Management of Cancer of the Head and Neck — A Cocktail with Your PORT?
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《新英格兰医药杂志》
Squamous-cell cancer of the head and neck is the sixth most common cancer worldwide, with a lifetime risk of 2 percent for men and 0.6 percent for women. There are approximately 76,000 and 37,000 new cases of oral-cavity, pharyngeal, and laryngal cancer diagnosed each year in Western Europe and the United States, respectively. The presence or absence of local and regional disease primarily determines the treatment outcome among these patients. Nonetheless, although the incidence of distant metastases is relatively low, as compared with that of other cancers of the upper aerodigestive tract, distant metastases will develop in almost one third of patients. There is thus a need for improvement in the management of local and regional disease as well as systemic disease. Early disease is generally treated with either definitive radiotherapy or conservative surgery, two approaches that have a similar likelihood of controlling the tumor. Locally advanced disease, particularly in patients with other risk factors, requires a more sophisticated, usually multidisciplinary, approach, ranging from radical radiotherapy combined with either concurrent or adjuvant chemotherapy to radical radiotherapy combined with surgery.
For patients at high risk for local recurrence, the treatment of choice has long been surgery combined with postoperative radiotherapy (also known as PORT). Although a randomized comparison of surgery alone with postoperative radiotherapy has not been undertaken, retrospective analysis indicates that postoperative radiotherapy significantly improves the outcome of treatment in this category of patients.1 A randomized study of dose escalation coordinated by the Radiation Therapy Oncology Group (RTOG) showed that the achievement of adequate local and regional control required a minimal dose of 57.6 Gy to the surgical bed, given in 1.8-Gy fractions, plus a booster dose to high-risk sites, and that the therapeutic ratio was not improved with doses above 63 Gy.2
Meta-analyses of randomized trials have shown that in patients with head and neck cancer, concurrent use of radiotherapy and chemotherapy confers a small but significant survival advantage over radiotherapy alone.3,4 Although long-term morbidity data from these trials are sparse and therefore prevent a definitive evaluation of a therapeutic index, concurrent radiotherapy and chemotherapy has been adopted as the standard of care in treatment protocols that previously used radiotherapy as a sole agent. Therefore, the addition of concurrent chemotherapy to improve the outcome of postoperative radiotherapy represented a logical extension of these protocols.
The two phase 3 trials whose results are published in this issue of the Journal, one conducted by the RTOG with the support of the Eastern Cooperative Oncology Group and the Southwest Oncology Group and the other conducted by the European Organization for Research and Treatment of Cancer (EORTC), were designed to test the hypothesis that the addition of concurrent cisplatin to postoperative radiotherapy improves the outcome of treatment among patients with high-risk, resected head and neck cancer.5,6 The interim report by the RTOG is based on results in 416 patients (210 assigned to postoperative radiotherapy and 206 to combined therapy; minimal duration of follow-up, 24.8 months; median, 45.9 months). The trial was designed to detect an absolute increase of 15 percent in the two-year rate of local and regional control. The European study (with 167 patients in each group) had a median follow-up of 60 months and was designed to detect an absolute increase of 15 percent in disease-free survival.
In the two trials, the intention was to perform ablative surgery 4 to 6 weeks before the administration of 60 to 66 Gy of radical conventional radiotherapy over a period of 6 to 6.6 weeks, with or without three cycles of 100 mg of cisplatin per square meter of body-surface area (on days 1, 22, and 43 of radiotherapy). Both studies were well designed, with balanced groups and good compliance with respect to surgery, radiotherapy, and, to a lesser extent, chemotherapy.
Interim analyses show that concomitant chemotherapy and postoperative radiotherapy enhanced the two-year rate of local and regional control by 10 percentage points in the RTOG trial (P=0.01) and the five-year rate of disease-free survival by 11 percentage points in the EORTC trial (P=0.02). However, only the European trial demonstrated a significant increase in survival (40 percent in the postoperative-radiotherapy group, as compared with 53 percent in the combined-therapy group; P=0.04), and neither trial showed a reduction in distant metastases.
Differences in the presentation of morbidity data make comparisons of the two trials somewhat difficult. In both studies, the incidence of severe early adverse effects was significantly increased by the addition of concurrent cisplatin, but the incidence of severe late adverse effects was similar in the two groups in each trial. It is commendable that these two major cancer-research organizations coordinated trials, using similar treatment protocols and patient populations. They are excellent examples of evidence-based research and provide a strong basis for the inclusion of concurrent chemotherapy in postoperative regimens of radiotherapy for high-risk patients.
Although both trials convincingly show that concurrent chemotherapy reduces the rate of failure of postoperative radiotherapy, the disease nevertheless recurs locally in approximately 30 percent of patients and, therefore, further improvement is necessary. The radiobiology of radiotherapy as the sole agent in the treatment of squamous-cell cancer of the head and neck is well understood,7,8,9 but the optimal dose, time frame, and regimen of fractionation in a multidisciplinary setting are not. Two recent phase 3 trials indicate that the use of a shorter-than-conventional overall treatment time for postoperative radiotherapy could improve tumor control and survival.10,11 The Medical Research Council of the United Kingdom is currently coordinating a randomized phase 3 trial comparing the use of an accelerated, three-week schedule of postoperative radiotherapy with a conventional seven-week regimen.12 Most trials of concurrent radiotherapy and chemotherapy have used conventional radiotherapy regimens of six or seven weeks, and there is an indication that the impact of adding chemotherapy may be reduced if it is given in conjunction with an accelerated regimen of radiotherapy.13
Although a hard estimate of the magnitude of therapeutic gain afforded by concurrent radiotherapy and chemotherapy is not yet available, the late-morbidity results seen so far in the RTOG and EORTC trials indicate that this approach provides a real benefit. Therefore, the next obvious step toward further improving the outcome of concomitant chemotherapy and postoperative radiotherapy is identifying which radiotherapy regimen is most effective. Ultimately, the intensity of treatment is limited by the patient's ability to tolerate it. As anticancer treatments become more successful and multidisciplinary, the ability to select an obvious winner becomes more elusive. An informed decision can be made only by weighing the benefits against the harmful effects of the treatment. To do this, early and late adverse effects of treatment must be assessed, recorded, analyzed, and reported with the use of the same rigorous statistical criteria that are mandatory for the reporting of treatment outcomes in clinical trials of radiotherapy in patients with cancer.14
Source Information
From the Academic Department of Oncology, University College London, London (M.I.S.), and the Marie Curie Research Wing, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom (M.I.S., A.R.).
References
Huang DT, Johnson CR, Schmidt-Ullrich R, Grimes M. Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: a comparative study. Int J Radiat Oncol Biol Phys 1992;23:737-742.
Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol Phys 1993;26:3-11.
Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. Lancet 2000;355:949-955.
Browman GP, Hodson DI, Mackenzie RJ, et al. Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: a systematic review of the published literature with subgroup analysis. Head Neck 2001;23:579-589.
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.
Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy in high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-1944.
Dische S, Saunders M, Barrett A, Harvey A, Gibson D, Parmar M. A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;44:123-136.
Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48:7-16.
Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial. Radiother Oncol 1997;44:111-121.
Awwad HK, Lotayef M, Shouman T, et al. Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cancer: influence of proliferation. Br J Cancer 2002;86:517-523.
Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;51:571-578.
CHARTWEL, a randomised controlled trial of continuous hyperfractionated accelerated radiotherapy, versus conventional radiotherapy in post-operative head and neck cancer. London: Medical Research Council, 2004. (ISRCTN no. 62576956.)
Staar S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy -- results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;50:1161-1171.
Trotti A, Bentzen SM. The need for adverse effects reporting standards in oncology clinical trials. J Clin Oncol 2004;22:19-22.(Michele I. Saunders, M.D.)
For patients at high risk for local recurrence, the treatment of choice has long been surgery combined with postoperative radiotherapy (also known as PORT). Although a randomized comparison of surgery alone with postoperative radiotherapy has not been undertaken, retrospective analysis indicates that postoperative radiotherapy significantly improves the outcome of treatment in this category of patients.1 A randomized study of dose escalation coordinated by the Radiation Therapy Oncology Group (RTOG) showed that the achievement of adequate local and regional control required a minimal dose of 57.6 Gy to the surgical bed, given in 1.8-Gy fractions, plus a booster dose to high-risk sites, and that the therapeutic ratio was not improved with doses above 63 Gy.2
Meta-analyses of randomized trials have shown that in patients with head and neck cancer, concurrent use of radiotherapy and chemotherapy confers a small but significant survival advantage over radiotherapy alone.3,4 Although long-term morbidity data from these trials are sparse and therefore prevent a definitive evaluation of a therapeutic index, concurrent radiotherapy and chemotherapy has been adopted as the standard of care in treatment protocols that previously used radiotherapy as a sole agent. Therefore, the addition of concurrent chemotherapy to improve the outcome of postoperative radiotherapy represented a logical extension of these protocols.
The two phase 3 trials whose results are published in this issue of the Journal, one conducted by the RTOG with the support of the Eastern Cooperative Oncology Group and the Southwest Oncology Group and the other conducted by the European Organization for Research and Treatment of Cancer (EORTC), were designed to test the hypothesis that the addition of concurrent cisplatin to postoperative radiotherapy improves the outcome of treatment among patients with high-risk, resected head and neck cancer.5,6 The interim report by the RTOG is based on results in 416 patients (210 assigned to postoperative radiotherapy and 206 to combined therapy; minimal duration of follow-up, 24.8 months; median, 45.9 months). The trial was designed to detect an absolute increase of 15 percent in the two-year rate of local and regional control. The European study (with 167 patients in each group) had a median follow-up of 60 months and was designed to detect an absolute increase of 15 percent in disease-free survival.
In the two trials, the intention was to perform ablative surgery 4 to 6 weeks before the administration of 60 to 66 Gy of radical conventional radiotherapy over a period of 6 to 6.6 weeks, with or without three cycles of 100 mg of cisplatin per square meter of body-surface area (on days 1, 22, and 43 of radiotherapy). Both studies were well designed, with balanced groups and good compliance with respect to surgery, radiotherapy, and, to a lesser extent, chemotherapy.
Interim analyses show that concomitant chemotherapy and postoperative radiotherapy enhanced the two-year rate of local and regional control by 10 percentage points in the RTOG trial (P=0.01) and the five-year rate of disease-free survival by 11 percentage points in the EORTC trial (P=0.02). However, only the European trial demonstrated a significant increase in survival (40 percent in the postoperative-radiotherapy group, as compared with 53 percent in the combined-therapy group; P=0.04), and neither trial showed a reduction in distant metastases.
Differences in the presentation of morbidity data make comparisons of the two trials somewhat difficult. In both studies, the incidence of severe early adverse effects was significantly increased by the addition of concurrent cisplatin, but the incidence of severe late adverse effects was similar in the two groups in each trial. It is commendable that these two major cancer-research organizations coordinated trials, using similar treatment protocols and patient populations. They are excellent examples of evidence-based research and provide a strong basis for the inclusion of concurrent chemotherapy in postoperative regimens of radiotherapy for high-risk patients.
Although both trials convincingly show that concurrent chemotherapy reduces the rate of failure of postoperative radiotherapy, the disease nevertheless recurs locally in approximately 30 percent of patients and, therefore, further improvement is necessary. The radiobiology of radiotherapy as the sole agent in the treatment of squamous-cell cancer of the head and neck is well understood,7,8,9 but the optimal dose, time frame, and regimen of fractionation in a multidisciplinary setting are not. Two recent phase 3 trials indicate that the use of a shorter-than-conventional overall treatment time for postoperative radiotherapy could improve tumor control and survival.10,11 The Medical Research Council of the United Kingdom is currently coordinating a randomized phase 3 trial comparing the use of an accelerated, three-week schedule of postoperative radiotherapy with a conventional seven-week regimen.12 Most trials of concurrent radiotherapy and chemotherapy have used conventional radiotherapy regimens of six or seven weeks, and there is an indication that the impact of adding chemotherapy may be reduced if it is given in conjunction with an accelerated regimen of radiotherapy.13
Although a hard estimate of the magnitude of therapeutic gain afforded by concurrent radiotherapy and chemotherapy is not yet available, the late-morbidity results seen so far in the RTOG and EORTC trials indicate that this approach provides a real benefit. Therefore, the next obvious step toward further improving the outcome of concomitant chemotherapy and postoperative radiotherapy is identifying which radiotherapy regimen is most effective. Ultimately, the intensity of treatment is limited by the patient's ability to tolerate it. As anticancer treatments become more successful and multidisciplinary, the ability to select an obvious winner becomes more elusive. An informed decision can be made only by weighing the benefits against the harmful effects of the treatment. To do this, early and late adverse effects of treatment must be assessed, recorded, analyzed, and reported with the use of the same rigorous statistical criteria that are mandatory for the reporting of treatment outcomes in clinical trials of radiotherapy in patients with cancer.14
Source Information
From the Academic Department of Oncology, University College London, London (M.I.S.), and the Marie Curie Research Wing, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom (M.I.S., A.R.).
References
Huang DT, Johnson CR, Schmidt-Ullrich R, Grimes M. Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: a comparative study. Int J Radiat Oncol Biol Phys 1992;23:737-742.
Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol Phys 1993;26:3-11.
Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. Lancet 2000;355:949-955.
Browman GP, Hodson DI, Mackenzie RJ, et al. Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: a systematic review of the published literature with subgroup analysis. Head Neck 2001;23:579-589.
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.
Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy in high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-1944.
Dische S, Saunders M, Barrett A, Harvey A, Gibson D, Parmar M. A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;44:123-136.
Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48:7-16.
Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial. Radiother Oncol 1997;44:111-121.
Awwad HK, Lotayef M, Shouman T, et al. Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cancer: influence of proliferation. Br J Cancer 2002;86:517-523.
Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;51:571-578.
CHARTWEL, a randomised controlled trial of continuous hyperfractionated accelerated radiotherapy, versus conventional radiotherapy in post-operative head and neck cancer. London: Medical Research Council, 2004. (ISRCTN no. 62576956.)
Staar S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy -- results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001;50:1161-1171.
Trotti A, Bentzen SM. The need for adverse effects reporting standards in oncology clinical trials. J Clin Oncol 2004;22:19-22.(Michele I. Saunders, M.D.)