- Email: [email protected]
Targeted therapy and chemoradiotherapy in oesophageal cancer
Comment
Surrogate endpoints in future trials could become extremely interesting if the proposal of using the surrogate threshold effect3 as the upper limit of the CI in sample-size calculation were accepted. With this method, a significant positive result for the surrogate endpoint would probably reflect a significant benefit in overall survival, although the size of the survival benefit would not necessarily be clinically relevant. This proposal uses a principle commonly applied to non-inferiority trials but not to superiority trials, yet the concept might be of wide general interest and warrants attention from the scientific community. Its application would mitigate the risk of introducing into clinical practice drugs that in reality have no effect on survival. Thus, the development of new drugs that add only marginal benefits over what is already available might be discouraged, which would spare study participants and patients from toxic effects and save money. Against the use of this approach is that some drugs used in clinical practice might not have reached the market, from which the sum of marginal benefits might have improved the prognosis of some types of cancer (eg, metastatic colorectal cancer or metastatic NSCLC). Of course, reasonable non-superiority limits would need to be decided. A range of 1·15–1·25 is widely deemed acceptable for the upper 95% CI in
non-inferiority trials (dependent on setting and type of treatment). A range of 0·80–0·90 for superiority trials seems feasible. The 0·88 threshold found by Mauguen and colleagues1 for the adjuvant chemotherapy setting in NSCLC is consistent with this idea. Further research in this direction would be useful in other common settings, such as breast and colorectal cancers in the adjuvant and metastatic phases, and with new drugs directed against molecular targets. Good use of surrogate endpoints could help to raise the bar of efficacy for innovative treatments.4 Francesco Perrone Clinical Trials Unit, National Cancer Institute of Naples, via Mariano Semmola, 80131 Naples, Italy [email protected] I declare that I have no conflicts of interest. 1
2 3 4
Mauguen A, Pignon J-P, Burdett S, Domerg C, et al, for the Surrogate Lung Project Collaborative Group. Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a reanalysis of meta-analyses of individual patients’ data. Lancet Oncol 2013; published online May 14. http://dx.doi.org/10.1016/ S1470-2045(13)70158-X. Prentice RL. Surrogate endpoints in clinical trials: definitions and operational criteria. Stat Medicine 1989; 8: 431–30. Burzykowski T, Buyse M. Surrogate threshold effect: an alternative measure for metaanalytic surrogate endpoint validation. Pharm Stat 2006; 5: 173–86. Sobrero A, Bruzzi P. Incremental advance or seismic shift? The need to raise the bar of efficacy for drug approval. J Clin Oncol 2009; 27: 5868–73.
Treatment intensification for a range of cancers through combined modality treatment with systemic therapy and radiotherapy can improve locoregional control and overall survival, but can also result in increased toxicity and a loss in the therapeutic ratio. Outcomes of a randomised phase 3 study by Bonner and colleagues1 that tested the efficacy of the addition of cetuximab to radiotherapy in head and neck cancer provided proof of concept for selective tumour radiosensitisation targeting a perturbed signalling pathway, resulting in an improvement in locoregional control and survival compared with radiotherapy alone, but no difference in in-field toxicity or quality of life. Cetuximab-based therapy has also been shown to improve survival in patients with advanced colorectal cancer.2 These encouraging results have led to trials combining www.thelancet.com/oncology Vol 14 June 2013
cetuximab with established chemoradiotherapy protocols for various disease sites, such as the SCOPE1 trial in patients with oesophageal cancer,3 published in The Lancet Oncology. Oesophageal cancer consists predominantly of either squamous-cell carcinoma or adenocarcinoma, which have differing causes, natural histories, patterns of relapse, and responses to therapy; however, both histological subtypes do overexpress EGFR.4,5 Many trials have combined both subtypes in an effort to maximise accrual in this relatively uncommon disease, which has led to some difficulty in interpretation of results because equivalent outcomes to the same therapeutic intervention might be overstated. The phase 2/3 SCOPE1 trial, reported by Thomas Crosby and colleagues, assessed the addition of cetuximab to chemoradiotherapy (cisplatin and capecitabine for four
CNRI/Science Photo Library
Targeted therapy and chemoradiotherapy in oesophageal cancer
Published Online April 25, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70157-8 See Articles page 627
569
Comment
cycles plus 50 Gy of radiotherapy given concurrently during cycles three and four), with well defined stopping rules. The investigators chose to use two cycles of induction chemotherapy, which is not widely used in definitive chemoradiotherapy of oesophageal cancer, but has been extensively tested in head and neck cancer, and as a prelude to surgery in gastric cancer.6,7 Treatment was intensified with the addition of cetuximab to both the induction and the definitive phase of therapy. Arguably, any benefit in locoregional control and overall survival with such treatment intensification could have been offset by the resulting toxicity. A more considered approach might have been to test the addition of cetuximab to concurrent chemoradiotherapy or radiotherapy alone, with or without a standardised induction chemotherapy phase. The addition of cetuximab to chemoradiotherapy in SCOPE1 resulted in a lower proportion of patients who were treatment failure free at 24 weeks after randomisation, a lower median survival, and more nonhaematological toxicity than with chemoradiotherapy alone.3 In particular, the addition of cetuximab affected protocol compliance, including radiotherapy delivery. These outcomes resulted in the trial being closed prematurely. Results of a study by the Radiation Therapy Oncology Group (0522)8 that tested the efficacy of the addition of cetuximab to cisplatin-based chemoradiotherapy in head and neck squamous-cell carcinoma did not show a benefit in progression-free survival or overall survival, and showed an increase in grade 3–4 mucositis and skin reaction.8 Similar results were noted in the recently published PARADIGM trial.9 So is this the end for cetuximab and other targeted therapies in this disease? Clearly, the design of this trial— ie, the addition of a new agent at several points in the regimen for both histological subtypes—was not ideal. For oesophageal adenocarcinoma, the principal modality is surgery. New combinations of neoadjuvant systemic therapy might affect survival outcomes, but are less likely to affect locoregional control. Patients with squamous-cell carcinoma are still the predominant histological subtype worldwide. They frequently receive chemoradiotherapy or radiotherapy alone as definitive treatment. The only agent with a confirmed benefit in combination with radiotherapy is cisplatin.10 However, many patients are elderly and cisplatin-intolerant, and no combined therapy regimen has been deemed superior to radiotherapy alone for them. This group might benefit from a combination 570
of cetuximab and radiotherapy, similar to the benefits reported in the experimental group in Bonner and colleagues’ trial.1 As Crosby and colleagues discuss, radiation doses of 60 Gy or higher are now practical and safe to deliver to patients with these cancers and do not cause significant morbidity. A successful combination of radiotherapy and a targeted therapy would be a substantial advance against this disease and well worth investigating. The other question is whether combining cetuximab with standard cisplatin-based chemoradiotherapy in platinumtolerant patients improves regional control or survival. This question has been answered in the SCOPE1 trial in the setting of induction chemotherapy, but not in the setting of definitive combined therapy alone. The investigators question whether unknown interactions might exist between targeted therapies and chemotherapeutic agents that could compromise patient outcomes and at the same time increase toxicity. Further work needs to be done in this area. *Bryan H Burmeister, Sandro V Porceddu Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, QLD, Australia [email protected] We declare that we have no conflicts of interest. 1
2
3
4
5
6
7
8
9
10
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Eng J Med 2006; 354: 567–78. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Eng J Med 2004; 351: 337–45. Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol 2013; published online April 25. http://dx.doi.org/10.1016/S1470-2045(13)70136-0. Yu WW, Guo YM, Zhu M, et al. Clinicopathological and prognostic significance of EGFR over-expression in esophageal squamous cell carcinoma: a meta-analysis. Hepatogastroenterology 2011; 58: 426–31. Cronin J, McAdam E, Danikas A, et al. Epidermal growth factor receptor (EGFR) is overexpressed in high-grade dysplasia and adenocarcinoma of the esophagus and may represent a biomarker of histological progression in Barrett’s esophagus (BE). Am J Gastroenterol 2011; 106: 46–56. Ma J, Liu Y, Huang X, et al. Induction chemotherapy decreases the rate of distant metastasis in patients with head and neck squamous cell carcinoma but does not improve survival or locoregional control: a meta-analysis. Oral Oncol 2012; 48: 1076–84. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. J Clin Oncol 2006; 355: 11–20. Ang KK, Zhang QE, Rosenthal DI, et al. A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC). Proc Am Soc Clin Oncol 2011; 29 (suppl): abstr 5500. Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol 2013; 14: 257–64. Wong RK, Malthaner RA, Zuraw L, et al. Combined modality radiotherapy and chemotherapy in nonsurgical management of localized carcinoma of the esophagus: a practice guideline. Int J Rad Oncol Biol Phys 2003; 55: 930–42.
www.thelancet.com/oncology Vol 14 June 2013
Surrogate endpoints in future trials could become extremely interesting if the proposal of using the surrogate threshold effect3 as the upper limit of the CI in sample-size calculation were accepted. With this method, a significant positive result for the surrogate endpoint would probably reflect a significant benefit in overall survival, although the size of the survival benefit would not necessarily be clinically relevant. This proposal uses a principle commonly applied to non-inferiority trials but not to superiority trials, yet the concept might be of wide general interest and warrants attention from the scientific community. Its application would mitigate the risk of introducing into clinical practice drugs that in reality have no effect on survival. Thus, the development of new drugs that add only marginal benefits over what is already available might be discouraged, which would spare study participants and patients from toxic effects and save money. Against the use of this approach is that some drugs used in clinical practice might not have reached the market, from which the sum of marginal benefits might have improved the prognosis of some types of cancer (eg, metastatic colorectal cancer or metastatic NSCLC). Of course, reasonable non-superiority limits would need to be decided. A range of 1·15–1·25 is widely deemed acceptable for the upper 95% CI in
non-inferiority trials (dependent on setting and type of treatment). A range of 0·80–0·90 for superiority trials seems feasible. The 0·88 threshold found by Mauguen and colleagues1 for the adjuvant chemotherapy setting in NSCLC is consistent with this idea. Further research in this direction would be useful in other common settings, such as breast and colorectal cancers in the adjuvant and metastatic phases, and with new drugs directed against molecular targets. Good use of surrogate endpoints could help to raise the bar of efficacy for innovative treatments.4 Francesco Perrone Clinical Trials Unit, National Cancer Institute of Naples, via Mariano Semmola, 80131 Naples, Italy [email protected] I declare that I have no conflicts of interest. 1
2 3 4
Mauguen A, Pignon J-P, Burdett S, Domerg C, et al, for the Surrogate Lung Project Collaborative Group. Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a reanalysis of meta-analyses of individual patients’ data. Lancet Oncol 2013; published online May 14. http://dx.doi.org/10.1016/ S1470-2045(13)70158-X. Prentice RL. Surrogate endpoints in clinical trials: definitions and operational criteria. Stat Medicine 1989; 8: 431–30. Burzykowski T, Buyse M. Surrogate threshold effect: an alternative measure for metaanalytic surrogate endpoint validation. Pharm Stat 2006; 5: 173–86. Sobrero A, Bruzzi P. Incremental advance or seismic shift? The need to raise the bar of efficacy for drug approval. J Clin Oncol 2009; 27: 5868–73.
Treatment intensification for a range of cancers through combined modality treatment with systemic therapy and radiotherapy can improve locoregional control and overall survival, but can also result in increased toxicity and a loss in the therapeutic ratio. Outcomes of a randomised phase 3 study by Bonner and colleagues1 that tested the efficacy of the addition of cetuximab to radiotherapy in head and neck cancer provided proof of concept for selective tumour radiosensitisation targeting a perturbed signalling pathway, resulting in an improvement in locoregional control and survival compared with radiotherapy alone, but no difference in in-field toxicity or quality of life. Cetuximab-based therapy has also been shown to improve survival in patients with advanced colorectal cancer.2 These encouraging results have led to trials combining www.thelancet.com/oncology Vol 14 June 2013
cetuximab with established chemoradiotherapy protocols for various disease sites, such as the SCOPE1 trial in patients with oesophageal cancer,3 published in The Lancet Oncology. Oesophageal cancer consists predominantly of either squamous-cell carcinoma or adenocarcinoma, which have differing causes, natural histories, patterns of relapse, and responses to therapy; however, both histological subtypes do overexpress EGFR.4,5 Many trials have combined both subtypes in an effort to maximise accrual in this relatively uncommon disease, which has led to some difficulty in interpretation of results because equivalent outcomes to the same therapeutic intervention might be overstated. The phase 2/3 SCOPE1 trial, reported by Thomas Crosby and colleagues, assessed the addition of cetuximab to chemoradiotherapy (cisplatin and capecitabine for four
CNRI/Science Photo Library
Targeted therapy and chemoradiotherapy in oesophageal cancer
Published Online April 25, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70157-8 See Articles page 627
569
Comment
cycles plus 50 Gy of radiotherapy given concurrently during cycles three and four), with well defined stopping rules. The investigators chose to use two cycles of induction chemotherapy, which is not widely used in definitive chemoradiotherapy of oesophageal cancer, but has been extensively tested in head and neck cancer, and as a prelude to surgery in gastric cancer.6,7 Treatment was intensified with the addition of cetuximab to both the induction and the definitive phase of therapy. Arguably, any benefit in locoregional control and overall survival with such treatment intensification could have been offset by the resulting toxicity. A more considered approach might have been to test the addition of cetuximab to concurrent chemoradiotherapy or radiotherapy alone, with or without a standardised induction chemotherapy phase. The addition of cetuximab to chemoradiotherapy in SCOPE1 resulted in a lower proportion of patients who were treatment failure free at 24 weeks after randomisation, a lower median survival, and more nonhaematological toxicity than with chemoradiotherapy alone.3 In particular, the addition of cetuximab affected protocol compliance, including radiotherapy delivery. These outcomes resulted in the trial being closed prematurely. Results of a study by the Radiation Therapy Oncology Group (0522)8 that tested the efficacy of the addition of cetuximab to cisplatin-based chemoradiotherapy in head and neck squamous-cell carcinoma did not show a benefit in progression-free survival or overall survival, and showed an increase in grade 3–4 mucositis and skin reaction.8 Similar results were noted in the recently published PARADIGM trial.9 So is this the end for cetuximab and other targeted therapies in this disease? Clearly, the design of this trial— ie, the addition of a new agent at several points in the regimen for both histological subtypes—was not ideal. For oesophageal adenocarcinoma, the principal modality is surgery. New combinations of neoadjuvant systemic therapy might affect survival outcomes, but are less likely to affect locoregional control. Patients with squamous-cell carcinoma are still the predominant histological subtype worldwide. They frequently receive chemoradiotherapy or radiotherapy alone as definitive treatment. The only agent with a confirmed benefit in combination with radiotherapy is cisplatin.10 However, many patients are elderly and cisplatin-intolerant, and no combined therapy regimen has been deemed superior to radiotherapy alone for them. This group might benefit from a combination 570
of cetuximab and radiotherapy, similar to the benefits reported in the experimental group in Bonner and colleagues’ trial.1 As Crosby and colleagues discuss, radiation doses of 60 Gy or higher are now practical and safe to deliver to patients with these cancers and do not cause significant morbidity. A successful combination of radiotherapy and a targeted therapy would be a substantial advance against this disease and well worth investigating. The other question is whether combining cetuximab with standard cisplatin-based chemoradiotherapy in platinumtolerant patients improves regional control or survival. This question has been answered in the SCOPE1 trial in the setting of induction chemotherapy, but not in the setting of definitive combined therapy alone. The investigators question whether unknown interactions might exist between targeted therapies and chemotherapeutic agents that could compromise patient outcomes and at the same time increase toxicity. Further work needs to be done in this area. *Bryan H Burmeister, Sandro V Porceddu Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, QLD, Australia [email protected] We declare that we have no conflicts of interest. 1
2
3
4
5
6
7
8
9
10
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Eng J Med 2006; 354: 567–78. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Eng J Med 2004; 351: 337–45. Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol 2013; published online April 25. http://dx.doi.org/10.1016/S1470-2045(13)70136-0. Yu WW, Guo YM, Zhu M, et al. Clinicopathological and prognostic significance of EGFR over-expression in esophageal squamous cell carcinoma: a meta-analysis. Hepatogastroenterology 2011; 58: 426–31. Cronin J, McAdam E, Danikas A, et al. Epidermal growth factor receptor (EGFR) is overexpressed in high-grade dysplasia and adenocarcinoma of the esophagus and may represent a biomarker of histological progression in Barrett’s esophagus (BE). Am J Gastroenterol 2011; 106: 46–56. Ma J, Liu Y, Huang X, et al. Induction chemotherapy decreases the rate of distant metastasis in patients with head and neck squamous cell carcinoma but does not improve survival or locoregional control: a meta-analysis. Oral Oncol 2012; 48: 1076–84. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. J Clin Oncol 2006; 355: 11–20. Ang KK, Zhang QE, Rosenthal DI, et al. A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC). Proc Am Soc Clin Oncol 2011; 29 (suppl): abstr 5500. Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol 2013; 14: 257–64. Wong RK, Malthaner RA, Zuraw L, et al. Combined modality radiotherapy and chemotherapy in nonsurgical management of localized carcinoma of the esophagus: a practice guideline. Int J Rad Oncol Biol Phys 2003; 55: 930–42.
www.thelancet.com/oncology Vol 14 June 2013