Postoperative Concurrent Radiotherapy and Chemotherapy for High-Risk Squamous-Cell Carcinoma of the Head and Neck
Jay S. Cooper, M.D., Thomas F. Pajak, Ph.D., Arlene A. Forastiere, M.D., John Jacobs, M.D., Bruce H. Campbell, M.D., Scott B. Saxman, M.D., Julie A. Kish, M.D., Harold E. Kim, M.D., Anthony J. Cmelak, M.D., Marvin Rotman, M.D., Mitchell Machtay, M.D., John F. Ensley, M.D., K.S. Clifford Chao, M.D., Christopher J. Schultz, M.D., Nancy Lee, M.D., Karen K. Fu, M.D., for the Radiation Therapy Oncology Group 9501/Intergroup
Methods Between September 9, 1995, and April 28, 2000, 459 patientswere enrolled. After undergoing total resection of all visibleand palpable disease, 231 patients were randomly assigned toreceive radiotherapy alone (60 to 66 Gy in 30 to 33 fractionsover a period of 6 to 6.6 weeks) and 228 patients to receivethe identical treatment plus concurrent cisplatin (100 mg persquare meter of body-surface area intravenously on days 1, 22,and 43).
Despite regimens that permit organ preservation in selectedpatients with advanced carcinomas of the head and neck,1,2,3ablative surgical resection and postoperative radiotherapy arerequired in many patients. Typically, local or regional diseaserecurs in 30 percent of patients, and distant metastases appearin 25 percent; the five-year survival rate is 40 percent.4 Patientswho have two or more regional lymph nodes involved, extracapsularspread of disease, or microscopically involved mucosal marginsof resection have particularly high rates of local recurrence(27 to 61 percent) and distant metastases (18 to 21 percent)and a high risk of death (five-year survival rate, 27 to 34percent).5
Advanced tumors at some sites respond better to concurrent chemotherapyand radiotherapy than to radiotherapy alone.6,7,8,9,10,11 However,there are insufficient data to permit evaluation of this combinationfor resected cancers of the head and neck. This trial was basedon our previous analysis5 and was designed to determine whetherconcurrent cisplatin therapy and postoperative radiotherapyimprove the rates of local and regional control among patientswho have high-risk operable head and neck cancer.
Methods
The Radiation Therapy Oncology Group (RTOG), supported by theEastern Cooperative Oncology Group (ECOG) and the SouthwestOncology Group (SWOG), conducted this intergroup phase 3 trial(RTOG 9501, ECOG R9501, and SWOG 9515). Eligible patients hadsquamous-cell carcinoma arising in the oral cavity, oropharynx,larynx, or hypopharynx; had undergone macroscopically completeresection of disease; had high-risk characteristics (any orall of the following: histologic evidence of invasion of twoor more regional lymph nodes, extracapsular extension of nodaldisease, and microscopically involved mucosal margins of resection);and could tolerate chemotherapy, as defined by a Karnofsky performancescore of at least 60, a white-cell count of at least 3500 percubic millimeter, a platelet count of at least 100,000 per cubicmillimeter, and a creatinine clearance of more than 50 ml perminute. All patients gave written informed consent in accordancewith institutional guidelines. The study was approved by theinstitutional review board of each center.
Pretreatment Procedures
Before surgery, a medical history was obtained for each patient;each patient underwent a physical examination, complete bloodcount, serum chemical profile, urinalysis, chest radiography,and dental evaluation; and a diagram of the primary tumor andneck nodes was made. The protocol required radiotherapy to beginas soon after surgery as adequate healing had occurred. Normally,this occurs four to six weeks after the surgical procedure;the protocol required radiotherapy to begin no later than 8weeks (56 calendar days) after surgery. Patients were stratifiedaccording to age (younger than 70 years vs. 70 years or more)and the presence or absence of microscopic tumor at the mucosalsurgical margins, and then randomly assigned at RTOG headquartersto receive radiotherapy alone (60 Gy in 30 fractions over asix-week period, with or without a boost of 6 Gy in 3 fractionsover a period of three days to high-risk sites) or concurrentlywith cisplatin (100 mg per square meter of body-surface areaintravenously on days 1, 22, and 43). In the cisplatin group,hydration was prescribed before and after treatment; the useand choice of antiemetics were left to the physician's discretion.In both groups, the use and timing of feeding tubes were optional.The permuted-block allocation scheme described by Zelen wasused, in which the treatment assignments were balanced initiallywithin the institution and then according to patient factors.12
Treatment Modification
A continuous course of radiotherapy was maintained if at allpossible; any interruptions resulting from treatment-relatedadverse effects had to be kept to a minimum and reported. Cisplatintherapy was postponed if, on the day of scheduled treatment,the absolute neutrophil count was below 1000 per cubic millimeteror the platelet count was below 75,000 per cubic millimeter.The dose of cisplatin was reduced by 40 percent if neurotoxicityoccurred, decreased to 75 mg per square meter if the creatinineclearance dropped to 40 to 50 ml per minute, and discontinuedin the event of lower values.
Follow-up
During treatment, patients were examined at least weekly. Oncetreatment ended, an evaluation was required at nine weeks, thenevery three months for the first year, twice annually in years2 and 3, and annually thereafter. The tumor status, the patient'sstatus, and treatment-related adverse effects were recorded.
Study End Points
The primary end point was local and regional tumor control;failure was defined as the reappearance of tumor in the originaltumor bed or the development of cervical-node metastases aftertreatment. Secondary end points were disease-free survival,overall survival, and adverse effects. Disease-free survivalwas measured from the time of randomization to the time of discoveryof the first evidence after treatment of any tumor (local, regional,metastatic, or second primary) or death from any cause. Overallsurvival was measured from the date of randomization to thedate of death from any cause. Treatment-related adverse effectswere scored according to the Common Toxicity Criteria of theNational Cancer Institute, version 2.0, for chemotherapy andaccording to RTOG criteria for radiotherapy.13 Treatment-relatedadverse effects were categorized as acute (occurring within90 days after the start of radiotherapy) or late (continuingor occurring after 90 days).
Statistical Analysis
On the basis of the previous trials of the RTOG, patients treatedwith postoperative radiation were expected to have a two-yearrate of local or regional recurrence of 38 percent. The studyrequired the randomization of 398 eligible patients to havethe statistical power to detect an absolute improvement of 15percent in this rate with the use of a two-sided test with 0.80statistical power and a significance level of 0.05. To compensatefor an expected rate of ineligibility and loss to follow-upof up to 10 percent, 438 patients were scheduled to be enrolled.The study was overseen by an independent data-monitoring committee.The analytic plan called for early significance testing at an value of 0.001 when 50 percent and then 100 percent of thetargeted number of patients had been enrolled and for the definitiveanalysis to be performed after each patient had potentiallybeen followed for two years. The reported P values are unadjusted.
Rates of local and regional control were estimated accordingto the method of cumulative incidence,14 and differences wereassessed by means of Gray's test.15 Rates of overall and disease-freesurvival were estimated according to the Kaplan–Meiermethod,16 and differences between groups were assessed by meansof the log-rank statistic.17 The hazard ratios are reportedwith 95 percent confidence intervals.
Results
Patients
Between September 9, 1995, and April 28, 2000, 459 patientswere enrolled: 231 were randomly assigned to receive radiotherapyalone, and 228 to receive concurrent combined therapy. All informationreceived at RTOG headquarters by June 20, 2003, is includedin this report. After a case-by-case nonblinded review by thestudy chairs, 43 patients (21 assigned to radiotherapy and 22to concurrent combined therapy) were deemed ineligible. Of these43 patients, 23 (11 in the radiotherapy group and 12 in thecombined-therapy group) did not have one of the specified high-riskcharacteristics; 10 (5 in each group) did not have tumors thatclearly arose in one of the specified sites; 7 (4 in the radiotherapygroup and 3 in the combined-therapy group) did not undergo macroscopicallycomplete resection of disease, 2 (1 in each group) had metastaticdisease at study entry, and 1 (in the combined-therapy group)had an inadequate creatinine clearance. Thus, we report theoutcome among 416 patients (210 in the radiotherapy group and206 in the combined-therapy group). All surviving eligible patientswere followed for a minimum of 24 months; as of June 20, 2003,45 percent of the patients were alive. Table 1 lists the baselinecharacteristics of the patients. There were no significant differencesin these characteristics between the groups.
Table 1. Pretreatment Characteristics of the Patients.
Compliance with and Delivery of Treatment
Compliance with the treatment plan was assessed by each of thestudy chairs. The specified surgery was performed (accordingto the protocol or with only minor deviations) in 97 percentof patients. Three patients (less than 1 percent) had an unacceptableinterval of more than 62 days from surgery to the start of postoperativetreatment. The specified radiotherapy was delivered in 80 percentof patients. The treatment portals were inadequate to coverall high-risk disease in 8 percent of patients treated by irradiationand in 10 percent treated by combined therapy; the treatmentportals were adequate, but the dose, number of fractions, ortotal time was unacceptable in 6 percent treated by irradiationand 5 percent treated by combined therapy. The specified chemotherapywas delivered in 83 percent of patients.
Tumor Control
After a median follow-up among surviving patients of 45.9 months(range, 24.8 to 85.1), 104 local or regional recurrences wereobserved: 64 in the radiotherapy group (30 percent) and 40 inthe combined-treatment group (19 percent) (hazard ratio forlocal or regional recurrence, 0.61; 95 percent confidence interval,0.41 to 0.91; P=0.01) (Figure 1). Including all ineligible randomizedpatients in the analysis did not change the qualitative result(hazard ratio, 0.58; 95 percent confidence interval, 0.40 to0.85; P=0.003). The estimated two-year rate of local and regionalcontrol was 72 percent for radiotherapy alone and 82 percentfor combined therapy. Only eight local and regional recurrenceshave been observed beyond two years. Of the 189 patients whowere alive on June 20, 2003, 177 (94 percent) had not had alocal or regional recurrence.
Patients assigned to receive radiotherapy and concurrent chemotherapy had a higher rate of local and regional control than patients assigned to receive radiotherapy alone (P=0.01 by Gray's test). Tick marks indicate censored data.
Patterns of Failure
Local or regional recurrence as the first site of treatmentfailure occurred in 61 of 210 patients who received radiotherapy(29 percent) and in 33 of 206 patients given combined therapy(16 percent) (P=0.002). The incidence of distant metastasisas the first evidence of treatment failure was similar in thetwo groups (23 percent in the radiotherapy group and 20 percentin the combined-therapy group, P=0.46).
Survival
Disease-free survival was significantly longer after concurrentcombined therapy than after radiotherapy alone (hazard ratiofor disease or death, 0.78; 95 percent confidence interval,0.61 to 0.99; P=0.04) (Figure 2). A total of 148 treatment failureswere associated with radiotherapy (70 percent), and 124 (60percent) with combined therapy. However, overall survival didnot differ significantly between groups (hazard ratio for death,0.84; 95 percent confidence interval, 0.65 to 1.09; P=0.19)(Figure 3), with 123 deaths associated with radiotherapy and104 associated with combined therapy.
Figure 2. Kaplan–Meier Estimates of Disease-free Survival.
Patients assigned to receive radiotherapy and concurrent chemotherapy had a higher rate of disease-free survival than patients assigned to receive radiotherapy alone (P=0.04 by the log-rank test). Tick marks indicate censored data.
Figure 3. Kaplan–Meier Estimates of Overall Survival.
Overall survival did not differ significantly between groups (P=0.19 by the log-rank test). Tick marks indicate censored data.
Compliance with Chemotherapy
A total of 125 patients (61 percent) received all three plannedcycles of cisplatin, 47 (23 percent) received two cycles, 27(13 percent) received one cycle, and 4 (2 percent) receivedno chemotherapy. In three other patients documentation of chemotherapywas insufficient. The 171 patients (83 percent) who receivedchemotherapy exactly as planned in the protocol or with onlyminor variations had a two-year rate of local and regional controlof 82 percent, which is indistinguishable from the 82 percentrate among all patients assigned to concurrent combined therapy.
Adverse Effects
The addition of chemotherapy to radiotherapy increased the incidenceof severe adverse effects (Table 2). Acute adverse effects ofgrade 3 or greater occurred in 34 percent of patients who receivedradiotherapy alone and in 77 percent of patients who receivedconcurrent combined therapy (P<0.001). This increase resultedlargely from an increased incidence of hematologic, mucous-membrane,and gastrointestinal adverse effects related to chemotherapy.The incidence of severe late adverse effects did not differsignificantly between the groups (17 percent in the radiotherapygroup and 21 percent in the combined-therapy group, P=0.29).Combining acute and late adverse effects resulted in a significantlyhigher likelihood of an adverse effect of grade 3 or greaterat any time among patients receiving combined therapy than amongthose receiving radiotherapy alone (78 percent vs. 46 percent,P<0.001). No patient treated with radiotherapy alone diedof a protocol-related adverse effect, whereas four patients(2 percent) who received concurrent combined therapy did so.Four patients died within 30 days after the end of treatment:one in the radiotherapy group (who died of tumor progression)and three in the combined-therapy group (one of whom died oftumor progression).
While our trial was being conducted, the European Organizationfor Research and Treatment of Cancer (EORTC) was conductinga similar, large-scale trial.18 (The final results appear elsewherein this issue of the Journal.19) The eligibility criteria weresimilar to ours except with respect to high-risk status. Inthe EORTC trial, high risk was defined by the presence of anyof the following pathological features: involved surgical margins,extranodal spread of disease, nodal tumor at level 4 or 5 inthe case of oral-cavity or oropharyngeal primaries, perineuraldisease, or vascular tumor emboli. The radiotherapy and chemotherapyregimens were identical in the two trials. The EORTC trial wasdesigned to detect a 15 percent increase in the rate of disease-freesurvival (from 40 percent to 55 percent at three years), whereasour trial was designed to detect a 15 percent increase in therate of local and regional control.
After a median follow-up of 34 months, the estimated 3-yeardisease-free survival rates in the EORTC trial were 41 percentin the radiotherapy group and 59 percent in the combined-therapygroup (P=0.009). The rates of overall survival and of localand regional control were significantly higher and the timeto progression was significantly longer in the group given concurrentcombined therapy. However, the concurrent administration ofcisplatin increased the incidence of grade 3 or 4 functionalmucosal reactions (21.3 percent vs. 44.5 percent, P<0.001)and caused granulocytopenia and thrombocytopenia of grade 3or more in 12.8 percent of patients. The authors concluded thatpostoperative concurrent combined therapy significantly improvesthe outcome among selected high-risk patients.
Our results also demonstrate a significant improvement in localand regional control with concurrent postoperative chemotherapyand radiotherapy (our primary end point) and disease-free survival(a secondary end point). However, unlike the EORTC trial, overallsurvival in our trial was not significantly longer in the combined-therapygroup than in the radiotherapy group (median, 31.9 vs. 44.9months). In this regard, it is important to emphasize that theeligibility criteria for the two trials differed. Preciselyhow much of the difference in overall survival between the twotrials is directly attributable to the type of patients selectedis unknown. Overall survival among patients with head and neckcancer is a complex issue because of the common occurrence ofdeath from other diseases related to alcohol use, smoking, orboth. At the time of the last analysis of this study, the overallsurvival curves were separating in favor of combined treatment,and if this trend continues, there may eventually be a significantdifference in survival between the two groups.
The human cost of intensified treatment with concurrent postoperativechemotherapy and radiotherapy was a significant increase insevere adverse effects. Four patients (2 percent) assigned toconcurrent therapy died as a direct result of the treatment(as compared with none of those who were assigned to radiotherapyalone). In addition, 27 percent of patients assigned to concurrenttherapy had an adverse effect of grade 4 or 5, as compared with7 percent of those who received radiotherapy alone.
The frequency of distant metastases in both groups was similar,suggesting that the concurrently administered regimen of chemotherapythat we evaluated did not exert its principal beneficial effectby preventing metastases. Rather, its predominant effect wasprobably to potentiate both the beneficial and the adverse effectsof the radiotherapy. A radiosensitizing regimen that would increasethe benefit of radiotherapy without increasing its toxicitywould be highly desirable.
In summary, our trial establishes the proof of principle thatconcurrent postoperative administration of chemotherapy andradiotherapy is a way to intensify treatment for resectablehigh-risk head and neck tumors. Our results should not be appliedto all patients who require postoperative irradiation; in particular,they cannot be applied to patients who would not have qualifiedfor this trial. However, we believe that our data, in combinationwith the EORTC data, establish a new standard of care for adjuvanttherapy of physically fit patients with high-risk head and neckcancer.
Supported by grants (CA21661 and CA32115) from the NationalCancer Institute.
We are indebted to the following, without whose support thiswork would not have been possible: the patients who volunteeredto participate in this trial; the physicians, nurses, researchassociates, and staff members of the RTOG headquarters, whoassisted in providing care and safeguarding the validity ofthe collected data; and, in particular, Brian A. Berkey, RebeccaAllegretto, Betty Martin, and Bernadine Dunning.
Source Information
From New York University Medical Center, New York (J.S.C.); Radiation Therapy Oncology Group Headquarters, Philadelphia (T.F.P.); Johns Hopkins Oncology Center, Baltimore (A.A.F.); Wayne State University School of Medicine, Detroit (J.J., H.E.K., J.F.E.); Medical College of Wisconsin, Milwaukee (B.H.C., C.J.S.); National Cancer Institute, Bethesda, Md. (S.B.S.); H. Lee Moffitt Cancer Center, Tampa, Fla. (J.A.K.); Vanderbilt Cancer Center, Nashville (A.J.C.); State University of New York Health Center at Brooklyn, Brooklyn (M.R.); University of Pennsylvania Health System, Philadelphia (M.M.); Mallinckrodt Institute of Radiology, St. Louis (K.S.C.C.); and the University of California, San Francisco, San Francisco (N.L., K.K.F.).
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Treatment of Advanced Head and Neck Cancer
Fortin A., Audet N., Caouette R., Yalçn B., Büyükçelik A., Utkan G., Sonpavde G., Cooper J. S., Forastiere A. A., Jacobs J., Bernier J., the European Organization for Research and Treatment of Cancer
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value of 0.001 when 50 percent and then 100 percent of the targeted number of patients had been enrolled and for the definitive analysis to be performed after each patient had potentially been followed for two years. The reported P values are unadjusted. 
n B., Büyükçelik A., Utkan G., Sonpavde G., Cooper J. S., Forastiere A. A., Jacobs J., Bernier J., the European Organization for Research and Treatment of Cancer
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