NEWS & VIEWS
‘‘
…we believe the pendulum will swing towards smaller and molecular-based trials
’’
Notably, specific landmark advances in science would change clinical trial design. There have been significant changes in the systemic management of patients with advanced-stage NSCLC over the past three decades. The key milestones of these changes are the discovery in 2004 of driver oncogenes such as EGFR and in 2007 the identification of the translocation mutation of anaplastic lymphoma kinase (ALK).4,5 With a better understanding of molecular subtypes of NSCLC, specific tyrosine kinase inhibitors, such as gefitinib, were shown to be superior to standard platinum-based cytotoxic chemo therapy, whereas treatment outcomes were the opposite in patients without EGFR mutation.6 Since then, patient selection according to the tumour molecular profile has become a crucial component of many monumental phase III trials in patients with advancedstage NSCLC. We believe that if an analysis of patterns and interpretation of NSCLC trials is to be done fairly, these particular milestones should be taken into account and grouping of trials should be based on the disease biology. As we move towards a new era of molecular targeted therapy trials according to the genetic profile of each patient, it is only natural to adopt PFS as the primary study end point. Improvement in overall survival might not be reflected in these clinical trials given that it would be unethical not to offer the experimental drug to patients (with the driver oncogene) in the control arm upon a clear PFS advantage. For example, Kwak and colleagues have established in a phase I study that patients with an ALK mutation attained high tumour response rates (overall response rate 57%, stable disease 33%) and prolonged PFS (probability of 6‑month PFS is 72%) with crizotinib.7 Thus, in the randomized phase III study comparing crizotinib with single-agent chemotherapy, Shaw et al.8 intentionally (and ethically) allowed all patients to receive crizotinib upon disease progression following chemotherapy. This study has successfully demonstrated prolongation of PFS, which proves the true efficacy of crizotinib, whereas the lack of overall survival benefit is merely a reflection of the crossover-effect. The proposal that the ‘bar is dropping’ could be correct if lung cancer remained a homogenous disease. Clinical trials that used overall survival as the primary end point might have made a small impact on survival 382 | JULY 2014 | VOLUME 11
in the past. However, the one-size-fits-all approach of large phase III trials comprising of a ‘basket’ of NSCLC patients with diverse molecular subtypes is unlikely to provide further improvement in clinical outcomes. As we understand more about the heterogeneity of NSCLC and its reliance on different driver oncogenes for propagation, we believe the pendulum will swing towards smaller and molecular-based trials. We, therefore, believe that the bar is not dropping; rather, the opposite effect is true. The design and interpretation of clinical trials for NSCLC will likely become more stringent and complex given the smaller numbers of patients available as we break NSCLC down into numerous molecular subtypes. Further advances in the science of this disease will likely produce more bars and possibly even hoops, which we will need to overcome. Department of Clinical Oncology, Faculty of Medicine, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Prince of Wales Hospital, 30–32 Ngan Shing Street, Shatin NT, Hong Kong SAR, China (H.H.L., T.S.K.M.). Correspondence to: T.S.K.M. [email protected]
Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
6.
7.
8.
National Cancer Institute. SEER Stat Fact Sheets: Lung and Bronchus Cancer. Surveillance, Epidemiology and End Results Program [online], http://seer.cancer.gov/ statfacts/html/lungb.html (2014). Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin. 63, 11–30 (2013). Sacher, A. G., Le, L. W. & Leighl, N. B. Shifting patterns in the interpretation of phase III clinical trial outcomes in advanced non‑small‑cell lung cancer: the bar is dropping. J. Clin. Oncol. http://dx.doi.org/10.1200/ JCO.2013.52.7804 (2014). Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non‑small‑cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004). Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non‑small‑cell lung cancer. Nature 448, 561–566 (2007). Mok, T. S. et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009). Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non‑small‑cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010). Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).
BREAST CANCER
Post-mastectomy radiotherapy reduces recurrence and mortality Roberto Orecchia
The recent results of the Early Breast Cancer Trialists’ Cooperative Group meta-analysis have demonstrated that post-mastectomy radiotherapy reduces breast cancer recurrence and mortality in women with positive axillary lymph nodes—independently from the number of the lymph nodes involved—with no significant effect in patients with node-negative axillary status. Orecchia, R. Nat. Rev. Clin. Oncol. 11, 382–384 (2014); published online 3 June 2014; doi:10.1038.nrclinonc.2014.95
Current guidelines concerning post- mastectomy radiotherapy (PMRT) include only the general recommendation of administering radiation to patients with four or more positive lymph nodes or T3–T4 lesions. There are, however, conflicting indications and results on the use of PMRT in patients with one-to-three positive lymph nodes, and even in patients with node-negative disease, for whom the expected benefit from localregional radiotherapy is more limited. Now, the recent results of the Early Breast Cancer Trialists’ Cooperative Group meta-analysis
have demonstrated that PMRT strongly reduces breast cancer recurrence and mortality in all women with positive axillary lymph nodes—independently from the number of the lymph nodes involved —whereas no significant effect of radiotherapy has been observed in patients with node-negative axillary status.1 The study included data from 22 trials that were carried out from 1964 to 1986 with a total of 8,135 patients—most of the patients from the Danish Breast Cancer Coopera tive Group trials2,3—who were randomly www.nature.com/nrclinonc
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS assigned, after mastectomy, to two treatment groups: radiotherapy to the chest wall and regional lymph nodes versus no radiotherapy. In 1,772 women with four or more positive lymph nodes, radiotherapy significantly reduced the 10-year risk of locoregional and overall recurrence and 20-year risk of breast cancer mortality.1 In the same meta-analysis, radiotherapy also reduced locoregional recurrence (two-sided significance level [2p]
‘‘
…we believe the pendulum will swing towards smaller and molecular-based trials
’’
Notably, specific landmark advances in science would change clinical trial design. There have been significant changes in the systemic management of patients with advanced-stage NSCLC over the past three decades. The key milestones of these changes are the discovery in 2004 of driver oncogenes such as EGFR and in 2007 the identification of the translocation mutation of anaplastic lymphoma kinase (ALK).4,5 With a better understanding of molecular subtypes of NSCLC, specific tyrosine kinase inhibitors, such as gefitinib, were shown to be superior to standard platinum-based cytotoxic chemo therapy, whereas treatment outcomes were the opposite in patients without EGFR mutation.6 Since then, patient selection according to the tumour molecular profile has become a crucial component of many monumental phase III trials in patients with advancedstage NSCLC. We believe that if an analysis of patterns and interpretation of NSCLC trials is to be done fairly, these particular milestones should be taken into account and grouping of trials should be based on the disease biology. As we move towards a new era of molecular targeted therapy trials according to the genetic profile of each patient, it is only natural to adopt PFS as the primary study end point. Improvement in overall survival might not be reflected in these clinical trials given that it would be unethical not to offer the experimental drug to patients (with the driver oncogene) in the control arm upon a clear PFS advantage. For example, Kwak and colleagues have established in a phase I study that patients with an ALK mutation attained high tumour response rates (overall response rate 57%, stable disease 33%) and prolonged PFS (probability of 6‑month PFS is 72%) with crizotinib.7 Thus, in the randomized phase III study comparing crizotinib with single-agent chemotherapy, Shaw et al.8 intentionally (and ethically) allowed all patients to receive crizotinib upon disease progression following chemotherapy. This study has successfully demonstrated prolongation of PFS, which proves the true efficacy of crizotinib, whereas the lack of overall survival benefit is merely a reflection of the crossover-effect. The proposal that the ‘bar is dropping’ could be correct if lung cancer remained a homogenous disease. Clinical trials that used overall survival as the primary end point might have made a small impact on survival 382 | JULY 2014 | VOLUME 11
in the past. However, the one-size-fits-all approach of large phase III trials comprising of a ‘basket’ of NSCLC patients with diverse molecular subtypes is unlikely to provide further improvement in clinical outcomes. As we understand more about the heterogeneity of NSCLC and its reliance on different driver oncogenes for propagation, we believe the pendulum will swing towards smaller and molecular-based trials. We, therefore, believe that the bar is not dropping; rather, the opposite effect is true. The design and interpretation of clinical trials for NSCLC will likely become more stringent and complex given the smaller numbers of patients available as we break NSCLC down into numerous molecular subtypes. Further advances in the science of this disease will likely produce more bars and possibly even hoops, which we will need to overcome. Department of Clinical Oncology, Faculty of Medicine, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Prince of Wales Hospital, 30–32 Ngan Shing Street, Shatin NT, Hong Kong SAR, China (H.H.L., T.S.K.M.). Correspondence to: T.S.K.M. [email protected]
Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
6.
7.
8.
National Cancer Institute. SEER Stat Fact Sheets: Lung and Bronchus Cancer. Surveillance, Epidemiology and End Results Program [online], http://seer.cancer.gov/ statfacts/html/lungb.html (2014). Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin. 63, 11–30 (2013). Sacher, A. G., Le, L. W. & Leighl, N. B. Shifting patterns in the interpretation of phase III clinical trial outcomes in advanced non‑small‑cell lung cancer: the bar is dropping. J. Clin. Oncol. http://dx.doi.org/10.1200/ JCO.2013.52.7804 (2014). Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non‑small‑cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004). Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non‑small‑cell lung cancer. Nature 448, 561–566 (2007). Mok, T. S. et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009). Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non‑small‑cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010). Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).
BREAST CANCER
Post-mastectomy radiotherapy reduces recurrence and mortality Roberto Orecchia
The recent results of the Early Breast Cancer Trialists’ Cooperative Group meta-analysis have demonstrated that post-mastectomy radiotherapy reduces breast cancer recurrence and mortality in women with positive axillary lymph nodes—independently from the number of the lymph nodes involved—with no significant effect in patients with node-negative axillary status. Orecchia, R. Nat. Rev. Clin. Oncol. 11, 382–384 (2014); published online 3 June 2014; doi:10.1038.nrclinonc.2014.95
Current guidelines concerning post- mastectomy radiotherapy (PMRT) include only the general recommendation of administering radiation to patients with four or more positive lymph nodes or T3–T4 lesions. There are, however, conflicting indications and results on the use of PMRT in patients with one-to-three positive lymph nodes, and even in patients with node-negative disease, for whom the expected benefit from localregional radiotherapy is more limited. Now, the recent results of the Early Breast Cancer Trialists’ Cooperative Group meta-analysis
have demonstrated that PMRT strongly reduces breast cancer recurrence and mortality in all women with positive axillary lymph nodes—independently from the number of the lymph nodes involved —whereas no significant effect of radiotherapy has been observed in patients with node-negative axillary status.1 The study included data from 22 trials that were carried out from 1964 to 1986 with a total of 8,135 patients—most of the patients from the Danish Breast Cancer Coopera tive Group trials2,3—who were randomly www.nature.com/nrclinonc
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS assigned, after mastectomy, to two treatment groups: radiotherapy to the chest wall and regional lymph nodes versus no radiotherapy. In 1,772 women with four or more positive lymph nodes, radiotherapy significantly reduced the 10-year risk of locoregional and overall recurrence and 20-year risk of breast cancer mortality.1 In the same meta-analysis, radiotherapy also reduced locoregional recurrence (two-sided significance level [2p]
