1991, The British Journal of Radiology, 64, 941-946
Concomitant chemo/radiotherapy for advanced carcinoma of the head and neck By C. H. Macmillan, MRCP, FRCR, K. Carrick, DCR(T),*P. J . Bradley, FRCS and D. A. L Morgan, FRCR Department of Clinical Oncology, The General Hospital, Park Row, Nottingham NG1 6HA, and 'Department of Otolaryngology, University Hospital, Nottingham NG7 2UH, UK
{Received November 1990 and in revised form February 1991)
Keywords: Head and neck cancer, Radiotherapy, Chemotherapy, S5-Fluorouracil, Mitomycin-C
Abstract. Giving chemotherapy and radiotherapy simultaneously (concomitant therapy) is one approach to improving results in advanced head and neck cancer. To assess the feasibility of one such regimen, 25 patients with advanced squamous carcinoma of the head and neck were treated with a continuous intravenous infusion of 5-fluorouracil, 1 g/m2 per 24 h for Days 1-5 (105 h) and mitomycin-C 14 mg/m2 intravenously on Day 3 during the first week of radiotherapy. Twenty had Stage IV disease; four Stage III; and one Stage II. Ages ranged from 21 to 73 years (median 60 years). The tumours involved were as follows: oral cavity (6); nasopharynx (8); oropharynx (5); secondary node from unknown primary (3); hypopharynx (2); paranasal sinus (1). Radiotherapy was delivered as 10 Gy per week (total dose 60-70 Gy). Chemotherapy was well tolerated and all received the intended dose. Mild nausea occurred in five patients and three experienced transient vomiting. A generalized "early" mucositis affected 16 out of 25 (64%), caused interruption of radiotherapy in three patients, and is thought to be chemotherapy related. Twenty-two patients received the dose of radiotherapy intended, and two stopped prematurely at 53 and 56 Gy. Three episodes of neutropaenic infection occurred. Two recovered uneventfully, but one toxic death occurred in a patient with alcoholic cirrhosis. A complete response was seen in 21 (84%). For 17 patients with non-nasopharyngeal carcinoma the 2-year survival is 40%, 24% disease free. The concomitant use of 5-fluorouracil, mitomycin and radiotherapy is well tolerated in this group of patients.
The results from treatment of advanced carcinoma of the head and neck are poor. The traditional treatment techniques of surgery and radiotherapy, which are often curative in early-stage disease, are less effective in more advanced patients. Although squamous carcinoma of the head and neck is chemosensitive, it is not curable by chemotherapy alone and attempts to combine chemotherapy with surgery and/or radiotherapy have generally been disappointing (Stell et al, 1983; Taylor, 1987a,b; Tannock, 1989; Stell & Rawson, 1990). One approach to try to improve results is to give chemotherapy and radiotherapy concomitantly (Vokes & Weichselbaum, 1990). 5-Fluorouracil (5-FU) is cytotoxic with activity against squamous carcinoma, and mitomycin-C may be selectively toxic to hypoxic cells. The concomitant use of these drugs with radiotherapy has shown promise in the treatment of squamous carcinoma arising in various sites, most notably the anal canal (Cummings et al, 1984), but also the oesophagus (Keane et al, 1985) and uterine cervix (Evans et al, 1988; Ludgate et al, 1988), as well as the head and neck (Kaplan et al, 1985; Dobrowsky et al, 1989). In 1987 a Phase II study was commenced in order to assess the feasibility of adding 5-fluorouracil and mitomycin-C to the first week of a conventionally fractionated course of radical radiotherapy in patients with advanced head and neck cancer. Previous published studies have either employed non-standard radiotherapy fractionation schedules, or given a lower radiation dose Vol. 64, No. 766
as planned pre-operative treatment (Kaplan et al, 1985; Keane et al, 1988; Dobrowsky et al, 1989). Patients and methods
Between 1987 and 1990, 25 patients were treated with 5-FU at a dose of 1 g/m2 body surface area per 24 h continuous intravenous infusion starting at 9 a.m. on Monday and continuing until 6 p.m. on Friday (105 h), and mitomycin-C (14 mg/m2) intravenous bolus on Day 3. Radiotherapy started a minimum of 3 h following the commencement of the infusion of 5-FU and was given as 2 Gy/day, 5 days per week to an intended dose of 60-70 Gy depending on tumour site and stage (Fig. 1). During the study period patients with advanced head and neck cancer were preferentially treated either within a randomized study of the hypoxic cell sensitizer etani5-Fluorouracil
1 g / m 2 / 24 hours continuous IV infusion Day 1 -5
Mrtomycin C
14mg / m 2 IV Day 3.
Radiotherapy
Week
2Gy / day, 5 days / week to 50-70Gy.
1
Mitomycin C 5-Fluorouracil Radiotherapy
Figure 1. Treatment schedule.
941
C. H. Macmillan, K. Carrick, P. J. Bradley and D. A. L. Morgan
dazole, or those with advanced laryngeal cancer were treated with a hyperfractionated and accelerated radiotherapy schedule. Patients with inoperable head and neck cancer (as assessed at the Combined Head & Neck Oncology Clinic by the surgeon and radiotherapist) not eligible for those studies, and adult patients with nasopharyngeal carcinoma, were given concomitant chemotherapy and radiotherapy. No prior treatment had been carried out other than biopsy. The majority of patients were male (19 out of 25) and ages ranged from 21 to 73 years, median 60 years. World Health Organization (WHO) performance status ranged from category 0 to 3 (Table I). The tumours arose in various sites throughout the head and neck (Table II). Eighty per cent of patients had Stage IV disease; the stage grouping is shown in Tables III and IV. One patient with Stage II carcinoma of the hypopharynx is included in the series. This large tumour extended into the oropharynx, and the hypopharynx also bore a further satellite lesion. Radiotherapy was delivered using fields to treat the primary tumour and the whole neck, and using two or Table I. Performance status, World Health Organization grade Number of patients
Grade
7 12 5 1 Table II. Site of origin of tumour Oral cavity Oropharynx Occult primary Hypopharynx Paranasal sinus Nasopharynx Table III. Stage grouping, UICC 1987 Stage II Stage III Stage IV
1 4 20
Table IV. TNM stage, UICC 1987 'N' stage
T ' stage
942
0 1 2 3 4
0
1
2
3
0 0 1 0 3
1 2 1 0 2
1 1 0 0 2
4 1 1 1 4
4
6
4
11
6 4 3 1 11
15—1
No. of
10 —
Patients 5—
40
50
60
70
Gy
Figure 2. Dose histogram.
three phases of treatment to a total dose of 60-70 Gy depending on the site and extent of disease. The first phase delivered a dose of 40 Gy with parallel opposed 5 MV photons to the primary tumour and the first echelon nodes, including the spinal cord within this volume. A direct anterior field was matched on to the inferior border to treat the lower neck bilaterally, shielding the spinal cord with a midline lead block. The match was achieved using a couch twist of 90° with the gantry angled to match the divergence of the anterior field along the inferior border of the lateral field. A prophylactic dose of 50 Gy at 3 cm depth was delivered to the lower neck. 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 a further 20-25 Gy to the tumour. Asymmetric jaws were used to give minimum penumbra posteriorly, and an electron field was matched on to treat the upper posterior neck to a minimum of 50 Gy total dose. A third phase of treatment used electrons to boost the site of any lymph node masses up to a maximum of 70 Gy. The median dose to the tumour was 60 Gy; the actual doses received are shown in Fig. 2. Photon treatment was delivered using a Philips SL75-5 linear accelerator, with electrons obtained from a Philips SL75-14 linear accelerator. The prescribed dose for photons and electrons was defined as the target absorbed dose (ICRU, 1978). Tissue compensators were used as necessary to keep the dose as nearly as possible homogeneous to within + 5 % of the tumour dose. Results Toxicity All 25 patients received the intended dose of chemotherapy, and this was well tolerated. Mild nausea occurred in five patients, but settled with oral antiemetics. Three patients (12%) experienced vomiting following the administration of mitomycin-C but this was successfully controlled with anti-emetics in each case. No patient required a wig, although slight thinning of the hair was usually evident. Twenty-three of the 25 patients developed a confluent mucositis by the end of treatment. A distinct "early" The British Journal of Radiology, October 1991
Chemo/radiotherapy for head and neck cancer
mucositis occurred, with time of onset ranging from the end of the first week of treatment to the third week. It occurred inside and outside the irradiated areas, affecting 16 of the 25 (64%) patients, and as treatment progressed, was replaced by a mucositis confined to the irradiated volume. The radiotherapy schedule required modification in five patients. Three patients were rested for 1 week due to early mucositis; two of these continued to the intended dose. Two other patients stopped treatment prematurely at 53 and 56 Gy with necrosis of the hard palate (since healed) and severe mucositis, respectively. The fifth patient died from chemotherapy toxicity during radiotherapy. The patient who died was known to have alcoholic liver disease, and had abnormal liver function tests at the time of treatment. Following the development of a severe early mucositis requiring interruption of radiotherapy, he became pancytopaenic and speticaemic and, despite intravenous antibiotics and platelet support, he died of haemorrhage from his primary tumour. Two other episodes of neutropaenic infection occurred, but the patients recovered uneventfully following treatment with intravenous antibiotics. Twenty-two patients (88%) received the intended dose of radiotherapy. Response Response to treatment was assessed clinically at the Combined Head & Neck Oncology Clinic. No patients have been lost to follow-up, and the median duration of follow-up of survivors is 23 months (range 6-41 months). Twenty-one of the 25 patients (84%) showed a complete response to treatment (8/8 nasopharynx, 13/17 others). Death has occurred in 13 patients. In each case the patient either died from carcinoma, or had active disease at the time of death. Relapse has occurred in 14 patients (including four who failed to achieve initial complete remission (CR). The initial site of relapse was local in 12, with two cases of distant metastasis (one pulmonary, one osseous). One patient with initial local relapse subsequently developed generalized metastases. Surgical salvage has been successful in one patient who relapsed locally in the oral cavity at 9 months and he is free of disease 25 months post-surgery. Two other attempts at surgical salvage were not successful as the patients were found to be inoperable when examined under anaesthetic. Life table analyses of the overall and disease-free survival are shown in Figs 3 and 4. In view of the differences in natural history between carcinoma of the nasopharynx and squamous carcinoma in other head and neck sites (Ho, 1978), the eight patients with nasopharyngeal carcinoma have been analysed separately. The 17 patients with non-nasopharyngeal carcinoma have an overall actuarial survival of 40% at 2 years, with 24% disease-free actuarial survival. All of the eight patients with nasopharyngeal carcinoma obtained initial Vol. 64, No. 766
100 90 80 " 70 Nasopharynx (8)
60 50 40 " 30 20 -
Others (17)
10 1
Years
2
3
Figure 3. Actuarial overall survival. * 100
Nasopharynx (8)
Years Figure 4. Actuarial disease free survival.
CR, with one man relapsing at 29 months with osseous metastases. Discussion In order to try and 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, loco-regional control of tumours remains the major problem (Marcial & Pajak, 1985). We found 12 out of 14 relapses to be local. Intercurrent diseases brought on by the same factors that predispose to head and neck cancer become a major factor in long-term survivors. The main methods of treatment remain surgery and radiotherapy. Surgery can be mutilating, and tends to fail at the margins of resection, whereas radiotherapy retains function, but is more likely to fail where the bulk of tumour is greatest, i.e. in the centre of the field. These techniques are therefore complementary to each other. In the 1950s it was realized that there were hypoxic areas within carcinomas (Thomlinson & Gray, 1955) and that hypoxic cells were relatively radioresistant. Therapeutic attempts were made during the 1960s and 1970s to improve hypoxic cell killing in the expectation 943
C. H. Macmillan, K. Carrick, P. J. Bradley and D. A. L. Morgan
that these cells limited the curability of tumours by radiotherapy. Hyperbaric oxygen, hypoxic cell sensitizers (Dische, 1988) and high-LET radiation (Duncan et al, 1987) were used, but the results have been generally disappointing and these treatments have not found a routine clinical use. Cytotoxic drugs have shown consistent activity against squamous carcinoma of the head and neck, and complete responses can be achieved in up to 42% of patients (Weaver et al, 1982). However, chemotherapy has not been shown to improve the long-term survival and recurrence is rapid. Chemotherapy can be used as induction treatment to reduce tumour bulk prior to definitive local treatment with surgery or radiotherapy, but studies using this approach have generally shown no advantage for chemotherapy, with few studies showing advantage and others disadvantage (Taylor, 1987a, b). Indeed this approach may be theoretically harmful, since the clonogenic cells within the tumour may have increased their rate of proliferation in response to chemotherapy by the time radiotherapy commences (Tannock, 1989). Normally proliferation does not increase until 4 weeks following the start of radiotherapy (Withers et al, 1988). Simultaneous chemotherapy and radiotherapy (concomitant treatment) has been used to treat squamous carcinoma arising in various sites, and a number of chemotherapy agents and radiotherapy schedules have been reported. 5-FU and mitomycin have been used concomitantly with radiotherapy in the treatment of squamous carcinoma of the oesophagus (Keane et al, 1985), uterine cervix (Thomas et al, 1984; Ludgate et al, 1988) and, most notably, the anal canal (Cummings et al, 1984), as well as in head and neck cancer (Keane et al, 1988; Dobrowsky et al, 1989), with apparently good results (although only the study of Keane et al was controlled and randomized, and this study used a split course of radiotherapy with the chemotherapy arm). 5-Fluorouracil has activity against squamous carcinoma, and when combined with radiotherapy it can cause cell kill greater than the additive effects of these agents given alone (Vietti et al, 1971; Byfield et al, 1982). The mode of action of 5-FU in causing this 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 (1971) suggested that part of its action is to "fix" sub-lethal damage, but Byfield et al (1982) felt that it was dependent on an undefined alternative mechanism. Owing to its short half-life when given by bolus injection it must be administered as a continuous infusion for this effect to occur. Delivering 5-FU by infusion is less toxic than bolus administration (Seifert et al, 1975), and may also improve the cell kill by exposing tumour cells to the drug as they move through the cell cycle. Mitomycin-C is the prototype quinone bioreductive agent. It requires metabolic reduction to form an active bifunctional alkylating species (Sartorelli, 1988). The presence of oxygen results in the competitive reversal of this reaction. Both in vivo and in vitro experiments with 944
animal models have demonstrated a selective toxicity of mitomycin towards hypoxic cells (Kennedy et al, 1980; Rockwell, 1983). In a randomized study, Weisberg et al (1989) treated 120 patients with head and neck carcinoma with radiotherapy or radiotherapy and mitomycin-C. Overall actuarial survival at 5 years was not significantly different at 40% versus 48% (p > 0.3), but loco-regional disease-free survival was significantly improved from 55% to 75% (p < 0.01) for radiotherapy against radiotherapy plus mitomycin. Dobrowsky et al (1989) treated 51 advanced head and neck cancer patients with pre-operative chemo/radiotherapy using a similar schedule to ourselves, but giving only 50 Gy of radiotherapy. They found that none of their patients required interruption of radiotherapy, and achieved a complete pathological response in 56%, with clinical complete response in 95%. Kaplan et al (1985) reported their experience with a split course of radiotherapy and concomitant chemotherapy with 5-FU and mitomycin in a mixed group of head and neck patients, some being treated prior to planned surgery, and some for palliation only. They found a pathological CR in 77% of primary tumours and 69% of involved nodes. Keane et al (1988) randomized patients to receive a continuous course of radiotherapy or a split course with concomitant chemotherapy. The results were not significantly different, but this implies that the addition of chemotherapy was able to compensate for the gap in treatment, calculated by Overgaard et al (1988) to be the equivalent of 0.5 Gy per day. 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 upset or acute toxicity. Within such a group of patients are many who continue to smoke and consume alcohol, and it is common for such patients not to complete their treatment. In this study 22 out of 25 (88%) did complete the planned treatment with the encouragement of staff. The early generalized mucositis we observed necessitated a rest from treatment in three cases, and was probably due to the chemotherapy. Evans et al (1988) reported a similar finding in 12 out of 25 patients treated with slightly lower doses of 5-FU and mitomycin. Others using similar regimens have found minimal acute toxicity, but Ludgate et al (1988), who treated patients with advanced carcinoma of the cervix with concomitant 5FU infusion at weeks 1 and 4 plus mitomycin on Day 1, noted an increase in gastrointestinal symptoms requiring modification of the radiotherapy schedule. They also delivered 30 Gy to Point A with a single intracavitary insertion prior to external-beam treatment. Cummings et al (1984) found that their initial radiotherapy schedule of 50 Gy in 20 fractions for the treatment of anal carcinoma combined with 5-FU and mitomycin caused excessive haematological and gastrointestinal toxicity, unless a split course of radiotherapy was used. We had the impression that the later acute radiation mucositis was more pronounced than we would The British Journal of Radiology, October 1991
Chemo I radiotherapy for head and neck cancer
normally expect, but although two patients stopped treatment prematurely we feel that this is comparable to our previous experience in the treatment of similar patients with radiotherapy alone. Of the three episodes of neutropaenic infection that occurred, two patients recovered uneventfully, but the other patient who had alcoholic liver disease also became thrombocytopaenic and died of haemorrhage from the primary tumour. In retrospect this patient would have been best treated with radiotherapy alone and caution should be used in the treatment of patients with liver impairment using this regimen. The number of patients treated is relatively small, and follow-up is limited, but it is of interest to examine the results of treatment. We noted a high rate of initial complete response (21/25, 84%). However response was assessed clinically, and microscopic disease was clearly present in eight out of 21 patients who experienced local recurrence after CR. So far only one of eight patients with nasopharyngeal carcinoma has relapsed, but it is premature to draw any definite conclusion. The finding of a 40% 2-year survival (23% disease-free survival) following 76% initial CR in the group with non-nasopharyngeal cancer is encouraging. The advanced nature of these cancers must be stressed as they had inoperable disease and 18 were of WHO performance status Grade 1 or worse. We conclude that the addition of 5-FU and mitomycin-C to a conventionally fractionated course of radical radiotherapy in patients with inoperable advanced carcinoma of the head and neck is feasible and that the initial results are promising. The true worth of this regimen can only be shown in a randomized and controlled trial, and such a trial should have sufficient power to detect a real difference of 5-10% in survival. This would involve the recruitment of very large numbers of patients and would require multicentre participation, thereby competing against existing studies of patients. Centres wishing to investigate the use of adjuvant chemotherapy in head and neck cancer in Phase III studies should therefore consider participating in existing large multicentre trials such as the current UKCCCR study. Reference BYFIELD, J. E., CALABRO-JONES, P., KLISAK, I. & KULHANTAN,
F., 1982. Pharmacologic requirements for obtaining sensitization of human tumour cells in vitro to combined 5fluorouracil or ftorafur and X-rays. International Journal of Radiation Oncology, Biology, Physics, 8, 1923-1933. CUMMINGS, B., KEANE, T., THOMAS, G., HARWOOD, A. &
DUNCAN, W., ORR, J. A., ARNOTT, S. J., JACK, W. J. L., KERR,
G. R. & WILLIAMS, J. R., 1987. Fast neutron therapy for squamous cell carcinoma in the head and neck region: results of a randomized trial. International Journal of Radiation Oncology, Biology, Physics, 13, 201-208. EVANS, L. S., KERSCH, C. R., CONSTABLE, W. C. & CANTRELL,
R. W., 1988. Concomitant 5-fluorouracil, mitomycin C, and radiotherapy for advanced gynaecological malignancies. International Journal of Radiation Oncology, Biology, Physics, 15, 901-906. Ho, J. H. C , 1978. An epidemiologic and clinical study of nasopharyngeal carcinoma. International Journal of Radiation Oncology, Biology, Physics, 4, 182-198. ICRU, 1978. Dose Specification for Reporting External Beam Therapy with Photons and Electrons. International Commission for Radiological Units and Measurements, Report No. 29 (ICRU, Bethesda, Maryland). KAPLAN, M. J., SEUNG, S. H., JOHNS, M. E., STEWART, F. M., CONSTABLE, W. C. & CANTRELL, R. W., 1985. Mitomycin
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randomised trial of radiation compared to radiation and chemotherapy for advanced laryngeal and hypopharyngeal squamous carcinoma. Second International Conference on Head and Neck Cancer, Abstr. No. 167, p. 89. KENNEDY, K. A., ROCKWELL, S. & SARTORELLI, A. C , 1980.
Preferential activation of mitomycin C to cytotoxic metabolites by hypoxic tumour cells. Cancer Research, 40, 2356-2360. LUDGATE, S. M., CRANDON, A. J., HUDSON, C. N., WALKER, Q.
& LANGLANDS, A. O., 1988. Synchronous 5-fluorouracil, mitomycin C and radiation therapy in the treatment of locally advanced carcinoma of the cervix. International Journal of Radiation Oncology, Biology, Physics, 15, 893-899. MARCIAL, V. A. & PAJAK, T. F., 1985. Radiation therapy alone or in combination with surgery in head and neck cancer. Cancer, 55, 2259-2265. OVERGAARD,
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during
The British Journal of Radiology, October 1991
Concomitant chemo/radiotherapy for advanced carcinoma of the head and neck By C. H. Macmillan, MRCP, FRCR, K. Carrick, DCR(T),*P. J . Bradley, FRCS and D. A. L Morgan, FRCR Department of Clinical Oncology, The General Hospital, Park Row, Nottingham NG1 6HA, and 'Department of Otolaryngology, University Hospital, Nottingham NG7 2UH, UK
{Received November 1990 and in revised form February 1991)
Keywords: Head and neck cancer, Radiotherapy, Chemotherapy, S5-Fluorouracil, Mitomycin-C
Abstract. Giving chemotherapy and radiotherapy simultaneously (concomitant therapy) is one approach to improving results in advanced head and neck cancer. To assess the feasibility of one such regimen, 25 patients with advanced squamous carcinoma of the head and neck were treated with a continuous intravenous infusion of 5-fluorouracil, 1 g/m2 per 24 h for Days 1-5 (105 h) and mitomycin-C 14 mg/m2 intravenously on Day 3 during the first week of radiotherapy. Twenty had Stage IV disease; four Stage III; and one Stage II. Ages ranged from 21 to 73 years (median 60 years). The tumours involved were as follows: oral cavity (6); nasopharynx (8); oropharynx (5); secondary node from unknown primary (3); hypopharynx (2); paranasal sinus (1). Radiotherapy was delivered as 10 Gy per week (total dose 60-70 Gy). Chemotherapy was well tolerated and all received the intended dose. Mild nausea occurred in five patients and three experienced transient vomiting. A generalized "early" mucositis affected 16 out of 25 (64%), caused interruption of radiotherapy in three patients, and is thought to be chemotherapy related. Twenty-two patients received the dose of radiotherapy intended, and two stopped prematurely at 53 and 56 Gy. Three episodes of neutropaenic infection occurred. Two recovered uneventfully, but one toxic death occurred in a patient with alcoholic cirrhosis. A complete response was seen in 21 (84%). For 17 patients with non-nasopharyngeal carcinoma the 2-year survival is 40%, 24% disease free. The concomitant use of 5-fluorouracil, mitomycin and radiotherapy is well tolerated in this group of patients.
The results from treatment of advanced carcinoma of the head and neck are poor. The traditional treatment techniques of surgery and radiotherapy, which are often curative in early-stage disease, are less effective in more advanced patients. Although squamous carcinoma of the head and neck is chemosensitive, it is not curable by chemotherapy alone and attempts to combine chemotherapy with surgery and/or radiotherapy have generally been disappointing (Stell et al, 1983; Taylor, 1987a,b; Tannock, 1989; Stell & Rawson, 1990). One approach to try to improve results is to give chemotherapy and radiotherapy concomitantly (Vokes & Weichselbaum, 1990). 5-Fluorouracil (5-FU) is cytotoxic with activity against squamous carcinoma, and mitomycin-C may be selectively toxic to hypoxic cells. The concomitant use of these drugs with radiotherapy has shown promise in the treatment of squamous carcinoma arising in various sites, most notably the anal canal (Cummings et al, 1984), but also the oesophagus (Keane et al, 1985) and uterine cervix (Evans et al, 1988; Ludgate et al, 1988), as well as the head and neck (Kaplan et al, 1985; Dobrowsky et al, 1989). In 1987 a Phase II study was commenced in order to assess the feasibility of adding 5-fluorouracil and mitomycin-C to the first week of a conventionally fractionated course of radical radiotherapy in patients with advanced head and neck cancer. Previous published studies have either employed non-standard radiotherapy fractionation schedules, or given a lower radiation dose Vol. 64, No. 766
as planned pre-operative treatment (Kaplan et al, 1985; Keane et al, 1988; Dobrowsky et al, 1989). Patients and methods
Between 1987 and 1990, 25 patients were treated with 5-FU at a dose of 1 g/m2 body surface area per 24 h continuous intravenous infusion starting at 9 a.m. on Monday and continuing until 6 p.m. on Friday (105 h), and mitomycin-C (14 mg/m2) intravenous bolus on Day 3. Radiotherapy started a minimum of 3 h following the commencement of the infusion of 5-FU and was given as 2 Gy/day, 5 days per week to an intended dose of 60-70 Gy depending on tumour site and stage (Fig. 1). During the study period patients with advanced head and neck cancer were preferentially treated either within a randomized study of the hypoxic cell sensitizer etani5-Fluorouracil
1 g / m 2 / 24 hours continuous IV infusion Day 1 -5
Mrtomycin C
14mg / m 2 IV Day 3.
Radiotherapy
Week
2Gy / day, 5 days / week to 50-70Gy.
1
Mitomycin C 5-Fluorouracil Radiotherapy
Figure 1. Treatment schedule.
941
C. H. Macmillan, K. Carrick, P. J. Bradley and D. A. L. Morgan
dazole, or those with advanced laryngeal cancer were treated with a hyperfractionated and accelerated radiotherapy schedule. Patients with inoperable head and neck cancer (as assessed at the Combined Head & Neck Oncology Clinic by the surgeon and radiotherapist) not eligible for those studies, and adult patients with nasopharyngeal carcinoma, were given concomitant chemotherapy and radiotherapy. No prior treatment had been carried out other than biopsy. The majority of patients were male (19 out of 25) and ages ranged from 21 to 73 years, median 60 years. World Health Organization (WHO) performance status ranged from category 0 to 3 (Table I). The tumours arose in various sites throughout the head and neck (Table II). Eighty per cent of patients had Stage IV disease; the stage grouping is shown in Tables III and IV. One patient with Stage II carcinoma of the hypopharynx is included in the series. This large tumour extended into the oropharynx, and the hypopharynx also bore a further satellite lesion. Radiotherapy was delivered using fields to treat the primary tumour and the whole neck, and using two or Table I. Performance status, World Health Organization grade Number of patients
Grade
7 12 5 1 Table II. Site of origin of tumour Oral cavity Oropharynx Occult primary Hypopharynx Paranasal sinus Nasopharynx Table III. Stage grouping, UICC 1987 Stage II Stage III Stage IV
1 4 20
Table IV. TNM stage, UICC 1987 'N' stage
T ' stage
942
0 1 2 3 4
0
1
2
3
0 0 1 0 3
1 2 1 0 2
1 1 0 0 2
4 1 1 1 4
4
6
4
11
6 4 3 1 11
15—1
No. of
10 —
Patients 5—
40
50
60
70
Gy
Figure 2. Dose histogram.
three phases of treatment to a total dose of 60-70 Gy depending on the site and extent of disease. The first phase delivered a dose of 40 Gy with parallel opposed 5 MV photons to the primary tumour and the first echelon nodes, including the spinal cord within this volume. A direct anterior field was matched on to the inferior border to treat the lower neck bilaterally, shielding the spinal cord with a midline lead block. The match was achieved using a couch twist of 90° with the gantry angled to match the divergence of the anterior field along the inferior border of the lateral field. A prophylactic dose of 50 Gy at 3 cm depth was delivered to the lower neck. 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 a further 20-25 Gy to the tumour. Asymmetric jaws were used to give minimum penumbra posteriorly, and an electron field was matched on to treat the upper posterior neck to a minimum of 50 Gy total dose. A third phase of treatment used electrons to boost the site of any lymph node masses up to a maximum of 70 Gy. The median dose to the tumour was 60 Gy; the actual doses received are shown in Fig. 2. Photon treatment was delivered using a Philips SL75-5 linear accelerator, with electrons obtained from a Philips SL75-14 linear accelerator. The prescribed dose for photons and electrons was defined as the target absorbed dose (ICRU, 1978). Tissue compensators were used as necessary to keep the dose as nearly as possible homogeneous to within + 5 % of the tumour dose. Results Toxicity All 25 patients received the intended dose of chemotherapy, and this was well tolerated. Mild nausea occurred in five patients, but settled with oral antiemetics. Three patients (12%) experienced vomiting following the administration of mitomycin-C but this was successfully controlled with anti-emetics in each case. No patient required a wig, although slight thinning of the hair was usually evident. Twenty-three of the 25 patients developed a confluent mucositis by the end of treatment. A distinct "early" The British Journal of Radiology, October 1991
Chemo/radiotherapy for head and neck cancer
mucositis occurred, with time of onset ranging from the end of the first week of treatment to the third week. It occurred inside and outside the irradiated areas, affecting 16 of the 25 (64%) patients, and as treatment progressed, was replaced by a mucositis confined to the irradiated volume. The radiotherapy schedule required modification in five patients. Three patients were rested for 1 week due to early mucositis; two of these continued to the intended dose. Two other patients stopped treatment prematurely at 53 and 56 Gy with necrosis of the hard palate (since healed) and severe mucositis, respectively. The fifth patient died from chemotherapy toxicity during radiotherapy. The patient who died was known to have alcoholic liver disease, and had abnormal liver function tests at the time of treatment. Following the development of a severe early mucositis requiring interruption of radiotherapy, he became pancytopaenic and speticaemic and, despite intravenous antibiotics and platelet support, he died of haemorrhage from his primary tumour. Two other episodes of neutropaenic infection occurred, but the patients recovered uneventfully following treatment with intravenous antibiotics. Twenty-two patients (88%) received the intended dose of radiotherapy. Response Response to treatment was assessed clinically at the Combined Head & Neck Oncology Clinic. No patients have been lost to follow-up, and the median duration of follow-up of survivors is 23 months (range 6-41 months). Twenty-one of the 25 patients (84%) showed a complete response to treatment (8/8 nasopharynx, 13/17 others). Death has occurred in 13 patients. In each case the patient either died from carcinoma, or had active disease at the time of death. Relapse has occurred in 14 patients (including four who failed to achieve initial complete remission (CR). The initial site of relapse was local in 12, with two cases of distant metastasis (one pulmonary, one osseous). One patient with initial local relapse subsequently developed generalized metastases. Surgical salvage has been successful in one patient who relapsed locally in the oral cavity at 9 months and he is free of disease 25 months post-surgery. Two other attempts at surgical salvage were not successful as the patients were found to be inoperable when examined under anaesthetic. Life table analyses of the overall and disease-free survival are shown in Figs 3 and 4. In view of the differences in natural history between carcinoma of the nasopharynx and squamous carcinoma in other head and neck sites (Ho, 1978), the eight patients with nasopharyngeal carcinoma have been analysed separately. The 17 patients with non-nasopharyngeal carcinoma have an overall actuarial survival of 40% at 2 years, with 24% disease-free actuarial survival. All of the eight patients with nasopharyngeal carcinoma obtained initial Vol. 64, No. 766
100 90 80 " 70 Nasopharynx (8)
60 50 40 " 30 20 -
Others (17)
10 1
Years
2
3
Figure 3. Actuarial overall survival. * 100
Nasopharynx (8)
Years Figure 4. Actuarial disease free survival.
CR, with one man relapsing at 29 months with osseous metastases. Discussion In order to try and 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, loco-regional control of tumours remains the major problem (Marcial & Pajak, 1985). We found 12 out of 14 relapses to be local. Intercurrent diseases brought on by the same factors that predispose to head and neck cancer become a major factor in long-term survivors. The main methods of treatment remain surgery and radiotherapy. Surgery can be mutilating, and tends to fail at the margins of resection, whereas radiotherapy retains function, but is more likely to fail where the bulk of tumour is greatest, i.e. in the centre of the field. These techniques are therefore complementary to each other. In the 1950s it was realized that there were hypoxic areas within carcinomas (Thomlinson & Gray, 1955) and that hypoxic cells were relatively radioresistant. Therapeutic attempts were made during the 1960s and 1970s to improve hypoxic cell killing in the expectation 943
C. H. Macmillan, K. Carrick, P. J. Bradley and D. A. L. Morgan
that these cells limited the curability of tumours by radiotherapy. Hyperbaric oxygen, hypoxic cell sensitizers (Dische, 1988) and high-LET radiation (Duncan et al, 1987) were used, but the results have been generally disappointing and these treatments have not found a routine clinical use. Cytotoxic drugs have shown consistent activity against squamous carcinoma of the head and neck, and complete responses can be achieved in up to 42% of patients (Weaver et al, 1982). However, chemotherapy has not been shown to improve the long-term survival and recurrence is rapid. Chemotherapy can be used as induction treatment to reduce tumour bulk prior to definitive local treatment with surgery or radiotherapy, but studies using this approach have generally shown no advantage for chemotherapy, with few studies showing advantage and others disadvantage (Taylor, 1987a, b). Indeed this approach may be theoretically harmful, since the clonogenic cells within the tumour may have increased their rate of proliferation in response to chemotherapy by the time radiotherapy commences (Tannock, 1989). Normally proliferation does not increase until 4 weeks following the start of radiotherapy (Withers et al, 1988). Simultaneous chemotherapy and radiotherapy (concomitant treatment) has been used to treat squamous carcinoma arising in various sites, and a number of chemotherapy agents and radiotherapy schedules have been reported. 5-FU and mitomycin have been used concomitantly with radiotherapy in the treatment of squamous carcinoma of the oesophagus (Keane et al, 1985), uterine cervix (Thomas et al, 1984; Ludgate et al, 1988) and, most notably, the anal canal (Cummings et al, 1984), as well as in head and neck cancer (Keane et al, 1988; Dobrowsky et al, 1989), with apparently good results (although only the study of Keane et al was controlled and randomized, and this study used a split course of radiotherapy with the chemotherapy arm). 5-Fluorouracil has activity against squamous carcinoma, and when combined with radiotherapy it can cause cell kill greater than the additive effects of these agents given alone (Vietti et al, 1971; Byfield et al, 1982). The mode of action of 5-FU in causing this 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 (1971) suggested that part of its action is to "fix" sub-lethal damage, but Byfield et al (1982) felt that it was dependent on an undefined alternative mechanism. Owing to its short half-life when given by bolus injection it must be administered as a continuous infusion for this effect to occur. Delivering 5-FU by infusion is less toxic than bolus administration (Seifert et al, 1975), and may also improve the cell kill by exposing tumour cells to the drug as they move through the cell cycle. Mitomycin-C is the prototype quinone bioreductive agent. It requires metabolic reduction to form an active bifunctional alkylating species (Sartorelli, 1988). The presence of oxygen results in the competitive reversal of this reaction. Both in vivo and in vitro experiments with 944
animal models have demonstrated a selective toxicity of mitomycin towards hypoxic cells (Kennedy et al, 1980; Rockwell, 1983). In a randomized study, Weisberg et al (1989) treated 120 patients with head and neck carcinoma with radiotherapy or radiotherapy and mitomycin-C. Overall actuarial survival at 5 years was not significantly different at 40% versus 48% (p > 0.3), but loco-regional disease-free survival was significantly improved from 55% to 75% (p < 0.01) for radiotherapy against radiotherapy plus mitomycin. Dobrowsky et al (1989) treated 51 advanced head and neck cancer patients with pre-operative chemo/radiotherapy using a similar schedule to ourselves, but giving only 50 Gy of radiotherapy. They found that none of their patients required interruption of radiotherapy, and achieved a complete pathological response in 56%, with clinical complete response in 95%. Kaplan et al (1985) reported their experience with a split course of radiotherapy and concomitant chemotherapy with 5-FU and mitomycin in a mixed group of head and neck patients, some being treated prior to planned surgery, and some for palliation only. They found a pathological CR in 77% of primary tumours and 69% of involved nodes. Keane et al (1988) randomized patients to receive a continuous course of radiotherapy or a split course with concomitant chemotherapy. The results were not significantly different, but this implies that the addition of chemotherapy was able to compensate for the gap in treatment, calculated by Overgaard et al (1988) to be the equivalent of 0.5 Gy per day. 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 upset or acute toxicity. Within such a group of patients are many who continue to smoke and consume alcohol, and it is common for such patients not to complete their treatment. In this study 22 out of 25 (88%) did complete the planned treatment with the encouragement of staff. The early generalized mucositis we observed necessitated a rest from treatment in three cases, and was probably due to the chemotherapy. Evans et al (1988) reported a similar finding in 12 out of 25 patients treated with slightly lower doses of 5-FU and mitomycin. Others using similar regimens have found minimal acute toxicity, but Ludgate et al (1988), who treated patients with advanced carcinoma of the cervix with concomitant 5FU infusion at weeks 1 and 4 plus mitomycin on Day 1, noted an increase in gastrointestinal symptoms requiring modification of the radiotherapy schedule. They also delivered 30 Gy to Point A with a single intracavitary insertion prior to external-beam treatment. Cummings et al (1984) found that their initial radiotherapy schedule of 50 Gy in 20 fractions for the treatment of anal carcinoma combined with 5-FU and mitomycin caused excessive haematological and gastrointestinal toxicity, unless a split course of radiotherapy was used. We had the impression that the later acute radiation mucositis was more pronounced than we would The British Journal of Radiology, October 1991
Chemo I radiotherapy for head and neck cancer
normally expect, but although two patients stopped treatment prematurely we feel that this is comparable to our previous experience in the treatment of similar patients with radiotherapy alone. Of the three episodes of neutropaenic infection that occurred, two patients recovered uneventfully, but the other patient who had alcoholic liver disease also became thrombocytopaenic and died of haemorrhage from the primary tumour. In retrospect this patient would have been best treated with radiotherapy alone and caution should be used in the treatment of patients with liver impairment using this regimen. The number of patients treated is relatively small, and follow-up is limited, but it is of interest to examine the results of treatment. We noted a high rate of initial complete response (21/25, 84%). However response was assessed clinically, and microscopic disease was clearly present in eight out of 21 patients who experienced local recurrence after CR. So far only one of eight patients with nasopharyngeal carcinoma has relapsed, but it is premature to draw any definite conclusion. The finding of a 40% 2-year survival (23% disease-free survival) following 76% initial CR in the group with non-nasopharyngeal cancer is encouraging. The advanced nature of these cancers must be stressed as they had inoperable disease and 18 were of WHO performance status Grade 1 or worse. We conclude that the addition of 5-FU and mitomycin-C to a conventionally fractionated course of radical radiotherapy in patients with inoperable advanced carcinoma of the head and neck is feasible and that the initial results are promising. The true worth of this regimen can only be shown in a randomized and controlled trial, and such a trial should have sufficient power to detect a real difference of 5-10% in survival. This would involve the recruitment of very large numbers of patients and would require multicentre participation, thereby competing against existing studies of patients. Centres wishing to investigate the use of adjuvant chemotherapy in head and neck cancer in Phase III studies should therefore consider participating in existing large multicentre trials such as the current UKCCCR study. Reference BYFIELD, J. E., CALABRO-JONES, P., KLISAK, I. & KULHANTAN,
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during
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