Small Cell Lung Cancer Pts Research Articles

The impact of shortened vitamin supplementation lead-in time before pemetrexed (P) in patients with relapsed small cell lung cancer (SCLC)

7726 Background: Clinical studies of P have shown less overall toxicity and reductions in Grades 3–4 hematologic and nonhematologic toxicities when pts are pretreated with folic acid and vitamin B12. Current recommendations are to give folic acid 350 μg - 1,000 μg by mouth for at least 5 of 7 days prior to the 1st dose of P, and 1 injection of vitamin B12 1000 μg during the week preceding the 1st P dose. Treatment delay to allow this supplementation may be clinically undesirable, particularly in pts with aggressive malignancies. A trial evaluating single-agent P for the treatment of relapsed SCLC gave us opportunity to observe the effects of a shortened lead-in time for vitamin supplementation. Methods: We reviewed data from a U.S. trial designed to assess the safety and efficacy of single-agent P in chemosensitive and chemorefractory relapsed SCLC pts. Eligible pts had limited or extensive-stage SCLC, PS 0 to 2, and 1 prior chemo regimen. Pts received P doses of 500 mg/m2 or 900 mg/m2 q 21 d. The protocol required the administration of folic acid for at least 5 of 7 days prior to the 1st P dose, and vitamin B12 administration on Day 1, Cycle 1, or up to 14 days prior to the 1st P dose. Included in the analysis were pts who received at least 1 dose of folic acid prior to 1st P dose. We then analyzed preliminary toxicity results for pts receiving vitamin B12 for 0–3, 4–6 and =7 days prior to 1st P dose. Results: From 7/2004 to 3/2006, 116 pts were treated with P. At baseline M/F 57%/59%; median age 64.5 years (range 35–85); PS 0/1/2 was 39%/57%/20%. Cycle 1 vitamin administration timing data is available for 109 pts. Data for all 116 pts will be reported at time of meeting. Because toxicities observed between the 2 P doses were not significantly different, the combined toxicities for both dosing groups are reported here. Conclusions: Based on this data, Vitamin B12 given less than 7 days prior to P does not appear to be associated with increased serious toxicities. No significant financial relationships to disclose. [Table: see text]

The efficacy of second line chemotherapy (CHT) in platinum-sensitive advanced/metastatic small cell lung cancer (SCLC) patients: Results of an ongoing Italian multicenter survey

18090 Background: Despite CHT and radiotherapy for SCLC, most patients (pts) die within 2 years. Response rates for second-line CHT are low, with a median survival of 5 months in platinum-refractory pts. Re-challenge with platinum salts or salvage regimens is a standard option for pts with platinum-sensitive disease with a median overall survival (OS) of 6.5–8 months (Chua et al., Cancer Treat Rev. 2004). The purpose of this study was to explore the benefits of different second line regimens in this platiunum sensitive population. Methods: Clinical records of 73 platinum sensitive SCLC pts (first line relapse free survival > 6 months) were reviewed from 13 medical oncology departments in Italy from January 1993 to December 2006. Pt. characteristics: 59 males, 14 females, median age 64 years (range 27–93), median ECOG performance status (PS): 1, limited/extended disease: 33/40 pts. Pts received salvage chemotherapy which consisted of monotherapy in 37% and platinum-containing doublets in 55%. Doublets without platinum salts were administered in the remaining 8%. Results: Of 67 evaluable pt, second line CHT produced partial responses (PR) in 58 (79%) and stable disease (SD) in 9 pts (12%) by RECIST criteria. Overall tumor growth control (PR+SD) was 91%. Despite these encouraging results, the median TTP was 3 months and OS for all evaluable pts was 6.5 months. Survival at 1 year was 11%. Multivariate analysis revealed that the most important prognostic factor for response was age ( p<0.04) and there was no statistically significant difference between platinum-based regimens and monotherapy. Multivariate analysis showed no impact on survival by prior response to first line treatment, female sex or smoking status. Conclusions: Within the limits of a retrospective study, despite the high rate of responses obtainable in this setting, TTP and OS do not appear significantly improved by salvage regimens. Second line CHT has marginal activity and should be considered only in younger pts with a good PS. On the basis of these results, re-treatment with platinum salts could be avoided in these pts. No significant financial relationships to disclose.

Pemetrexed (P) in relapsed small cell lung cancer (SCLC): Preliminary results of a phase II trial

7716 Background: Pts with relapsed SCLC have a poor prognosis and few effective treatment options. P is a novel multitargeted antifolate that is active and well-tolerated as a single agent in lung cancer. We undertook a trial to assess the efficacy and safety of single- agent P in both chemosensitive (S) and chemorefractory (R) relapsed SCLC pts. Methods: Eligible pts had limited or extensive- stage SCLC, PS 0 to 2, and only 1 prior chemo regimen. S pts were defined as having had a prior response with disease progression >2 mos from end of 1st-line chemo. R pts were those who progressed while on 1st-line therapy, or had any response but progression <2 mos from end of 1st-line chemo. The initial P dose tested was 500 mg/m2 q 21 d. Planned sample sizes were 36 S pts in a 2-stage sequential fashion with potential early stopping for lack of efficacy or unacceptable toxicity, and 25 R pts in a single-stage design with no stopping rule. The stopping rule was invoked when <3 of 14 qualified S pts responded. The protocol was then amended to evaluate P at 900 mg/m2 in additional cohorts of 40 S and 40 R pts. Pts were to receive folic acid and Vitamin B12 prior to treatment with P. The primary outcome measure was response rate. Results: From 7/04 to 3/06, 121 pts were enrolled, with 116 pts treated. S and R pts were analyzed separately at both dose levels. S pts (n=56): M/F, 29/27; median age 65 (range 43–82); PS 0/1/2, 25/23/8. R pts (n=65): M/F, 31/34; median age 64 (range, 35–85); PS 0/1/2, 16/37/12. *3 S pts treated with P 900 mg/m2 remain with disease control after a minimum of 11 mos of follow-up. Conclusions: Preliminary clinical benefit rates (CR+PR+SD) of 20% and 17.4% achieved respectively in S and R pts treated with P 500 mg/m2 suggest modest activity of single-agent P in relapsed SCLC. P can be given at a dose of 900 mg/m2 without a significant increase in Grades 3–4 toxicities, although this does not appear to increase efficacy. [Table: see text] [Table: see text]

A phase II study of picoplatin (pico) as second-line therapy for patients (pts) with small cell lung cancer (SCLC) who have resistant or refractory disease or have relapsed within 180 days of completing first-line, platinum (plat)-containing chemotherapy

7722 Background: Pico is a sterically hindered plat analogue designed to overcome plat resistance with improved safety and efficacy. In >600 pts pico had single-agent activity in lung, prostate, ovarian and other malignancies with rare significant nephro-, oto-, or neurotoxicity (∼2% grade 3 and 0% grade 4). In a previous phase 2 study of single agent pico as 2nd line therapy in SCLC, 4 of 48 pts (8%) had a partial response and 21 (44%) stable disease. Median survival was 27.0 (95% CI = 16–35) wks. This multi-center phase 2 trial was designed to confirm the activity of pico as 2nd line monotherapy for plat-resistant SCLC. Methods: Pts with SCLC who either 1) failed or progressed through 1st line plat-containing chemo (refractory disease), or 2) initially responded to 1st line plat-containing chemo and then relapsed/ progressed within 3 months (resistant disease), or 3) initially responded and then relapsed/progressed between 90 to 180 days (sensitive, relapsed 90 to 180 days), had measurable disease and ECOG PS 0–2 were treated with pico, 150 mg/m2 iv over1–2 hrs, q 21 days. Tumor response was assessed q 6 wks. Adverse events (AEs) were graded using the NCI CTCAE. Results: 77 pts received pico (45 refractory, 27 resistant, 5 sensitive). The median number of cycles received was 2 (mean = 2.9). The most frequently reported AEs of any severity were thrombocytopenia (39% of pts), anemia (35%), neutropenia (22%), nausea (20%), emesis (14%) and dyspnea (25%). Neutropenic fever occurred in 1 pt; there were no treatment related deaths. One pt had grade 3 neuropathy; there was no grade 3 or 4 ototoxicity or nephrotoxicity. Median overall survival is 28.1 (95% CI = 26–37) wks. Median progression free survival is 9.3 (95% CI = 7–12) wks. Of 63 pts with at least 1 post-treatment assessment of disease status, 33 (52%) had stable disease. Conclusion: Median survival compares favorably with other therapeutic options and toxicity is reduced in pico treated SCLC pts who have failed prior plat-containing first-line chemo or who have progressed within 180 days of first-line chemo. A phase III trial to confirm these results has been initiated. No significant financial relationships to disclose.

Two-drug gemcitabine-based first-line treatment of elderly patients (pts) with small cell lung cancer (SCLC): The G-STEP program

7089 Background: Trials testing chemotherapy for elderly pts with SCLC are scanty. Gemcitabine (Gem) is active and well tolerated. The G-STEP program looked for optimal 2-drug combination of G with either vinorelbine (Vin), etoposide (Eto), cisplatin (Cis), or carboplatin (Car). Methods: Extended stage SCLC pts, aged >70 years, PS 0–2, were eligible. Dose of G was 1,000 mg/m2, dd 1&8, every 3 weeks in all the four combinations. As safety data in the elderly were already available for Gem+Vin (Vin dose 25 mg/m2, dd 1&8), a two-stage minimax flexible design was applied with response as end-point: ≥13 responses/30 pts required at 1st stage, with p0=0.40, p1=0.60, α and β=0.10. For Gem+Car, Gem+Cis, Gem+Eto a phase 1–2 Bayesian design to select optimal dose was applied (Thall & Russell, Biometrics, 1998), with 3 possible outcomes for each patient: “active” (response and no unacceptable toxicity [UT]), “inactive” (no response, no UT), or “toxic” (UT independently of response). A response rate [RR] ≥60% and a rate of UT ≤25% were acceptable. Dose levels to explore were: Car: AUC 3.5 / 4 / 4.5, d1; Cis: 50 / 60 / 70 mg/m2, d1; Eto: 60 / 70 / 80 mg/m2, dd 1,2,3. Results: From May 2000 to September 2005, 78 eligible pts were enrolled; median age was 74 years (42% of pts older than 75yrs). In the whole group, median progression-free survival and overall survival were 20.3 weeks (95% CI 17.6 - 24.1) and 33.7 weeks (95% CI 23.7 - 41.6), respectively. Study of Gem+Vin was closed for inactivity after 1st stage with 11 responses / 30 pts (RR 36.7%, 95% exact CI: 19.9–56.1). Gem+Eto arm was closed after 10 pts (5 inactive and 5 toxic) because too high probability (0.994) of inactivity. Gem+Cis arm was closed after 12 pts (2 active, 5 inactive, 5 toxic) because too high probability (0.988) of inactivity. With Gem+Car (December 2005: 2 pts ongoing, 24 analysed: 12 active, 6, inactive and 6 toxic), RR in the 20 pts receiving Car at AUC 3.5 was 60% (95% exact CI: 36.1–80.9). Conclusions: The combination of gemcitabine and carboplatin seems promising for future trials in elderly patients with extended SCLC. The G-STEP program was supported by GIOGER. No significant financial relationships to disclose.

64 Consequences of prophylactic cranial irradiation (PCI) in small cell lung cancer pts (SCLC) after complete response to chemotherapy (CH)

64 Consequences of prophylactic cranial irradiation (PCI) in small cell lung cancer pts (SCLC) after complete response to chemotherapy (CH)

A phase II NCCTG/CALGB trial of imatinib (STI571) in patients (pts) with c-kit-expressing relapsed small cell lung cancer (SCLC)

7048 Background c-Kit over-expression is found in multiple cancers including up to 70% of SCLC. STI571 can inhibit c-kit tyrosine kinase activity and has high efficacy in chemoresistant c-kit positive (c-kit+) gastrointestinal stromal tumors. A phase II study of STI571 in unselected SCLC pts by Johnson et al., was negative, but inconclusive for proof- of - principle purposes, since 80% of tumors did not express c-kit. We therefore sought to evaluate clinical activity of STI571 in the treatment of patients with recurrent and refractory c-kit+ SCLC. Methods Only c-kit+ SCLC cases were enrolled on this study (≥ 1+ by immunohistochemistry). Arm A included pts progressing < 3 months and Arm B included pts progressing ≥ 3 months after previous treatment. STI571 was administered at a dose of 400 mg bid continuously, with a cycle length of 28 days. A single stage Simon design with a planned interim analysis was used to evaluate the 16 week progression free rate in each arm. Results A total of 29 evaluable pts were entered into the study (7 arm A, median age 68; 22 arm B, median age 65). Median number of treatment cycles was 1 in both arms. All pts are now off active treatment. Grade3+ non-hematologic adverse events were seen in 15(52%) pts, with nausea, vomiting, dyspnea, fatigue, anorexia and dehydration occurring in at least 10% of pts. Median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 month for arms A and B, respectively. Enrollment to arm A was temporarily suspended prior to reaching interim analysis due to progression (29%), early deaths (29%), and refusal (42%). No objective responses and no confirmed stable disease ≥ 6 weeks were seen in either arm. Accrual was permanently terminated to both arms as no patient was progression-free at 16 weeks. Conclusion STI571 was inactive in spite of pt selection for c-kit+ SCLC. Our results strengthen the collective evidence that prediction of efficacy of novel therapeutic agents based on target expression, rather than pathway activation (for example through activating mutations), may not be a valid paradigm for drug development. No significant financial relationships to disclose.

Small cell lung cancer in the elderly: factors influencing treatment decision and effect on survival

The prognostic relevance of age is not well defined. The aim of the study was to review the characteristics of elderly patients (pts) with small cell lung cancer (SCLC) diagnosed and treated at a single institution over an 11-year period. Prognostic factors for survival were investigated.Between Nov/1981 and Jan/1993, out of 405 SCLC pts diagnosed, 152 were aged 65 years or older (median 70). One hundred and four pts aged 65–86 were treated with chemotherapy with or without surgery or radiotherapy. Distribution, univariate and multivariate analysis of prognostic factors were performed.Comorbidity, early death in treated pts, neutrophilia, hypoalbuminemia and poor performance status (ECOG, PS = 2-3) were more frequent in older pts (p < 0.05). Elderly pts underwent lesser extensive staging and received less than optimal treatment (p < 0.05). Factors that influenced the decision to treat with chemotherapy for elderly pts were: age, disease stage (VALG) and PS (0-1-3). Two-year survival of treated pts according to age was [8.2%/< 70 and 3.2%/≥ 70 (Wilcoxon, p > 0.05)] and [6.2%/65-69 and 3.2%/≥70 (Wilcoxon, p < 0.05)]. Univariate analysis in older population showed a significative statistical prognostic importance (p < 0.05) for: disease extent, hyperglycemia, hyponatremia, hypoalbuminemia, bilirubin, AST, ALT, LDH and paraneoplastic syndrome. Multiple regression analysis showed independent prognostic value for LDH, hyponatremia, hyperglycemia, disease extent and number of cycles of chemotherapy.Age and PS influenced the decision to treat with chemotherapy. In the older population, early deaths were more frequent than in younger pts. However only pts aged 70 years or older showed a worse outcome. The last suggests that specific therapeutic regimens are needed for SCLC in this population of pts. Various prognostic parameters should be considered in the management of elderly pts: PS, hypoalbuminemia and neutrophilia.

The clinical value of Cyfra 21-1 estimation for lung cancer patients.

Cytokeratin-19, one of the cytoskeletal proteins, is expressed both in bronchial epithelium and in lung cancer cells. The aim of our study was to establish the value of serum cytokeratin-19 soluble fragment (Cyfra 21-1) measurement in lung cancer patients. Cyfra 21-1 levels were estimated in 35 patients (pts) with benign lung diseases and in 116 lung cancer patients: 55 pts with squamous cell lung cancer, 38 pts with small cell lung cancer and 23 pts with adenocarcinoma. The cutoff level was set at 4 ng/ml with a specificity of 94% and a sensitivity of 40%. Elevated Cyfra 21-1 values were found in 44% of squamous cell lung cancer, 39% of adenocarcinoma and 34% of small cell lung cancer pts (the difference was not significant). In squamous cell lung cancer and in adenocarcinoma elevated Cyfra 21-1 values were observed more often in patients with advanced disease than in patients with limited disease. There was no significant correlation between the initial Cyfra 21-1 level and the response to chemotherapy. Cyfra 21-1 was not a prognostic indicator, although in operable squamous cell lung cancer the proportion of survivors in the second year of observation was higher among the patients with normal preoperative Cyfra 21-1 levels.

39 P - Chemotherapy induced leukopenia as a predictor of response in small cell lung cancer (SCLC)

The correlation between chemotherapy (CT) induced toxicity and therapeutic efficacy in cancer patients (pts) has been studied only occasionally. Our aim was to evaluate the possible relationship between CT induced leukopenia and response to treatment in 238 SCLC pts treated within two prospective multicenter studies. CT regimens included CEE (cyclophosphamide, etoposide, epirubicin; in 128 pts) or VEC (vincristine, epirubicin, cyclophosphamide; in 110 pts). both given every 3 weeks. The highest score of leukopenia within the first 2 CT cycles was recorded. The response was evaluated after a median of 4 cycles (range 2–5). The objective response rate (CR and PR) for the whole group was 68%. Response was seen in 92% of pts who developed leukopenia and in 43% of pts whose WBC remained normal (p 0.000, coef = 0.2), the CT regimen used (p = 0.002, CEE being more toxic and more effective) and the number of CT cycles. Response was not related to patient sex, age, performance status, pre-study weight loss, extent of disease and dose intensity. No significantly better survival was observed in pts who developed leukopenia during the first 2 cycles (p = 0.09). Additional analysis showed however, that both response rate (p = 0.009) was better in pts who developed leukopenia during the first 4 CT cycles. It seems that there is a close relationship between CT induced leukopenia and tumor response. Further studies concerning other tumors or other side effects are warranted.

234 Reduction of the risk of transfusion in patients with small cell lung cancer (SCLC) undergoing chemotherapy

This open-label, controlled, multicentre study examined the efficacy of subcutaneous (SC) Epoetin alfa (administered 3 times weekly) in preventing anaemia in 130 initially non-anaemic (Hb ≥ 10.5 g/dl) SCLC patients (pts) scheduled to receive 4–6 cycles of platinum-based combination chemotherapy. Patients were randomized to receive Epoetin alfa 300 IU/kg (group A, n = 44), 150 IU/kg (group B, n = 42) or no Epoetin alfa (group C). Treatment began 1 day after completion of the monthly chemotherapy cycle, and finished 3 days before initiation of the next cycle, for up to 6 cycles. Reductions in Epoetin alfa dose were made if Hb ≥ 15 gjdl. Logistic regression analysis of group C pts showed that low baseline Hb levels or a reduction in Hb level from higher baseline Hb levels, during the first cycle of chemotherapy, were important risk factors for transfusion. Group C required significantly more transfusions than Groups A and B (59%, 21%,45%, respectively; P ≥ 0.05). In addition, significantly more pts in group C experienced reduced Hb levels (Hb In conclusion, Epoetin alfa is effective and well tolerated in preventing anaemia and reducing the risk of transfusion in SCLC pts undergoing cyclic chemotherapy.

91 Delivered dose intensity with an induction chemotherapy (CT) by ifosfamide, etoposide and anthracyclin for patients (PTS) with small cell lung cancer (SCLC): A report by the european lung cancer working party

We conducted a randomized trial comparing a maintenance CT versus a simple follow-up in SCLC pts having achieved a complete response after 6 induction CT courses, given at theoretical 3 week intervals, with ifosfamide (IFO) (1.5 mg/m2 dl–3, iv), etoposide (VP) (80 mg/m2 dl–3, iv) and, with a random allocation, epirubicin (EPI) (60 mg/m2 d1) -IVE- versus adriamycin (ADR) (45 mg/m2 d1) -IVA- in a first set of pts or epirubicin (60 mg/m2 dl) -IVE60- versus epirubicin (90 mg/m2) -IVE90- in a second set of pts. The mean absolute delivered dose intensities (ADI) of the anthracyclin in mg/m2/week were as following: First set Second set IVE IVA IVE60 IVE90 At 3 courses n = 47 n = 47 n = 55 n = 54 18.1 13.1 16.4 23.1 At 6 courses n = 40 n = 37 n = 41 n = 38 17.6 13.0 16.1 23.3 Each theoretical schedule was feasible as by Mann-Whitney tests, the distributions of the relative intensities were not statistically different. Comparisons of response rates at 3 courses and of overall survival curves by treatment arm were not statistically different in the 2 series of pts and remained not significant when stratified by relative global dose intensity. However, in responders to the induction CT, using a Cox model, administration of a maintenance CT as well as an increased ADI of the anthracyclin drug -with the equivalence of 60 mg epirubicin to 45 mg adriamycin- (P = 0.03) had a positive impact on survival in both series of pts suggesting a potential benefit of a prolonged treatment when adjusting for the intensity of the first regimen.

Chronic oral etoposide in small-cell lung cancer: Clinical and pharmacokinetic results

To evaluate antitumour activity, toxicity, pharmacokinetics, and the pharmacodynamic relationship with neutropenia of chronic oral etoposide (E) in patients (pts) with small-cell lung cancer (SCLC) previously untreated with chemotherapy. Twenty-seven (14 extensive-, 13 limited-stage) pts receiving 100 mg daily of oral E for 21 days every 4 weeks. CBC with differential repeated every week. E plasma levels determined by HPLC method (sensitivity limit: 0.1 microgram/ml) with evaluation during the first cycle of weekly 24-hour drug concentrations. Among 25 evaluable pts, 60% (95% CI: 39%-79%) overall response, 144 and 217 days of median PFS and survival. Dose-limiting non-cumulative neutropenia of high interpatient variability. Linear reduction (30% per week) of absolute neutrophil counts (ANC) up to the 3rd week, recovering the following week. Risk factors for neutropenia (age, PS, serum creatinine and albumin) not identified. High inter-patient variability of 24-hour E plasma levels. A weak correlation between mean 24-hour E plasma levels and ANC nadir or relative decrease of ANC, but higher relative decrease of ANC in pts with 24-hour E plasma levels of > 0.32 microgram/ml. Chronic oral E is effective in SCLC pts previously untreated with chemotherapy. Careful hematological monitoring is essential to avoid severe myelosuppression. The degree of neutropenia might be related to the maintenance of a critical drug concentration level for a critical period of time.