Japanese Journal of Clinical Oncology Advance Access originally published online on September 26, 2005
Japanese Journal of Clinical Oncology 2005 35(10):572-579; doi:10.1093/jjco/hyi155
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© 2005 Foundation for Promotion of Cancer Research
Mitomycin and Fluorouracil in Combination with Concomitant Radiotherapy: A Potentially Curable Approach for Locally Advanced Head and Neck Squamous Cell Carcinoma
1 Department of Radiotherapy, King George's Medical University, Lucknow, Uttar Pradesh and 2 Department of Oncology, Batra Hospital and Medical Research Center, New Delhi, India
For reprints and all correspondence: Madhup Rastogi, Senior Resident, Department of Radiotherapy, King George's Medical University, Chowk, Lucknow 226003, Uttar Pradesh, India. E-mail: drmadhup1{at}rediffmail.com
Received May 10, 2005; accepted July 18, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: The purpose of this study was to evaluate the efficacy of radiotherapy and concurrent mitomycin-C (MC) plus 5-fluorouracil (5FU) infusion in locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Methods: Sixty-nine patients with SCCHN (6 Stage III and 63 Stage IV patients) were treated with external beam radiotherapy (70 Gy) and simultaneous intravenous chemotherapy with 5FU (600 mg/m2/day, Days 1–5) and MC (10 mg/m2, Days 5 and 36).
Results: After a mean follow-up of 28.5 months, 59.4% of patients were alive without disease. Complete response was seen in 76.8% of patients. The 3 years overall survival, locoregional relapse-free survival and disease-free survival was 62.3, 89.8 and 49.5%, respectively. Treatment was well tolerated (Grade III mucositis in 43.5% and Grade II leukopenia in 5.8%).
Conclusions: This concurrent chemoradiotherapy regimen offers a curative option for our patients where primary and nodal disease is fairly large resulting in hypoxic radioresistant tumors.
Key Words: head and neck cancer • radiotherapy • concurrent • mitomycin-C • hemoglobin
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Radiation therapy used either as a primary treatment or in combination with surgical resection remains the cornerstone of management for the majority of patients with locally advanced Stages III and IV squamous cell carcinoma of head and neck (SCCHN) (1). Locoregional recurrence of disease continues to be a major cause of treatment failure in this patient population (2,3). The natural history of this disease is remarkable in that locoregional disease is paramount to achieve cure and distant metastases occur infrequently when locoregional disease is controlled (4,5). The effectiveness of radiotherapy is thought to be limited by the existence within tumor of hypoxic cells with diminished radiation sensitivity (6). Today locoregional control rates and disease-free survival (DFS) rates had improved significantly using concurrent chemoradiotherapy (CCRT) regimens (7–26). Two modalities attacking the same target (e.g. DNA is a target for both cisplatin and radiation) seems logical in terms of radiosensitization. But one should not forget that tumor population is heterogeneous with different cell subpopulations (27–28). Among them there are well oxygenated cells, which respond to radiation while there are also hypoxic cells, which are considered to be radioresistant (29). Targeting hypoxic cells with mitomycin-C (MC) and thus improving the overall response to radiation also seems to be a logical approach while dealing with SCCHN. This approach has been further validated in Phases II and III trials (15–26). Although evidence for the hypothesis that hypoxic cells limit the radiocurability of human tumors is mainly circumstantial, the existence of radioresistant hypoxic cells in both animal and human tumor models has been demonstrated (30,31). In our population, patients have more incidence of higher stage tumors with N3 (node >6 cm) disease, and moreover anemia is prevalent in most patients owing to poor nutrition. Both these findings logically entails that these patients will also have the higher incidence of hypoxia (27). Both laboratory and clinical data suggest that the existence within tumors of relatively radioresistant hypoxic cells contributes substantially to failure of radiation to control the disease locally (32,33). The use of bioreductive alkylating agents as an alternative approach to address the problem of hypoxic cells was suggested by Sartorelli et al. (34). MC, a naturally occurring prototype of the quinone bioreductive alkylating agents was shown in extensive laboratory and animal studies to be selectivity cytotoxic to hypoxic cells compared with their well oxygenated counterparts (34). Since the drug is not a radiosensitizer but rather independently cytotoxic, it was postulated that the use of MC, with its selective toxicity towards hypoxic cells, in combination with radiation therapy, which is most effective against well oxygenated cells, should result in enhanced effects on solid tumors. Two randomized trials using mitomycin (+/– dicumarol) as an adjunct to radiation therapy for patients with SCCHN were reported by Haffty et al. (15). These trials, which enrolled 203 patients (195 eligible for analysis), demonstrated a statistically significant benefit in drug-treated group with respect to locoregional control. However, no statistically significant difference in overall survival (OS) was obtained. 5-Fluorouracil (5FU) and MC in combination with radiotherapy have shown encouraging results (14,27). Simultaneous 5FU infusion in the first week of radiotherapy leads to an additive cytotoxic effect for the tumor and mucosa. The early stem cell depletion of the mucosa acts as a strong stimulus for regeneration and possibly reduces mucositis during the phase of accelerated radiotherapy. The rationale for combining MC in the first and sixth treatment week is to kill the hypoxic cells. Dinges et al. (23) used a similar approach, but with an accelerated radiotherapeutic regimen to reduce stem cell repopulation. While analysing the results of these positive trials we were wondering whether MC is more helpful in our patients where disease is in advanced stage leading to more hypoxic cell subpopulation. Invoking considerations on these thoughts, we initiated a Phase II study where we tried to explore the full potential of MC for our patients and moving one step further we also tried to find out in subset analysis, whether there are group of patients who will be most benefited by MC. Here, we used a chemotherapy protocol similar to one described by Dinges et al. (23), but we treated our patients with a standard fractionated radiotherapy to reduce the side effects and to assess the effectiveness of this regimen.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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STUDY DESIGN
Between November 2001 and December 2002, 69 patients with previously untreated, advanced SCCHN entered in a protocol based at Department of Radiotherapy, King George's Medical University. Before enrollment of patients, our institutional review board and clinical research committee approved the trial. Written informed consent was obtained from each patient before his or her participation in the study. Eligibility was limited to patients with primary tumors of oropharynx, larynx and hypopharynx with Stages III and IV (M0) disease according to AJCC Cancer Staging Manual, Fifth Edition. All patients had clinical examination, contrast-enhanced computed tomography of head and neck region, flexible endoscopy, X-ray chest PA view and USG abdomen to assess the primary status of the disease and to rule out distant metastases. Patients were required to have pathologically confirmed SCCHN, a Karnofsky performance status of 70–100, an adequate enteral diet, adequate bone marrow reserve (leukocyte count >4 x109/l and platelet count >10 x 109/l), a normal aspartate aminotransferase and bilirubin levels, a creatinine level <1.2 mg/dl. None of the patients with oral cavity tumors were included. Patients with multiple primary carcinomas were excluded from this study, as were patients whose tumor represented a second primary carcinoma. All patients were evaluated by a head and neck surgeon, radiation oncologist and an otolaryngologist at King George's Medical University. According to treatment plan (Fig. 1), all patients were treated with continuous intravenous infusion of 5FU (600 mg/m2 for Days 1–5 (120 h) and MMC (10 mg/m2 intravenously) on Day 5 during the first week of radiotherapy and on Day 36, i.e. on the 26th fraction. Radiotherapy commenced a minimum of 3 h following the start of 5FU infusion. All patients received a conventionally fractionated irradiation, i.e. 2 Gy per fraction five times in a week to a total of 70 Gy in 7 weeks in two phases.
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RADIATION TREATMENT
All patients underwent simulation using a Tele simulator (SAT 10, Shimadzu, Japan) with neck in neutral position. Immobilization was done with the help of orfit cast. The patients were planned using two-field that is parallel opposed lateral portals by SSD technique and treatment was delivered via Telecobalt Unit Theratron 780C (AECL, Ottawa, Canada) with dose normalized at tumor center. Dose homogeneity requirements was 95–105% of the specified centrally absorbed dose, as mentioned in the ICRU 50 reference point. Tissue equivalent compensators were made for all patients. Two-dimensional computer planning was done on Radplan software (TSG Corporation, India). The first phase delivered a total dose of 46 Gy by parallel and opposed fields to the primary and whole neck including spinal cord within this volume. Customized shoulder retractors were used to include supraclavicular region within the lateral field. The second phase treatment was given by reducing the marks anteriorly in order to save the spinal cord and clinically negative neck received a total dose of 54 Gy at 2 Gy per fraction. Primary disease and clinically palpable nodes received 70 Gy dose at 2 Gy per fraction. If there were residual nodes after 46 Gy lying over the spinal cord, oblique field plans were generated to deliver the radical dose and restricting the spinal cord dose to <50 Gy. Patients were reviewed weekly for mucosal and skin reactions. Weekly hemogram was performed during the treatment. All toxicities were scored according to Radiation Therapy Oncology Group (RTOG) criteria (35).
RESPONSE ASSESSMENT, END POINTS AND STATISTICS
Patients were followed weekly during treatment, response and treatment-related toxicities were quantified by clinical and radiographic examinations (contrast-enhanced computed tomography and USG neck). Response evaluation was done as per WHO criteria (36). Primary site and lymph node responses were scored separately, and overall responses were determined according to site showing the lesser response after 6 weeks of completion of treatment. A complete response (CR) was defined as the disappearance of all clinically or radiographically evident tumors. A partial response (PR) was defined as a reduction of >50% in the product of the two greatest perpendicular diameters of all measurable disease. No response (NR) was defined as any response less than a PR and progressive disease (PD) was defined as increase of >25% in the product of the two greatest perpendicular diameters of all measurable disease. If there was a residual node or primary disease after completion of treatment and if it was still responding, no active intervention was done and it was followed up till the end of 6 months. Responses were assessed again and if node or primary disease at any time appeared to be non-responsive or progressive, then the patients were send to the surgical oncology clinics for the assessment of surgical intervention.
Primary end points of this study were overall response, locoregional relapse-free survival (LRFS) and treatment mortality and morbidity having impact on total treatment time (TTT). Secondary end points were DFS and OS. The data were analysed using the SPSS version 10 statistical software. Times for end points were calculated from the date of registration. The time-dependent variables were analysed using Kaplan–Meier methods and differences in end points within the subgroups identified in the study were tested using the log-rank test. Events for LRFS included first recurrence of disease at local or regional site or persistant disease. Persistant disease was regarded as a failure on last date of radiotherapy. Events for DFS included first recurrences at a local, regional or distant site and because of disease, i.e. disease was present at the time of death. Events for OS included all deaths. All patients who were lost to follow-up with or without disease were counted as events and time to event was their last follow-up visit.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Between November 2001 and December 2002, 74 patients were enrolled in this study. Five patients were not included in the final analysis. Reasons for exclusion were incomplete treatment (two patients), refusal to receive Day 36 chemotherapy (one patient), death during treatment because of myocardial infarction not related to treatment (one patient) and lost to follow-up just after completion of treatment (one patient). Detailed analysis presented here includes 69 patients. Patient's characteristics and treatment-related parameters are shown in Table 1. Frequency distribution as per TNM staging revealed that 42 (60.9%) patients were of T4 tumor stage and 24 (34.8%) were having N3 nodal stage. Overall, 63 (91.3%) patients were of Stage IV disease. Pretreatment hemoglobin (Hb) level was 10.9 ± 2.1 g/dl, whereas average weekly Hb level (AWHL) was 10.5 ± 1.8 g/dl. Significant treatment interruptions were present in six patients where length of gap was
5 days. Mean TTT for all 69 patients was 52.3 days with SD of ±5 days. Median follow-up time was 28.5 months with SD of ±7.3 months (range 3.5–39.3 months).
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TOXICITY
Detail of treatment-related toxicity is shown in Table 2. There was no significant toxicity related to treatment. Confluent oral mucositis was present in 31 patients (44.9%), whereas pharyngitis of Grade III nature was present in 33 (47.5%) patients. Eighteen (26%) patients required nasogastric feeding. With proper enteral and parenteral nutrition and symptomatic treatment, all patients were managed comfortably. Treatment interruption owing to toxicity was present in most patients but in none of them it was >5 days except in six patients. Leukopenia, neutropenia, thrombocytopenia and gastrointestinal toxicity were also seen but they did not impose any impact on TTT. Whenever Hb level was <10 gm%, blood transfusion (BT) was done and this was required in 14 patients. Multiple BT was required in only four patients to keep their Hb level >10 gm%. Overall, there was no treatment-related death and compliance to treatment was good. Sixty patients received the intended dose of radiation (70 Gy), whereas nine patients received 68 Gy because of Grade III mucositis (n = 5), Grade III skin reactions (n = 2) and Grade IV skin reactions (n = 2). All patients received the full course of chemotherapy as planned.
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RESPONSE
Response with this CCRT protocol was time bound that is nodal response was seen as long as 6 months after completion of treatment (Table 3). At the end of 6 weeks, 49 (71%) were having CR at nodal site while at the end of 6 months there were 57 patients (82.6%) with CR. Overall, CR at 6 weeks and 6 months was 69.6 and 76.8%, respectively, while there were 14 (20.3%) patients with PR and 2 (2.9%) patients with PD. After 6 months of completion of treatment, 10 patients had residual nodes. Two were deemed unfit for surgery while eight patients underwent radical neck dissection. CR rate after surgical salvage increased up to 81.2%.
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SURVIVAL
As of January 2005, there were 24 relapses or treatment failure. Majority of recurrences were locoregional (Table 4) while there were seven distant metastases. Sites of distant metastases were lung (3), liver (2), mediastinal node (1) and skin metastases (1). Presently, 41 (59.4%) patients are alive without disease. Life table analysis of the survival function revealed that 3 year LRFS was 89.8% with a mean LRFS time of 38.2 months [95% confidence interval (CI) = 36.8–39.5] while median LRFS time was not reached (Fig. 2). Three year OS was 62.3% and mean OS time for all 69 patients was 33.9 months (95% CI = 31.7–36). Median OS time was not reached (Fig. 3). Three year DFS was 49.4% with a mean DFS time of 32.4 months (95% CI = 30.2–34.6). Median DFS time was 34.8 months (Fig. 4).
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When these survival functions were separately analysed among complete responders at the end of 6 months, there was definite improvement and OS, DFS and LRFS were 78.2, 68.7 and 91.3%, respectively (Table 5). There was no difference in survival function among different nodal stage and tumor stage while patients with N2 disease were having better survival (71.7%) compared to patients with N3 disease (56.5%), but the difference was statistically not significant (P = 0.0654). Similarly, when the patients were subgrouped according to AWHL and tested for survival function, there was no difference in LRFS, OS and DFS at 3 year whether Hb was
10.5 g/dl or >10.5 g/dl.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Selective activity of MC against hypoxic cells, already reported in many experimental studies (15,27), prompted us to choose this chemotherapy regimen concurrently along with radiotherapy. Rationale for using MC and 5FU along with radiation was discussed in detail by Pradier et al. (24) and we were fully convinced with the evidence presented there to substantiate the logics anticipated by them. In our study, 55 (79.5%) patients were having either N2 or N3 disease and 42 (60.9%) patients were having T4 disease. Overall, 63 (91.3%) patients were having Stage IV disease leaving only six patients with Stage III disease. In view of the facts mentioned above, we can emphasize that our results were addressing the issue for fairly advanced disease in head and neck cancers in our country. Hypoxia and radioresistance are consorted and so is the tumor size and hypoxia (27,37). In India, especially from rural area, most of the patients present in very advance stage with poor nutrition, so CCRT regimen should be planned considering these facts. The question of cost-effectiveness is a separate issue and it will be dealt separately and published later independently of this study. There were few but promising data in literature in favor of MC as part of CCRT protocol (Tables 6 and 7). Published data from our country are scanty. High proportion of patients with head and neck cancer are found in India and most of them are fairly advanced. We thought these will be patients who will be most benefited from MC used concurrently with radiation as it can take care of hypoxia-related radioresistant cells. 5FU has activity against squamous cell carcinoma and when combined with radiotherapy it can cause cell kill greater than the additive effects of these treatments given alone (14). Majority of the studies using CCRT schedule use cisplatin and 5FU as a chemotherapeutic agent and the results are promising with 3 year survival in the range of 30–76% (Table 6), although toxicities are significantly high. In a study of 78 patients by Taylor et al. (9), where he used concurrent cisplatin and 5FU with radiotherapy, six patients died during therapy due to the effects of the treatment. Pradier et al. (24) used the same CCRT schedule as used by us and reported a mean OS of 20% at 2 year. Acute toxicity in terms of Grade III mucositis was present in 17% of patients. Initial CR was present in 77% (27/35) patients but unlike our study this did not transformed into improved survival. One explanation given by the author was 31% of the patients were having carcinoma of oral cavity with poor prognosis. Worth mentioning is a randomized trial comparing concurrent MC with radiotherapy against porfiromycin (POR) with radiotherapy in SCCHN by Haffty et al. (25). They concluded that POR was inferior to MC as an adjunct to radiotherapy in the management of SCCHN. The 5 year actuarial local-relapse-free rate and local-regional relapse-free rate was 91.6 and 82%, respectively, in MC arm. This also translated into a significant advantage in DFS rate and cause-specific survival rate of 72.8 and 82.8%, respectively. In their subset analysis for primary radiation patients (excluding post-operative patients) MC group had 56% OS at 5 year. Mean radiation dose was 67 Gy ± 4.9 while TTT for primary radiation group was 51 days ± 6.9.
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In our study, CR at the end of 6 weeks after finishing treatment was 69.6% and this percentage increased up to 76.8% at the end of 6 months (Table 3). With responding residual nodes we did not subject them to neck dissection, and out of 20 residual nodes 10 had CR at the end of 6 months. Our CR rates were comparable with those mentioned in the literature (19,24,25). Also CRs were transformed into better survival (Table 5). Three year OS, RFS and DFS in our study were 62.3, 89.8 and 49.5%, respectively. All patients in our study except nine received full planned course of radiotherapy treatment (70 Gy/35 fractions) and all received >67 Gy dose with MC plus 5FU. Only six patients had a gap of >5 days. Overall compliance to the treatment was good and even the patients with poor nutrition and advanced disease also tolerated the treatment well. AWHL among all 69 patients was 10.5 gm% ± 1.8 and subgroup analysis revealed that OS, RFS and DFS was same for the patients with AWHL
10.5 gm% or >10.5 gm% and so patients with anemia were equally benefited. We are not drawing conclusion but it can be logically presumed that MC with 5FU is effective for patients with poor nutrition having anemia and advanced disease. These are the patients where there are high chances of encountering radioresistant hypoxic subvolumes of tumor and thus using MC with radiotherapy is a novel approach to improve the results especially in developing countries. There is only one randomized trial, which is multi-institutional (26) and involves patients from Indian subcontinent. They tested MC and radiotherapy against radiotherapy alone. In this trial there was no benefit of adding MC to radiotherapy and OS for radiotherapy alone group and radiotherapy plus MC group was 29 and 31% at 3 year (P-value was not significant). Similarly, locoregional control rate for both groups was 18 and 21% (P-value was not significant). Three year survival for mitomycin arm was far below the values reported in literature as well as in our study. Appropriate explanation would be that the dose of radiotherapy (66 Gy in 33 fractions) was not sufficient according to the current standards. In addition, MC was used only once on Day 5 while it is most effective when used twice (15,24,25), i.e. on Days 5 and 36. Also, they used MC alone while we used it in conjunction with 5FU which was more appropriate and logical, being well supported by the evidence in literature (24,34,38). Same authors in their subset analysis found MC was effective for laryngeal and hypopharyngeal tumor while they were having 48 and 49% of patients with oral cavity tumors in their radiotherapy alone arm and radiotherapy plus MC arm. In our study we did not have the patients with oral cavity tumors. Explanations given by author for not using MC twice were concerns regarding toxicity but now with our Phase II study including patients from same geographical region showed that using MC twice with 5FU is an effective and safe with good locoregional control rate and OS in patients with fairly advanced disease. We do not think that it is ethical to compare our treatment protocol with radiotherapy alone as various Phases II and III studies have already shown that CCRT is more effective than radiotherapy alone (Tables 6 and 7). If MC is combined decently with radiotherapy, it may be more effective especially for our patients where primary and nodal disease is fairly large resulting in hypoxic radioresistant tumors (37). Probably what we reflect in our study is a need of Phase III trial comparing the CCRT using MC with other effective CCRT using cisplatin-based chemotherapy.
With present body of evidence we are sure that CCRT is definitely better than radiotherapy alone and also has its impact on OS (Tables 6 and 7). Different regimens with different chemotherapy drugs with different radiotherapy protocol are being used. Now it is high time to have a Phase III trial that could compare the two most effective CCRT protocols. Our early results are promising and match with the literature (Table 7) so this Phase II trial has formed the base on which one can build a Phase III trial comparing this CCRT protocol with one of the most effective cisplatin-based CCRT protocol.
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References |
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