Simultaneous chemoradiotherapy with irinotecan and cisplatin in limited disease small cell lung cancer: a phase I study

INTRODUCTION: Early radiotherapy concurrent with chemotherapy appears to have prognostic benefits in patients with limited disease SCLC. Irinotecan/cisplatin have been shown to be superior to a standard treatment with etoposide/cisplatin in extensive disease SCLC. The present phase I study aims to assess the feasibility of irinotecan/cisplatin administered concurrently with radiotherapy. PATIENTS AND METHODS: Twelve patients were treated concurrently with conventional fractionated radiotherapy (1.8-45 Gy + 9 Gy (RP)) and two cycles of irinotecan (40/50/60 mg/m2, Day 1/8/15, 29/36/43) and cisplatin (20 mg/m2, Days 1-3, 29-31), and four cycles of consolidation chemotherapy (CT). In addition, patients in complete remission (CR) received prophylactic cranial irradiation (PCI). Dose-limiting toxicity (DLT) was defined as any case grade III/IV non-hematological toxicity (esophagitis grade IV), grade IV leukopenia or grades III/IV thrombopenia (CTC) during RCT. RESULTS: No DLT was observed; an irinotecan dose of 60 mg/m2 is recommended. 3/12 patients developed grade III leukopenia, one grade II pneumonitis. The predominant toxicity was esophagitis, grade II in 7/12 patients, grade III in 5/12. After RCT 7/12 patients were in CR, systemic progression was not observed during RCT. CONCLUSION: Concurrent RCT with irinotecan (60 mg/m2) and cisplatin followed by four cycles of CT can be safely administered.     

A Phase II Study of Carboplatin and Prolonged Administration of Oral Etoposide in Patients with Small-Cell Lung Cancer

Prolonged oral administration of etoposide may have a theoretical advantage over intravenous infusion, and carboplatin has a more favorable toxicity profile than cisplatin. A combination of carboplatin 300 mg/m² and oral etoposide 40 mg/m²/day for 21 days was assessed in 74 (42 limited, 32 extensive disease) previously untreated patients with small-cell lung cancer. Response rate was 69% (CR 19%, PR 50%) for limited disease and 72% (CR 9%. PR 63%) for extensive disease. Median response duration and overall survival was 6.6 and 10.1 months for limited disease, and 5.3 and 9.1 months for extensive disease, respectively. One-year and two-year survival was 36 and 10% for limited disease and 31 and 2% for extensive disease, respectively. The major toxicity was hematological with grade 4 or greater neutropenia in 36% and grade 4 thrombocytopenia in 16% and one patient died of neutropenic fever. Non-hematologic toxicities were mild and grade 3 emesis was observed in 5% of patients. Carboplatin combined with 21-day oral etoposide showed only modest activity against small-cell lung cancer with high toxicity and did not merit further evaluation.     

Etoposide,carboplatin, cyclophosphamide and vincristine in previously untreated patients with small-cell lung cancer

Summary The efficacy and toxicity of 120 mg/m² etoposide and 100 mg/m² carboplatin given i.v. daily x 3 together with 750 mg/m² cyclophosphamide and 14 mg/m² vincristine given i.v. on day 1 (ECCO) in a regimen given every 28 days for 6 courses was assessed in 90 (40 limited stage, 50 extensive stage) previously untreated patients with small-cell lung cancer. Mediastinal irradiation using 50 Gy in 25 fractions was given to limitedstage patients without progression after 3 courses of chemotherapy. Cranial irradiation with 30 Gy in 10 fractions was given to all patients attaining a complete response (CR). Objective responses were seen in 83% [CR, 60%; partial response (PR), 23%] of patients with limited and 76% (CR, 22%; PR, 54%) of those with extensive disease. The median relapse-free survival for objective responders with limited disease was 13.4 months, with a median of 8.0 months for extensive-stage patients. The median relapse-free survival for patients achieving a CR was 13.4 months, with a median of 7.8 months for those undergoing a PR. The median survival was 13.3 months for patients with limited disease, with a median of 9.6 months for those with extensive disease. The median survival following a CR was 18.2 months, with a median survival of 9.9 months for those showing a PR. The combination was well tolerated, with either no nausea or nausea only (WHO grade 0 or 1) in 56% of patients and minimal mucositis, renal toxicity, neurotoxicity or ototoxicity. Neutropenia measuring <1.0×10⁹ WBC/l (WHO grade 3 or 4) was seen in 74% of patients, with two deaths due to infection occurring during neutropenia. Thrombocytopenia of <50×10⁹ platelets/l (WHO grade 3 or 4) occurred in 24% of patients. ECCO is a new, active, welltolerated program for previously untreated patients with small-cell lung cancer.This study was partly supported by David Bull Laboratories, Melbourne, and the Anti-Cancer Council of Victoria     

Cisplatin/etoposide versus ifosfamide/etoposide combination chemotherapy in small-cell lung cancer: a multicenter German randomized trial

A total of 144 patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin/etoposide (PE) or ifosfamide/etoposide (IE) combination chemotherapy. PE consisted of cisplatin, 80 mg/m2, intravenously (IV) on day 1, and etoposide, 150 mg/m2, IV on days 3 through 5. IE consisted of ifosfamide, 1,500 mg/m2, IV on days 1 through 5, and etoposide, 120 mg/m2, IV on days 3 through 5. Six cycles were administered in 3-week intervals. Nonresponders were switched immediately to CAV, consisting of cyclophosphamide, 600 mg/m2, IV on days 1 and 2, Adriamycin (Adria Laboratories, Columbus, OH), 50 mg/m2, IV on day 1, and vincristine, 2 mg, IV on day 1. Patients obtaining complete remission (CR) received prophylactic cranial irradiation with 30 Gy. After completion of chemotherapy, patients with limited disease received chest irradiation with 45 Gy. No maintenance therapy was given to patients in CR. Minimum follow-up was 2 years. Of the 141 patients evaluable, the overall response rate was 65% in PE therapy and 68% in IE therapy. The CR rate was 32% v 20% for all patients, 50% v 24% for limited disease, and 22% v 18% for extensive disease, all in favor of PE therapy. Median survival for all patients was 11.6 months v 9.4 months, for limited disease 14.8 months v 11.0 months, and for extensive disease 8.9 months v 7.5 months, all preferring PE therapy. The 2-year survival rate was higher in PE therapy than in IE therapy for all patients (12% v 9%) and for limited disease (23% v 10%), but not for extensive disease (5% v 9%). Median progression-free survival was 7.5 months v 6.0 months for all patients, 12.2 months v 8.8 months for limited disease, and 5.9 months v 4.4 months for extensive disease, all in favor of PE. Relapse in the area of the primary tumor was found less often after PE than after IE therapy (25% v 38%). Response to second-line CAV was seen in 30% of patients with prior PE and 43% with prior IE therapy, but was usually short lasting, and only one patient achieved CR. Toxicity included three lethal complications. Nausea, vomiting, diarrhea, and skin lesions occurred more often after PE than after IE therapy. These results suggest that PE is superior to IE chemotherapy in limited-stage, but not in extensive-stage SCLC, and that CAV is cross-resistant to PE, as well as to IE in the majority of patients.     

Combination chemotherapy with cisplatin and etoposide associated with radiotherapy in the treatment of small-cell lung cancer

Summary A total of 52 consecutive, previously untreated patients with small-cell lung cancer (SCLC) were scheduled to receive six cycles of a combination of etoposide (75 mg/m² per day) and cisplatin (20 mg/m² per day), each cycle given over 5 consecutive days. In all, 28 patients had extensive disease (ED) and 24, limited disease (LD). After three cycles of chemotherapy, all responding patients were given chest radiotherapy (RT) (45 Gy in two split courses and 30 Gy in LD and ED, respectively); only patients with LD who achieved complete remission (CR) after three cycles of chemotherapy were given prophylactic brain irradiation (30 Gy). In the 51 evaluable patients, the overall response rate was 90%, with a 31% CR and a 59% partial remission (PR) rate. In LD and ED patients, 57% and 11% CR rates and 30% and 82% PR rates were noted, respectively. Myelosuppression was the most frequently observed toxicity. The median duration of response was 12 months in LD (range, 3–41+months) and 7 months (range, 2–12 months) in ED; the median survival was 15 months in LD and 9.3 months in ED, respectively. In all 30% of LD patients are alive and well at a minimal follow-up of 18 months. This trial confirms the activity of the cisplatinetoposide combination in SCLC.Bursar, Italian Association for Cancer Research (AIRC)     

Results of a combined chemo-radiotherapeutic program in 61 patients affected by small cell lung cancer

Sixty-one patients affected by small cell lung cancer (SCLC) entered in the study. Eighteen had limited disease and 43 extensive disease. Treatment consisted of: induction chemotherapy with 3 courses of CAV (cyclophosphamide, adriamycin, vincristine) in limited disease patients or 2 courses of CAV plus 2 courses of DDP-VP16 (cisplatin, etoposide) in extensive disease patients, followed by chest radiotherapy and CNS prophylaxis in responsive patients. Subsequently, responders and stable patients received maintenance chemotherapy by the alternation of cycles of CAV, DDP-VP16 and C'MP (CCNU, methotrexate, procarbazine), which lasted 1 year or until relapse. Four of 17 limited disease patients (23%) obtained a CR and 11 (65%) a PR; their median survival was 11 months (range, 2+-36+). One of the 7 extensive disease patients (3%) achieved a CR and 19 (51%) a PR; their median survival was 6 months (range, 1-22). Median duration of response was 12 months for CR and 5 months for PR. Responders (CR and PR) survived 11.5 months versus 3.5 months for failures (P less than 0.05); 3/61 (5%) showed long-term survival, in the absence of disease. The overall median survival was 7 months (range, 1-36+). The main toxic effects were myelosuppression and vomiting (WHO grade 3). From our results, this program does not offer further substantial gains in patients with SCLC.     

Etoposide versus methotrexate in small cell bronchial carcinoma. A randomized study of two types of four-drug chemotherapy regimens.

Seventy-nine patients with small bronchial carcinoma randomly received cyclophosphamide, doxorubicin, vincristine, and methotrexate, alternating after four cycles with cyclophosphamide, lomustine, vincristine and methotrexate or the same with replacement of methotrexate by etoposide in lomustine cycles. Patients with limited disease received radiotherapy with 40 Gy. In 34 patients with extensive disease the total response in the groups with and without etoposide was 89% and 69% and the median survival 10.9 and 8.2 months respectively. In 45 patients with limited disease, the complete remission rates in the groups with and without etoposide were 57% and 67%, partial remission rates 38% and 25%, and the median survival times 12.3 and 17.8 months respectively. The disease-free survival exceeding 5 years in the respective groups was 4.2% and 14.3%. A slightly better response in extensive disease and a tendency to better long-term survival in limited disease was noted but the price was increased toxicity in the latter group.     

Phase II study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer

In this phase II multicenter trial, 67 evaluable patients with advanced measurable gastric carcinoma were treated with a combination of etoposide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (EAP). The overall response rate was 64%, including 21% complete responses (CRs). In 55 patients with metastatic disease, 31 responses (51%) including eight CRs (15%) were achieved. Responses were seen in all metastatic sites, but the response rate was lower in patients with peritoneal carcinomatosis. In 12 patients with locoregional disease, six CRs and six partial responses (PRs) were observed. Eight CRs (three and five in patients with metastatic and locoregional disease, respectively) were pathologically confirmed. The overall median response duration was 7 months; it was 16 months for patients achieving CR (22 months for pathologically confirmed CR [pCR]), and 6 months for PR. The median survival time for all patients was 9 months, for the patients who achieved CR 17 months, for pCR 23 months, and for PR 9.5 months. Median survival time for all patients with metastatic disease was 8 months, and for locoregional disease 12.5 months. Six patients (9%) (four local, two metastatic disease) were alive at 2 years, and four patients are alive and disease free at 35+ to 56+ months. Main toxicities were leukopenia and thrombocytopenia, with 64% of patients developing grade 3 to 4 myelosuppression and 12% severe infections. Nonhematologic toxicities of World Health Organization (WHO) grade 4 were not observed.     

Phase II clinical evaluation of etoposide (VP-16-213, Vepesid) as a second-line treatment in ovarian cancer. Results of the South-East European Oncology Group (SEEOG) Study

The objective of this trial was to define the antitumor activity and toxicity of etoposide for second-line treatment of patients with bulky ovarian carcinoma. Between February 1, 1986 and November 1, 1988 we recruited 82 patients. Out of them 77 (93.9%) were evaluable for toxicity and 71 (86.6%) for response. Patient characteristics are as follows: median age 57 years (range 15-75), median performance status: WHO 1, prior chemotherapy with more than 3 drugs 24 patients, with previous cisplatin 63 patients, with previous adriamycin 47 patients, with previous irradiation plus chemotherapy 17 patients. The following treatment schedule was applied: each patient started with 150 mg/m2 of etoposide administered i.v. on days 1-3. If this first cycle was well tolerated the dosage was escalated to 200 mg/m2 days 1-3. This higher dosage was then repeated at 4-week intervals. For evaluation of response the WHO criteria were used. One patient (1.4%) achieved complete remission and 5 (7.0%) partial remission. In 48 patients (67.6%) minor response or stabilisation of the disease were observed. Seventeen patients (24%) showed no response. The median duration of remission was 5.5 months (range 2-20). The median duration of stabilisation was 3 months (range 2-24). The median survival time was 10 months with a range of 2-30 months. The myelotoxic side-effects are as follows: WBC less than 2,000 was recorded in 6 patients and greater than 1,000 in 2 patients. Thrombocytopaenia with platelet count less than 50,000 occurred in 1 patient. 26 patients had anaemia WHO grades 2 and 3. Non-haematological toxicity consisted of nausea and vomiting (WHO grade 2:20 patients and grade 3:2 patients), alopecia (WHO grades 2-3:14 and 24 patients, respectively). Though the remission rate in this trial was low, the 10-month median survival with an acceptable quality of life can be taken as a fairly good salvage therapy result.     

足叶乙甙,顺氯氨铂联合胸部放疗治疗局限性晚期肺鳞癌疗效观察

应用前瞻性研究方法，对５３例（Ⅲａ２０例，Ⅲｂ期３３例）局限性晚期未行手术治疗的肺鳞癌患者采用足叶乙甙及顺氯氨铂化疗，并加用胸部６０Ｃｏ照射。平均接受化疗２．４疗程，放疗总量６０Ｇｙ。结果：２例完全缓解（ＣＲ），２３例部分缓解（ＰＲ），总有效率４７．２％（ＣＲ＋ＰＲ），中位生存期１５．８个月，平均缓解期７．５个月。化疗中出现恶心、呕吐Ⅰ度者９例，Ⅱ度者４例，粒细胞减少Ⅰ度者７例，Ⅱ度者６例，Ⅲ度者１例。连续放疗组中发生放射性肺炎者占２８．２％（１１／３９），放射性心肌心包炎１例，分段放疗组中无此类副作用，认为该方案治疗肺鳞癌效果显著，分段放疗可减少副作用且疗效不受影响。     

Vincristine-cyclophosphamide, the classical two-drug regimen for small-cell lung cancer, evaluated in a randomized study with vindesine

We performed a randomized study from February 1979 to August 1981 in patients with small-cell lung cancer (SCLC) with the aim of defining the potential advantages of replacing vincristine (VCR) with vindesine (VDS), at that time a new semisynthetic vinca alcaloid, in the classical two-drug combination cyclophosphamide (CTX)-VCR. A total of 116 previously untreated patients were admitted to the study. Of 104 patients evaluable for response, 49 had limited disease and 55 extensive disease. Patients received 10 mg/kg CTX i.v. on days 1-4 and either 1 mg VCR i.v. or 2 mg/m2 VDS i.v. on days 1 and 4, and repeatedly every 4 weeks for 12 courses. In addition, the patients with limited disease received split-course radiotherapy (30 Gy/10 F, 3 or 5 weeks rest, 25 Gy/10 F, total treatment time 7 or 9 weeks) to the primary tumor, the mediastinum, and the supraclavicular areas between the second and third cycles of chemotherapy. The response rate to the first two chemotherapy cycles was 47% (4 complete response [CR] and 22 partial response [PR]) to CTX-VCR and 47% (4 CR and 19 PR) to CTX-VDS. Subsequent to radiotherapy the response rate increased to 93% for CTX-VCR and 100% to CTX-VDS, respectively, in the patients with limited disease. Local recurrence and/or progression occurred in 49% of limited disease responders and in 96% of extensive disease responders. In responders with limited disease, the first site of relapse was loco-regional in 25% for the VDS group as opposed to 15% in VCR group. In the patients with extensive disease, the corresponding figures were 62% for the VDS and 50% for the VCR group. Median duration of remission in all patients treated with CTX-VCR was 132 days compared to 203 days in the CTX-VDS group (not significant, NS). Median survival was 338 days for CTX-VCR vs. 342 for CTX-VDS in patients with limited disease, and 214 days for CTX-VCR vs. 312 days for CTX-VDS in extensive disease (NS). One-year survival figures were 47% for CTX-VDS and 35% for CTX-VCR patients. Two-year survivals were 4 and 9%, respectively. Neurotoxicity was the main toxic manifestation in both treatment groups. Severe peripheral neuropathy (grade 4, World Health Organization [WHO]) did not occur with either drug regimen. Treatment was discontinued because of grade 2-3 neuropathy in one patient after 6 cycles of CTX-VCR and in five patients after 1-6 cycles of CTX-VDS.(ABSTRACT TRUNCATED AT 400 WORDS)     

Intensive alternating combination chemotherapy and high dose chest radiotherapy in small cell lung cancer.

Sixty-nine patients, 32 with limited and 37 with extensive small cell lung cancer (SCLC), were admitted to the present study. Patients with limited disease underwent alternating combination chemotherapy consisting of CAV (cyclophosphamide, adriamycin, vincristine) and PE (cisplatin and etoposide) regimens and concurrent high dose thoracic radiotherapy (6,000 cGy); prophylactic brain irradiation (3,000 cGy) was administered to complete responders. Patients with extensive disease received the same alternating chemotherapy but not radiotherapy. In the 25 evaluable patients with limited disease we obtained an objective response (OR) in 80% with a complete response (CR) in 54% and partial response (PR) in 24%, stable disease (SD) in 4% and progressive disease (PD) in 16%. Median duration of response was 9.5 months for CR and 8.5 months for PR. Median survival was 14 months for all patients with 12% long-term survivors. Toxicity was acceptable. In the 32 evaluable patients with extensive disease we observed 65.6% OR with 18.7% CR and 46.8% PR, 9.3% minimal response and 25% PD. Median duration of response was 7 months for CR and 8 months for PR. Median survival was 10 months for all patients. The treatment was well tolerated. Our study did not show a therapeutic advantage for alternating combination chemotherapy in SCLC and failed to show the use of high dose chest radiotherapy in combined modality for limited disease.     

Cisplatin, ifosfamide, oral etoposide, and concurrent accelerated hyperfractionated thoracic radiation for patients with limited small-cell lung carcinoma: results of radiation therapy oncology group trial 93-12.

PURPOSE: The combination of cisplatin, ifosfamide, and oral etoposide (PIEo) given concurrently with accelerated hyperfractionated thoracic radiation was studied in patients with limited small-cell lung cancer in a phase II trial to assess response, survival, and toxicity. PATIENTS AND METHODS: Sixty-seven patients were accrued between March 1994 and April 1996. Chemotherapy doses were cisplatin 20 mg/m(2) and ifosfamide 1,200 mg/m(2) on days 1 to 3 and etoposide 40 mg/m(2) administered orally days 1 through 14. Radiation consisted of accelerated hyperfractionated thoracic radiation (AHTRT) 1.5 Gy bid x 30 fractions (total 45 Gy) days 1 through 19, concurrent with cycle 1 of chemotherapy. Three additional cycles of chemotherapy were given every 4 weeks after completion of chemoradiation. Prophylactic cranial radiation (25 Gy in 10 fractions) was offered to patients for whom complete response (CR) after completion of chemotherapy was achieved. RESULTS: An overall objective response rate of 78% (41 CRs [67%] and seven partial responses [11%]) was seen in 61 patients whose disease response could be evaluated. Median progression-free and overall survival estimates were 12.7 and 23.7 months, respectively. Two- and 3-year survival rates were estimated at 50% and 39%, respectively. Major toxic effects included grade 4 granulocytopenia in 34 (55%), grade 4 thrombocytopenia in 16 (26%), grade 3 to 5 fever/infection in six (10%; with one death resulting from sepsis), and grade 3/4 esophagitis in 27 patients (43%). Other nonhematologic toxic greater than grade 2 occurred in 11 patients (18%). CONCLUSION: Relative to conventional etoposide/cisplatin and concurrent AHTRT, chemoradiation with PIEo produced similar median and 2-year survival rates and a higher rate of acute esophageal toxicity. However, the locoregional control rate with a minimum follow-up of 2 years is excellent at 80%. It is conceivable that longer follow-up will prove this regimen more promising. Research efforts should focus on other methods to improve disease control in all potential sites of recurrence.     

Alternating chemotherapy for small-cell lung cancer. A twelve-week schedule of six drugs.

We have treated sixty-two patients (21 with limited disease, 41 with extensive disease), on an outpatient-basis schedule of six drugs administered weekly for twelve weeks. Cyclophosphamide, 400 mg/m2, adriamycin, 20 mg/m2 and vincristine, 2 mg, full dose, were administered during weeks 1, 5 and 9; cisplatin, 50 mg/m2 and etoposide, 100 mg/m2 during weeks 2, 6 and 10; adriamycin and vincristine at the same doses during weeks 3, 7 and 11; methotrexate 30 mg/m2, during weeks 4, 8 and 12. After the first 28 patients vincristine was replaced by teniposide (VM-26) due to neurotoxicity. The overall response rate was 64.5% (complete remission 13 p., partial remission 27 p.). Toxicity grade 3-4, mainly nausea and vomiting or neutropenia, was recorded in 17 patients. Alopecia grade 1-2 was universal. One toxic death occurred from sepsis. The overall survival was 8 months (range 1-40), (95% CL: 53-77%); 8 months in limited disease (range 1-40), and 7 months in extensive disease (range 1-23). Time to treatment failure was 6 months (7 limited disease, 5 extensive disease). In conclusion, the results of this alternating schedule are poorer than those attained with standard, high-dose treatments, mainly in limited disease, but could be a less toxic option for patients with extensive disease.     

Limited stage small cell lung cancer: Treatment and therapy

Opinion statement Chemotherapy remains the key treatment for small cell lung cancer; today, that chemotherapy remains cisplatin and etoposide in a variety of acceptable schedules. Attempts to use new drugs in extensive disease have not been as successful as hoped; however, a recent trial from Japan supports the use of irinotecan and cisplatin over the standard cisplatin and etoposide, but these facts need to be verified in western countries. For limited disease, the addition of thoracic radiotherapy for all patients and prophylactic cranial irradiation (PCI) in complete, or near complete, responders have resulted in improved survival. The best results occur with early, intensive thoracic radiotherapy concurrent with chemotherapy and PCI after completion of systemic and local therapy. The use of PCI and thoracic radiotherapy in extensive disease is more controversial and less evidence based. PCI and thoracic radiotherapy may be considered only in patients who have achieved a “systemic” complete response and excellent response in the chest. However, both prospects should be supported if there is complete response systemically and near complete response locally. The role of surgery is of limited value in the unusual cases of mediastinal negative disease, but it is a good treatment for patients with peripheral nodules and sufficient pulmonary function to withstand thoracotomy.     

Carboplatin (CBDCA, JM-8) and VP-16-213 in previously untreated patients with small-cell lung cancer

The efficacy and toxicity of carboplatin 100 mg/m2, administered intravenously (IV) daily X 3, and VP-16-213 120 mg/m2, IV daily X 3, administered every 28 days for six courses, was assessed in 94 (36 limited stage, 58 extensive stage) previously untreated patients with small-cell lung cancer. Mediastinal irradiation using 50 Gy in 25 fractions was given to all limited-stage patients with a complete (CR) or partial response (PR) after three chemotherapy courses. Cranial irradiation was administered to all patients with CR. Objective responses were seen in 77% (CR 40%, PR 37%) of patients with limited-stage and 58% (CR, 9%; PR, 49%) with extensive-stage disease. Median relapse-free survival for objective responders with limited stage was 14.6 months and 7.9 months for extensive-stage patients. Median relapse-free survival following CR was 15.4 months and 8.5 months for PR. Median survival was 15.3 months for limited-stage and 8.1 months for extensive-stage patients. The combination was well tolerated with mild nausea or less (World Health Organization [WHO] grade 0 or 1) in 62% of patients and minimal mucositis, renal, neurotoxicity, or ototoxicity. Neutropenia less than 1.0 X 10(9)/L (WHO grade 3 or 4) was seen in 63% of patients, with two deaths from infection while neutropenic. The combination of carboplatin and VP-16-213 is a new, active program with low toxicity when applied intensively in previously untreated patients with small-cell lung cancer.     

Induction chemo-radiotherapy and maintenance alternating chemotherapy for small cell lung cancer

Seventy-four patients with small cell lung cancer (SCLC) entered a program consisting of induction with three courses of CAV (cyclophosphamide, doxorubicin and vincristine) in limited disease or two courses of CAV plus two courses of DDP-VP16 (cisplatin, etoposide) in extensive disease, followed by chest radiotherapy (45 Gy) and prophylactic brain irradiation (30 Gy) in responsive patients. Subsequently, patients with response or stable disease received maintenance therapy by alternating courses of CAV, DDP-VP16 and C'MP (CCNU, methotrexate, procarbazine) during 1 year or until relapse. Sixty-seven patients were evaluable. Among 24 patients with limited disease 7/23 (30%) showed complete response, 15/23 (65%) partial response and 1/23 (5%) stable disease. Among 50 patients with extensive disease 1/44 (2%) showed complete response, 21/44 (48%) partial response, 13/44 (30%) stable disease and 9/44 (20%) progressive disease. Actuarial median survival in all patients was 8 months, in responders 11 months, and in failures (stable plus progressive patients) 4 months. Median survival was 11 months in limited disease patients and 7 months in extensive disease patients. Six patients became long-term survivors (8%). Despite the maintenance therapy with three different alternating chemotherapy regimens, our results were not superior to those obtained by more conventional chemotherapy.     

Cisplatin, adriamycin, and etoposide (CAV) for remission induction of small-cell bronchogenic carcinoma

Chemotherapy with a combination of cisplatin (60 mg/m2), Adriamycin (45 mg/m2), and etoposide (120 mg/m2 X 3) (CAV) has been evaluated in 36 patients with small-cell bronchogenic carcinoma (SCBC) after two full courses. The complete response (CR) rate was 23% in patients with extensive disease and 64% in patients with limited disease; the partial remission (PR) rate was 59% in patients with extensive disease and 22% in those with limited disease after two cycles (six weeks) of therapy. Patients with CR survived significantly longer than patients with PR (P = 0.02). Side effects were acceptable and consisted mostly of nausea, vomiting, alopecia, and myelosuppression. Thirteen patients were included into a "late intensification" program that was performed with increased doses of CAV regimen used for remission induction. This intensification of chemotherapy was carried out in a protective environment and with autologous bone marrow transfusion. In two patients with PR, CR could be obtained after late intensification and in one patient whose disease was progressing, PR had been achieved. However, excessive extramedullary toxicity of the late intensification regimen, consisting of mucositis, suggested that CAV does not appear to be the optimal therapy for further intensification.     

Accelerated hyperfractionated radiotherapy and concomitant chemotherapy in small cell lung cancer limited-disease. Dose response, feasibility and outcome for patients treated in western Sweden, 1998-2004

Addition of thoracic radiation therapy (TRT) to chemotherapy (CHT) can increase overall survival in patients with small cell lung cancer limited-disease (SCLC-LD). Accelerated fractionation and early concurrent platinum-based CHT, in combination with prophylactic cranial irradiation, represent up-front treatment for this group of patients. Optimised and tailored local and systemic treatment is important. These concepts were applied when a new regional treatment programme was designed at Sahlgrenska University Hospital in 1997. The planned treatment consisted of six courses of CHT (carboplatin/etoposide)+TRT±prophylactic cranial irradiation (PCI). Standard TRT was prescribed as 1.5 Gy BID to a total of 60 Gy during 4 weeks, starting concomitantly with the second or third course of CHT. However, patients with large tumour burdens, poor general condition and/or poor lung function received 45 Gy, 1.5 Gy BID, during 3 weeks. PCI in 15 fractions to a total dose of 30 Gy was administered to all patients with complete remission (CR) and “good” partial remission (PR) at response evaluation.

Eighty consecutive patients were treated between January 1998 and December 2004. Forty-six patients were given 60 Gy and 34 patients 45 Gy. Acute toxicity occurred as esophagitis grade III (RTOG/EORTC) in 16% and as pneumonitis grade I-II in10%. There were no differences in toxicity between the two groups. Three- and five-year overall survival was 25% and 16%, respectively. Median survival was 20.8 months with no significant difference between the two groups. In conclusion, TRT with a total dose of 60 or 45 Gy is feasible with comparable toxicity and no difference in local control or survival. Distant metastasis is the main cause of death in this disease; the future challenge is thus further improvement of the systemic therapy combined with optimised local TRT.     

Combined-modality treatment of small-cell lung cancer: Randomized comparison of three induction chemotherapies followed by maintenance chemotherapy with or without radiotherapy to the chest

BACKGROUND: From 1980 to 1983 the Swiss Group for Clinical Cancer Research(SAKK) performed a randomised phase HI trial in patients withsmall-cell lung cancer with the objective of improving the resultsof induction chemotherapy and defining the role of consolidatingchest irradiation. PATIENTS AND METHODS: Patients were initially randomised to induction arms AVP (adriamycin,etoposide and cisplatin given every four weeks for four cycles),EVA (cyclophospha-mide, etoposide and adriamycin given everyfour weeks for four cycles) or MOC/AVP (methotrexate, vincristine,cyclo-phosphamide alternating with adriamycin, etoposide andcisplatin given for two cycles). All patients received prophylacticcranial irradiation with 30 Gy, and after four months of inductionchemotherapy were randomized to maintenance chemotherapy withor without consolidating chest irradiation. The patients inthe combined-modality maintenance arm first received radiationtherapy to the chest (45 Gy) followed by MOC/EVA chemotherapy. RESULTS: 266 patients were eligible and evaluable. An overall responserate of 70% with 21% of complete remissions, a median survivalof 9.3 months and survival of 8% of the patients at two yearswere observed. The highest objective response rate was achievedwith the AVP-induction chemotherapy with an 80% response rateand 32% complete remissions. Similar results were achieved withthe alternating regimen of MOC/AVP. In contrast, patients treatedwith the EVA induction regimen had significantly lower overallremission (56%) and complete remission rates (7%). The roleof consolidating chest irradiation could not be clarified inlimited-disease patients due to the small number of them whowere randomised to the maintenance part of the study. However,in patients with extensive disease in partial remission afterinduction treatment, combined maintenance therapy had a moresignificant adverse effect on survival than maintenance chemotherapyalone (median survival in the maintenance phase of 148 daysversus 239 days, p = 0.011). CONCLUSION: We conclude that the combination of adriamycin, etoposide andcisplatin is an active induction treatment. Consolidating chestirradiation is contraindicated in patients with extensive diseasein partial remission after induction when given in a sequentialmanner, as in our trial. small-cell lung cancer, chemotherapy, alternating chemotherapy, combined-modality treatment, radiotherapy