Japanese Journal of Clinical Oncology 30:253-258 (2000)
© 2000 Foundation for Promotion of Cancer Research
Survival Results of Neoadjuvant Chemotherapy for Advanced Squamous Cell Carcinoma of the Head and Neck
1Department of Otolaryngology, National Defense Medical College, Saitama, 2Department of Otolaryngology, Ohtsuka Metropolitan Hospital, Tokyo, 3Department of Otolaryngology, Yokohama Municipal Hospital, Yokohama, 4Department of Otolaryngology, Keiyu Hospital, Yokohama, 5Department of Otolaryngology, Tochigi National Hospital, Utsunomiya and 6Department of Otolaryngology, Nihon Medical College, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: We carried out an open, randomized multi-center clinical trial for advanced head and neck cancer between April 1991 and December 1992. In this report, we update the results and analyze the 5-year survival results.
Methods: Thirty-two patients with previously untreated stage III and IV resectable squamous cell carcinoma of the oral cavity and pharynx were entered into the study. The PEM regimen consisted of cisplatin 60 mg/m2 2 h infusion on day 1, etoposide 40 mg/m2 1 h infusion on days 1, 2 and 3 and mitomycin-C 7 mg/m2 i.v. bolus on day 1.
Results: Among the 32 patients entered into this trial, eight were disqualified from the analysis. Of the remaining 24 patients, 13 were given neoadjuvant chemotherapy (NAC) and 11 underwent surgery alone. Among the 13 patients who received NAC, four achieved a complete response (31%) and three a partial response (23%), with an overall response rate of 54%. Myelosuppression was a major side effect. Thrombocytopenia and anemia were dose-limiting toxicities. Other adverse reactions, including mucositis, were all mild and transient. The overall 5-year survival after NAC and without NAC were 83 and 62%, respectively. The survival difference was not statistically significant (p = 0.33).
Conclusions: NAC does not appear to play a role in the treatment of cancer of the oral cavity and pharynx with our PEM regimen. However, the degree of toxicity was limited in our trial and therefore attempts to increase the dosage and/or revise the administration schedule for cancer of the pharynx and T1 to T3 tumor disease appear warranted.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Historically, for head and neck carcinoma, surgery and radiotherapy have been the main treatments of choice for early-stage cancers and can result in 5-year survival rates ranging from 70 to 90%. More advanced tumors have had poorer survival rates owing to their propensity for both local recurrence and distant metastatic spread (1–3). Chemotherapy has thus been added with the aim of increasing the curability of these advanced lesions (4,5).
Theoretically, the main advantage of neoadjuvant chemotherapy (NAC) for head and neck carcinoma is that it induces tumor reduction before definitive local therapy is performed. However, many clinical studies frequently suffer as a result of such factors as a short duration of follow-up, poorly controlled local–regional treatments or the use of low-magnitude activity regimens (6–9).
The goal of NAC has been to enhance local control, decrease local recurrence and decrease the distant metastatic rate (10,11). Since these factors affect survival, it has been hypothesized that survival may therefore improve as well. We report here the long-term results of a multi-center clinical trial with cisplatin (CDDP) (P), etoposide (VP-16) (E) and mitomycin-C (M) (PEM) which demonstrated the same magnitude of activity but lower toxicities than such conventional regimens as CDDP + 5-fluorouracil (5FU) and CDDP + methotrexate + bleomycin. In this report, we update the results and analyze the 5-year survival results.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients and Tumor Characteristics
From April 1991 to December 1992, 32 patients with histologically confirmed, technically resectable untreated stage III and IV squamous cell carcinoma of the oral cavity and pharynx were entered into the study. All patients gave their informed consent before enrollment. All patients were required to have an Eastern Cooperative Oncology Group (ECOG) criteria performance status score of less than two and two-dimensionally measurable disease. Other eligibility criteria included an age between 15 and 80 years and normal hepatic, renal and bone marrow functions. Patients were excluded if there was any evidence of distant metastatic disease beyond the head and neck region or if they did not give their written informed consent. The initial evaluation included complete physical examinations, blood cell counts, liver biochemical tests, chest radiographs and an oropharyngolaryngeal fiber-optic examination. All patients were required to have normal renal [blood urea nitrogen (BUN) <20 mg/dl and serum creatinine level <1.5 mg/dl] and hepatic functions [serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) <40 U/dl, bilirubin <1.5 mg/dl]. The patients’ characteristics are given in Table 1. The staging classification criteria were determined according to the International Union Against Cancer staging system.
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Treatment
The chemotherapy regimen was as follows: the PEM regimen consisted of cisplatin (CDDP) (P) (CDDP 60 mg/m2 2 h infusion on day 1), etoposide (VP-16) (E) (VP-16 40 mg/m2 1 h infusion on days 1, 2 and 3) and mitomycin-C (MMC) (M) (MMC 7 mg/m2 i.v. bolus on day 1). The PEM regimen was given on an inpatient basis. This regimen was repeated at 3–4 week intervals for two cycles unless the tumor did not respond to the treatment. The patients whose tumors did not respond were considered to have progressive disease and therefore were excluded from further chemotherapy treatment and were administered other treatments.
The response to treatment was assessed as a decrease in the total tumor area measured directly with calipers or through radiological features.
Patients fulfilling the enrollment criteria were centrally ran-domized by fax or telephone after individually checking the eligibility criteria and completing the workup.
After completing the NAC, the patients underwent radical surgery to extirpate the tumor according to the initial limits of the cancer with either a radical or a functional neck dissection. For the non-NAC patients, radical surgery with radical or functional neck dissection was immediately performed.
Evaluation of Chemotherapy
Both the objective tumor regression and toxicity were evaluated according to the WHO criteria (12,13). Briefly, a complete response (CR) was defined as the disappearance of all measurable and assessable disease for a minimum duration of 4 weeks. A partial response (PR) was defined as a 
50% reduction in the sum of the products of the perpendicular diameters of all measured lesions without an increase in the size of any lesion or the appearance of any new lesions for at least 4 weeks. A minor response (MR) was defined as a decrease of 25–50%. No change (NC) was defined as a change in the sum of the products of the perpendicular diameter of all measured lesions of <25%. Progressive disease (PD) was defined as an increase of 25% in the sum of the products of the perpendicular diameters of all measured lesions from the point of maximum response or the appearance of new lesions. All patients not meeting the criteria for either a partial or complete response (stable disease, minor response and progressive disease) were classified as non-responders.
Survival
The primary objective of the study was to compare the overall survival at 5 years in the two treatment arms. The survival was calculated from the first day of treatment with the protocol until death or the last patient contact. The time to progression was calculated from either the first day of treatment by the protocol until either the first evidence of disease progression, e.g. tumor progression while receiving neoadjuvant chemotherapy or tumor regrowth after completing local therapy. The survival and time to progression were calculated by the Kaplan–Meier method. Statistical analyses were done for comparisons of the proportions using the log-rank test. All p-values are two-sided; significance was defined as p < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Treatment Results
Thirty-two patients were entered into this study between April 1991 and December 1992. The results were analyzed in December 1997 and the follow-up duration ranged from 60 to 80 months, with a median of 68 months. Of the 32 randomized patients, 18 were assigned to NAC and 14 to surgery alone. In the NAC group, five patients were not eligible because of protocol violation (three) or an inadequate follow-up (two). In the non-NAC group, three patients were ineligible because of an inadequate follow-up (two) or protocol violation (one). In total, eight patients (25%) were not evaluable. Of the 24 evaluable patients, 13 were treated with NAC and 11 with surgery alone. As Table 1 illustrates, the two groups were comparable with regard to the patients’ characteristics. The treatment arms were well balanced with respect to gender, nodal status, primary site and performance status.
The mean number of cycles given was 1.7, two cycles being given for 12 patients and one cycle for two patients. These two patients underwent only one cycle of chemotherapy and proceeded with surgery because of a limited local response.
For the NAC group, of the 13 patients evaluable for response, four achieved CR (31%), three PR (23%) and six MR (46%), with an overall response rate of 54% (Table 2).
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Toxicities
All 13 patients treated with PEM were assessable for toxicity and the findings are listed in Table 3. Myelosuppression was a major side effect and anemia and thrombocytopenia (7% greater than WHO grade II) were dose-limiting toxicities. Leukopenia was noted in approximately 46% of the patients. Leukopenia was transient, generally occurring 10 days after the onset of chemotherapy and resolving before the next cycle. No colony-stimulating factors were used. Two patients developed grade I renal toxicity (serum creatinine concentration 2.2–2.8 mg/dl) and one patient developed grade II (serum creatinine concentration 3.2 mg/dl). The creatinine values returned to the normal range before the next scheduled course of therapy. Acute nausea and vomiting were not significant problems, although one patient did show prolonged delayed nausea with the introduction of 5-HT3 receptor inhibitors. Other toxicities included oral stomatitis, alopecia, lassitude, hyponatremia and facial edema; however, all were mild and transient. No clinically significant ototoxicity was seen and no neurotoxicity or cardiac toxicity was documented. Chemotherapy was not terminated in any cases owing to toxicities.
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Survival
The survival of the 24 patients is presented in Figure 1 and Table 4. Six patients treated with NAC and five patients without NAC have died. In the NAC group and the non-NAC group, four patients (cerebral embolism, multiple myeloma, aspiration pneumonia, liver cirrhosis) and one patient (small cell carcinoma of lung), respectively, died from other causes. When we exclude these patients, the overall 5-year survival after NAC and without NAC were 83 and 62%, respectively. The survival difference between the patients given NAC and those who underwent surgery alone was not statistically significant (p = 0.33). The data stratified by actuarial analyses by the primary site, tumor and nodal stages are presented in Table 4 and Figures 2, 3, 4, 5. The NAC group tended to show a better survival for the pharynx, stage III and T1–T3 tumor disease compared with the oral cavity, stage IV and T4.
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The survival curves by response to NAC are illustrated in Figure 6.
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There were two recurrences in the NAC group, including two local failures. There were five recurrences in the non-NAC group including three local, one distant and one local plus distant failure (Figure 7). In the patients treated with NAC, no distant failure was detected. Moreover, for the patients who achieved a complete response to NAC, distant and local failures were the lowest. The failure rate analyzed by primary site and stage are presented in Table 5. Again, the NAC group tended to show better control rates for the pharynx, stage III and T1–T3 tumor disease. However, the failure rate difference between the patients with NAC and those who underwent surgery alone was not statistically significant (p = 0.15).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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For head and neck cancer, the most commonly used chemotherapy regimen is CDDP plus 5FU. This regimen was originally reported by Kish et al. in 1982 and has been shown to have high overall response and complete response rates (14). However, mucosal toxicity is sometimes so severe that the subsequent treatment including surgery and/or radiotherapy sometimes cannot be performed satisfactorily.
In our previously reported study, we evaluated the response rates of the PEM regimen for patients with advanced recurrent head and neck cancers that had already been treated. The results of this initial study, which included 10 patients, showed this regimen to have tolerable toxicities and a 38% overall response rate (15). Since this regimen is less toxic for the oral mucosa, we thought that the subsequent treatment including surgery and/or radiotherapy could be performed satisfactorily. We therefore studied the PEM regimen in a neoadjuvant setting. In this study, the immediate clinical response rate to chemotherapy was 54%, which was substantially lower than the 88% we previously reported in our phase II trial, although both studies showed similar CR rates, 31 and 32% (16).
The incidence of head and neck cancer in Japan is approximately 2.3% of all cancers, i.e. 8.3 per 100 000. Therefore, multi-institutional group studies seem to be necessary to achieve new findings. Until now, most Japanese studies have been performed by individual institutions, restricting the pursuit of novel treatment programs only to the phase I/II level. In contrast to Japanese studies, international studies have mainly consisted of phase III trials by cooperative groups except for phase I and II trials on new drugs (17). We therefore carried out a multi-institutional group study.
For head and neck cancer, the number of patients with each primary site is much smaller. To prevent anatomical heterogeneity, in this study we selected only two anatomical sites, namely the oral cavity and pharynx.
Since our study was a multi-institute randomized trial, the number of ineligible patients (25%) was fairly large. Initially, four patients were ineligible. However, in this study, four inadequate follow-up patients were also considered to be ineligible and therefore were later excluded from the analysis. As a result, the total number of ineligible patients exceeded 15% (18).
Although the advantages of neoadjuvant chemotherapy in head and neck cancer have been suggested by several authors, few clear conclusions regarding the role of NAC have yet been demonstrated.
In an Italian multi-center study, Paccagnella et al. (19) randomized 237 patients in a prospective trial who received either NAC with CDDP and infusional 5FU followed by locoregional therapy or locoregional therapy alone. Resectable patients received surgery and adjuvant radiotherapy whereas unresectable patients received radiotherapy alone. Approximately equal numbers of patients were free of disease in both treatment groups after completion of treatment. NAC improved the time to distant metastases and there were no differences in the regional failure rate, disease-free survival rate or overall survival rate. However, the operable patient subgroup analyses showed that NAC induced a significant reduction in the incidence of distant metastases, while it also resulted in a better overall survival rate.
Our subset analysis also demonstrated that NAC has a potential advantage for locally non-advanced (T1–T3) disease. However, the main weakness of our trial is probably the limited number of enrolled patients.
The formula used to calculate an adequate sample size to prove the superiority of a certain treatment against a control is widely known. According to this superiority testing, if the 5-year survival rates were 50 and 90%, the minimum sample size for equivalency testing would be 16 patients for each group (20,21). Moreover, assuming the 5-year survival difference between NAC (83%) and non-NAC (62%) was 21%, then the minimum sample size required for a two-group study would be estimated at 22 patients in each gruop to obtain a statistically significant result. We therefore need to include more patients in a future study in order to make our results statistically valid.
Turner et al. (22) reported their experience with advanced head and neck cancer treated with NAC. Of 39 patients receiving NAC, 10 achieved a clinical CR. Eight of these 10 patients elected not to proceed with surgery and were therefore treated with radiotherapy. In this group of eight patients, only two were alive at a median follow-up of 12 months; the local and nodal control rates of the patients are 38% (3/8) and 25% (2/8), respectively. In our trial, in the group of NAC, all 13 patients were treated by the originally planned surgery following the treatment. The pattern of failure in the two treatment groups was interesting. Local failure occurred in 2/13 (15%) of the patients treated with NAC and in 4/11 (36%) of those treated without NAC (p = 0.15). There were no distant failures in the NAC group, but distant failure was more common (18%) in the non-NAC group. Despite the marginal advantages in the progression free-survival, no survival benefit was found in the NAC group, although it is too early to conclude a lack of survival difference because the initially planned number of events needed to show a statistically significant difference has not yet been reached.
Detailed statistical analyses of these data were not possible because of the limited number of enrolled patients. However, we considered that improvements in local control in patients with clinical CR and increased survival rates in cancer of the pharynx and T3–T4 lesions might be essential.
The most important positive finding in this study may be the marginal increase in the progression-free survival for cancer of the pharynx and T1–T3 tumor disease and the decrease in the incidence of distant metastasis in the NAC group.
This open, randomized multi-center clinical trial with PEM regimen did not show any statistically significant difference in the overall 5-year survival. We therefore concluded that NAC does not play a role in the treatment of cancer of the oral cavity and pharynx with our PEM regimen. Since the toxicities in our trial were limited, further studies on increasing the dose and/or changing the administration schedule for cancer of the pharynx and T1–T3 tumor disease based on a multi-center study appear warranted.
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FOOTNOTES |
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+ For reprints and all correspondence: Naoyuki Kohno, Department of Otorhinolaryngology, National Defense Medical College, 3–2 Namiki, Tokorosawa, Saitama 359–8513, JapanPart of this work was presented at the 35th Annual Meeting of the Japan Society of Clinical Oncology, Kyoto, October 7–9, 1997. Abbreviations: NAC, neoadjuvant chemotherapy; CDDP, cisplatin; VP-16, etoposide; MMC, mitomycin-C; 5FU, 5-fluorouracil; CR, complete response; PR, partial response; MR, minor response; NC, no change; PD, progressive disease
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Received November 16, 1999; accepted April 12, 2000.
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