Thorax 1989;44:215-219 Thorax: first published as 10.1136/thx.44.3.215 on 1 March 1989. Downloaded from Etoposide compared with the combination of vincristine, doxorubicin, and cyclophosphamide in the treatment of small cell lung cancer M B McILLMURRAY, R J BIBBY, BE TAYLOR, L P ORMEROD, J R EDGE, R J WOLSTENHOLME, R F WILLEY, J F O'REILLY, N HORSFIELD, C E JOHNSON, C P MUSTCHIN, D BRISCOE From the Royal Lancaster Infirmary, Lancaster; Victoria Hospital, Blackpool; Royal Preston Hospital, Preston; Blackburn Royal Infirmary, Blackburn; Marsden Hospital, Burnley; Furness General Hospital, Cumbria; Cumberland Infirmary, Carlisle; and Royal Albert Edward Infirmary, Wigan ABSTRACT One hundred and three patients with small cell lung carcinoma were stratified according to stage ofdisese (47 limited disease, 56 extensive disease) and then randomised to receive etoposide 300 mg/m2 alone for two days or a combination (VAC) of vincristine 1 mg/m2, doxorubicin (Adriamycin) 50 mg/m2, and cyclophosphamide 1000 mg/m2. The drugs were given at three week intervals. Patients were assessed after three cycles of treatment and continued with the same regimen ifin complete remission and with the alternative regimen ifin partial remission; they were withdrawn if the disease had progressed. Twenty four patients (23%) achieved complete remission and this copyright. occurred more often when patients were receiving VAC (19 of82) than etoposide (5 of75). There was no difference, however, in overall survival between those initially treated with etoposide and those having combination chemotherapy, whether for limited disease (both 8 months) or extensive disease (7 and 5 5 months). Toxicity was less with etoposide. Survival was disappointing, especially with limited disease, even in patients who showed a complete response to treatment. http://thorax.bmj.com/ Introduction regimens. We have evaluated the response and survival of patients with small cell lung cancer using Small cell lung cancer disseminates early and is two simple treatment regimens in a comparative study: generally treated with chemotherapy rather than sur- a combination of vincristine, doxorubicin (Adria- gery or radiotherapy. Widely varying chemoth- mycin), and cyclophosphamide (VAC), which is erapeutic regimens have been used and response rates relatively safe but unpleasant because of gastrointes- on September 26, 2021 by guest. Protected are high.' Relapse is common, however, and most tinal side effects and hair loss2; and a single agent patients die from their disease. A complete response to regimen using the podophyllotoxin derivative treatment is associated with prolonged survival and etoposide, one of the most active drugs against small treatment regimens have become more complex and cell lung cancer,3 which may be less toxic. The aggressive in the hope of increasing the proportion of comparison was made in a randomised study with a patients achieving a complete response. The toxicity of crossover design, so that patients not responding these regimens, however, is such that their use is completely to one treatment were not denied the questionable for all but a few selected patients; for possibility of a response to the other. most patients treatment offers palliation rather than cure. Small cell lung cancer is therefore often treated Methods with less toxic, easily manageable, outpatient Ethical approval was granted by the district ethical Address for reprint requests: Dr M B Mclllmurray, Royal Lancaster committees and informed consent was obtained from Infirmary, Lancaster LAI 4RR. patients participating in the study. Accepted 9 December 1988 Patients were eligible if they had histologically 215 216 McIllmurray, Bibby, Taylor, et al Thorax: first published as 10.1136/thx.44.3.215 on 1 March 1989. Downloaded from confirmed small cell lung cancer not previously treated Table 1 Patients' characteristics with drugs or radiotherapy, were aged less than 70 years, and had a Karnofsky performance score of Etoposide VAC more than 40.4 Patients with evidence of cerebral metastases were not included. Number 51 52 Extent ofdisease Patients were stratified into two groups according to Limited 25 22 the extent of their disease after clinical, biochemical, Extensive 26 30 Age (y): mean 62 58 radiological and bronchoscopic evaluation. Com- range 38-75 37-70 puted tomography and bone marrow examinations Sex (M:F): 28:23 24:28 were not out. tumour to Performance score (Karnofsky) carried Patients with limited mean 84 83 one hemithorax, the mediastinum, or the ipsilateral range 40-100 50-100 supraclavicular lymph nodes or any combination of VAC-vincristine, doxorubicin, cyclophosphamide. these were defined as having limited disease. Patients not fulfilling these criteria were defined as having groups were evenly matched for age, sex, performance extensive disease. score, and extent of disease. Patients were randomly allocated either to a group receiving etoposide 300 mg/m2 in 0 9% saline given LIMITED DISEASE intravenously over one hour on day 1 and the same Ofthe 47 patients with limited disease, 25 were initially dose orally on day 2 or to a group receiving the randomised to receive etoposide. After three courses combination of vincristine 1 mg/m2, doxorubicin of treatment three patients were in complete and 13 in 50 mg/m2, and cyclophosphamide 1000 mg/m2 given partial remission (combined response rate 64%). Five intravenously on day 1. Treatment was repeated at patients with progressive disease were withdrawn. Of three weekly intervals, with dose adjustments for bone the remaining 20 patients, 17 were given VAC and marrow toxicity based on pretreatment blood counts three of these were in complete remission after three (reduction to 75% dose for leucocyte count < 3000/ courses of treatment. mm3 or platelet count < 100 000/mm3; reduction to Twenty two patients with limited disease were < or 50% dose for leucocyte count 2500/mm3 platelet initially randomised to receive VAC. After threecopyright. count < 75 000/mm3; delay in treatment of one week courses oftreatment five patients were in complete and for leucocyte count < 2000/mm3 or platelet count < 10 in partial remission (combined response rate 68%). 50 000/mm3). Four patients with progressive disease were with- All patients were assessed for response in the week drawn. Of the remaining 18 patients 13 were given before the fourth cycle of treatment. Patients in etoposide and one of these patients was in complete http://thorax.bmj.com/ complete remission-that is, no detectable tumour on remission after three courses of treatment. chest radiograph or at bronchoscopy-were given the Complete remission was attributable to VAC in same regimen until relapse or for a total of 12 courses eight patients and to etoposide in four, the overall rate of treatment. Patients in partial remission-that is, being 25%. The median survival for both treatment over 50% reduction in all measurable features of the groups was eight months. Actuarial survival curves are tumour-and patients with stable disease were given shown in figure 1. the alternative regimen for three further courses of treatment and were then reassessed. If they were then EXTENSIVE DISEASE in complete remission the same regimen was continued Of the 56 patients with extensive disease, 26 were on September 26, 2021 by guest. Protected for a further six cycles or until relapse. Doxorubicin initially randomised to receive etoposide. After three was dropped from the combination when the maxi- courses of treatment one patient was in complete and mum recommended doses had been reached. Patients six in partial remission (combined response rate 27%). showing disease progression were withdrawn. Meto- Twelve patients with progressive disease were with- clopramide 20 mg intravenously was given as standard drawn. Of the remaining 14 patients, 13 were given antiemetic treatment with chemotherapy, followed VAC and a further four patients were in complete by prochlorperazine suppositories. No patient was remission after three courses of treatment. treated with radiotherapy. Of the 30 patients initially randomised to receive VAC, seven patients were in complete and nine in Results partial remission (combined response rate 53%) after three courses of treatment. Twelve patients with One hunded and three patients were recruited to the progressive disease were withdrawn. Eleven of the study from eight treatment centres in North West remaining 18 patients were given etoposide but none England from April 1983 to April 1986. Their charac- had achieved a complete response after three courses teristics are shown in table 1. The two treatment of treatment. Thorax: first published as 10.1136/thx.44.3.215 on 1 March 1989. Downloaded from Etoposide compared with vincristine, doxorubicin, and cyclophosphamide in small cell lung cancer 217 - - Extensive disease - ETOPOSIDE -A- " " - VAC - - Limited disease - ETOPOSIDE - VAC -j Fig 1 Actuarial WIL survival rates in patients with 0 limited disease and )I- extensive disease treated I' by vincristine, doxorubicin, and cyclophosphamide (VAC) or by etoposide. 2 4 6 8 10 12 14 16 18 20 22 40 MONTHS copyright. _ http://thorax.bmj.com/ : _ _ .. _ 90 * § I *. _ * , C R so- l___ _ ___--- p R 70 : : £ 60- : on September 26, 2021 by guest. Protected : ,_, ILU. 0 50 - : 2 1_ _ Fig Actuarial - : survival rates in all U ..: , - 40- to * I___ patients according 0 response to : chemotherapy. CR- 8 30- ...... complete response; PR- * _ _ .........................,_, partial response; NR- no 20- ........................... , : @_ _ _ response. ... _ *§§.§...... , _ ,_, 10- : ....... , * I___ f * * 2 4 6 8 10 12 14 16 18 20 22 40 :MONTHS a Thorax: first published as 10.1136/thx.44.3.215 on 1 March 1989. Downloaded from 218 McIllmurray, Bibby, Taylor, et al 100- 90- 80- - 0- ETOPOSIDE - - VAC (ALL PATIENTS) 70- K 60- Fig 3 Actuarial survival ratesfor all to M patients according - initial treatment. VAC- C 40- vincristine, doxorubicin, 0 10 30- and cyclophosphamide. 10 lfiillIlIlIlIj,,L 2 4 6 8 10 12 14 16 18 20 22 40 MONTHS copyright. Complete remission was attributable to VAC in 11 TOXICITY patients and to etoposide in one patient, the overall There were no drug related deaths.