Treatment of Advanced Head and Neck Cancer
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In our clinic, we use postoperative radiotherapy for advanced head and neck carcinoma. For nonoperable tumors, we use the toxic regimen of radiochemotherapy described in the May 6 issue by Cooper et al. in their report on the Radiation Therapy Oncology Group (RTOG) trial1 and by Bernier et al. in their report on the European Organization for Research and Treatment of Cancer (EORTC) trial,2 with radiation doses of 66 to 70 Gy. Between 1998 and 2002, we treated 197 patients with advanced, nonoperable head and neck cancer with the use of radiochemotherapy alone. We performed a retrospective analysis comparing the results of this regimen with the results obtained in 474 patients treated with postoperative radiotherapy. Locoregional and disease-free survival were significantly better with radiochemotherapy than with postoperative radiotherapy. The three-year rates of locoregional control were 79 percent and 69 percent with radiochemotherapy and postoperative radiotherapy, respectively (P=0.01). The three-year rates of disease-free survival were 70 percent and 60 percent with radiochemotherapy and postoperative radiotherapy, respectively (P=0.01). Our results with radiochemotherapy alone are very similar to those reported by the RTOG and EORTC investigators for patients treated with surgery and postoperative radiochemotherapy.
Major surgery followed by postoperative radiotherapy is already a very difficult treatment. It is our opinion that if chemotherapy is to be added to this approach, patients should be treated by radiochemotherapy alone.
André Fortin, M.Sc.
L'H?tel-Dieu de Québec
Quebec, QC G1R 2J6, Canada
andrefor@hotmail.com
Nathalie Audet, M.D.
H?pital Enfant-Jésus
Quebec, QC G1J 1Z4, Canada
Richard Caouette, M.D.
Laval University
Quebec, QC G1K 7P4, Canada
References
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 2004;350:1937-1944.
Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952.
To the Editor: Cooper and colleagues demonstrate that concurrent postoperative chemotherapy and radiotherapy, when compared with radiotherapy alone, improve disease-free survival among high-risk patients with resected head and neck cancer. However, no survival advantage was achieved in this study, as it was in EORTC trial 22931, as reported by Bernier and colleagues. On the other hand, the toxicity of combined therapy is considerable; in the study by Cooper and colleagues, the incidence of severe acute adverse effects was higher in the combined-therapy group than in the radiotherapy group (77 percent vs. 34 percent). Furthermore, three deaths related to combined treatment were observed, and only 61 percent of the patients received all three planned cycles of cisplatin. The most important deficiency of this study was the absence of a quality-of-life assessment.
Cisplatin is commonly used as a radiosensitizer agent. It is not clear whether the use of small, weekly doses or larger doses (100 mg per square meter of body-surface area) every three weeks during radiotherapy is better.1 A regimen of small, weekly doses of cisplatin in this setting is expected to have lower toxicity and thus may be better tolerated by patients.
Bülent Yal?n, M.D.
Abdullah Büyük?elik, M.D.
Güngor Utkan, M.D.
Ankara University School of Medicine
Ankara 06100, Turkey
bulyalcin@yahoo.com
References
Al-Sarraf M, Pajak TF, Marcial VA, et al. Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck: an RTOG study. Cancer 1987;59:259-265.
To the Editor: The EORTC study did not include patients older than 70 years of age. In the RTOG intergroup study, only 14 patients (7 percent) in the radiotherapy group and 11 patients (5 percent) in the combined-therapy group were 70 years of age or older. Given the significantly higher prevalence of acute toxic effects from combined chemotherapy and radiotherapy and the dearth of elderly patients in these studies, these data probably should not be universally applied to patients older than 70.
Guru Sonpavde, M.D.
Baylor College of Medicine
Houston, TX 77030
gurus@bcm.tmc.edu
Dr. Cooper and colleagues reply: Dr. Yal?n and colleagues express concern about the toxicity of concurrent radiotherapy and chemotherapy. We, too, are concerned; patients and physicians contemplating the regimen we tested should be fully aware of its toxic effects. However, the hypothesis that smaller, weekly doses of cisplatin will be equally effective and less toxic in this setting needs to be tested; one cannot simply assume that it is true.
Dr. Fortin and colleagues cite their own retrospective data, presumably unpublished, to hypothesize that concurrent radiochemotherapy is sufficiently effective in advanced head and neck cancer and that surgery is unnecessary. Appealing as this hypothesis may be, level 1 evidence in support of it does not exist. In addition, our use of surgery to test for eligibility according to the presence or absence of high-risk features in the pathological specimen spared patients who had low-risk tumors from the toxic effects of postoperative radiotherapy and chemotherapy.
As we concluded in our article, "our trial establishes the proof of principle that concurrent postoperative administration of chemotherapy and radiotherapy is a way to intensify treatment for resectable high-risk head and neck tumors." The regimen we tested probably is not the only way to deliver intensified treatment, and we expect that future studies will build on our work. For the present, however, we believe that the data from the RTOG and EORTC trials provide reliable, level 1 evidence that should not be confused with less definitive evidence or untested hypotheses.
Jay S. Cooper, M.D.
Maimonides Medical Center
Brooklyn, NY 11219
Arlene A. Forastiere, M.D.
Johns Hopkins Oncology Center
Baltimore, MD 21231
John Jacobs, M.D.
Wayne State University School of Medicine
Detroit, MI 48201
Dr. Bernier replies: The eligibility criteria for EORTC trial 22931 excluded patients older than 70 years of age because in many European countries, patients in this age range are treated conservatively, and the proportion of older patients randomized in the trial would therefore have been extremely limited. Actually, adjuvant chemoradiotherapy may be successful in elderly persons. Airoldi et al.1 recently reported that in a study of 40 patients with head and neck cancer (median age, 73.5 years; range, 70 to 78) who underwent radical surgery and were treated with carboplatin concomitantly with radiotherapy, compliance with treatment was satisfactory (80 percent of the patients received three chemotherapy cycles), and the efficacy results were similar to those in a younger group treated with adjuvant carboplatin plus radiotherapy. The conclusions drawn from EORTC trial 22931 data are, by definition, valid within the range of ages eligible for the study — namely, 18 to 70 years — but it cannot be ruled out that similar results may be observed in fit, older patients as well.
EORTC trial 22931 was designed to randomly assign patients to two types of adjuvant treatment. In their letter, Dr. Fortin and colleagues report a historical comparison between the results of postoperative radiotherapy and those of definitive chemoradiotherapy. It is likely that a number of confounding factors jeopardize the validity of their analysis. First, the results may be biased by differences in patient selection between the two cohorts considered in their historical comparison. Second, randomization is the only method to demonstrate, in terms of evidence-based medicine, the superiority of a given therapeutic approach over another, and this concept applies when comparisons are made within the same institution or team as well. In addition, in comparisons of approaches based on postoperative radiotherapy and those based on definitive chemoradiotherapy, conclusions should be drawn with caution because of differences in the trial setting (single center vs. multicenter). The merit of Dr. Fortin and colleagues' letter is that it emphasizes, once more, the difficulties faced by institutions or cooperative groups in their efforts to perform randomized trials that compare first-line surgery with conservative approaches in patients with head and neck cancer.
Jacques Bernier, M.D., Ph.D.
Oncology Institute of Southern Switzerland
CH-6504 Bellinzona, Switzerland
jacques.bernier@hcuge.ch
for the European Organization for Research and Treatment of Cancer
References
Airoldi M, Cortesina G, Giordano C, et al. Postoperative adjuvant chemotherapy in older patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2004;13:161-166.
Major surgery followed by postoperative radiotherapy is already a very difficult treatment. It is our opinion that if chemotherapy is to be added to this approach, patients should be treated by radiochemotherapy alone.
André Fortin, M.Sc.
L'H?tel-Dieu de Québec
Quebec, QC G1R 2J6, Canada
andrefor@hotmail.com
Nathalie Audet, M.D.
H?pital Enfant-Jésus
Quebec, QC G1J 1Z4, Canada
Richard Caouette, M.D.
Laval University
Quebec, QC G1K 7P4, Canada
References
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 2004;350:1937-1944.
Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-1952.
To the Editor: Cooper and colleagues demonstrate that concurrent postoperative chemotherapy and radiotherapy, when compared with radiotherapy alone, improve disease-free survival among high-risk patients with resected head and neck cancer. However, no survival advantage was achieved in this study, as it was in EORTC trial 22931, as reported by Bernier and colleagues. On the other hand, the toxicity of combined therapy is considerable; in the study by Cooper and colleagues, the incidence of severe acute adverse effects was higher in the combined-therapy group than in the radiotherapy group (77 percent vs. 34 percent). Furthermore, three deaths related to combined treatment were observed, and only 61 percent of the patients received all three planned cycles of cisplatin. The most important deficiency of this study was the absence of a quality-of-life assessment.
Cisplatin is commonly used as a radiosensitizer agent. It is not clear whether the use of small, weekly doses or larger doses (100 mg per square meter of body-surface area) every three weeks during radiotherapy is better.1 A regimen of small, weekly doses of cisplatin in this setting is expected to have lower toxicity and thus may be better tolerated by patients.
Bülent Yal?n, M.D.
Abdullah Büyük?elik, M.D.
Güngor Utkan, M.D.
Ankara University School of Medicine
Ankara 06100, Turkey
bulyalcin@yahoo.com
References
Al-Sarraf M, Pajak TF, Marcial VA, et al. Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck: an RTOG study. Cancer 1987;59:259-265.
To the Editor: The EORTC study did not include patients older than 70 years of age. In the RTOG intergroup study, only 14 patients (7 percent) in the radiotherapy group and 11 patients (5 percent) in the combined-therapy group were 70 years of age or older. Given the significantly higher prevalence of acute toxic effects from combined chemotherapy and radiotherapy and the dearth of elderly patients in these studies, these data probably should not be universally applied to patients older than 70.
Guru Sonpavde, M.D.
Baylor College of Medicine
Houston, TX 77030
gurus@bcm.tmc.edu
Dr. Cooper and colleagues reply: Dr. Yal?n and colleagues express concern about the toxicity of concurrent radiotherapy and chemotherapy. We, too, are concerned; patients and physicians contemplating the regimen we tested should be fully aware of its toxic effects. However, the hypothesis that smaller, weekly doses of cisplatin will be equally effective and less toxic in this setting needs to be tested; one cannot simply assume that it is true.
Dr. Fortin and colleagues cite their own retrospective data, presumably unpublished, to hypothesize that concurrent radiochemotherapy is sufficiently effective in advanced head and neck cancer and that surgery is unnecessary. Appealing as this hypothesis may be, level 1 evidence in support of it does not exist. In addition, our use of surgery to test for eligibility according to the presence or absence of high-risk features in the pathological specimen spared patients who had low-risk tumors from the toxic effects of postoperative radiotherapy and chemotherapy.
As we concluded in our article, "our trial establishes the proof of principle that concurrent postoperative administration of chemotherapy and radiotherapy is a way to intensify treatment for resectable high-risk head and neck tumors." The regimen we tested probably is not the only way to deliver intensified treatment, and we expect that future studies will build on our work. For the present, however, we believe that the data from the RTOG and EORTC trials provide reliable, level 1 evidence that should not be confused with less definitive evidence or untested hypotheses.
Jay S. Cooper, M.D.
Maimonides Medical Center
Brooklyn, NY 11219
Arlene A. Forastiere, M.D.
Johns Hopkins Oncology Center
Baltimore, MD 21231
John Jacobs, M.D.
Wayne State University School of Medicine
Detroit, MI 48201
Dr. Bernier replies: The eligibility criteria for EORTC trial 22931 excluded patients older than 70 years of age because in many European countries, patients in this age range are treated conservatively, and the proportion of older patients randomized in the trial would therefore have been extremely limited. Actually, adjuvant chemoradiotherapy may be successful in elderly persons. Airoldi et al.1 recently reported that in a study of 40 patients with head and neck cancer (median age, 73.5 years; range, 70 to 78) who underwent radical surgery and were treated with carboplatin concomitantly with radiotherapy, compliance with treatment was satisfactory (80 percent of the patients received three chemotherapy cycles), and the efficacy results were similar to those in a younger group treated with adjuvant carboplatin plus radiotherapy. The conclusions drawn from EORTC trial 22931 data are, by definition, valid within the range of ages eligible for the study — namely, 18 to 70 years — but it cannot be ruled out that similar results may be observed in fit, older patients as well.
EORTC trial 22931 was designed to randomly assign patients to two types of adjuvant treatment. In their letter, Dr. Fortin and colleagues report a historical comparison between the results of postoperative radiotherapy and those of definitive chemoradiotherapy. It is likely that a number of confounding factors jeopardize the validity of their analysis. First, the results may be biased by differences in patient selection between the two cohorts considered in their historical comparison. Second, randomization is the only method to demonstrate, in terms of evidence-based medicine, the superiority of a given therapeutic approach over another, and this concept applies when comparisons are made within the same institution or team as well. In addition, in comparisons of approaches based on postoperative radiotherapy and those based on definitive chemoradiotherapy, conclusions should be drawn with caution because of differences in the trial setting (single center vs. multicenter). The merit of Dr. Fortin and colleagues' letter is that it emphasizes, once more, the difficulties faced by institutions or cooperative groups in their efforts to perform randomized trials that compare first-line surgery with conservative approaches in patients with head and neck cancer.
Jacques Bernier, M.D., Ph.D.
Oncology Institute of Southern Switzerland
CH-6504 Bellinzona, Switzerland
jacques.bernier@hcuge.ch
for the European Organization for Research and Treatment of Cancer
References
Airoldi M, Cortesina G, Giordano C, et al. Postoperative adjuvant chemotherapy in older patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2004;13:161-166.