preferred type of SCT for patients with testicular cancer and involves delivery of high doses of chemotherapy followed by infusion of patient-derived myeloid stem cells. While the details of this treatment are outside the scope of this review, decades of experience has shown that this is an effective curative option for a subset of patients with poor prognosis, such as those with platinum-refractory or relapsed disease.³⁶

Clinical Trials

Due to excellent clinical outcomes with front-line therapy, as described, and the relatively low incidence of testicular and other germ cell tumors, clinical trial options for patients with testicular cancer are limited. The TIGER trial is an ongoing international, randomized, phase 3 trial comparing conventional TIP (paclitaxel, ifosfamide, and cisplatin) chemotherapy with high-dose chemotherapy with SCT as the first salvage treatment for relapsed/refractory germ cell tumors (NCT02375204). It is enrolling at multiple centers in the United States and results are expected in 2022. At least 2 ongoing trials are evaluating the role of immunotherapy in patients with relapsed/refractory germ cell tumors (NCT03081923 and NCT03726281). Cluster of differentiation antigen-30 (CD30) has emerged as a potential target of interest in germ cell tumors, and brentuximab vedotin, an anti-CD30 monoclonal antibody, is undergoing evaluation in a phase 2 trial of CD-30–expressing germ cell tumors (NCT01851200). This trial has completed enrollment and results are expected to be available in late 2019 or early 2020.

When possible, patients with relapsed/refractory germ cell tumors should be referred to centers of excellence with access to either testicular/germ-cell tumor specific clinical trials or phase 1 clinical trials.

Radiation Therapy

Adjuvant radiation to the retroperitoneum has a role in the management of stage I and IIA seminomas (Table 3). In a randomized noninferiority trial of radiation therapy versus single-dose carboplatin in stage I seminoma patients, 5-year recurrence-free survival was comparable at approximately 95% in either arm.^37,38 In a retrospective database review of 2437 patients receiving either radiation therapy or multi-agent chemotherapy for stage II seminoma, the 5-year survival exceeded 90% in both treatment groups.³⁹ Typically, a total of 30 to 36 Gy of radiation is delivered to para-aortic and ipsilateral external iliac lymph nodes (“dog-leg” field), followed by an optional boost to the involved nodal areas.⁴⁰ Radiation is associated with acute side effects such as fatigue, gastrointestinal effects, myelosuppression as well as late side effects such as second cancers in the irradiated field (eg, sarcoma, bladder cancer).

Evaluation of Treatment Response

Monitoring of treatment response is fairly straightforward for patients with testicular cancer. Our practice is the following:

1. Measure tumor markers on day 1 of each chemotherapy cycle and 3 to 4 weeks after completion of treatment.
2. CT of the chest, abdomen, and pelvis with intravenous contrast prior to chemotherapy and upon completion of chemotherapy. Interim imaging is only needed for a small subset of patients with additional clinical indications (eg, new symptoms, lack of improvement in existing symptoms).
3. For patients with stage II/III seminoma who have a residual mass ≥ 3 cm on post-treatment CT scan, a PET-CT scan is indicated 6 to 8 weeks after the completion of chemotherapy to determine the need for further treatment.

Active Surveillance

Because testicular cancer has high cure rates even when patients have disease relapse after primary therapy, and additional therapies have significant short- and long-term side effects in these generally young patients, active surveillance is a critical option used in the management of testicular cancer.⁴¹

Patients must be counseled that active surveillance is a form of treatment itself in that it involves close clinical and radiographic monitoring. Because there is a risk of disease relapse, patients opting to undergo active surveillance must fully understand the risks of disease recurrence and be willing to abide by the recommended follow-up schedule.

Surveillance is necessary for a minimum of 5 years and possibly 10 years following orchiectomy, and most relapses tend to occur within the first 2 years. Late relapses such as skeletal metastatic disease from seminoma have been reported to occur more than 15 years after orchiectomy, but are generally rare and unpredictable.

The general guidelines for active surveillance are as follows:

For patients with seminoma, history and physical exam and tumor marker assessment should be performed every 3 to 6 months for the first year, then every 6 to 12 months in years 2 and 3, and then annually. CT of the abdomen and pelvis should be done at 3, 6, and 12 months, every 6 to 12 months in years 2 and 3, and then every 12 to 24 months in years 4 and 5. A chest radiograph is performed only if clinically indicated, as the likelihood of distant metastatic recurrence is low.

For patients with nonseminoma, history and physical exam and tumor markers assessment should be performed every 2 to 3 months for first 2 years, every 4 to 6 months in years 3 and 4, and then annually. CT of the abdomen and pelvis should be obtained every 4 to 6 months in year 1, gradually decreasing to annually in year 3 or 4. Chest radiograph is indicated at 4 and 12 months and annually thereafter for stage IA disease. For those with stage IB disease, chest radiograph is indicated every 2 months during the first year and then gradually decreasing to annually beginning year 5.

These recommendations are expected to change over time, and treating physicians are recommended to exercise discretion and consider the patient and tumor characteristics to develop the optimal surveillance plan.

 

 

Conclusion

Testicular cancer is the most common cancer afflicting young men. Prompt diagnostic workup initiated in a primary care or hospital setting followed by a referral to a multidisciplinary team of urologists, medical oncologists, and radiation oncologists enables cure in a majority of patients. For patients with stage I seminoma, a radical inguinal orchiectomy followed by active surveillance may offer the best long-term outcome with minimal side effects. For patients with relapsed/refractory testicular cancers, clinical trial participation is strongly encouraged. Patients with a history of testicular cancer benefit from robust survivorship care tailored to their prior therapies. This can be safely delivered through their primary care providers in collaboration with the multidisciplinary oncology team.

Malignant testicular neoplasms can arise from either the germ cells or sex-cord stromal cells, with the former comprising approximately 95% of all testicular cancers (Table 1). Germ cell tumors may contain a single histology or a mix of multiple histologies. For clinical decision making, testicular tumors are categorized as either pure seminoma (no nonseminomatous elements present) or nonseminomatous germ cell tumors (NSGCT). The prevalence of seminoma and NSGCT is roughly equal. If a testicular tumor contains both seminomatous and nonseminomatous components, it is called a mixed germ cell tumor. Because of similarities in biological behavior, the approach to treatment of mixed germ cell tumors is similar to that for NSGCT.

The key points to remember for testicular cancer are:

1. With early diagnosis and aggressive multidisciplinary therapy, the overwhelming majority of patients can be cured;
2. Specialized care is often critical and affects outcomes; and
3. Survivorship, or post-treatment care, is very important for these patients, as they often have lifespan of several decades and a unique set of short- and long-term treatment-related complications.

Developmental Biology and Genetics

The developmental biology of germ cells and germ cell neoplasms is beyond the scope of this review, and interested readers are recommended to refer to pertinent articles on the topic.^1,2 A characteristic genetic marker of all germ cell tumors is an isochromosome of the short arm of chromosome 12, i(12p). This is present in testicular tumors regardless of histologic subtype as well as in carcinoma-in-situ. In germ cell tumors without i(12p) karyotype, excess 12p genetic material consisting of repetitive segments has been found, suggesting that this is an early and potentially critical change in oncogenesis.³ Several recent studies have revealed a diverse genomic landscape in testicular cancers, including KIT, KRAS and NRAS mutations in addition to a hyperdiploid karyotype.^4,5

Evaluation and Diagnosis

Case Presentation

A 23-year-old Caucasian man presents to a primary care clinic for a pre-employment history and physical exam. He reports testicular pain on the sexually transmitted infections screening questionnaire. On examination, the physician finds a firm, mobile, minimally-tender, 1.5-cm mass in the inferior aspect of left testicle. No contralateral testicular mass or inguinal lymphadenopathy is noted, and a detailed physical exam is otherwise unremarkable. The physician immediately orders an ultrasound of the testicles, which shows a 1.5-cm hypoechoic mass in the inferior aspect of the left testicle, with an unremarkable contralateral testicle. After discussion of the results, the patient is referred a urologic oncologist with expertise in testicular cancer for further care.

The urologic oncologist orders a computed tomography (CT) abdomen and pelvis with and without contrast, which shows a 1.8-cm pathologic-appearing retroperitoneal lymph node at the level of the left renal vein. Chest radiograph with anteroposterior and lateral views is unremarkable. Tumor markers are as follows: beta human chorionic gonadotropin (beta-HCG) 8 mIU/mL (normal range, 0–4 mIU/mL), alpha-fetoprotein (AFP) 2 ng/mL (normal range, 0–8.5 ng/mL), and lactate dehydrogenase (LDH) 195 U/L (normal range, 119–213 U/L).

What is the approach to the initial workup and diagnosis of testicular cancer?

Clinical Presentation and Physical Exam

The majority of testicular cancers are diagnosed on work-up of a nodule or painless swelling of one testicle, usually noted incidentally by the patient. Approximately 30% to 40% of patients complain of a dull ache or heavy sensation in the lower abdomen, perianal area, or scrotum, while acute pain is the presenting symptom in 10%.³

In approximately 10% of patients, the presenting symptom is a result of distant metastatic involvement, such as cough and dyspnea on exertion (pulmonary or mediastinal metastasis), intractable bone pain (skeletal metastasis), intractable back/flank pain, presence of psoas sign or unexplained lower extremity deep vein thrombosis (bulky retroperitoneal metastasis), or central nervous system symptoms (vertebral, spinal or brain metastasis). Constitutional symptoms (unexplained weight loss, anorexia, fatigue) often accompany these symptoms.³

Rarely (5% or less), testicular cancer may present with systemic endocrine symptoms or paraneoplastic symptoms. Gynecomastia is the most common in this category, occurring in approximately 2% of germ cell tumors and more commonly (20%–30%) in Leydig cell tumors of testis.⁶ Classically, these patients are either 6- to 10-year-old boys with precocious puberty or young men (mid 20s-mid 30s) with a combination of testicular mass, gynecomastia, loss of libido, and impotence. Workup typically reveals increased beta-HCG levels in blood.

Anti-Ma2-antibody-associated limbic encephalitis is the most common (and still quite rare) paraneoplastic complication associated with testicular germ cell tumors. The Ma2 antigen is selectively expressed in the neuronal nucleoli of normal brain tissue and the testicular tumor of the patient. Importantly, in a subset of these patients, the treatment of testicular cancer may result in improvement of symptoms of encephalitis.⁷

The first step in the diagnosis of testicular neoplasm is a physical exam. This should include a bimanual examination of the scrotal contents, starting with the normal contralateral testis. Normal testicle has a homogeneous texture and consistency, is freely movable, and is separable from the epididymis. Any firm, hard, or fixed mass within the substance of the tunica albuginea should be considered suspicious until proven otherwise. Spread to the epididymis or spermatic cord occurs in 10% to 15% of patients and examination should include these structures as well.³ A comprehensive system-wise examination for features of metastatic spread as discussed above should then be performed. If the patient has cryptorchidism, ultrasound is a mandatory part of the diagnostic workup.

If clinical evaluation suggests a possibility of testicular cancer, the patient must be counseled to undergo an expedited diagnostic workup and specialist evaluation, as a prompt diagnosis and treatment is key to not only improving the likelihood of cure, but also minimizing the treatments needed to achieve it.

Role of Imaging

Scrotal Ultrasound

Scrotal ultrasound is the first imaging modality used in the diagnostic workup of patient with suspected testicular cancer. Bilateral scrotal ultrasound can detect lesions as small as 1 to 2 mm in diameter and help differentiate intratesticular lesions from extrinsic masses. A cystic mass on ultrasound is unlikely to be malignant. Seminomas appear as well-defined hypoechoic lesions without cystic areas, while NSGCTs are typically inhomogeneous with calcifications, cystic areas, and indistinct margins. However, this distinction is not always apparent or reliable. Ultrasound alone is also insufficient for tumor staging.⁸ For these reasons, a radical inguinal orchiectomy must be pursued for accurate determination of histology and local stage.

If testicular ultrasound shows a suspicious intratesticular mass, the following workup is typically done:

• Measurement of serum tumor markers (beta-HCG, AFP and LDH);
• CT abdomen and pelvis with and without contrast;
• Chest radiograph anteroposterior and lateral views, or CT chest with and without contrast if clinically indicated;
• Any additional focal imaging based on symptoms (eg, magnetic resonance imaging [MRI] scan with and without contrast to evaluate the brain if the patient has CNS symptoms).

CT Scan

CT scan is the preferred imaging modality for staging of testicular cancers, specifically for evaluation of the retroperitoneum, as it is the predominant site for metastases.⁹ CT scan should encompass the abdomen and pelvis, and contrast-enhanced sequences should be obtained unless medically contraindicated. CT scan of the chest (if not initially done) is compulsory should a CT of abdomen and pelvis and/or a chest radiograph show abnormal findings.

The sensitivity and specificity of CT scans for detection of nodal metastases can vary significantly based on the cutoff. For example, in a series of 70 patients using a cutoff of 10 mm, the sensitivity and specificity of CT scans for patients undergoing retroperitoneal lymph node dissection were 37% and 100%, respectively.¹⁰ In the same study, a cutoff of 4 mm increased the sensitivity to 93% and decreased the specificity to 58%. The current general consensus for this cutoff value is 8 to 10 mm measured in the short axis in the transverse (axial) plane.

Approximately 20% of men with clinical stage I testicular cancer (ie, those with non-enlarged retroperitoneal lymph nodes) who do not undergo any adjuvant therapy will have disease relapse in the retroperitoneum, suggesting that they had occult micrometastases that were missed on the initial CT scans.^11,12

MRI/Radionuclide Bone Scan/PET Scan

Abdominal or pelvic MRI, whole-body radionuclide bone scan, and positron emission tomography (PET) scans are almost never needed as part of the initial staging workup for testicular cancers due to several limitations, including a high false-negative rate, specifically for the PET scans, and lack of any additional value compared with CT and testicular ultrasound alone.^9,13,14 If necessary, these should only be ordered after a multidisciplinary oncology consultation to prevent unnecessary delays in treatment, inappropriate changes to treatment, and unnecessary increases in cost of care.

Tumor Markers, Biopsy, and Staging

What is the role of tumor markers in the management of testicular cancers?

Serum AFP, beta-hCG, and LDH have a well-established role as tumor markers in testicular cancer. The alpha subunit of hCG is shared between multiple pituitary hormones and hence does not serve as a specific marker for testicular cancer. Serum levels of AFP and/or beta-hCG are elevated in approximately 80% percent of men with NSGCTs, even in absence of metastatic spread. On the other hand, serum beta-hCG is elevated in less than 20% and AFP is not elevated in pure seminomas.³

Tumor markers by themselves are not sufficiently sensitive or specific for the diagnosis of testicular cancer, in general, or to differentiate among its subtypes. Despite this limitation, marked elevations in these markers are rarely due to causes other than germ cell tumor. For example, serum beta-hCG concentrations greater than 10,000 mIU/mL occur only in germ cell tumors, trophoblastic differentiation of a primary lung or gastric cancer, gestational trophoblastic disease, or pregnancy. Serum AFP concentrations greater than 10,000 ng/mL occur almost exclusively in germ cell tumors and hepatocellular carcinoma.¹⁵

The pattern of marker elevation may play an important role in management of testicular cancer patients. For example, in our practice, several patients have had discordant serum tumor markers and pathology results (eg, elevated AFP with pure seminoma on orchiectomy). One of these patients was treated with adjuvant retroperitoneal lymph node dissection, which confirmed that he had a NSGCT with a seminoma, choriocarcinoma, and teratoma on pathology evaluation of retroperitoneal lymph nodes.

Serum tumor markers have 2 additional critical roles—(1) in the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging¹⁶ and International Germ Cell Cancer Collaboration Group (IGCCCG) risk stratification of testicular cancer,¹⁷ and (2) in post-treatment disease monitoring.

Is a testicular biopsy necessary for diagnosis?

A testicular biopsy is almost never pursued to confirm the diagnosis of testicular cancer. There is a concern that percutaneous testicular biopsy, which is associated with scrotal skin violation, can adversely affect outcomes due to tumor seeding of scrotal sac or metastatic spread into the inguinal nodes via scrotal skin lymphatics.

Tissue diagnosis is made by radical orchiectomy in a majority of cases. Rarely in our practice, we obtain a biopsy of metastatic lesion for a tissue diagnosis. This is only done in cases where chemotherapy must be started urgently to prevent worsening of complications from metastatic spread. This decision should be made only after a multidisciplinary consultation with urologic and medical oncology teams.

How is testicular cancer staged?

Both seminomatous and nonseminomatous germ cell tumors of the testis are staged using the AJCC/UICC staging system, which incorporates assessments of the primary tumor (T), lymph nodes (N), and distant metastases (M) and serum tumor marker values (S). Details of this staging system are beyond the scope of this review and further information can be obtained through the AJCC website (www.cancerstaging.org). This TNMS staging enables a prognostic assessment and helps with the therapeutic approach.

For patients with advanced germ cell tumors, a risk group classification developed by the IGCCCG is used to classify patients into good-risk, intermediate-risk, and poor-risk category (Table 2). This classification has been extensively validated for the past 2 decades, provides important prognostic information, and helps inform therapy decisions.

 

 

Treatment

Case 1 Continued

Based on the patient’s imaging and biomarker results, the patient undergoes a left radical inguinal orchiectomy. The physician’s operative note mentions that the left testicle was delivered without violation of scrotal integrity. A pathology report shows pure spermatocytic seminoma (unifocal, 1.4 cm size) with negative margins and no evidence of lymphovascular invasion. No lymph nodes are identified in the resection specimen. Post-orchiectomy markers are “negative,” meaning within normal range. After discussions with medical and radiation oncology physicians, the patient opts to pursue active surveillance.

Surgery alone followed by active surveillance is an appropriate option for this patient, as the likelihood of recurrence is low and most recurrences can be subsequently salvaged using treatment options detailed below.

What are the therapeutic options for testicular cancer?

An overview of management for most testicular cancers is presented in Table 3. Note that the actual treatments are significantly more complex and need a comprehensive multidisciplinary consultation (urologic, medical and radiation oncology) at centers with specialized testicular cancer teams, if possible.

Fertility Preservation

All patients initiating treatment for testicular cancer must be offered options for fertility preservation and consultation with a reproductive health team, if available. At the time of diagnosis, approximately 50% patients have some degree of impairment in spermatogenesis, but with effective fertility preservation, successful pregnancy can occur for as many as 30% to 60% of patients.^18,19

Orchiectomy

Radical inguinal orchiectomy with high ligation of the spermatic cord at the level of the internal ring is the procedure of choice for suspected testicular cancer. The goal is to provide a definitive tissue diagnosis and local tumor control with minimal morbidity. It can be performed under general, regional, or local anesthesia. Depending on the complexity and surgical expertise, it can be done in an inpatient or outpatient setting. During the procedure, the testicle is delivered from the scrotum through an incision in the inguinal region and then resected. A testicular prosthesis is usually inserted, with resultant excellent cosmetic and patient satisfaction outcomes.²⁰

Testicular sparing surgery (TSS) has been explored as an alternative to radical orchiectomy but is not considered a standard-of-care option at this time. Small studies have shown evidence for comparable short-term oncologic outcomes in a very select group of patients, generally with solitary tumors < 2 cm in size and solitary testicle. If this is being considered as an option, we recommended obtaining a consultation from a urologist at a high-volume center. For a majority of patients, the value of a TSS is diminished due to excellent anatomic/cosmetic outcomes with a testicular prosthesis implanted during the radical orchiectomy, and resumption of sexual functions by the unaffected contralateral testicle.

Retroperitoneal Lymph Node Dissection

As discussed, conventional cross-sectional imaging has a high false-negative rate for detection of retroperitoneal involvement. General indications for RPLND in various stages and histologies of testicular cancer germ cell tumors are outlined in Table 3. Seminoma tends to most commonly metastasize to retroperitoneum, but RPLND for seminoma is generally reserved for a very small subset of these patients. Patterns of metastases of NSGCT (except choriocarcinoma) are considered to be well-defined. In a series of patients with stage II NSGCTs, left-sided tumors metastasized to the pre- and para-aortic nodes in 88% and 86% of cases, respectively (drainage basin of left testicular vein); and right-sided tumors involved the interaortocaval nodes in 93% of patients.³ Inguinal and pelvic nodal metastases may rarely be seen and should not be used to rule out the diagnosis of testicular cancer.

Choriocarcinoma is an exception to this pattern of retroperitoneal spread, as it tends to have a higher likelihood of hematogenous metastases to distant organs. Compared with NSGCTs, pure seminomas are either localized to the testis (80% of all cases) or limited to the retroperitoneum (an additional 15% of all cases) at presentation.³

Depending on the case and expertise of the surgical team, robotic or open RPLND can be performed.²¹ Regardless of the approach used, RPLND remains a technically challenging surgery. The retroperitoneal “landing zone” lymph nodes lie in close proximity to, and are often densely adherent to, the abdominal great vessels. Complication rates vary widely in the reported literature, but can be as high as 50%.^21-23 As detailed in Table 2, the number and size of involved retroperitoneal lymph nodes have prognostic importance.

In summary, RPLND is considered to be a viable option for a subset of early-stage NSGCT (T1-3, N0-2, M0) and for those with advanced seminoma, NSGCT, or mixed germ cell tumors with post-chemotherapy residual disease.

Systemic Chemotherapy

Except for the single-agent carboplatin, most chemotherapy regimens used to treat testicular cancer are combinations of 2 or more chemotherapy agents. For this review, we will focus on the 3 most commonly used regimens: bleomycin, etoposide, and cisplatin (BEP), etoposide and cisplatin (EP), and etoposide, ifosfamide, and cisplatin (VIP).

The core principles of testicular cancer chemotherapy are:

1. Minimize dose interruptions, delays, or reductions, as these adversely affect outcomes without clearly improving side effect profile;
2. Do not substitute carboplatin for cisplatin in combination regimens because carboplatin-containing combination regimens have been shown to result in significantly poorer outcomes in multiple trials of adults with germ cell tumors;^24-27 and
3. Give myeloid growth factor support, if necessary.

BEP

The standard BEP regimen comprises a 21-day cycle with bleomycin 30 units on days 1, 8, and 15; etoposide 100 mg/m² on days 1 to 5; and cisplatin 20 mg/m² on days 1 to 5. Number of cycles varies based on histology and stage (Table 3). A strong justification to maintain treatment intensity comes from the Australian and New Zealand Germ Cell Trial Group trial. In this study, 166 men were randomly assigned to treatment using 3 cycles of standard BEP or 4 cycles of a modified BEP regimen (bleomycin 30 units day 1; etoposide 120 mg/m² days 1 to 3; cisplatin 100 mg/m² day 1) every 21 days. This trial was stopped at interim analyses because the modified BEP arm was inferior to the standard BEP arm. With a median follow-up of 8.5 years, 8-year overall survival was 92% with standard BEP and 83% with modified BEP (P = 0.037).²⁸

Bleomycin used in the BEP regimen has been associated with uncommon but potentially fatal pulmonary toxicity that tends to present as interstitial pneumonitis, which may ultimately progress to fibrosis or bronchiolitis obliterans with organizing pneumonia.²⁹ This has led to evaluation of EP as an alternative to BEP.

EP

The standard EP regimen consists of a 21-day cycle with etoposide 100 mg/m² on days 1 to 5, and cisplatin 20 mg/m² on days 1 to 5. Due to conflicting data from multiple randomized trials, there is considerable debate in the field regarding whether 4 cycles of EP are equivalent to 3 cycles of BEP.^30,31 The benefit of the EP regimen is that it avoids the higher rates of pulmonary, cutaneous, and neurologic toxicities associated bleomycin, but it does result in the patient receiving an up to 33% higher cumulative dose of cisplatin and etoposide due to the extra cycle of treatment. This has important implications in terms of tolerability and side effects, including delayed toxicities such as second malignancies, which increase with a higher cumulative dose of these agents (etoposide in particular).

VIP

The standard VIP regimen consists of a 21-day cycle with etoposide 75 mg/m² on days 1 to 5; cisplatin 20 mg/m² on days 1 to 5; ifosfamide 1200 mg/m² on days 1 to 5; and mesna 120 mg/m² IV push on day 1 followed by 1200 mg/m² on days 1 to 5. For patients with intermediate- or poor-risk disease, 4 cycles of VIP has demonstrated comparable efficacy but higher rates of hematologic toxicities compared with 4 cycles of BEP.^32-34 It remains an option for upfront treatment of patients who are not good candidates for a bleomycin-based regimen, and for patients who need salvage chemotherapy.

Adverse Effects of Chemotherapy

Acute and late chemotherapy toxicities vary significantly between regimens depending on the chemotherapy drugs used. Bleomycin-induced pneumonitis may masquerade as a “pneumonia,” which can lead to a delay in diagnosis or institution of treatment, as well as institution of an incorrect treatment (for example, there is a concern that bleomycin toxicity can be precipitated or worsened by a high fraction of inspired oxygen). Chemotherapy-associated neutropenia tends to occur a few days (7–10 days) after initiation of chemotherapy, and neutrophil counts recover without intervention in most patients after an additional 7 to 10 days. Myeloid growth factor support (eg, filgrastim, pegfilgrastim) can be given to patients either prophylactically (if they had an episode of febrile or prolonged neutropenia with the preceding cycle) or secondarily if they present with neutropenia (an absolute neutrophil count ≤ 500 cells/µL) with fever or active infection. Such interventions tend to shorten the duration of neutropenia but does not affect overall survival. Patients with asymptomatic neutropenia do not benefit from growth factor use.³⁵

 

 

Stem Cell Transplant

Autologous stem cell transplant (SCT) is the preferred type of SCT for patients with testicular cancer and involves delivery of high doses of chemotherapy followed by infusion of patient-derived myeloid stem cells. While the details of this treatment are outside the scope of this review, decades of experience has shown that this is an effective curative option for a subset of patients with poor prognosis, such as those with platinum-refractory or relapsed disease.³⁶

Clinical Trials

Due to excellent clinical outcomes with front-line therapy, as described, and the relatively low incidence of testicular and other germ cell tumors, clinical trial options for patients with testicular cancer are limited. The TIGER trial is an ongoing international, randomized, phase 3 trial comparing conventional TIP (paclitaxel, ifosfamide, and cisplatin) chemotherapy with high-dose chemotherapy with SCT as the first salvage treatment for relapsed/refractory germ cell tumors (NCT02375204). It is enrolling at multiple centers in the United States and results are expected in 2022. At least 2 ongoing trials are evaluating the role of immunotherapy in patients with relapsed/refractory germ cell tumors (NCT03081923 and NCT03726281). Cluster of differentiation antigen-30 (CD30) has emerged as a potential target of interest in germ cell tumors, and brentuximab vedotin, an anti-CD30 monoclonal antibody, is undergoing evaluation in a phase 2 trial of CD-30–expressing germ cell tumors (NCT01851200). This trial has completed enrollment and results are expected to be available in late 2019 or early 2020.

When possible, patients with relapsed/refractory germ cell tumors should be referred to centers of excellence with access to either testicular/germ-cell tumor specific clinical trials or phase 1 clinical trials.

Radiation Therapy

Adjuvant radiation to the retroperitoneum has a role in the management of stage I and IIA seminomas (Table 3). In a randomized noninferiority trial of radiation therapy versus single-dose carboplatin in stage I seminoma patients, 5-year recurrence-free survival was comparable at approximately 95% in either arm.^37,38 In a retrospective database review of 2437 patients receiving either radiation therapy or multi-agent chemotherapy for stage II seminoma, the 5-year survival exceeded 90% in both treatment groups.³⁹ Typically, a total of 30 to 36 Gy of radiation is delivered to para-aortic and ipsilateral external iliac lymph nodes (“dog-leg” field), followed by an optional boost to the involved nodal areas.⁴⁰ Radiation is associated with acute side effects such as fatigue, gastrointestinal effects, myelosuppression as well as late side effects such as second cancers in the irradiated field (eg, sarcoma, bladder cancer).

Evaluation of Treatment Response

Monitoring of treatment response is fairly straightforward for patients with testicular cancer. Our practice is the following:

1. Measure tumor markers on day 1 of each chemotherapy cycle and 3 to 4 weeks after completion of treatment.
2. CT of the chest, abdomen, and pelvis with intravenous contrast prior to chemotherapy and upon completion of chemotherapy. Interim imaging is only needed for a small subset of patients with additional clinical indications (eg, new symptoms, lack of improvement in existing symptoms).
3. For patients with stage II/III seminoma who have a residual mass ≥ 3 cm on post-treatment CT scan, a PET-CT scan is indicated 6 to 8 weeks after the completion of chemotherapy to determine the need for further treatment.

Active Surveillance

Because testicular cancer has high cure rates even when patients have disease relapse after primary therapy, and additional therapies have significant short- and long-term side effects in these generally young patients, active surveillance is a critical option used in the management of testicular cancer.⁴¹

Patients must be counseled that active surveillance is a form of treatment itself in that it involves close clinical and radiographic monitoring. Because there is a risk of disease relapse, patients opting to undergo active surveillance must fully understand the risks of disease recurrence and be willing to abide by the recommended follow-up schedule.

Surveillance is necessary for a minimum of 5 years and possibly 10 years following orchiectomy, and most relapses tend to occur within the first 2 years. Late relapses such as skeletal metastatic disease from seminoma have been reported to occur more than 15 years after orchiectomy, but are generally rare and unpredictable.

The general guidelines for active surveillance are as follows:

For patients with seminoma, history and physical exam and tumor marker assessment should be performed every 3 to 6 months for the first year, then every 6 to 12 months in years 2 and 3, and then annually. CT of the abdomen and pelvis should be done at 3, 6, and 12 months, every 6 to 12 months in years 2 and 3, and then every 12 to 24 months in years 4 and 5. A chest radiograph is performed only if clinically indicated, as the likelihood of distant metastatic recurrence is low.

For patients with nonseminoma, history and physical exam and tumor markers assessment should be performed every 2 to 3 months for first 2 years, every 4 to 6 months in years 3 and 4, and then annually. CT of the abdomen and pelvis should be obtained every 4 to 6 months in year 1, gradually decreasing to annually in year 3 or 4. Chest radiograph is indicated at 4 and 12 months and annually thereafter for stage IA disease. For those with stage IB disease, chest radiograph is indicated every 2 months during the first year and then gradually decreasing to annually beginning year 5.

These recommendations are expected to change over time, and treating physicians are recommended to exercise discretion and consider the patient and tumor characteristics to develop the optimal surveillance plan.

 

 

Conclusion

Testicular cancer is the most common cancer afflicting young men. Prompt diagnostic workup initiated in a primary care or hospital setting followed by a referral to a multidisciplinary team of urologists, medical oncologists, and radiation oncologists enables cure in a majority of patients. For patients with stage I seminoma, a radical inguinal orchiectomy followed by active surveillance may offer the best long-term outcome with minimal side effects. For patients with relapsed/refractory testicular cancers, clinical trial participation is strongly encouraged. Patients with a history of testicular cancer benefit from robust survivorship care tailored to their prior therapies. This can be safely delivered through their primary care providers in collaboration with the multidisciplinary oncology team.

Malignant testicular neoplasms can arise from either the germ cells or sex-cord stromal cells, with the former comprising approximately 95% of all testicular cancers (Table 1). Germ cell tumors may contain a single histology or a mix of multiple histologies. For clinical decision making, testicular tumors are categorized as either pure seminoma (no nonseminomatous elements present) or nonseminomatous germ cell tumors (NSGCT). The prevalence of seminoma and NSGCT is roughly equal. If a testicular tumor contains both seminomatous and nonseminomatous components, it is called a mixed germ cell tumor. Because of similarities in biological behavior, the approach to treatment of mixed germ cell tumors is similar to that for NSGCT.

The key points to remember for testicular cancer are:

1. With early diagnosis and aggressive multidisciplinary therapy, the overwhelming majority of patients can be cured;
2. Specialized care is often critical and affects outcomes; and
3. Survivorship, or post-treatment care, is very important for these patients, as they often have lifespan of several decades and a unique set of short- and long-term treatment-related complications.

Developmental Biology and Genetics

The developmental biology of germ cells and germ cell neoplasms is beyond the scope of this review, and interested readers are recommended to refer to pertinent articles on the topic.^1,2 A characteristic genetic marker of all germ cell tumors is an isochromosome of the short arm of chromosome 12, i(12p). This is present in testicular tumors regardless of histologic subtype as well as in carcinoma-in-situ. In germ cell tumors without i(12p) karyotype, excess 12p genetic material consisting of repetitive segments has been found, suggesting that this is an early and potentially critical change in oncogenesis.³ Several recent studies have revealed a diverse genomic landscape in testicular cancers, including KIT, KRAS and NRAS mutations in addition to a hyperdiploid karyotype.^4,5

Evaluation and Diagnosis

Case Presentation

A 23-year-old Caucasian man presents to a primary care clinic for a pre-employment history and physical exam. He reports testicular pain on the sexually transmitted infections screening questionnaire. On examination, the physician finds a firm, mobile, minimally-tender, 1.5-cm mass in the inferior aspect of left testicle. No contralateral testicular mass or inguinal lymphadenopathy is noted, and a detailed physical exam is otherwise unremarkable. The physician immediately orders an ultrasound of the testicles, which shows a 1.5-cm hypoechoic mass in the inferior aspect of the left testicle, with an unremarkable contralateral testicle. After discussion of the results, the patient is referred a urologic oncologist with expertise in testicular cancer for further care.

The urologic oncologist orders a computed tomography (CT) abdomen and pelvis with and without contrast, which shows a 1.8-cm pathologic-appearing retroperitoneal lymph node at the level of the left renal vein. Chest radiograph with anteroposterior and lateral views is unremarkable. Tumor markers are as follows: beta human chorionic gonadotropin (beta-HCG) 8 mIU/mL (normal range, 0–4 mIU/mL), alpha-fetoprotein (AFP) 2 ng/mL (normal range, 0–8.5 ng/mL), and lactate dehydrogenase (LDH) 195 U/L (normal range, 119–213 U/L).

What is the approach to the initial workup and diagnosis of testicular cancer?

Clinical Presentation and Physical Exam

The majority of testicular cancers are diagnosed on work-up of a nodule or painless swelling of one testicle, usually noted incidentally by the patient. Approximately 30% to 40% of patients complain of a dull ache or heavy sensation in the lower abdomen, perianal area, or scrotum, while acute pain is the presenting symptom in 10%.³

In approximately 10% of patients, the presenting symptom is a result of distant metastatic involvement, such as cough and dyspnea on exertion (pulmonary or mediastinal metastasis), intractable bone pain (skeletal metastasis), intractable back/flank pain, presence of psoas sign or unexplained lower extremity deep vein thrombosis (bulky retroperitoneal metastasis), or central nervous system symptoms (vertebral, spinal or brain metastasis). Constitutional symptoms (unexplained weight loss, anorexia, fatigue) often accompany these symptoms.³

Rarely (5% or less), testicular cancer may present with systemic endocrine symptoms or paraneoplastic symptoms. Gynecomastia is the most common in this category, occurring in approximately 2% of germ cell tumors and more commonly (20%–30%) in Leydig cell tumors of testis.⁶ Classically, these patients are either 6- to 10-year-old boys with precocious puberty or young men (mid 20s-mid 30s) with a combination of testicular mass, gynecomastia, loss of libido, and impotence. Workup typically reveals increased beta-HCG levels in blood.

Anti-Ma2-antibody-associated limbic encephalitis is the most common (and still quite rare) paraneoplastic complication associated with testicular germ cell tumors. The Ma2 antigen is selectively expressed in the neuronal nucleoli of normal brain tissue and the testicular tumor of the patient. Importantly, in a subset of these patients, the treatment of testicular cancer may result in improvement of symptoms of encephalitis.⁷

The first step in the diagnosis of testicular neoplasm is a physical exam. This should include a bimanual examination of the scrotal contents, starting with the normal contralateral testis. Normal testicle has a homogeneous texture and consistency, is freely movable, and is separable from the epididymis. Any firm, hard, or fixed mass within the substance of the tunica albuginea should be considered suspicious until proven otherwise. Spread to the epididymis or spermatic cord occurs in 10% to 15% of patients and examination should include these structures as well.³ A comprehensive system-wise examination for features of metastatic spread as discussed above should then be performed. If the patient has cryptorchidism, ultrasound is a mandatory part of the diagnostic workup.

If clinical evaluation suggests a possibility of testicular cancer, the patient must be counseled to undergo an expedited diagnostic workup and specialist evaluation, as a prompt diagnosis and treatment is key to not only improving the likelihood of cure, but also minimizing the treatments needed to achieve it.

Role of Imaging

Scrotal Ultrasound

Scrotal ultrasound is the first imaging modality used in the diagnostic workup of patient with suspected testicular cancer. Bilateral scrotal ultrasound can detect lesions as small as 1 to 2 mm in diameter and help differentiate intratesticular lesions from extrinsic masses. A cystic mass on ultrasound is unlikely to be malignant. Seminomas appear as well-defined hypoechoic lesions without cystic areas, while NSGCTs are typically inhomogeneous with calcifications, cystic areas, and indistinct margins. However, this distinction is not always apparent or reliable. Ultrasound alone is also insufficient for tumor staging.⁸ For these reasons, a radical inguinal orchiectomy must be pursued for accurate determination of histology and local stage.

If testicular ultrasound shows a suspicious intratesticular mass, the following workup is typically done:

• Measurement of serum tumor markers (beta-HCG, AFP and LDH);
• CT abdomen and pelvis with and without contrast;
• Chest radiograph anteroposterior and lateral views, or CT chest with and without contrast if clinically indicated;
• Any additional focal imaging based on symptoms (eg, magnetic resonance imaging [MRI] scan with and without contrast to evaluate the brain if the patient has CNS symptoms).

CT Scan

CT scan is the preferred imaging modality for staging of testicular cancers, specifically for evaluation of the retroperitoneum, as it is the predominant site for metastases.⁹ CT scan should encompass the abdomen and pelvis, and contrast-enhanced sequences should be obtained unless medically contraindicated. CT scan of the chest (if not initially done) is compulsory should a CT of abdomen and pelvis and/or a chest radiograph show abnormal findings.

The sensitivity and specificity of CT scans for detection of nodal metastases can vary significantly based on the cutoff. For example, in a series of 70 patients using a cutoff of 10 mm, the sensitivity and specificity of CT scans for patients undergoing retroperitoneal lymph node dissection were 37% and 100%, respectively.¹⁰ In the same study, a cutoff of 4 mm increased the sensitivity to 93% and decreased the specificity to 58%. The current general consensus for this cutoff value is 8 to 10 mm measured in the short axis in the transverse (axial) plane.

Approximately 20% of men with clinical stage I testicular cancer (ie, those with non-enlarged retroperitoneal lymph nodes) who do not undergo any adjuvant therapy will have disease relapse in the retroperitoneum, suggesting that they had occult micrometastases that were missed on the initial CT scans.^11,12

MRI/Radionuclide Bone Scan/PET Scan

Abdominal or pelvic MRI, whole-body radionuclide bone scan, and positron emission tomography (PET) scans are almost never needed as part of the initial staging workup for testicular cancers due to several limitations, including a high false-negative rate, specifically for the PET scans, and lack of any additional value compared with CT and testicular ultrasound alone.^9,13,14 If necessary, these should only be ordered after a multidisciplinary oncology consultation to prevent unnecessary delays in treatment, inappropriate changes to treatment, and unnecessary increases in cost of care.

Tumor Markers, Biopsy, and Staging

What is the role of tumor markers in the management of testicular cancers?

Serum AFP, beta-hCG, and LDH have a well-established role as tumor markers in testicular cancer. The alpha subunit of hCG is shared between multiple pituitary hormones and hence does not serve as a specific marker for testicular cancer. Serum levels of AFP and/or beta-hCG are elevated in approximately 80% percent of men with NSGCTs, even in absence of metastatic spread. On the other hand, serum beta-hCG is elevated in less than 20% and AFP is not elevated in pure seminomas.³

Tumor markers by themselves are not sufficiently sensitive or specific for the diagnosis of testicular cancer, in general, or to differentiate among its subtypes. Despite this limitation, marked elevations in these markers are rarely due to causes other than germ cell tumor. For example, serum beta-hCG concentrations greater than 10,000 mIU/mL occur only in germ cell tumors, trophoblastic differentiation of a primary lung or gastric cancer, gestational trophoblastic disease, or pregnancy. Serum AFP concentrations greater than 10,000 ng/mL occur almost exclusively in germ cell tumors and hepatocellular carcinoma.¹⁵

The pattern of marker elevation may play an important role in management of testicular cancer patients. For example, in our practice, several patients have had discordant serum tumor markers and pathology results (eg, elevated AFP with pure seminoma on orchiectomy). One of these patients was treated with adjuvant retroperitoneal lymph node dissection, which confirmed that he had a NSGCT with a seminoma, choriocarcinoma, and teratoma on pathology evaluation of retroperitoneal lymph nodes.

Serum tumor markers have 2 additional critical roles—(1) in the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging¹⁶ and International Germ Cell Cancer Collaboration Group (IGCCCG) risk stratification of testicular cancer,¹⁷ and (2) in post-treatment disease monitoring.

Is a testicular biopsy necessary for diagnosis?

A testicular biopsy is almost never pursued to confirm the diagnosis of testicular cancer. There is a concern that percutaneous testicular biopsy, which is associated with scrotal skin violation, can adversely affect outcomes due to tumor seeding of scrotal sac or metastatic spread into the inguinal nodes via scrotal skin lymphatics.

Tissue diagnosis is made by radical orchiectomy in a majority of cases. Rarely in our practice, we obtain a biopsy of metastatic lesion for a tissue diagnosis. This is only done in cases where chemotherapy must be started urgently to prevent worsening of complications from metastatic spread. This decision should be made only after a multidisciplinary consultation with urologic and medical oncology teams.

How is testicular cancer staged?

Both seminomatous and nonseminomatous germ cell tumors of the testis are staged using the AJCC/UICC staging system, which incorporates assessments of the primary tumor (T), lymph nodes (N), and distant metastases (M) and serum tumor marker values (S). Details of this staging system are beyond the scope of this review and further information can be obtained through the AJCC website (www.cancerstaging.org). This TNMS staging enables a prognostic assessment and helps with the therapeutic approach.

For patients with advanced germ cell tumors, a risk group classification developed by the IGCCCG is used to classify patients into good-risk, intermediate-risk, and poor-risk category (Table 2). This classification has been extensively validated for the past 2 decades, provides important prognostic information, and helps inform therapy decisions.

 

 

Treatment

Case 1 Continued

Based on the patient’s imaging and biomarker results, the patient undergoes a left radical inguinal orchiectomy. The physician’s operative note mentions that the left testicle was delivered without violation of scrotal integrity. A pathology report shows pure spermatocytic seminoma (unifocal, 1.4 cm size) with negative margins and no evidence of lymphovascular invasion. No lymph nodes are identified in the resection specimen. Post-orchiectomy markers are “negative,” meaning within normal range. After discussions with medical and radiation oncology physicians, the patient opts to pursue active surveillance.

Surgery alone followed by active surveillance is an appropriate option for this patient, as the likelihood of recurrence is low and most recurrences can be subsequently salvaged using treatment options detailed below.

What are the therapeutic options for testicular cancer?

An overview of management for most testicular cancers is presented in Table 3. Note that the actual treatments are significantly more complex and need a comprehensive multidisciplinary consultation (urologic, medical and radiation oncology) at centers with specialized testicular cancer teams, if possible.

Fertility Preservation

All patients initiating treatment for testicular cancer must be offered options for fertility preservation and consultation with a reproductive health team, if available. At the time of diagnosis, approximately 50% patients have some degree of impairment in spermatogenesis, but with effective fertility preservation, successful pregnancy can occur for as many as 30% to 60% of patients.^18,19

Orchiectomy

Radical inguinal orchiectomy with high ligation of the spermatic cord at the level of the internal ring is the procedure of choice for suspected testicular cancer. The goal is to provide a definitive tissue diagnosis and local tumor control with minimal morbidity. It can be performed under general, regional, or local anesthesia. Depending on the complexity and surgical expertise, it can be done in an inpatient or outpatient setting. During the procedure, the testicle is delivered from the scrotum through an incision in the inguinal region and then resected. A testicular prosthesis is usually inserted, with resultant excellent cosmetic and patient satisfaction outcomes.²⁰

Testicular sparing surgery (TSS) has been explored as an alternative to radical orchiectomy but is not considered a standard-of-care option at this time. Small studies have shown evidence for comparable short-term oncologic outcomes in a very select group of patients, generally with solitary tumors < 2 cm in size and solitary testicle. If this is being considered as an option, we recommended obtaining a consultation from a urologist at a high-volume center. For a majority of patients, the value of a TSS is diminished due to excellent anatomic/cosmetic outcomes with a testicular prosthesis implanted during the radical orchiectomy, and resumption of sexual functions by the unaffected contralateral testicle.

Retroperitoneal Lymph Node Dissection

As discussed, conventional cross-sectional imaging has a high false-negative rate for detection of retroperitoneal involvement. General indications for RPLND in various stages and histologies of testicular cancer germ cell tumors are outlined in Table 3. Seminoma tends to most commonly metastasize to retroperitoneum, but RPLND for seminoma is generally reserved for a very small subset of these patients. Patterns of metastases of NSGCT (except choriocarcinoma) are considered to be well-defined. In a series of patients with stage II NSGCTs, left-sided tumors metastasized to the pre- and para-aortic nodes in 88% and 86% of cases, respectively (drainage basin of left testicular vein); and right-sided tumors involved the interaortocaval nodes in 93% of patients.³ Inguinal and pelvic nodal metastases may rarely be seen and should not be used to rule out the diagnosis of testicular cancer.

Choriocarcinoma is an exception to this pattern of retroperitoneal spread, as it tends to have a higher likelihood of hematogenous metastases to distant organs. Compared with NSGCTs, pure seminomas are either localized to the testis (80% of all cases) or limited to the retroperitoneum (an additional 15% of all cases) at presentation.³

Depending on the case and expertise of the surgical team, robotic or open RPLND can be performed.²¹ Regardless of the approach used, RPLND remains a technically challenging surgery. The retroperitoneal “landing zone” lymph nodes lie in close proximity to, and are often densely adherent to, the abdominal great vessels. Complication rates vary widely in the reported literature, but can be as high as 50%.^21-23 As detailed in Table 2, the number and size of involved retroperitoneal lymph nodes have prognostic importance.

In summary, RPLND is considered to be a viable option for a subset of early-stage NSGCT (T1-3, N0-2, M0) and for those with advanced seminoma, NSGCT, or mixed germ cell tumors with post-chemotherapy residual disease.

Systemic Chemotherapy

Except for the single-agent carboplatin, most chemotherapy regimens used to treat testicular cancer are combinations of 2 or more chemotherapy agents. For this review, we will focus on the 3 most commonly used regimens: bleomycin, etoposide, and cisplatin (BEP), etoposide and cisplatin (EP), and etoposide, ifosfamide, and cisplatin (VIP).

The core principles of testicular cancer chemotherapy are:

1. Minimize dose interruptions, delays, or reductions, as these adversely affect outcomes without clearly improving side effect profile;
2. Do not substitute carboplatin for cisplatin in combination regimens because carboplatin-containing combination regimens have been shown to result in significantly poorer outcomes in multiple trials of adults with germ cell tumors;^24-27 and
3. Give myeloid growth factor support, if necessary.

BEP

The standard BEP regimen comprises a 21-day cycle with bleomycin 30 units on days 1, 8, and 15; etoposide 100 mg/m² on days 1 to 5; and cisplatin 20 mg/m² on days 1 to 5. Number of cycles varies based on histology and stage (Table 3). A strong justification to maintain treatment intensity comes from the Australian and New Zealand Germ Cell Trial Group trial. In this study, 166 men were randomly assigned to treatment using 3 cycles of standard BEP or 4 cycles of a modified BEP regimen (bleomycin 30 units day 1; etoposide 120 mg/m² days 1 to 3; cisplatin 100 mg/m² day 1) every 21 days. This trial was stopped at interim analyses because the modified BEP arm was inferior to the standard BEP arm. With a median follow-up of 8.5 years, 8-year overall survival was 92% with standard BEP and 83% with modified BEP (P = 0.037).²⁸

Bleomycin used in the BEP regimen has been associated with uncommon but potentially fatal pulmonary toxicity that tends to present as interstitial pneumonitis, which may ultimately progress to fibrosis or bronchiolitis obliterans with organizing pneumonia.²⁹ This has led to evaluation of EP as an alternative to BEP.

EP

The standard EP regimen consists of a 21-day cycle with etoposide 100 mg/m² on days 1 to 5, and cisplatin 20 mg/m² on days 1 to 5. Due to conflicting data from multiple randomized trials, there is considerable debate in the field regarding whether 4 cycles of EP are equivalent to 3 cycles of BEP.^30,31 The benefit of the EP regimen is that it avoids the higher rates of pulmonary, cutaneous, and neurologic toxicities associated bleomycin, but it does result in the patient receiving an up to 33% higher cumulative dose of cisplatin and etoposide due to the extra cycle of treatment. This has important implications in terms of tolerability and side effects, including delayed toxicities such as second malignancies, which increase with a higher cumulative dose of these agents (etoposide in particular).

VIP

The standard VIP regimen consists of a 21-day cycle with etoposide 75 mg/m² on days 1 to 5; cisplatin 20 mg/m² on days 1 to 5; ifosfamide 1200 mg/m² on days 1 to 5; and mesna 120 mg/m² IV push on day 1 followed by 1200 mg/m² on days 1 to 5. For patients with intermediate- or poor-risk disease, 4 cycles of VIP has demonstrated comparable efficacy but higher rates of hematologic toxicities compared with 4 cycles of BEP.^32-34 It remains an option for upfront treatment of patients who are not good candidates for a bleomycin-based regimen, and for patients who need salvage chemotherapy.

Adverse Effects of Chemotherapy

Acute and late chemotherapy toxicities vary significantly between regimens depending on the chemotherapy drugs used. Bleomycin-induced pneumonitis may masquerade as a “pneumonia,” which can lead to a delay in diagnosis or institution of treatment, as well as institution of an incorrect treatment (for example, there is a concern that bleomycin toxicity can be precipitated or worsened by a high fraction of inspired oxygen). Chemotherapy-associated neutropenia tends to occur a few days (7–10 days) after initiation of chemotherapy, and neutrophil counts recover without intervention in most patients after an additional 7 to 10 days. Myeloid growth factor support (eg, filgrastim, pegfilgrastim) can be given to patients either prophylactically (if they had an episode of febrile or prolonged neutropenia with the preceding cycle) or secondarily if they present with neutropenia (an absolute neutrophil count ≤ 500 cells/µL) with fever or active infection. Such interventions tend to shorten the duration of neutropenia but does not affect overall survival. Patients with asymptomatic neutropenia do not benefit from growth factor use.³⁵

 

 

Stem Cell Transplant

Autologous stem cell transplant (SCT) is the preferred type of SCT for patients with testicular cancer and involves delivery of high doses of chemotherapy followed by infusion of patient-derived myeloid stem cells. While the details of this treatment are outside the scope of this review, decades of experience has shown that this is an effective curative option for a subset of patients with poor prognosis, such as those with platinum-refractory or relapsed disease.³⁶

Clinical Trials

Due to excellent clinical outcomes with front-line therapy, as described, and the relatively low incidence of testicular and other germ cell tumors, clinical trial options for patients with testicular cancer are limited. The TIGER trial is an ongoing international, randomized, phase 3 trial comparing conventional TIP (paclitaxel, ifosfamide, and cisplatin) chemotherapy with high-dose chemotherapy with SCT as the first salvage treatment for relapsed/refractory germ cell tumors (NCT02375204). It is enrolling at multiple centers in the United States and results are expected in 2022. At least 2 ongoing trials are evaluating the role of immunotherapy in patients with relapsed/refractory germ cell tumors (NCT03081923 and NCT03726281). Cluster of differentiation antigen-30 (CD30) has emerged as a potential target of interest in germ cell tumors, and brentuximab vedotin, an anti-CD30 monoclonal antibody, is undergoing evaluation in a phase 2 trial of CD-30–expressing germ cell tumors (NCT01851200). This trial has completed enrollment and results are expected to be available in late 2019 or early 2020.

When possible, patients with relapsed/refractory germ cell tumors should be referred to centers of excellence with access to either testicular/germ-cell tumor specific clinical trials or phase 1 clinical trials.

Radiation Therapy

Adjuvant radiation to the retroperitoneum has a role in the management of stage I and IIA seminomas (Table 3). In a randomized noninferiority trial of radiation therapy versus single-dose carboplatin in stage I seminoma patients, 5-year recurrence-free survival was comparable at approximately 95% in either arm.^37,38 In a retrospective database review of 2437 patients receiving either radiation therapy or multi-agent chemotherapy for stage II seminoma, the 5-year survival exceeded 90% in both treatment groups.³⁹ Typically, a total of 30 to 36 Gy of radiation is delivered to para-aortic and ipsilateral external iliac lymph nodes (“dog-leg” field), followed by an optional boost to the involved nodal areas.⁴⁰ Radiation is associated with acute side effects such as fatigue, gastrointestinal effects, myelosuppression as well as late side effects such as second cancers in the irradiated field (eg, sarcoma, bladder cancer).

Evaluation of Treatment Response

Monitoring of treatment response is fairly straightforward for patients with testicular cancer. Our practice is the following:

1. Measure tumor markers on day 1 of each chemotherapy cycle and 3 to 4 weeks after completion of treatment.
2. CT of the chest, abdomen, and pelvis with intravenous contrast prior to chemotherapy and upon completion of chemotherapy. Interim imaging is only needed for a small subset of patients with additional clinical indications (eg, new symptoms, lack of improvement in existing symptoms).
3. For patients with stage II/III seminoma who have a residual mass ≥ 3 cm on post-treatment CT scan, a PET-CT scan is indicated 6 to 8 weeks after the completion of chemotherapy to determine the need for further treatment.

Active Surveillance

Because testicular cancer has high cure rates even when patients have disease relapse after primary therapy, and additional therapies have significant short- and long-term side effects in these generally young patients, active surveillance is a critical option used in the management of testicular cancer.⁴¹

Patients must be counseled that active surveillance is a form of treatment itself in that it involves close clinical and radiographic monitoring. Because there is a risk of disease relapse, patients opting to undergo active surveillance must fully understand the risks of disease recurrence and be willing to abide by the recommended follow-up schedule.

Surveillance is necessary for a minimum of 5 years and possibly 10 years following orchiectomy, and most relapses tend to occur within the first 2 years. Late relapses such as skeletal metastatic disease from seminoma have been reported to occur more than 15 years after orchiectomy, but are generally rare and unpredictable.

The general guidelines for active surveillance are as follows:

For patients with seminoma, history and physical exam and tumor marker assessment should be performed every 3 to 6 months for the first year, then every 6 to 12 months in years 2 and 3, and then annually. CT of the abdomen and pelvis should be done at 3, 6, and 12 months, every 6 to 12 months in years 2 and 3, and then every 12 to 24 months in years 4 and 5. A chest radiograph is performed only if clinically indicated, as the likelihood of distant metastatic recurrence is low.

For patients with nonseminoma, history and physical exam and tumor markers assessment should be performed every 2 to 3 months for first 2 years, every 4 to 6 months in years 3 and 4, and then annually. CT of the abdomen and pelvis should be obtained every 4 to 6 months in year 1, gradually decreasing to annually in year 3 or 4. Chest radiograph is indicated at 4 and 12 months and annually thereafter for stage IA disease. For those with stage IB disease, chest radiograph is indicated every 2 months during the first year and then gradually decreasing to annually beginning year 5.

These recommendations are expected to change over time, and treating physicians are recommended to exercise discretion and consider the patient and tumor characteristics to develop the optimal surveillance plan.

 

 

Conclusion

Testicular cancer is the most common cancer afflicting young men. Prompt diagnostic workup initiated in a primary care or hospital setting followed by a referral to a multidisciplinary team of urologists, medical oncologists, and radiation oncologists enables cure in a majority of patients. For patients with stage I seminoma, a radical inguinal orchiectomy followed by active surveillance may offer the best long-term outcome with minimal side effects. For patients with relapsed/refractory testicular cancers, clinical trial participation is strongly encouraged. Patients with a history of testicular cancer benefit from robust survivorship care tailored to their prior therapies. This can be safely delivered through their primary care providers in collaboration with the multidisciplinary oncology team.

Selinexor (Xpovio) has been approved for use in combination with dexamethasone for the treatment of select adult patients with relapsed refractory multiple myeloma (RRMM), the Food and Drug Administration announced in a statement.

The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.

The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.

The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.

“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.

Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.

Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.

Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.

The FDA granted the approval of Xpovio to Karyopharm Therapeutics.

mdales@mdedge.com

Selinexor (Xpovio) has been approved for use in combination with dexamethasone for the treatment of select adult patients with relapsed refractory multiple myeloma (RRMM), the Food and Drug Administration announced in a statement.

The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.

The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.

The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.

“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.

Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.

Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.

Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.

The FDA granted the approval of Xpovio to Karyopharm Therapeutics.

mdales@mdedge.com

Selinexor (Xpovio) has been approved for use in combination with dexamethasone for the treatment of select adult patients with relapsed refractory multiple myeloma (RRMM), the Food and Drug Administration announced in a statement.

The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.

The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.

The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.

“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.

Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.

Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.

Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.

The FDA granted the approval of Xpovio to Karyopharm Therapeutics.

mdales@mdedge.com

Radioactive iodine therapy for hyperthyroidism may be associated with an increased risk of death from cancer, according to a longitudinal cohort study published in the July 1 issue of JAMA Internal Medicine.

Sebastian Kaulitzki/Fotolia

The study followed 18,805 individuals whose hyperthyroidism was treated with radioactive iodine in the United States and United Kingdom between 1946 and 1964.

Researchers found positive dose-response relationships between radioactive iodine therapy and most of the solid cancers that were evaluated. However these only attained statistical significance in the case of female breast cancer – where there was a 12% increase in the risk of death from breast cancer from a 100-mGy tissue- or organ-absorbed dose – or for all solid cancers combined, where a 100-mGy dose to the stomach was associated with a 6% increase in death from all solid cancers.

Based on this, the authors estimated that 8% of solid cancer deaths, including 14% of breast cancer deaths, could be attributed to the radiation. When combined with current US mortality rates, that translated to around 13 excess solid cancer deaths, including three deaths from breast cancer, for every 1000 patients receiving a 100 mGy absorbed dose to the stomach or breast at age 40 years.

However they noted that patients with Graves disease are now recommended to receive higher doses, and calculated that for 150-mGy, 200-mGy and 250-mGy dosages there would be 19-32 excess solid cancer deaths per 1000 patients treated at age 40 years.

“To our knowledge, this is the first study to characterize the dose-response relationship between RAI treatment and site-specific cancer mortality in patients with hyperthyroidism using reliable estimates of absorbed dose to exposed organs or tissues,” wrote Cari M. Kitahara, PhD, from the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and co-authors.

Radioactive iodine therapy did not appear to be associated with an increased risk of death from leukemia, non-Hodgkin lymphoma or multiple myeloma.

The authors noted that this was unexpected given previous findings of an elevated risk of leukemia in patients with thyroid cancer who received higher levels of radiation. They suggested that the greater uncertainty in calculation of red bone marrow exposure compared to that of other organs and tissue, as well as the relatively small number of leukemia deaths, may have limited their ability to detect a dose-response relationship.

The study was funded by the National Cancer Institute. One author declared membership of a consortium supported by the pharmaceutical sector.
 

SOURCE: Kitahara C et al. JAMA Internal Medicine 2019, July 1. DOI:10.1001/jamainternmed.2019.0981.

Radioactive iodine therapy for hyperthyroidism may be associated with an increased risk of death from cancer, according to a longitudinal cohort study published in the July 1 issue of JAMA Internal Medicine.

Sebastian Kaulitzki/Fotolia

The study followed 18,805 individuals whose hyperthyroidism was treated with radioactive iodine in the United States and United Kingdom between 1946 and 1964.

Researchers found positive dose-response relationships between radioactive iodine therapy and most of the solid cancers that were evaluated. However these only attained statistical significance in the case of female breast cancer – where there was a 12% increase in the risk of death from breast cancer from a 100-mGy tissue- or organ-absorbed dose – or for all solid cancers combined, where a 100-mGy dose to the stomach was associated with a 6% increase in death from all solid cancers.

Based on this, the authors estimated that 8% of solid cancer deaths, including 14% of breast cancer deaths, could be attributed to the radiation. When combined with current US mortality rates, that translated to around 13 excess solid cancer deaths, including three deaths from breast cancer, for every 1000 patients receiving a 100 mGy absorbed dose to the stomach or breast at age 40 years.

However they noted that patients with Graves disease are now recommended to receive higher doses, and calculated that for 150-mGy, 200-mGy and 250-mGy dosages there would be 19-32 excess solid cancer deaths per 1000 patients treated at age 40 years.

“To our knowledge, this is the first study to characterize the dose-response relationship between RAI treatment and site-specific cancer mortality in patients with hyperthyroidism using reliable estimates of absorbed dose to exposed organs or tissues,” wrote Cari M. Kitahara, PhD, from the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and co-authors.

Radioactive iodine therapy did not appear to be associated with an increased risk of death from leukemia, non-Hodgkin lymphoma or multiple myeloma.

The authors noted that this was unexpected given previous findings of an elevated risk of leukemia in patients with thyroid cancer who received higher levels of radiation. They suggested that the greater uncertainty in calculation of red bone marrow exposure compared to that of other organs and tissue, as well as the relatively small number of leukemia deaths, may have limited their ability to detect a dose-response relationship.

The study was funded by the National Cancer Institute. One author declared membership of a consortium supported by the pharmaceutical sector.
 

SOURCE: Kitahara C et al. JAMA Internal Medicine 2019, July 1. DOI:10.1001/jamainternmed.2019.0981.

Radioactive iodine therapy for hyperthyroidism may be associated with an increased risk of death from cancer, according to a longitudinal cohort study published in the July 1 issue of JAMA Internal Medicine.

Sebastian Kaulitzki/Fotolia

The study followed 18,805 individuals whose hyperthyroidism was treated with radioactive iodine in the United States and United Kingdom between 1946 and 1964.

Researchers found positive dose-response relationships between radioactive iodine therapy and most of the solid cancers that were evaluated. However these only attained statistical significance in the case of female breast cancer – where there was a 12% increase in the risk of death from breast cancer from a 100-mGy tissue- or organ-absorbed dose – or for all solid cancers combined, where a 100-mGy dose to the stomach was associated with a 6% increase in death from all solid cancers.

Based on this, the authors estimated that 8% of solid cancer deaths, including 14% of breast cancer deaths, could be attributed to the radiation. When combined with current US mortality rates, that translated to around 13 excess solid cancer deaths, including three deaths from breast cancer, for every 1000 patients receiving a 100 mGy absorbed dose to the stomach or breast at age 40 years.

However they noted that patients with Graves disease are now recommended to receive higher doses, and calculated that for 150-mGy, 200-mGy and 250-mGy dosages there would be 19-32 excess solid cancer deaths per 1000 patients treated at age 40 years.

“To our knowledge, this is the first study to characterize the dose-response relationship between RAI treatment and site-specific cancer mortality in patients with hyperthyroidism using reliable estimates of absorbed dose to exposed organs or tissues,” wrote Cari M. Kitahara, PhD, from the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and co-authors.

Radioactive iodine therapy did not appear to be associated with an increased risk of death from leukemia, non-Hodgkin lymphoma or multiple myeloma.

The authors noted that this was unexpected given previous findings of an elevated risk of leukemia in patients with thyroid cancer who received higher levels of radiation. They suggested that the greater uncertainty in calculation of red bone marrow exposure compared to that of other organs and tissue, as well as the relatively small number of leukemia deaths, may have limited their ability to detect a dose-response relationship.

The study was funded by the National Cancer Institute. One author declared membership of a consortium supported by the pharmaceutical sector.
 

SOURCE: Kitahara C et al. JAMA Internal Medicine 2019, July 1. DOI:10.1001/jamainternmed.2019.0981.

AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.

Will Pass/MDedge News

A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.

“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.

To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.

The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).

Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.

A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).

“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”

Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.

The investigators reported no disclosures.

SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.

AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.

Will Pass/MDedge News

A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.

“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.

To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.

The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).

Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.

A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).

“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”

Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.

The investigators reported no disclosures.

SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.

AMSTERDAM – When predicting the risk of thromboembolism in lymphoma patients receiving chemotherapy, clinicians can rely on a routine diagnostic tool: complete blood count, investigators reported.

Will Pass/MDedge News

A recent study found that high neutrophil to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios were prognostic for thromboembolism in this setting, reported lead author Vladimir Otasevic, MD, of the Clinical Centre of Serbia in Belgrade.

“Because of the presence of a broad spectrum of risk factors [in patients with lymphoma undergoing chemotherapy], some authors have published risk-assessment models for prediction of thromboembolism,” Dr. Otasevic said during a presentation at the annual congress of the European Hematology Association. While the underlying pathophysiology that precedes thromboembolism is complex, Dr. Otasevic suggested that risk prediction may not have to be, noting that NLR and PLR were recently proposed as risk biomarkers.

To test the utility of these potential biomarkers, Dr. Otasevic and his colleagues retrospectively analyzed data from 484 patients with non-Hodgkin and Hodgkin lymphoma who had undergone at least one cycle of chemotherapy at the Clinic for Hematology, Clinical Centre of Serbia. Patients were followed for venous and arterial thromboembolic events from the time of diagnosis to 3 months beyond their final cycle of chemotherapy. NLR and PLR ratios were calculated from complete blood count. Thromboembolism was diagnosed by radiography, clinical exam, and laboratory evaluation, with probable diagnoses reviewed by an internist and radiologist.

The median patient age was 53 years with a range from 18 to 89 years. Most patients were recently diagnosed with advanced disease (21.1% stage III and 42.5% stage IV). Half of the population had high-grade non-Hodgkin lymphoma (50.0%) and slightly more than a quarter had low-grade non-Hodgkin lymphoma (28.3%). Low-grade Hodgkin lymphoma was less common (17.4%) and followed distantly by other forms (4.3%).

Thirty-five patients (7.2%) developed thromboembolic events; of these, 30 had venous thromboembolism (6.2%), 6 had arterial thromboembolism (1.2%), and 1 had both. Patients who experienced thromboembolic events had significantly higher NLR and PLR than patients without thromboembolism, and both ratios were significantly associated with one another.

A positive NLR, defined as a ratio of 3.1 or more, was associated with a relative risk of 4.1 for thromboembolism (P less than .001), while a positive PLR, defined as a ratio of 10 or more, was associated with a relative risk of 2.9 (P = .008). Using a multivariate model, a positive NLR was associated with an even higher relative risk (RR = 4.5; P less than .001).

“NLR and PLR demonstrated significant powerfulness in prediction of future risk of [thromboembolism] in lymphoma patients,” the investigators concluded. “Simplicity, effectiveness, modesty, and practicability qualify these new tools for routine [thromboembolism] prognostic assessment.”

Dr. Otasevic said that he and his colleagues have plans to build on these findings with further analysis involving progression-free and overall survival.

The investigators reported no disclosures.

SOURCE: Otasevic V et al. EHA Congress, Abstract S1645.

Patients benefit from multidisciplinary care that coordinates management of complex medical problems. Traditionally, multidisciplinary cancer care involves oncology specialty providers in fields that include medical oncology, radiation oncology, and surgical oncology. Multidisciplinary cancer care intends to improve patient outcomes by bringing together different health care providers (HCPs) who are involved in the treatment of patients with cancer. Because new therapies are more effective and allow patients with cancer to live longer, adverse effects (AEs) are more likely to impact patients’ well-being, both while receiving treatment and long after it has completed. Thus, this population may benefit from an expanded approach to multidisciplinary care that includes input from specialty and primary care providers (PCPs), clinical pharmacy specialists (CPS), physical and occupational therapists, and patient navigators and educators.

We present 4 hypothetical cases, based on actual patients, that illustrate opportunities where multidisciplinary care coordination may improve patient experiences. These cases draw on current quality initiatives from the National Cancer Institute Community Cancer Centers Program, which has focused on improving the quality of multidisciplinary cancer care at selected community centers, and the Veterans Health Administration (VHA) patient-aligned care team (PACT) model, which brings together different health professionals to optimize primary care coordination.^1,2 In addition, the National Committee for Quality Assurance has introduced an educational initiative to facilitate implementation of an oncologic medical home.³ This initiative stresses increased multidisciplinary communication, patient-centered care delivery, and reduced fragmentation of care for this population. Despite these guidelines and experiences from other medical specialties, models for integrated cancer care have not been implemented in a prospective fashion within the VHA.

In this article, we focus on opportunities to take collaborative care approaches for the treatment of patients with follicular lymphoma (FL): a common, incurable, and often indolent B-cell non-Hodgkin lymphoma.⁴ FL was selected because these patients may be treated numerous times and long-term sequalae can accumulate throughout their cancer continuum (a series of health events encompassing cancer screening, diagnosis, treatment, survivorship, relapse, and death).⁵ HCPs in distinct roles can assist patients with cancer in optimizing their health outcomes and overall wellbeing.⁶

Case Example 1

A 70-year-old male was diagnosed with stage IV FL. Because of his advanced disease, he began therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Prednisone was administered at 100 mg daily on the first 5 days of each 21-day cycle. On day 4 of the first treatment cycle, the patient notified his oncologist that he had been very thirsty and his random blood sugar values on 2 different days were 283 mg/dL and 312 mg/dL. A laboratory review revealed his hemoglobin A_1c (HbA_1c) 7 months prior was 5.6%.

Discussion

The high-dose prednisone component of this and other lymphoma therapy regimens can worsen diabetes mellitus (DM) control and/or worsen prediabetes. Patient characteristics that increase the risk of developing glucocorticoid-induced DM after CHOP chemotherapy include age ≥ 60 years, HbA_1c > 6.1%, and body mass index > 30.⁷ This patient did not have DM prior to the FL therapy initiation, but afterwards he met diagnostic criteria for DM. For completeness, other causes for elevated blood glucose should be ruled out (ie, infection, laboratory error, etc.). An oncologist often will triage acute hyperglycemia, treating immediately with IV fluids and/or insulin. Thereafter, ongoing chronic disease management for DM may be best managed by PCPs, certified DM educators, and registered dieticians.

Several programs involving multidisciplinary DM care, comprised of physicians, advanced practice providers, nurses, certified DM educators, and/or pharmacists have been shown to improve HbA_1c, cardiovascular outcomes, and all-cause mortality, while reducing health care costs.⁸ In addition, patient navigators can assist patients with coordinating visits to disease-state specialists and identifying further educational needs. For example, in 1 program, nonclinical peer navigators were shown to improve the number of appointments attended and reduce HbA_1c in a population of patients with DM who were primarily minority, urban, and of low socioeconomic status.⁹ Thus, integrating DM care shows potential to improve outcomes for patients with lymphoma who develop glucocorticoid-induced DM.

Case Example 2

A 75-year-old male was diagnosed with FL. He was treated initially with bendamustine and rituximab. He required reinitiation of therapy 20 months later when he developed lymphadenopathy, fatigue, and night sweats and began treatment with oral idelalisib, a second-line therapy. Later, the patient presented to his PCP for a routine visit, and on medication reconciliation review, the patient reported regular use of trimethoprim-sulfamethoxazole.

Discussion

Upon consultation with the CPS and the patient’s oncologist, the PCP confirmed trimethoprim-sulfamethoxazole should be continued during therapy and for about 6 months following completion of therapy. Trimethoprim-sulfamethoxazole is used for prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). While use of prophylactic therapy is not necessary for all patients with FL, idelalisib impairs the function of circulating lymphoid B-cells and thus has been associated with an increased risk of serious infection.¹⁰ A CPS can provide insight that maximizes medication adherence and efficacy while minimizing food-drug, drug-drug interactions, and AEs. CPS have been shown to: improve adherence to oral therapies, increase prospective monitoring required for safe therapy dose selection, and document assessment of chemotherapy-related AEs.^11,12 Thus, multidisciplinary, integrated care is an important component of providing quality oncology care.

Case Example 3

A 60-year-old female presented to her PCP with a 2-week history of shortness of breath and leg swelling. She was treated for FL 4 years previously with 6 cycles of R-CHOP. She reported no chest pain and did not have a prior history of hypertension, DM, or heart disease. On physical exam, she had elevated jugular venous pressure to jaw at 45°, bilateral pulmonary rales, and 2+ pitting pretibial edema. Laboratory tests that included complete blood count, basic chemistries, and thyroid stimulating hormone were unremarkable, though brain natriuretic peptide (BNP) was elevated at 425 pg/mL.

As this patient’s laboratory results and physical examination suggested new-onset congestive heart failure, the PCP obtained an echocardiogram, which demonstrated an ejection fraction of 35% and global hypokinesis. Because the patient was symptomatic, she was admitted to the hospital to begin guideline-directed medical therapy (GDMT) including IV diuresis.

Discussion

Given the absence of significant risk factors and prior history of coronary artery disease, the most probable cause for this patient’s cardiomyopathy is doxorubicin. Doxorubicin is an anthracycline chemotherapy that can cause nonischemic, dilated cardiomyopathy, particularly when cumulative doses > 400 mg/m² are administered, or when combined with chest radiation.¹³ This patient benefited from GDMT for reduced ejection-fraction heart failure (HFrEF). Studies have demonstrated positive outcomes when HFrEF patients are cared for by a multidisciplinary team who focus of volume management as well as uptitration of therapies to target doses.¹⁴

Case Example 4

An 80-year-old female was diagnosed with stage III FL but did not require immediate therapy. After developing discomfort due to enlarging lymphadenopathy, she initiated therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). She presented to her oncologist for consideration of her fifth cycle of R-CVP and reported a burning sensation on the soles of her feet and numbness in her fingertips and toes. On examination, her pulses were intact and there were no signs of infection, reduced blood flow, or edema. The patient demonstrated decreased sensation on monofilament testing. She had no history of DM and a recent HbA_1c test was 4.9% An evaluation for other causes of neuropathy, such as hypothyroidism and vitamin B₁₂ deficiency was negative. Thus, vincristine therapy was identified as the most likely etiology for her peripheral neuropathy. The oncologist decided to proceed with cycle 5 of chemotherapy but reduced the dose of vincristine by 50%.

Discussion

Vincristine is a microtubule inhibitor used in many chemotherapy regimens and may cause reversible or permanent neuropathy, including autonomic (constipation), sensory (stocking-glove distribution), or motor (foot-drop).¹⁵ A nerve conduction study may be indicated as part of the diagnostic evaluation. Treatment for painful sensory neuropathy may include pharmacologic therapy (such as gabapentin, pregabalin, capsaicin cream).¹⁶ Podiatrists can provide foot care and may provide shoes and inserts if appropriate. Physical therapists may assist with safety and mobility evaluations and can provide therapeutic exercises and assistive devices that improve function and quality of life.¹⁷

Conclusion

As cancer becomes more curable and more manageable, patients with cancer and survivors no longer rely exclusively on their oncologists for medical care. This is increasingly prevalent for patients with incurable but indolent cancers that may be present for years to decades, as acute and cumulative toxicities may complicate existing comorbidities. Thus, in this era of increasingly complex cancer therapies, multidisciplinary medical care that involves PCPs, specialists, and allied medical professionals, is essential for providing care that optimizes health and fully addresses patients’ needs.

Patients benefit from multidisciplinary care that coordinates management of complex medical problems. Traditionally, multidisciplinary cancer care involves oncology specialty providers in fields that include medical oncology, radiation oncology, and surgical oncology. Multidisciplinary cancer care intends to improve patient outcomes by bringing together different health care providers (HCPs) who are involved in the treatment of patients with cancer. Because new therapies are more effective and allow patients with cancer to live longer, adverse effects (AEs) are more likely to impact patients’ well-being, both while receiving treatment and long after it has completed. Thus, this population may benefit from an expanded approach to multidisciplinary care that includes input from specialty and primary care providers (PCPs), clinical pharmacy specialists (CPS), physical and occupational therapists, and patient navigators and educators.

We present 4 hypothetical cases, based on actual patients, that illustrate opportunities where multidisciplinary care coordination may improve patient experiences. These cases draw on current quality initiatives from the National Cancer Institute Community Cancer Centers Program, which has focused on improving the quality of multidisciplinary cancer care at selected community centers, and the Veterans Health Administration (VHA) patient-aligned care team (PACT) model, which brings together different health professionals to optimize primary care coordination.^1,2 In addition, the National Committee for Quality Assurance has introduced an educational initiative to facilitate implementation of an oncologic medical home.³ This initiative stresses increased multidisciplinary communication, patient-centered care delivery, and reduced fragmentation of care for this population. Despite these guidelines and experiences from other medical specialties, models for integrated cancer care have not been implemented in a prospective fashion within the VHA.

In this article, we focus on opportunities to take collaborative care approaches for the treatment of patients with follicular lymphoma (FL): a common, incurable, and often indolent B-cell non-Hodgkin lymphoma.⁴ FL was selected because these patients may be treated numerous times and long-term sequalae can accumulate throughout their cancer continuum (a series of health events encompassing cancer screening, diagnosis, treatment, survivorship, relapse, and death).⁵ HCPs in distinct roles can assist patients with cancer in optimizing their health outcomes and overall wellbeing.⁶

Case Example 1

A 70-year-old male was diagnosed with stage IV FL. Because of his advanced disease, he began therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Prednisone was administered at 100 mg daily on the first 5 days of each 21-day cycle. On day 4 of the first treatment cycle, the patient notified his oncologist that he had been very thirsty and his random blood sugar values on 2 different days were 283 mg/dL and 312 mg/dL. A laboratory review revealed his hemoglobin A_1c (HbA_1c) 7 months prior was 5.6%.

Discussion

The high-dose prednisone component of this and other lymphoma therapy regimens can worsen diabetes mellitus (DM) control and/or worsen prediabetes. Patient characteristics that increase the risk of developing glucocorticoid-induced DM after CHOP chemotherapy include age ≥ 60 years, HbA_1c > 6.1%, and body mass index > 30.⁷ This patient did not have DM prior to the FL therapy initiation, but afterwards he met diagnostic criteria for DM. For completeness, other causes for elevated blood glucose should be ruled out (ie, infection, laboratory error, etc.). An oncologist often will triage acute hyperglycemia, treating immediately with IV fluids and/or insulin. Thereafter, ongoing chronic disease management for DM may be best managed by PCPs, certified DM educators, and registered dieticians.

Several programs involving multidisciplinary DM care, comprised of physicians, advanced practice providers, nurses, certified DM educators, and/or pharmacists have been shown to improve HbA_1c, cardiovascular outcomes, and all-cause mortality, while reducing health care costs.⁸ In addition, patient navigators can assist patients with coordinating visits to disease-state specialists and identifying further educational needs. For example, in 1 program, nonclinical peer navigators were shown to improve the number of appointments attended and reduce HbA_1c in a population of patients with DM who were primarily minority, urban, and of low socioeconomic status.⁹ Thus, integrating DM care shows potential to improve outcomes for patients with lymphoma who develop glucocorticoid-induced DM.

Case Example 2

A 75-year-old male was diagnosed with FL. He was treated initially with bendamustine and rituximab. He required reinitiation of therapy 20 months later when he developed lymphadenopathy, fatigue, and night sweats and began treatment with oral idelalisib, a second-line therapy. Later, the patient presented to his PCP for a routine visit, and on medication reconciliation review, the patient reported regular use of trimethoprim-sulfamethoxazole.

Discussion

Upon consultation with the CPS and the patient’s oncologist, the PCP confirmed trimethoprim-sulfamethoxazole should be continued during therapy and for about 6 months following completion of therapy. Trimethoprim-sulfamethoxazole is used for prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). While use of prophylactic therapy is not necessary for all patients with FL, idelalisib impairs the function of circulating lymphoid B-cells and thus has been associated with an increased risk of serious infection.¹⁰ A CPS can provide insight that maximizes medication adherence and efficacy while minimizing food-drug, drug-drug interactions, and AEs. CPS have been shown to: improve adherence to oral therapies, increase prospective monitoring required for safe therapy dose selection, and document assessment of chemotherapy-related AEs.^11,12 Thus, multidisciplinary, integrated care is an important component of providing quality oncology care.

Case Example 3

A 60-year-old female presented to her PCP with a 2-week history of shortness of breath and leg swelling. She was treated for FL 4 years previously with 6 cycles of R-CHOP. She reported no chest pain and did not have a prior history of hypertension, DM, or heart disease. On physical exam, she had elevated jugular venous pressure to jaw at 45°, bilateral pulmonary rales, and 2+ pitting pretibial edema. Laboratory tests that included complete blood count, basic chemistries, and thyroid stimulating hormone were unremarkable, though brain natriuretic peptide (BNP) was elevated at 425 pg/mL.

As this patient’s laboratory results and physical examination suggested new-onset congestive heart failure, the PCP obtained an echocardiogram, which demonstrated an ejection fraction of 35% and global hypokinesis. Because the patient was symptomatic, she was admitted to the hospital to begin guideline-directed medical therapy (GDMT) including IV diuresis.

Discussion

Given the absence of significant risk factors and prior history of coronary artery disease, the most probable cause for this patient’s cardiomyopathy is doxorubicin. Doxorubicin is an anthracycline chemotherapy that can cause nonischemic, dilated cardiomyopathy, particularly when cumulative doses > 400 mg/m² are administered, or when combined with chest radiation.¹³ This patient benefited from GDMT for reduced ejection-fraction heart failure (HFrEF). Studies have demonstrated positive outcomes when HFrEF patients are cared for by a multidisciplinary team who focus of volume management as well as uptitration of therapies to target doses.¹⁴

Case Example 4

An 80-year-old female was diagnosed with stage III FL but did not require immediate therapy. After developing discomfort due to enlarging lymphadenopathy, she initiated therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). She presented to her oncologist for consideration of her fifth cycle of R-CVP and reported a burning sensation on the soles of her feet and numbness in her fingertips and toes. On examination, her pulses were intact and there were no signs of infection, reduced blood flow, or edema. The patient demonstrated decreased sensation on monofilament testing. She had no history of DM and a recent HbA_1c test was 4.9% An evaluation for other causes of neuropathy, such as hypothyroidism and vitamin B₁₂ deficiency was negative. Thus, vincristine therapy was identified as the most likely etiology for her peripheral neuropathy. The oncologist decided to proceed with cycle 5 of chemotherapy but reduced the dose of vincristine by 50%.

Discussion

Vincristine is a microtubule inhibitor used in many chemotherapy regimens and may cause reversible or permanent neuropathy, including autonomic (constipation), sensory (stocking-glove distribution), or motor (foot-drop).¹⁵ A nerve conduction study may be indicated as part of the diagnostic evaluation. Treatment for painful sensory neuropathy may include pharmacologic therapy (such as gabapentin, pregabalin, capsaicin cream).¹⁶ Podiatrists can provide foot care and may provide shoes and inserts if appropriate. Physical therapists may assist with safety and mobility evaluations and can provide therapeutic exercises and assistive devices that improve function and quality of life.¹⁷

Conclusion

As cancer becomes more curable and more manageable, patients with cancer and survivors no longer rely exclusively on their oncologists for medical care. This is increasingly prevalent for patients with incurable but indolent cancers that may be present for years to decades, as acute and cumulative toxicities may complicate existing comorbidities. Thus, in this era of increasingly complex cancer therapies, multidisciplinary medical care that involves PCPs, specialists, and allied medical professionals, is essential for providing care that optimizes health and fully addresses patients’ needs.

Patients benefit from multidisciplinary care that coordinates management of complex medical problems. Traditionally, multidisciplinary cancer care involves oncology specialty providers in fields that include medical oncology, radiation oncology, and surgical oncology. Multidisciplinary cancer care intends to improve patient outcomes by bringing together different health care providers (HCPs) who are involved in the treatment of patients with cancer. Because new therapies are more effective and allow patients with cancer to live longer, adverse effects (AEs) are more likely to impact patients’ well-being, both while receiving treatment and long after it has completed. Thus, this population may benefit from an expanded approach to multidisciplinary care that includes input from specialty and primary care providers (PCPs), clinical pharmacy specialists (CPS), physical and occupational therapists, and patient navigators and educators.

We present 4 hypothetical cases, based on actual patients, that illustrate opportunities where multidisciplinary care coordination may improve patient experiences. These cases draw on current quality initiatives from the National Cancer Institute Community Cancer Centers Program, which has focused on improving the quality of multidisciplinary cancer care at selected community centers, and the Veterans Health Administration (VHA) patient-aligned care team (PACT) model, which brings together different health professionals to optimize primary care coordination.^1,2 In addition, the National Committee for Quality Assurance has introduced an educational initiative to facilitate implementation of an oncologic medical home.³ This initiative stresses increased multidisciplinary communication, patient-centered care delivery, and reduced fragmentation of care for this population. Despite these guidelines and experiences from other medical specialties, models for integrated cancer care have not been implemented in a prospective fashion within the VHA.

In this article, we focus on opportunities to take collaborative care approaches for the treatment of patients with follicular lymphoma (FL): a common, incurable, and often indolent B-cell non-Hodgkin lymphoma.⁴ FL was selected because these patients may be treated numerous times and long-term sequalae can accumulate throughout their cancer continuum (a series of health events encompassing cancer screening, diagnosis, treatment, survivorship, relapse, and death).⁵ HCPs in distinct roles can assist patients with cancer in optimizing their health outcomes and overall wellbeing.⁶

Case Example 1

A 70-year-old male was diagnosed with stage IV FL. Because of his advanced disease, he began therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Prednisone was administered at 100 mg daily on the first 5 days of each 21-day cycle. On day 4 of the first treatment cycle, the patient notified his oncologist that he had been very thirsty and his random blood sugar values on 2 different days were 283 mg/dL and 312 mg/dL. A laboratory review revealed his hemoglobin A_1c (HbA_1c) 7 months prior was 5.6%.

Discussion

The high-dose prednisone component of this and other lymphoma therapy regimens can worsen diabetes mellitus (DM) control and/or worsen prediabetes. Patient characteristics that increase the risk of developing glucocorticoid-induced DM after CHOP chemotherapy include age ≥ 60 years, HbA_1c > 6.1%, and body mass index > 30.⁷ This patient did not have DM prior to the FL therapy initiation, but afterwards he met diagnostic criteria for DM. For completeness, other causes for elevated blood glucose should be ruled out (ie, infection, laboratory error, etc.). An oncologist often will triage acute hyperglycemia, treating immediately with IV fluids and/or insulin. Thereafter, ongoing chronic disease management for DM may be best managed by PCPs, certified DM educators, and registered dieticians.

Several programs involving multidisciplinary DM care, comprised of physicians, advanced practice providers, nurses, certified DM educators, and/or pharmacists have been shown to improve HbA_1c, cardiovascular outcomes, and all-cause mortality, while reducing health care costs.⁸ In addition, patient navigators can assist patients with coordinating visits to disease-state specialists and identifying further educational needs. For example, in 1 program, nonclinical peer navigators were shown to improve the number of appointments attended and reduce HbA_1c in a population of patients with DM who were primarily minority, urban, and of low socioeconomic status.⁹ Thus, integrating DM care shows potential to improve outcomes for patients with lymphoma who develop glucocorticoid-induced DM.

Case Example 2

A 75-year-old male was diagnosed with FL. He was treated initially with bendamustine and rituximab. He required reinitiation of therapy 20 months later when he developed lymphadenopathy, fatigue, and night sweats and began treatment with oral idelalisib, a second-line therapy. Later, the patient presented to his PCP for a routine visit, and on medication reconciliation review, the patient reported regular use of trimethoprim-sulfamethoxazole.

Discussion

Upon consultation with the CPS and the patient’s oncologist, the PCP confirmed trimethoprim-sulfamethoxazole should be continued during therapy and for about 6 months following completion of therapy. Trimethoprim-sulfamethoxazole is used for prophylaxis against Pneumocystis jirovecii (formerly Pneumocystis carinii). While use of prophylactic therapy is not necessary for all patients with FL, idelalisib impairs the function of circulating lymphoid B-cells and thus has been associated with an increased risk of serious infection.¹⁰ A CPS can provide insight that maximizes medication adherence and efficacy while minimizing food-drug, drug-drug interactions, and AEs. CPS have been shown to: improve adherence to oral therapies, increase prospective monitoring required for safe therapy dose selection, and document assessment of chemotherapy-related AEs.^11,12 Thus, multidisciplinary, integrated care is an important component of providing quality oncology care.

Case Example 3

A 60-year-old female presented to her PCP with a 2-week history of shortness of breath and leg swelling. She was treated for FL 4 years previously with 6 cycles of R-CHOP. She reported no chest pain and did not have a prior history of hypertension, DM, or heart disease. On physical exam, she had elevated jugular venous pressure to jaw at 45°, bilateral pulmonary rales, and 2+ pitting pretibial edema. Laboratory tests that included complete blood count, basic chemistries, and thyroid stimulating hormone were unremarkable, though brain natriuretic peptide (BNP) was elevated at 425 pg/mL.

As this patient’s laboratory results and physical examination suggested new-onset congestive heart failure, the PCP obtained an echocardiogram, which demonstrated an ejection fraction of 35% and global hypokinesis. Because the patient was symptomatic, she was admitted to the hospital to begin guideline-directed medical therapy (GDMT) including IV diuresis.

Discussion

Given the absence of significant risk factors and prior history of coronary artery disease, the most probable cause for this patient’s cardiomyopathy is doxorubicin. Doxorubicin is an anthracycline chemotherapy that can cause nonischemic, dilated cardiomyopathy, particularly when cumulative doses > 400 mg/m² are administered, or when combined with chest radiation.¹³ This patient benefited from GDMT for reduced ejection-fraction heart failure (HFrEF). Studies have demonstrated positive outcomes when HFrEF patients are cared for by a multidisciplinary team who focus of volume management as well as uptitration of therapies to target doses.¹⁴

Case Example 4

An 80-year-old female was diagnosed with stage III FL but did not require immediate therapy. After developing discomfort due to enlarging lymphadenopathy, she initiated therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). She presented to her oncologist for consideration of her fifth cycle of R-CVP and reported a burning sensation on the soles of her feet and numbness in her fingertips and toes. On examination, her pulses were intact and there were no signs of infection, reduced blood flow, or edema. The patient demonstrated decreased sensation on monofilament testing. She had no history of DM and a recent HbA_1c test was 4.9% An evaluation for other causes of neuropathy, such as hypothyroidism and vitamin B₁₂ deficiency was negative. Thus, vincristine therapy was identified as the most likely etiology for her peripheral neuropathy. The oncologist decided to proceed with cycle 5 of chemotherapy but reduced the dose of vincristine by 50%.

Discussion

Vincristine is a microtubule inhibitor used in many chemotherapy regimens and may cause reversible or permanent neuropathy, including autonomic (constipation), sensory (stocking-glove distribution), or motor (foot-drop).¹⁵ A nerve conduction study may be indicated as part of the diagnostic evaluation. Treatment for painful sensory neuropathy may include pharmacologic therapy (such as gabapentin, pregabalin, capsaicin cream).¹⁶ Podiatrists can provide foot care and may provide shoes and inserts if appropriate. Physical therapists may assist with safety and mobility evaluations and can provide therapeutic exercises and assistive devices that improve function and quality of life.¹⁷

Conclusion

As cancer becomes more curable and more manageable, patients with cancer and survivors no longer rely exclusively on their oncologists for medical care. This is increasingly prevalent for patients with incurable but indolent cancers that may be present for years to decades, as acute and cumulative toxicities may complicate existing comorbidities. Thus, in this era of increasingly complex cancer therapies, multidisciplinary medical care that involves PCPs, specialists, and allied medical professionals, is essential for providing care that optimizes health and fully addresses patients’ needs.

AMSTERDAM – Patients with relapsed or refractory acute myeloid leukemia (AML) may be more likely to respond when selinexor is added to standard chemotherapy, according to investigators.

Will Pass/MDedge News

In a recent phase 2 trial, selinexor given with cytarabine and idarubicin led to a 50% overall response rate, reported lead author Walter Fiedler, MD, of University Medical Center Hamburg-Eppendorf (Germany). This response rate is at the upper end of what has been seen in published studies, Dr. Fiedler said at the annual congress of the European Hematology Association.

He also noted that giving a flat dose of selinexor improved tolerability in the trial, a significant finding in light of common adverse events and recent concerns from the Food and Drug Administration about the safety of selinexor for patients with multiple myeloma.

“The rationale to employ selinexor in this study is that there is a synergy between anthracyclines and selinexor,” Dr. Fiedler said, which may restore anthracycline sensitivity in relapsed or refractory patients. “Secondly, there is a c-myc reduction pathway that leads to a reduction of DNA damage repair genes such as Rad51 and Chk1, and this might result in inhibition of homologous recombination.”

The study involved 44 patients with relapsed or refractory AML, of whom 17 (39%) had previously received stem cell transplantation and 11 (25%) exhibited therapy-induced or secondary disease. The median patient age was 59.5 years.

Patients were given idarubicin 10 mg/m² on days 1, 3, and 5, and cytarabine 100 mg/m² on days 1-7. Initially, selinexor was given at a dose of 40 mg/m² twice per week for 4 weeks, but this led to high rates of febrile neutropenia and grade 3 or higher diarrhea, along with prolonged aplasia. In response to this issue, after the first 27 patients, the dose was reduced to a flat amount of 60 mg, given twice weekly for 3 weeks.

For patients not undergoing transplantation after the first or second induction cycle, selinexor maintenance monotherapy was offered for up to 1 year.

The primary endpoint was overall remission rate, reported as complete remission, complete remission with incomplete blood count recovery, and morphological leukemia-free status. Secondary endpoints included the rate of partial remissions, percentage of patients being transplanted after induction, early death rate, overall survival, event-free survival, and relapse-free survival.

The efficacy analysis revealed an overall response rate of 50%. A total of 9 patients had complete remission (21.4%), 11 achieved complete remission with incomplete blood count recovery (26.2%), and 1 exhibited morphological leukemia-free status (2.4%). Of note, almost half of the patients (47%) who had relapsed after previous stem cell transplantation responded, as did three-quarters who tested positive for an NPM1 mutation. After a median follow-up of 8.2 months, the median overall survival was 8.2 months, relapse-free survival was 17.7 months, and event-free survival was 4.9 months.

Adverse events occurred frequently, with a majority of patients experiencing nausea (86%), diarrhea (83%), vomiting (74%), decreased appetite (71%), febrile neutropenia (67%), fatigue (64%), leukopenia (62%), thrombocytopenia (62%), or anemia (60%).

Grade 3 or higher adverse events were almost as common, and included febrile neutropenia (67%), leukopenia (62%), thrombocytopenia (62%), anemia (57%), and diarrhea (50%). Reducing the dose did improve tolerability, with notable drops in the rate of severe diarrhea (56% vs. 40%) and febrile neutropenia (85% vs. 33%). In total, 19% of patients discontinued treatment because of adverse events.

A total of 25 patients (60%) died during the study, with about half dying from disease progression (n = 12), and fewer succumbing to infectious complications, graft-versus-host disease, multiorgan failure, multiple brain infarct, or asystole. Two deaths, one from suspected hemophagocytosis and another from systemic inflammatory response syndrome, were considered possibly related to selinexor.

“The results should be further evaluated in a phase 3 study,” Dr. Fiedler said. However, plans for this are not yet underway, he said, adding that Karyopharm Therapeutics will be focusing its efforts on selinexor for myeloma first.

The study was funded by Karyopharm. Dr. Fielder reported financial relationships with Amgen, Pfizer, Jazz Pharmaceuticals, and other companies.

SOURCE: Fiedler W et al. EHA Congress, Abstract S880.

AMSTERDAM – Patients with relapsed or refractory acute myeloid leukemia (AML) may be more likely to respond when selinexor is added to standard chemotherapy, according to investigators.

Will Pass/MDedge News

In a recent phase 2 trial, selinexor given with cytarabine and idarubicin led to a 50% overall response rate, reported lead author Walter Fiedler, MD, of University Medical Center Hamburg-Eppendorf (Germany). This response rate is at the upper end of what has been seen in published studies, Dr. Fiedler said at the annual congress of the European Hematology Association.

He also noted that giving a flat dose of selinexor improved tolerability in the trial, a significant finding in light of common adverse events and recent concerns from the Food and Drug Administration about the safety of selinexor for patients with multiple myeloma.

“The rationale to employ selinexor in this study is that there is a synergy between anthracyclines and selinexor,” Dr. Fiedler said, which may restore anthracycline sensitivity in relapsed or refractory patients. “Secondly, there is a c-myc reduction pathway that leads to a reduction of DNA damage repair genes such as Rad51 and Chk1, and this might result in inhibition of homologous recombination.”

The study involved 44 patients with relapsed or refractory AML, of whom 17 (39%) had previously received stem cell transplantation and 11 (25%) exhibited therapy-induced or secondary disease. The median patient age was 59.5 years.

Patients were given idarubicin 10 mg/m² on days 1, 3, and 5, and cytarabine 100 mg/m² on days 1-7. Initially, selinexor was given at a dose of 40 mg/m² twice per week for 4 weeks, but this led to high rates of febrile neutropenia and grade 3 or higher diarrhea, along with prolonged aplasia. In response to this issue, after the first 27 patients, the dose was reduced to a flat amount of 60 mg, given twice weekly for 3 weeks.

For patients not undergoing transplantation after the first or second induction cycle, selinexor maintenance monotherapy was offered for up to 1 year.

The primary endpoint was overall remission rate, reported as complete remission, complete remission with incomplete blood count recovery, and morphological leukemia-free status. Secondary endpoints included the rate of partial remissions, percentage of patients being transplanted after induction, early death rate, overall survival, event-free survival, and relapse-free survival.

The efficacy analysis revealed an overall response rate of 50%. A total of 9 patients had complete remission (21.4%), 11 achieved complete remission with incomplete blood count recovery (26.2%), and 1 exhibited morphological leukemia-free status (2.4%). Of note, almost half of the patients (47%) who had relapsed after previous stem cell transplantation responded, as did three-quarters who tested positive for an NPM1 mutation. After a median follow-up of 8.2 months, the median overall survival was 8.2 months, relapse-free survival was 17.7 months, and event-free survival was 4.9 months.

Adverse events occurred frequently, with a majority of patients experiencing nausea (86%), diarrhea (83%), vomiting (74%), decreased appetite (71%), febrile neutropenia (67%), fatigue (64%), leukopenia (62%), thrombocytopenia (62%), or anemia (60%).

Grade 3 or higher adverse events were almost as common, and included febrile neutropenia (67%), leukopenia (62%), thrombocytopenia (62%), anemia (57%), and diarrhea (50%). Reducing the dose did improve tolerability, with notable drops in the rate of severe diarrhea (56% vs. 40%) and febrile neutropenia (85% vs. 33%). In total, 19% of patients discontinued treatment because of adverse events.

A total of 25 patients (60%) died during the study, with about half dying from disease progression (n = 12), and fewer succumbing to infectious complications, graft-versus-host disease, multiorgan failure, multiple brain infarct, or asystole. Two deaths, one from suspected hemophagocytosis and another from systemic inflammatory response syndrome, were considered possibly related to selinexor.

“The results should be further evaluated in a phase 3 study,” Dr. Fiedler said. However, plans for this are not yet underway, he said, adding that Karyopharm Therapeutics will be focusing its efforts on selinexor for myeloma first.

The study was funded by Karyopharm. Dr. Fielder reported financial relationships with Amgen, Pfizer, Jazz Pharmaceuticals, and other companies.

SOURCE: Fiedler W et al. EHA Congress, Abstract S880.

AMSTERDAM – Patients with relapsed or refractory acute myeloid leukemia (AML) may be more likely to respond when selinexor is added to standard chemotherapy, according to investigators.

Will Pass/MDedge News

In a recent phase 2 trial, selinexor given with cytarabine and idarubicin led to a 50% overall response rate, reported lead author Walter Fiedler, MD, of University Medical Center Hamburg-Eppendorf (Germany). This response rate is at the upper end of what has been seen in published studies, Dr. Fiedler said at the annual congress of the European Hematology Association.

He also noted that giving a flat dose of selinexor improved tolerability in the trial, a significant finding in light of common adverse events and recent concerns from the Food and Drug Administration about the safety of selinexor for patients with multiple myeloma.

“The rationale to employ selinexor in this study is that there is a synergy between anthracyclines and selinexor,” Dr. Fiedler said, which may restore anthracycline sensitivity in relapsed or refractory patients. “Secondly, there is a c-myc reduction pathway that leads to a reduction of DNA damage repair genes such as Rad51 and Chk1, and this might result in inhibition of homologous recombination.”

The study involved 44 patients with relapsed or refractory AML, of whom 17 (39%) had previously received stem cell transplantation and 11 (25%) exhibited therapy-induced or secondary disease. The median patient age was 59.5 years.

Patients were given idarubicin 10 mg/m² on days 1, 3, and 5, and cytarabine 100 mg/m² on days 1-7. Initially, selinexor was given at a dose of 40 mg/m² twice per week for 4 weeks, but this led to high rates of febrile neutropenia and grade 3 or higher diarrhea, along with prolonged aplasia. In response to this issue, after the first 27 patients, the dose was reduced to a flat amount of 60 mg, given twice weekly for 3 weeks.

For patients not undergoing transplantation after the first or second induction cycle, selinexor maintenance monotherapy was offered for up to 1 year.

The primary endpoint was overall remission rate, reported as complete remission, complete remission with incomplete blood count recovery, and morphological leukemia-free status. Secondary endpoints included the rate of partial remissions, percentage of patients being transplanted after induction, early death rate, overall survival, event-free survival, and relapse-free survival.

The efficacy analysis revealed an overall response rate of 50%. A total of 9 patients had complete remission (21.4%), 11 achieved complete remission with incomplete blood count recovery (26.2%), and 1 exhibited morphological leukemia-free status (2.4%). Of note, almost half of the patients (47%) who had relapsed after previous stem cell transplantation responded, as did three-quarters who tested positive for an NPM1 mutation. After a median follow-up of 8.2 months, the median overall survival was 8.2 months, relapse-free survival was 17.7 months, and event-free survival was 4.9 months.

Adverse events occurred frequently, with a majority of patients experiencing nausea (86%), diarrhea (83%), vomiting (74%), decreased appetite (71%), febrile neutropenia (67%), fatigue (64%), leukopenia (62%), thrombocytopenia (62%), or anemia (60%).

Grade 3 or higher adverse events were almost as common, and included febrile neutropenia (67%), leukopenia (62%), thrombocytopenia (62%), anemia (57%), and diarrhea (50%). Reducing the dose did improve tolerability, with notable drops in the rate of severe diarrhea (56% vs. 40%) and febrile neutropenia (85% vs. 33%). In total, 19% of patients discontinued treatment because of adverse events.

A total of 25 patients (60%) died during the study, with about half dying from disease progression (n = 12), and fewer succumbing to infectious complications, graft-versus-host disease, multiorgan failure, multiple brain infarct, or asystole. Two deaths, one from suspected hemophagocytosis and another from systemic inflammatory response syndrome, were considered possibly related to selinexor.

“The results should be further evaluated in a phase 3 study,” Dr. Fiedler said. However, plans for this are not yet underway, he said, adding that Karyopharm Therapeutics will be focusing its efforts on selinexor for myeloma first.

The study was funded by Karyopharm. Dr. Fielder reported financial relationships with Amgen, Pfizer, Jazz Pharmaceuticals, and other companies.

SOURCE: Fiedler W et al. EHA Congress, Abstract S880.

Giving steroids for indications other than cancer palliation doesn’t compromise the effectiveness of immunotherapy for advanced non–small cell lung cancer (NSCLC), suggests a single-center retrospective cohort study.

The immunosuppressant activity of corticosteroids and recent reports linking them to poorer outcomes has raised concern about their use during immunotherapy, noted Biagio Ricciuti, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, and coinvestigators. But mechanisms underpinning this association are unclear.

The investigators studied 650 patients with NSCLC treated with immunotherapy targeting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1), either as monotherapy or with other immunotherapy. Overall, 14.3% were receiving 10 mg or more of prednisone daily when they started the immunotherapy, a cutoff selected for study because it has been used an exclusion criterion for clinical trials.

Results reported in the Journal of Clinical Oncology showed that, compared with other patients, those who received 10 mg or more of steroids indeed had poorer median progression-free survival (2.0 vs. 3.4 months; P = .01) and overall survival (4.9 vs. 11.2 months; P less than .001).

However, when the indication for steroid therapy was considered, median progression-free survival was just 1.4 months among patients who received 10 mg or more prednisone for cancer-related palliation, compared with 4.6 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons (for example, autoimmune disease, chronic obstructive pulmonary disease flare, hypersensitivity prophylaxis, or management of noncancer pain) and 3.4 months among patients who received 0-10 mg of prednisone (P less than .001 across groups).

Similarly, median overall survival was just 2.2 months among patients who received 10 mg or more prednisone for palliative indications, but 10.7 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons and 11.2 months among patients who received less than 10 mg prednisone (P less than .001 across groups).

In a multivariate analysis that adjusted for performance status and PD-L1 positivity and that used patients receiving up to 10 mg prednisone as the comparator, patients receiving 10 mg or more for cancer palliation had a trend toward high risk of progression-free survival events and a higher risk of death (hazard ratio, 1.40; P less than .06 and HR, 1.60; P = .02, respectively). In contrast, patients receiving 10 mg or more for cancer-unrelated reasons did not have elevated risks (HR, 0.62; P = .14 and HR, 0.91; P = .79, respectively).

“These data suggest that the significantly worse outcomes among patients who receive corticosteroids before immunotherapy are driven by the group of patients treated with corticosteroids for palliative oncologic symptom management, rather than by patients receiving corticosteroids for other reasons,” Dr. Ricciuti and coinvestigators wrote. “Corticosteroid use for cancer symptom management might simply correlate with patients who have adverse prognostic factors (e.g., brain metastases and poor performance status) rather than cause a clinically significant blunting of the response to [immune checkpoint inhibitors].

“Our data suggest that corticosteroids should not necessarily be decreased or discontinued before the start of immunotherapy out of a theoretical concern that corticosteroids could impair a response to immunotherapy,” the investigators concluded. “Additional mechanistic studies are needed to identify whether the use of corticosteroids affects specific aspects of the immune system necessary for immunotherapy activity.”

Dr. Ricciuti reported that he has no relevant conflicts of interest. The study did not receive any funding.

SOURCE: Ricciuti B et al. J Clin Oncol. 2019 Jun 17. doi: 10.1200/JCO.19.00189.

Giving steroids for indications other than cancer palliation doesn’t compromise the effectiveness of immunotherapy for advanced non–small cell lung cancer (NSCLC), suggests a single-center retrospective cohort study.

The immunosuppressant activity of corticosteroids and recent reports linking them to poorer outcomes has raised concern about their use during immunotherapy, noted Biagio Ricciuti, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, and coinvestigators. But mechanisms underpinning this association are unclear.

The investigators studied 650 patients with NSCLC treated with immunotherapy targeting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1), either as monotherapy or with other immunotherapy. Overall, 14.3% were receiving 10 mg or more of prednisone daily when they started the immunotherapy, a cutoff selected for study because it has been used an exclusion criterion for clinical trials.

Results reported in the Journal of Clinical Oncology showed that, compared with other patients, those who received 10 mg or more of steroids indeed had poorer median progression-free survival (2.0 vs. 3.4 months; P = .01) and overall survival (4.9 vs. 11.2 months; P less than .001).

However, when the indication for steroid therapy was considered, median progression-free survival was just 1.4 months among patients who received 10 mg or more prednisone for cancer-related palliation, compared with 4.6 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons (for example, autoimmune disease, chronic obstructive pulmonary disease flare, hypersensitivity prophylaxis, or management of noncancer pain) and 3.4 months among patients who received 0-10 mg of prednisone (P less than .001 across groups).

Similarly, median overall survival was just 2.2 months among patients who received 10 mg or more prednisone for palliative indications, but 10.7 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons and 11.2 months among patients who received less than 10 mg prednisone (P less than .001 across groups).

In a multivariate analysis that adjusted for performance status and PD-L1 positivity and that used patients receiving up to 10 mg prednisone as the comparator, patients receiving 10 mg or more for cancer palliation had a trend toward high risk of progression-free survival events and a higher risk of death (hazard ratio, 1.40; P less than .06 and HR, 1.60; P = .02, respectively). In contrast, patients receiving 10 mg or more for cancer-unrelated reasons did not have elevated risks (HR, 0.62; P = .14 and HR, 0.91; P = .79, respectively).

“These data suggest that the significantly worse outcomes among patients who receive corticosteroids before immunotherapy are driven by the group of patients treated with corticosteroids for palliative oncologic symptom management, rather than by patients receiving corticosteroids for other reasons,” Dr. Ricciuti and coinvestigators wrote. “Corticosteroid use for cancer symptom management might simply correlate with patients who have adverse prognostic factors (e.g., brain metastases and poor performance status) rather than cause a clinically significant blunting of the response to [immune checkpoint inhibitors].

“Our data suggest that corticosteroids should not necessarily be decreased or discontinued before the start of immunotherapy out of a theoretical concern that corticosteroids could impair a response to immunotherapy,” the investigators concluded. “Additional mechanistic studies are needed to identify whether the use of corticosteroids affects specific aspects of the immune system necessary for immunotherapy activity.”

Dr. Ricciuti reported that he has no relevant conflicts of interest. The study did not receive any funding.

SOURCE: Ricciuti B et al. J Clin Oncol. 2019 Jun 17. doi: 10.1200/JCO.19.00189.

Giving steroids for indications other than cancer palliation doesn’t compromise the effectiveness of immunotherapy for advanced non–small cell lung cancer (NSCLC), suggests a single-center retrospective cohort study.

The immunosuppressant activity of corticosteroids and recent reports linking them to poorer outcomes has raised concern about their use during immunotherapy, noted Biagio Ricciuti, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, and coinvestigators. But mechanisms underpinning this association are unclear.

The investigators studied 650 patients with NSCLC treated with immunotherapy targeting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1), either as monotherapy or with other immunotherapy. Overall, 14.3% were receiving 10 mg or more of prednisone daily when they started the immunotherapy, a cutoff selected for study because it has been used an exclusion criterion for clinical trials.

Results reported in the Journal of Clinical Oncology showed that, compared with other patients, those who received 10 mg or more of steroids indeed had poorer median progression-free survival (2.0 vs. 3.4 months; P = .01) and overall survival (4.9 vs. 11.2 months; P less than .001).

However, when the indication for steroid therapy was considered, median progression-free survival was just 1.4 months among patients who received 10 mg or more prednisone for cancer-related palliation, compared with 4.6 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons (for example, autoimmune disease, chronic obstructive pulmonary disease flare, hypersensitivity prophylaxis, or management of noncancer pain) and 3.4 months among patients who received 0-10 mg of prednisone (P less than .001 across groups).

Similarly, median overall survival was just 2.2 months among patients who received 10 mg or more prednisone for palliative indications, but 10.7 months among patients who received 10 mg or more prednisone for cancer-unrelated reasons and 11.2 months among patients who received less than 10 mg prednisone (P less than .001 across groups).

In a multivariate analysis that adjusted for performance status and PD-L1 positivity and that used patients receiving up to 10 mg prednisone as the comparator, patients receiving 10 mg or more for cancer palliation had a trend toward high risk of progression-free survival events and a higher risk of death (hazard ratio, 1.40; P less than .06 and HR, 1.60; P = .02, respectively). In contrast, patients receiving 10 mg or more for cancer-unrelated reasons did not have elevated risks (HR, 0.62; P = .14 and HR, 0.91; P = .79, respectively).

“These data suggest that the significantly worse outcomes among patients who receive corticosteroids before immunotherapy are driven by the group of patients treated with corticosteroids for palliative oncologic symptom management, rather than by patients receiving corticosteroids for other reasons,” Dr. Ricciuti and coinvestigators wrote. “Corticosteroid use for cancer symptom management might simply correlate with patients who have adverse prognostic factors (e.g., brain metastases and poor performance status) rather than cause a clinically significant blunting of the response to [immune checkpoint inhibitors].

“Our data suggest that corticosteroids should not necessarily be decreased or discontinued before the start of immunotherapy out of a theoretical concern that corticosteroids could impair a response to immunotherapy,” the investigators concluded. “Additional mechanistic studies are needed to identify whether the use of corticosteroids affects specific aspects of the immune system necessary for immunotherapy activity.”

Dr. Ricciuti reported that he has no relevant conflicts of interest. The study did not receive any funding.

SOURCE: Ricciuti B et al. J Clin Oncol. 2019 Jun 17. doi: 10.1200/JCO.19.00189.