Long-term survivors in resected and nonresected small cell lung cancer.

Long-term survival (greater than or equal to 3 years) was evaluated in 164 patients with small cell lung cancer (SCLC). Thirty-seven patients underwent surgical resection, and 127 did not. All but one resected patient received combination chemotherapy. Of the 20 (12%) long-term survivors, 13 (35%) were resected, and 7 (6%) were not. Eleven of these resected patients had pathologically confirmed stage I disease. All of the 7 nonresected patients achieved complete remission by treatment, 6 of these having presented with limited disease. In addition, all patients received thoracic irradiation combined with chemotherapy. Two of the 20 patients who survived beyond 3 years developed a second malignancy 11.3 and 12 years, respectively, after initial treatment for SCLC. In conclusion, surgical resection for stage I, and probably stage II SCLC followed by chemotherapy may be an appropriate therapeutic approach. For advanced limited disease, thoracic irradiation, in addition to chemotherapy, seems to improve long-term survival.     

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 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.     

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)     

Sequential hemibody irradiation integrated into a chemotherapy-local radiotherapy program for limited disease small cell lung cancer

Twenty-four patients with limited disease small cell lung cancer (SCLC) were treated with sequential hemibody irradiation (SHB) integrated into a conventional chemotherapy-local radiotherapy (LRT) program. Among 23 evaluable patients, 12 (52%) attained a complete response (CR) and 8 (35%) attained a partial response for an overall major response rate of 87%. The median time since study entry is 29 months. Durations of response are 9.9 months for all patients and 16.5 months for patients who achieved a CR. The primary site was the predominant area of recurrence. The median survival is 13.2 months for all patients and 23.2 months for the 12 patients who attained a CR. Myelosuppression, especially thrombocytopenia, was the major toxicity. Acute radiation toxicities and subacute pneumonitis previously associated with hemibody radiotherapy were well controlled or prevented using the current dose, premedication, and shielding techniques. This integrated program of systemic therapies with SHB and combination chemotherapy plus LRT is feasible for limited disease SCLC; it may prolong survival in patients who attain a CR but compared to similar programs without hemibody irradiation, there was no improvement in overall response rate, response duration, or survival.     

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.     

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 (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.     

Sequential hemibody and local irradiation with combination chemotherapy for small cell lung carcinoma: a preliminary analysis

Sequential hemibody irradiation (SHB) was integrated with combination chemotherapy and local irradiation (LRT) in the induction and consolidation phases of a therapeutic protocol for small cell lung carcinoma (SCLC). Forty-one previously untreated patients were entered into this program. Among 38 evaluable patients (20 with limited disease [LD] and 18 with extensive disease [ED], the overall response rate was 63% (90% in LD and 33% in ED patients). The estimated overall survival is 8.1 months. The major toxicity has been myelosuppression--especially thrombocytopenia. The frequency of previously described "acute radiation syndromes" and radiation pneumonitis associated with hemibody irradiation have been substantially decreased at the current dosage with premedication and shielding techniques. The integration of SHB as a systemic therapy with combination chemotherapy and LRT is a feasible program for sequential administration of non-cross-resistant agents in SCLC and may be beneficial in patients with limited disease.     

Improved local control of thoracic disease in small cell lung cancer with higher dose thoracic irradiation and cyclic chemotherapy

Over the past decade, improvement in survival has developed for patients with small cell lung carcinoma (SCLC) due to treatment strategies that include: cyclic combination chemotherapy, thoracic irradiation, and prophylactic cranial irradiation. In this study, we assess the outcome of treatment with initial cyclic combination chemotherapy including: cyclophosphamide, VP 16-123 and methotrexate combined with radiotherapy (RT), 6000 cGY [corrected] to the thorax for patients with limited disease and 3000 cGy [corrected] for patients with extensive disease. Forty-six patients are evaluated: 26 patients with limited disease and 20 with extensive disease. In patients who received 6000 cGy [corrected], to thoracic lesions, in combination with chemotherapy, administered for 3 courses prior to and following RT, the rate of clinically detected failure in the thorax was 3.8%. Morbidity was considered acceptable, although the occurrence of encephalopathy in 6 of 19 cases who received cranial irradiation, 3000 cGy [corrected], and concomitant chemotherapy was a serious consequence. Control of the primary tumor achieved by the use of higher dose RT is shown to be superior to that observed at lower doses of RT. This suggests that for the small cohort of patients whose disease is truly limited at the time of diagnosis, therapeutic regimens, which include higher dose RT, could increase the number of long term survivors of SCLC.     

Doxorubicin,cyclophosphamide and VP16-213 (ACE) in the treatment of small cell lung cancer

Summary Small cell lung cancer requires aggressive combination chemotherapy. The three active agents, doxorubicin (A) 45 mg/m² i.v. day 1, cyclophosphamide (C) 1.0 mg/m² i.v. day 1 and VP16-213 (E) 50 mg/m²/day i.v. days 1–5 were given together. The combination (ACE) was given every 21 days without chest irradiation. One hundred and seventy-four patients have been stratified for extent of disease and randomized on three sequential studies testing ACE vs ACE + MER immunotherapy (38 patients), or ACE vs ACE alternating with CCNU, methotrexate, vincristine and procarbazine (109 patients), or ACE vs ACE II (ACE with continuous VP16-213-100 mg/m²/dayx5 days-27 patients-ongoing). The immunotherapy and the alternating non-cross resistant combination have not proven beneficial with respect to response or survival. The ACE combination, regardless of additional treatments, has produced greater than 90% response overall. In limited disease the complete response (CR) frequency is 65%. The median survival for limited disease overall is 14 months and 18 months for patients achieving CR. In extensive disease the CR frequency is 40% with a median survival of 9 months overall and 13 months for patients achieving CR. Response frequency and survival are identical in the first two studies and 20–30% of patients with limited disease are long-term survivors with one late relapse (>3 years). Patients who achieved CR had a significantly longer survival regardless of other factors such as performance status or extent of disease. Prophylactic cranial irradiation was demonstrated to be useful in prevention or delaying CNS metastases in patients who achieved CR. The third generation study of high-dose VP16-213 infusion seeks to increase the CR frequency. ACE chemotherapy without chest irradiation is a highly effective treatment for all patients with small cell lung cancer and compares favorably with all other studies with or without adjuvant radiotherapy.This investigation was supported in part by PHS Grant Number 1 P50CA 32107-01 awarded by the National Cancer Institute, DHHS     

Combined modality therapy for limited-disease small cell lung cancer

Opinion statement Small Cell Lung Cancer (SCLC) is highly sensitive to chemotherapy and radiotherapy. However, despite initial responses, relapses are common and most patients eventually succumb to this disease. Patients with limited-disease SCLC represent approximately 30% of all patients with SCLC, and are potentially curable when treated with combined chemotherapy and thoracic radiotherapy (TRT). Chemotherapy consists of four cycles of the combination of cisplatin and etoposide (PE). Thoracic radiotherapy should be started with the first or second cycle of chemotherapy, and preferably administered twice daily for 3 weeks. Prophylactic cranial irradiation (PCI) is recommended for patients who achieve a complete response. Surgery is of limited value in SCLC, except in patients who present with a solitary pulmonary nodule. Approximately 20% to 25% of patients with limited disease (LD)-SCLC can be cured with this aggressive approach. Newer treatment modalities are currently under investigation.     

Impact of positron emission tomography on the management of patients with small-cell lung cancer: preliminary experience

Accurate staging is important in small-cell lung cancer (SCLC). Patients with limited stage may benefit from chemoradiation, whereas those with extensive stage conventionally receive chemotherapy. Prophylactic cranial irradiation may benefit those attaining complete remission (CR). 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) enhances accuracy of staging in non-SCLC. Its role in SCLC remains unclear. We reviewed 36 consecutive SCLC patients who underwent 47 PET studies between December 1996 and January 2001, for either staging (n = 11), restaging after therapy (n = 21), or both (n = 4). Conventional imaging was also performed. Of 15 patients who had PET for staging, 5 (33%) were upstaged from limited to extensive disease and treated without thoracic radiotherapy. Twenty-five patients underwent 32 restaging PET scans, of which 20 (63%) were discordant with conventional imaging. In 8 cases PET showed more extensive disease than conventional imaging, and in 12 cases PET-apparent disease appeared less extensive. In 13 patients, 14 untreated discordant lesions were evaluable; PET was confirmed accurate in 11 (79%) sites by last follow-up. Restaging PET influenced management in 13 cases (52%). PET-CR conferred longer median time to progression (13.7 months) than no CR (9.7 months). FDG-PET for SCLC was often discordant with conventional assessment and frequently influenced management.     

Standard- and high-dose etoposide, ifosfamide, carboplatin, and epirubicin in 100 patients with small-cell lung cancer: A mature follow-up report

Background: We conducted a phase I–II trial to assess the feasibility and activity of a combination chemotherapy regimen with etoposide, ifosfamide, cisplatin or carboplatin, and epirubicin in limited-disease (LD, stages I–IIIB) and extensive-stage (ED, stage IV) small-cell lung cancer (SCLC).Patients and methods: Standard-dose chemotherapy (SDC) consisting of etoposide (500 mg/m2), ifosfamide (4000 mg/m2), cisplatin (50 mg/m2) and epirubicin (50 mg/m2) (VIP-E), followed by granulocyte colony-stimulating factor (G-CSF), was given to 100 patients with SCLC. Thirty patients with qualifying responses to VIP-E proceeded to high-dose chemotherapy (HDC) with autologous peripheral blood stem-cell transplantation (PBSCT) after etoposide (1,500 mg/m2), ifosfamide (12,000 mg/m2), carboplatin (750 mg/m2) and epirubicin (150 mg/m2) (VIC-E) conditioning.Results of standard-dose VIP-E: Ninety-seven patients were evaluable for response. The objective response rate was 81% in LD SCLC (33% CR, 48% PR; excluding patients in surgical CR) and 77% in ED SCLC (18% CR, 58% PR). The treatment-related mortality (TRM) of SDC was 2%. Two additional patients in CR from their SCLC developed secondary non-small-cell lung cancers (NSCLC), and both were cured by surgery. The median survival was 19 months in LD SCLC and 6 months in ED SCLC. The five-year survivals were 36% in LD and 0% in ED SCLC.Results of high-dose VIC-E: HDC was feasible in 16% of ED-, and 58% of LD-patients. All HDC patients (n = 30) improved or maintained prior responses. Four patients died of early treatment-related complications (TRM 13%). Two additional patients in CR from their SCLC developed secondary malignancies (esophageal cancer, secondary chronic myelogenous leukemia). The median survivals were 26 months in LD SCLC, and 8 months in ED SCLC. The five-year survival was 50% in LD and 0% in ED SCLC.Conclusions: Despite high response rates, survival after VIP-E SDC and VIC-E HDC in patients with ED SCLC is not superior to that achieved with less toxic traditional regimens. The high five-year survival rates achieved with these protocols in LD SCLC probably reflect both patient selection (high proportion of patients with prior surgical resection) and the high activity of our chemotherapy regimen in combination with radiotherapy. A study comparing protocols using simultaneous radiation therapy and chemotherapy, and other dose-escalated forms of SDC with HDC is needed to further define the role of this treatment modality in SCLC. Given the high rate of secondary malignancies observed in patients in CR >2 years in our study, close follow-up and early treatment of these neoplasms may contribute to maintaining overall survival in patients with SCLC.     

Cisplatin and etoposide (VP-16) as a single regimen for small cell lung cancer. A phase II trial

Forty-seven consecutive patients with small cell lung cancer (SCLC) were treated with a combination chemotherapy program including 60 mg/m2 of cisplatin (P) on day 1 and 120 mg/m2 of etoposide (E) on day 4, 6, 8, every 21 days. Limited disease (LD) patients, achieving complete response (CR) or partial response (PR) after the three initial courses, received radiotherapy (RT) to the pretreatment primary tumor volume and, those achieving CR, additional RT to the brain. During RT, chemotherapy was administered with 50% dose reduction. Forty-three patients were evaluable for therapeutic response. In the 19 patients with LD, CR was achieved in 63% of patients and the PR rate was 32%. In 24 patients with extensive disease (ED), CR was 34% and PR rate was 54%. Median duration of survival was 66 weeks for LD and 48 weeks for ED. Six patients were disease-free after 2 years. Leucocyte count less than 2000/mm3 was seen in 26% of patients; platelet count less than 50000/mm3 was observed in 9%. Nonhematologic toxicity included universal nausea or vomiting and severe neurotoxicity in 7%. These data indicate that PE combination is a very active front-line regimen in SCLC and could be suggested as one of the reference treatments.     

Intensive weekly chemotherapy for the treatment of extensive-stage small-cell lung cancer.

The regimen of cisplatin, vincristine, doxorubicin, and etoposide (CODE) was designed to double the dose intensity of these drugs in comparison with a standard regimen (alternating cyclophosphamide, doxorubicin, and vincristine [CAV] and etoposide-cisplatin [EP]) for extensive-stage small-cell lung cancer (SCLC). The dose intensity was increased by more frequent treatments rather than by increasing the dose size. The structure of this outpatient protocol includes weekly administration of chemotherapy, alternation of myelosuppressive and nonmyelosuppressive treatments, supportive corticosteroids, gastroprotective agents, and prophylactic antibiotics. Although the duration of chemotherapy was brief (9 to 12 weeks), the total cumulative doses of drugs delivered were similar to the standard regimen. Patients with no residual disease outside the chest after chemotherapy received thoracic irradiation, and patients with complete responses (CRs) received prophylactic cranial irradiation. Eligible extensive-stage SCLC patients were ambulatory, younger than 66 years of age, and free of brain metastasis. Forty-eight extensive-stage SCLC patients were treated. Forty-five (94%) responded to chemotherapy, with 19 (40%) attaining CR. After consolidative thoracic irradiation, the CR rate was 56%. The median time to progression was 43 weeks, and the median survival was 61 weeks. The 2-year survival rate was 30%. The most common site of first relapse was brain (38%). Although two patients (4%) died of toxicity, overall toxicity was acceptable for an outpatient regimen. We conclude that the CODE regimen reliably produces palliative remissions for selected extensive-stage SCLC patients, and it may be associated with durable remissions for some patients. The results of this pilot study are sufficiently promising to justify a phase III trial of CODE versus standard (alternating CAV and EP) chemotherapy.     

Cisplatin etoposide versus cisplatin/etoposide/ifosfamide combination chemotherapy in small-cell lung cancer: a multicenter randomized controlled study. Hokkaido Study Group of Treatment for Small-Cell Lung Cancer]

Ninety-two patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin (80 mg/m2, day 1)/etoposide (100 mg/m2, day 1, 3, 5) (PE) or cisplatin (80 mg/m2, day 1)/etoposide (100 mg/m2 1, 3, 5)/ifosfamide (2 g/m2, day 1, 2, 3) (PEI) combination chemotherapy. After 2 courses of chemotherapy, patients with limited disease (LD) received chest irradiation with 40-50 Gr. Of the 89 patients evaluable, the overall response rate was 77.8% in PE therapy, and 73.7% in PEI therapy (NS). The complete response rate (CR) of PE v PEI was 13.9% v 21.2% for all patients (NS), 22.2% v 30.4% for LD. Median survival times of PE v PEI for all patients were 55 weeks v 56 weeks (NS). The 2-year survival rate of PE v PEI was 15.4% v 16.5% for all patients (NS). There was no difference of the duration of response in cases with CR or PR between PE and PEI therapy. Leucopenia occurred more often after PEI than after PE therapy (p less than 0.01). These results suggest that PEI is not superior to PE chemotherapy in SCLC.     

Intensive weekly chemotherapy for good-prognosis patients with small-cell lung cancer.

A weekly, intensive chemotherapy regimen has been used to treat 70 patients with small-cell lung cancer (SCLC). Forty-five patients had limited disease (LD) and 25 extensive disease (ED) with good prognostic features. The regimen consisted of cisplatin 50 mg/m2 intravenously (IV) day 1 and etoposide 75 mg/m2 IV days 1 and 2, alternating weekly with ifosfamide 2 g/m2 IV day 8 and doxorubicin 25 mg/m2 IV day 8, for a total of 12 weeks. Dose modifications were made according to defined hematologic criteria. Responding patients with limited disease subsequently received mediastinal radiotherapy. Overall response to chemotherapy was 91% with a complete response (CR) rate of 50%. Forty-five patients with limited disease (LD) achieved an overall response rate of 91% with a CR rate of 51%, and 25 patients with extensive disease (ED) achieved an overall response rate of 92% with a CR rate of 48%. Median survival for the whole group was 54 weeks (LD, 58 weeks; ED, 42 weeks). Hematologic toxicity was predictable, without the wide fluctuations in WBC count seen in conventional 3-weekly regimens. In all, one quarter of treatment courses were delayed, most frequently because of leukopenia. Dose reductions were required in 63% of cases. The average delivered dose intensity was calculated and shown to be 73% of projected. Nonhematologic toxicity was mild with nausea and vomiting being the most common. This weekly schedule of chemotherapy has proved to be active and well tolerated and is currently being compared with conventional 3-weekly chemotherapy in a randomized study.     

Current perspectives in the management of small cell lung cancer

Considerable progress has been made within the last decade in the management of small cell lung cancer (SCLC) resulting in prolongation of median survival by 4 to 5 times (about 14 and 9 months in limited and extensive disease, respectively), improved quality of life, and an increase of cure rates in 15 approximately 20% of the patients with limited disease. In this review, we are focusing on the details in update treatment schedules of combination chemotherapy against SCLC, prognostic features and staging of SCLC, the role of non-cross resistant alternating chemotherapy, radiotherapy to the primary site including hilar and mediastinal lymph nodes, prophylactic cranial irradiation and surgery in the treatment of SCLC, as well as the complications of treatment.