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British Journal of Radiology 74 (2001),368-374 © 2001 The British Institute of Radiology

Full paper

Radiotherapy combined with simultaneous chemotherapy with mitomycin-C and 5-fluorouracil for inoperable head and neck cancer

O Pradier, MD1, K Eberlein, MD1, E Weiss, MD1, M C Jackel, MD2 and C F Hess, MD, PhD1

1 Radiotherapy
2 Otorhinolaryngology, University of Göttingen, Robert Koch Strasse 40, D 37075 Göttingen, Germany

in final form 12 October 2000


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
The feasibility and effectiveness of a combined chemoradiotherapy treatment modality for locally advanced head and neck cancer was tested in a phase II trial. From March 1995 to June 1998, 35 patients with advanced squamous cell carcinoma of the head and neck were treated with a continuous intravenous infusion of 5-fluorouracil (600 mg m-2 24 h-1 for Days 1 to 5 (120 h)) and mitomycin-C (10 mg m-2 intravenously) on Day 5 during the first week of radiotherapy and on Day 36. 31 patients had stage IV disease; 4 patients had stage III; and 1 patient had stage II. Patient ages ranged from 42–69 years (median 56.7 years). The tumours involved were as follows: oral cavity (n=11); oropharynx (n=14); hypopharynx/larynx (n=10). Radiotherapy was delivered to a total dose of 70 Gy with conventional fractionation (2 Gy per fraction, five times a week). Chemotherapy was well tolerated and all patients received the intended dose. Mild nausea occurred in five patients. After a mean follow-up of 21 months (range 10–44 months), 8 (23%) patients remain alive. A complete response was seen in 28 (80%) patients. When a recurrence appeared, it was within the first year after treatment. 1- and 2-year overall survival rates were 46% and 23%, respectively. Grade 3 mucositis occurred in 17% of patients. Grade 1–2 thrombopaenia occurred in 3 (9%) patients, grade >2 leukopaenia in 4 (11%) patients, and grade =>2 anaemia in 3 (9%) patients. We observed a treatment interruption of maximum 1 week for six patients owing to mucositis. Febrile neutropaenia or aplasia were not observed. The concomitant use of 5-fluorouracil, mitomycin-C and radiotherapy in locally advanced head and neck carcinoma is well tolerated in this group of patients. This protocol showed good locoregional response with a very low toxicity profile.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Radiation therapy used either as primary treatment or in combination with surgical resection remains the cornerstone of management for the majority of patients with advanced squamous cell carcinoma (SCC) of the head and neck [1, 2]. Despite near-tolerance doses of radiation therapy with or without surgical resection, locoregional recurrence of disease continues to be a major cause of treatment failure in this patient population [3, 4]. The natural history of this disease is remarkable in that locoregional disease control is paramount to achieving cure, and distant metastases occur infrequently when locoregional disease is controlled [5, 6]. The effectiveness of radiation therapy is thought to be limited by the existence within tumours of hypoxic cells with diminished radiation sensitivity [7]. Many of the current investigative methods in clinical radiotherapy are directed toward the hypoxic cell problem. Thus, it is evident that optimization of locoregional control is an important goal in patients presenting with SCC of the head and neck.

Theoretically, one of the causes of failure of radiation therapy to control SCC of the head and neck is the existence of viable hypoxic cells of decreased radiosensitivity within the tumours [8–10]. Although evidence that hypoxic cells limit the radiocurability of human tumours is mainly circumstantial, the existence of radioresistant hypoxic cells in both animal and human tumour models has been demonstrated [11, 12]. Several strategies have been used to overcome the hypoxic cell problem in patients with SCC of the head and neck, including the use of high linear energy transfer radiation [13], hyperbaric oxygen [14], electron affinic cell radiation sensitizers, perfluorocarbon oxygen transport preparations [15] and correction of anaemia [16, 17]. The use of bioreductive alkylating agents as an alternative approach to address the problem of hypoxic cells was suggested by Sartorelli et al [18]. Mitomycin, a naturally occurring prototype of the quinone bioreductive alkylating agents, was shown in extensive laboratory and animal studies to be selectively cytotoxic to hypoxic cells compared with their well oxygenated counterparts [8, 18]. Since the drug is not a radiation sensitizer but rather independently cytotoxic, it was postulated that the use of mitomycin, with its selective toxicity toward hypoxic cells, in combination with radiation therapy, which is most effective against well oxygenated cells, should result in enhanced effects on solid tumours. Two randomized trials using mitomycin (±dicumarol) as an adjunct to radiation therapy for patients with SCC of the head and neck were reported by Haffty et al [19]. These trials, which enrolled 203 patients (195 eligible for analysis), demonstrated a statistically significant benefit in the drug-treated group with respect to locoregional control. However, no statistically significant difference in overall survival was obtained.

5-Fluorouracil (5-FU) or mitomycin C (MMC) in combination with radiotherapy have shown encouraging results in five phase III trials [19–22]. Simultaneous 5-FU infusion (120 h continuously) in the first week of radiotherapy leads to an additive cytotoxic effect for the tumour and mucosa. This 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 MMC in the first and sixth treatment week is to kill the hypoxic tumour cells. Dinges et al [23] used a similar approach, but with an accelerated radiotherapeutic regimen to reduce stem cell repopulation. In this phase II study, we used a chemotherapy protocol similar to the one described by Dinges et al, but we treated our patients with a standard fractionated radiotherapy to reduce the side effects and to assess the effectiveness of this regimen. There are very few studies in the literature combining 5-FU and MMC with normally fractionated radiotherapy in head and neck cancer.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
From March 1995 to June 1998, 35 patients with advanced SCC of the head and neck were treated with a continuous intravenous infusion of 5-FU (600 mg m-2 24 h-1 for Days 1 to 5 (120 h)) and MMC (10 mg m-2 intravenously) on Day 5 during the first week of radiotherapy and on Day 36. Radiotherapy commenced a minimum of 3 h following the start of 5-FU infusion (Figure 1Go).



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  		Figure 1. Treatment schedule for chemoradiotherapy.

 
No prior treatment had been carried out other than biopsy. The majority of patients were male (29 out of 35) and patient age ranged from 42–69 years (median 56.7 years). World Health Organisation (WHO) performance ranged from category 0 to 2. The tumours arose in various sites throughout the head and neck: oral cavity (n=11); oropharynx (n=14); hypopharynx/larynx (n=10). 31 out of 35 patients had stage IV tumours and 4 patients had stage III.

All patients received fractionated irradiation, 2 Gy per fraction five times per week to a total dose of 70 Gy. The first phase delivered a dose of 36 Gy with parallel opposed 6 MV photon fields to the primary tumour and the first echelon nodes, including the spinal cord within this volume. To cover the lower neck and the supraclavicular nodes, one anterior portal was used; a prophylactic dose of 50 Gy at 3 cm depth was delivered. The second phase of treatment to the tumour involved a reduction in size of the field to bring the posterior border off the spinal cord. This phase delivered 14 Gy to the tumour. Asymmetric jaws were used to give the minimum penumbra posteriorly, and an electron field was matched to treat the upper posterior neck to 50 Gy total dose. A third phase of treatment used photon beams. A CT was performed on each patient where the clinical target volume and the planning target volume were defined. A total dose of 70 Gy was reached. Photon treatment was delivered using a Varian Clinac 600 C accelerator (Varian, Palo Alto, USA), with electrons from a Varian Clinac 2300 C/D accelerator (Varian, Palo Alto, USA). The prescribed dose for photons and electrons was defined in accordance with the International Commission on Radiation Units and Measurements Report 50 [24]. Initial tumour response was evaluated by clinical examination and CT 2 months following radiotherapy. Mucosal and skin reactions were monitored every second week following therapy until normalization. The side effects are classified according to the common toxicity criteria) classification (Table 1Go).


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  		Table 1. Acute side effects of chemoradiotherapy according to the RTOG-EORTC score

 

   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Response
All 35 patients were available for assessment of tumour response, toxicity and disease-free survival. The median duration of follow-up of survivors was 21 months (range 10–44 months).

Complete remission was seen in 77% (27/35) of patients treated by radiochemotherapy. Death has occurred in 27 patients. In each case, the patient either died from carcinoma or had active disease at the time of death.

Relapse occurred in 27 patients, the initial site of relapse being local (5), regional (3), or locoregional (9), as well as 10 cases of distant metastasis (4 pulmonary, 1 associated with bone metastasis and another with cutaneous metastasis, and 6 associated with a local recurrence (3patients) or locoregional recurrence (3 patients). In one patient with a relapse of a carcinoma of the tongue, attempts at surgical salvage were not successful as the tumour could not be completely excised.

Life table analyses of the overall survival is shown in Figure 2Go. The 35 patients have a mean overall survival of 20% at 2 years.



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  		Figure 2. Disease-free survival. Patients at risk were monitored over time.

 
Acute toxicity
There were no treatment-related deaths. All 35 patients received the intended dose of chemotherapy, which was well tolerated. Mild nausea occurred in six patients, but this was easily controlled with oral antiemetics.

Acute toxicity is shown in Table 1Go. 24 of the 35 patients developed a confluent mucositis grade 2–3 during treatment. The radiotherapy schedule required modification in six patients. Two patients were rested from treatment for 4 days and four for 5 days owing to mucositis.

Haematologic toxicities are listed in Table 2Go. Generally, chemotherapy was well tolerated, with only transient side effects. Bone marrow suppression manifested as leukopaenia, anaemia andthrombocytopaenia (grade =>3) in 14% of patients. There was no prolonged myelosuppression and no patient required any antibiotic treatment. We did not observe any pulmonary side effects.


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  		Table 2. Haematological side effects of chemoradiotherapy according to the RTOG-EORTC score

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Rationale for selection of the chemotherapeutic regimen
According to some basic experimental studies, the bioreductive alkylating agent MMC is selectively toxic to radioresistant hypoxic cells [11, 25, 26]. From the clinical studies of Haffty et al [19] and Dobrowsky et al [27], it appears that its use in patients with advanced head and neck carcinoma is justified. In the majority of these patients, a high percentage of hypoxic cells can be expected owing to large tumour mass [10]. Some studies [19, 28, 29] indicate that repeated treatment with MMC improves the response. Stadler et al [17, 30] evaluated the changes in tumour oxygenation during split course radiotherapy combined with chemotherapy (5-FU+MMC) in locally advanced head and neck cancer. They observed a decrease in the tumour oxygenation status during the last 4 weeks of therapy, and low pre-therapy pO2 values indicated a worse prognosis. In accordance with this observation, a second dose of MMC before the end of therapy (Day 36) was planned.

5-FU has activity against SCC, and when combined with radiotherapy it can cause cell kill greater than the additive effects of these treatments given alone [31, 32]. The mode of action of 5-FU is uncertain, but for this effect to be maximal 5-FU must be present during irradiation and for up to 48 h afterwards. Vietti et al [32] suggested that part of its action is to fix sublethal damage, but Byfield et al [31] felt that it was dependent on an undefined alternative mechanism. Owing to its short half-life when given by bolus injection, 5-FU must be administered as a continuous infusion for this effect to occur. Delivering 5-FU by infusion is less toxic than bolus administration [33] and may also improve the cell kill by exposing tumour cells to the drug as they move through the cell cycle.

To try to improve the results of treatment of advanced head and neck cancer, various approaches have been used over the years. Although many patients with advanced disease will develop distant metastases, locoregional control of tumours remains the major problem [34]. Surgery and radiotherapy remain the main methods of treatment.

Simultaneous chemotherapy and radiotherapy (concomitant treatment) have been used to treat SCC arising in various sites, and a number of chemotherapy agents and radiotherapy schedules have been reported. 5-FU and MMC have been used concomitantly with radiotherapy in the treatment of SCC of the oesophagus [35], uterine cervix [36, 37] and most notably the anal canal [38], as well as in head and neck cancer with good results [19, 23, 39].

The intent of concomitant treatment was to achieve a higher percentage of complete response rates by enhancing the effect of radiotherapy with the two additional drugs. The choice of chemotherapeutic agents used in this study was based on their effectiveness on hypoxic tumour cells as well as their radiosensitizing effect. The latter is believed to be responsible for marked acute mucositis. The time of the first dose of MMC was chosen to coincide with the moment when the relative number of hypoxic cells was believed to be the greatest, i.e. after 10 Gy of radiotherapy.

We found that even in this group of patients with advanced disease and only fair general condition, combined treatment was well tolerated. The chemotherapy was accepted with minimal systemic acute toxicity. The early generalized mucositis observed necessitated a rest from treatment for 5 days in six cases. Evans et al [40] and Macmillan et al [41] reported the same incidence. Other series using a similar regimen for carcinoma of the cervix [36] and the anal canal [38] reported excessive haematological and gastrointestinal toxicity.

The number of patients in this study is relatively small, and follow-up is limited, but it is of interest to examine the results of treatment. The finding of a 23% disease-free survival following 80% initial complete response is surprising. At the same time, we observed very good tolerance of treatment. With this combination of chemotherapy and radiotherapy we anticipated a high rate of complete response without major side effects for patients with poor buccal hygiene (smokers, alcohol abuse), but we had expected the early promising results to translate into improved survival. One explanation may be the biological effect of the chosen schedule, as toxicity is much lower than in other studies.

Recent studies have combined cisplatin/5-FU infusion with uninterrupted radiotherapy, with promising results [42–44]. Mucosal toxicity is considerable, however, and most of the radiation is given separately from the chemotherapy. Taylor et al [45] have shown a 5-year overall survival of 43% (confidence interval 33–56%) with cisplatin/5-FU. In this study of 78 patients, 6 (8%) patients died during therapy owing to the effects of treatment.

In comparison with a study of hyperfractionated radiotherapy, this treatment is well tolerated. Dinges et al [23] evaluated the feasibility and effectiveness of a concurrent radiochemotherapy regimen for locally advanced head and neck carcinoma. The patients received 72 Gy in 6 weeks. In the last 3 weeks, treatment was accelerated by giving two daily fractions of 1.4 Gy with a minimum interval of 6 h. On Day 1, 350 mg m-2 5-FU and 50 mg m-2 folinic acid were given as iv bolus followed by continuous infusion of 350 mg m-2 5-FU and 100 mg m-2 folinic acid for Days 1–5. 10 mg m-2 mitomycin was given on Day 5 and Day 36 of the treatment. Complete remission was seen in 76% (56/74) of patients and, after subsequent resection of residual lymph nodes, another 8 patients achieved complete remission. The cumulative local control rate was 72% and the disease-specific survival rate was 59% at 4 years. These results appear to be better than those described here, but in this population 16.5% had nasopharyngeal carcinoma with a good prognosis compared with 11 (31%) patients in our study suffering from carcinoma of the oral cavity with a poor prognosis. The major difference in that study was the high rate of side effects due to accelerated treatment. The authors described 70% mucositis grade 3 and 23 % late toxicity of mucosa. 2 (3%) patients died during a phase of severe leukopaenia or thrombocytopaenia.

Dobrowsky et al [27] evaluated the effects ofMMC with accelerated hyperfractionated radiation therapy. They tested a conventional fractionation (CF) (70 Gy in 35 fractions over 7 weeks) with a continuous hyperfractionated accelerated radiation therapy (CHART)±MMC (20 mg m-2 on Day 5). Overall survival was significantly improved in the patients treated with the combination. Local tumour control was 28%, 32% and 56% following CF, CHART and CHART+MMC, respectively (p<0.05).

Current place of concurrent chemoradiotherapy
The concept that concurrent chemoradiotherapy can improve overall survival and locoregional disease control by exploiting chemotherapeutic radiosensitization appears to be validated by an ever increasing number of phase III studies.

Several promising randomised trials have been reported (Table 3Go). In all studies, a survival benefit was found if chemotherapy was associated with radiotherapy [42, 44, 46–48]. Only one study, by Keane et al [49], did not find differences in any endpoints between the treatment groups. The authors felt that the split course radiation therapy and the limitation of total radiation dose to only 50 Gy may have contributed to this negative result.


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  		Table 3. Randomized trials of definitive radiotherapy concurrent with multi-agent chemotherapy

 
The study by Zakotnik et al [48], which is an update analysis of a study by Smid et al [50], compared the efficacy of concomitant irradiation with MMC and bleomycin in inoperable head and neck carcinoma with radiotherapy alone (conventionally fractionated). The overall survival in the radiotherapy only group was 7% vs 26% in the radiochemotherapy group (p=0.01). The complete response rate was 29% in the first group and 75% in the combined group (p=0.08). The chemoradiotherapy group, however, also received nicotinamide, chlorpromazine and dicoumarol as radiotherapy enhancers.

The results that we describe are of the same order as those soon to be published using other chemotherapy drugs. Following the German Multicentric Study launched in 1995, it will be very interesting to see whether it is possible todouble the survival rate with accelerated hyperfractionated radiotherapy with acceptable side effects.

It should not be assumed that a combination of radiotherapy and chemotherapy improves the overall survival in these patients. 5-FU, methotrexate and cisplatin are the only drugs that have shown a significant improvement in survival without local or locoregional recurrence [21, 22, 51–54].

We conclude that the addition of 5-FU and MMC to a conventionally fractionated course of radical radiotherapy in patients with inoperable advanced carcinoma of the head and neck is feasible, well tolerated and acceptable to our patients. In future, a combination of this chemotherapy with a modified radiotherapy fractionation (accelerated hyperfractionated radiotherapy) might improve the results.

Received for publication December 8, 1999. Accepted for publication October 20, 2000.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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M. Rastogi, M. Srivastava, K. S. Chufal, M. C. Pant, K. Srivastava, and M. B. Bhatt
Mitomycin and Fluorouracil in Combination with Concomitant Radiotherapy: A Potentially Curable Approach for Locally Advanced Head and Neck Squamous Cell Carcinoma
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