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.     

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.     

Etoposide (VP-16) and cisplatin: an effective treatment for relapse in small-cell lung cancer

Seventy-eight patients with evaluable small-cell lung cancer (SCLC) were treated with etoposide (VP-16) and cisplatin after their disease failed to respond to, or relapsed after, induction combination chemotherapy, consisting primarily of cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV). Twenty-four patients had limited disease (LD) and 54 had extensive disease (ED). In six (8%) patients, a complete response (CR) was achieved and in 37 (47%), there was a partial response (PR). The median duration of response for responding patients was 22 weeks (range, 4 to 50 weeks) for patients with LD and 18 weeks (range, 4 to 49 weeks) for those with ED. Twelve percent of patients demonstrated stable disease, and 33% of patients had progressive disease on treatment. The median survival times of LD patients achieving a CR or PR were 59 and 34 weeks, respectively, whereas the comparable figures for ED patients were 45 and 23 weeks, respectively. Gastrointestinal toxicity was mild, but myelosuppression, predominantly leukopenia and thrombocytopenia, was common. Mild to moderate nephrotoxicity occurred in 11 patients, but was reversible in all cases. Two febrile episodes occurred during periods of drug-induced neutropenia, but no other significant toxicities were identified. These results provide further evidence that VP-16 and cisplatin is an effective and tolerable combination chemotherapy regimen for SCLC resistant to CAV.     

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)     

Treatment of lung cancer--state of the art in 2000

Small-cell lung cancer (SCLC) is, in general, sensitive to anti-cancer chemotherapy and radiotherapy. Standard therapies for extensive SCLC are combination chemotherapies with cyclophosphamide, adriamycin and vincristine (CAV), with cisplatin and etoposide (PE), as well as an alternating CAV/PE program. On the other hand, the standard therapy for limited SCLC is chemoradiotherapy, especially PE and concurrent accelerated hyperfractionated radiotherapy. Based on the therapy, the current state of treatment of small cell lung disease is a median survival time of 10 months and a 3-year survival in 10% of patients with extensive disease, and a median survival time of 30 months and a 3-year survival in 30% of patients with limited disease. Promising trials under investigation including those for dose-intensive chemotherapy, multimodality treatment and combination chemotherapy adopting new drugs are introduced. The standard therapy for inoperable stage III non-small cell lung cancer is a multimodality therapy employing chemotherapy and radiotherapy. However, neither the timing of the radiotherapy nor the optimal combination of anti-cancer agents has yet been established. Nowadays, the combination of cisplatin-based chemotherapy and radiotherapy is expected to bring a median survival time of 15 months and a 3-year survival in 25% of patients. For stage IV non-small cell lung cancer, chemotherapy prolongs survival time by a modest but statistically significant amount of time. For the treatment of inoperable lung cancer, the survival benefit from the use of newly developed drugs with or without platinum is under investigation.     

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.     

CMC chemotherapy regimen combined with surgery of small cell lung cancer (SCLC)

From Dec. 1982 to Oct. 1984, 35 patients with SCLC proved by pathology or cytology, were treated by cyclophosphamide + methotrexate + CCNU (CMC) regimen combined with surgery in our hospital. All the patients received chemotherapy for more than 2 courses and the overall response rate was 85.7%, complete remission (CR) rate was 14.3%. Toxic reactions were tolerable to the patients. Treatment result was better in SCLC with localized than extensive disease. Operation was done for 9 out of 21 patients with localized lesions which had responded to chemotherapy. Of them, 1 died of postoperative complication, 2 were lost in follow-up and the rest 6 were disease-free for 8-32 months with a median survival time of 19 months. The 1 year survival rate was 75%. The results indicate that in limited disease of SCLC, successful chemotherapy combined with surgery can prolong the survival time. For patients with an limited disease which has given a CR, surgical resection should be strived for.     

Retrospective review of chemotherapy for small cell lung cancer in the elderly: Does the end justify the means?

Between 1978 and 1983, 72 patients aged 70 years or older (median 72, range 70–80) were treated for biopsy-proven, small cell lung cancer (SCLC). Intercurrent disorders were common, including ischaemic heart disease, peripheral vascular disease, chronic airflow limitation and second malignancies. 26 patients (36%) had limited extent of disease, and 46 (64%) had extensive disease. “Intensive” chemotherapy incorporating vincristine, cyclophosphamide and doxorubicin (OCA regimen) was administered to 32 patients [complete response (CR) + partial response (PR) = 84%]; less rigorous regimens (e.g. single agent chemotherapy, planned dose reductions, radiotherapy only) were used in 34 cases (CR + PR = 52%); and 6 received no active treatment. In the intensively treated group, there were 3 treatment-related deaths and 26 episodes of WHO grade 3–4 toxicity. In the less intensively treated group, there were no treatment-induced deaths and only 1 episode of severe toxicity. The overall median survival was 25 weeks (36 weeks for intensive treatment, 16 weeks with less intense treatment). For patients with limited disease only, the median survival in each group was 43 and 26 weeks, respectively. Intensive treatment for elderly patients with small cell lung cancer is associated with substantially increased toxicity and higher response rates than for gentle treatment, but without a major survival benefit.     

Alternating chemotherapy with cyclophosphamide, doxorubicin, vincristine and cisplatin, etoposide followed by prophylactic cranial and thoracic irradiation for small cell lung cancer (SCLC): long-term results.

Both CAV (Cyclophosphamide, Doxorubicin, Vincristine) and PE (Cisplatin, Etoposide) are effective and non cross-resistant regimens in the treatment of SCLC. We designed a chemotherapeutic scheme including CAV and PE given in an alternating fashion with the following schedule: Cyclophosphamide 1000 mg/sm, Doxorubicin 50 mg/sm, Vincristine 2 mg/sm I.V. on day 1, alternated every 21 days with Cisplatin 20 mg/sm and Etoposide 80 mg/sm I.V. days 1-5 for 6 cycles. Following chemotherapy (CT) chest radiotherapy in patients (pts) with limited disease (LD) in complete response (CR) or partial response (PR) and prophylactic cranial irradiation (PCI) in CRs were given, 32 pts entered the study and 27 were evaluable: 9/27 (33.3%) had CR (8/15 with LD had CR) and 15/27 (55.5%) PR. The overall median survival was 53.71 weeks: 79.85 weeks for LD pts and 32.86 for ED.4 pts with LD were alive after 2 years and 2 of them are still alive without disease at 44 and 46 months. Toxicity was acceptable in all patients. Alternating chemotherapy with CAV and PE followed by chest and brain RT in responding LD pts is an effective induction treatment for SCLC although long-term survival still remains disappointing.     

Alternating versus sequential chemotherapy in small cell lung cancer. A randomized German multicenter trial

A total of 306 patients with small cell lung cancer (SCLC) were randomized to receive chemotherapy in a sequential or alternating mode. Sequential chemotherapy consisted of eight cycles of cyclophosphamide, Adriamycin (doxorubicin), and vincristine (CAV) and alternating chemotherapy consisted of three cycles (1, 3, 5) of etoposide, vindesine, and ifosfamide (EVI); three cycles (2, 4, 6) of cisplatin, Adriamycin, and vincristine (PAV); and two cycles (7, 8) of cyclophosphamide, methotrexate, and CCNU (CMC). Responsive patients received prophylactic cranial irradiation after three cycles and chest irradiation after eight cycles of chemotherapy. No maintenance therapy was applied to patients achieving complete remission. Minimum follow-up was 2 years. Of the 302 patients evaluable, overall response rate was 59% in the sequential arm and 70% in the alternating arm. Patients treated with CAV had a complete response rate of 21% in contrast to 36% for those receiving alternating therapy. The median survival for all patients was 9.8 versus 11.3 months, for limited disease 11.1 versus 13.4 months, and for extensive disease 8.9 versus 9.9 months, all in favor of the alternating treatment. Two-year survival rate for all patients was 6% versus 9%, for limited disease 11% versus 14%, and for extensive disease 3% versus 6%, all preferring the alternating treatment mode. Progression-free survival demonstrated a strong correlation to the extent of response irrespective of the treatment regimen applied. Toxicity included 11 lethal and 8 life-threatening complications with a higher frequency in the alternating treatment arm. These results suggest that alternating treatment of SCLC with different drug combinations is more effective than sequential application of CAV.     

Urokinase combination chemotherapy in small cell lung cancer. A phase II study.

BACKGROUND AND METHODS. Fifty-one patients with small cell lung cancer (SCLC) were treated with alternating urokinase (UK)-cyclophosphamide-doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH)-vincristine and cisplatin-etoposide-vincristine. UK was given as a loading dose of 3000 micrograms/kg body weight, followed by 3000 micrograms/kg/h for 6 hours. Thoracic irradiation with split technique (46 Gy) and prophylactic cranial irradiation (25 Gy) were administered to responding patients. A second staging was performed in patients exhibiting a clinical complete response (CR) after 1 year. RESULTS. In 27 patients with limited disease, there were 23 CR and 8 partial responses (PR) (CR, 85.1%; 66.2-95.8% at 95% confidence intervals); in 24 patients with extensive disease, there were 17 CR, 4 PR, and 3 cases with progression. Pathologically proven CR were observed in 59.2% patients with limited disease and 33.3% patients with extensive disease. Survival rates were as follows: in patients with limited disease, 1 year, 85.1%; 2 years, 55.5%; and 3 years, 25.9%; in patients with extensive disease, 1 year, 54.1; and 2 years, 16.9%. Median survival times were 26.3 months (patients with limited disease) and 13.3 months (patients with extensive disease). UK-related toxic effects included four episodes of mild to moderate bleeding, one allergic reaction, and one cerebrovascular accident. Myelotoxicity was severe, with a median of two episodes of Grade III-IV (World Health Organization classification) aplasia per patient. CONCLUSIONS. These results are consistent with a potential benefit of fibrinolytic therapy in combination with chemotherapy in patients with SCLC with limited disease. Additional trials are indicated.     

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     

A pilot study of MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in small-cell lung cancer.

MVP chemotherapy (mitomycin C 8 mg m(-2), courses 1, 2, 4 and 6, vinblastine 6 mg m(-2), cisplatin 50 mg m(-2)) is an active low-toxicity regimen in non-small-cell lung cancer (NSCLC). Based on the single-agent activity of these agents in SCLC, we have conducted a phase II trial of MVP in SCLC. Fifty chemo-naive patients with SCLC were entered in this trial. There were 33 men and 17 women with median age 66 years (range 46-83 years); 18 patients had limited disease (LD) and 32 extensive disease (ED). WHO performance status (PS) was: three patients PS 0, 33 patients PS 1, ten patients PS 2, four patients PS 3. A maximum of six cycles was given in responding patients. On completion of chemotherapy, patients with LD obtaining complete response (CR)/good partial response (PR) received thoracic irradiation and those obtaining CR were offered entry into the ongoing MRC Prophylactic Cranial Irradiation Trial. The overall response was 79% with 17% CR and 62% PR. For LD patients, 38% obtained CR but for ED only one patient achieved CR. Median response duration for LD patients was 8 months and for ED patients 5 months. Median survival was 10 months for LD patients and 6 months for ED patients. There was complete resolution of symptoms in 24%, partial improvement in 68%, no change in 2% and progressive symptoms in 6%. As regards toxicity, 24% developed WHO grade 3/4 neutropenia, 16% grade 3/4 thrombocytopenia and 6% significant hair loss. Two patients died during the first week of treatment with neutropenic infection. Quality of life using the EORTC questionnaire (QLC-C30) with lung cancer module demonstrated significant improvements from baseline levels in emotional and cognitive functioning, global QOL, of pain, dyspnoea and cough. MVP, an effective palliative regimen for NSCLC, is also active against SCLC with low toxicity and merits comparison with more toxic conventional schedules.     

Etoposide and split-dose cisplatin in small-cell lung cancer

Forty-seven untreated patients with small-cell lung cancer (SCLC) were treated with a combination of etoposide (170 mg/m2 intravenously, i.v., days 3-5) and cisplatin (50 mg/m2 i.v., days 1 and 7). Responding patients with limited disease received four cycles followed by irradiation (delivered to the primary site, mediastinum, and supraclavicular region) with 50 Gy. Prophylactic cranial irradiation (PCI) with 30 Gy was performed in patients who achieved complete remission. Responding patients with extensive disease received four to six cycles of chemotherapy. The overall objective response rate (complete response plus partial response, CR + PR) was 94% (44 of 47). CR rate (all patients) was 57% (27 of 47), 51% (19 of 37) in extensive disease and 80% (8 of 10) in limited disease. The median remission duration is 13 months (12 months in extensive disease and 26 months in limited disease). The median survival is 16 months for all patients (15 months in extensive disease, 28 months in limited disease). Mean follow-up is 13 months. Toxicity was primarily hematologic. Twelve of 47 patients had leukopenia of WHO grade 4, 30 of 47 of grade 3. Thrombocytopenia of WHO grade 3 and 4 occurred in 6 of 47 and 2 of 47 patients, respectively. There were four severe infections in neutropenic patients, but no chemotherapy-related lethal complications. The only treatment-related death was that of one patient who died in CR of progressive neurologic dysfunction 11 months after PCI. This schedule of etoposide and cisplatin induces high CR rates and a prolonged survival, especially in patients with extensive disease.     

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.     

Circulating arginine-vasopressin, calcitonin, carcinoembryonic antigen, neuron-specific enolase, and beta-2 microglobulin fluctuations during combined modality induction therapy for small-cell bronchogenic carcinoma. Association of postchemotherapy AVP surge with high tumor response rate and durable remission.

While on combined modality induction therapy, 88 small-cell lung cancer (SCLC) patients were studied longitudinally for changes in circulating tumor-associated substances (TAS). Chemotherapy protocols were CAV (cyclophosphamide, doxorubicin, vincristine), PE (cisplatin, etoposide), sequential CAV greater than PE and alternate CAV/PE. Sixty patients were given prophylactic cranial irradiation (PCI) and 40 remitting patients were irradiated to the primary thoracic tumor. Of 73 evaluable patients, 43 had blood sampling adequate for analysis of treatment-related TAS fluctuations. Fourteen patients demonstrated 16 events of transient arginine-vasopressin surge following chemotherapy. In decreasing order of frequency, the surge occurred after the first (9), second (6) and third (1 event) course of chemotherapy. Three patients had a concomitant increase of one of the following markers: carcinoembryonic antigen (CEA), calcitonin and neuron-specific enolase. Another patient showed an exclusive CEA surge. This group of patients (10 with limited, 4 with extensive disease) had a 93% objective response rate (57% complete, 36% partial) with a median duration of 9 months and a survival of 15 months. Five other patients, 2 with limited and 3 with extensive disease, showed a TAS surge after PCI. Their response was complete in 1 (8 months' duration) and partial in 3 cases (2, 4 and 4 months' duration, respectively) with a median survival lasting only 8 months. This study suggests that a chemotherapy-related TAS surge may be an early indicator of a favorable tumor response in SCLC.     

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.     

High-dose induction chemotherapy with cyclophosphamide, etoposide, and cisplatin for extensive-stage small-cell lung cancer

To exploit possible dose-response and combination drug synergism, 20 previously untreated patients with extensive-stage small-cell lung cancer (SCLC) received one or two courses of high-dose induction chemotherapy consisting of cyclophosphamide (100 mg/kg), etoposide (1,200 mg/m2), and cisplatin (120 mg/m2) (HDCEP). HDCEP was followed by four cycles of standard-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1.4 mg/m2) (CAV). Response was determined after HDCEP and following CAV. Reevaluation included repeat bronchoscopy and chest computerized tomography (CT), as well as repetition of all initially abnormal studies. All patients were evaluable for response and toxicity. Overall response to HDCEP was 90%, with a complete response (CR) rate of 65% (95% confidence limits, 44% to 86%) and a partial response (PR) rate of 25% (95% confidence limits, 6% to 44%). All patients either maintained or improved their initial response while receiving CAV. Median duration of response was 6 months (range, 2 to 12 months) and median survival was 9.5 + months (range, 2 to 21 + months). All 37 courses of HDCEP were associated with leukopenia (less than 1,000/microL), 92% with thrombocytopenia (less than 20,000/microL), and 84% with fever of greater than 38.5 degrees C. Additional toxicities included bacteremia (24%), nausea and emesis (59%), mucositis (57%), diarrhea (38%), and hemorrhagic cystitis (5%). There were two treatment-related deaths due to infection. A third patient died 4 months after completing HDCEP with pulmonary fibrosis. Although response duration and median survival were not improved, HDCEP produced a high CR rate in ambulatory patients with extensive-stage SCLC.     

Long-term effects of intravenous hyperalimentation administered during intensive chemotherapy for small cell bronchogenic carcinoma

Sixty-five patients with small cell bronchogenic carcinoma received their first two of three courses of intensive induction chemotherapy with (30 patients) or without (35 patients) intravenous hyperalimentation (IVH). Patients predominantly had extensive disease (55%), Zubrod's performance status 0 to 2 (63%) and less than or equal to 6% pretreatment weight loss (68%). Both treatment arms were comparable by prognostic factors. The chemotherapy included six remission induction courses of ECHO chemotherapy (E: epipodophyllotoxin VP-16-213; C: cyclophosphamide; H: hydroxydaunorubicin; O: oncovin [vincristine]) followed by six courses of maintenance with PRIME (PR: procarbazine; I: ifosfamide; ME: methotrexate). Prophylactic brain irradiation was given to all patients. Patients with limited disease received chest irradiation at the completion of ECHO. Fifty of 52 (96%) evaluable patients responded with a complete (56%) or partial (40%) remission. The complete remission (CR) rate was higher in the control arm (66% versus 43%; P = 0.11). Response duration and survival of patients was similar for both treatment arms. Combined median survival duration for all patients with limited and extensive disease was 15.75 and 11.50 months, respectively. Combined median survival duration for CR patients with limited and extensive disease was 25 and 13 months, respectively. Administration of IVH did not ameliorate the hematologic, gastrointestinal and infectious morbidity of ECHO chemotherapy. The IVH was effective in preserving body weight and improving delayed hypersensitivity reaction to a battery of skin test antigens. Administration of intensive ECHO chemotherapy to patients with small cell bronchogenic carcinoma resulted in high response rates, acceptable toxicities and improved survival. Administration of IVH did not improve the short- and long-term results of chemotherapy, and did not ameliorate its morbidity. Nutritional support, however, was helpful in preventing patient's weight loss.     

High-dose cyclophosphamide and VP 16 as late dosage intensification therapy for small cell carcinoma of lung

Summary This study investigated the use of late dose intensification therapy (LDIT) with cyclophosphamide (180 mg/kg) and VP 16 (1 g/m²) plus autologous bone marrow rescue in 22 patients with small cell lung cancer (SCLC). These patients were selected from a group of 95 patients who received three courses of a five-drug induction regimen comprising cyclophosphamide (750–1000 mg/m²), adriamycin (40 mg/m²), VP 16 (100 mg/m²) for 3 days, methotrexate (50 mg/m²) and vincristine (2 mg) (CAVMO). There were 16 patients with limited disease, 8 of whom were in complete remission (CR) and 8 in partial remission (PR) after the induction therapy. The other 6 patients had extensive disease; 3 of these achieved CR and 3 PR after induction therapy. Of the 11 patients in PR, 5 responded to LDIT; 3 had a further PR, and 2 CR. Subsequent to LDIT radiotherapy 4000 cGy was given to the primary site in 10 of the 22 patients. Since the start of the study, 19 of the 22 patients have relapsed and died (median survival 11 months), while 3 remain alive and in remission at 11, 11, and 24 moths. Comparison of the survival of patients receiving LDIT with that of an equivalent group (with respect to staging and response to induction chemotherapy) of patients who received induction chemotherapy alone showed no significant difference. In this study, LDIT following conventional induction therapy in patients with chemosensitive tumours did not improve survival.