Correspondence
Panitumumab for locally advanced head and neck squamous-cell carcinoma We read the Article by Ricard Mesía and colleagues1 with great interest. The CONCERT-1 trial did not show a survival benefit in patients with locally advanced squamous-cell carcinoma of the head and neck who were treated with panitumumab in addition to chemoradiotherapy. Patients receiving panitumumab plus chemoradiotherapy did not have any benefit in terms of the primary endpoint, local-regional control at 2 years. Although the authors also compared overall survival and progression-free survival between patients matched by tumour p16 status, no survival benefits were seen in the panitumumab plus chemoradiotherapy group. A comparison of patients requiring cisplatin dose reduction (≤225 mg/m2) in the chemoradiotherapy group with all patients in the panitumumab plus chemoradiotherapy group showed that the panitumumab plus chemoradiotherapy group had a nonsignificant increase in local-regional control at 2 years, suggesting a possible benefit of panitumumab. Patients requiring a cisplatin dose reduction are likely to have more comorbidities than patients who do not. Generally, cisplatin dose reduction is considered when a patient has a relatively poor performance status, poor organ (especially kidney) function, advanced age, or a history of severe adverse events during a previous treatment course. Accordingly, the population who received a reduced dose of cisplatin is more likely to have included older patients and patients who were more frail, compared with the overall patient population. In contrast, patients who completed the planned dose of panitumumab plus chemoradiotherapy are probably in better physical condition than patients in the chemoradiotherapy www.thelancet.com/oncology Vol 16 April 2015
group who received a reduced dose of chemoradiotherapy. Frail patients are more likely to have a poorer prognosis. We think Mesía and colleagues should have taken into consideration that comparison of a frail group of patients with a more robust population is scientifically inaccurate. Although the authors reported that some outcomes favoured the panitumumab plus chemoradiotherapy group, there was no significant difference. We would like to know the patient characteristics, the dose intensity for cisplatin, panitumumab, and radiotherapy, and the reason for the dose reductions to assess the benefits of combined panitumumab plus chemoradiotherapy. The CONCERT-1 trial was a phase 2 trial with a relatively small number of participants, and a decisive conclusion cannot be made on the basis of these results alone. Nevertheless, we are doubtful of the additional benefit of panitumumab for the treatment of head and neck squamous-cell carcinoma. We are not sure why two similar anti-EGFR inhibitor antibodies, cetuximab and panitumumab, cause discrepant results.2–5 Cetuximab has shown promising results and is recommended in treatment guidelines for head and neck squamous cell carcinoma.6 The difference in immunoglobulin classes between cetuximab (IgG1) and panitumumab (IgG2) might affect their efficacies. We would like to know why these differences arise. We declare no competing interests.
*Hiroto Ishiki, Satoru Iwase, Naoki Shimada, Tsukuru Chiba, Kohzoh Imai [email protected] Department of Palliative Medicine (HI, SI, NS, TC) and The Advanced Clinical Research Center (KI), The Institute of Medical Science, The University of Tokyo, Tokyo, Japan 1
Mesía R, Henke M, Fortin A, et al. Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Lancet Oncol 2015; 16: 208–20.
2
3
4
5
6
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 2010; 11: 21–28. Giralt J, Trigo J, Nuyts S, et al. Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial. Lancet Oncol 2015; 16: 221–32. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116–27. Vermorken JB, Stöhlmacher-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 2013; 14: 697–710. NCCN. Clinical practice guidelines for treatment of head and neck cancers. 2014. http://www. nccn.org/ (accessed March 11, 2015).
Radiotherapy dose and fractionation for stage III NSCLC The Article by Jeffrey Bradley and colleagues1 reports on the outcome of a randomised phase 3 trial (RTOG 0617). Within this trial, patients with non-small-cell lung cancer (NSCLC) were randomly allocated to receive either 60 Gy in 6 weeks or 74 Gy in 7·5 weeks, with or without cetuximab. After completion of the radiotherapy, patients in all study groups received two additional cycles of consolidation chemotherapy, with or without cetuximab. The authors showed that concurrent treatment with cetuximab did not improve overall survival in either the 60 Gy or the 74 Gy groups. Surprisingly, patients in the 74 Gy group had worse local control and significantly worse overall survival compared with the 60 Gy group. Dose escalation with prolonged overall treatment time for patients with NSCLC has previously proven disappointing because of accelerated repopulation.2 e156
Correspondence
Nonetheless, the results of RTOG 0617 are significant because a positive dose–response relation is one of the fundamental premises of radiotherapy. Many oncologists now challenge the usefulness of radiotherapy dose escalation and intensification for patients with stage III NSCLC. Consequently, the result of this trial raises the question, what is the optimum radiotherapy dose scheme to improve local control and overall survival? Although RTOG 0617 provides novel and compelling results in favour of a 60 Gy radical scheme, there are several considerations worth mentioning before radiation dose intensification is discontinued or treatment policies are changed. The authors suggest that the elevated heart dose might have increased mortality. The increase in mortality started within 3 months after randomisation, during the period when patients received consolidation paclitaxel plus carboplatin chemotherapy. Generally, taxanes taken after radiotherapy increases toxicity3 and are therefore not prescribed in Europe for the treatment of NSCLC.4 Therefore, the combination of high radiation dose to the heart and taxane consolidation
e157
therapy might have biased the results and caused lethal toxicity. Variability in heart contouring in centres that are less experienced with intensitymodulated radiation therapy (185 centres included 544 patients) and less accurate dose calculation algorithms (which might have caused up to 20% dose deviations) are additional issues that could have affected the results. Furthermore, the gross tumour volumes were larger in the 74 Gy groups. Gross tumour volume has been shown to be a highly significant factor for the prediction of survival in patients with NSCLC.5 The 74 Gy groups were enrolled only before June, 2011, whereas enrolment of patients in the 60 Gy groups continued thereafter. The median follow-up periods for the different subgroups were not mentioned in the paper, but these varying enrolment periods probably resulted in dissimilar follow-up durations for the 74 Gy group and the 60 Gy group. In conclusion, we believe that radiotherapy dose intensification while using accelerated schemes is an important area of ongoing clinical research and should not be discontinued on the basis of the RTOG 0617 results.
We declare no competing interests.
*José Belderbos, Iris Walraven, Judi van Diessen, Marcel Verheij, Dirk de Ruysscher [email protected] Department of Radiation Oncology, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands (JB, IW, JvD, MV); and Department of Radiation Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium (DdR) 1
2
3
4
5
Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015; 16: 187–99. Machtay M, Hsu C, Komaki R, et al. Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced non–small-cell lung carcinoma: analysis of the Radiation Therapy Oncology Group (RTOG) experience. Int J Radiat Oncol Biol Phys 2005; 63: 667–71. Palma DA, Senan S, Tsujino K, et al. Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 2013; 85: 444–50. Vansteenkiste J, De Ruysscher D, Eberhardt W, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24: vi89–98. Werner-Wasik M, Swann RS, Bradley J, et al. Increasing tumor volume is predictive of poor overall and progression-free survival: secondary analysis of the Radiation Therapy Oncology Group 93-11 phase I-II radiation dose-escalation study in patients with inoperable non–small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008; 70: 385–90.
www.thelancet.com/oncology Vol 16 April 2015
Panitumumab for locally advanced head and neck squamous-cell carcinoma We read the Article by Ricard Mesía and colleagues1 with great interest. The CONCERT-1 trial did not show a survival benefit in patients with locally advanced squamous-cell carcinoma of the head and neck who were treated with panitumumab in addition to chemoradiotherapy. Patients receiving panitumumab plus chemoradiotherapy did not have any benefit in terms of the primary endpoint, local-regional control at 2 years. Although the authors also compared overall survival and progression-free survival between patients matched by tumour p16 status, no survival benefits were seen in the panitumumab plus chemoradiotherapy group. A comparison of patients requiring cisplatin dose reduction (≤225 mg/m2) in the chemoradiotherapy group with all patients in the panitumumab plus chemoradiotherapy group showed that the panitumumab plus chemoradiotherapy group had a nonsignificant increase in local-regional control at 2 years, suggesting a possible benefit of panitumumab. Patients requiring a cisplatin dose reduction are likely to have more comorbidities than patients who do not. Generally, cisplatin dose reduction is considered when a patient has a relatively poor performance status, poor organ (especially kidney) function, advanced age, or a history of severe adverse events during a previous treatment course. Accordingly, the population who received a reduced dose of cisplatin is more likely to have included older patients and patients who were more frail, compared with the overall patient population. In contrast, patients who completed the planned dose of panitumumab plus chemoradiotherapy are probably in better physical condition than patients in the chemoradiotherapy www.thelancet.com/oncology Vol 16 April 2015
group who received a reduced dose of chemoradiotherapy. Frail patients are more likely to have a poorer prognosis. We think Mesía and colleagues should have taken into consideration that comparison of a frail group of patients with a more robust population is scientifically inaccurate. Although the authors reported that some outcomes favoured the panitumumab plus chemoradiotherapy group, there was no significant difference. We would like to know the patient characteristics, the dose intensity for cisplatin, panitumumab, and radiotherapy, and the reason for the dose reductions to assess the benefits of combined panitumumab plus chemoradiotherapy. The CONCERT-1 trial was a phase 2 trial with a relatively small number of participants, and a decisive conclusion cannot be made on the basis of these results alone. Nevertheless, we are doubtful of the additional benefit of panitumumab for the treatment of head and neck squamous-cell carcinoma. We are not sure why two similar anti-EGFR inhibitor antibodies, cetuximab and panitumumab, cause discrepant results.2–5 Cetuximab has shown promising results and is recommended in treatment guidelines for head and neck squamous cell carcinoma.6 The difference in immunoglobulin classes between cetuximab (IgG1) and panitumumab (IgG2) might affect their efficacies. We would like to know why these differences arise. We declare no competing interests.
*Hiroto Ishiki, Satoru Iwase, Naoki Shimada, Tsukuru Chiba, Kohzoh Imai [email protected] Department of Palliative Medicine (HI, SI, NS, TC) and The Advanced Clinical Research Center (KI), The Institute of Medical Science, The University of Tokyo, Tokyo, Japan 1
Mesía R, Henke M, Fortin A, et al. Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Lancet Oncol 2015; 16: 208–20.
2
3
4
5
6
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 2010; 11: 21–28. Giralt J, Trigo J, Nuyts S, et al. Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial. Lancet Oncol 2015; 16: 221–32. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116–27. Vermorken JB, Stöhlmacher-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 2013; 14: 697–710. NCCN. Clinical practice guidelines for treatment of head and neck cancers. 2014. http://www. nccn.org/ (accessed March 11, 2015).
Radiotherapy dose and fractionation for stage III NSCLC The Article by Jeffrey Bradley and colleagues1 reports on the outcome of a randomised phase 3 trial (RTOG 0617). Within this trial, patients with non-small-cell lung cancer (NSCLC) were randomly allocated to receive either 60 Gy in 6 weeks or 74 Gy in 7·5 weeks, with or without cetuximab. After completion of the radiotherapy, patients in all study groups received two additional cycles of consolidation chemotherapy, with or without cetuximab. The authors showed that concurrent treatment with cetuximab did not improve overall survival in either the 60 Gy or the 74 Gy groups. Surprisingly, patients in the 74 Gy group had worse local control and significantly worse overall survival compared with the 60 Gy group. Dose escalation with prolonged overall treatment time for patients with NSCLC has previously proven disappointing because of accelerated repopulation.2 e156
Correspondence
Nonetheless, the results of RTOG 0617 are significant because a positive dose–response relation is one of the fundamental premises of radiotherapy. Many oncologists now challenge the usefulness of radiotherapy dose escalation and intensification for patients with stage III NSCLC. Consequently, the result of this trial raises the question, what is the optimum radiotherapy dose scheme to improve local control and overall survival? Although RTOG 0617 provides novel and compelling results in favour of a 60 Gy radical scheme, there are several considerations worth mentioning before radiation dose intensification is discontinued or treatment policies are changed. The authors suggest that the elevated heart dose might have increased mortality. The increase in mortality started within 3 months after randomisation, during the period when patients received consolidation paclitaxel plus carboplatin chemotherapy. Generally, taxanes taken after radiotherapy increases toxicity3 and are therefore not prescribed in Europe for the treatment of NSCLC.4 Therefore, the combination of high radiation dose to the heart and taxane consolidation
e157
therapy might have biased the results and caused lethal toxicity. Variability in heart contouring in centres that are less experienced with intensitymodulated radiation therapy (185 centres included 544 patients) and less accurate dose calculation algorithms (which might have caused up to 20% dose deviations) are additional issues that could have affected the results. Furthermore, the gross tumour volumes were larger in the 74 Gy groups. Gross tumour volume has been shown to be a highly significant factor for the prediction of survival in patients with NSCLC.5 The 74 Gy groups were enrolled only before June, 2011, whereas enrolment of patients in the 60 Gy groups continued thereafter. The median follow-up periods for the different subgroups were not mentioned in the paper, but these varying enrolment periods probably resulted in dissimilar follow-up durations for the 74 Gy group and the 60 Gy group. In conclusion, we believe that radiotherapy dose intensification while using accelerated schemes is an important area of ongoing clinical research and should not be discontinued on the basis of the RTOG 0617 results.
We declare no competing interests.
*José Belderbos, Iris Walraven, Judi van Diessen, Marcel Verheij, Dirk de Ruysscher [email protected] Department of Radiation Oncology, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands (JB, IW, JvD, MV); and Department of Radiation Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium (DdR) 1
2
3
4
5
Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015; 16: 187–99. Machtay M, Hsu C, Komaki R, et al. Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced non–small-cell lung carcinoma: analysis of the Radiation Therapy Oncology Group (RTOG) experience. Int J Radiat Oncol Biol Phys 2005; 63: 667–71. Palma DA, Senan S, Tsujino K, et al. Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 2013; 85: 444–50. Vansteenkiste J, De Ruysscher D, Eberhardt W, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24: vi89–98. Werner-Wasik M, Swann RS, Bradley J, et al. Increasing tumor volume is predictive of poor overall and progression-free survival: secondary analysis of the Radiation Therapy Oncology Group 93-11 phase I-II radiation dose-escalation study in patients with inoperable non–small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008; 70: 385–90.
www.thelancet.com/oncology Vol 16 April 2015
