The Oncologist, Vol. 2, No. 3, 135–141,
June 1997
© 1997 AlphaMed Press
Adjuvant Chemotherapy in Advanced Head and Neck Cancer
Philip C. Amreina,
Christopher H. Colecchib,
Dianne M. Finkelsteinc,
Richard L. Fabiand
a Hematology-Oncology Unit,
b Protocol Office,
c Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA;
d Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA
Correspondence:
Philip C. Amrein, M.D., Hematology-Oncology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Telephone: 617-726-8748; Fax: 617-724-1137; e-mail: Amrein.Philip{at}MGH.Harvard.Edu
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ABSTRACT
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Purpose. Chemotherapy has been tested extensively in conjunction with standard therapy in the treatment of head and neck cancer, primarily in the form of neoadjuvant chemotherapy, but few trials have shown a survival benefit. Although a few studies have suggested that adjuvant chemotherapy given after standard treatment may improve survival, to date these trials have been troubled by various problems in design and dosing. The purpose of our trial was to determine the feasibility of giving moderately intensive chemotherapy exclusively after standard therapy, and to determine whether survival appeared to be improved as measured against historical data.
Methods. We used adjuvant chemotherapy in two groups of patients with squamous cell carcinoma of the head and neck: group A consisted of 46 patients with newly diagnosed stage III and IV disease, and group B consisted of 46 patients with relapsed disease having been treated with salvage surgery. In all patients, the intended adjuvant chemotherapy consisted of two cycles of combination cisplatin, bleomycin, and infusional 5-fluorouracil (5-FU) given three weeks apart, followed by four cycles of bolus methotrexate, 5-FU, and bleomycin given every two weeks.
Results. In group A, the two-year survival was 72%. In group B, the two-year survival was 58%.
Conclusion. Compared to the vast majority of similarly staged patients with head and neck cancer reported in the literature, the survival of our group seemed considerably better, suggesting that a definitive randomized study testing this schedule of adjuvant chemotherapy is warranted.
Key Words. Adjuvant chemotherapy • Head and neck cancer • Cisplatin • Bleomycin • 5-Fluorouracil • Methotrexate
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INTRODUCTION
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Chemotherapy has been used extensively over the past two decades in the treatment of advanced squamous cell carcinomas of the head and neck, but few trials have suggested a survival benefit from its use [1–4]. Induction chemotherapy, or neoadjuvant chemotherapy, may be used to select a responding subset of patients for subsequent treatment with radiotherapy alone to avoid surgery in resectable stage III and IV disease [5, 6, 7]. However, this strategy has not suggested an overall survival benefit for the patients entering into this type of program [8, 9]. The concurrent use of chemotherapy and radiotherapy for patients with advanced disease is popular now and results in a high proportion of complete responders and patients surviving at three to five years, but it is unclear yet whether survival is improved with this strategy over conventional surgery and radiotherapy [10–13]. Of great interest is the improvement in results with modern radiotherapy techniques using accelerated hyperfractionation without surgery or chemotherapy [14–17]. Indeed, a recently conducted large randomized trial [18] not only showed that the twice-daily technique resulted in a significantly higher local control rate at five years than the once-daily technique, but also showed that advanced disease patients initially treated with radiotherapy alone could have a two-year survival of 50% and a five-year survival of 40%, which is no different from the vast majority of combined therapy trials cited above.
Adjuvant chemotherapy given after standard surgery and/or radiotherapy has not been adequately explored. Trials reported to date have been inconclusive, mainly due to the difficulty in giving the therapy [3, 19]. Nevertheless, available data suggest that survival may be enhanced with this treatment. A subset analysis of the Head and Neck Contracts Program sponsored by the National Cancer Institute showed that some groups of patients did seem to have a survival benefit from chemotherapy given after standard surgery and radiotherapy, even when more than half of the patients randomized to that group never got the treatment due to patient refusal [20]. Johnson reported the use of methotrexate and 5-fluorouracil (5-FU) given for six months after standard surgery and radiotherapy in head and neck cancer patients at high risk for recurrence due to extracapsular spread of disease in cervical lymph nodes [21]. At approximately two years, over half of the patients were both alive and without relapse compared with an expected rate of 38%. Ervin tested the use of three cycles of adjuvant cisplatin, bleomycin, and methotrexate after standard surgery and radiotherapy in stage III and IV patients who had shown a response to induction chemotherapy [22]. In this subset, the 26 patients randomized to adjuvant chemotherapy had a 30% improvement in failure-free survival at five years. Contrary to these positive findings, Volkes treated 51 patients with stage III and IV head and neck cancer with three cycles of adjuvant chemotherapy after they had already been treated with induction chemotherapy, surgery, and radiotherapy [9]. Only 63% actually received any of the adjuvant chemotherapy. The median survival was only 22 months, and the projected five-year survival was only 25%. The authors offer no explanation for the poor results in this trial. Finally, a recently conducted intergroup trial of concurrent cisplatin and radiotherapy followed by three cycles of adjuvant chemotherapy in advanced nasopharyngeal cancer had to be stopped early due to a 25% improvement in survival of patients at two years as compared with patients randomized to receive radiotherapy alone [23]. The authors do not know which chemotherapy component of the program was the more important, but at least one published randomized trial of the same schedule of concurrent cisplatin and radiotherapy proved to be no better than their induction chemotherapy control group or even their historical controls receiving radiotherapy alone [24]. This information suggests that in the intergroup trial, the adjuvant chemotherapy might have played a more significant role in prolonging survival than the cisplatin given concurrently with the radiotherapy.
The chemotherapy treatment we used in this trial for adjuvant therapy is the four-drug program previously shown by us to be superior to what has been the best standard combination of drugs, cisplatin, and 5-FU [25]. In our randomized trial we found that in patients with unresectable recurrent disease adding bleomycin on day 1 with cisplatin and adding methotrexate with leucovorin on day 16 increased the response rate and failure-free survival without increasing toxicity. This high level of activity in a reasonably tolerable combination of drugs seemed ideal for testing as adjuvant treatment in patients with resectable disease. In addition to its use in stage III and IV patients without prior treatment, this adjuvant program was open to patients who relapsed after surgery and/or radiotherapy and underwent salvage surgery of their recurrence. Typically, these patients have a very poor prognosis, and any therapy that could prolong their survival is important to be tested [1]. Hence, we report the results of our trial using adjuvant cisplatin, bleomycin, 5-FU, and methotrexate in advanced head and neck cancer patients, both those with newly diagnosed stage III and IV disease and those who had failed initial therapy and undergone salvage treatment.
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MATERIALS AND METHODS
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Patients
Patients with histologically documented squamous cell carcinoma of the head and neck region with either newly diagnosed stage III or IV disease (group A) or with recurrent disease surgically resected (group B) were eligible for this trial. The staging system of the American Joint Committee on Cancer was used [26]. In this system, generally, T1 tumors are <2 cm, T2 tumors are 2 cm to 4 cm, T3 tumors are 4 cm to 6 cm, and T4 tumors are >6 cm. Also, N1 nodal disease is <3 cm, N2 disease is 3 cm to 6 cm, and N3 disease is >6 cm. M0 and M1 disease refers to the absence or presence of distant metastatic disease, respectively. Stage III refers to T3 N0 M0 or T1-3 N1 M0. Stage IV refers to T4 N0-3 M0, T1-3 N2-3 M0, and T1-4 N0-3 M1 (note that patients with metastatic disease were excluded from this trial). Patients were entered in this trial in a prospective, consecutive manner, although many patients with newly diagnosed stage III and IV disease were not referred by surgeons or radiotherapists because they considered the prognosis good or the patients refused any consideration of chemotherapy treatment. In group A, most patients had poor prognostic features such as close or positive margins or extranodal extent at the time of surgery. Some had residual disease after surgery or no surgery at all (as with patients with nasopharyngeal cancer), but these patients were eligible, if the intent of the radiotherapy was curative. In group B, all but three patients had failed prior radiotherapy, and many had failed combined radiotherapy and surgery. Since, in this group, no significant further radiotherapy can generally be given, all patients were required to have no gross residual disease left after salvage surgery was completed. However, close or positive margins were allowed, and many patients had these findings. Patients in both groups had to have an ECOG performance status of 2 or better, a serum creatinine <1.5, liver function tests <3 times normal, a WBC >4,000, and a platelet count >100,000. All patients signed chemotherapy consent forms, and all patients were closely followed by our multidisciplinary group at the Massachusetts General Hospital and the Massachusetts Eye and Ear Infirmary using serial CT scans and blood studies.
Treatment
The intent of treatment for all patients entering the study was to use two cycles of the inpatient chemotherapy treatment regimen followed by four cycles of the outpatient regimen. The details of the inpatient regimen have been reviewed previously [23], but, in brief, on day 1, patients received cisplatin 80 mg/m2 and bleomycin 15 units (total) as a 24-h infusion with forced diuresis. On days 2 through 6, patients received a five-day continuous infusion of 5-FU 800 mg/m2/day. Considered as part of the inpatient cycle was one dose of methotrexate 100 mg/m2 on day 16 (followed in 24 h by leucovorin 15 mg every six h for six doses) in the outpatient setting. The outpatient regimen consisted of methotrexate 100 mg/m2 i.v., 5-FU 500 mg/m2 i.v., and bleomycin 15 units i.v. on day 1 of each two-week cycle. Patients received leucovorin 15 mg by mouth every six h for six doses starting on day 2, 24 h after the methotrexate.
All patients had serum electrolytes and renal function tested daily while receiving cisplatin and 5-FU. They also had CBCs and liver function tests monitored weekly. An audiogram was performed with each inpatient treatment. CT scans of the head and neck were performed before and after the adjuvant chemotherapy program and then every six months until year 3, when scanning went to every 12 months for another two years.
Response
Since in no patient was a tumor mass measurable initially, the success of therapy was measured in duration of disease-free survival (DFS), event-free survival, and in duration of overall survival. All times started with the onset of cycle 1 of chemotherapy. If a patient died of a non-cancer cause or of a treatment-related cause without relapse of his tumor, he was censored at that point in the analysis of disease-free survival, but considered a failure in the analysis of event-free survival. All causes of death were considered failures in the analysis of the overall survival. Survival estimates were calculated according to the life-table methods of Kaplan and Meier.
Toxicity Analysis
Nausea, vomiting, diarrhea, stomatitis, and dyspnea were routinely assessed by the nurse and physician caring for the patient, with documentation in the chart as well as on flow sheets for both inpatient and outpatient encounters. Test results of blood studies and CT scans were also entered onto flow sheets. Grading of toxicities was as follows: nausea and vomiting, none = 0; nausea only = 1+; vomiting, 1-3 times per day = 2+; vomiting >3 times per day = 3+; vomiting requiring i.v. support = 4+; diarrhea, none = 0; 1-3 loose stools per day = 1+; 4-6 loose stools per day = 2+; >6 loose stools per day = 3+; diarrhea requiring i.v. support = 4+; stomatitis, none = 0; minimal soreness = 1+; many sores and some pain but no interference with food intake = 2+; interference with food intake = 3+; need for i.v. support = 4+.
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RESULTS
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From 1987 to 1993, 92 patients were entered in this study, 46 patients with newly diagnosed stage III or IV disease and 46 patients treated with salvage surgery after failure of prior surgery and/or radiotherapy. Patient characteristics are listed in Table 1 .
Survival, Group A
DFS for patients with newly diagnosed disease is shown in Figure 1. The median DFS was 31 months. At two years, the DFS was 54% (95% exact confidence limits of 38% and 70%). The median and two-year event-free survivals for this group were 23 months and 49%, respectively (data not shown). The overall survival for patients with newly diagnosed disease is shown in Figure 2. The median overall survival cannot be estimated. At two years, the overall survival was 72% (95% exact confidence limits of 58% and 85%). There were four deaths in this group that were not due to the patient’s head and neck cancer. Two of these deaths may be considered due to treatment toxicity (Toxicity section, below). The other two deaths occurred as follows: one at three months with sudden death at home while apparently tolerating chemotherapy well, and one at 15 months with sudden death at home due to a tracheal plug. In this group are 13 patients alive and without recurrence of their cancer over three years after starting the adjuvant chemotherapy program. The clinical history of these patients is outlined in Table 2.
Survival, Group B
The DFS for patients in the surgical salvage group is shown in Figure 3. The median DFS for this group was 25 months. At two years, the DFS was 50% (95% exact confidence limits of 35% and 65%). The median and two-year event-free survivals were 14 months and 40%, respectively (data not shown). The overall survival for patients in the surgical salvage group is shown in Figure 4. The median overall survival was 30 months. At two years, the overall survival was 58% (95% exact confidence limits of 43% and 72%). There were seven deaths in this group apparently not related to the patient’s head and neck cancer. One of these deaths may have been a treatment toxicity (Toxicity section, below), and the other six are as follows: three with cardiac failure at five to six months, one at four months having been lost to follow-up for two months, one of oat cell lung cancer at 14 months, and one of esophageal varices at 21 months. In this group, there were 11 patients alive without recurrence of their cancer over three years after starting the adjuvant chemotherapy program. These patients are listed in Table 3. Of note are the high numbers of patients with microscopic disease likely left behind after the salvage surgery due to the presence of close margins, positive margins, or extranodal disease.
Toxicity
The toxicity profile of the newly diagnosed group was nearly identical to that of the salvage treatment group (Table 4). The numbers represent the worst toxicity in each category for each patient for the whole chemotherapy program. Generally, the treatment was very well tolerated, but there were three deaths on therapy which may be considered toxic deaths: A) a 58-year-old woman who died at two months from colitis due to E. coli 0157:H7; B) a 65-year-old man who died at one month due to pneumonia with a WBC = 1,700/µl, and C) a 53-year-old man who died at two months due to hemorrhage into his throat, possibly due to tumor or a surgical wound problem.
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DISCUSSION
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There continues to be much investigational use of chemotherapy in the overall treatment of advanced squamous cell cancers of the head and neck despite the minimal evidence for any survival benefit from its use. This study was initiated to test whether moderately intensive chemotherapy could be given after standard surgery and/or radiotherapy since few studies in the past have given chemotherapy this way, but there have been suggestions that survival might be positively influenced if the treatment were not too toxic. Although not a prospective randomized study, this study suggests that these patients can tolerate moderately intensive chemotherapy, and survival seems better than in previous studies reported in the literature.
In our newly diagnosed patients with very advanced stage III and IV disease, our overall survival at two years was 72% (95% exact confidence limits of 58% and 85%). This two-year survival seems better than the 50% two-year survival reported in the vast majority of recently published trials of patients treated for stage III and IV resectable disease [2, 19]. Critics might argue that our patients were selected to do well due to their good performance status, but the high incidence of close margins, positive margins, and findings of extranodal spread of tumor at the time of surgery would suggest that these patients would do very poorly. To prove that adjuvant chemotherapy given after standard therapy improves survival, one would still need to do a randomized prospective study, and such a study seems appropriate at this time.
More dramatic than the results in the newly diagnosed patient group are the results in the salvage treatment group. Over the years, patients who failed initial therapy have had a very poor prognosis, and five-year survival has not been considered likely [1]. Many trials in unresectable recurrent disease have reported median survivals of 4 to 10 months, with few alive at two years [1, 2, 25]. Outcome would be expected to be somewhat better in patients undergoing surgical removal of recurrent disease, but few trials exist reporting survival results in such patients. Our patients undergoing surgical salvage of recurrent disease followed by adjuvant chemotherapy had a two-year survival of 58%, and many patients were alive and disease-free at three to five years. These results look much like those reported in the literature for patients with newly diagnosed stage III and IV resectable disease [2, 19]. Of particular interest is the group surviving over three years without relapse. Among these 11 patients, seven had either close margins, positive margins, or extranodal spread at the time of salvage surgery and would be expected to have relapsed within 6 to 12 months without further treatment. It would seem that chemotherapy may be capable of eradicating minimal to microscopic disease in this setting. These encouraging results, nevertheless, must be considered preliminary and need to be confirmed in a prospective, randomized study.
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accepted for publication March 19, 1997.
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Abstract
Introduction
