AVAHO

The combination of radiotherapy plus pembrolizumab (Keytruda, Merck) leads to good disease control in recurrent or metastatic head and neck squamous cell cancer (HNSCC) in patients for whom cisplatin would prove to be too toxic, a phase 2 trial suggests.

“There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects,” Jared Weiss, MD, associate professor of medicine, UNC Lineberger Comprehensive Cancer, Chapel Hill, North Carolina, said in a statement.

“And the opposite direction also seems to be true – radiation therapy needs a functional immune system to work. Our hope was that pembrolizumab might be a radiation sensitizer for these patients,” he said.

The study was presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

Both modalities have had some outstanding results in the past, observed Weiss. “If you look back to the historic studies, radiation alone often cures patients with this disease, while some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease,” he said.

“Our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it as a ‘second shot on goal’ towards a cure, because there is durable control with drug alone,” he added.

Single-arm trial

The single-arm trial included 29 patients with locally advanced HNSCC.

Only about 10% of patients were current smokers, but more than half of the study group had a history of smoking. Of those, more than 55% had a history of 10 pack-years or more.

In slightly more than one third of patients, the primary site of the cancer was the base of the tongue. The tonsils were the primary site in slightly more than one third.

Platinum ineligibility was defined by provider and standard measures.

More than two thirds of patients were ineligible to receive cisplatin because of preexisting otopathy, including hearing impairment and tinnitus.

The combination of cisplatin and definitive-dose radiotherapy is standard treatment for locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice. Weiss noted that contraindications are present in about one third of his patients.

“We replaced standard, every-3-week cisplatin with pembrolizumab every 3 weeks,” Weiss explained, “and we hypothesized that with the ongoing effects of radiation therapy after completion, that additional adjuvant cycles could further sensitize patients [to the effects of radiation] without impairing recovery, so we added three adjuvant cycles as well,” he added.

With six cycles of an every-3-week drug, patients received 18 weeks of pembrolizumab in total.

Echoing results from the previously reported KEYNOTE-48 trial, pembrolizumab given with radiotherapy instead of chemotherapy led to an overall progression-free survival (PFS) rate of 76% at 1 year and an estimated PFS of 71% at 2 years.

At 1 year, 86% of patients were still alive, and at 2 years, an estimated 75% of patients were still alive, Weiss added.

For patients with human papillomavirus 16–positive cancer, rates of PFS and overall survival were slightly better, at 88% and 94%, respectively.

With regard to toxicities, “For the most part, this [treatment regimen] looks like radiation alone with one very notable exception, which was lymphopenia,” Weiss observed. Grade 3-4 lymphopenia affected 59% of patients.

Lymphocyte count hit bottom at week 4, he added, with only partial recovery at week 20 and no further recovery at 40 weeks. Lymphocyte count alone or any change in it was not predictive of early progression.

However, in comparing patients who experienced early disease progression to patients who did not experience progression, levels of baseline naive B cells in peripheral blood were higher and levels of circulating marginal zone B cells were lower in patients with progressive disease, Weiss reported.

Patient-reported outcomes indicated that common symptoms of treatment peaked at week 10, and there was relative recovery by week 20.

As reflected by Functional Assessment of Cancer Therapy (FACT) scores, which include social, emotional, and functional well-being, as well as the head and neck cancer scale, “we again see a nadir at 10 weeks with relative recovery at 20 weeks,” Weiss noted.

“We found that concurrent pembrolizumab with radiotherapy is a safe and feasible option for locally advanced head and neck cancer patients with cisplatin ineligibility,” Weiss concluded.

More research is being conducted in this area, and multiple ongoing studies will further elucidate the value of PD-1 or PD-L1 checkpoint blockade with definitive radiation therapy, he added.

The study was funded by Merck & Co. Weiss’ institution has received research funding from Celgene, Pfizer, Merck, AZ/Medimmmune, Amgen, Carefusion, G1 Therapeutics, Immunicum, Loxo/Lilly, and the Jimmy V Foundation. Weiss has received honoraria for consulting from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, Abbvie, Rakuten, Nanobiotix, Azitra, Loxo/Lilly, Pfizer, and Blueprint had has stock in Nektar and Vesselon.

This article first appeared on Medscape.com.

The combination of radiotherapy plus pembrolizumab (Keytruda, Merck) leads to good disease control in recurrent or metastatic head and neck squamous cell cancer (HNSCC) in patients for whom cisplatin would prove to be too toxic, a phase 2 trial suggests.

“There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects,” Jared Weiss, MD, associate professor of medicine, UNC Lineberger Comprehensive Cancer, Chapel Hill, North Carolina, said in a statement.

“And the opposite direction also seems to be true – radiation therapy needs a functional immune system to work. Our hope was that pembrolizumab might be a radiation sensitizer for these patients,” he said.

The study was presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

Both modalities have had some outstanding results in the past, observed Weiss. “If you look back to the historic studies, radiation alone often cures patients with this disease, while some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease,” he said.

“Our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it as a ‘second shot on goal’ towards a cure, because there is durable control with drug alone,” he added.

Single-arm trial

The single-arm trial included 29 patients with locally advanced HNSCC.

Only about 10% of patients were current smokers, but more than half of the study group had a history of smoking. Of those, more than 55% had a history of 10 pack-years or more.

In slightly more than one third of patients, the primary site of the cancer was the base of the tongue. The tonsils were the primary site in slightly more than one third.

Platinum ineligibility was defined by provider and standard measures.

More than two thirds of patients were ineligible to receive cisplatin because of preexisting otopathy, including hearing impairment and tinnitus.

The combination of cisplatin and definitive-dose radiotherapy is standard treatment for locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice. Weiss noted that contraindications are present in about one third of his patients.

“We replaced standard, every-3-week cisplatin with pembrolizumab every 3 weeks,” Weiss explained, “and we hypothesized that with the ongoing effects of radiation therapy after completion, that additional adjuvant cycles could further sensitize patients [to the effects of radiation] without impairing recovery, so we added three adjuvant cycles as well,” he added.

With six cycles of an every-3-week drug, patients received 18 weeks of pembrolizumab in total.

Echoing results from the previously reported KEYNOTE-48 trial, pembrolizumab given with radiotherapy instead of chemotherapy led to an overall progression-free survival (PFS) rate of 76% at 1 year and an estimated PFS of 71% at 2 years.

At 1 year, 86% of patients were still alive, and at 2 years, an estimated 75% of patients were still alive, Weiss added.

For patients with human papillomavirus 16–positive cancer, rates of PFS and overall survival were slightly better, at 88% and 94%, respectively.

With regard to toxicities, “For the most part, this [treatment regimen] looks like radiation alone with one very notable exception, which was lymphopenia,” Weiss observed. Grade 3-4 lymphopenia affected 59% of patients.

Lymphocyte count hit bottom at week 4, he added, with only partial recovery at week 20 and no further recovery at 40 weeks. Lymphocyte count alone or any change in it was not predictive of early progression.

However, in comparing patients who experienced early disease progression to patients who did not experience progression, levels of baseline naive B cells in peripheral blood were higher and levels of circulating marginal zone B cells were lower in patients with progressive disease, Weiss reported.

Patient-reported outcomes indicated that common symptoms of treatment peaked at week 10, and there was relative recovery by week 20.

As reflected by Functional Assessment of Cancer Therapy (FACT) scores, which include social, emotional, and functional well-being, as well as the head and neck cancer scale, “we again see a nadir at 10 weeks with relative recovery at 20 weeks,” Weiss noted.

“We found that concurrent pembrolizumab with radiotherapy is a safe and feasible option for locally advanced head and neck cancer patients with cisplatin ineligibility,” Weiss concluded.

More research is being conducted in this area, and multiple ongoing studies will further elucidate the value of PD-1 or PD-L1 checkpoint blockade with definitive radiation therapy, he added.

The study was funded by Merck & Co. Weiss’ institution has received research funding from Celgene, Pfizer, Merck, AZ/Medimmmune, Amgen, Carefusion, G1 Therapeutics, Immunicum, Loxo/Lilly, and the Jimmy V Foundation. Weiss has received honoraria for consulting from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, Abbvie, Rakuten, Nanobiotix, Azitra, Loxo/Lilly, Pfizer, and Blueprint had has stock in Nektar and Vesselon.

This article first appeared on Medscape.com.

The combination of radiotherapy plus pembrolizumab (Keytruda, Merck) leads to good disease control in recurrent or metastatic head and neck squamous cell cancer (HNSCC) in patients for whom cisplatin would prove to be too toxic, a phase 2 trial suggests.

“There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects,” Jared Weiss, MD, associate professor of medicine, UNC Lineberger Comprehensive Cancer, Chapel Hill, North Carolina, said in a statement.

“And the opposite direction also seems to be true – radiation therapy needs a functional immune system to work. Our hope was that pembrolizumab might be a radiation sensitizer for these patients,” he said.

The study was presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.

Both modalities have had some outstanding results in the past, observed Weiss. “If you look back to the historic studies, radiation alone often cures patients with this disease, while some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease,” he said.

“Our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it as a ‘second shot on goal’ towards a cure, because there is durable control with drug alone,” he added.

Single-arm trial

The single-arm trial included 29 patients with locally advanced HNSCC.

Only about 10% of patients were current smokers, but more than half of the study group had a history of smoking. Of those, more than 55% had a history of 10 pack-years or more.

In slightly more than one third of patients, the primary site of the cancer was the base of the tongue. The tonsils were the primary site in slightly more than one third.

Platinum ineligibility was defined by provider and standard measures.

More than two thirds of patients were ineligible to receive cisplatin because of preexisting otopathy, including hearing impairment and tinnitus.

The combination of cisplatin and definitive-dose radiotherapy is standard treatment for locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice. Weiss noted that contraindications are present in about one third of his patients.

“We replaced standard, every-3-week cisplatin with pembrolizumab every 3 weeks,” Weiss explained, “and we hypothesized that with the ongoing effects of radiation therapy after completion, that additional adjuvant cycles could further sensitize patients [to the effects of radiation] without impairing recovery, so we added three adjuvant cycles as well,” he added.

With six cycles of an every-3-week drug, patients received 18 weeks of pembrolizumab in total.

Echoing results from the previously reported KEYNOTE-48 trial, pembrolizumab given with radiotherapy instead of chemotherapy led to an overall progression-free survival (PFS) rate of 76% at 1 year and an estimated PFS of 71% at 2 years.

At 1 year, 86% of patients were still alive, and at 2 years, an estimated 75% of patients were still alive, Weiss added.

For patients with human papillomavirus 16–positive cancer, rates of PFS and overall survival were slightly better, at 88% and 94%, respectively.

With regard to toxicities, “For the most part, this [treatment regimen] looks like radiation alone with one very notable exception, which was lymphopenia,” Weiss observed. Grade 3-4 lymphopenia affected 59% of patients.

Lymphocyte count hit bottom at week 4, he added, with only partial recovery at week 20 and no further recovery at 40 weeks. Lymphocyte count alone or any change in it was not predictive of early progression.

However, in comparing patients who experienced early disease progression to patients who did not experience progression, levels of baseline naive B cells in peripheral blood were higher and levels of circulating marginal zone B cells were lower in patients with progressive disease, Weiss reported.

Patient-reported outcomes indicated that common symptoms of treatment peaked at week 10, and there was relative recovery by week 20.

As reflected by Functional Assessment of Cancer Therapy (FACT) scores, which include social, emotional, and functional well-being, as well as the head and neck cancer scale, “we again see a nadir at 10 weeks with relative recovery at 20 weeks,” Weiss noted.

“We found that concurrent pembrolizumab with radiotherapy is a safe and feasible option for locally advanced head and neck cancer patients with cisplatin ineligibility,” Weiss concluded.

More research is being conducted in this area, and multiple ongoing studies will further elucidate the value of PD-1 or PD-L1 checkpoint blockade with definitive radiation therapy, he added.

The study was funded by Merck & Co. Weiss’ institution has received research funding from Celgene, Pfizer, Merck, AZ/Medimmmune, Amgen, Carefusion, G1 Therapeutics, Immunicum, Loxo/Lilly, and the Jimmy V Foundation. Weiss has received honoraria for consulting from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, Abbvie, Rakuten, Nanobiotix, Azitra, Loxo/Lilly, Pfizer, and Blueprint had has stock in Nektar and Vesselon.

This article first appeared on Medscape.com.

Combining magnetic resonance imaging (MRI)–targeted biopsy and systematic biopsy improved detection of prostate cancer among men with MRI-visible lesions in a single-center study.

Compared with either method alone, a combination of the two biopsy methods resulted in 9.9% more prostate cancer diagnoses, explained study author Michael Ahdoot, MD, of the National Institutes of Health and colleagues. Their report was published in the New England Journal of Medicine.

“With the addition of MRI-targeted biopsy to systematic biopsy, we may have entered an era of increased diagnostic certainty in prostate cancer,” the researchers wrote.

Their single-center, comparative diagnostic study included 2,103 patients with MRI-visible prostate lesions who underwent both systematic and MRI-targeted biopsy. In cases of multiple biopsies, only the results of the initial biopsies were included.

Each individual specimen was assigned a Gleason score by a genitourinary pathologist and was subsequently categorized into a grade group on a scale of 1-5, with higher scores reflecting greater cancer risk. Grade group 1 was defined as clinically insignificant disease. Grade group 2 was defined as favorable intermediate-risk disease. Grade group 3 or higher was defined as unfavorable intermediate-risk disease or worse.

The primary endpoints were cancer detection rates for each biopsy method, based on grade group. “Among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens [was also assessed],” the researchers explained.

Among patients who underwent combined biopsy, prostate cancer was identified in 62.4% of patients, and 19.2% underwent radical prostatectomy.

For grade groups 3-5, rates of cancer detection were significantly higher with MRI-targeted biopsy than with systematic biopsy (P less than .01 for all). For grade group 1, detection rates were significantly lower with MRI-targeted biopsy (P less than .01).

“Although many of [the] benefits resulted from MRI-targeted biopsy alone, omission of systematic biopsy would have led to missing the diagnosis of 8.8% of clinically significant cancers,” the researchers reported.

In addition, among patients who underwent radical prostatectomy, the rates of upgrading (grade group 3 or higher) on histopathological analysis were lower for combined biopsy (3.5%) than for MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%).

The researchers acknowledged that a key limitation of this study was the single-center design. As a result, the findings may not be generalizable to other institutions.

However, the researchers concluded that “these findings suggest that combined biopsy provides improved diagnostic accuracy over either systematic or MRI-targeted biopsy alone and better predicts the results of final histopathological analysis.”

The study was funded by the National Institutes of Health, Philips, and the Dr. Mildred Scheel Foundation for Cancer Research. The authors disclosed financial affiliations with Philips, Biocompatibles UK, Boston Scientific, Celsion, and other companies.

SOURCE: Ahdoot M et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1910038.

Combining magnetic resonance imaging (MRI)–targeted biopsy and systematic biopsy improved detection of prostate cancer among men with MRI-visible lesions in a single-center study.

Compared with either method alone, a combination of the two biopsy methods resulted in 9.9% more prostate cancer diagnoses, explained study author Michael Ahdoot, MD, of the National Institutes of Health and colleagues. Their report was published in the New England Journal of Medicine.

“With the addition of MRI-targeted biopsy to systematic biopsy, we may have entered an era of increased diagnostic certainty in prostate cancer,” the researchers wrote.

Their single-center, comparative diagnostic study included 2,103 patients with MRI-visible prostate lesions who underwent both systematic and MRI-targeted biopsy. In cases of multiple biopsies, only the results of the initial biopsies were included.

Each individual specimen was assigned a Gleason score by a genitourinary pathologist and was subsequently categorized into a grade group on a scale of 1-5, with higher scores reflecting greater cancer risk. Grade group 1 was defined as clinically insignificant disease. Grade group 2 was defined as favorable intermediate-risk disease. Grade group 3 or higher was defined as unfavorable intermediate-risk disease or worse.

The primary endpoints were cancer detection rates for each biopsy method, based on grade group. “Among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens [was also assessed],” the researchers explained.

Among patients who underwent combined biopsy, prostate cancer was identified in 62.4% of patients, and 19.2% underwent radical prostatectomy.

For grade groups 3-5, rates of cancer detection were significantly higher with MRI-targeted biopsy than with systematic biopsy (P less than .01 for all). For grade group 1, detection rates were significantly lower with MRI-targeted biopsy (P less than .01).

“Although many of [the] benefits resulted from MRI-targeted biopsy alone, omission of systematic biopsy would have led to missing the diagnosis of 8.8% of clinically significant cancers,” the researchers reported.

In addition, among patients who underwent radical prostatectomy, the rates of upgrading (grade group 3 or higher) on histopathological analysis were lower for combined biopsy (3.5%) than for MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%).

The researchers acknowledged that a key limitation of this study was the single-center design. As a result, the findings may not be generalizable to other institutions.

However, the researchers concluded that “these findings suggest that combined biopsy provides improved diagnostic accuracy over either systematic or MRI-targeted biopsy alone and better predicts the results of final histopathological analysis.”

The study was funded by the National Institutes of Health, Philips, and the Dr. Mildred Scheel Foundation for Cancer Research. The authors disclosed financial affiliations with Philips, Biocompatibles UK, Boston Scientific, Celsion, and other companies.

SOURCE: Ahdoot M et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1910038.

Combining magnetic resonance imaging (MRI)–targeted biopsy and systematic biopsy improved detection of prostate cancer among men with MRI-visible lesions in a single-center study.

Compared with either method alone, a combination of the two biopsy methods resulted in 9.9% more prostate cancer diagnoses, explained study author Michael Ahdoot, MD, of the National Institutes of Health and colleagues. Their report was published in the New England Journal of Medicine.

“With the addition of MRI-targeted biopsy to systematic biopsy, we may have entered an era of increased diagnostic certainty in prostate cancer,” the researchers wrote.

Their single-center, comparative diagnostic study included 2,103 patients with MRI-visible prostate lesions who underwent both systematic and MRI-targeted biopsy. In cases of multiple biopsies, only the results of the initial biopsies were included.

Each individual specimen was assigned a Gleason score by a genitourinary pathologist and was subsequently categorized into a grade group on a scale of 1-5, with higher scores reflecting greater cancer risk. Grade group 1 was defined as clinically insignificant disease. Grade group 2 was defined as favorable intermediate-risk disease. Grade group 3 or higher was defined as unfavorable intermediate-risk disease or worse.

The primary endpoints were cancer detection rates for each biopsy method, based on grade group. “Among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens [was also assessed],” the researchers explained.

Among patients who underwent combined biopsy, prostate cancer was identified in 62.4% of patients, and 19.2% underwent radical prostatectomy.

For grade groups 3-5, rates of cancer detection were significantly higher with MRI-targeted biopsy than with systematic biopsy (P less than .01 for all). For grade group 1, detection rates were significantly lower with MRI-targeted biopsy (P less than .01).

“Although many of [the] benefits resulted from MRI-targeted biopsy alone, omission of systematic biopsy would have led to missing the diagnosis of 8.8% of clinically significant cancers,” the researchers reported.

In addition, among patients who underwent radical prostatectomy, the rates of upgrading (grade group 3 or higher) on histopathological analysis were lower for combined biopsy (3.5%) than for MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%).

The researchers acknowledged that a key limitation of this study was the single-center design. As a result, the findings may not be generalizable to other institutions.

However, the researchers concluded that “these findings suggest that combined biopsy provides improved diagnostic accuracy over either systematic or MRI-targeted biopsy alone and better predicts the results of final histopathological analysis.”

The study was funded by the National Institutes of Health, Philips, and the Dr. Mildred Scheel Foundation for Cancer Research. The authors disclosed financial affiliations with Philips, Biocompatibles UK, Boston Scientific, Celsion, and other companies.

SOURCE: Ahdoot M et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1910038.

More than a third (35%) of patients with relapsed non–small cell lung cancer (NSCLC) treated with pembrolizumab (Keytruda, Merck) were still alive at 3 years, according to long-term results from a pivotal clinical trial.

The results also showed that, among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.

“It is too soon to say that pembrolizumab is a potential cure...and we know that it doesn’t work for all patients, but the agent remains very, very promising,” said lead investigator Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut.

These new results come from the KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.

The results were published online on February 20 in the Journal of Clinical Oncology and were previously presented at the 2018 annual meeting of the European Society of Medical Oncology.

Overall survival at 3 years was 35% in patients with PD-L1 expression ≥ 50% in the tumor, and 23% in those with PD-L1 ≥ 1%.

This compares with 3-year overall survival of 11-13% with docetaxel.

These results are “really extraordinary,” Herbst commented to Medscape Medical News.

The 3-year overall survival rate of 35% in patients with PD-L1 ≥ 50% “is huge,” he said. “It really shows the durability of the response.”

Herbst commented that the “almost 100%” survival at 3 years among patients who completed 35 cycles of pembrolizumab shows that this treatment period (of about 2 years) is “probably about the right time to treat.”

“Currently, the agent is being used in all potential settings, before any other treatment, after other treatment, and with other treatments,” he said.

“Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on. This is the story of tailored therapy,” Herbst said.

Approached for comment, Solange Peters, MD, PhD, Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said that the results are “very good” and “confirm the paradigms we have been seeing in melanoma,” with good long-term control, which is “very reassuring.”

However, she told Medscape Medical News that the trial raises an important question: «How long do you need to expose your patient with lung cancer to immunotherapy in order to get this long-term control?»

She said the “good news” is that, for the 10% of patients who completed 2 years of treatment per protocol, almost all of them are still alive at 3 years, “which is not observed with chemotherapy.”

The question for Peters is “more about the definition of long-term control,” as it was seen that almost one in three patients nevertheless had some form of progression.

This suggests that you have a group of people “who are nicely controlled, you stop the drug, and 1 year later a third of them have progressed.”

Peters said: “So how long do you need to treat these patients? I would say I still don’t know.”

“If I were one of these patients probably I would still want to continue [on the drug]. Of course, some might have progressed even while remaining on the drug, but the proportion who would have progressed is probably smaller than this one.”
 

Responses on Re-introduction of Therapy

The study also allowed patients who had completed 35 cycles of pembrolizumab to be restarted on the drug if they experienced progression.

The team found that, among 14 patients, 43% had a partial response and 36% had stable disease.

Herbst highlighted this finding and told Medscape Medical News that this «could be very important to physicians because they might want to think about using the drug again» in patients who have progressed on it.

He believes that the progression was not because of any resistance per se but rather a slowing down of the adaptive immune response.

“It’s just that it needs a boost,” he said, while noting that tissue specimens will nevertheless be required to demonstrate the theory.

Peters agreed that these results are “very promising,” but questioned their overall significance, as it is “a very small number of patients” from a subset whose disease was controlled while on treatment and then progressed after stopping.

She also pointed out that, in another study in patients with lung cancer (CheckMate-153), some patients were rechallenged with immunotherapy after having stopped treatment at 1 year “with very poor results.”

Peters said studies in melanoma have shown “rechallenge can be useful in a significant proportion of patients, but still you have not demonstrated that stopping and rechallenging is the same as not stopping.”

Study Details

KEYNOTE-010 involved patients with NSCLC from 202 centers in 24 countries with stage IIIB/IV disease expressing PD-L1 who had experienced disease progression after at least two cycles of platinum-based chemotherapy.

They were randomized 1:1:1 to open-label pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m² every 3 weeks.

Pembrolizumab was continued for 35 treatment cycles over 2 years and docetaxel was continued for the maximum duration allowed by local regulators.

Patients who stopped pembrolizumab after a complete response or completing all 35 cycles, and who subsequently experienced disease progression, could receive up to 17 additional cycles over 1 year if they had not received another anticancer therapy in the meantime.

Among the 1,034 patients originally recruited between August 2013 and February 2015, 691 were assigned to pembrolizumab at 3 mg/kg or 10 mg/kg and 343 to docetaxel.

For the intention-to-treat analysis in 1033 patients, the mean duration of follow-up was 42.6 months, with a median treatment duration of 3.5 months in the pembrolizumab group and 2.0 months in the docetaxel group.

Compared with docetaxel, pembrolizumab was associated with a significant reduction in the risk of death, at a hazard ratio of 0.53 in patients with PD-L1 ≥ 50% and 0.69 in those with PD-L1 ≥ 1% (both P < .0001).

In patients with PD-L1 ≥ 50%, median overall survival was 16.9 months in those given pembrolizumab and 8.2 months with docetaxel. Among those with PD-L1 ≥ 1%, median overall survival was 11.8 months with pembrolizumab versus 8.4 months with docetaxel.

Overall survival on Kaplan-Meier analysis was 34.5% with pembrolizumab and 12.7% with docetaxel in the PD-L1 ≥ 50% group, and 22.9% versus 11.0% in the PD-L1 ≥ 1% group.

PFS significantly improved with pembrolizumab versus docetaxel, at a hazard ratio of 0.57 (P < .00001) among patients with PD-L1 ≥ 50% and 0.83 (P < .005) in those with PD-L1 ≥ 1%.

In terms of safety, 17.7% of patients who completed 2 years of pembrolizumab had grade 3-5 treatment-related adverse events, compared with 16.6% among all pembrolizumab-treated patients and 36.6% of those given docetaxel.

The team reports that 79 patients completed 35 cycles of pembrolizumab, with a median follow-up of 43.4 months.

Compared with the overall patient group, these patients were less likely to be aged ≥ 65 years and to have received two or more prior treatment lines, although they were more likely to be current or former smokers and to have squamous tumor histology.

Patients who completed 35 cycles had an objective response rate of 94.9%, and 91.0% were still alive at the data cutoff. Overall survival rates were 98.7% at 12 months and 86.3% at 24 months.

Of 71 patients eligible for analysis, 23 experienced progression after completing pembrolizumab, at PFS rates at 12 and 24 months of 72.5% and 57.7%, respectively.

A total of 14 patients were given a second course of pembrolizumab, of whom six had a partial response and five had stable disease. At the data cutoff, five patients had completed 17 additional cycles and 11 were alive.

Pembro Approved at Fixed Dose

One notable aspect of the study is that patients in the pembrolizumab arm were given two different doses of the drug based on body weight, whereas the drug is approved in the United States at a fixed dose of 200 mg.

Herbst told Medscape Medical News he considers the 200-mg dose to be appropriate.

“I didn’t think that the 3-mg versus 10-mg dose per kg that we used in our study made much difference in an average-sized person,” he said, adding that the 200-mg dose “is something a little bit more than 3 mg/kg.”

“So I think that this is clearly the right dos, and I don’t think more would make any difference,” he said.

The study was funded by Merck, the manufacturer of pembrolizumab. Herbst has reported having a consulting or advisory role for many pharmaceutical companies. Other coauthors have also reported relationships with industry, and some of the authors are Merck employees. Peters has reported receiving education grants, providing consultation, attending advisory boards, and/or providing lectures for many pharmaceutical companies.
 

This article first appeared on Medscape.com.

More than a third (35%) of patients with relapsed non–small cell lung cancer (NSCLC) treated with pembrolizumab (Keytruda, Merck) were still alive at 3 years, according to long-term results from a pivotal clinical trial.

The results also showed that, among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.

“It is too soon to say that pembrolizumab is a potential cure...and we know that it doesn’t work for all patients, but the agent remains very, very promising,” said lead investigator Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut.

These new results come from the KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.

The results were published online on February 20 in the Journal of Clinical Oncology and were previously presented at the 2018 annual meeting of the European Society of Medical Oncology.

Overall survival at 3 years was 35% in patients with PD-L1 expression ≥ 50% in the tumor, and 23% in those with PD-L1 ≥ 1%.

This compares with 3-year overall survival of 11-13% with docetaxel.

These results are “really extraordinary,” Herbst commented to Medscape Medical News.

The 3-year overall survival rate of 35% in patients with PD-L1 ≥ 50% “is huge,” he said. “It really shows the durability of the response.”

Herbst commented that the “almost 100%” survival at 3 years among patients who completed 35 cycles of pembrolizumab shows that this treatment period (of about 2 years) is “probably about the right time to treat.”

“Currently, the agent is being used in all potential settings, before any other treatment, after other treatment, and with other treatments,” he said.

“Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on. This is the story of tailored therapy,” Herbst said.

Approached for comment, Solange Peters, MD, PhD, Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said that the results are “very good” and “confirm the paradigms we have been seeing in melanoma,” with good long-term control, which is “very reassuring.”

However, she told Medscape Medical News that the trial raises an important question: «How long do you need to expose your patient with lung cancer to immunotherapy in order to get this long-term control?»

She said the “good news” is that, for the 10% of patients who completed 2 years of treatment per protocol, almost all of them are still alive at 3 years, “which is not observed with chemotherapy.”

The question for Peters is “more about the definition of long-term control,” as it was seen that almost one in three patients nevertheless had some form of progression.

This suggests that you have a group of people “who are nicely controlled, you stop the drug, and 1 year later a third of them have progressed.”

Peters said: “So how long do you need to treat these patients? I would say I still don’t know.”

“If I were one of these patients probably I would still want to continue [on the drug]. Of course, some might have progressed even while remaining on the drug, but the proportion who would have progressed is probably smaller than this one.”
 

Responses on Re-introduction of Therapy

The study also allowed patients who had completed 35 cycles of pembrolizumab to be restarted on the drug if they experienced progression.

The team found that, among 14 patients, 43% had a partial response and 36% had stable disease.

Herbst highlighted this finding and told Medscape Medical News that this «could be very important to physicians because they might want to think about using the drug again» in patients who have progressed on it.

He believes that the progression was not because of any resistance per se but rather a slowing down of the adaptive immune response.

“It’s just that it needs a boost,” he said, while noting that tissue specimens will nevertheless be required to demonstrate the theory.

Peters agreed that these results are “very promising,” but questioned their overall significance, as it is “a very small number of patients” from a subset whose disease was controlled while on treatment and then progressed after stopping.

She also pointed out that, in another study in patients with lung cancer (CheckMate-153), some patients were rechallenged with immunotherapy after having stopped treatment at 1 year “with very poor results.”

Peters said studies in melanoma have shown “rechallenge can be useful in a significant proportion of patients, but still you have not demonstrated that stopping and rechallenging is the same as not stopping.”

Study Details

KEYNOTE-010 involved patients with NSCLC from 202 centers in 24 countries with stage IIIB/IV disease expressing PD-L1 who had experienced disease progression after at least two cycles of platinum-based chemotherapy.

They were randomized 1:1:1 to open-label pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m² every 3 weeks.

Pembrolizumab was continued for 35 treatment cycles over 2 years and docetaxel was continued for the maximum duration allowed by local regulators.

Patients who stopped pembrolizumab after a complete response or completing all 35 cycles, and who subsequently experienced disease progression, could receive up to 17 additional cycles over 1 year if they had not received another anticancer therapy in the meantime.

Among the 1,034 patients originally recruited between August 2013 and February 2015, 691 were assigned to pembrolizumab at 3 mg/kg or 10 mg/kg and 343 to docetaxel.

For the intention-to-treat analysis in 1033 patients, the mean duration of follow-up was 42.6 months, with a median treatment duration of 3.5 months in the pembrolizumab group and 2.0 months in the docetaxel group.

Compared with docetaxel, pembrolizumab was associated with a significant reduction in the risk of death, at a hazard ratio of 0.53 in patients with PD-L1 ≥ 50% and 0.69 in those with PD-L1 ≥ 1% (both P < .0001).

In patients with PD-L1 ≥ 50%, median overall survival was 16.9 months in those given pembrolizumab and 8.2 months with docetaxel. Among those with PD-L1 ≥ 1%, median overall survival was 11.8 months with pembrolizumab versus 8.4 months with docetaxel.

Overall survival on Kaplan-Meier analysis was 34.5% with pembrolizumab and 12.7% with docetaxel in the PD-L1 ≥ 50% group, and 22.9% versus 11.0% in the PD-L1 ≥ 1% group.

PFS significantly improved with pembrolizumab versus docetaxel, at a hazard ratio of 0.57 (P < .00001) among patients with PD-L1 ≥ 50% and 0.83 (P < .005) in those with PD-L1 ≥ 1%.

In terms of safety, 17.7% of patients who completed 2 years of pembrolizumab had grade 3-5 treatment-related adverse events, compared with 16.6% among all pembrolizumab-treated patients and 36.6% of those given docetaxel.

The team reports that 79 patients completed 35 cycles of pembrolizumab, with a median follow-up of 43.4 months.

Compared with the overall patient group, these patients were less likely to be aged ≥ 65 years and to have received two or more prior treatment lines, although they were more likely to be current or former smokers and to have squamous tumor histology.

Patients who completed 35 cycles had an objective response rate of 94.9%, and 91.0% were still alive at the data cutoff. Overall survival rates were 98.7% at 12 months and 86.3% at 24 months.

Of 71 patients eligible for analysis, 23 experienced progression after completing pembrolizumab, at PFS rates at 12 and 24 months of 72.5% and 57.7%, respectively.

A total of 14 patients were given a second course of pembrolizumab, of whom six had a partial response and five had stable disease. At the data cutoff, five patients had completed 17 additional cycles and 11 were alive.

Pembro Approved at Fixed Dose

One notable aspect of the study is that patients in the pembrolizumab arm were given two different doses of the drug based on body weight, whereas the drug is approved in the United States at a fixed dose of 200 mg.

Herbst told Medscape Medical News he considers the 200-mg dose to be appropriate.

“I didn’t think that the 3-mg versus 10-mg dose per kg that we used in our study made much difference in an average-sized person,” he said, adding that the 200-mg dose “is something a little bit more than 3 mg/kg.”

“So I think that this is clearly the right dos, and I don’t think more would make any difference,” he said.

The study was funded by Merck, the manufacturer of pembrolizumab. Herbst has reported having a consulting or advisory role for many pharmaceutical companies. Other coauthors have also reported relationships with industry, and some of the authors are Merck employees. Peters has reported receiving education grants, providing consultation, attending advisory boards, and/or providing lectures for many pharmaceutical companies.
 

This article first appeared on Medscape.com.

More than a third (35%) of patients with relapsed non–small cell lung cancer (NSCLC) treated with pembrolizumab (Keytruda, Merck) were still alive at 3 years, according to long-term results from a pivotal clinical trial.

The results also showed that, among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.

“It is too soon to say that pembrolizumab is a potential cure...and we know that it doesn’t work for all patients, but the agent remains very, very promising,” said lead investigator Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut.

These new results come from the KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.

The results were published online on February 20 in the Journal of Clinical Oncology and were previously presented at the 2018 annual meeting of the European Society of Medical Oncology.

Overall survival at 3 years was 35% in patients with PD-L1 expression ≥ 50% in the tumor, and 23% in those with PD-L1 ≥ 1%.

This compares with 3-year overall survival of 11-13% with docetaxel.

These results are “really extraordinary,” Herbst commented to Medscape Medical News.

The 3-year overall survival rate of 35% in patients with PD-L1 ≥ 50% “is huge,” he said. “It really shows the durability of the response.”

Herbst commented that the “almost 100%” survival at 3 years among patients who completed 35 cycles of pembrolizumab shows that this treatment period (of about 2 years) is “probably about the right time to treat.”

“Currently, the agent is being used in all potential settings, before any other treatment, after other treatment, and with other treatments,” he said.

“Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on. This is the story of tailored therapy,” Herbst said.

Approached for comment, Solange Peters, MD, PhD, Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said that the results are “very good” and “confirm the paradigms we have been seeing in melanoma,” with good long-term control, which is “very reassuring.”

However, she told Medscape Medical News that the trial raises an important question: «How long do you need to expose your patient with lung cancer to immunotherapy in order to get this long-term control?»

She said the “good news” is that, for the 10% of patients who completed 2 years of treatment per protocol, almost all of them are still alive at 3 years, “which is not observed with chemotherapy.”

The question for Peters is “more about the definition of long-term control,” as it was seen that almost one in three patients nevertheless had some form of progression.

This suggests that you have a group of people “who are nicely controlled, you stop the drug, and 1 year later a third of them have progressed.”

Peters said: “So how long do you need to treat these patients? I would say I still don’t know.”

“If I were one of these patients probably I would still want to continue [on the drug]. Of course, some might have progressed even while remaining on the drug, but the proportion who would have progressed is probably smaller than this one.”
 

Responses on Re-introduction of Therapy

The study also allowed patients who had completed 35 cycles of pembrolizumab to be restarted on the drug if they experienced progression.

The team found that, among 14 patients, 43% had a partial response and 36% had stable disease.

Herbst highlighted this finding and told Medscape Medical News that this «could be very important to physicians because they might want to think about using the drug again» in patients who have progressed on it.

He believes that the progression was not because of any resistance per se but rather a slowing down of the adaptive immune response.

“It’s just that it needs a boost,” he said, while noting that tissue specimens will nevertheless be required to demonstrate the theory.

Peters agreed that these results are “very promising,” but questioned their overall significance, as it is “a very small number of patients” from a subset whose disease was controlled while on treatment and then progressed after stopping.

She also pointed out that, in another study in patients with lung cancer (CheckMate-153), some patients were rechallenged with immunotherapy after having stopped treatment at 1 year “with very poor results.”

Peters said studies in melanoma have shown “rechallenge can be useful in a significant proportion of patients, but still you have not demonstrated that stopping and rechallenging is the same as not stopping.”

Study Details

KEYNOTE-010 involved patients with NSCLC from 202 centers in 24 countries with stage IIIB/IV disease expressing PD-L1 who had experienced disease progression after at least two cycles of platinum-based chemotherapy.

They were randomized 1:1:1 to open-label pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m² every 3 weeks.

Pembrolizumab was continued for 35 treatment cycles over 2 years and docetaxel was continued for the maximum duration allowed by local regulators.

Patients who stopped pembrolizumab after a complete response or completing all 35 cycles, and who subsequently experienced disease progression, could receive up to 17 additional cycles over 1 year if they had not received another anticancer therapy in the meantime.

Among the 1,034 patients originally recruited between August 2013 and February 2015, 691 were assigned to pembrolizumab at 3 mg/kg or 10 mg/kg and 343 to docetaxel.

For the intention-to-treat analysis in 1033 patients, the mean duration of follow-up was 42.6 months, with a median treatment duration of 3.5 months in the pembrolizumab group and 2.0 months in the docetaxel group.

Compared with docetaxel, pembrolizumab was associated with a significant reduction in the risk of death, at a hazard ratio of 0.53 in patients with PD-L1 ≥ 50% and 0.69 in those with PD-L1 ≥ 1% (both P < .0001).

In patients with PD-L1 ≥ 50%, median overall survival was 16.9 months in those given pembrolizumab and 8.2 months with docetaxel. Among those with PD-L1 ≥ 1%, median overall survival was 11.8 months with pembrolizumab versus 8.4 months with docetaxel.

Overall survival on Kaplan-Meier analysis was 34.5% with pembrolizumab and 12.7% with docetaxel in the PD-L1 ≥ 50% group, and 22.9% versus 11.0% in the PD-L1 ≥ 1% group.

PFS significantly improved with pembrolizumab versus docetaxel, at a hazard ratio of 0.57 (P < .00001) among patients with PD-L1 ≥ 50% and 0.83 (P < .005) in those with PD-L1 ≥ 1%.

In terms of safety, 17.7% of patients who completed 2 years of pembrolizumab had grade 3-5 treatment-related adverse events, compared with 16.6% among all pembrolizumab-treated patients and 36.6% of those given docetaxel.

The team reports that 79 patients completed 35 cycles of pembrolizumab, with a median follow-up of 43.4 months.

Compared with the overall patient group, these patients were less likely to be aged ≥ 65 years and to have received two or more prior treatment lines, although they were more likely to be current or former smokers and to have squamous tumor histology.

Patients who completed 35 cycles had an objective response rate of 94.9%, and 91.0% were still alive at the data cutoff. Overall survival rates were 98.7% at 12 months and 86.3% at 24 months.

Of 71 patients eligible for analysis, 23 experienced progression after completing pembrolizumab, at PFS rates at 12 and 24 months of 72.5% and 57.7%, respectively.

A total of 14 patients were given a second course of pembrolizumab, of whom six had a partial response and five had stable disease. At the data cutoff, five patients had completed 17 additional cycles and 11 were alive.

Pembro Approved at Fixed Dose

One notable aspect of the study is that patients in the pembrolizumab arm were given two different doses of the drug based on body weight, whereas the drug is approved in the United States at a fixed dose of 200 mg.

Herbst told Medscape Medical News he considers the 200-mg dose to be appropriate.

“I didn’t think that the 3-mg versus 10-mg dose per kg that we used in our study made much difference in an average-sized person,” he said, adding that the 200-mg dose “is something a little bit more than 3 mg/kg.”

“So I think that this is clearly the right dos, and I don’t think more would make any difference,” he said.

The study was funded by Merck, the manufacturer of pembrolizumab. Herbst has reported having a consulting or advisory role for many pharmaceutical companies. Other coauthors have also reported relationships with industry, and some of the authors are Merck employees. Peters has reported receiving education grants, providing consultation, attending advisory boards, and/or providing lectures for many pharmaceutical companies.
 

This article first appeared on Medscape.com.

While more than half of women aged 75 years and older receive annual mammograms, they do not see a reduced risk of death from breast cancer, compared with women who have stopped regular screening, according to a study published in Annals of Internal Medicine.

copyright/Thinkstock

The lack of benefit is not because older women’s cancer risk is low; a third of breast cancer deaths occur in women diagnosed at or after age 70 years, according to study author Xabier García-Albéniz, MD, PhD, of Harvard University in Boston, and colleagues.

The lack of benefit is not because mammography is less effective in women older than 75 years; indeed, it becomes a better diagnostic tool as women age, said Otis Brawley, MD, of Johns Hopkins University, Baltimore, the author of an editorial related to the study. Rather, the lack of benefit is because breast cancer treatment in older women is less successful, he clarified.
 

Study details

Dr. García-Albéniz and colleagues looked at data from 1,058,013 women enrolled in Medicare across the United States during 2000-2008. All subjects were aged 70-84 years and had a life expectancy of at least 10 years, at least one recent mammogram, and no history of breast cancer.

There are little randomized trial data available on mammography and breast cancer deaths for women in their early 70s and none for women older than 75 years. To compensate for this, the researchers aimed to emulate a prospective trial by looking at deaths over an 8-year period for women aged 70 and older who either continued annual screening or stopped it. The investigators conducted separate analyses for women aged 70-74 years and those 75-84 years of age.

Diagnoses of breast cancer were, not surprisingly, higher in the continued-screening group, but this did not translate to serious reductions in death.

In the continued-screening group, the estimated 8-year risk for breast cancer was 5.5% in women aged 70-74 and 5.8% in women aged 75-84 years. Among women who stopped screening, the estimated 8-year risk for breast cancer was 3.9% in both age groups.

Among women aged 70-74 years, the estimated 8-year risk for breast cancer death was slightly reduced with continued screening: 2.7 deaths per 1,000 women, compared with 3.7 deaths per 1,000 women for those who stopped screening. The risk difference was –1.0 deaths per 1,000 women, and the hazard ratio was 0.78.

Among women aged 75-84 years, there was no difference in estimated 8-year risk for breast cancer death. Women treated under a continued screening protocol had 3.8 deaths per 1,000, while the stop-screening group had 3.7 deaths per 1,000. The risk difference was 0.07 deaths per 1,000 women, and the hazard ratio was 1.00.

Interpreting the results

In the editorial accompanying this study, Dr. Brawley praised its design as “especially useful in breast cancer screening,” as “prospective randomized studies of mammography are not feasible and are perhaps no longer ethical in older women … because mammography is so widely accepted.”

In an interview, Dr. Brawley stressed that the findings do not argue for denying women aged 75 years and older mammography screening. Decisions about screening require a value judgment tailored to each individual patient’s perceived risks and benefits, he said.

In the absence of randomized trial evidence, “the jury will always be out” on the benefits of regular mammography for women 75 and older, Dr. Brawley said. “A clinical trial or a modeling study always tells you about an average person who doesn’t exist,” he added. “I predict that, in the future, we will have more parameters to tell us, ‘this is a person who’s 80 years old who is likely to benefit from screening; this is a person who is 75 years old who is unlikely to benefit.’ ”

And focusing too much on screening, he said, can divert attention from a key driver of breast cancer mortality in older women: inadequate treatment.

In the United States, Dr. Brawley said, “There’s a lot of emphasis on screening but fewer people writing about the fact that nearly 40% of American women get less than optimal treatment once they’re diagnosed.”

Dr. Brawley cited a 2013 modeling study showing that improvements in delivering current treatments would save more women even if screening rates remained unaltered (Cancer. 2013 Jul 15;119[14]:2541-8).

Among women in their 70s and 80s, Dr. Brawley said, some of the barriers to effective breast cancer care aren’t related to treatment efficacy but to travel and other logistical issues that can become more pronounced with age. “Unfortunately, there’s very little research on why, for women in their 70s and 80s, the treatments don’t work as well as they work in women 20 years younger,” he said.

Dr. García-Albéniz and colleagues’ study was funded by the National Institutes of Health. One coauthor reported financial ties to industry. Dr. Brawley discloses no conflicts of interest related to his editorial.

SOURCE: García-Albéniz X et al. Ann Intern Med 2020. doi: 10.7326/M18-1199.

While more than half of women aged 75 years and older receive annual mammograms, they do not see a reduced risk of death from breast cancer, compared with women who have stopped regular screening, according to a study published in Annals of Internal Medicine.

copyright/Thinkstock

The lack of benefit is not because older women’s cancer risk is low; a third of breast cancer deaths occur in women diagnosed at or after age 70 years, according to study author Xabier García-Albéniz, MD, PhD, of Harvard University in Boston, and colleagues.

The lack of benefit is not because mammography is less effective in women older than 75 years; indeed, it becomes a better diagnostic tool as women age, said Otis Brawley, MD, of Johns Hopkins University, Baltimore, the author of an editorial related to the study. Rather, the lack of benefit is because breast cancer treatment in older women is less successful, he clarified.
 

Study details

Dr. García-Albéniz and colleagues looked at data from 1,058,013 women enrolled in Medicare across the United States during 2000-2008. All subjects were aged 70-84 years and had a life expectancy of at least 10 years, at least one recent mammogram, and no history of breast cancer.

There are little randomized trial data available on mammography and breast cancer deaths for women in their early 70s and none for women older than 75 years. To compensate for this, the researchers aimed to emulate a prospective trial by looking at deaths over an 8-year period for women aged 70 and older who either continued annual screening or stopped it. The investigators conducted separate analyses for women aged 70-74 years and those 75-84 years of age.

Diagnoses of breast cancer were, not surprisingly, higher in the continued-screening group, but this did not translate to serious reductions in death.

In the continued-screening group, the estimated 8-year risk for breast cancer was 5.5% in women aged 70-74 and 5.8% in women aged 75-84 years. Among women who stopped screening, the estimated 8-year risk for breast cancer was 3.9% in both age groups.

Among women aged 70-74 years, the estimated 8-year risk for breast cancer death was slightly reduced with continued screening: 2.7 deaths per 1,000 women, compared with 3.7 deaths per 1,000 women for those who stopped screening. The risk difference was –1.0 deaths per 1,000 women, and the hazard ratio was 0.78.

Among women aged 75-84 years, there was no difference in estimated 8-year risk for breast cancer death. Women treated under a continued screening protocol had 3.8 deaths per 1,000, while the stop-screening group had 3.7 deaths per 1,000. The risk difference was 0.07 deaths per 1,000 women, and the hazard ratio was 1.00.

Interpreting the results

In the editorial accompanying this study, Dr. Brawley praised its design as “especially useful in breast cancer screening,” as “prospective randomized studies of mammography are not feasible and are perhaps no longer ethical in older women … because mammography is so widely accepted.”

In an interview, Dr. Brawley stressed that the findings do not argue for denying women aged 75 years and older mammography screening. Decisions about screening require a value judgment tailored to each individual patient’s perceived risks and benefits, he said.

In the absence of randomized trial evidence, “the jury will always be out” on the benefits of regular mammography for women 75 and older, Dr. Brawley said. “A clinical trial or a modeling study always tells you about an average person who doesn’t exist,” he added. “I predict that, in the future, we will have more parameters to tell us, ‘this is a person who’s 80 years old who is likely to benefit from screening; this is a person who is 75 years old who is unlikely to benefit.’ ”

And focusing too much on screening, he said, can divert attention from a key driver of breast cancer mortality in older women: inadequate treatment.

In the United States, Dr. Brawley said, “There’s a lot of emphasis on screening but fewer people writing about the fact that nearly 40% of American women get less than optimal treatment once they’re diagnosed.”

Dr. Brawley cited a 2013 modeling study showing that improvements in delivering current treatments would save more women even if screening rates remained unaltered (Cancer. 2013 Jul 15;119[14]:2541-8).

Among women in their 70s and 80s, Dr. Brawley said, some of the barriers to effective breast cancer care aren’t related to treatment efficacy but to travel and other logistical issues that can become more pronounced with age. “Unfortunately, there’s very little research on why, for women in their 70s and 80s, the treatments don’t work as well as they work in women 20 years younger,” he said.

Dr. García-Albéniz and colleagues’ study was funded by the National Institutes of Health. One coauthor reported financial ties to industry. Dr. Brawley discloses no conflicts of interest related to his editorial.

SOURCE: García-Albéniz X et al. Ann Intern Med 2020. doi: 10.7326/M18-1199.

While more than half of women aged 75 years and older receive annual mammograms, they do not see a reduced risk of death from breast cancer, compared with women who have stopped regular screening, according to a study published in Annals of Internal Medicine.

copyright/Thinkstock

The lack of benefit is not because older women’s cancer risk is low; a third of breast cancer deaths occur in women diagnosed at or after age 70 years, according to study author Xabier García-Albéniz, MD, PhD, of Harvard University in Boston, and colleagues.

The lack of benefit is not because mammography is less effective in women older than 75 years; indeed, it becomes a better diagnostic tool as women age, said Otis Brawley, MD, of Johns Hopkins University, Baltimore, the author of an editorial related to the study. Rather, the lack of benefit is because breast cancer treatment in older women is less successful, he clarified.
 

Study details

Dr. García-Albéniz and colleagues looked at data from 1,058,013 women enrolled in Medicare across the United States during 2000-2008. All subjects were aged 70-84 years and had a life expectancy of at least 10 years, at least one recent mammogram, and no history of breast cancer.

There are little randomized trial data available on mammography and breast cancer deaths for women in their early 70s and none for women older than 75 years. To compensate for this, the researchers aimed to emulate a prospective trial by looking at deaths over an 8-year period for women aged 70 and older who either continued annual screening or stopped it. The investigators conducted separate analyses for women aged 70-74 years and those 75-84 years of age.

Diagnoses of breast cancer were, not surprisingly, higher in the continued-screening group, but this did not translate to serious reductions in death.

In the continued-screening group, the estimated 8-year risk for breast cancer was 5.5% in women aged 70-74 and 5.8% in women aged 75-84 years. Among women who stopped screening, the estimated 8-year risk for breast cancer was 3.9% in both age groups.

Among women aged 70-74 years, the estimated 8-year risk for breast cancer death was slightly reduced with continued screening: 2.7 deaths per 1,000 women, compared with 3.7 deaths per 1,000 women for those who stopped screening. The risk difference was –1.0 deaths per 1,000 women, and the hazard ratio was 0.78.

Among women aged 75-84 years, there was no difference in estimated 8-year risk for breast cancer death. Women treated under a continued screening protocol had 3.8 deaths per 1,000, while the stop-screening group had 3.7 deaths per 1,000. The risk difference was 0.07 deaths per 1,000 women, and the hazard ratio was 1.00.

Interpreting the results

In the editorial accompanying this study, Dr. Brawley praised its design as “especially useful in breast cancer screening,” as “prospective randomized studies of mammography are not feasible and are perhaps no longer ethical in older women … because mammography is so widely accepted.”

In an interview, Dr. Brawley stressed that the findings do not argue for denying women aged 75 years and older mammography screening. Decisions about screening require a value judgment tailored to each individual patient’s perceived risks and benefits, he said.

In the absence of randomized trial evidence, “the jury will always be out” on the benefits of regular mammography for women 75 and older, Dr. Brawley said. “A clinical trial or a modeling study always tells you about an average person who doesn’t exist,” he added. “I predict that, in the future, we will have more parameters to tell us, ‘this is a person who’s 80 years old who is likely to benefit from screening; this is a person who is 75 years old who is unlikely to benefit.’ ”

And focusing too much on screening, he said, can divert attention from a key driver of breast cancer mortality in older women: inadequate treatment.

In the United States, Dr. Brawley said, “There’s a lot of emphasis on screening but fewer people writing about the fact that nearly 40% of American women get less than optimal treatment once they’re diagnosed.”

Dr. Brawley cited a 2013 modeling study showing that improvements in delivering current treatments would save more women even if screening rates remained unaltered (Cancer. 2013 Jul 15;119[14]:2541-8).

Among women in their 70s and 80s, Dr. Brawley said, some of the barriers to effective breast cancer care aren’t related to treatment efficacy but to travel and other logistical issues that can become more pronounced with age. “Unfortunately, there’s very little research on why, for women in their 70s and 80s, the treatments don’t work as well as they work in women 20 years younger,” he said.

Dr. García-Albéniz and colleagues’ study was funded by the National Institutes of Health. One coauthor reported financial ties to industry. Dr. Brawley discloses no conflicts of interest related to his editorial.

SOURCE: García-Albéniz X et al. Ann Intern Med 2020. doi: 10.7326/M18-1199.

Oncology will account for a substantial majority of clinical trials to be launched in 2020, as well as accounting for most of those to be completed this year, according to a new analysis.

“A large number of early stage clinical trials within this field are likely to be due to the demand for novel therapeutic approaches addressing unmet medical need,” commented Mohamed Abukar, pharma analyst at GlobalData.

Most oncology studies planned to start in 2020 are phase 1 and 2, and 61.9% are industry sponsored. Eli Lilly and Novartis have announced the most upcoming studies.

Among the new drugs being evaluated in these clinical trials, four of the top seven drugs in phase 1–3 development are monoclonal antibodies, with the most studies being conducted on the experimental agents ZW25 (Zymeworks) and KSI-301 (Kodiak Sciences), the report notes.

As for clinical trials due for completion this year, many are funded by nonindustry sources, with Memorial Sloan Kettering Cancer Center accounting for the most number of trials.

Top Indications Explored in Clinical Trials

Oncology also accounts for eight of the top ten indications for clinical trials planned to start in 2020, with solid tumors, breast cancer, and non–small cell lung cancer accounting for the second, third, and fourth top spots, respectively, regardless of sponsor type.

However, for industry-sponsored clinical trials, the predominant area is solid tumors for new investigations to start this year, followed by breast cancer, then pain.

“This is attributed to the manner in which the burden of cancer worldwide necessitates industry investment to allow for capitalization on the increasing market size,” Abukar said.

This article first appeared on Medscape.com.

Oncology will account for a substantial majority of clinical trials to be launched in 2020, as well as accounting for most of those to be completed this year, according to a new analysis.

“A large number of early stage clinical trials within this field are likely to be due to the demand for novel therapeutic approaches addressing unmet medical need,” commented Mohamed Abukar, pharma analyst at GlobalData.

Most oncology studies planned to start in 2020 are phase 1 and 2, and 61.9% are industry sponsored. Eli Lilly and Novartis have announced the most upcoming studies.

Among the new drugs being evaluated in these clinical trials, four of the top seven drugs in phase 1–3 development are monoclonal antibodies, with the most studies being conducted on the experimental agents ZW25 (Zymeworks) and KSI-301 (Kodiak Sciences), the report notes.

As for clinical trials due for completion this year, many are funded by nonindustry sources, with Memorial Sloan Kettering Cancer Center accounting for the most number of trials.

Top Indications Explored in Clinical Trials

Oncology also accounts for eight of the top ten indications for clinical trials planned to start in 2020, with solid tumors, breast cancer, and non–small cell lung cancer accounting for the second, third, and fourth top spots, respectively, regardless of sponsor type.

However, for industry-sponsored clinical trials, the predominant area is solid tumors for new investigations to start this year, followed by breast cancer, then pain.

“This is attributed to the manner in which the burden of cancer worldwide necessitates industry investment to allow for capitalization on the increasing market size,” Abukar said.

This article first appeared on Medscape.com.

Oncology will account for a substantial majority of clinical trials to be launched in 2020, as well as accounting for most of those to be completed this year, according to a new analysis.

“A large number of early stage clinical trials within this field are likely to be due to the demand for novel therapeutic approaches addressing unmet medical need,” commented Mohamed Abukar, pharma analyst at GlobalData.

Most oncology studies planned to start in 2020 are phase 1 and 2, and 61.9% are industry sponsored. Eli Lilly and Novartis have announced the most upcoming studies.

Among the new drugs being evaluated in these clinical trials, four of the top seven drugs in phase 1–3 development are monoclonal antibodies, with the most studies being conducted on the experimental agents ZW25 (Zymeworks) and KSI-301 (Kodiak Sciences), the report notes.

As for clinical trials due for completion this year, many are funded by nonindustry sources, with Memorial Sloan Kettering Cancer Center accounting for the most number of trials.

Top Indications Explored in Clinical Trials

Oncology also accounts for eight of the top ten indications for clinical trials planned to start in 2020, with solid tumors, breast cancer, and non–small cell lung cancer accounting for the second, third, and fourth top spots, respectively, regardless of sponsor type.

However, for industry-sponsored clinical trials, the predominant area is solid tumors for new investigations to start this year, followed by breast cancer, then pain.

“This is attributed to the manner in which the burden of cancer worldwide necessitates industry investment to allow for capitalization on the increasing market size,” Abukar said.

This article first appeared on Medscape.com.

Researchers have developed chimeric antigen receptor (CAR) T cells expressing a fully human antibody against CD229, a surface antigen that shows universal and strong tumor expression in patients with multiple myeloma (MM). These cells proved to be active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells, according to a report in Nature Communications.

Wikimedia Commons/KGH/Creative Commons License

This research is important because most MM patients eventually succumb to the disease and previously developed CAR T cells targeting B-cell maturation antigen (BCMA) on MM cells have shown high-response rates but limited durability.

Previous research showed that CD229/LY9 is a potential target for CAR T-cell therapy in MM because of its strong and homogeneous expression on the bulk of tumor cells, as well as chemotherapy-resistant myeloma progenitors; its absence from most normal cells; and dependence of MM cells on CD229 for their survival, according to Sabarinath V. Radhakrishnan, MD, of the University of Utah, Salt Lake City, and colleagues.

Using primary CD138+ tumor cells from three patients with plasma cell leukemia, a highly aggressive form of MM, which all showed high expression of CD229, the researchers found that CD229 CAR T cells exhibited high cytotoxic activity against these cells. In addition, when assessing two MM cell lines, U-266 and RPMI-8226, expressing different levels of CD229, they found that CD229 CAR T cells efficiently killed both cell lines in vitro.

“We do not observe fratricide during CD229 CAR T-cell production, as CD229 is downregulated in T cells during activation. In addition, while CD229 CAR T cells target normal CD229^high T cells, they spare functional CD229^neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM,” the authors concluded.

The study was funded by several nongovernmental organizations and the National Cancer Institute. Three of the authors are inventors on PCT application US2017/42840 “Antibodies and CAR T Cells for the Treatment of Multiple Myeloma” describing the therapeutic use of CD229 CAR T cells.

mlesney@mdedge.com

SOURCE: Radhakrishnan SV et al. Nat Commun. 2020 Feb 7;11(1):798. doi: 10.1038/s41467-020-14619-z.

Researchers have developed chimeric antigen receptor (CAR) T cells expressing a fully human antibody against CD229, a surface antigen that shows universal and strong tumor expression in patients with multiple myeloma (MM). These cells proved to be active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells, according to a report in Nature Communications.

Wikimedia Commons/KGH/Creative Commons License

This research is important because most MM patients eventually succumb to the disease and previously developed CAR T cells targeting B-cell maturation antigen (BCMA) on MM cells have shown high-response rates but limited durability.

Previous research showed that CD229/LY9 is a potential target for CAR T-cell therapy in MM because of its strong and homogeneous expression on the bulk of tumor cells, as well as chemotherapy-resistant myeloma progenitors; its absence from most normal cells; and dependence of MM cells on CD229 for their survival, according to Sabarinath V. Radhakrishnan, MD, of the University of Utah, Salt Lake City, and colleagues.

Using primary CD138+ tumor cells from three patients with plasma cell leukemia, a highly aggressive form of MM, which all showed high expression of CD229, the researchers found that CD229 CAR T cells exhibited high cytotoxic activity against these cells. In addition, when assessing two MM cell lines, U-266 and RPMI-8226, expressing different levels of CD229, they found that CD229 CAR T cells efficiently killed both cell lines in vitro.

“We do not observe fratricide during CD229 CAR T-cell production, as CD229 is downregulated in T cells during activation. In addition, while CD229 CAR T cells target normal CD229^high T cells, they spare functional CD229^neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM,” the authors concluded.

The study was funded by several nongovernmental organizations and the National Cancer Institute. Three of the authors are inventors on PCT application US2017/42840 “Antibodies and CAR T Cells for the Treatment of Multiple Myeloma” describing the therapeutic use of CD229 CAR T cells.

mlesney@mdedge.com

SOURCE: Radhakrishnan SV et al. Nat Commun. 2020 Feb 7;11(1):798. doi: 10.1038/s41467-020-14619-z.

Researchers have developed chimeric antigen receptor (CAR) T cells expressing a fully human antibody against CD229, a surface antigen that shows universal and strong tumor expression in patients with multiple myeloma (MM). These cells proved to be active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells, according to a report in Nature Communications.

Wikimedia Commons/KGH/Creative Commons License

This research is important because most MM patients eventually succumb to the disease and previously developed CAR T cells targeting B-cell maturation antigen (BCMA) on MM cells have shown high-response rates but limited durability.

Previous research showed that CD229/LY9 is a potential target for CAR T-cell therapy in MM because of its strong and homogeneous expression on the bulk of tumor cells, as well as chemotherapy-resistant myeloma progenitors; its absence from most normal cells; and dependence of MM cells on CD229 for their survival, according to Sabarinath V. Radhakrishnan, MD, of the University of Utah, Salt Lake City, and colleagues.

Using primary CD138+ tumor cells from three patients with plasma cell leukemia, a highly aggressive form of MM, which all showed high expression of CD229, the researchers found that CD229 CAR T cells exhibited high cytotoxic activity against these cells. In addition, when assessing two MM cell lines, U-266 and RPMI-8226, expressing different levels of CD229, they found that CD229 CAR T cells efficiently killed both cell lines in vitro.

“We do not observe fratricide during CD229 CAR T-cell production, as CD229 is downregulated in T cells during activation. In addition, while CD229 CAR T cells target normal CD229^high T cells, they spare functional CD229^neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM,” the authors concluded.

The study was funded by several nongovernmental organizations and the National Cancer Institute. Three of the authors are inventors on PCT application US2017/42840 “Antibodies and CAR T Cells for the Treatment of Multiple Myeloma” describing the therapeutic use of CD229 CAR T cells.

mlesney@mdedge.com

SOURCE: Radhakrishnan SV et al. Nat Commun. 2020 Feb 7;11(1):798. doi: 10.1038/s41467-020-14619-z.

SAN FRANCISCO – A novel gene therapy may expand treatment options for non–muscle invasive bladder cancer that does not respond to Bacillus Calmette-Guerin (BCG), new research suggests.

Susan London/MDedge News

The therapy, nadofaragene firadenovec, is a recombinant adenovirus that is instilled into the bladder and delivers the human interferon alpha-2b gene, leading to expression of the immune cytokine.

At 3 months, nadofaragene firadenovec had produced a complete response in 53.4% of patients with carcinoma in situ (CIS), and the rate of high-grade recurrence-free survival was 59.6% in all patients. Although most patients (70.1%) experienced adverse events in this trial, few had serious events (1.9%).

Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minn., presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“The optimal management for patients with BCG-unresponsive non–muscle invasive bladder cancer remains to be established,” Dr. Boorjian said. “National and organizational guidelines recommend radical cystectomy in this setting, but we have to acknowledge that many of our patients will be either unwilling or unfit to undergo what is often a highly morbid operation.”

Dr. Boorjian and coinvestigators tested nadofaragene firadenovec in 107 patients with CIS, with or without high-grade Ta or T1 papillary disease, as well as 50 patients with high-grade Ta or T1 papillary disease only.

All patients received nadofaragene firadenovec once every 3 months for up four doses, with additional dosing at the investigator’s discretion. Although the trial was designated as phase 3, it did not have the typical randomized comparative design.

“The challenge in the BCG-unresponsive disease state is that, historically, there has been no validated good comparator to use here; there’s no standard of care for these patients,” Dr. Boorjian explained, noting that the design was chosen after discussion with the Food and Drug Administration.
 

Efficacy

The complete response rate among CIS patients at any time after instillation, the trial’s primary objective, was 53.4%. All of these responses occurred after a single dose of nadofaragene firadenovec. Responses were considered durable, as 45.5% of CIS patients who had a complete response at 3 months still had a complete response at 12 months.

The rate of high-grade recurrence-free survival at 3 months was 59.6% in the overall population, 53.4% in patients with CIS, and 72.9% in patients with papillary disease. At 12 months, the rate of high-grade recurrence-free survival was 30.5%, 24.3%, and 43.8%, respectively.

The rate of high-grade recurrence without muscle invasive bladder cancer was 71.8% in the CIS group and 52.1% in the papillary group. The rate of progression to muscle invasive bladder cancer or more advanced disease was 4.9% and 6.3%, respectively. The overall 2-year rate of cystectomy-free survival was 64%, and there were no bladder cancer deaths.
 

Safety

Nadofaragene firadenovec was considered safe and well tolerated. The most common study drug–related adverse events were irritative voiding symptoms, such as discharge, bladder spasm, micturition urgency, and hematuria.

Although 70.1% of patients experienced a local or systemic adverse event related to the study drug or procedure, few experienced serious adverse events (1.9%), grade 3 adverse events (3.8%), or treatment-emergent adverse events leading to discontinuation (1.9%). The serious adverse events were sepsis, syncope, and hematuria.
 

Next steps

“Nadofaragene firadenovec represents a promising option for patients with BCG-unresponsive [non–muscle invasive bladder cancer],” Dr. Boorjian said. “What we want to see going forward is durability of response, cystectomy-free survival, and metastasis-free and cancer-specific survival. Those are the harder endpoints that, as these data mature, we will want to see so that we are able to counsel our patients accordingly.”

Susan London/MDedge News

The FDA recently approved pembrolizumab for this patient population, noted session cochair Guru Sonpavde, MD, of the Dana-Farber Cancer Institute in Boston.

“But nadofaragene firadenovec is much less toxic, it is given intravesically, and it’s only given once every 3 months,” he said. “The outcomes at the 1-year point look similar in terms of the durable complete response rate. So we hope that this therapy will be able to get to the clinic, but we have to wait for the FDA to decide.”

It remains to be seen how nadofaragene firadenovec compares with other emerging therapies for high-risk BCG-unresponsive non–muscle invasive bladder cancer, including pembrolizumab and potentially intravesical oportuzumab monatox (a targeted immunotoxin) and intravesical combination BCG and superagonist interleukin-15 (ALT-803), according to Dr. Boorjian.

“A unique feature of the trial I presented was that the results were validated by a mandatory 12-month study biopsy, which has not been the case in other trials,” he pointed out. “So this separates it a little bit when you are looking at pathologic response rates and high-grade recurrence–free rates. They are based on pathologic confirmation.”

Evaluators will ultimately compare these therapies on safety, efficacy, ease of administration, delivery schedule, and cost, Dr. Boorjian said. “At this stage, it’s very difficult to start to say which agent is going to be placed where in our management paradigm. We have to go step by step: Do the trial that we did, show our data, put it out for review, and then allow the community to engage in a discussion about which agent, and why, for which patient.”

This trial was funded by FKD Therapies Oy. Dr. Boorjian disclosed relationships with Ferring and Sanofi. Dr. Sonpavde disclosed relationships with many companies.

SOURCE: Boorjian SA et al. GUCS 2020, Abstract 442.

SAN FRANCISCO – A novel gene therapy may expand treatment options for non–muscle invasive bladder cancer that does not respond to Bacillus Calmette-Guerin (BCG), new research suggests.

Susan London/MDedge News

The therapy, nadofaragene firadenovec, is a recombinant adenovirus that is instilled into the bladder and delivers the human interferon alpha-2b gene, leading to expression of the immune cytokine.

At 3 months, nadofaragene firadenovec had produced a complete response in 53.4% of patients with carcinoma in situ (CIS), and the rate of high-grade recurrence-free survival was 59.6% in all patients. Although most patients (70.1%) experienced adverse events in this trial, few had serious events (1.9%).

Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minn., presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“The optimal management for patients with BCG-unresponsive non–muscle invasive bladder cancer remains to be established,” Dr. Boorjian said. “National and organizational guidelines recommend radical cystectomy in this setting, but we have to acknowledge that many of our patients will be either unwilling or unfit to undergo what is often a highly morbid operation.”

Dr. Boorjian and coinvestigators tested nadofaragene firadenovec in 107 patients with CIS, with or without high-grade Ta or T1 papillary disease, as well as 50 patients with high-grade Ta or T1 papillary disease only.

All patients received nadofaragene firadenovec once every 3 months for up four doses, with additional dosing at the investigator’s discretion. Although the trial was designated as phase 3, it did not have the typical randomized comparative design.

“The challenge in the BCG-unresponsive disease state is that, historically, there has been no validated good comparator to use here; there’s no standard of care for these patients,” Dr. Boorjian explained, noting that the design was chosen after discussion with the Food and Drug Administration.
 

Efficacy

The complete response rate among CIS patients at any time after instillation, the trial’s primary objective, was 53.4%. All of these responses occurred after a single dose of nadofaragene firadenovec. Responses were considered durable, as 45.5% of CIS patients who had a complete response at 3 months still had a complete response at 12 months.

The rate of high-grade recurrence-free survival at 3 months was 59.6% in the overall population, 53.4% in patients with CIS, and 72.9% in patients with papillary disease. At 12 months, the rate of high-grade recurrence-free survival was 30.5%, 24.3%, and 43.8%, respectively.

The rate of high-grade recurrence without muscle invasive bladder cancer was 71.8% in the CIS group and 52.1% in the papillary group. The rate of progression to muscle invasive bladder cancer or more advanced disease was 4.9% and 6.3%, respectively. The overall 2-year rate of cystectomy-free survival was 64%, and there were no bladder cancer deaths.
 

Safety

Nadofaragene firadenovec was considered safe and well tolerated. The most common study drug–related adverse events were irritative voiding symptoms, such as discharge, bladder spasm, micturition urgency, and hematuria.

Although 70.1% of patients experienced a local or systemic adverse event related to the study drug or procedure, few experienced serious adverse events (1.9%), grade 3 adverse events (3.8%), or treatment-emergent adverse events leading to discontinuation (1.9%). The serious adverse events were sepsis, syncope, and hematuria.
 

Next steps

“Nadofaragene firadenovec represents a promising option for patients with BCG-unresponsive [non–muscle invasive bladder cancer],” Dr. Boorjian said. “What we want to see going forward is durability of response, cystectomy-free survival, and metastasis-free and cancer-specific survival. Those are the harder endpoints that, as these data mature, we will want to see so that we are able to counsel our patients accordingly.”

Susan London/MDedge News

The FDA recently approved pembrolizumab for this patient population, noted session cochair Guru Sonpavde, MD, of the Dana-Farber Cancer Institute in Boston.

“But nadofaragene firadenovec is much less toxic, it is given intravesically, and it’s only given once every 3 months,” he said. “The outcomes at the 1-year point look similar in terms of the durable complete response rate. So we hope that this therapy will be able to get to the clinic, but we have to wait for the FDA to decide.”

It remains to be seen how nadofaragene firadenovec compares with other emerging therapies for high-risk BCG-unresponsive non–muscle invasive bladder cancer, including pembrolizumab and potentially intravesical oportuzumab monatox (a targeted immunotoxin) and intravesical combination BCG and superagonist interleukin-15 (ALT-803), according to Dr. Boorjian.

“A unique feature of the trial I presented was that the results were validated by a mandatory 12-month study biopsy, which has not been the case in other trials,” he pointed out. “So this separates it a little bit when you are looking at pathologic response rates and high-grade recurrence–free rates. They are based on pathologic confirmation.”

Evaluators will ultimately compare these therapies on safety, efficacy, ease of administration, delivery schedule, and cost, Dr. Boorjian said. “At this stage, it’s very difficult to start to say which agent is going to be placed where in our management paradigm. We have to go step by step: Do the trial that we did, show our data, put it out for review, and then allow the community to engage in a discussion about which agent, and why, for which patient.”

This trial was funded by FKD Therapies Oy. Dr. Boorjian disclosed relationships with Ferring and Sanofi. Dr. Sonpavde disclosed relationships with many companies.

SOURCE: Boorjian SA et al. GUCS 2020, Abstract 442.

SAN FRANCISCO – A novel gene therapy may expand treatment options for non–muscle invasive bladder cancer that does not respond to Bacillus Calmette-Guerin (BCG), new research suggests.

Susan London/MDedge News

The therapy, nadofaragene firadenovec, is a recombinant adenovirus that is instilled into the bladder and delivers the human interferon alpha-2b gene, leading to expression of the immune cytokine.

At 3 months, nadofaragene firadenovec had produced a complete response in 53.4% of patients with carcinoma in situ (CIS), and the rate of high-grade recurrence-free survival was 59.6% in all patients. Although most patients (70.1%) experienced adverse events in this trial, few had serious events (1.9%).

Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minn., presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“The optimal management for patients with BCG-unresponsive non–muscle invasive bladder cancer remains to be established,” Dr. Boorjian said. “National and organizational guidelines recommend radical cystectomy in this setting, but we have to acknowledge that many of our patients will be either unwilling or unfit to undergo what is often a highly morbid operation.”

Dr. Boorjian and coinvestigators tested nadofaragene firadenovec in 107 patients with CIS, with or without high-grade Ta or T1 papillary disease, as well as 50 patients with high-grade Ta or T1 papillary disease only.

All patients received nadofaragene firadenovec once every 3 months for up four doses, with additional dosing at the investigator’s discretion. Although the trial was designated as phase 3, it did not have the typical randomized comparative design.

“The challenge in the BCG-unresponsive disease state is that, historically, there has been no validated good comparator to use here; there’s no standard of care for these patients,” Dr. Boorjian explained, noting that the design was chosen after discussion with the Food and Drug Administration.
 

Efficacy

The complete response rate among CIS patients at any time after instillation, the trial’s primary objective, was 53.4%. All of these responses occurred after a single dose of nadofaragene firadenovec. Responses were considered durable, as 45.5% of CIS patients who had a complete response at 3 months still had a complete response at 12 months.

The rate of high-grade recurrence-free survival at 3 months was 59.6% in the overall population, 53.4% in patients with CIS, and 72.9% in patients with papillary disease. At 12 months, the rate of high-grade recurrence-free survival was 30.5%, 24.3%, and 43.8%, respectively.

The rate of high-grade recurrence without muscle invasive bladder cancer was 71.8% in the CIS group and 52.1% in the papillary group. The rate of progression to muscle invasive bladder cancer or more advanced disease was 4.9% and 6.3%, respectively. The overall 2-year rate of cystectomy-free survival was 64%, and there were no bladder cancer deaths.
 

Safety

Nadofaragene firadenovec was considered safe and well tolerated. The most common study drug–related adverse events were irritative voiding symptoms, such as discharge, bladder spasm, micturition urgency, and hematuria.

Although 70.1% of patients experienced a local or systemic adverse event related to the study drug or procedure, few experienced serious adverse events (1.9%), grade 3 adverse events (3.8%), or treatment-emergent adverse events leading to discontinuation (1.9%). The serious adverse events were sepsis, syncope, and hematuria.
 

Next steps

“Nadofaragene firadenovec represents a promising option for patients with BCG-unresponsive [non–muscle invasive bladder cancer],” Dr. Boorjian said. “What we want to see going forward is durability of response, cystectomy-free survival, and metastasis-free and cancer-specific survival. Those are the harder endpoints that, as these data mature, we will want to see so that we are able to counsel our patients accordingly.”

Susan London/MDedge News

The FDA recently approved pembrolizumab for this patient population, noted session cochair Guru Sonpavde, MD, of the Dana-Farber Cancer Institute in Boston.

“But nadofaragene firadenovec is much less toxic, it is given intravesically, and it’s only given once every 3 months,” he said. “The outcomes at the 1-year point look similar in terms of the durable complete response rate. So we hope that this therapy will be able to get to the clinic, but we have to wait for the FDA to decide.”

It remains to be seen how nadofaragene firadenovec compares with other emerging therapies for high-risk BCG-unresponsive non–muscle invasive bladder cancer, including pembrolizumab and potentially intravesical oportuzumab monatox (a targeted immunotoxin) and intravesical combination BCG and superagonist interleukin-15 (ALT-803), according to Dr. Boorjian.

“A unique feature of the trial I presented was that the results were validated by a mandatory 12-month study biopsy, which has not been the case in other trials,” he pointed out. “So this separates it a little bit when you are looking at pathologic response rates and high-grade recurrence–free rates. They are based on pathologic confirmation.”

Evaluators will ultimately compare these therapies on safety, efficacy, ease of administration, delivery schedule, and cost, Dr. Boorjian said. “At this stage, it’s very difficult to start to say which agent is going to be placed where in our management paradigm. We have to go step by step: Do the trial that we did, show our data, put it out for review, and then allow the community to engage in a discussion about which agent, and why, for which patient.”

This trial was funded by FKD Therapies Oy. Dr. Boorjian disclosed relationships with Ferring and Sanofi. Dr. Sonpavde disclosed relationships with many companies.

SOURCE: Boorjian SA et al. GUCS 2020, Abstract 442.

SAN FRANCISCO – For years, 50 years old has been the age at which screening for colorectal cancer (CRC) began in the United States, but recently, one group lowered the starting age to 45 years.

pixologicstudio/Thinkstock

This move by the American Cancer Society in 2018 was made in reaction to reports of an increase in the incidence of CRC in younger adults.

However, other groups have stayed with the benchmark 50 years. This includes the U.S. Preventive Services Task Force and the National Comprehensive Cancer Network.

Should the age be lowered in view of the mounting reports of an increase in CRC in younger adults? Experts argued both for and against the move here at the 2020 Gastrointestinal Cancers Symposium.

“We’re having this debate because the health of more than 20 million Americans is in the balance,” commented David Weinberg, MD, MSc, chairman of the department of medicine at Fox Chase Cancer Center in Philadelphia. “This is not just an academic discussion.” If the screening age shifts to 5 years earlier, the impact nationally would be about 30,000 colorectal cancers and 11,000 deaths averted.

“It will take about 11 million additional colonoscopies ... and the overall bill would be $10 billion. That’s not a small number, but if the country has the resources and we want to do this, I would say we can,” argued Uri Ladabaum, MD, director of the gastrointestinal cancer prevention program and the clinical chief of the division of gastroenterology and hepatology at Stanford (Calif.) University.

Lower the age

Dr. Ladabaum argued in favor of lowering the age to 45 years to start screening. “In life, 60 may be the new 40, but for colorectal cancer screening, 45 is definitely the new 50,” he said. Anticipating arguments against such a move, he focused on several points.

First, the magnitude of the problem is certainly not small, he noted, pointing to a 2017 study showing that colorectal cancer rates have increased by 1%-2.4% annually since the mid-1980s in persons aged 20-39 years and by 0.5%-1.3% since the mid-1990s in adults aged 40-54 years (J Natl Cancer Inst. 2017;109:djw322). Rectal cancer incidence has been increasing even more rapidly, at a rate of about 3.2% annually during 1974-2013 in adults aged 20-29 years.

Overall, people who were born around 1990 and later have double the risk of colon cancer (incidence rate ratio, 2.40) and quadruple the risk of rectal cancer (IRR, 4.32) as compared with those born circa 1950.

“Thus, 45- to 49-year-olds are beginning to look like yesterday’s 50- to 54-year-olds used to be,” said Dr. Ladabaum.

One issue that has been raised is lead-time bias, with the burning question: Are the cancers found in adults in their 40s simply the same ones that would have eventually been detected in their 50s? Dr. Ladabaum argued that they are not, referencing a 2019 study showing that among persons aged 40 through 49 years, the disease was diagnosed at later stages (JAMA. 2019;321:1933-4).

For those aged 40- 49 years, there was a significant increase in incidence during 1995-2015. The proportion of distant cancers increased significantly (from 21.7% to 26.6%; P less than .001), and the authors of the study had noted that this increase of 4.9% could not be explained by a decrease in unstaged cases. “In the early ’90s and mid-’90s, we began to see an increase in all stages,” Dr. Ladabaum noted. “And the most important thing here is the distant cancers over time. They’ve gone up.” If the only explanation was lead time bias in people aged 40- 49 years, then a person screened and diagnosed with cancer at age 48 would have earlier-stage disease than if it had been found at age 51. “So is this all lead-time bias?” he said. “I think the answer is no.”

Next, Dr. Ladabaum tackled the issue of whether benefit/risk ratio of CRC screening is different among younger vs. older adults. This is difficult to tease out, he suggested, as the data are sparse and there were no controlled studies to date to address that. One study from Taiwan, which looked at the outcomes of fecal immunochemical testing (FIT), showed that in different age groups, the hazard ratio for detecting cancer in those with positive results is higher in younger people vs. older ones (J Clin Gastroenterol. 2016 Oct;50[9]:761-8).

“Indirect evidence shows that if we do a FIT test and it’s positive, it probably means something,” he said. “But is there something magical that at age 50 and older – that it becomes a screenable disease, and through age 49 it’s not screenable? I would say no. Biology is not like this.”

Finally, is it cost effective to start earlier? In a modeling projection published last summer by Dr. Ladabaum and colleagues, starting at 45 years would avert about four colorectal cancers and two colorectal cancer deaths per 1,000 people, and the cohort would gain approximately 14 quality-adjusted life years (Gastroenterology. 2019;157:137-48).

“The incremental cost per quality-adjusted life year gained is highly acceptable,” said Dr. Ladabaum. “This is well within the range of what’s considered cost-effective in the United States – under $35,000 for colonoscopy, and under $8,000 for fecal immunochemical tests.”

Therefore, the answer is yes, it is cost effective, he concluded.

Not so fast ...

Arguing the case against a lowering of the starting age, Dr. Weinberg agreed with Dr. Ladabaum that colon cancer risk for younger people is rising.

That risk has increased from 5.9/100,000 to 7.2/100,000, which is a relative increase of 22%, he noted.

“That is what newspapers will want to put on their headlines to sensationalize it – that the risk of colon cancer for young people is up by over 20%,” said Dr. Weinberg. “But that represents an absolute risk of just 1.3 more people/100,000. Put in some context, 99.9% of people in their 40s will not develop colon cancer.”

This observation was not to “make light of the remainder,” he emphasized, but “the overwhelming majority are not going to get this disease at this age,” he noted.

“It’s also not entirely clear that starting screening at 45 is the right answer,” he added.

“Taken to a somewhat ridiculous extreme,” he continued, “why not start at 40? You’ll catch more people that way, but no one is advocating that.”

A better understanding of the factors contributing to the increased CRC incidence seen in younger adults is very important, he argued, and he suggested that some of it may occur because of screening, along with factors such as obesity, diabetes, and childhood exposures.

Modeling has been done to calculate the risk and benefit of early screening, but while useful for decision making, models are “usually wrong and sit near the bottom of the evidence hierarchy.”

“Models help inform decisions, but they don’t define the standard of care,” Dr. Weinberg said. “No one would vaccinate a population based on a model.”

Dr. Weinberg also emphasized that the new recommendation from the American Cancer Society to start screening at age 45 years is qualified. This means that while “clear evidence of benefit exists,” so does uncertainty about whether “the benefits really outweigh the harms.”

The current evidence for reducing the screening age is not yet clear, he believes, and he questioned the premise that age should be the only criteria for cancer stratification.

Dr. Weinberg cited one study that looked at early-onset colon cancer (ages 18-49 years) and compared it with two groups: patients diagnosed at 50 years and older and matched controls (Clin Gastroenterol Hepatol. 2019;S1542-3565[19]31108-5). Besides age, the study authors identified several nonmodifiable risk factors that were associated with early-onset disease, including sex, race, history of inflammatory bowel disease (IBD), and family history of colorectal cancer.

“Being male was a risk factor and having a family history increased your risk by three times,” said Dr. Weinberg. “And I would note that this study had removed people, at least as best one can, who were known to have syndromic risks of early-onset colon cancer (such as familial adenomatous polyposis.”

Earlier screening (by age 40 years) should already be taking place in people with such syndromes, he commented, as well as those with a known family history and IBD. “Those recommendations were there before the ACS, and we don’t necessarily need another one,” he added.

To make things a little more confusing, a second recent study, using National Cancer Data Base data from 2004 to 2015, identified another set of factors associated with colon cancer in younger adults (Cancer. 2019 Nov 1;125:3828-35). This study showed diagnosis younger than 50 years rose only in non-Hispanic white men, in Hispanic and non-Hispanic white women, and in those living in urban vs. rural areas.

“But it gets more interesting,” Dr. Weinberg pointed out. “Risk increased over time for people in the highest zip code income quartile and those with private insurance, and risk was lower for people with Medicaid and no insurance at all,” he noted. “Well, that smacks of access to me,” he commented.

Another issue is the possibility of lead-time bias. During 1975-2015, incidence rose over time, according to Surveillance, Epidemiology, and End Results data (J Natl Cancer Inst. 2017 Aug;109:djw322). Screening of persons younger than age 49 years also more than doubled, from a low level in 2000 of about 6% to more than 15% by 2010. As screening increases, the incidence increases, Dr. Weinberg pointed out. “But mortality doesn’t change. And despite what Dr. Ladabaum said a moment ago about lead-time bias, that is textbook lead-time bias in any epidemiology study.”

Finally, it is essential to carefully weigh the benefit against the risk, Dr. Weinberg said.

A core principle of population screening is to create more future health benefits than harms, and if the screening age is lowered, several million additional colonoscopies will be performed.

Colonoscopy reduces the colorectal cancer mortality risk by about 75%, and the incidence of the disease is 7.2/100,000 in the younger age group. But colonoscopy-specific mortality – just having the test – is associated with a death rate of 7/100,000,” Dr. Weinberg pointed out. “Let’s not forget that there is a risk associated with this procedure.” (Gastrointest Endosc. 2011 Oct;74:745-52).

Dr. Weinberg emphasized that everyone wants to reduce the burden of cancer, and models are helpful for that purpose. “They’re obviously thought provoking, but they’re not adequate to drive change without additional evidence of clinical and cost-effectiveness,” he said. “These are important questions that need better data.”

He added that without changing the current screening protocol, “we could certainly emphasize more than ever the impact of family history and IBD on colon cancer risk and colon cancer prevention.”

“And certainly, there’s plenty of evidence that patients with a known family history of colon cancer are not getting screened at the right age or with the right frequency,” Dr. Weinberg concluded. “We can do better. All of us can do better.”

Dr. Weinberg has disclosed relationships with Fujifilm and Exact Sciences. Dr. Ladabaum has disclosed relationships with Lean Medical, Universal Dx, Clinical Genomics, Medtronic, Modus GI, and Quorum Consulting.
 

This article first appeared on Medscape.com.

SAN FRANCISCO – For years, 50 years old has been the age at which screening for colorectal cancer (CRC) began in the United States, but recently, one group lowered the starting age to 45 years.

pixologicstudio/Thinkstock

This move by the American Cancer Society in 2018 was made in reaction to reports of an increase in the incidence of CRC in younger adults.

However, other groups have stayed with the benchmark 50 years. This includes the U.S. Preventive Services Task Force and the National Comprehensive Cancer Network.

Should the age be lowered in view of the mounting reports of an increase in CRC in younger adults? Experts argued both for and against the move here at the 2020 Gastrointestinal Cancers Symposium.

“We’re having this debate because the health of more than 20 million Americans is in the balance,” commented David Weinberg, MD, MSc, chairman of the department of medicine at Fox Chase Cancer Center in Philadelphia. “This is not just an academic discussion.” If the screening age shifts to 5 years earlier, the impact nationally would be about 30,000 colorectal cancers and 11,000 deaths averted.

“It will take about 11 million additional colonoscopies ... and the overall bill would be $10 billion. That’s not a small number, but if the country has the resources and we want to do this, I would say we can,” argued Uri Ladabaum, MD, director of the gastrointestinal cancer prevention program and the clinical chief of the division of gastroenterology and hepatology at Stanford (Calif.) University.

Lower the age

Dr. Ladabaum argued in favor of lowering the age to 45 years to start screening. “In life, 60 may be the new 40, but for colorectal cancer screening, 45 is definitely the new 50,” he said. Anticipating arguments against such a move, he focused on several points.

First, the magnitude of the problem is certainly not small, he noted, pointing to a 2017 study showing that colorectal cancer rates have increased by 1%-2.4% annually since the mid-1980s in persons aged 20-39 years and by 0.5%-1.3% since the mid-1990s in adults aged 40-54 years (J Natl Cancer Inst. 2017;109:djw322). Rectal cancer incidence has been increasing even more rapidly, at a rate of about 3.2% annually during 1974-2013 in adults aged 20-29 years.

Overall, people who were born around 1990 and later have double the risk of colon cancer (incidence rate ratio, 2.40) and quadruple the risk of rectal cancer (IRR, 4.32) as compared with those born circa 1950.

“Thus, 45- to 49-year-olds are beginning to look like yesterday’s 50- to 54-year-olds used to be,” said Dr. Ladabaum.

One issue that has been raised is lead-time bias, with the burning question: Are the cancers found in adults in their 40s simply the same ones that would have eventually been detected in their 50s? Dr. Ladabaum argued that they are not, referencing a 2019 study showing that among persons aged 40 through 49 years, the disease was diagnosed at later stages (JAMA. 2019;321:1933-4).

For those aged 40- 49 years, there was a significant increase in incidence during 1995-2015. The proportion of distant cancers increased significantly (from 21.7% to 26.6%; P less than .001), and the authors of the study had noted that this increase of 4.9% could not be explained by a decrease in unstaged cases. “In the early ’90s and mid-’90s, we began to see an increase in all stages,” Dr. Ladabaum noted. “And the most important thing here is the distant cancers over time. They’ve gone up.” If the only explanation was lead time bias in people aged 40- 49 years, then a person screened and diagnosed with cancer at age 48 would have earlier-stage disease than if it had been found at age 51. “So is this all lead-time bias?” he said. “I think the answer is no.”

Next, Dr. Ladabaum tackled the issue of whether benefit/risk ratio of CRC screening is different among younger vs. older adults. This is difficult to tease out, he suggested, as the data are sparse and there were no controlled studies to date to address that. One study from Taiwan, which looked at the outcomes of fecal immunochemical testing (FIT), showed that in different age groups, the hazard ratio for detecting cancer in those with positive results is higher in younger people vs. older ones (J Clin Gastroenterol. 2016 Oct;50[9]:761-8).

“Indirect evidence shows that if we do a FIT test and it’s positive, it probably means something,” he said. “But is there something magical that at age 50 and older – that it becomes a screenable disease, and through age 49 it’s not screenable? I would say no. Biology is not like this.”

Finally, is it cost effective to start earlier? In a modeling projection published last summer by Dr. Ladabaum and colleagues, starting at 45 years would avert about four colorectal cancers and two colorectal cancer deaths per 1,000 people, and the cohort would gain approximately 14 quality-adjusted life years (Gastroenterology. 2019;157:137-48).

“The incremental cost per quality-adjusted life year gained is highly acceptable,” said Dr. Ladabaum. “This is well within the range of what’s considered cost-effective in the United States – under $35,000 for colonoscopy, and under $8,000 for fecal immunochemical tests.”

Therefore, the answer is yes, it is cost effective, he concluded.

Not so fast ...

Arguing the case against a lowering of the starting age, Dr. Weinberg agreed with Dr. Ladabaum that colon cancer risk for younger people is rising.

That risk has increased from 5.9/100,000 to 7.2/100,000, which is a relative increase of 22%, he noted.

“That is what newspapers will want to put on their headlines to sensationalize it – that the risk of colon cancer for young people is up by over 20%,” said Dr. Weinberg. “But that represents an absolute risk of just 1.3 more people/100,000. Put in some context, 99.9% of people in their 40s will not develop colon cancer.”

This observation was not to “make light of the remainder,” he emphasized, but “the overwhelming majority are not going to get this disease at this age,” he noted.

“It’s also not entirely clear that starting screening at 45 is the right answer,” he added.

“Taken to a somewhat ridiculous extreme,” he continued, “why not start at 40? You’ll catch more people that way, but no one is advocating that.”

A better understanding of the factors contributing to the increased CRC incidence seen in younger adults is very important, he argued, and he suggested that some of it may occur because of screening, along with factors such as obesity, diabetes, and childhood exposures.

Modeling has been done to calculate the risk and benefit of early screening, but while useful for decision making, models are “usually wrong and sit near the bottom of the evidence hierarchy.”

“Models help inform decisions, but they don’t define the standard of care,” Dr. Weinberg said. “No one would vaccinate a population based on a model.”

Dr. Weinberg also emphasized that the new recommendation from the American Cancer Society to start screening at age 45 years is qualified. This means that while “clear evidence of benefit exists,” so does uncertainty about whether “the benefits really outweigh the harms.”

The current evidence for reducing the screening age is not yet clear, he believes, and he questioned the premise that age should be the only criteria for cancer stratification.

Dr. Weinberg cited one study that looked at early-onset colon cancer (ages 18-49 years) and compared it with two groups: patients diagnosed at 50 years and older and matched controls (Clin Gastroenterol Hepatol. 2019;S1542-3565[19]31108-5). Besides age, the study authors identified several nonmodifiable risk factors that were associated with early-onset disease, including sex, race, history of inflammatory bowel disease (IBD), and family history of colorectal cancer.

“Being male was a risk factor and having a family history increased your risk by three times,” said Dr. Weinberg. “And I would note that this study had removed people, at least as best one can, who were known to have syndromic risks of early-onset colon cancer (such as familial adenomatous polyposis.”

Earlier screening (by age 40 years) should already be taking place in people with such syndromes, he commented, as well as those with a known family history and IBD. “Those recommendations were there before the ACS, and we don’t necessarily need another one,” he added.

To make things a little more confusing, a second recent study, using National Cancer Data Base data from 2004 to 2015, identified another set of factors associated with colon cancer in younger adults (Cancer. 2019 Nov 1;125:3828-35). This study showed diagnosis younger than 50 years rose only in non-Hispanic white men, in Hispanic and non-Hispanic white women, and in those living in urban vs. rural areas.

“But it gets more interesting,” Dr. Weinberg pointed out. “Risk increased over time for people in the highest zip code income quartile and those with private insurance, and risk was lower for people with Medicaid and no insurance at all,” he noted. “Well, that smacks of access to me,” he commented.

Another issue is the possibility of lead-time bias. During 1975-2015, incidence rose over time, according to Surveillance, Epidemiology, and End Results data (J Natl Cancer Inst. 2017 Aug;109:djw322). Screening of persons younger than age 49 years also more than doubled, from a low level in 2000 of about 6% to more than 15% by 2010. As screening increases, the incidence increases, Dr. Weinberg pointed out. “But mortality doesn’t change. And despite what Dr. Ladabaum said a moment ago about lead-time bias, that is textbook lead-time bias in any epidemiology study.”

Finally, it is essential to carefully weigh the benefit against the risk, Dr. Weinberg said.

A core principle of population screening is to create more future health benefits than harms, and if the screening age is lowered, several million additional colonoscopies will be performed.

Colonoscopy reduces the colorectal cancer mortality risk by about 75%, and the incidence of the disease is 7.2/100,000 in the younger age group. But colonoscopy-specific mortality – just having the test – is associated with a death rate of 7/100,000,” Dr. Weinberg pointed out. “Let’s not forget that there is a risk associated with this procedure.” (Gastrointest Endosc. 2011 Oct;74:745-52).

Dr. Weinberg emphasized that everyone wants to reduce the burden of cancer, and models are helpful for that purpose. “They’re obviously thought provoking, but they’re not adequate to drive change without additional evidence of clinical and cost-effectiveness,” he said. “These are important questions that need better data.”

He added that without changing the current screening protocol, “we could certainly emphasize more than ever the impact of family history and IBD on colon cancer risk and colon cancer prevention.”

“And certainly, there’s plenty of evidence that patients with a known family history of colon cancer are not getting screened at the right age or with the right frequency,” Dr. Weinberg concluded. “We can do better. All of us can do better.”

Dr. Weinberg has disclosed relationships with Fujifilm and Exact Sciences. Dr. Ladabaum has disclosed relationships with Lean Medical, Universal Dx, Clinical Genomics, Medtronic, Modus GI, and Quorum Consulting.
 

This article first appeared on Medscape.com.

SAN FRANCISCO – For years, 50 years old has been the age at which screening for colorectal cancer (CRC) began in the United States, but recently, one group lowered the starting age to 45 years.

pixologicstudio/Thinkstock

This move by the American Cancer Society in 2018 was made in reaction to reports of an increase in the incidence of CRC in younger adults.

However, other groups have stayed with the benchmark 50 years. This includes the U.S. Preventive Services Task Force and the National Comprehensive Cancer Network.

Should the age be lowered in view of the mounting reports of an increase in CRC in younger adults? Experts argued both for and against the move here at the 2020 Gastrointestinal Cancers Symposium.

“We’re having this debate because the health of more than 20 million Americans is in the balance,” commented David Weinberg, MD, MSc, chairman of the department of medicine at Fox Chase Cancer Center in Philadelphia. “This is not just an academic discussion.” If the screening age shifts to 5 years earlier, the impact nationally would be about 30,000 colorectal cancers and 11,000 deaths averted.

“It will take about 11 million additional colonoscopies ... and the overall bill would be $10 billion. That’s not a small number, but if the country has the resources and we want to do this, I would say we can,” argued Uri Ladabaum, MD, director of the gastrointestinal cancer prevention program and the clinical chief of the division of gastroenterology and hepatology at Stanford (Calif.) University.

Lower the age

Dr. Ladabaum argued in favor of lowering the age to 45 years to start screening. “In life, 60 may be the new 40, but for colorectal cancer screening, 45 is definitely the new 50,” he said. Anticipating arguments against such a move, he focused on several points.

First, the magnitude of the problem is certainly not small, he noted, pointing to a 2017 study showing that colorectal cancer rates have increased by 1%-2.4% annually since the mid-1980s in persons aged 20-39 years and by 0.5%-1.3% since the mid-1990s in adults aged 40-54 years (J Natl Cancer Inst. 2017;109:djw322). Rectal cancer incidence has been increasing even more rapidly, at a rate of about 3.2% annually during 1974-2013 in adults aged 20-29 years.

Overall, people who were born around 1990 and later have double the risk of colon cancer (incidence rate ratio, 2.40) and quadruple the risk of rectal cancer (IRR, 4.32) as compared with those born circa 1950.

“Thus, 45- to 49-year-olds are beginning to look like yesterday’s 50- to 54-year-olds used to be,” said Dr. Ladabaum.

One issue that has been raised is lead-time bias, with the burning question: Are the cancers found in adults in their 40s simply the same ones that would have eventually been detected in their 50s? Dr. Ladabaum argued that they are not, referencing a 2019 study showing that among persons aged 40 through 49 years, the disease was diagnosed at later stages (JAMA. 2019;321:1933-4).

For those aged 40- 49 years, there was a significant increase in incidence during 1995-2015. The proportion of distant cancers increased significantly (from 21.7% to 26.6%; P less than .001), and the authors of the study had noted that this increase of 4.9% could not be explained by a decrease in unstaged cases. “In the early ’90s and mid-’90s, we began to see an increase in all stages,” Dr. Ladabaum noted. “And the most important thing here is the distant cancers over time. They’ve gone up.” If the only explanation was lead time bias in people aged 40- 49 years, then a person screened and diagnosed with cancer at age 48 would have earlier-stage disease than if it had been found at age 51. “So is this all lead-time bias?” he said. “I think the answer is no.”

Next, Dr. Ladabaum tackled the issue of whether benefit/risk ratio of CRC screening is different among younger vs. older adults. This is difficult to tease out, he suggested, as the data are sparse and there were no controlled studies to date to address that. One study from Taiwan, which looked at the outcomes of fecal immunochemical testing (FIT), showed that in different age groups, the hazard ratio for detecting cancer in those with positive results is higher in younger people vs. older ones (J Clin Gastroenterol. 2016 Oct;50[9]:761-8).

“Indirect evidence shows that if we do a FIT test and it’s positive, it probably means something,” he said. “But is there something magical that at age 50 and older – that it becomes a screenable disease, and through age 49 it’s not screenable? I would say no. Biology is not like this.”

Finally, is it cost effective to start earlier? In a modeling projection published last summer by Dr. Ladabaum and colleagues, starting at 45 years would avert about four colorectal cancers and two colorectal cancer deaths per 1,000 people, and the cohort would gain approximately 14 quality-adjusted life years (Gastroenterology. 2019;157:137-48).

“The incremental cost per quality-adjusted life year gained is highly acceptable,” said Dr. Ladabaum. “This is well within the range of what’s considered cost-effective in the United States – under $35,000 for colonoscopy, and under $8,000 for fecal immunochemical tests.”

Therefore, the answer is yes, it is cost effective, he concluded.

Not so fast ...

Arguing the case against a lowering of the starting age, Dr. Weinberg agreed with Dr. Ladabaum that colon cancer risk for younger people is rising.

That risk has increased from 5.9/100,000 to 7.2/100,000, which is a relative increase of 22%, he noted.

“That is what newspapers will want to put on their headlines to sensationalize it – that the risk of colon cancer for young people is up by over 20%,” said Dr. Weinberg. “But that represents an absolute risk of just 1.3 more people/100,000. Put in some context, 99.9% of people in their 40s will not develop colon cancer.”

This observation was not to “make light of the remainder,” he emphasized, but “the overwhelming majority are not going to get this disease at this age,” he noted.

“It’s also not entirely clear that starting screening at 45 is the right answer,” he added.

“Taken to a somewhat ridiculous extreme,” he continued, “why not start at 40? You’ll catch more people that way, but no one is advocating that.”

A better understanding of the factors contributing to the increased CRC incidence seen in younger adults is very important, he argued, and he suggested that some of it may occur because of screening, along with factors such as obesity, diabetes, and childhood exposures.

Modeling has been done to calculate the risk and benefit of early screening, but while useful for decision making, models are “usually wrong and sit near the bottom of the evidence hierarchy.”

“Models help inform decisions, but they don’t define the standard of care,” Dr. Weinberg said. “No one would vaccinate a population based on a model.”

Dr. Weinberg also emphasized that the new recommendation from the American Cancer Society to start screening at age 45 years is qualified. This means that while “clear evidence of benefit exists,” so does uncertainty about whether “the benefits really outweigh the harms.”

The current evidence for reducing the screening age is not yet clear, he believes, and he questioned the premise that age should be the only criteria for cancer stratification.

Dr. Weinberg cited one study that looked at early-onset colon cancer (ages 18-49 years) and compared it with two groups: patients diagnosed at 50 years and older and matched controls (Clin Gastroenterol Hepatol. 2019;S1542-3565[19]31108-5). Besides age, the study authors identified several nonmodifiable risk factors that were associated with early-onset disease, including sex, race, history of inflammatory bowel disease (IBD), and family history of colorectal cancer.

“Being male was a risk factor and having a family history increased your risk by three times,” said Dr. Weinberg. “And I would note that this study had removed people, at least as best one can, who were known to have syndromic risks of early-onset colon cancer (such as familial adenomatous polyposis.”

Earlier screening (by age 40 years) should already be taking place in people with such syndromes, he commented, as well as those with a known family history and IBD. “Those recommendations were there before the ACS, and we don’t necessarily need another one,” he added.

To make things a little more confusing, a second recent study, using National Cancer Data Base data from 2004 to 2015, identified another set of factors associated with colon cancer in younger adults (Cancer. 2019 Nov 1;125:3828-35). This study showed diagnosis younger than 50 years rose only in non-Hispanic white men, in Hispanic and non-Hispanic white women, and in those living in urban vs. rural areas.

“But it gets more interesting,” Dr. Weinberg pointed out. “Risk increased over time for people in the highest zip code income quartile and those with private insurance, and risk was lower for people with Medicaid and no insurance at all,” he noted. “Well, that smacks of access to me,” he commented.

Another issue is the possibility of lead-time bias. During 1975-2015, incidence rose over time, according to Surveillance, Epidemiology, and End Results data (J Natl Cancer Inst. 2017 Aug;109:djw322). Screening of persons younger than age 49 years also more than doubled, from a low level in 2000 of about 6% to more than 15% by 2010. As screening increases, the incidence increases, Dr. Weinberg pointed out. “But mortality doesn’t change. And despite what Dr. Ladabaum said a moment ago about lead-time bias, that is textbook lead-time bias in any epidemiology study.”

Finally, it is essential to carefully weigh the benefit against the risk, Dr. Weinberg said.

A core principle of population screening is to create more future health benefits than harms, and if the screening age is lowered, several million additional colonoscopies will be performed.

Colonoscopy reduces the colorectal cancer mortality risk by about 75%, and the incidence of the disease is 7.2/100,000 in the younger age group. But colonoscopy-specific mortality – just having the test – is associated with a death rate of 7/100,000,” Dr. Weinberg pointed out. “Let’s not forget that there is a risk associated with this procedure.” (Gastrointest Endosc. 2011 Oct;74:745-52).

Dr. Weinberg emphasized that everyone wants to reduce the burden of cancer, and models are helpful for that purpose. “They’re obviously thought provoking, but they’re not adequate to drive change without additional evidence of clinical and cost-effectiveness,” he said. “These are important questions that need better data.”

He added that without changing the current screening protocol, “we could certainly emphasize more than ever the impact of family history and IBD on colon cancer risk and colon cancer prevention.”

“And certainly, there’s plenty of evidence that patients with a known family history of colon cancer are not getting screened at the right age or with the right frequency,” Dr. Weinberg concluded. “We can do better. All of us can do better.”

Dr. Weinberg has disclosed relationships with Fujifilm and Exact Sciences. Dr. Ladabaum has disclosed relationships with Lean Medical, Universal Dx, Clinical Genomics, Medtronic, Modus GI, and Quorum Consulting.
 

This article first appeared on Medscape.com.

SAN FRANCISCO – Use of FDG-PET early in the course of chemotherapy can identify men with low-volume seminoma who have highly chemosensitive disease, enabling them to safely skip the standard chemotherapy regimen with its toxicity. This was among key findings of the phase 2 SEMITEP trial reported at the 2020 Genitourinary Cancers Symposium.

Susan London/MDedge News

Although four cycles of etoposide-cisplatin cure almost all cases of good-prognosis metastatic seminoma (Eur Urol. 2014;65:381-6), long-term cisplatin toxicity in this predominantly young population remains problematic, noted lead investigator Yohann Loriot, MD, PhD, a medical oncologist at Gustave Roussy Institute, Villejuif, France.

In SEMITEP, he and his colleagues tested a risk-adapted strategy among 98 patients with metastatic seminoma who met International Germ Cell Cancer Collaboration Group criteria for good prognosis and had not received any chemotherapy or radiotherapy.

Fully 68.4% had a negative FDG-PET result after two cycles of etoposide-cisplatin and were given only one cycle of carboplatin to complete treatment (based on that drug’s activity in low-volume disease), Dr. Loriot reported. The rest went on to receive an additional two cycles of etoposide-cisplatin, completing the standard regimen.

At 3 years, 9 in 10 patients were alive and free of progression in both the deescalated chemotherapy group and the standard chemotherapy group. The cumulative incidence of peripheral neuropathy, however, was about 10 times higher in the standard chemotherapy group.

“Deescalating chemotherapy based on an early FDG-PET is safe and feasible in metastatic seminoma,” Dr. Loriot said. “This strategy provides shorter treatment, reduces neuropathy, and eliminates need for bleomycin and its associated toxicity. SEMITEP supports the deescalating strategy in metastatic seminoma.”

Ready for prime time?

The SEMITEP trial achieved the main goal of reducing toxicity but had several noteworthy caveats, according to invited discussant Peter Albers, MD, professor and chairman of the department of urology, Heinrich-Heine University Düsseldorf, Germany.

Susan London/MDedge News

First, in an “astonishing” feat, FDG-PET was performed and evaluable after just two cycles of chemotherapy, or 3 weeks, when typical practice is to wait until 8 or 10 weeks, he said.

“Second, I really don’t understand why carboplatin was given in an FDG-PET–negative seminoma,” Dr. Albers said. “There is, in my view, no reason to add another chemotherapy agent to this patient population if you really claim this to be a biomarker. Carboplatin is known to be inferior to cisplatin in metastatic seminoma.”

Third, enrolled patients predominantly had low-volume disease, with about two-thirds having clinical stage IIA or IIB. “So this study is not representative for all metastatic seminoma patients,” Dr. Albers cautioned. “But obviously, it gives a good signal, and those patients who had IIC disease in the deescalation arm have shown no recurrences so far.

“This trial is important and obviously accurately done, but to my mind, it’s not yet practice-changing. We need a clear comparison to standard treatment before we introduce FDG-PET as a biomarker in this indication,” he concluded, recommending that, for now, risk-stratified approaches should be limited to clinical trials.

Study details

Although 72% of patients in SEMITEP had a negative early FDG-PET result, four of them requested standard chemotherapy anyway and were analyzed in that group, Dr. Loriot noted at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

With a median follow-up of 33.9 months, the 36-month rate of progression-free survival was 89.9% in the deescalated chemotherapy group, essentially the same as the 90% in the standard chemotherapy group. There were no deaths during follow-up in either group.

During chemotherapy, the deescalation group had lower rates of grade 3 or 4 nausea and vomiting and ototoxicity, and a higher rate of grade 3 or 4 thrombocytopenia.

At 3 years, the cumulative incidence of any-grade peripheral neuropathy was less than 5% in the deescalated chemotherapy group, compared with about 50% in the standard chemotherapy group (P less than .001). There was also a trend toward a lower incidence of ototoxicity with deescalation.

The trial was funded by Institut National du Cancer (Programme Hospitalier de Recherche Clinique). Dr. Loriot disclosed no relevant conflicts of interest. Dr. Albers disclosed relationships with Sanofi, Roche, and Merck Sharp & Dohme Corp.

SOURCE: Loriot Y et al. GUCS 2020. Abstract 387.

SAN FRANCISCO – Use of FDG-PET early in the course of chemotherapy can identify men with low-volume seminoma who have highly chemosensitive disease, enabling them to safely skip the standard chemotherapy regimen with its toxicity. This was among key findings of the phase 2 SEMITEP trial reported at the 2020 Genitourinary Cancers Symposium.

Susan London/MDedge News

Although four cycles of etoposide-cisplatin cure almost all cases of good-prognosis metastatic seminoma (Eur Urol. 2014;65:381-6), long-term cisplatin toxicity in this predominantly young population remains problematic, noted lead investigator Yohann Loriot, MD, PhD, a medical oncologist at Gustave Roussy Institute, Villejuif, France.

In SEMITEP, he and his colleagues tested a risk-adapted strategy among 98 patients with metastatic seminoma who met International Germ Cell Cancer Collaboration Group criteria for good prognosis and had not received any chemotherapy or radiotherapy.

Fully 68.4% had a negative FDG-PET result after two cycles of etoposide-cisplatin and were given only one cycle of carboplatin to complete treatment (based on that drug’s activity in low-volume disease), Dr. Loriot reported. The rest went on to receive an additional two cycles of etoposide-cisplatin, completing the standard regimen.

At 3 years, 9 in 10 patients were alive and free of progression in both the deescalated chemotherapy group and the standard chemotherapy group. The cumulative incidence of peripheral neuropathy, however, was about 10 times higher in the standard chemotherapy group.

“Deescalating chemotherapy based on an early FDG-PET is safe and feasible in metastatic seminoma,” Dr. Loriot said. “This strategy provides shorter treatment, reduces neuropathy, and eliminates need for bleomycin and its associated toxicity. SEMITEP supports the deescalating strategy in metastatic seminoma.”

Ready for prime time?

The SEMITEP trial achieved the main goal of reducing toxicity but had several noteworthy caveats, according to invited discussant Peter Albers, MD, professor and chairman of the department of urology, Heinrich-Heine University Düsseldorf, Germany.

Susan London/MDedge News

First, in an “astonishing” feat, FDG-PET was performed and evaluable after just two cycles of chemotherapy, or 3 weeks, when typical practice is to wait until 8 or 10 weeks, he said.

“Second, I really don’t understand why carboplatin was given in an FDG-PET–negative seminoma,” Dr. Albers said. “There is, in my view, no reason to add another chemotherapy agent to this patient population if you really claim this to be a biomarker. Carboplatin is known to be inferior to cisplatin in metastatic seminoma.”

Third, enrolled patients predominantly had low-volume disease, with about two-thirds having clinical stage IIA or IIB. “So this study is not representative for all metastatic seminoma patients,” Dr. Albers cautioned. “But obviously, it gives a good signal, and those patients who had IIC disease in the deescalation arm have shown no recurrences so far.

“This trial is important and obviously accurately done, but to my mind, it’s not yet practice-changing. We need a clear comparison to standard treatment before we introduce FDG-PET as a biomarker in this indication,” he concluded, recommending that, for now, risk-stratified approaches should be limited to clinical trials.

Study details

Although 72% of patients in SEMITEP had a negative early FDG-PET result, four of them requested standard chemotherapy anyway and were analyzed in that group, Dr. Loriot noted at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

With a median follow-up of 33.9 months, the 36-month rate of progression-free survival was 89.9% in the deescalated chemotherapy group, essentially the same as the 90% in the standard chemotherapy group. There were no deaths during follow-up in either group.

During chemotherapy, the deescalation group had lower rates of grade 3 or 4 nausea and vomiting and ototoxicity, and a higher rate of grade 3 or 4 thrombocytopenia.

At 3 years, the cumulative incidence of any-grade peripheral neuropathy was less than 5% in the deescalated chemotherapy group, compared with about 50% in the standard chemotherapy group (P less than .001). There was also a trend toward a lower incidence of ototoxicity with deescalation.

The trial was funded by Institut National du Cancer (Programme Hospitalier de Recherche Clinique). Dr. Loriot disclosed no relevant conflicts of interest. Dr. Albers disclosed relationships with Sanofi, Roche, and Merck Sharp & Dohme Corp.

SOURCE: Loriot Y et al. GUCS 2020. Abstract 387.

SAN FRANCISCO – Use of FDG-PET early in the course of chemotherapy can identify men with low-volume seminoma who have highly chemosensitive disease, enabling them to safely skip the standard chemotherapy regimen with its toxicity. This was among key findings of the phase 2 SEMITEP trial reported at the 2020 Genitourinary Cancers Symposium.

Susan London/MDedge News

Although four cycles of etoposide-cisplatin cure almost all cases of good-prognosis metastatic seminoma (Eur Urol. 2014;65:381-6), long-term cisplatin toxicity in this predominantly young population remains problematic, noted lead investigator Yohann Loriot, MD, PhD, a medical oncologist at Gustave Roussy Institute, Villejuif, France.

In SEMITEP, he and his colleagues tested a risk-adapted strategy among 98 patients with metastatic seminoma who met International Germ Cell Cancer Collaboration Group criteria for good prognosis and had not received any chemotherapy or radiotherapy.

Fully 68.4% had a negative FDG-PET result after two cycles of etoposide-cisplatin and were given only one cycle of carboplatin to complete treatment (based on that drug’s activity in low-volume disease), Dr. Loriot reported. The rest went on to receive an additional two cycles of etoposide-cisplatin, completing the standard regimen.

At 3 years, 9 in 10 patients were alive and free of progression in both the deescalated chemotherapy group and the standard chemotherapy group. The cumulative incidence of peripheral neuropathy, however, was about 10 times higher in the standard chemotherapy group.

“Deescalating chemotherapy based on an early FDG-PET is safe and feasible in metastatic seminoma,” Dr. Loriot said. “This strategy provides shorter treatment, reduces neuropathy, and eliminates need for bleomycin and its associated toxicity. SEMITEP supports the deescalating strategy in metastatic seminoma.”

Ready for prime time?

The SEMITEP trial achieved the main goal of reducing toxicity but had several noteworthy caveats, according to invited discussant Peter Albers, MD, professor and chairman of the department of urology, Heinrich-Heine University Düsseldorf, Germany.

Susan London/MDedge News

First, in an “astonishing” feat, FDG-PET was performed and evaluable after just two cycles of chemotherapy, or 3 weeks, when typical practice is to wait until 8 or 10 weeks, he said.

“Second, I really don’t understand why carboplatin was given in an FDG-PET–negative seminoma,” Dr. Albers said. “There is, in my view, no reason to add another chemotherapy agent to this patient population if you really claim this to be a biomarker. Carboplatin is known to be inferior to cisplatin in metastatic seminoma.”

Third, enrolled patients predominantly had low-volume disease, with about two-thirds having clinical stage IIA or IIB. “So this study is not representative for all metastatic seminoma patients,” Dr. Albers cautioned. “But obviously, it gives a good signal, and those patients who had IIC disease in the deescalation arm have shown no recurrences so far.

“This trial is important and obviously accurately done, but to my mind, it’s not yet practice-changing. We need a clear comparison to standard treatment before we introduce FDG-PET as a biomarker in this indication,” he concluded, recommending that, for now, risk-stratified approaches should be limited to clinical trials.

Study details

Although 72% of patients in SEMITEP had a negative early FDG-PET result, four of them requested standard chemotherapy anyway and were analyzed in that group, Dr. Loriot noted at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

With a median follow-up of 33.9 months, the 36-month rate of progression-free survival was 89.9% in the deescalated chemotherapy group, essentially the same as the 90% in the standard chemotherapy group. There were no deaths during follow-up in either group.

During chemotherapy, the deescalation group had lower rates of grade 3 or 4 nausea and vomiting and ototoxicity, and a higher rate of grade 3 or 4 thrombocytopenia.

At 3 years, the cumulative incidence of any-grade peripheral neuropathy was less than 5% in the deescalated chemotherapy group, compared with about 50% in the standard chemotherapy group (P less than .001). There was also a trend toward a lower incidence of ototoxicity with deescalation.

The trial was funded by Institut National du Cancer (Programme Hospitalier de Recherche Clinique). Dr. Loriot disclosed no relevant conflicts of interest. Dr. Albers disclosed relationships with Sanofi, Roche, and Merck Sharp & Dohme Corp.

SOURCE: Loriot Y et al. GUCS 2020. Abstract 387.

Psoriasis patients are at increased risk for several types of cancer, notably lymphoma and keratinocyte cancer, based on data from a systematic review and meta-analysis of more than 2 million patients.

Previous studies have identified an increased overall cancer risk in psoriasis patients, compared with the general population or controls without psoriasis, and both lymphomas and keratinocyte cancers occur more often in psoriasis patients, compared with controls, but additional larger studies have been conducted since the last meta-analysis was published in 2013, wrote Sofie Vaengebjerg, MD, of the University of Copenhagen and colleagues.

To better identify the risk of cancer in psoriasis and psoriatic arthritis patients and to explore the impact of biologics, the researchers reviewed data from 112 studies totaling 2,053,932 patients in a study published in JAMA Dermatology.

Overall, the risk of any cancer was slightly higher in psoriasis patients (risk ratio, 1.21; 95% confidence interval, 1.11-1.33), compared with controls, with a prevalence of 4.78% and an incidence rate of 11.75 per 1,000 person-years. The most common cancer among psoriasis patients was keratinocyte cancer, with a risk ratio of 2.28 (95% CI, 1.73-3.01), a prevalence of 2.55%, and an incidence rate of 4.35 per 1,000 person-years.

Other cancers with significantly elevated risk among psoriasis patients were lymphomas (RR, 1.56; 95% CI, 1.37-1.78), lung cancer (RR, 1.26; 95% CI, 1.13-1.40), and bladder cancer (RR, 1.12; 95% CI, 1.04-1.19).

No increased risk of cancer was noted among psoriasis patients who were treated with biologics. “However, patients receiving biologic agents are selected and the results might be reliant on selection bias, and studies investigating long-term safety of these drugs are still limited,” the researchers wrote.

In addition, psoriatic arthritis was not associated with any overall increase in cancer risk, with the exception of three studies showing an increased risk for breast cancer, the researchers noted. The overall cancer prevalence for psoriatic arthritis patients was 5.74%, with an incidence rate of 6.44 per 1,000 person-years.

The study findings were limited by several factors, including the inconsistencies in study design and characteristics and the small amount of data on biologic agents and psoriatic arthritis, the researchers noted. However, the results were strengthened by the large number of patients, real-world study settings, inclusion of biologics, and analysis of cancer in psoriatic arthritis patients.

“Clinicians treating patients with psoriasis should be aware of this increased risk, especially for lymphomas, as immunogenic treatment might be associated with exacerbations,” and should be aware that more research is needed to assess cancer risk associated with biologics, they concluded.

The study received no outside funding. Lead author Dr. Vaengebjerg had no financial conflicts to disclose. Several coauthors disclosed relationships with multiple companies, including AbbVie, Janssen, Novartis, Eli Lilly, LEO Pharma, UCB, Almirall, and Sanofi.

SOURCE: Vaengebjerg S et al. JAMA Dermatol. 2020 Feb 19. doi:10.1001/jamadermatol.2020.0024.

Psoriasis patients are at increased risk for several types of cancer, notably lymphoma and keratinocyte cancer, based on data from a systematic review and meta-analysis of more than 2 million patients.

Previous studies have identified an increased overall cancer risk in psoriasis patients, compared with the general population or controls without psoriasis, and both lymphomas and keratinocyte cancers occur more often in psoriasis patients, compared with controls, but additional larger studies have been conducted since the last meta-analysis was published in 2013, wrote Sofie Vaengebjerg, MD, of the University of Copenhagen and colleagues.

To better identify the risk of cancer in psoriasis and psoriatic arthritis patients and to explore the impact of biologics, the researchers reviewed data from 112 studies totaling 2,053,932 patients in a study published in JAMA Dermatology.

Overall, the risk of any cancer was slightly higher in psoriasis patients (risk ratio, 1.21; 95% confidence interval, 1.11-1.33), compared with controls, with a prevalence of 4.78% and an incidence rate of 11.75 per 1,000 person-years. The most common cancer among psoriasis patients was keratinocyte cancer, with a risk ratio of 2.28 (95% CI, 1.73-3.01), a prevalence of 2.55%, and an incidence rate of 4.35 per 1,000 person-years.

Other cancers with significantly elevated risk among psoriasis patients were lymphomas (RR, 1.56; 95% CI, 1.37-1.78), lung cancer (RR, 1.26; 95% CI, 1.13-1.40), and bladder cancer (RR, 1.12; 95% CI, 1.04-1.19).

No increased risk of cancer was noted among psoriasis patients who were treated with biologics. “However, patients receiving biologic agents are selected and the results might be reliant on selection bias, and studies investigating long-term safety of these drugs are still limited,” the researchers wrote.

In addition, psoriatic arthritis was not associated with any overall increase in cancer risk, with the exception of three studies showing an increased risk for breast cancer, the researchers noted. The overall cancer prevalence for psoriatic arthritis patients was 5.74%, with an incidence rate of 6.44 per 1,000 person-years.

The study findings were limited by several factors, including the inconsistencies in study design and characteristics and the small amount of data on biologic agents and psoriatic arthritis, the researchers noted. However, the results were strengthened by the large number of patients, real-world study settings, inclusion of biologics, and analysis of cancer in psoriatic arthritis patients.

“Clinicians treating patients with psoriasis should be aware of this increased risk, especially for lymphomas, as immunogenic treatment might be associated with exacerbations,” and should be aware that more research is needed to assess cancer risk associated with biologics, they concluded.

The study received no outside funding. Lead author Dr. Vaengebjerg had no financial conflicts to disclose. Several coauthors disclosed relationships with multiple companies, including AbbVie, Janssen, Novartis, Eli Lilly, LEO Pharma, UCB, Almirall, and Sanofi.

SOURCE: Vaengebjerg S et al. JAMA Dermatol. 2020 Feb 19. doi:10.1001/jamadermatol.2020.0024.

Psoriasis patients are at increased risk for several types of cancer, notably lymphoma and keratinocyte cancer, based on data from a systematic review and meta-analysis of more than 2 million patients.

Previous studies have identified an increased overall cancer risk in psoriasis patients, compared with the general population or controls without psoriasis, and both lymphomas and keratinocyte cancers occur more often in psoriasis patients, compared with controls, but additional larger studies have been conducted since the last meta-analysis was published in 2013, wrote Sofie Vaengebjerg, MD, of the University of Copenhagen and colleagues.

To better identify the risk of cancer in psoriasis and psoriatic arthritis patients and to explore the impact of biologics, the researchers reviewed data from 112 studies totaling 2,053,932 patients in a study published in JAMA Dermatology.

Overall, the risk of any cancer was slightly higher in psoriasis patients (risk ratio, 1.21; 95% confidence interval, 1.11-1.33), compared with controls, with a prevalence of 4.78% and an incidence rate of 11.75 per 1,000 person-years. The most common cancer among psoriasis patients was keratinocyte cancer, with a risk ratio of 2.28 (95% CI, 1.73-3.01), a prevalence of 2.55%, and an incidence rate of 4.35 per 1,000 person-years.

Other cancers with significantly elevated risk among psoriasis patients were lymphomas (RR, 1.56; 95% CI, 1.37-1.78), lung cancer (RR, 1.26; 95% CI, 1.13-1.40), and bladder cancer (RR, 1.12; 95% CI, 1.04-1.19).

No increased risk of cancer was noted among psoriasis patients who were treated with biologics. “However, patients receiving biologic agents are selected and the results might be reliant on selection bias, and studies investigating long-term safety of these drugs are still limited,” the researchers wrote.

In addition, psoriatic arthritis was not associated with any overall increase in cancer risk, with the exception of three studies showing an increased risk for breast cancer, the researchers noted. The overall cancer prevalence for psoriatic arthritis patients was 5.74%, with an incidence rate of 6.44 per 1,000 person-years.

The study findings were limited by several factors, including the inconsistencies in study design and characteristics and the small amount of data on biologic agents and psoriatic arthritis, the researchers noted. However, the results were strengthened by the large number of patients, real-world study settings, inclusion of biologics, and analysis of cancer in psoriatic arthritis patients.

“Clinicians treating patients with psoriasis should be aware of this increased risk, especially for lymphomas, as immunogenic treatment might be associated with exacerbations,” and should be aware that more research is needed to assess cancer risk associated with biologics, they concluded.

The study received no outside funding. Lead author Dr. Vaengebjerg had no financial conflicts to disclose. Several coauthors disclosed relationships with multiple companies, including AbbVie, Janssen, Novartis, Eli Lilly, LEO Pharma, UCB, Almirall, and Sanofi.

SOURCE: Vaengebjerg S et al. JAMA Dermatol. 2020 Feb 19. doi:10.1001/jamadermatol.2020.0024.