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Sequential chemotherapy and radiotherapy in advanced head and neck cancer
CliniealRadiology (1983) 34, 463-467 © 1983 Royal College of Radiologists
0009 9260/83/00560463502.00
Sequential Chemotherapy and Radiotherapy in Advanced Head and Neck Cancer P. M. STELL*, J. E. DALBYt, P. STRICKLAND~, J. G. FRASER§, P. J. BRADLEY* and L. M. FLOOD§
*Department of Otorhinolaryngology, University of Liverpool, Royal Liverpool Hospital; t Mersey Regional Centre for Radiotherapy and Oncology, Clatterbridge Hospital, Merseyside; SRegional Radiotherapy Centre, Mount Vernon Hospital, Northwood, Middlesex; and § University College Hospital, London Eiglaty-six previously untreated patients with advanced squamous-cell carcinoma of the head and neck were entered into a prospective randomised controlled trial to evaluate whether the addition of a kinetically based chemotherapy regimen before and after radiotherapy would improve survival compared with radiotherapy alone. Survival at 30 months showed there was no evidence that the addition of chemotherapy to radiotherapy improved survival and that the chance of obtaining a significant result in favour of adjuvant chemotherapy was remote. We make a strong plea that all chemotherapy regimens for the treatment of squamous-cell carcinoma of the head and neck regions should be subjected to controlled prospective trials before they are widely adopted.
The survival of patients with head and neck cancer has not greatly improved during the last decade. It is hoped that the addition of chemotherapy to local treatment will improve survival (Green, 1978; Wittes, 1979, 1980). Indeed, it is said that the management team for patients with head and neck cancer should now include a medical oncologist in addition to the surgeon and radiotherapist (Chilchik, 1981). It has been shown in animal experiments that many cytotoxic agents can potentiate the effect of radiotherapy on squamous-cell carcinoma (Shigematsu et al., 1971). However, preliminary reports of the results in head and neck cancer have been disappointing; the duration of tumour control has been short (Taylor, 1980). Many non-randomised trials have reported short-term benefit when chemotherapy was given before radiotherapy, but the patients still died of persistent tumour (Ervin et al., 1981). A non-randomised study of synchronous chemotherapy with radiotherapy showed a twofold improvement in survival compared with historical controls treated by radiotherapy alone (O'Connor, 1980; O'Connor et al., 1979). To date, randomised trials of chemotherapy given before radiotherapy to patients with head and neck cancer have not consistenfly shown any sustained improvement (Oster, 1981, Stefani et al., 1971; GoUins et al., 1972; Kirkwood et al., 1979; Petrovich et al., 1981; Kramer, 1975; Cachin, 1982). At present a kinetically based chemotherapeutic regimen (Price and Hill, 1977) is claimed to have the highest tumour response of the regimens available,
with minimum toxic effect (Hill and Price, 1980). This regimen, when given before radiotherapy, has been reported in uncontrolled trials to improve survival (Price and Hill, 1980; Sergant and Deutsch, 1981). We report a randomised controlled prospective trial to evaluate whether the addition of the kinetic chemotherapy regimen, designed by Price and Hill (Price and Hill, 1977; Norton and Simon, 1977), before and after radiotherapy, improved survival compared with radiotherapy alone. PATIENTS The trial was coordinated from Liverpool and included patients who presented to the Royal Liverpool Hospital, University College Hospital, London, and Mount Vernon Hospital, Middlesex. All patients presenting with previously untreated Stage III or Stage IV squamous carcinoma of the head and neck were considered for entry. After histological confirmation of the disease and classification according to the UICC scheme (Harmer, 1978), the patients were seen jointly by a surgeon and a radiotherapist, and a decision made that the patient could be treated radically. If the patient had an advanced tumour fulfilling the criteria shown in Table 1, he was entered into the trial. Patients were excluded from entry for the following reasons: pregnancy, unavailability for follow-up, poor general condition, second simultaneous malignancy, or age over 80 years. The details of the patients were then
464
CLINICAL RADIOLOGY f~
Table 1 - Conditions o f entry All patients m u s t have squamous-cell carcinoma at the following sites: Oral cavity Orophaxynx Pyriform fossa Larynx
}
METHOD T3N x or T4N x
Nasopharynx
TxN x
T x = any T; N x = any N. All patients M 0 .
Table 2 - Patients
Larynx Oral cavity Oropharynx Nasopharynx Pyriform fossa
oropharynx, nasopharynx or pyriform fossa; these were grouped together and are collectively referred to in this paper as 'buccopharynx' (Table 2).
Ch emo therapy group
Radiotherapy group
25 5 7 4 6
23 4 5 3 4
communicated to the secretary of the ENT Department at the Royal Liverpool Hospital, and were entered in a register. The register consisted of a line for each patient, and each line had the word 'With' or 'Without' assigned to it at the start of the trial. Each two lines formed a pair of 'With-Without ~ or 'Without-With', the order in each pair being determined from random-number tables. There was a separate page for each site for each treatment centre. The clinician was not told whether the patient was to receive chemotherapy until the details of the patient had been entered in the register. Thirty-six men with a median age of 63 years (range 3 9 - 7 5 years) and 11 women with a median age of 59 years (range 5 0 - 6 8 years) were randomised to be treated by chemotherapy and radiotherapy. Twenty-eight men with a median age of 58 years (range 4 3 - 7 9 years) and 11 women with a median age of 63 years (range 4 1 - 7 4 years) were randomised to be treated by radiotherapy alone. Each patient before, during and after chemotherapy, had regular monitoring of peripheral blood count, absolute platelet count, liver-function studies, and urinary creatinine clearance. Administration of chemotherapy was delayed if the haematological and biochemical results were unsatisfactory (Rowland, 1981). Twenty-five patients in the chemotherapy + radiotherapy group and 23 in the radiotherapy group had a carcinoma of the larynx. There were small numbers of patients with carcinoma of the oral cavity,
All patients randomised to receive chemotherapy were given two regimens of cytotoxic drugs as shown in Table 3. Schedule I was given on day 1 and schedule II on day 14. Radiotherapy began about day 28. Patients who were randomised to be treated by radiotherapy alone began treatment on day 1 and received no cytotoxic drugs at any stage of treatment. Megavoltage radiation was given to all patients and a dose of 4000-6000 cGy was delivered in a 3 - 6 week period. Patients who received chemotherapy before radiotherapy were to receive further chemotherapy on completion of radiotherapy, alternating between schedule I and schedule II at 21-day intervals, commencing about day 56, for a total of 12 courses over 36 weeks. The aim of alternating the schedules was to allow drag doses to be given in full without the risk of cumulative toxic effects. If there was objective evidence of progression of disease in spite of treatment, patients were to be withdrawn from the trial. Patients were followed up by the referring consultants at regular intervals to assess the patient's
Table 3 - C h e m o t h e r a p y regimens Schedulel
5-FU (350 mg/m = i.v )
Hydrocortlsone (500 mg L.V.)
1
MTX (75 mg/m2 i v.)
Vlncrlstlne (1.5 mg/m 2 Lv.)
Hydrocortisone (500 mg t v.)
MTX (75 mg/m 2 J.v.)
Bleomycm (60 mg mfusion) I 15 Hours
l
MTX (75 mg/m2 i.v.) l
Fohmc acid (15 mg t.m. or orally X 4 6~ourly)
18
2~6
Schedule I1 Hydroxyurea (3g/m 2)
6-MP (150 mg/rn 2 orally)
Hours
Cyclophosphamlde (500mg/m 2 [.v.)
CHEMOTHERAPY
AND RADIOTHERAPY
response to treatment. If local treatment failed the patient was then considered for radical surgery.
IN H E A D
AND
NECK
465
CANCER
100x ~"3.03 NS
80 ¸
FOLLOW-UP AND ANALYSIS OF THE DATA All patients have been followed up either by personal contact, or by information from the Office of Population Censuses and Statistics in the case of patients who are dead. Survival curves are given by the life table method and have been analysed by Peto's log rank method.
-~ so ~o * 4o
DXRT
~1
RESULTS Toxicity Four patients, all in the 'buccopharyrL~' group, ceased chemotherapy because of toxicity; one patient died from septicaemia following pancytopoenia, one developed pulmonary fibrosis, one autonomic neuropathy and one alopecia.
CT*DXRT
2o
12
1'8 Months
2~4
3£1
36
Fig. 1 - All patients. DXRT = radiotherapy group; CT + DXRT = chemotherapy + radiotherapy group. 100x2=9 82 p
Follow-up Chemotherapy Chemotherapy was stopped temporarily in four instances: three because of depression of bone marrow and one because of reduced renal function. Twenty-two patients withdrew from further chemotherapy because of tumour growth in spite of chemotherapy after radiotherapy. Only six of the 47 patients in the chemotherapy group completed all 12 courses of chemotherapy after radiotherapy. Four patients, all with laryngeal carcinoma, are currently still receiving therapy.
----i
"~ 60>
DXRT
5 g, 40,
20. CT DXRT 6
12
18
24
30
36
Months
Fig. 2 - Buccopharynx. DXRT= radiotherapy group; CT + DXRT = chemotherapy + radiotherapy group.
Salvage Surgery Seventeen patients had salvage surgery, six in the chemotherapy group and 11 in the radiotherapy only group: 10 had a laryngectomy, three a pharyngolaryngectomy, two a pelvimandibulectomy, one exploration of the post-nasal space and one had bilateral radical neck dissection. Four patients in the chemotherapy group, and four of six patients treated by radiotherapy who underwent a laryngectomy, are still alive. Three of the seven patients in the 'buccopharyngeal' group who underwent salvage surgery are still alive. All three were treated by radiotherapy alone.
Survival The survival at 30 months for the chemotherapy group was 22% and the radiotherapy group 55% (Fig. 1), but the chemotherapy group had a greater proportion of patients with Stage IV disease. A Peto's log rank test with allowance for the difference in
staging showed that this difference in survival was not significant (X~ = 2.53 ; P = 0.11). The patients with a tumour of the buccopharynx did particularly badly with combined therapy: all patients died within 24 months (Fig. 2).
DISCUSSION In brief, the above results showed that the addition of the Price-Hill regime was reasonably safe (only one patient (2.1%) died of toxicity) but there was no evidence that it improved survival when given before radiotherapy to patients with advanced squamous carcinoma of the head and neck. The presence of metastatic cervical lymph nodes in a patient with a head and neck malignancy is associated with a poor prognosis (Schuller et al., 1980). In this series only five patients (10%), all in the radiotherapy group, who presented with evidence of
466
CLINICAL RADIOLOGY
cervical-node disease are alive at 2 years, whereas eight patients (25.8%) w h o presented w i t h no cervicalnode disease are alive at 2 years. It has b e e n previously n o t e d t h a t nodal disease is resistant to c h e m o t h e r a p y even t h o u g h the primary disease m a y show a response ( T r e m o n t et aL, 1981). M u c h h o p e was generated b y the i n t r o d u c t i o n o f the kinetically based c h e m o t h e r a p y regimen for t r e a t m e n t of patients w i t h a head and neck cancer (Price and Hill, 1977). This regimen has been r e p o r t e d to give t h e best t u m o u r response with m i n i m u m t o x i c effect o f all the regimens advocated for the t r e a t m e n t o f patients with head and n e c k cancer (Price et al., 1978; Price and Hill, 1981). H o w e v e r , these claims have n o t b e e n substantiated b y o t h e r authors (Dalley, 1978; Raafat and Oster, 1980; T a n n o c k et al., 1982). It has also been s h o w n that some single regimens using one drag are just as g o o d as multiple regimes (Muggia et al., 1980; De C o n t e and Schoenfeld, 1982). We have n o t included an assessment o f the response o f the t u m o u r in this report. There are t w o reasons for this: first, at m a n y sites in the head and neck, for e x a m p l e , the n a s o p h a r y n x and h y p o p h a r y n x , accurate m e a s u r e m e n t of the size of the t u m o u r is impossible. Second, response o f the t u m o u r is irrelevant to the patient: w h a t matters is w h e t h e r he survives in reasonably good health. A l t h o u g h the n u m b e r of patients in this trial is small it is big e n o u g h to render virtually impossible the chance o f obtaining a significant result in favour o f adjuvant c h e m o t h e r a p y . As t r e a t m e n t by c h e m o t h e r a p y in any f o r m is toxic and expensive we therefore s t o p p e d this trial. We m a k e a strong plea t h a t all c h e m o t h e r a p y regimens for squamous-cell c a r c i n o m a of the head and n e c k should be subjected to c o n t r o l l e d prospective trials before t h e y are a d o p t e d widely. REFERENCES
Cachin, Y. (1982). Adjuvant chemotherapy in head and neck carcinoma. Clinical Otolaryngology, 7, 131-132. Chilchik, M. W. (1981). In Safer Cancer Chemotherapy, ed. Price, L. A., Hill, B. T. & Chilchik, M. W. Bailli~re Tindall, London. Dalley, V. M. (1978). Radiotherapy and chemotherapy in treatment of head and neck cancer. International Journal o f Radiation Oncology, Biology and Physics, 4, 1 7 3 179. De Conte, R. C. & Schoenfeld, D. (1982). Randomized prospective comparison of intermittent methotrexate, methotrexate with leucovorin, and a methotrexate combination in head and neck cancer. Cancer, 48, 1061-1072. Ervin, T. J., Karp, D. D., Weichselbanm, R. R., Posher, M. R., Fabian, R. L. & Miller, D. (1981). Role of chemotherapy in the multidisciplinary approach to advanced head and neck cancer; potentials and problems. Annals of Otolaryngology, 90, 506-511.
Gollins, F. F., Ansfield, F. J. & Brandenberg, J. H. (1972). Combined therapy in head and neck cancer. American Journal o f Roentgenology, 114, 83-88. Green, M. (1978). Chemotherapy of head and neck cancer. Head andNeek, 1, 75-86. Harmer, M. H. (ed.) (1978). TNMClassification of Malignant Tumours - UICC, 3rd edn. Geneva. Hill, B. T. & Price, L. A. (1980). The changing role of chemotherapy in the treatment of head and neck cancer. Cancer Topics, 2, 5 - 7 . Kirkwood, J. M., Miller, D., Weichselbaum, R. & Pitman, S. (!979). Predefinitive and postdefinitive chemotherapy for locally advanced squamous carcinoma of the head and neck. Laryngoscope, 89, 573-581. Kramer, S. (1975). Methotrexate and radiation therapy in the treatment of advanced squamous cell carcinoma of the oral cavity, oropharynx, supraglottic larynx and hypopharynx. Canadian Journal of Otolaryngology, 4, 213218. Muggia, F. M., Rozensweig, M. & Louie, A. E. (1980). Role of chemotherapy in head and neck cancer: systemic use of single agents and combinations in advanced disease. Head and Neck Surgery, 2, 196-205. Norton, L. & Simon, R. (1977). Turnout size, sensitivity to therapy and design of treatment schedules. Cancer Treatment Reports, 61, 1307-1316. O'Connor, A. D., Clifford, P., Dalley, V. M., Durden-Smith, D. J., Edwards, W. & Hollis, B. A. (1979). Advanced head and neck cancer treated by combined radiotherapy and VBM cytotoxic regimens - four-year results. Clinical Otolaryngology, 4 , 3 2 9 - 3 3 7 . O'Connor, A. D. (1980). Head and neck cancer: 5 year experience with VBM and radiotherapy. Cancer Topics, 2, 8-9. Oster, M. W. (1981). Chemotherapy before radiotherapy and/or surgery for locally advanced squamous carcinomas of the head and neck. Archives of Otolaryngology, 107, 297-299. Petrovich, Z., Block, J., Kuisk, H., Mackintosh, R., Casiato, D., Jose, L. & Barton, R. (1981). A randomised comparison of radiotherapy with a radiotherapy-chemotherapy combination in Stage IV carcinoma of the head and neck. Cancer, 47, 2259-2264. Price, L. A., & Hill, B. T. (1977). A kinetically-based logical approach to the chemotherapy of head and neck cancer. Clinical Otolaryngology , 2, 339-345. Price, L. A. & Hill, B. T. (1980). Safe and effective combination chemotherapy for squamous cell carcinoma of the head and neck. Journal of Laryngology and Otology, 94, 89 90. Price, L. A. & Hill, B. T. (1981). Safe and effective combination chemotherapy without cis-platinum for squamous cell carcinoma of the head and neck. Cancer Treatment Reports, 65 (Suppl. 1), 149-154. Price, L. A., Hill, B. T., Calvert, A. H., Dalley, M., Levene, A., Busby, E. R. Schachter, M. & Shaw, M. A. (1978). Improved results in combined chemotherapy of head and neck cancer using a kinetically-based approach. A randomised study with and without adriamycin. Oncology, 35, 26-28. Raafat, J. & Oster, M. W. (1980). Combined chemotherapy for advanced squamous cell carcinoma of the head and neck. Cancer Treatment Reports, 64,187-189. Rowland, C. G. (1981). In Safer Cancer Chemotherapy, ed. Price, L. A., Hill, B. T. & Chilchik, M. W., pp. 53-57. Bailligre Tindall, London. Schuller, D. E., McGuirt, W. F., McCabe, B. F. & Young, D.
C H E M O T H E R A P Y AND R A D I O T H E R A P Y IN HEAD AND NECK CANCER (1980). The piognostic significance of metastatic cervical lymph nodes. Laryngoscope, 40, 557-570. Sergant, R. & Deutsch, G. (1981). A preliminary repoIt on the combination of initial chemotherapy and radiotherapy for advanced head and neck cancer. Journal of Laryngology and Otology, 95, 69-74. Shigematsu, T., Sakai, S. & Fucjibata, H. (1971). Recent trials in the treatment of maxillary carcinoma with special reference to the clinical potentiation of radiation therapy. Acta Otolaryngologica, 71, 6 3 - 7 0 . Stefani, A., EeUs, R. & Abbat, S. (1971). Hydroxyrea and radiotherapy in head and neck cancer. Radiology, 101, 391-396. Tannock, I., Suthedand, D. & Osoba, D. (1982). Failure of
467
short course multiple drug chemotherapy to benefit patients with recurrent or metastatic head and neck cancer. Caneer, 49, 1358-1361. Taylor, S. G. (1980). Cancer Chemotherapy 1980, EORTC Cancer Chemotherapy Annual 2, pp. 263-278. Excerpta Medica, Amsterdam. Tremont, S., Capizzi, L., Browden, J. P., Kirsck, M., Wood, H., Kahn, L. & Salisbury, L. (1981). Methotrexate, vincristine and bleomycin (MVB) in Stage III and IV squamous cell carcinoma of the head and neck (abstract). Head and Neck Surgery, 3, 262. Wittes, R. E. (1979/80). Head and Neck Cancer: Chemotherapy. Bristol-Meyers Co.
0009 9260/83/00560463502.00
Sequential Chemotherapy and Radiotherapy in Advanced Head and Neck Cancer P. M. STELL*, J. E. DALBYt, P. STRICKLAND~, J. G. FRASER§, P. J. BRADLEY* and L. M. FLOOD§
*Department of Otorhinolaryngology, University of Liverpool, Royal Liverpool Hospital; t Mersey Regional Centre for Radiotherapy and Oncology, Clatterbridge Hospital, Merseyside; SRegional Radiotherapy Centre, Mount Vernon Hospital, Northwood, Middlesex; and § University College Hospital, London Eiglaty-six previously untreated patients with advanced squamous-cell carcinoma of the head and neck were entered into a prospective randomised controlled trial to evaluate whether the addition of a kinetically based chemotherapy regimen before and after radiotherapy would improve survival compared with radiotherapy alone. Survival at 30 months showed there was no evidence that the addition of chemotherapy to radiotherapy improved survival and that the chance of obtaining a significant result in favour of adjuvant chemotherapy was remote. We make a strong plea that all chemotherapy regimens for the treatment of squamous-cell carcinoma of the head and neck regions should be subjected to controlled prospective trials before they are widely adopted.
The survival of patients with head and neck cancer has not greatly improved during the last decade. It is hoped that the addition of chemotherapy to local treatment will improve survival (Green, 1978; Wittes, 1979, 1980). Indeed, it is said that the management team for patients with head and neck cancer should now include a medical oncologist in addition to the surgeon and radiotherapist (Chilchik, 1981). It has been shown in animal experiments that many cytotoxic agents can potentiate the effect of radiotherapy on squamous-cell carcinoma (Shigematsu et al., 1971). However, preliminary reports of the results in head and neck cancer have been disappointing; the duration of tumour control has been short (Taylor, 1980). Many non-randomised trials have reported short-term benefit when chemotherapy was given before radiotherapy, but the patients still died of persistent tumour (Ervin et al., 1981). A non-randomised study of synchronous chemotherapy with radiotherapy showed a twofold improvement in survival compared with historical controls treated by radiotherapy alone (O'Connor, 1980; O'Connor et al., 1979). To date, randomised trials of chemotherapy given before radiotherapy to patients with head and neck cancer have not consistenfly shown any sustained improvement (Oster, 1981, Stefani et al., 1971; GoUins et al., 1972; Kirkwood et al., 1979; Petrovich et al., 1981; Kramer, 1975; Cachin, 1982). At present a kinetically based chemotherapeutic regimen (Price and Hill, 1977) is claimed to have the highest tumour response of the regimens available,
with minimum toxic effect (Hill and Price, 1980). This regimen, when given before radiotherapy, has been reported in uncontrolled trials to improve survival (Price and Hill, 1980; Sergant and Deutsch, 1981). We report a randomised controlled prospective trial to evaluate whether the addition of the kinetic chemotherapy regimen, designed by Price and Hill (Price and Hill, 1977; Norton and Simon, 1977), before and after radiotherapy, improved survival compared with radiotherapy alone. PATIENTS The trial was coordinated from Liverpool and included patients who presented to the Royal Liverpool Hospital, University College Hospital, London, and Mount Vernon Hospital, Middlesex. All patients presenting with previously untreated Stage III or Stage IV squamous carcinoma of the head and neck were considered for entry. After histological confirmation of the disease and classification according to the UICC scheme (Harmer, 1978), the patients were seen jointly by a surgeon and a radiotherapist, and a decision made that the patient could be treated radically. If the patient had an advanced tumour fulfilling the criteria shown in Table 1, he was entered into the trial. Patients were excluded from entry for the following reasons: pregnancy, unavailability for follow-up, poor general condition, second simultaneous malignancy, or age over 80 years. The details of the patients were then
464
CLINICAL RADIOLOGY f~
Table 1 - Conditions o f entry All patients m u s t have squamous-cell carcinoma at the following sites: Oral cavity Orophaxynx Pyriform fossa Larynx
}
METHOD T3N x or T4N x
Nasopharynx
TxN x
T x = any T; N x = any N. All patients M 0 .
Table 2 - Patients
Larynx Oral cavity Oropharynx Nasopharynx Pyriform fossa
oropharynx, nasopharynx or pyriform fossa; these were grouped together and are collectively referred to in this paper as 'buccopharynx' (Table 2).
Ch emo therapy group
Radiotherapy group
25 5 7 4 6
23 4 5 3 4
communicated to the secretary of the ENT Department at the Royal Liverpool Hospital, and were entered in a register. The register consisted of a line for each patient, and each line had the word 'With' or 'Without' assigned to it at the start of the trial. Each two lines formed a pair of 'With-Without ~ or 'Without-With', the order in each pair being determined from random-number tables. There was a separate page for each site for each treatment centre. The clinician was not told whether the patient was to receive chemotherapy until the details of the patient had been entered in the register. Thirty-six men with a median age of 63 years (range 3 9 - 7 5 years) and 11 women with a median age of 59 years (range 5 0 - 6 8 years) were randomised to be treated by chemotherapy and radiotherapy. Twenty-eight men with a median age of 58 years (range 4 3 - 7 9 years) and 11 women with a median age of 63 years (range 4 1 - 7 4 years) were randomised to be treated by radiotherapy alone. Each patient before, during and after chemotherapy, had regular monitoring of peripheral blood count, absolute platelet count, liver-function studies, and urinary creatinine clearance. Administration of chemotherapy was delayed if the haematological and biochemical results were unsatisfactory (Rowland, 1981). Twenty-five patients in the chemotherapy + radiotherapy group and 23 in the radiotherapy group had a carcinoma of the larynx. There were small numbers of patients with carcinoma of the oral cavity,
All patients randomised to receive chemotherapy were given two regimens of cytotoxic drugs as shown in Table 3. Schedule I was given on day 1 and schedule II on day 14. Radiotherapy began about day 28. Patients who were randomised to be treated by radiotherapy alone began treatment on day 1 and received no cytotoxic drugs at any stage of treatment. Megavoltage radiation was given to all patients and a dose of 4000-6000 cGy was delivered in a 3 - 6 week period. Patients who received chemotherapy before radiotherapy were to receive further chemotherapy on completion of radiotherapy, alternating between schedule I and schedule II at 21-day intervals, commencing about day 56, for a total of 12 courses over 36 weeks. The aim of alternating the schedules was to allow drag doses to be given in full without the risk of cumulative toxic effects. If there was objective evidence of progression of disease in spite of treatment, patients were to be withdrawn from the trial. Patients were followed up by the referring consultants at regular intervals to assess the patient's
Table 3 - C h e m o t h e r a p y regimens Schedulel
5-FU (350 mg/m = i.v )
Hydrocortlsone (500 mg L.V.)
1
MTX (75 mg/m2 i v.)
Vlncrlstlne (1.5 mg/m 2 Lv.)
Hydrocortisone (500 mg t v.)
MTX (75 mg/m 2 J.v.)
Bleomycm (60 mg mfusion) I 15 Hours
l
MTX (75 mg/m2 i.v.) l
Fohmc acid (15 mg t.m. or orally X 4 6~ourly)
18
2~6
Schedule I1 Hydroxyurea (3g/m 2)
6-MP (150 mg/rn 2 orally)
Hours
Cyclophosphamlde (500mg/m 2 [.v.)
CHEMOTHERAPY
AND RADIOTHERAPY
response to treatment. If local treatment failed the patient was then considered for radical surgery.
IN H E A D
AND
NECK
465
CANCER
100x ~"3.03 NS
80 ¸
FOLLOW-UP AND ANALYSIS OF THE DATA All patients have been followed up either by personal contact, or by information from the Office of Population Censuses and Statistics in the case of patients who are dead. Survival curves are given by the life table method and have been analysed by Peto's log rank method.
-~ so ~o * 4o
DXRT
~1
RESULTS Toxicity Four patients, all in the 'buccopharyrL~' group, ceased chemotherapy because of toxicity; one patient died from septicaemia following pancytopoenia, one developed pulmonary fibrosis, one autonomic neuropathy and one alopecia.
CT*DXRT
2o
12
1'8 Months
2~4
3£1
36
Fig. 1 - All patients. DXRT = radiotherapy group; CT + DXRT = chemotherapy + radiotherapy group. 100x2=9 82 p
Follow-up Chemotherapy Chemotherapy was stopped temporarily in four instances: three because of depression of bone marrow and one because of reduced renal function. Twenty-two patients withdrew from further chemotherapy because of tumour growth in spite of chemotherapy after radiotherapy. Only six of the 47 patients in the chemotherapy group completed all 12 courses of chemotherapy after radiotherapy. Four patients, all with laryngeal carcinoma, are currently still receiving therapy.
----i
"~ 60>
DXRT
5 g, 40,
20. CT DXRT 6
12
18
24
30
36
Months
Fig. 2 - Buccopharynx. DXRT= radiotherapy group; CT + DXRT = chemotherapy + radiotherapy group.
Salvage Surgery Seventeen patients had salvage surgery, six in the chemotherapy group and 11 in the radiotherapy only group: 10 had a laryngectomy, three a pharyngolaryngectomy, two a pelvimandibulectomy, one exploration of the post-nasal space and one had bilateral radical neck dissection. Four patients in the chemotherapy group, and four of six patients treated by radiotherapy who underwent a laryngectomy, are still alive. Three of the seven patients in the 'buccopharyngeal' group who underwent salvage surgery are still alive. All three were treated by radiotherapy alone.
Survival The survival at 30 months for the chemotherapy group was 22% and the radiotherapy group 55% (Fig. 1), but the chemotherapy group had a greater proportion of patients with Stage IV disease. A Peto's log rank test with allowance for the difference in
staging showed that this difference in survival was not significant (X~ = 2.53 ; P = 0.11). The patients with a tumour of the buccopharynx did particularly badly with combined therapy: all patients died within 24 months (Fig. 2).
DISCUSSION In brief, the above results showed that the addition of the Price-Hill regime was reasonably safe (only one patient (2.1%) died of toxicity) but there was no evidence that it improved survival when given before radiotherapy to patients with advanced squamous carcinoma of the head and neck. The presence of metastatic cervical lymph nodes in a patient with a head and neck malignancy is associated with a poor prognosis (Schuller et al., 1980). In this series only five patients (10%), all in the radiotherapy group, who presented with evidence of
466
CLINICAL RADIOLOGY
cervical-node disease are alive at 2 years, whereas eight patients (25.8%) w h o presented w i t h no cervicalnode disease are alive at 2 years. It has b e e n previously n o t e d t h a t nodal disease is resistant to c h e m o t h e r a p y even t h o u g h the primary disease m a y show a response ( T r e m o n t et aL, 1981). M u c h h o p e was generated b y the i n t r o d u c t i o n o f the kinetically based c h e m o t h e r a p y regimen for t r e a t m e n t of patients w i t h a head and neck cancer (Price and Hill, 1977). This regimen has been r e p o r t e d to give t h e best t u m o u r response with m i n i m u m t o x i c effect o f all the regimens advocated for the t r e a t m e n t o f patients with head and n e c k cancer (Price et al., 1978; Price and Hill, 1981). H o w e v e r , these claims have n o t b e e n substantiated b y o t h e r authors (Dalley, 1978; Raafat and Oster, 1980; T a n n o c k et al., 1982). It has also been s h o w n that some single regimens using one drag are just as g o o d as multiple regimes (Muggia et al., 1980; De C o n t e and Schoenfeld, 1982). We have n o t included an assessment o f the response o f the t u m o u r in this report. There are t w o reasons for this: first, at m a n y sites in the head and neck, for e x a m p l e , the n a s o p h a r y n x and h y p o p h a r y n x , accurate m e a s u r e m e n t of the size of the t u m o u r is impossible. Second, response o f the t u m o u r is irrelevant to the patient: w h a t matters is w h e t h e r he survives in reasonably good health. A l t h o u g h the n u m b e r of patients in this trial is small it is big e n o u g h to render virtually impossible the chance o f obtaining a significant result in favour o f adjuvant c h e m o t h e r a p y . As t r e a t m e n t by c h e m o t h e r a p y in any f o r m is toxic and expensive we therefore s t o p p e d this trial. We m a k e a strong plea t h a t all c h e m o t h e r a p y regimens for squamous-cell c a r c i n o m a of the head and n e c k should be subjected to c o n t r o l l e d prospective trials before t h e y are a d o p t e d widely. REFERENCES
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