Sensitive Small Cell Lung Cancer Research Articles

Phase II trial of becatecarin (rebeccamycin analogue) in relapsed sensitive small cell lung cancer (SCLC)

19060 Background: Relapsed SCLC carries a poor prognosis. Toposiomerase I and II inhibitors are considered amongst the most active agents against SCLC. Becatecarin (rebeccamaycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase II trial of RA in relapsed sensitive SCLC with the primary endpoint of determining the response rate, survival and toxicities related to this agent. Methods: A Simon 2-stage design was employed were initially 20 patients would be treated; if > 1 response was observed a total of 35 would be enrolled. Patients received RA at a dose of 140 mg/m2/d i.v. over 1 hour on daily × 5 schedule repeated every 21 days for a maximum of 6 cycles. Response was evaluated every 2 cycles. Eligibility included relapsed SCLC (i.e. recurrence > 60 days from completion of first line chemotherapy), ECOG PS 0,1,2 and adequate organ function. Results: The first stage of enrollment has been completed with 20 evaluable patients (M/F:10/10). A total of 49 cycles have been administered to date (median 2.4 range 1–6). Two partial responses have been observed. Four patients had stable disease. No treatment-related deaths have been reported. Grade 4 neutropenia and thrombocytopenia occurred in 10% and 4% of cycles respectively. Two cases of febrile neutropenia occurred. Other grade 3 toxicities coded as possibly or definitely related to treatment include 1 instance of grade 3 nausea and vomiting and one case of ataxia. Conclusions: Early evidence suggests that RA has activity in relapsed SCLC and toxicities are manageable. (Supported by Grants U01 CA62502 and K23 CA109348–01) No significant financial relationships to disclose.

A randomized phase 2 trial of amrubicin compared to topotecan as second-line treatments in extensive disease small cell lung cancer (SCLC) sensitive to platinum-based first-line chemotherapy

18064 Background: SCLC accounts for about 13% of lung cancers and presents as extensive disease (ED-SCLC) in 60%-70% of patients (pts). Treatment options have been limited for ED-SCLC and survival enhanced by a median of only 2–3 months over the past 20 years. Our trial assessed response rates with amrubicin, a fully synthetic anthracycline and inhibitor of DNA topoisomerase II, versus standard therapy topotecan, for second-line treatment of sensitive SCLC. Methods: This phase 2, open-label, multicenter trial compares second-line therapy with amrubicin versus topotecan in ED-SCLC pts (=18 years, ECOG performance status =2), sensitive to first-line platinum-based therapy but with recurrence or progression =90 days later. Pts are randomized to amrubicin (40 mg/m2 via 5-minute bolus infusion daily x 3 days) or topotecan (1.5 mg/m2 via 30-minute infusion daily x 5 days), both starting on Day 1 of a 21 day cycle. Treatment is continued until disease progression, unacceptable toxicity, or withdrawal. Response is assessed using RECIST criteria. In all, 75 evaluable pts (50 randomized to amrubicin and 25 to topotecan; 2:1 per the standard topotecan therapy reference group) are planned to be enrolled. Results: To date, 22 pts are enrolled with 15 evaluable for response: 10 on amrubicin; 5 on topotecan. After 1–6 cycles, 5/10 amrubicin pts have responded (1 CR, 4 PRs). One topotecan patient responded (PR) but had progressive disease at the next visit. Seventeen pts are evaluable for safety. Hematological adverse events (AEs, = Grade 3) were the most commonly reported and were similarly observed across treatments (Table). Tachycardia (< Grade 3) was recorded for 1 amrubicin and 2 topotecan pts. No other cardiac AEs were observed. Conclusions: Amrubicin compares favorably with standard therapy topotecan as second-line treatment in sensitive ED-SCLC patients. No anthracycline- induced cardiomyopathy has been observed to date. [Table: see text] No significant financial relationships to disclose.

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.

Single agent Gemcitabine in Refractory or Relapsed Small-Cell Lung Cancer. Phase II Study

Purpose: Gemcitabine has shown a broad range of activity in solid tumors, including previously untreated small-cell lung cancer (SCLC). The objective of this phase II trial was to investigate the activity of gemcitabine in patients with relapsed SCLC.Patients and Methods: SCLC patients with measurable disease who had experienced treatment failure with one prior chemotherapy regimen were considered eligible. Patients were required to have performance status of 0 to 2 and adequate organ function. Treatment consisted of gemcitabine 1,000 mg/m2 on days 1, 8 and 15 of a 28-day cycle. Patients were stratified according to their previous response to first-line chemotherapy (primary refractory v primary sensitive disease). Results: Twenty eight patients were enrolled onto this study (12 refractory and 16 sensitive patients). Twenty eight were assessable for response, survival and toxicity. Median patient age was 60 years, and median ECOG performance status was 1. Principal grade 3/4 hematologic toxicities included neutropenia (28.6%) and thrombocytopenia (25%). The main grade 3/4 non-hematologic toxicities were pulmonary (7.1%) and neurologic toxicity (14.3%). Objective responses occurred in 14.3% of patients overall, including one patient with refractory SCLC (8.3%) and three patients with sensitive SCLC (18.8%). Median survival for the overall group was 7.1 months. Survival was not significantly different for patients with refractory versus sensitive disease.Conclusion: Gemcitabine has modest activity in previously treated SCLC patients. The favorable toxicity profile warrants further investigation, either in combination chemotherapy regimens or with targeted biologic compounds

Second-line chemotherapy with weekly paclitaxel and gemcitabine in patients with small-cell lung cancer pretreated with platinum and etoposide: a single institution phase II trial

The safety and efficacy of a combined regimen of weekly paclitaxel and gemcitabine was tested in patients with refractory and sensitive small-cell lung cancer (SCLC). Treatment consisted of paclitaxel 80 mg/m(2) on days 1, 8, 15 and gemcitabine 1,000 mg/m(2) on days 1 and 8 every 3 weeks. Of the 31 patients enrolled, 10 had refractory and 21 had sensitive disease. Objective responses occurred in 8 patients (26%), including 2 out of 10 patients with refractory- and 6 out of 21 patients with sensitive SCLC. Median time to progression and median survival were 9.4 and 32 weeks, respectively. The schedule was very well tolerated, with grade 3-4 thrombocytopenia in 26% of the patients, grade 3 neutropenia in 26%, grade 3-4 asthenia in 13% and grade 1-2 sensory neuropathy in 32%. To conclude, this weekly schedule of paclitaxel and gemcitabine was found to have moderate activity in platinum-etoposide pretreated SCLC patients and a favorable toxicity profile.

RFS2000 (9-nitrocamptothecin) in advanced small cell lung cancer, a phase II study of the EORTC New Drug Development Group

Camptothecins have shown efficacy in terms of response rate in patients with small cell lung cancer (SCLC). RFS2000 is a new camptothecin derivative, which has shown objective responses in various tumour types. The aim of this phase II study was to determine the objective response rate of RFS2000 in patients with sensitive and refractory SCLC. RFS2000 was given orally at 1.5 mg/m 2 per day for five consecutive days (five days on – two days off) on a continuous basis. Patients were evaluated weekly for toxicity and every six weeks for response. Thirty seven patients were included, 36 patients (14 with sensitive and 22 with refractory SCLC) were evaluable for toxicity, and 35 patients were evaluable for response. No objective responses were observed. Toxicity was acceptable, with myelosuppression, nausea/vomiting, and diarrhoea as the main toxicities. RFS2000 therefore has an acceptable toxicity profile but is not active as a single agent in SCLC.

ZD0473 treatment in lung cancer: an overview of the clinical trial results

Three open-label, non-comparative, multicentre Phase II trials have examined the efficacy and tolerability of ZD0473 as first- and second-line therapy in non-small-cell lung cancer (NSCLC) patients and second-line therapy in small-cell lung cancer (SCLC) patients. Patients with second-line NSCLC or SCLC were evaluated as either platinum-sensitive or -resistant, based upon their time to relapse/progression after platinum-based therapy. First-line NSCLC patients ( n = 18) received a total of 60 treatment cycles (median number per patient 2.5) whilst second-line NSCLC ( n = 50) and SCLC ( n = 48) patients both received a total of 127 treatment cycles (median number per patient 2.0). Grade 3 4 anaemia, neutropenia and thrombocytopenia was observed in: 38.8%, 22.2> and 27.7% of first-line NSCLC patients; 12.0%, 24.0% and 50% of second-line NSCLC patients; and 10.4%, 25.0% and 47.9% of second-line SCLC patients, respectively. The most common grade 3 4 non-haematological toxicities in all three trials were lethargy and dyspnoea. No clinically significant oto-, nephro- or neurotoxicity was observed. The first-line treatment of NSCLC produced an overall response rate (OR) of 6.3%. No OR was seen after second-line treatment of NSCLC, while ORs of 15.4% and 8.3% were seen in the platinum-resistant and -sensitive second-line SCLC patients, respectively.

1041 - Pooled analysis of topotecan (T) in the second-line treatment of patients (pts) with sensitive small cell lung cancer (SCLC)

1041 - Pooled analysis of topotecan (T) in the second-line treatment of patients (pts) with sensitive small cell lung cancer (SCLC)

Mechanisms of resistance of human small cell lung cancer lines selected in VP-16 and cisplatin

The combination of VP-16 and cisplatin is one of the most active regimens available for the treatment of small cell lung cancer (SCLC), however, most tumors eventually become resistant to these drugs. To investigate the problem of resistance to VP-16 and cisplatin in patients with SCLC, we established two resistant sublines from the drug sensitive human SCLC line, NCI-H209, by in vitro selection in VP-16 and cisplatin. The VP-16-selected cell line, H209/VP, was more than 100-fold resistant to VP-16, and displayed cross-resistance to VM-26 and other topoisomerase II interactive drugs, but not to vinca alkaloids. There was no difference in accumulation of VP-16 in H209/VP compared with its parent cell line. The level of topoisomerase II-alpha was reduced to 8% of that in the parent cell line, and there was an altered form of this enzyme with a molecular weight of 160 kilodaltons (kDa), in addition to the normal 170 kDa protein. The cisplatin-selected cell line, H209/CP, was 11.5-fold resistant to cisplatin, with only a low level of cross-resistance to other platinum compounds including carboplatin, tetraplatin, iproplatin, and lobaplatin. This line was highly cross-resistant to vinca alkaloids, but not to anthracyclines or epipodophyllotoxins. The H209/CP cell line was not resistant to cadium chloride, suggesting that alterations in metallothionein are unlikely to be a cause of resistance. Although glutathione (GSH) levels were increased nearly 2-fold in H209/CP, there was no difference in levels of the GSH-related enzymes glutathione-S-transferase, glutathione peroxidase, and glutathione reductase, compared with the parent line. The H209/CP line had a 1.4-fold elevation of topoisomerase II-alpha. The accumulation of cisplatin was reduced in this cell line, and there were fewer DNA-interstrand cross links formed in the presence of cisplatin in H209/CP, compared with the parent line. Neither H209/VP nor H209/CP expressed MDR1, the gene for P-glycoprotein. The MRP gene was expressed at a slightly higher level in the H209/VP cell line, but there was no significant increase in expression of this gene in the H209/CP cell line. The resistance of the H209/VP cell line is associated with an alteration of topoisomerase II-alpha, whereas the resistance in the H209/CP line is associated with reduced drug accumulation.

84 Phase II study of topotecan in refractory and sensitive small cell lung cancer (SCLC)

Topotecan (T) is a semisynthetic-camptothecin analog with specific topoisomerase I inhibitory effect and preclinical activity in a broad range of tumors including SCLC. A multicentre Phase II study to assess activity and toxicity in pretreated SCLC patients (pts) has recently been closed. Two groups of pts were enrolled: "sensitive" (S) pts who responded to 1st line chemotherapy (CT) but progressed <3 months afterwards and "refractory" (R) pts who never responded to 1st line CT or progressed <3 months after 1st line CT. T was administered iv at a dose of I. 5 mg/m² d×5 q3 weeks until progression or excessive toxicity. A total of 94 eligible pts were entered and 353 courses (crs) and 87 pts (48 R, 39 S) have been evaluated. Pts characteristics are: median age 59, median PS 1, median duration of prior CT 4 months and median No. of prior drugs 3. In 39 S pts 5 CR and 13 PR were observed (46%), in 48 R pts 1 CR and 3 PR (8%). Toxicity (NCI grading) was mainly hematological. Leucopenia, although short lived was common with gr. III and IV neutropenia occurring in 78% of crs. Nine pts developed infections, 2 died while neutropenic. Gr. III and IV thrombocytopenia was observed in 29% of crs and 54% of pts. Anemia gr. III and IV occurred in 29% of pts. Non-hematological toxicity was mild. Asthenia was observed in 35% of crs with only 3 gr. IV episodes. Diarrhea was reported in 12 crs (1 gr. III), vomiting gr. III in only I crs. Toxicity required dose reduction in 10% of courses, treatment delay in 18% of crs. Preliminary results indicate that the concept of testing new drugs in S and R pts is feasible, that T has significant activity, especially in S, but even in R pts, and that toxicity is manageable. The study is closed for patient entry and final results will be available in October 1995.