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In this edition of “How I Will Treat My Next Patient,” I highlight the potential role of new models for predicting risks of common, clinically important situations in general oncology practice: severe neutropenia in lung cancer patients and locoregional recurrence of breast cancer.
Predicting neutropenia
Accurate, lung cancer–specific prediction models would be useful to estimate risk of chemotherapy-induced neutropenia (CIN), especially febrile neutropenia (FN), since that particular toxicity is linked to infection, dose delays and dose reductions that can compromise treatment efficacy, and poor health-related quality of life. Lung cancer patients are often older adults, with advanced disease and comorbid conditions, so they are a particularly vulnerable population for CIN.
Xiaowen Cao of Duke University, Durham, N.C., and coinvestigators published a model for predicting risk of severe CIN in advanced lung cancer patients, based on 10 pretreatment variables (Lung Cancer. 2020 Jan 5. doi: 10.1016/j.lungcan.2020.01.004). They developed their model to overcome limitations of the previously published work of Gary H. Lyman, MD, and colleagues that is not specific to lung cancer and incorporated relative dose intensity as a predictor (Cancer. 2011;117:1917-27). Relative dose intensity is not determined until after a treatment course is completed.
The new prediction model was based on a lung cancer data set encompassing 11,352 patients from 67 phase 2-3 cooperative group studies conducted between 1991 and 2010. In this data set, the Lyman model had an area under the curve of 0.8772 in patients with small cell lung cancer, but an area under the curve of just 0.6787 in non–small cell lung cancer.
The derivation model was derived from about two-thirds of the patients, randomly selected. The validation set was conducted using the remaining third. The variables included were readily clinically available: age, gender, weight, body mass index, insurance status, disease stage, number of metastatic sites, chemotherapy agents used, number of chemotherapy agents, planned growth factor use, duration of planned therapy, pleural effusion, presence of symptoms, and performance status. Their model had an area under the curve of 0.8348 in the training set and 0.8234 in the testing set.
How these results influence practice
The risk of an initial episode of FN is highest during a patient’s initial cycle of chemotherapy, when most patients are receiving full-dose treatment, often without prophylactic measures. Guidelines from the National Comprehensive Cancer Network suggest the use of prophylactic growth factors in patients with more than a 20% risk of FN, and considering using prophylaxis in patients with 10%-20% risk of FN. Underestimating those risks and failure to take adequate precautions may be particularly important for patients with lung cancer who are generally older adults, with comorbid conditions.
The comprehensive risk model for neutropenic complications that was developed by Dr. Lyman and colleagues was based on a large, prospective cohort including nearly 3,800 patients. The model had a 90% sensitivity and 96% predictive value, but was not lung cancer specific and, in this latest study, did not perform as well in the 85% of lung cancer patients with non–small cell lung cancer. The Lyman data, however, was obtained in cancer patients treated with investigator-choice chemotherapy in community practices. It remains the National Comprehensive Cancer Network standard for evaluating FN risk in patients embarking on chemotherapy for advanced malignancies. That should remain the case, pending the additional validation testing of the new lung cancer–specific model at independent institutions, treating heterogeneous patients in real-world settings.
Locoregional recurrence
A retrospective cohort analysis of SWOG 8814, a phase 3 study of tamoxifen alone versus chemotherapy plus by tamoxifen in postmenopausal, node-positive, hormone receptor–positive breast cancer patients suggests that the 21-gene assay recurrence score (RS) can aid decisions about radiotherapy (RT).
Wendy A. Woodward, MD, PhD, and colleagues, analyzed patients who underwent mastectomy or breast-conserving surgery as their local therapy (JAMA Oncol. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5559). They found that patients with an intermediate or high RS – according to the 21-gene assay OncotypeDX – had more locoregional recurrences (LRR; breast, chest wall, axilla, internal mammary, supraclavicular or infraclavicular nodes).
There were 367 patients in SWOG 8814 who received tamoxifen alone or cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen. LRR was observed in 5.8% of patients with a low RS (less than 18) and in 13.8% of patients with an intermediate or high RS (more than 18). The estimated 10-year cumulative LRR incidence rates were 9.7% and 16.5%, respectively (P = .02).
In the subset of patients with one to three positive nodes who had mastectomy without radiotherapy, the LRR was 1.5% for those with low RS and 11.1% for those with intermediate or high RS (P = .051). No difference by RS was found in the 10-year rates of LRR among patients with four or more involved nodes who received a mastectomy without RT (25.9% vs. 27.0%; P = .27).
In multivariate analysis, incorporating RS, type of surgery, and number of involved nodes, intermediate or high RS was a significant predictor of LRR, with a hazard ratio of 2.36 (P = .04). The investigators suggested that RS, when available, should be one of the factors considered in selecting patients for postmastectomy RT.
How these results influence practice
Selecting the node-positive, hormone receptor–positive, breast cancer patients who should receive postmastectomy RT is difficult and controversial. This is particularly true for those postmenopausal patients with fewer than four involved nodes, no lymphatic or vascular invasion, and no extracapsular spread of disease into the axillary fat. Limited information exists on the ability of genomic assays to identify LRR risk.
Eleftherios P. Mamounas, MD, and colleagues examined the results of NSABP B-28, a trial of chemotherapy plus tamoxifen (J Natl Cancer Inst. 2017;109[4]. doi:10.1093/jnci/djw259). Postmastectomy RT was not permitted. They found high RS correlated with greater LRR and low RS with decreased LRR among patients with one to three positive nodes. At first blush, the prospectively treated cohort of SWOG 8814 represents a uniformly treated cohort with long-term follow-up (median, 8.5 years) and extends in an independent analysis the findings of NSABP B-28.
However, as Dr. Woodward and colleagues point out, the current study has limitations. The use of RT was extracted retrospectively and may be underreported. More modern chemotherapy and RT may lower LRR from the risks observed in SWOG 8814. Finally, the modest numbers of LRR events precluded secondary analysis of RS as a continuous variable. This is important because the risk group cutoffs suggested by the authors are not aligned with those in the recently published TailorRx study or the ongoing RxPonder trial.
The TailorRT (Regional Radiotherapy in Biomarker Low Risk Node Positive Breast Cancer) study examines the safety of omitting RT among patients with low RS and one to three positive nodes. Until the TailorRT results are reported, the controversy regarding the role of postmastectomy RT in this group will continue for patients with low nodal tumor burden and less aggressive tumor features, including low RS.
An observed LRR risk of 11.1% in SWOG 8814 among patients with N1 disease and an RS above 18 suggest that genomic risk could be one of the factors that may justify postmastectomy RT in postmenopausal patients with node-positive, hormone receptor–positive breast cancer until additional data emerge from the contemporary trials.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I Will Treat My Next Patient,” I highlight the potential role of new models for predicting risks of common, clinically important situations in general oncology practice: severe neutropenia in lung cancer patients and locoregional recurrence of breast cancer.
Predicting neutropenia
Accurate, lung cancer–specific prediction models would be useful to estimate risk of chemotherapy-induced neutropenia (CIN), especially febrile neutropenia (FN), since that particular toxicity is linked to infection, dose delays and dose reductions that can compromise treatment efficacy, and poor health-related quality of life. Lung cancer patients are often older adults, with advanced disease and comorbid conditions, so they are a particularly vulnerable population for CIN.
Xiaowen Cao of Duke University, Durham, N.C., and coinvestigators published a model for predicting risk of severe CIN in advanced lung cancer patients, based on 10 pretreatment variables (Lung Cancer. 2020 Jan 5. doi: 10.1016/j.lungcan.2020.01.004). They developed their model to overcome limitations of the previously published work of Gary H. Lyman, MD, and colleagues that is not specific to lung cancer and incorporated relative dose intensity as a predictor (Cancer. 2011;117:1917-27). Relative dose intensity is not determined until after a treatment course is completed.
The new prediction model was based on a lung cancer data set encompassing 11,352 patients from 67 phase 2-3 cooperative group studies conducted between 1991 and 2010. In this data set, the Lyman model had an area under the curve of 0.8772 in patients with small cell lung cancer, but an area under the curve of just 0.6787 in non–small cell lung cancer.
The derivation model was derived from about two-thirds of the patients, randomly selected. The validation set was conducted using the remaining third. The variables included were readily clinically available: age, gender, weight, body mass index, insurance status, disease stage, number of metastatic sites, chemotherapy agents used, number of chemotherapy agents, planned growth factor use, duration of planned therapy, pleural effusion, presence of symptoms, and performance status. Their model had an area under the curve of 0.8348 in the training set and 0.8234 in the testing set.
How these results influence practice
The risk of an initial episode of FN is highest during a patient’s initial cycle of chemotherapy, when most patients are receiving full-dose treatment, often without prophylactic measures. Guidelines from the National Comprehensive Cancer Network suggest the use of prophylactic growth factors in patients with more than a 20% risk of FN, and considering using prophylaxis in patients with 10%-20% risk of FN. Underestimating those risks and failure to take adequate precautions may be particularly important for patients with lung cancer who are generally older adults, with comorbid conditions.
The comprehensive risk model for neutropenic complications that was developed by Dr. Lyman and colleagues was based on a large, prospective cohort including nearly 3,800 patients. The model had a 90% sensitivity and 96% predictive value, but was not lung cancer specific and, in this latest study, did not perform as well in the 85% of lung cancer patients with non–small cell lung cancer. The Lyman data, however, was obtained in cancer patients treated with investigator-choice chemotherapy in community practices. It remains the National Comprehensive Cancer Network standard for evaluating FN risk in patients embarking on chemotherapy for advanced malignancies. That should remain the case, pending the additional validation testing of the new lung cancer–specific model at independent institutions, treating heterogeneous patients in real-world settings.
Locoregional recurrence
A retrospective cohort analysis of SWOG 8814, a phase 3 study of tamoxifen alone versus chemotherapy plus by tamoxifen in postmenopausal, node-positive, hormone receptor–positive breast cancer patients suggests that the 21-gene assay recurrence score (RS) can aid decisions about radiotherapy (RT).
Wendy A. Woodward, MD, PhD, and colleagues, analyzed patients who underwent mastectomy or breast-conserving surgery as their local therapy (JAMA Oncol. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5559). They found that patients with an intermediate or high RS – according to the 21-gene assay OncotypeDX – had more locoregional recurrences (LRR; breast, chest wall, axilla, internal mammary, supraclavicular or infraclavicular nodes).
There were 367 patients in SWOG 8814 who received tamoxifen alone or cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen. LRR was observed in 5.8% of patients with a low RS (less than 18) and in 13.8% of patients with an intermediate or high RS (more than 18). The estimated 10-year cumulative LRR incidence rates were 9.7% and 16.5%, respectively (P = .02).
In the subset of patients with one to three positive nodes who had mastectomy without radiotherapy, the LRR was 1.5% for those with low RS and 11.1% for those with intermediate or high RS (P = .051). No difference by RS was found in the 10-year rates of LRR among patients with four or more involved nodes who received a mastectomy without RT (25.9% vs. 27.0%; P = .27).
In multivariate analysis, incorporating RS, type of surgery, and number of involved nodes, intermediate or high RS was a significant predictor of LRR, with a hazard ratio of 2.36 (P = .04). The investigators suggested that RS, when available, should be one of the factors considered in selecting patients for postmastectomy RT.
How these results influence practice
Selecting the node-positive, hormone receptor–positive, breast cancer patients who should receive postmastectomy RT is difficult and controversial. This is particularly true for those postmenopausal patients with fewer than four involved nodes, no lymphatic or vascular invasion, and no extracapsular spread of disease into the axillary fat. Limited information exists on the ability of genomic assays to identify LRR risk.
Eleftherios P. Mamounas, MD, and colleagues examined the results of NSABP B-28, a trial of chemotherapy plus tamoxifen (J Natl Cancer Inst. 2017;109[4]. doi:10.1093/jnci/djw259). Postmastectomy RT was not permitted. They found high RS correlated with greater LRR and low RS with decreased LRR among patients with one to three positive nodes. At first blush, the prospectively treated cohort of SWOG 8814 represents a uniformly treated cohort with long-term follow-up (median, 8.5 years) and extends in an independent analysis the findings of NSABP B-28.
However, as Dr. Woodward and colleagues point out, the current study has limitations. The use of RT was extracted retrospectively and may be underreported. More modern chemotherapy and RT may lower LRR from the risks observed in SWOG 8814. Finally, the modest numbers of LRR events precluded secondary analysis of RS as a continuous variable. This is important because the risk group cutoffs suggested by the authors are not aligned with those in the recently published TailorRx study or the ongoing RxPonder trial.
The TailorRT (Regional Radiotherapy in Biomarker Low Risk Node Positive Breast Cancer) study examines the safety of omitting RT among patients with low RS and one to three positive nodes. Until the TailorRT results are reported, the controversy regarding the role of postmastectomy RT in this group will continue for patients with low nodal tumor burden and less aggressive tumor features, including low RS.
An observed LRR risk of 11.1% in SWOG 8814 among patients with N1 disease and an RS above 18 suggest that genomic risk could be one of the factors that may justify postmastectomy RT in postmenopausal patients with node-positive, hormone receptor–positive breast cancer until additional data emerge from the contemporary trials.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I Will Treat My Next Patient,” I highlight the potential role of new models for predicting risks of common, clinically important situations in general oncology practice: severe neutropenia in lung cancer patients and locoregional recurrence of breast cancer.
Predicting neutropenia
Accurate, lung cancer–specific prediction models would be useful to estimate risk of chemotherapy-induced neutropenia (CIN), especially febrile neutropenia (FN), since that particular toxicity is linked to infection, dose delays and dose reductions that can compromise treatment efficacy, and poor health-related quality of life. Lung cancer patients are often older adults, with advanced disease and comorbid conditions, so they are a particularly vulnerable population for CIN.
Xiaowen Cao of Duke University, Durham, N.C., and coinvestigators published a model for predicting risk of severe CIN in advanced lung cancer patients, based on 10 pretreatment variables (Lung Cancer. 2020 Jan 5. doi: 10.1016/j.lungcan.2020.01.004). They developed their model to overcome limitations of the previously published work of Gary H. Lyman, MD, and colleagues that is not specific to lung cancer and incorporated relative dose intensity as a predictor (Cancer. 2011;117:1917-27). Relative dose intensity is not determined until after a treatment course is completed.
The new prediction model was based on a lung cancer data set encompassing 11,352 patients from 67 phase 2-3 cooperative group studies conducted between 1991 and 2010. In this data set, the Lyman model had an area under the curve of 0.8772 in patients with small cell lung cancer, but an area under the curve of just 0.6787 in non–small cell lung cancer.
The derivation model was derived from about two-thirds of the patients, randomly selected. The validation set was conducted using the remaining third. The variables included were readily clinically available: age, gender, weight, body mass index, insurance status, disease stage, number of metastatic sites, chemotherapy agents used, number of chemotherapy agents, planned growth factor use, duration of planned therapy, pleural effusion, presence of symptoms, and performance status. Their model had an area under the curve of 0.8348 in the training set and 0.8234 in the testing set.
How these results influence practice
The risk of an initial episode of FN is highest during a patient’s initial cycle of chemotherapy, when most patients are receiving full-dose treatment, often without prophylactic measures. Guidelines from the National Comprehensive Cancer Network suggest the use of prophylactic growth factors in patients with more than a 20% risk of FN, and considering using prophylaxis in patients with 10%-20% risk of FN. Underestimating those risks and failure to take adequate precautions may be particularly important for patients with lung cancer who are generally older adults, with comorbid conditions.
The comprehensive risk model for neutropenic complications that was developed by Dr. Lyman and colleagues was based on a large, prospective cohort including nearly 3,800 patients. The model had a 90% sensitivity and 96% predictive value, but was not lung cancer specific and, in this latest study, did not perform as well in the 85% of lung cancer patients with non–small cell lung cancer. The Lyman data, however, was obtained in cancer patients treated with investigator-choice chemotherapy in community practices. It remains the National Comprehensive Cancer Network standard for evaluating FN risk in patients embarking on chemotherapy for advanced malignancies. That should remain the case, pending the additional validation testing of the new lung cancer–specific model at independent institutions, treating heterogeneous patients in real-world settings.
Locoregional recurrence
A retrospective cohort analysis of SWOG 8814, a phase 3 study of tamoxifen alone versus chemotherapy plus by tamoxifen in postmenopausal, node-positive, hormone receptor–positive breast cancer patients suggests that the 21-gene assay recurrence score (RS) can aid decisions about radiotherapy (RT).
Wendy A. Woodward, MD, PhD, and colleagues, analyzed patients who underwent mastectomy or breast-conserving surgery as their local therapy (JAMA Oncol. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5559). They found that patients with an intermediate or high RS – according to the 21-gene assay OncotypeDX – had more locoregional recurrences (LRR; breast, chest wall, axilla, internal mammary, supraclavicular or infraclavicular nodes).
There were 367 patients in SWOG 8814 who received tamoxifen alone or cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen. LRR was observed in 5.8% of patients with a low RS (less than 18) and in 13.8% of patients with an intermediate or high RS (more than 18). The estimated 10-year cumulative LRR incidence rates were 9.7% and 16.5%, respectively (P = .02).
In the subset of patients with one to three positive nodes who had mastectomy without radiotherapy, the LRR was 1.5% for those with low RS and 11.1% for those with intermediate or high RS (P = .051). No difference by RS was found in the 10-year rates of LRR among patients with four or more involved nodes who received a mastectomy without RT (25.9% vs. 27.0%; P = .27).
In multivariate analysis, incorporating RS, type of surgery, and number of involved nodes, intermediate or high RS was a significant predictor of LRR, with a hazard ratio of 2.36 (P = .04). The investigators suggested that RS, when available, should be one of the factors considered in selecting patients for postmastectomy RT.
How these results influence practice
Selecting the node-positive, hormone receptor–positive, breast cancer patients who should receive postmastectomy RT is difficult and controversial. This is particularly true for those postmenopausal patients with fewer than four involved nodes, no lymphatic or vascular invasion, and no extracapsular spread of disease into the axillary fat. Limited information exists on the ability of genomic assays to identify LRR risk.
Eleftherios P. Mamounas, MD, and colleagues examined the results of NSABP B-28, a trial of chemotherapy plus tamoxifen (J Natl Cancer Inst. 2017;109[4]. doi:10.1093/jnci/djw259). Postmastectomy RT was not permitted. They found high RS correlated with greater LRR and low RS with decreased LRR among patients with one to three positive nodes. At first blush, the prospectively treated cohort of SWOG 8814 represents a uniformly treated cohort with long-term follow-up (median, 8.5 years) and extends in an independent analysis the findings of NSABP B-28.
However, as Dr. Woodward and colleagues point out, the current study has limitations. The use of RT was extracted retrospectively and may be underreported. More modern chemotherapy and RT may lower LRR from the risks observed in SWOG 8814. Finally, the modest numbers of LRR events precluded secondary analysis of RS as a continuous variable. This is important because the risk group cutoffs suggested by the authors are not aligned with those in the recently published TailorRx study or the ongoing RxPonder trial.
The TailorRT (Regional Radiotherapy in Biomarker Low Risk Node Positive Breast Cancer) study examines the safety of omitting RT among patients with low RS and one to three positive nodes. Until the TailorRT results are reported, the controversy regarding the role of postmastectomy RT in this group will continue for patients with low nodal tumor burden and less aggressive tumor features, including low RS.
An observed LRR risk of 11.1% in SWOG 8814 among patients with N1 disease and an RS above 18 suggest that genomic risk could be one of the factors that may justify postmastectomy RT in postmenopausal patients with node-positive, hormone receptor–positive breast cancer until additional data emerge from the contemporary trials.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.