Phase II study of alternating combination chemotherapy in small cell lung cancer

Lung Cancer, 7 (1991) 285-294 01991 Elsevier Science Publishers B.V. All rights reserved. 0169-5002/1991/$3.50

285

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Phase II study of alternating combination chemotherapy in small cell lung cancer* J.-L. Pujol’, P. Demolyl, V. Gautier’, G. Romieu2, M. Dan Aoutal, R. Stengerl, E. Parrat’, 0. Tadlaoui’, A.M. Marcenac’, S.S. Benahmed’, F.-B. Michel’ and P. Godardl ‘Service des Maladies Respiratoires, H6pital de I’Aiguelongue, Rue du Major Flu&e,

34OS9 Montpellier Cede%,

France and 2Centre Val d’tlwelle, Rue de la Croix Verte, 35094 MontpelIier Cedex 2, France (Received 4 April 1991) (Accepted 8 July 1991) Key woruk Small cell lung cancer

Alternating

chemotherapy

Summary Forty small cell lung cancer (SCLC) patients took part in a phase II study of cyclophosphamide, adriamycin and vincristine combination chemotherapy (CAV) alternating with cisplatin and etoposide (PE). There were 35 men and 5 women with a mean age of 60 years. Most of them had poor prognostic factors: extensive disease (ED) in 26 (65%), poor performance status in 41% and weight loss in 50%. Chemotherapy consisted of three cycles of CAV (cycles 1, 3, and 5) alternating with three cycles of PE (cycles 2, 4, and 6). Objective responses were obtained in 33/40 patients (overall response rate 83%). Among these 17 (43%) achieved complete response (CR) and 16 (40%) partial response (PR). The respective CR and PR rates were 43% and 50% for limited disease (LD) and 42% and 35% for ED. Haematological toxicity was mildto-moderate and manageable. In particular, a neutropenia occurred in 85% of the patients inducing fever in 23%. Overall median survival was 48 weeks (88 weeks for the LD group and 45 weeks for the ED group; P
* This study has been suppotted by grant from the G&e Biologique et Midical, Pble Languedoc Roussillon. Correspondence: J-L. Pujol, Sewice des Maladies Respiratoires, H6pital de I’Aiguelongue, Rue de Major Flandrc, 34059 Montpellier Cedex, France.

286 Introduction Chemotherapy is the main treatment of small cell lung cancer (SCLC) [ 163, one of the solid tumors which responds best to general cytotoxic agents [4] and survival benefit has been widely demonstrated [16]. Multiple drug combinations have been used sequentially to improve both response rate and survival [3,101. However, survival benefit remains poor inasmuch as the 2-year survival does not exceed 10% [lo]. Development of chemoresistant relapses occurs in a great majority of responder patients and accounts for failures of primary therapy [16,27]. Fifty per cent of patients with chemoresistant SCLC respond to a combination of etoposide and cisplatin (PE) when cyclophosphamide, adriamycin, vincristine combination (CAV) has been used as the primary treatment [7,20,25]. On the other hand, CAV induces a lO-20% response rate in PE resistant SCLCs [27]. Thus, one might hypothesize that these two combinations are non cross resistant as defined by Goldie and Coldman [13]. Alternating chemotherapy trials have been introduced in an attempt to overcome drug resistance. Controlled studies to compare sequential vs. alternating chemotherapy of SCLC showed a trend to survival benefit for the alternating arm [6,8,15]. However, it is hitherto not possible to ascertain the superiority of an alternating regimen [18]. A recent study suggested a dose-response relationship of chemotherapy to SCLC inasmuch as the first dose of cisplatin may have an impact on response rate and probably on survival [2]. Thus, a possible improvement in the results of alternating chemotherapy might be obtained by a slight chemotherapy dose intensification in an alternating ‘non-cross-resistant’ regimen. A phase II bicentric study of CAV and PE alternating combination chemotherapy has been conducted to: (1) evaluate response rate; (2) assess clinical and biological toxicities; and (3) analyse survival. Patients and methods Selection ofpatients

Patients of both sexes with histologically proven SCLC according to the WHO classification 1331were entered into the study. Prerequesites for inclusion were: measurable disease, age ~75 years, WHO performance status [34] (PS) 13, weight loss 110%, normal serum creatinine and creatinine clearence, normal cardiac examination and electrocardiogram, baseline neutrophil count 22,OOO/p.land platelet count 21OO,OOO/pl.None of the patients had received prior therapy (except palliative radiation therapy for painful bone metastases or symptomatic brain metastases which was stopped more than 4 weeks before entry into the study) or had simultaneous malignant disease. All patients referred to our two institutions who fitted the eligibility criteria have been included in the study. Informed consent was obtained from each patient before treatment according to the Montpellier University Ethical Committee requirements.

Staging procedure

Staging was carried out by exhaustive procedure according to the 4* edition of the intemational TNM classification [29] and the American Thoracic Society map of regional pulmonary nodes [30]. For all patients staging procedure included clinical examination, chest X-rays, computed tomographic scan of chest and upper abdomen, fiberoptic bronchoscopy, liver sonography

287 Table 1 Drug reduction according to hematdogic conditions Neutrophils/@

Platelets/pi

DN~ dosage

2wJ 2,000-1,500 1,500-1,000 <1.000

100,000 80,000-100,cmO 80$00-100,OO
100% 75% 50% *O%

*Treatment delayed for 8 days.

and bone scanning. Brain computed tomographic scan was done in patients with central nervous signs and bone marrow aspirate was done if the serum lactate dehydrogenases were over 1.5 x normal values. Limited disease (LD) was defined as disease confined to one hemithorax including mediastinal lymph nodes and/or ipsilateraf supraclavicular lymph node; extensive disease (BD) was defined as a disease more advanced than limited [ 163.

Study design and treatment

Chemotherapy consisted of three cycles of CAV (cycles 1, 3, and 5) alternating with three cycles of PE (cycles 2,4, and 6). The CAV treatment schedule was: day 1 - cyclophosphamide 1000 mg/m2 intravenously (i.v.), adriamycin 50 mg/m2 i.v., and vincristine 2 mg. The PE schedule was day 1 through 4: etoposide 100 mg/m2 i.v. and cisplatin 25 mg/m2 i.v.. Haematological toxicities were assessed at days 10, 12 and 21 after each chemotherapy cycle. Additional haemograms were done when necessary. Treatment-related toxicities were graded according to the WHO scale [34]. A cycle started every 21 days if the neutrophil count was 22,OOO/pl,the platelet count was >lOO,OOO/pland creatinine clearance was 260 ml/min. Drug dosage reduction was applied for patients remaining leuko- or thrombopenic on day 1 of each cycle (Table 1). After the third cycle, patients were carefuly evaluated for response by the staging procedure described above evaluating bidimentional measurable targets defined at time of diagnosis. A complete clinical response (CR) was defined as complete disappearance of all tumor lesions with a negative histology of a bronchial biopsy lasting at least 6 weeks; a partial response (PR) was defined as a 250% reduction in the product of the two longest perpendicular diameters of the indicator lesions lasting at least 6 weeks; stable disease (SD) was defined as a ~50% reduction or a ~25% increase in the product of the longest perpendicular diameters of the indicator lesion; and progressive disease (PD) was defined as a ~25% increase in the product of the longest perpendicular diameters of the indicator lesions or appearance of new lesions [34]. At the time of response assessment, study design differed for responder patients according to pre-study staging; ED patients underwent chemotherapy cycles 4,5, and 6 directly whereas LD patients underwent radiation therapy delivered by a 6 MeV linear accelerator to the mediastinum (45 Gy) and the supraclavicular region (45 Gy). Afterwards, the treatment was completed by cycles 4,5, and 6 the same as for ED patients. Response was reassessed after the sixth cycle. No maintenance therapy was given if a complete response was obtained. Three additional cycles were given to partial responders. Patients who had definite evidence of tumor progression at any time were removed from the study and treated by other methods when possible. Prophylactic cranial radiation therapy was not included as a routine part of the protocol owing to the lack of evidence of its survival benefit at the time when the study was designed. After completion of the treatment program all patients were followed at 3-month intervals. Survival was

288 Table 2 Characteristics of the Patients Ek Mean age (SD. range) Extensive disease I limited disease

40 35/S 60 (9.41-75) 26(65%)/14(35%)

Performance status (*) 01 2 3 Weight loss none clO% >lO%

2&S%) 12(30%) 6(15%)

20(50%) 12(30%) 8(20%)

Carcinoembryonic antigen dngnTll S-20 z20 not available

2.5(62%) 5(13%) 8(20%) 2(5%)

Alkaline phosphatase IlOIllMl

abnormal < 2 x upper N abnormal 2 2 x upper N not available

27(68%) 6(15%) 6(15%) 1(2%)

defined as the time from the first day of treatment to death. Probability of survival was estimated by the Kaplan-Meier method [17]. Breslow-Mantel tests were used to compare survival of ED and LD patients. Results Patient characteristics Between October 1987 and December 1990.40 patients from two institutions were enrolled in the trial. Characteristics of these patients and value of known prognostic factors are shown in Table 2. All patients had pathologically confirmed SCLC. Main symptoms at presentation were tumor-induced locoregional signs in 25 patients, signs of metastatic disease in 10 patients, major weight loss in 5 patients and/or paraneoplastic syndrome in 5. According to the staging procedure described above, 14 patients (35%) had LD and 26 (65%) had ED. Distribution of distant metastases is shown in Table 3. Two out of the 5 patients who had brain metastases presented severe central nervous system symptoms requiring cranial radiation therapy, and 2 patients with painful bone metastases needed pre-study paliative radiation therapy. After a four week delay, these patients took part in the study and the tumor measurement was done on sites other than the irradiited lesions. All patients had a measurable disease except one who had only an evaluable disease.

289 Table 3 Metaatatic Locations *Number of patients

Location Liver Bone Adrenal Central nervous system Pancreas Lung skin

10 13 7 5 1 1 1

*Nine patients had more than one metastatic location

Response The 40 patients studied had a mean on-study time of 58f7 (SE; standard error) weeks.

Among these patients two died soon after the first cycle owing to a rapid progression and were evaluated as PD. Ninety four per cent of the patients received the three first cycles, 78% received the fourth and fifth cycles, and 64% received the sixth one. Thus, two thirds of the patients had completed the program at the time of the report and 6 are still on study. At the time of the first response evaluation, objective responses to alternating chemotherapy were obtained in 33/40 patients (overall response rate 83%). Among these 17 (43%) achieved CR and 16 (40%) PR. Four patients (10%) had SD, and 3 had PD (7%). The respective CR and PR rates were 43% and 50% for LD and, 42% and 35% for ED. After the sixth cycle SD or PD patients showed no completion of response at the final reassessment.

Toxicity of chemotherapy

Haematological toxicity was mild-to-moderate and manageable. Nadirs were completely evaluated in 90% of the patients during the first three cycles and in 74% of the patients during the following ones. Mean nadir white cell and neutrophil counts (x103/p1) were respectively 4.45 and 2.84 for the first cycle, 3.82 and 2.11 for the second cycle and 3.81 and 2.2 for the third cycle. Mean nadir platelet counts (per pl) were 240,000 for the first cycle 227,000 for the second cycle and 266,000 for the third cycle. Haematological toxicity evaluation according to Table 4 Toxic effects (% of affected patients)* WHO grade 0 Haemoalobin White cell count Neutrophil count Platelet count Infection Anaphylactic reaction Nausea & vomiting Cardiac toxicity Creatinine

46 23 15 69 71 97.5 40 97.5 97.5

1

2

3

4

33 8 8 8 3 0 5 0 0

13 15 13 8 13 0 32 2.5 2.5

8 36 33 10 7 2.5 20 0 0

0

18 31 5 0 0 3 0 n

*Haematologic toxicity was assessed in 90% of the patients during the first three cycles and 74% during the following ones. Other toxicities were assessed in all patients. All patients had grade 3-4 alopecia.

290 the WHO scale is shown in Table 4. Among the patients with neutropenia, 9 developed a grade l-3 infection requiring antibiotics. Blood transfusions were given to 3 patients owing to a grade 3 anemia and platelet transfusions were given to 2 patients owing to a grade 4 thrdmbopenia. Five patients received a dose reduction after severe haematologic toxicity. WC obscived no thrombopenia-induced hemorrhage. Toxcity was not higher in ED patients when compared with LD ones. Other notable toxicities were grade 2-4 nausea and vomiting in 55% of the patients requiring rehydration in 1 patient, anaplylactic reaction after CAV administration in 1 patient, renal failure in 1, and mild cardiac failure due to adriamycin in 1 (Table 4).

Survival Median progression-free survival was 37 weeks. Relapses occurred in 26 patients, these consisted of me&stases in 22 patients (central nervous system metastases in 12) and local reccurrences in 2. The relapses accounted for death in these 24 patients. One patient died owing to refractory hypercalcemia. We observed no toxicity-related death, Overall median survival was 48 weeks (confidence interval 43-53 weeks; Fig. 1). One-year and l&month survival rates were respectively 36% and 20% of the patients. Survival differed significantly according to the disease extent (P-zO.01): median survival was 88 weeks for the LD group (confidence interval 54-122 weeks) and 45 weeks for the ED group (confidence interval 41-49 weeks). Discussion In this phase II study we analysed the efficacy and tolerance of alternating non-cross-resistant chemotherapy with a slight intensification of PE doses in a group of patients most of whom presented pretreatment features considered as poor prognostic factors (ED in 65%, performance status 22 in 45%, and weight loss in 50%). We observed an 83% overall response rate including

0’ 0

I 10

20

I

I

I

I

I

30

40

50

60

70

/

80

90

100

110

120

Weeks Ftg. 1. Probability

of Survival. (-)

all patients, (-----) limited disease, (.....) extensive disease.

291

an over 40% complete response rate for both LD and ED. The protocol induced no life-threatening toxicity; in particular, haematological toxicity was moderate and manageable. However, the median survival was 48 weeks. This finding weakens the hypothesis that alternating combination chemotherapy delays the onset of drug resistance in SCLC. It is widely accepted that prognosis of SCLC is improved by chemotherapy [16]. Combination chemotherapy appeared as the main treatment in the 70’s [4]. Multiple drug combinations led to a longer survival than single drug treatment or radiation-therapy alone [163. Among the active drugs in SCLC, CAV [lo,191 or CAE [3] (cyclophosphamide-adriamycin-etoposide) combinations have long been known as having a good efficacy/toxicity ratio. Other combination chemotherapies such as cisplatin and etoposide have been tested successfully and have given encouraging results in terms of both response and survival rates [8,28]. It rapidly appeared that response to chemotherapy is one of the most important factors for SCLC patients to achieve a long term survival [223 in association with other known favorable prognostic factors, namely, limited disease, good performance status, lower age group, low serum lactate dehydrogenase and low serum carcinoembryonic antigen [26]. Other investigators have demonstrated that the PE combination is efficient as a rescue treatment for patients who relapsed after CAV, by inducing a 50% response rate in these poor conditions of second line treatment [7,20,25]. Conversely, patients previously treated with PE might respond to CAV combination, although in a lower proportion (lO-20%) [27]. According to the mathematical model described by Goldie and Coldman [ 131, the administration of two effective chemotherapy regimens in a rapid alternating schedule could potentially improve treatment outcome by circumventing the tumor cell resistance to cytotoxic agents [12J. This hypothesis supports the rationale of some studies designed in order to test the efficacy of alternating chemotherapy in SCLC, [1,5,14,15,311 (for review see [181), in particular of alternating CAV and PE [6,9,11,21,23], or CAV, PE, and, etoposide, vindesine and ifosfamide [ 151. However, these combination chemotherapies are not firmly established as non-cross-resistant, a prerequesite of the Goldie and Coldman model [181. This would appear particulaly evident when one considers the difference of response rates between PE following CAV [7,20,25] and CAV following PE [27J. Randomized trials conducted over the past 6 years have compared efficacy and tolerance of sequential vs. alternating regimens [5,9,11,14,15,31]. It appears that patients receiving alternating regimens achieved a complete response more frequently without inacceptable increase of toxicity. In particular, overall survival of patients treated by CAV-PE alternating regimen was higher when compared with survival of patients treated by CAV alone [8]. However, it must be stressed that this difference may be due in part to the fact that the PE regimen might be more effective that the CAV one. This has been suggested by the results of trials which tised one combination after the other in a second line setting [7,20,25,27]. Moreover, two arguments supporting this hypothesis have been published recently: (1) The study by Fukuoka et al. [l 11 have compared three chemotherapies: sequential CAV, sequential PE and alternating CAV-PE; if the CAV-PE alternating regimen was significantly better than the CAV arm in terms of response, it was not superior to the PE arm; (2) a Canadian multicenter randomized trial has been designed to compare alternation of CAV and PE for six cycles with these two combinations administered in a sequential schedule (3 cycles of CAV followed by 3 cycles of PE). There was no significant difference between the two treatments in terms of both survival and response rates [91. Authors’ comments suggest that early exposure to a PE regimen during the chemotherapy program could potentially improve results. Thus, it might be suggested that

292 the intrinsic superiority of the PE combination over the CAV combination may account for the higher rates of response and survival of patients treated by a CAV-PE alternating regimen; further randomized studies are needed to confirm this hypothesis. Effectiveness of a cisplatin-containing regimen in SCLC may be favorably influenced by the precocity of its use in the treatment schedule [9] and/or by the administered dose [2]. The concept of a dose-response effect has been supported by recent results showing a more favorable outcome of patients treated with cisplatin 100 mg/m2 vs. patients treated with a lower dose of cisplatin in an adriamycin, etoposide, cisplatin and cyclophosphamide combination regimen [2]. A recent study has compared cyclic-alternating ifosfamide/etoposide (IE) and CAV vs. response-oriented chemotherapy (sequential IE and subsequent CAV if progression occurred). The median survival time did not significantly differ between the two arms. The authors concluded that cyclic alternating treatment has no advantage over sequential treatment in which CAV is used as a second line protocol [32]. In our phase II study a slight intensification of cisplatin and etoposide was given in a 21-daycycle CAV-PE alternating regimen. Toxicity is acceptable and the shortness of the treatment program may potentially improve the quality of life. The overall reponse rate and the CR rate are in accordance with data obtained by others with the same treatment. However, overall survival of our patients is moderate with a 48-week median survival and a 20% 18-month survival rate. To explain this discrepency between response and survival results it might be emphasized that most of our patients had unfavorable prognostic factors (65% ED, among them 20% with central nervous system metastases and 35% with multiple location, poor performance status and old age). Moreover, we used a late radiation therapy for LD whereas it is strongly suggested now that early radiation therapy in the treatment schedule may improve survival of LD SCLC [2,24]. Despite the poor prognostic conditions, the subgroup of patients with ED SCLC presented in our trial a 42% complete response rate and a 45-week median survival. Thus, even if CAV-PE combination might not be recommended for LD patients as it seems hardly to achieve long term survival, its application to ED patients might be studied further as this treatment has acceptable tolerance and activity. Our study weakens the hypothesis that alternating combination chemotherapy circumvents the onset of drug resistance in SCLC. Further studies should be made to define the exact place of alternating chemotherapy regimen in ED SCLC patients. Acknowledgement The authors wish to thank Mrs Jo Baissus for help in preparing the manuscript. References 1 2 3 4

Aroney, R.S., Bell, D.R., Chan, W.K.. Dalley, D.N. and Levi, J.A. (1982) Alternating non-cross-resistant combination chemotherapy for small cell anaplastinc carcinoma of the lung. Cancer 49: 2449-2454. Arriagada, R.. De The, H., Le Chevalier, T. et al. (1989) Limited small cell lung cancer: Possible prognostic impact of the initial chemotherapy doses. Bull. Cancer 76: 605615. Boni, C., Cocconi, G.. Bisagni, G.. Ceci, G. and Peracchia, G. (1989) Cisplatine and etoposide (VP 16) as a single regimen for small celJ lung cancer: phase II trial. Cancer 63: 638642. De Vita, V.T., Young, R.C. and Canellos. J.P. (1975) Combination versus single agent chemotherapy: a review of the basis for selection of drug treament of cancer. Cancer 35: 98-l 10.

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Ettinger, D.S.. Finkestein, D.M., Abeloff, M.D., Ruckdeschel. J.C., Aisner, SC. and Eggleston, J.C. (1990) A ran domized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no mamtenance therapy for extensive-stage small cell lung cancer: a phase III study of the Eastern Cooperative Oncology Group. J. Clin. Oncol. 8: 230-240. Evans, W.K., Feld, R., Murray, N. et al. (1987) Superiority of alternating non-cross-resistant chemotherapy in extensive small cell lung cancer: a multicenter randomized clinical trial by the National Cancer Jnstitute of Canada. Ann. Int. Med. 107: 451-458. Evans, W.K., Osoba. D., Feld,R., Shepherd, F.A., Bazos, M.J. and De Boer, G. (1985) Etoposide (VP 16) and cisplatin: an effective treatment for relapse in small-cell lung cancer. J. Clin. Oncol. 3: 65-71. Evans, W.K., Shepherd, F.A., Feld, D., Osoba, D., Dang, P. and DeBoer, G. (1985) VP-16 and cisplatin as first line therapy for small cell lung cancer. J. Clin. Gncol. 3: 1471-1477. Feld, R., Evans, W.K., Coy, P. et al. (1987) Canadian multicenter randomized trial comparing sequential and alternating administration of two non-cross-resistant chemotherapy combinations in patients with limited small cell carcinoma of the lung. J. Clin. Oncol. 5: 1401-1409. Feld, R., Evans, W.K., De Boer, G. et al. (1984) Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung. J. Clin. Gncol. 2: 294-304. Fukuoka. M., Furuse, K., Saiio. N.. Nishiwaki, Y., Jkegami, H. and Suemasu, K. (1988) A randomized study in the treatment of small cell lung cancer: cyclophosphamide, adriamycin and vincristine vs. cisplatin and etoposide. In: Joss. R.A. and Brunner. K.W. (Eds) Proceedings of the 5th World Conference on Lung Cancer, Interlaken: Intcmational Association for the Study of Lung Cancer AlOl. Goldie, J.H., Coldman, A.J. and Gudanskas. G.A. (1982) Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat. Rep. 66: 439-449. Goldie, J.H. and Coldman. A.J. (1986) Application of theoretical models to chemotherapy protocol design. Cancer Treat. Rep. 70: 127-131. Goodman, G.E., Crowley, J.J.. Blasko, J.C. et al. (1990) Treatment of limited small cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin. and cyclophosphamide versus concurrent etoposide, vincristine, doxombicin, and cyclophosphamide and chest radiotherapy: a southwest Oncology Group Study. J. Cbn. Gncol. 8: 3947. Havemann, K.. Wolf, M., Holle, R. et al. (1987) Alternating versus sequential chemotherapy in small cell lung cancer: a randomized German multicenter trial. Cancer 59: 1072-1082. Iannuzzi, M.C. and Scoggin, C.H. (1986) State of art: small cell lung cancer. Am. Rev. Respir. Dis. 134: 593-608. Kaplan, E.L. and Meier, P. (1958) Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53: 457-481. Klastcrsky, J. (1989) Commentary: intensive chemotherapy in small cell lung cancer. Eur. J. Cancer Clin. Oncol. 25: 933-937. Livingstone. R.B., Moore, T.N., Heilbrun, L. et al. (1987) Small cell carcinoma of the lung combined chcmotherapy and radiation: a Southwest Oncology Group Study. Ann. Intern. Med. 88: 194-199. Lopez, J.A., Mann, J., Grapski, R.T. et al. (1985) Etoposide and cisplatine salvage chemotherapy for small cell lung cancer. Cancer Treat. Rep. 69: 369-371. Murray, N., Shah, A., Brown, E. et al. (1986) Alternating chemotherapy and thoracic radiotherapy with concurrent cisplatin-etoposide for limited stage small cell lung cancer. Semin. Oncol. 13: 24-30. Osterlind, K., Hansen, H.H., Hansen, M., Dombemowsky, P. and Andersen, P.K. (1986) Long-term disease-free survival in small-cell carcinoma of the lung: a study of clinical determinants. J. Clin. Oncol. 4: 1307-l 3 13. Park, Y.J., Koh, E.H., Kim, J. et al. (1989) Phase II study of cyclophosphamide, doxorubicin, and vincrisdne (CAV) and etoposide plus cisplatin (EP) alternating chemotherapy combined with radiotherapy in small cell lung cancer. Yonsei Med. J. 30: 30-37. Perry, M.C., Eaton, W.L., Prospert, K.J. et al. (1987) Chemotherapy with or without radiation therapy in limited small cell carcinoma of the lung. N. Engl. J. Med. 3 16: 912-918. Porter III, L.L.. Johnson, D.H., Hainsworth, J.D., Hande, K.R. and Greco, A. (1985) Cisplatine and etoposide combination chemotherapy for refractory small cell carcinoma of the lung. Cancer Treat. Rep. 69: 479-48 1. Sagman, U.. Feld, R., DeBoer, G. et al. (1986) Small cell carcinoma of the lung - derivation of a prognostic index. Proc. Am. Assoc. Cancer Res. 27: 189. Surlier, J.P., Klastersky, J., Libert, P. et al. (1990) A phase II study evaluating CAVi (cyclophosphamide, adriamycin, vincristme) potentiated or not by amphoteticin B entrapped into sonicated liposomes. as salvage therapy for small cell lung cancer. Lung Cancer 6: 110-l 18. Sierocki. J.S., Hilaris, B.S., Hopfan, S. et al. (1979) cir-Dichlorodiamminoplatinum @) and VP-16-213: An active induction regimen for small cell carcinoma of the lung. Cancer Treat. Rep. 63: 1593-1597. Sobin, LH.. Hennanek, P. and Hutter, R.V.P. (1987) TNM classification of malignant turnours. 4” edition, UICC, Geneva.

294 30 31 32 33 34

Tisi, GM., Friedman, P.J., Peters, R.M. et al. (1982) American Thoracic Society: clinical staging of primary lung cancer. Am. Rev. Respir. Dis. 125: 659-664. Wolf, M. and Haveman. K. (1990) Alternating chemotherapy in small cell lung cancer. Onkologie 13: 157-164. Wolf, M.. Pritsch, M., Drings, P. et al. (1991) Cyclic-alternating versus response-oriented chemotherapy in small cell lung cancer: a german multicenter randomized trial of 321 patients. J. Clin. Oncol. 9: 614624. World Health Organization (1982) The World Health Organization histological typing of lung tumors. 2nd Ed. Am. J. Clin. Pathol. 77: 123-136. World Health Organization (1979) WHO handbook for Reporting the Resulu of Cancer Treatment, Geneva, WHO Offset Publication No. 48.