VOLUME 32 䡠 NUMBER 27 䡠 SEPTEMBER 20 2014
JOURNAL OF CLINICAL ONCOLOGY
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Combining Cetuximab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: Is More Better? Amanda Psyrri, Attikon Hospital, University of Athens Medical School, Athens, Greece Urania Dafni, School of Health Sciences, University of Athens; and Frontier Science Foundation-Hellas, Athens, Greece See accompanying article on page 2940
The challenge in the treatment of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) is to optimize efficacy while minimizing treatment-related toxicity. The mortality rate of patients with locally advanced tobacco-induced HNSCC remains high despite advances in treatment.1 One strategy to improve the efficacy of treatment is to add molecular targeted agents to classical chemoradiotherapy regimens. Cetuximab, the first targeting strategy to demonstrate survival advantage for patients with HNSCC, has emerged in the context of epidermal growth factor receptor (EGFR) biology. Cetuximab is a chimeric immunoglobulin G1– human monoclonal antibody against the extracellular domain of EGFR, exerting its antineoplastic properties by blocking ligand binding to the receptor. The clinical efficacy of cetuximab appears to involve several mechanisms, including inhibition of cell cycle progression, induction of apoptosis, inhibition of angiogenesis, inhibition of metastasis, enhancement of the response to chemotherapy and radiation, and induction of antibody-dependent cellular cytotoxicity.2 A phase III study in locally advanced HNSCC demonstrated that cetuximab increases overall survival (OS) when combined with radiotherapy alone, while not enhancing local toxicities.3,4 In addition, following a proof of concept study in the recurrent metastatic setting,5 the EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head & Neck Cancer) study showed that addition of cetuximab to platinum-based chemotherapy with fluorouracil improved OS, progression-free survival (PFS), and response rates.6 On the basis of these two pivotal trials, cetuximab has been approved by the US Food and Drug Administration in combination with radiation in locally advanced HNSCC and as first-line treatment in combination with platinum/fluorouracil in the recurrent/metastatic setting. Cetuximab has also shown activity in recurrent/ metastatic patients with HNSCC refractory to platinum-based combination chemotherapy,7-9 and it is also US Food and Drug Administration approved for this indication. Two randomized trials conducted by the Radiation Therapy Oncology Group (RTOG) are reported in this issue of Journal of Clinical Oncology. Both studies attempt to intensify treatment in the locally advanced setting by incorporating cetuximab into concurrent chemoradiotherapy regimens in unselected populations. RTOG-0234 is a randomized phase II study in the postoperative setting in patients with Journal of Clinical Oncology, Vol 32, No 27 (September 20), 2014: pp 2929-2931
high-risk pathologic features. It was designed to select one of two chemoradiotherapy regimens for further testing against standard highdose cisplatin-based chemoradiotherapy in a phase III trial.10 The two chemoradiotherapy regimens, docetaxel-radiation-cetuximab triplet and weekly cisplatin-radiation-cetuximab triplet, were compared in terms of disease-free survival (DFS) to the historical cohort treated with chemoradiotherapy in RTOG-9501. Both arms performed better than historical RTOG-9501 results, and the docetaxel arm appeared better than the cisplatin arm. RTOG-9501 randomly allocated highrisk postoperative patients to either radiation alone or radiation with concurrent high-dose cisplatin.11 No significant impact on distant control was noted, although the addition of cisplatin did increase acute severe adverse events. Interestingly, in RTOG-0234, the primary benefit for the docetaxel arm appears related to improved systemic control, with a 2-year distant metastasis rate of 13% versus 25% in the cisplatin arm. As suggested by the authors, docetaxel can induce senescence in cancer cells in vitro irrespective of p53 gene status, whereas cisplatin-induced senescence requires wild-type p53.10 Because p53 mutation is the most common genetic alteration in tobacco-induced HNSCC, it is postulated that docetaxel is a more potent cetuximab partner than cisplatin in controlling disease dissemination. However, human papillomavirus (HPV) analysis of EXTREME,12 and SPECTRUM (Study of Panitumumab Efficacy in Patients With Recurrent and/or Metastatic Head and Neck Cancer)13 studies do not support this explanation. In EXTREME, HPV/p16-positive tumors, bearing wild-type p53, derived similar benefit from the addition of cetuximab to platinumfluorouracil combination compared with the HPV-negative tumors. In contrast, in SPECTRUM, the benefit from the addition of panitumumab to cisplatin/fluorouracil was restricted to p16-negative tumors. It is also worth noting that the differences between the two arms of RTOG-0234 in terms of progression events was trivial (48 on the cisplatin arm v 51 on the docetaxel arm), and the rates of mucositis were similar (56% v 54%, respectively). On the other hand, both had significantly better DFS and OS than the historical control. Acknowledging the lack of power for a head-to-head comparison of the two arms, and the fact that no difference between them is apparent in either efficacy or toxicity, the validity of the conclusion is © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on January 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
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Editorial
relying exclusively on the adequacy of the historical control. Importantly, this control comes from a study completed 4 years before the initiation of RTOG-0234. Over the past decade, HNSCC has been in flux with respect to incidence and prognosis.14 These shifting trends are associated with the involvement of HPV in a growing subset of oropharyngeal tumors. As the incidence of HPV-positive oropharyngeal cancers in the historical RTOG-9501 cohort is unknown, it is possible that the observed differences are partly related to a lower rate of HPV-positive oropharyngeal cancers in RTOG-9501. Taking into account the changes in the disease epidemiology during this period, caution should be exercised with conclusions based on a historical control in this setting.15-17 Therefore, it is not convincing that the observed improvement can be attributed only to the addition of cetuximab to chemoradiotherapy. Of note, patients with p16-positive tumors demonstrated markedly improved survival compared with their p16-negative counterparts, and this observation suggests the exploration of deintensification strategies in postoperative HNSCC with high-risk pathologic features. RTOG-052218 was conducted on a total of 940 patients, to test the hypothesis that the addition of cetuximab to cisplatin chemoradiotherapy in locally advanced HNSCC will improve PFS compared with standard cisplatin-based chemoradiotherapy. The addition of cetuximab to cisplatin chemoradiotherapy failed to meet the primary end point of improving PFS or the secondary end points of improving OS, local-regional control (LRC), and distant metastasis. To the contrary, a trend toward worse LRC was noted in the experimental arm. These negative results corroborated findings of other studies that combined anti-EGFR therapy with concurrent chemoradiotherapy in the locally advanced setting and consistently demonstrated lack of benefit of this chemoadditive strategy in unselected patient populations.19,20 Increased toxicities, mainly mucositis and skin reactions, were observed with EGFR inhibitors.20 Specifically in RTOG-0522, the cetuximab group had significantly higher rates of toxic adverse effects including grade 3 to 4 skin reactions and radiation dermatitis causing radiation interruptions in 26.9% of patients, despite incomplete cetuximab administration in 26.4% of them. This well-powered study concluded that concomitant cetuximab administration does not add clinical benefit to conventional cisplatin chemoradiotherapy in HNSCC. These results could not have been anticipated a priori for several reasons: first, pilot phase II studies of radiation-cisplatin-cetuximab triplet had shown promising 3-year OS and LRC.21,22 Second, data from HNSCC cell lines and xenografts have shown at least additive effects of cetuximab combined with cisplatin.23,24 Third, the EXTREME data in recurrent/metastatic setting had confirmed the additive effect of cetuximab to platinum-fluorouracil combination. Given the outcome of the RTOG-0522 trial, it is possible that some of these observations are incorrect or that some additional key determinants have not been taken into account. These negative results may demonstrate that preclinical models, although useful, do not dependably predict human tumor biology. Another possible explanation is the absence of selection of the subset of patients likely to respond to cetuximab. Many biomarkers, including tumor EGFR expression, have been suggested as predictive of cetuximab resistance in HNSCC,25-27; however, unfortunately to date none of them has been validated. It is therefore not surprising that, despite ubiquitous EGFR expression in HNSCC, cetuximab is associated with an objec2930
© 2014 by American Society of Clinical Oncology
tive response rate of only 13% when used as a single agent. This response rate is within the range of the observed response rate with single-agent trastuzumab when 2⫹HER2 overexpressing, fluorescent in situ hybridization–negative breast cancers were included in studies.28 Taken together, it is possible that in a situation in which the responding phenotype to cetuximab has not yet been characterized, the molecular heterogeneity of HNSCC could have resulted in a false negative result in the overall study population. However, it is instructive to again consider the EXTREME trial in this discussion. EXTREME was conducted in an unselected population and showed improvement in survival, even though the cetuximab-sensitive population was diluted as a result of the lack of a predictive test. Such a synergistic effect of cetuximab with chemotherapy did not emerge in RTOG-0522, possibly because of a lack of feasibility of the cisplatin-cetuximab-radiation triplet. The outcome of RTOG-0522 is consistent with recent results from the SCOPE1 (Chemoradiotherapy With or Without Cetuximab in Patients With Oesophageal Cancer) trial,29 in which patients with localized esophageal squamous cell cancer and adenocarcinoma were randomly allocated to receive cisplatin and fluoropyrimidine-based definitive chemoradiotherapy or the same combination with cetuximab. The addition of cetuximab to chemoradiotherapy resulted in more toxicity, less protocol treatment being delivered, and inferior OS compared with chemoradiotherapy alone. In summary, what have we learned from these two RTOG studies, and what are the implications for clinical trial design in HNSCC? More is not always better, especially when biology is not taken into account. In an era when next-generation sequencing is becoming increasingly available, identification of mutations that predict therapeutic response or resistance would be a major advance. Therefore, it seems mandatory that we focus our efforts at identifying an “EGFR sensitivity signature.” Until then, it would seem wise not to conduct large phase III studies with cetuximab in unselected patient populations. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org. AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Baxi S, Fury M, Ganly I, et al: Ten years of progress in head and neck cancers. J Natl Compr Canc Netw 10:806-810, 2012 2. Harari PM, Huang SM: Radiation response modification following molecular inhibition of epidermal growth factor receptor signaling. Semin Radiat Oncol 11:281-289, 2001 (abstr) 3. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006 4. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21-28, 2010 5. Burtness B, Goldwasser MA, Flood W, et al: Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/ recurrent head and neck cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 23:8646-8654, 2005 6. Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116-1127, 2008 7. Baselga J, Trigo JM, Bourhis J, et al: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on January 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Editorial
metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 23:5568-5577, 2005 8. Herbst RS, Arquette M, Shin DM, et al: Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 23:5578-5587, 2005 9. Vermorken JB, Trigo J, Hitt R, et al: Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 25:2171-2177, 2007 10. Harari PM, Harris J, Kies MS, et al: Postoperative chemoradiotherapy and cetuximab for high-risk squamous cell carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. J Clin Oncol 32:2486-2495, 2014 11. Cooper JS, Pajak TF, Forastiere AA, et al: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350:1937-1944, 2004 12. Vermorken JB, Psyrri A, Mesía R, et al: Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: Retrospective analysis of the phase III EXTREME trial. Ann Oncol 25:801-807, 2014 13. Vermorken JB, Sto¨hlmacher-Williams J, Davidenko I, et al: Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): An open-label phase 3 randomised trial. Lancet Oncol 14:697-710, 2013 14. Chaturvedi AK: Epidemiology and clinical aspects of HPV in head and neck cancers. Head Neck Pathol 6:S16-S24, 2012 (suppl 1) 15. Dixon DO, Simon R: Sample size considerations for studies comparing survival curves using historical controls. J Clin Epidemiol 41:1209-1213, 1988 16. Makuch RW, Simon RM: Sample size considerations for non-randomized comparative studies. J Chronic Dis 33:175-181, 1980 17. Pocock SJ: The combination of randomized and historical controls in clinical trials. J Chronic Dis 29:175-188, 1976 18. Ang KK, Zhang Q, Rosenthal DI, et al: Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck carcinoma: RTOG 0522. J Clin Oncol 32:29402950, 2014
19. Martins RG, Parvathaneni U, Bauman JE, et al: Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: A randomized phase II trial. J Clin Oncol 31:1415-1421, 2013 20. Giralt J, Fortin A, Mesia R, et al: A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients (pts) with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN). J Clin Oncol 30:356s, 2012 (suppl; abstr 5502) 21. Pfister DG, Su YB, Kraus DH, et al: Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: A pilot phase II study of a new combined-modality paradigm. J Clin Oncol 24:1072-1078, 2006 22. Fountzilas G, Kalogera-Fountzila A, Lambaki S, et al: MMP9 but not EGFR, MET, ERCC1, P16, and P-53 is associated with response to concomitant radiotherapy, cetuximab, and weekly cisplatin in patients with locally advanced head and neck cancer. J Oncol 2009:305908, 2009 23. Takaoka S, Iwase M, Uchida M, et al: Effect of combining epidermal growth factor receptor inhibitors and cisplatin on proliferation and apoptosis of oral squamous cell carcinoma cells. Int J Oncol 30:1469-1476, 2007 24. Fan Z, Baselga J, Masui H, et al: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53:4637-4642, 1993 25. Burtness B, Bauman JE, Galloway T: Novel targets in HPV-negative head and neck cancer: Overcoming resistance to EGFR inhibition. Lancet Oncol 14:e302-e309, 2013 26. Psyrri A, Lee JW, Pectasides E, et al: Prognostic biomarkers in phase II trial of cetuximab-containing induction and chemoradiation in resectable HNSCC: Eastern Cooperative Oncology Group E2303. Clin Cancer Res 20:3023-3032, 2014 27. Rampias T, Giagini A, Siolos S, et al: RAS/PI3K crosstalk and cetuximab resistance in head and neck squamous cell carcinoma. Clin Cancer Res 20:29332946, 2014 28. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002 29. 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 14:627-637, 2013
DOI: 10.1200/JCO.2014.56.1902; published online ahead of print at www.jco.org on July 7, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Combining Cetuximab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: Is More Better? The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Amanda Psyrri Honoraria: Merck Serono Consulting or Advisory Role: Merck Serono Research Funding: Bristol-Myers Squibb
© 2014 by American Society of Clinical Oncology
Urania Dafni Honoraria: Amgen
JOURNAL OF CLINICAL ONCOLOGY
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JOURNAL OF CLINICAL ONCOLOGY
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Combining Cetuximab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: Is More Better? Amanda Psyrri, Attikon Hospital, University of Athens Medical School, Athens, Greece Urania Dafni, School of Health Sciences, University of Athens; and Frontier Science Foundation-Hellas, Athens, Greece See accompanying article on page 2940
The challenge in the treatment of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) is to optimize efficacy while minimizing treatment-related toxicity. The mortality rate of patients with locally advanced tobacco-induced HNSCC remains high despite advances in treatment.1 One strategy to improve the efficacy of treatment is to add molecular targeted agents to classical chemoradiotherapy regimens. Cetuximab, the first targeting strategy to demonstrate survival advantage for patients with HNSCC, has emerged in the context of epidermal growth factor receptor (EGFR) biology. Cetuximab is a chimeric immunoglobulin G1– human monoclonal antibody against the extracellular domain of EGFR, exerting its antineoplastic properties by blocking ligand binding to the receptor. The clinical efficacy of cetuximab appears to involve several mechanisms, including inhibition of cell cycle progression, induction of apoptosis, inhibition of angiogenesis, inhibition of metastasis, enhancement of the response to chemotherapy and radiation, and induction of antibody-dependent cellular cytotoxicity.2 A phase III study in locally advanced HNSCC demonstrated that cetuximab increases overall survival (OS) when combined with radiotherapy alone, while not enhancing local toxicities.3,4 In addition, following a proof of concept study in the recurrent metastatic setting,5 the EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head & Neck Cancer) study showed that addition of cetuximab to platinum-based chemotherapy with fluorouracil improved OS, progression-free survival (PFS), and response rates.6 On the basis of these two pivotal trials, cetuximab has been approved by the US Food and Drug Administration in combination with radiation in locally advanced HNSCC and as first-line treatment in combination with platinum/fluorouracil in the recurrent/metastatic setting. Cetuximab has also shown activity in recurrent/ metastatic patients with HNSCC refractory to platinum-based combination chemotherapy,7-9 and it is also US Food and Drug Administration approved for this indication. Two randomized trials conducted by the Radiation Therapy Oncology Group (RTOG) are reported in this issue of Journal of Clinical Oncology. Both studies attempt to intensify treatment in the locally advanced setting by incorporating cetuximab into concurrent chemoradiotherapy regimens in unselected populations. RTOG-0234 is a randomized phase II study in the postoperative setting in patients with Journal of Clinical Oncology, Vol 32, No 27 (September 20), 2014: pp 2929-2931
high-risk pathologic features. It was designed to select one of two chemoradiotherapy regimens for further testing against standard highdose cisplatin-based chemoradiotherapy in a phase III trial.10 The two chemoradiotherapy regimens, docetaxel-radiation-cetuximab triplet and weekly cisplatin-radiation-cetuximab triplet, were compared in terms of disease-free survival (DFS) to the historical cohort treated with chemoradiotherapy in RTOG-9501. Both arms performed better than historical RTOG-9501 results, and the docetaxel arm appeared better than the cisplatin arm. RTOG-9501 randomly allocated highrisk postoperative patients to either radiation alone or radiation with concurrent high-dose cisplatin.11 No significant impact on distant control was noted, although the addition of cisplatin did increase acute severe adverse events. Interestingly, in RTOG-0234, the primary benefit for the docetaxel arm appears related to improved systemic control, with a 2-year distant metastasis rate of 13% versus 25% in the cisplatin arm. As suggested by the authors, docetaxel can induce senescence in cancer cells in vitro irrespective of p53 gene status, whereas cisplatin-induced senescence requires wild-type p53.10 Because p53 mutation is the most common genetic alteration in tobacco-induced HNSCC, it is postulated that docetaxel is a more potent cetuximab partner than cisplatin in controlling disease dissemination. However, human papillomavirus (HPV) analysis of EXTREME,12 and SPECTRUM (Study of Panitumumab Efficacy in Patients With Recurrent and/or Metastatic Head and Neck Cancer)13 studies do not support this explanation. In EXTREME, HPV/p16-positive tumors, bearing wild-type p53, derived similar benefit from the addition of cetuximab to platinumfluorouracil combination compared with the HPV-negative tumors. In contrast, in SPECTRUM, the benefit from the addition of panitumumab to cisplatin/fluorouracil was restricted to p16-negative tumors. It is also worth noting that the differences between the two arms of RTOG-0234 in terms of progression events was trivial (48 on the cisplatin arm v 51 on the docetaxel arm), and the rates of mucositis were similar (56% v 54%, respectively). On the other hand, both had significantly better DFS and OS than the historical control. Acknowledging the lack of power for a head-to-head comparison of the two arms, and the fact that no difference between them is apparent in either efficacy or toxicity, the validity of the conclusion is © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on January 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
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Editorial
relying exclusively on the adequacy of the historical control. Importantly, this control comes from a study completed 4 years before the initiation of RTOG-0234. Over the past decade, HNSCC has been in flux with respect to incidence and prognosis.14 These shifting trends are associated with the involvement of HPV in a growing subset of oropharyngeal tumors. As the incidence of HPV-positive oropharyngeal cancers in the historical RTOG-9501 cohort is unknown, it is possible that the observed differences are partly related to a lower rate of HPV-positive oropharyngeal cancers in RTOG-9501. Taking into account the changes in the disease epidemiology during this period, caution should be exercised with conclusions based on a historical control in this setting.15-17 Therefore, it is not convincing that the observed improvement can be attributed only to the addition of cetuximab to chemoradiotherapy. Of note, patients with p16-positive tumors demonstrated markedly improved survival compared with their p16-negative counterparts, and this observation suggests the exploration of deintensification strategies in postoperative HNSCC with high-risk pathologic features. RTOG-052218 was conducted on a total of 940 patients, to test the hypothesis that the addition of cetuximab to cisplatin chemoradiotherapy in locally advanced HNSCC will improve PFS compared with standard cisplatin-based chemoradiotherapy. The addition of cetuximab to cisplatin chemoradiotherapy failed to meet the primary end point of improving PFS or the secondary end points of improving OS, local-regional control (LRC), and distant metastasis. To the contrary, a trend toward worse LRC was noted in the experimental arm. These negative results corroborated findings of other studies that combined anti-EGFR therapy with concurrent chemoradiotherapy in the locally advanced setting and consistently demonstrated lack of benefit of this chemoadditive strategy in unselected patient populations.19,20 Increased toxicities, mainly mucositis and skin reactions, were observed with EGFR inhibitors.20 Specifically in RTOG-0522, the cetuximab group had significantly higher rates of toxic adverse effects including grade 3 to 4 skin reactions and radiation dermatitis causing radiation interruptions in 26.9% of patients, despite incomplete cetuximab administration in 26.4% of them. This well-powered study concluded that concomitant cetuximab administration does not add clinical benefit to conventional cisplatin chemoradiotherapy in HNSCC. These results could not have been anticipated a priori for several reasons: first, pilot phase II studies of radiation-cisplatin-cetuximab triplet had shown promising 3-year OS and LRC.21,22 Second, data from HNSCC cell lines and xenografts have shown at least additive effects of cetuximab combined with cisplatin.23,24 Third, the EXTREME data in recurrent/metastatic setting had confirmed the additive effect of cetuximab to platinum-fluorouracil combination. Given the outcome of the RTOG-0522 trial, it is possible that some of these observations are incorrect or that some additional key determinants have not been taken into account. These negative results may demonstrate that preclinical models, although useful, do not dependably predict human tumor biology. Another possible explanation is the absence of selection of the subset of patients likely to respond to cetuximab. Many biomarkers, including tumor EGFR expression, have been suggested as predictive of cetuximab resistance in HNSCC,25-27; however, unfortunately to date none of them has been validated. It is therefore not surprising that, despite ubiquitous EGFR expression in HNSCC, cetuximab is associated with an objec2930
© 2014 by American Society of Clinical Oncology
tive response rate of only 13% when used as a single agent. This response rate is within the range of the observed response rate with single-agent trastuzumab when 2⫹HER2 overexpressing, fluorescent in situ hybridization–negative breast cancers were included in studies.28 Taken together, it is possible that in a situation in which the responding phenotype to cetuximab has not yet been characterized, the molecular heterogeneity of HNSCC could have resulted in a false negative result in the overall study population. However, it is instructive to again consider the EXTREME trial in this discussion. EXTREME was conducted in an unselected population and showed improvement in survival, even though the cetuximab-sensitive population was diluted as a result of the lack of a predictive test. Such a synergistic effect of cetuximab with chemotherapy did not emerge in RTOG-0522, possibly because of a lack of feasibility of the cisplatin-cetuximab-radiation triplet. The outcome of RTOG-0522 is consistent with recent results from the SCOPE1 (Chemoradiotherapy With or Without Cetuximab in Patients With Oesophageal Cancer) trial,29 in which patients with localized esophageal squamous cell cancer and adenocarcinoma were randomly allocated to receive cisplatin and fluoropyrimidine-based definitive chemoradiotherapy or the same combination with cetuximab. The addition of cetuximab to chemoradiotherapy resulted in more toxicity, less protocol treatment being delivered, and inferior OS compared with chemoradiotherapy alone. In summary, what have we learned from these two RTOG studies, and what are the implications for clinical trial design in HNSCC? More is not always better, especially when biology is not taken into account. In an era when next-generation sequencing is becoming increasingly available, identification of mutations that predict therapeutic response or resistance would be a major advance. Therefore, it seems mandatory that we focus our efforts at identifying an “EGFR sensitivity signature.” Until then, it would seem wise not to conduct large phase III studies with cetuximab in unselected patient populations. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org. AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Baxi S, Fury M, Ganly I, et al: Ten years of progress in head and neck cancers. J Natl Compr Canc Netw 10:806-810, 2012 2. Harari PM, Huang SM: Radiation response modification following molecular inhibition of epidermal growth factor receptor signaling. Semin Radiat Oncol 11:281-289, 2001 (abstr) 3. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006 4. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21-28, 2010 5. Burtness B, Goldwasser MA, Flood W, et al: Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/ recurrent head and neck cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 23:8646-8654, 2005 6. Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116-1127, 2008 7. Baselga J, Trigo JM, Bourhis J, et al: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on January 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Editorial
metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 23:5568-5577, 2005 8. Herbst RS, Arquette M, Shin DM, et al: Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 23:5578-5587, 2005 9. Vermorken JB, Trigo J, Hitt R, et al: Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 25:2171-2177, 2007 10. Harari PM, Harris J, Kies MS, et al: Postoperative chemoradiotherapy and cetuximab for high-risk squamous cell carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. J Clin Oncol 32:2486-2495, 2014 11. Cooper JS, Pajak TF, Forastiere AA, et al: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350:1937-1944, 2004 12. Vermorken JB, Psyrri A, Mesía R, et al: Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: Retrospective analysis of the phase III EXTREME trial. Ann Oncol 25:801-807, 2014 13. Vermorken JB, Sto¨hlmacher-Williams J, Davidenko I, et al: Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): An open-label phase 3 randomised trial. Lancet Oncol 14:697-710, 2013 14. Chaturvedi AK: Epidemiology and clinical aspects of HPV in head and neck cancers. Head Neck Pathol 6:S16-S24, 2012 (suppl 1) 15. Dixon DO, Simon R: Sample size considerations for studies comparing survival curves using historical controls. J Clin Epidemiol 41:1209-1213, 1988 16. Makuch RW, Simon RM: Sample size considerations for non-randomized comparative studies. J Chronic Dis 33:175-181, 1980 17. Pocock SJ: The combination of randomized and historical controls in clinical trials. J Chronic Dis 29:175-188, 1976 18. Ang KK, Zhang Q, Rosenthal DI, et al: Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck carcinoma: RTOG 0522. J Clin Oncol 32:29402950, 2014
19. Martins RG, Parvathaneni U, Bauman JE, et al: Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: A randomized phase II trial. J Clin Oncol 31:1415-1421, 2013 20. Giralt J, Fortin A, Mesia R, et al: A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients (pts) with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN). J Clin Oncol 30:356s, 2012 (suppl; abstr 5502) 21. Pfister DG, Su YB, Kraus DH, et al: Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: A pilot phase II study of a new combined-modality paradigm. J Clin Oncol 24:1072-1078, 2006 22. Fountzilas G, Kalogera-Fountzila A, Lambaki S, et al: MMP9 but not EGFR, MET, ERCC1, P16, and P-53 is associated with response to concomitant radiotherapy, cetuximab, and weekly cisplatin in patients with locally advanced head and neck cancer. J Oncol 2009:305908, 2009 23. Takaoka S, Iwase M, Uchida M, et al: Effect of combining epidermal growth factor receptor inhibitors and cisplatin on proliferation and apoptosis of oral squamous cell carcinoma cells. Int J Oncol 30:1469-1476, 2007 24. Fan Z, Baselga J, Masui H, et al: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53:4637-4642, 1993 25. Burtness B, Bauman JE, Galloway T: Novel targets in HPV-negative head and neck cancer: Overcoming resistance to EGFR inhibition. Lancet Oncol 14:e302-e309, 2013 26. Psyrri A, Lee JW, Pectasides E, et al: Prognostic biomarkers in phase II trial of cetuximab-containing induction and chemoradiation in resectable HNSCC: Eastern Cooperative Oncology Group E2303. Clin Cancer Res 20:3023-3032, 2014 27. Rampias T, Giagini A, Siolos S, et al: RAS/PI3K crosstalk and cetuximab resistance in head and neck squamous cell carcinoma. Clin Cancer Res 20:29332946, 2014 28. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002 29. 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 14:627-637, 2013
DOI: 10.1200/JCO.2014.56.1902; published online ahead of print at www.jco.org on July 7, 2014
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Combining Cetuximab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: Is More Better? The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Amanda Psyrri Honoraria: Merck Serono Consulting or Advisory Role: Merck Serono Research Funding: Bristol-Myers Squibb
© 2014 by American Society of Clinical Oncology
Urania Dafni Honoraria: Amgen
JOURNAL OF CLINICAL ONCOLOGY
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