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Objective: To determine the efficacy and toxicity of oral topotecan and paclitaxel in untreated patients with extensive stage small cell lung cancer (SCLC)., Patients and Methods: Thirty-eight patients received 1.75 mg/m2 of oral topotecan days 1 to 5 and 175 mg/m2 paclitaxel IV over 3 hours on day 5 (after topotecan) every 4 weeks for 6 cycles. Subcutaneous G-CSF at a dose of 5 microg/kg was then given 24 to 48 hours after the last dose of chemotherapy and daily for 10 days., Results: All 38 patients were available for toxicity and response analysis. A median of 5 treatment cycles was given, with a range of 1 to 7 cycles. Seventeen (45%) patients received at least 6 cycles of treatment. The most common severe adverse events were neutropenia (42.1%), leukopenia (34.2%), thrombocytopenia (18.4%), nausea (18.4%), diarrhea (13.2%), and fatigue (13.2%). Two grade 5 treatment-related evens were seen. The median overall survival was 9.1 month (95% CI: 7.5-13.0 months), with a 1-year survival estimate of 44.7% (95% CI: 31.4-63.7%) and a 2-year survival rate of 5.3% (95% CI: 1.4-20.3%). The median time to progression was 5.0 months (95% CI: 3.8-6.6 months), with a 1-year progression-free rate of 5.8% (95% CI: 1.5-22.2%) and a 2-year progression-free rate of 2.9% (95% CI: 0.4-19.9%). The estimated confirmed response rate was 52.9%., Conclusion: This regimen has shown similar antitumor activity to that achieved with standard therapy. Because of unacceptable toxicity and cost, we do not recommend this regimen in a palliative setting.

Background: A Phase III trial was conducted by the North Central Cancer Treatment Group to determine whether chemotherapy (etoposide and cisplatin) plus either twice-daily radiotherapy (BIDRT) or once-daily radiotherapy (QDRT) resulted in a better outcome for patients with limited-stage small cell lung carcinoma (LD-SCLC). No difference in survival was identified between the two arms. The current analysis examined the relation between age and outcome for patients treated during this trial., Methods: The current study included 263 patients with LD-SCLC and an Eastern Cooperative Oncology Group performance status of < or = 2 who were randomized to receive QDRT or split-course BIDRT. The outcomes of the 209 (79%) younger patients (age < 70 years old) were compared with the 54 (21%) elderly patients (age > or = 70 years old)., Results: Elderly patients presented with significantly greater weight loss and poorer performance status. The 2-year and 5-year survival rates were 48% and 22% for younger patients compared with 33% and 17% for older patients (P = 0.14). One specific toxicity (i.e., Grade > or = 4 pneumonitis [according to National Cancer Institute Common Toxicity Criteria]) occurred in 0% of those patients age < 70 years compared with 6% of older patients (P = 0.008). Grade 5 toxicity occurred in 1 of 209 (0.5%) patients age < 70 years compared with 3 of 54 (5.6%) older patients (P = 0.03)., Conclusions: Despite having more weight loss, poorer performance status, increased pulmonary toxicity, and more deaths due to treatment, survival was not found to be significantly worse in older individuals. Fit elderly patients with LD-SCLC can receive combined-modality therapy with the expectation of relatively favorable long-term survival. Future research should focus on ways to decrease toxicity especially in the elderly.

Purpose: This Phase III study was performed to determine whether twice-daily (b.i.d.) radiotherapy (RT) resulted in better survival than once-daily (q.d.) RT for patients with limited-stage small-cell lung cancer (LD-SCLC)., Methods and Materials: A total of 310 patients with LD-SCLC initially received three cycles of etoposide and cisplatin. Subsequently, the 261 patients without significant progression were randomized to two cycles of etoposide and cisplatin plus either q.d. RT (50.4 Gy in 28 fractions) or split-course b.i.d. RT (24 Gy in 16 fractions, a 2.5-week break, and 24 Gy in 16 fractions) to the chest. Patients then received a sixth cycle of etoposide and cisplatin followed by prophylactic cranial RT., Results: Follow-up ranged from 4.6 to 11.9 years (median, 7.4 years). The median survival and 5-year survival rate from randomization was 20.6 months and 21% for patients who received q.d. RT compared with 20.6 months and 22% for those who received b.i.d. RT (p = 0.68), respectively. No statistically significant differences were found in the rates of progression (p = 0.68), intrathoracic failure (p = 0.45), in-field failure (p = 0.62), or distant failure (p = 0.82) between the two treatment arms. No statistically significant difference was found in the overall rate of Grade 3 or worse (p = 0.83) or Grade 4 or worse toxicity (p = 0.95). Grade 3 or worse esophagitis (p = 0.05) was more common in the b.i.d. arm. Grade 5 toxicity occurred in 4 (3%) of 130 patients who received b.i.d. RT compared with 0 (0%) of 131 who received q.d. RT (p = 0.04)., Conclusion: Although this study did not demonstrate an advantage to split-course b.i.d. RT, the long-term survival was favorable, likely reflecting the positive influences of concurrent combined modality therapy and prophylactic cranial RT.

A randomized two-stage, phase II study was conducted to assess the antitumor activity of two different schedules of topotecan in the treatment of extensive-stage small-cell lung cancer (SCLC) in chemotherapy-naive patients. A total of 40 eligible patients were randomized to receive either the daily schedule, with topotecan being administered intravenously at 1.5 mg/m2 daily for 5 days every 3 weeks, or the continuous-infusion schedule, with topotecan administered intravenously at a dosage of 1.3 mg/m2 per day over 72 hours every 4 weeks. Randomization to the continuous-infusion schedule was discontinued due to inactivity, and an additional 20 patients were treated on the daily schedule. Patients received an average of 5 courses (range: 1-13) of the daily schedule compared to an average of 2 courses (range: 1-7) of the continuous-infusion schedule (p < 0.01). Confirmed response rates for the daily and continuous-infusion schedules are 62.5% (90% CI: 49-75%) and 15% (90% CI: 1-29%), respectively. Toxicity was predominantly hematologic with 92% (55/60) having greater than or equal to grade III neutropenia and 58% (35/60) reporting greater than or equal to grade III leukopenia for both IV schedules. Nonhematologic toxicity was very mild, with only 10% (6/60) patients experiencing grade IV toxicities. One patient died of infection on the continuous-infusion arm. Median times to progression for the daily and continuous-infusion schedules are 5 months (90% CI: 4.4-7.2) and 2 months (90% CI: 1.1-2.1), respectively. Estimated 1-year survival rates for patients receiving daily and continuous-infusion schedules are 63% (90% CI: 51-76%) and 55% (90% CI: 39-77%), respectively. Fifty percent (30/60) of patients received second-line therapy with etoposide and cisplatin. Forty-three percent (13/30) of patients who received second-line therapy achieved a confirmed response. Topotecan showed significant activity in the treatment of extensive stage SCLC when administered as a brief daily IV repeated every 3 weeks.

Background: The objective of this study was to test the response rate and toxicity of alternating chemotherapy in previously untreated patients with extensive-stage small cell lung carcinoma (SCLC)., Methods: Patients with histologically proven, extensive-stage SCLC, with a performance status of 0-2, and who had received no prior chemotherapy were eligible. The design was a two-stage, Phase II, multicenter trial. Treatment consisted of alternating chemotherapy every 3 weeks with etoposide (100 mg/m(2) on Days 1-3) and cisplatin (30 mg/m(2) on Days 1-3) on Cycles 1, 3, 5 and with topotecan (1 mg/m(2) on Days 1-5) and paclitaxel (200 mg/m(2) on Day 5) on Cycles 2, 4, and 6. Filgrastim support was given with Cycles 2, 4, 6., Results: Forty-four patients were eligible and evaluable. The primary toxicity was myelosuppression. The median absolute neutrophil count was 300/microL with 70% Grade 4 neutropenia. The median platelet count was 58,000/microL with 23% Grade 4 thrombocytopenia. Grade 4 nonhematologic toxicities occurred in 16% of patients. Overall toxicities were not different between the two regimens. There were no treatment-related deaths. Complete or partial responses occurred in 34 patients (77%). The median time to progression was 6.9 months, with a median survival of 10.5 months and with 1-year and 2-year survival rates of 37% and 12%, respectively., Conclusions: The regimen of alternating chemotherapy was associated with substantial myelosuppression and resulted in a high response rate and good overall survival. The results were similar to those reported in prior trials and did not suggest any improvement in therapy for patients with SCLC., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11377)

The level of serum neuron-specific enolase (NSE) has been implicated as a prognostic factor for patients with small cell lung cancer (SCLC). A prospective evaluation was undertaken to assess the prognostic significance of pretreatment NSE and treatment-induced minimum NSE values in patients with SCLC. Patients from two Phase III North Central Cancer Treatment Group trials [one for patients with extensive stage SCLC and one for patients with limited stage SCLC] were asked to enter this laboratory correlational trial. Both trials included treatment with four to six cycles of etoposide and cisplatin, and 121 patients (71 extensive stage SCLC and 50 limited stage SCLC) were entered into the present study of NSE. Pretreatment NSE values and treatment-induced minimum NSE values were independent predictors of time to progression and survival in multivariate analysis. Hazard rate modeling allowed the formulation of specific relationships of NSE to time to progression and survival. Pretreatment NSE levels inversely correlated with time to progression and survival in these patients with SCLC. Pretreatment NSE accounted for 28% of the variance in survival. Both pretreatment NSE and treatment-induced minimum NSE were independent prognostic predictors of time to progression and survival.

Purpose: Because small-cell lung cancer is a rapidly proliferating tumor, it was hypothesized that it may be more responsive to thoracic irradiation (TI) given twice-daily than once-daily. This hypothesis was tested in a phase III trial., Patients and Methods: Patients with limited-stage small-cell lung cancer were entered onto a phase III trial, and all patients initially received three cycles of etoposide (130 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). Subsequently, patients who did not have progression to a distant site (other than brain) were randomized to twice-daily thoracic irradiation (TDTI) versus once-daily thoracic irradiation (ODTI) given concomitantly with two additional cycles of etoposide (100 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). The irradiation doses were TDTI, 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy, and ODTI, 50.4 Gy in 28 fractions. After thoracic irradiation, the patients received a sixth cycle of etoposide/cisplatin, followed by prophylactic cranial irradiation (30 Gy/15 fractions) if they had a complete response., Results: Of 311 assessable patients enrolled in the trial, 262 underwent randomization to TDTI or ODTI. There were no differences between the two treatments with respect to local-only progression rates, overall progression rates, or overall survival. The patients who received TDTI had greater esophagitis (> or = grade 3) than those who received ODTI (12.3% v 5.3%; P =.05). Although patients received thoracic irradiation encompassing the postchemotherapy volumes, only seven of 90 local failures were out of the portal of irradiation., Conclusion: When TI is delayed until the fourth cycle of chemotherapy, TDTI does not result in improvement in local control or survival compared with ODTI.

The authors conducted a phase II study of somatostatin analogue in 18 patients with extensive stage small cell lung cancer (four with previous treatment, 14 without previous treatment). Patients received 2,000 mg subcutaneously thrice daily. They were required to have an Eastern Cooperative Oncology Group performance score of 0-2 and acceptable pretreatment biochemical parameters. No patient responded to treatment. The median time to progression was 44 days. The median survival was 106 days. Toxicity related to treatment consisted of mild diarrhea and anorexia. Somatostatin analogue is not active as a single agent in the treatment of extensive-stage small cell lung cancer.

Purpose: Megestrol acetate has been reported to improve appetite and quality of life and to decrease nausea and vomiting in patients with cancer anorexia/cachexia. The present trial was formulated to evaluate the impact of megestrol acetate on quality of life, toxicity, response, and survival in individuals with extensive-stage small-cell lung cancer who received concomitant chemotherapy., Patients and Methods: Patients were randomized to receive megestrol acetate 800 mg/d orally or placebo. In addition, all patients were scheduled to receive a maximum of four cycles of cisplatin and etoposide chemotherapy. Quality of life was self-assessed at entry onto study, with every cycle of chemotherapy, and 4 months thereafter with a linear visual analog scale. Toxicity was evaluated by patient questionnaire and investigator reports., Results: A total of 243 eligible patients were randomized. Those who received megestrol acetate had increased nonfluid weight gain (P = .004) and significantly less nausea (P = .0002) and vomiting (P = .02). Significant thromboembolic phenomena occurred more often in patients who received megestrol acetate versus placebo (9% v 2%, P = .01). Patients who received megestrol acetate had more edema (30% v 20%, P = .002), an inferior response rate to chemotherapy (68% v 80%, P = .03), and a trend for inferior survival duration (median, 8.2 v 10.0 months, P = .49). These findings may have been influenced by a poorer quality of life of the megestrol acetate group at study initiation. There were no significant changes in quality of life scores over time between either of the study arms., Conclusion: Megestrol acetate cannot be routinely recommended for all patients with small-cell lung cancer at the time of chemotherapy initiation. Rather, its therapeutic ratio may be more favorable for patients with problematic cancer anorexia/cachexia.

Purpose: We evaluated the effect of recombinant interferon gamma (rIFN-gamma) on survival and toxicity in small-cell lung cancer (SCLC) patients in complete remission (CR)., Patients and Methods: One hundred patients in CR following treatment with six cycles of combination chemotherapy, thoracic radiotherapy (TRT), and prophylactic cranial irradiation (PCI) were studied. All patients had been enrolled onto a cooperative group trial (North Central Cancer Treatment Group [NCCTG] 86-20-51). Patients received observation only or rIFN-gamma at a dose of 4 x 10(6) U subcutaneously per day for 6 months., Results: Six patients (12%) did not comply with rIFN-gamma treatment. Substantial nonhematologic toxicities consisting of chills, myalgia, lethargy, and alteration of mood-personality were observed. No patient experienced life-threatening or fatal toxicity. The median times to progression for rIFN-gamma treatment or observation were 6.9 and 8.1 months (P = .54). The median survival times were 13.3 and 18.8 months, respectively (P = .43). Approximately 70% of all patients relapsed within 2 years., Conclusion: Time to progression and survival were inferior in patients treated with rIFN-gamma compared with randomized control subjects, although this difference was not statistically significant. These data indicate that rIFN-gamma treatment is not associated with a 33% improvement in survival (P = .04). Because of the high rate of relapse, SCLC patients in CR are an ideal group in which to evaluate novel and minimally toxic agents.

Background: Long-term survival with extensive stage small cell lung cancer is rare. There have been no major advances in the treatment of this stage of disease in the last 15-20 years. New agents with activity against this malignancy are needed. This study was designed to evaluate the efficacy of edatrexate against small cell lung cancer in a Phase II trial., Methods: This was a multicenter cooperative oncology group trial. Patients were either previously untreated or had failed only one prior chemotherapy regimen. All previously untreated patients had extensive stage disease. Patients in whom prior therapy had been unsuccessful had either limited or extensive stage disease. All cases had histologic documentation. Patients received edatrexate (80 mg/m2) intravenously over 20-30 minutes every 7 days. Previously untreated patients with disease progression at any time or stable disease after 6 weeks of treatment were crossed over to treatment with cisplatin and etoposide. The primary end points of the study were clinical response and toxicity to edatrexate. All patients were observed for survival., Results: Eleven previously untreated and 22 previously treated patients were enrolled. A median of five doses of chemotherapy was given to each group. No major clinical response was observed in either group. The median survival time for the 11 previously untreated patients was 9.8 months versus 3.7 months for individuals who had received prior therapy. Myelosuppression and stomatitis were the primary toxicities, and both were infrequent., Conclusions: Edatrexate is inactive against small cell lung cancer.

Purpose: The combination of etoposide (E) and cisplatin (P) is an accepted standard therapy for small-cell lung cancer (SCLC); however, the optimal sequencing and administration schedule has not been defined. This study was designed to evaluate different sequencing and administration schedules of E and P in the treatment of SCLC., Patients and Methods: Five hundred fifty-two eligible patients with limited-(LD) and extensive-stage (ED) SCLC were randomized to receive one of the following regimens: arm A, P 30 mg/m2 by intravenous (IV) bolus followed by E 130 mg/m2 bolus; arm B, E 130 mg/m2 bolus followed by P 30 mg/m2 bolus; arm C, E 130 mg/m2 by 24-hour infusion and P 30 mg/m2 bolus at the end of each 24-hour infusion of E; arm D, E 130 mg/m2 by 24-hour infusion and P 45 mg/m2 by 24-hour infusion on day 2 and 3 only. Two 3-day induction cycles of IV EP were administered 4 weeks apart. Subsequent therapy was the same for all arms, consisting of four cycles of cyclophosphamide, doxorubicin, and vincristine (CAV) at 4-week intervals. Consolidative thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) were administered to responders., Results: The overall response rate (84%) was similar in all treatment arms. Treatment arm A was associated with the best complete response (CR) rate (52%), the most favorable median survival time (MST) of 15 months, and a 26% 2-year survival rate. Patients with LD on arm A had a MST of 20 months and a 42% 2-year survival rate. Multivariate analysis indicated that extent of disease, performance status, arm of therapy, and sex were significant independent factors influencing survival. Toxicity of the four regimens was similar, except for greater thrombocytopenia on arm D., Conclusion: The bolus administration of EP with E following P for the first two cycles of chemotherapy was the most effective regimen, with especially encouraging survival for LD patients.

In this randomized study involving patients with limited-stage small-cell lung cancer (LD-SCC), we compared treatment with either cyclophosphamide; doxorubicin, and vincristine (CAV) or CAV plus etoposide (CAVE). All patients received identical thoracic radiation consisting of 3,750 cGy in 15 fractions and prophylactic cranial radiation (3,000 cGy in 10 fractions). Among 231 evaluable patients, the two treatment arms were well matched with respect to sex, age, performance score, and presence or absence of heart disease. A major regression (REGR) was observed in 83% of all patients and a complete response (CR) in 60%. There was no difference in the response rate between the two treatment regimens. The median time to progression is 10.4 months (95% confidence interval [Cl], 8.9 to 12 months) for CAVE versus 8.9 months (95% Cl, 7.9 to 10.4 months) for CAV (P = .04). The median survival is 15.1 months (95% Cl, 11.7 to 17.8 months) for CAVE versus 12.4 months (95% Cl, 11 to 14.4 months) for CAV. This difference is not significantly different (P = .13). Toxicity was primarily myelosuppression and was significantly greater for the four-drug regimen. Fatal treatment-related toxicity was observed in two patients on the CAVE regimen and no treatment-related deaths were observed on the CAV treatment. In conclusion, the addition of etoposide to the CAV regimen resulted in increased toxicity but did not lead to a meaningful improvement in survival.

In this study, we evaluated the role of alternating chemotherapy with or without etoposide (VP-16) in patients with extensive-stage small-cell carcinoma (SCC) of the lung. All patients received initial treatment with CMC [cyclophosphamide, methotrexate, and chloroethyl-cyclohexyl-nitrosourea (CCNU)]. Four weeks after initial treatment, patients were stratified by performance score, central nervous system (CNS) metastasis, age, and response to initial CMC therapy and randomized to receive AO (doxorubicin and vincristine) or AVO (doxorubicin, VP-16, and vincristine) alternating with CMC. One hundred eighty-two eligible patients were treated with the initial cycle of CMC and 98 responded (54%). One hundred fifty-four patients were randomized to either AO/CMC or AVO/CMC. The response rates to AO/CMC and AVO/CMC were similar (72 vs. 68%). The time to progression and survival were not significantly different on the two treatment regimens. Toxicity was significantly greater for patients receiving AVO/CMC with six treatment-related deaths. Etoposide as used in this regimen did not significantly influence response rates, time to progression, or survival of patients with extensive small-cell lung cancer.