Sensitive-relapsed Small-cell Lung Cancer Research Articles

Phase II trial of belotecan in patients with sensitive relapsed small-cell lung cancer after irinotecan-containing chemotherapy

8118 Background: Belotecan (CKD 602) is a novel camptothecin analogue, topoisomerase-I inhibitor. This phase II trial was conducted to evaluate the activity of belotecan against irinotecan-sensitive relapsed small-cell lung cancer (SCLC). Methods: A sensitive relapsed SCLC patients, who were defined as relapsed at least 3 months after having achieved complete or partial response to 1st line irinotecan-containing chemotherapy, were eligible for this trial. Belotecan was administered as a 30-minute daily intravenous injection at a dose of 0.5mg/m2/day for 5 consecutive days every 3 weeks. From the second cycle, the daily dose of belotecan was adjusted to one of three dose levels, 0.4, 0.5, or 0.6 mg/m2/day, based on the toxicities after the each cycle. The primary endpoint was response rate. The group sequential design of Chang et al. was utilized and the estimated sample size was 50 patients (stage I - 20 patients; stage 2 - 15 patients; stage 3 - 15 patients). The study has a 80% power to detect a response rate of 15%, with an alpha error 5%. Results: Between March 2006 and May 20007, a total of 20 patients were enrolled (median age 64, 16M/4F, ECOG PS 0–1 95%). A total of 96 cycles of belotecan were delivered with a median of 6 cycles. The dose level of belotecan was 0.4 mg/m2/ day in 23 cycles, 0.5 in 56, and 0.6 in 17. The most frequent grade 3/4 toxicities were related to myelosuppression including neutropenia in 95% of patients and thrombocytopenia in 45%. No febrile neutropenia or bleeding was observed. Nonhematol- ogic toxicities were mild. There was no treatment- related death. Overall objective response rates were 25% (95% CI, 4.2 - 45.8; 0 CR, 5 PR, 10 SD, 5 PD). With a median follow-up duration of 8.0 months, median time to progression was 4.7 months (95% CI, 3.9 - 5.5) and median overall survival wasn’t reached. Conclusions: Belotecan shows promising activity in relapsed SCLC, with predictable and manageable toxicities. Therefore, this topoisomerase-I inhibitor is a treatment option for patients with sensitive relapsed SCLC, who have responded to irinotecan-containing chemotherapy. No significant financial relationships to disclose.

Phase II trial of high-dose weekly topotecan in patients with relapsed small-cell lung cancer (SCLC)

19073 Background: Topotecan is FDA approved for the treatment of sensitive relapse SCLC using a 5-day IV schedule. A 4 mg/m2 weekly IV schedule studied by our group was associated with low grade (G...

Prognostic factors for response and survival of second-line chemotherapy in patients with relapsed small cell lung cancer (SCLC)

18023 Background: Despite high response rates to initial chemotherapy, the majority of patients with SCLC experience tumor progression. Previous studies showed that both the response to initial chemotherapy and the response duration are important for predicting the efficacy of second-line chemotherapy. Therefore, relapsed SCLC is commonly classified into two groups: sensitive relapse (respond to initial chemotherapy and relapse more than 3 months after the completion of initial chemotherapy) and refractory relapse (not respond to initial chemotherapy or respond but relapse within 3 months). However, prognostic factors of the second-line chemotherapy have not been fully understood. Methods: From July 1992 to December 2003, four hundred and seventy-four patients with SCLC received chemotherapy as initial treatment, subsequently 229 patients received second-line chemotherapy (144 sensitive relapse and 85 refractory relapse) in our hospital. We analyzed the association of patients’ clinical factors with response and survival of second-line chemotherapy in sensitive relapsed patients and refractory relapsed patients, separately. For sensitive relapsed patients, analyzed clinical factors were as follows: age (<70/=70), gender (M/F), response to initial chemotherapy (CR/PR), PS at relapse (<2/=2) and the extent of disease at relapse (LD/ED). For refractory relapsed patients, analyzed clinical factors were as follows: age (<70/=70), gender (M/F), response to initial chemotherapy (responder/non-responder), PS at relapse (<2/=2) and the extent of disease at relapse (LD/ED). Results: Response to second-line chemotherapy was significantly correlated with PS in sensitive relapsed patients, however, no significant factor was detected in refractory relapsed patients. For survival, PS was the only significant prognostic factor in both sensitive and refractory relapsed patients. The median survival time was 328 days (PS<2) and 128 days (PS=2) in sensitive relapsed patients (p<0.0001), while 195 days (PS<2) and 113 days (PS=2) in refractory relapsed patients (p=0.0001), respectively. Conclusions: PS was the only significant prognostic factor for survival both in sensitive and refractory relapsed SCLC. No significant financial relationships to disclose.

Topotecan: Weekly intravenous (IV) schedule similar to standard 5-day IV schedule as second-line therapy for relapsed small cell lung cancer (SCLC)—A Minnie Pearl Cancer Research Network phase II trial

7083 Background: Topotecan IV weekly produces significantly less myelotoxicity than the standard 5-day IV schedule and appears as active as the 5-day schedule in patients (pts) with relapsed ovarian cancer. Topotecan 5-day IV schedule is the standard for second-line therapy for sensitive relapse SCLC. Methods: The primary endpoints of this phase II trial were to determine the response rate and toxicity of topotecan IV weekly as second-line therapy in patients with sensitive relapse (SR) and resistant relapse (RR) SCLC. Topotecan 4mg/m2 IV over 30 minutes for 12 consecutive weeks was planned. Dose modifications were made based on toxicity. Pts were evaluated for response after 4 weeks; at least 3 weekly treatments were required to be evaluable. Results: A total of 103 pts (59 SR; 44 RR) were enrolled: 56 men, 48 women; age range 42–86 (median 65); performance status 0=18, 1=69, 2=16, 3=1. 47 pts with SR and 34 pts with RR were evaluable for response by WHO criteria. For SR, 3 pts had partial response (6.4%, 95% CI 1.3%-17.5%), 17 pts had stable disease (7 had minor responses with tumor shrinkage of 39%, 27%, 21%, 20%, 20%, 7%, and 3%, respectively). Using RECIST criteria 5 pts had PR (13%, 95% CI 6%-25%). For RR, 1 pt had a CR (3%, 95% CI 0.1%-15.3%), 6 pts had stable disease (2 had minor responses with 36%, 5% tumor shrinkage). Grade 3/4 neutropenia/thrombocytopenia was seen in 17 and 22pts, grade 3 infection 6 pts; grade 3/4 fatigue 16 pts. There was 1 treatment-related death. Median and 1-year survival for all patients was 4.5 months (SR = 5.6 months; RR 3.2 months, p = 0.05) and 19% (SR = 22%; RR = 10%). There was no difference in survival for PR versus stable pts, and PR/stable had 1-year survival of 46% compared to PD of 9% (p < 0.0001). Conclusions: Topotecan IV weekly has similar activity to the standard 5-day IV schedule in SR SCLC, and considerably less myelotoxicity. These data support the weekly schedule for standard therapy of SR SCLC, and further study of weekly topotecan as a component of combination therapy for SCLC. [Table: see text]

Phase II study of weekly cisplatin, etoposide and irinotecan (PE/CPT) for refractory relapsed small cell lung cancer (SCLC)

7088 Background: There is no standard treatment for relapsed SCLC. Irinotecan and etoposide has been studied in several phase II trials as active agents for relapsed SCLC. We reported the efficacy and tolerability of irinotecan combined with weekly cisplatin and etoposide (PE) in patients (pts) with sensitive relapsed SCLC (Goto, et al. Br J Cancer 2005). Methods: We conducted a phase II study to evaluate the efficacy and toxicity of PE/CPT regimen in pts with refractory relapsed SCLC, who had relapsed within 8 weeks after completion of first-line therapy. Pts must have measurable or assessable disease, age of 75 years or younger, performance status of 0 to 2 (ECOG), and adequate organ function. PE/CPT regimen consisted of cisplatin 25 mg/m2 on day 1 at one-week intervals for 9 weeks (at least 6 weeks), etoposide 60 mg/m2 on days 1–3 on week 1, 3, 5, 7, 9 (at least on week 1, 3, 5), and irinotecan 90 mg/m2 on day 1 on weeks 2, 4, 6, 8 (at least on week 2, 4, 6). After day 1 on week 2, G-CSF was administered on days when cytotoxic drugs were not given. Results: From May 2000 to January 2005, 30 pts were enrolled in this study. Pt characteristics were median age 64 years (range 44–75); 23 male and 7 female; 3 LD and 27 ED. Prior chemotherapy included PE in 13 pts, cisplatin and irinotecan in 7, carboplatin and etoposide in 5, and others in 5. 23 pts (77%) completed 6 or more weeks of chemotherapy. 2 CR and 19 PR were observed and the overall response rate was 70% (95% CI 50.6–85.3%). Grade 3/4 neutropenia, anemia and thrombocytopenia were observed in 60%, 73% and 47%, respectively. Grade 3/4 diarrhea was observed in only 7%. Coclusions: PE/CPT regimen was active and well tolerated for refractory relapsed SCLC. No significant financial relationships to disclose.

Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer

Background: R115777 (tipifarnib, Zarnestra™) is a farnesyl transferase inhibitor that blocks the farnesylation of proteins involved in signal transduction pathways critical for cell proliferation and survival. This multicenter phase II study was conducted to determine the efficacy, tolerability and pharmacokinetics of R115777 in patients with relapsed small-cell lung cancer (SCLC).Patients and methods: Patients who had a partial or complete response to their initial chemotherapy regimen, followed by at least 3 months off treatment before relapse (sensitive relapse) were eligible. R115777 was administered in 3-week cycles at a dose of 400 mg orally twice daily for 14 consecutive days followed by 7 days off treatment.Results: Twenty-two patients were enrolled. The median progression-free survival was 1.4 months and median overall survival was 6.8 months. Non-hematological toxicities were predominantly grade 1–2 and included nausea (64%) and fatigue (60%). Grade 3–4 granulocytopenia and thrombocytopenia occurred in 27% and 23% of patients, respectively. Febrile neutropenia was not observed. Pharmacokinetic studies demonstrated peak plasma concentrations of R115777 2.6–4.5 h after oral dosing and no significant drug accumulation. The trial was terminated because no objective responses were observed in 20 patients evaluable for response.Conclusions: R115777 showed no significant antitumor activity as a single agent in sensitive-relapse SCLC.

Imatinib in small cell lung cancer

Purpose: To evaluate the clinical efficacy of Imatinib Mesylate in untreated or sensitive relapsed small cell lung carcinoma patients. Secondary endpoints included assessment of the safety and tolerance of Imatinib, and an analysis of KIT expression in tumor samples. Patients and Methods: Patients with previously untreated small cell lung cancer (SCLC) or with a sensitive relapse (one prior regimen with a sustained response for over 60 days) were eligible. Imatinib was delivered at 600 mg on a daily basis. Response was evaluated at 6 weeks using SWOG criteria. Results: As planned in the study design, a total of 19 patients were included in the trial (9 chemonaive patients with extensive disease and 10 sensitive relapse SCLC patients). No objective responses were observed with most previously untreated patients staying on study for less than 30 days. The median time to progression was 1 and 1.2 month in the untreated and sensitive relapse groups, respectively. Only 4 out of 19 tumor samples (21%) stained for KIT by means of immunohistochemistry. Conclusions: No evidence of antitumor activity was observed in this small phase II trial including 19 SCLC patients treated with Imatinib Mesylate. KIT positivity in tumor samples appeared to be far less common than anticipated (21 vs. 70%). Future trials should include a screening procedure to evaluate KIT expression in SCLC samples. A better evaluation of KIT contribution to SCLC tumor progression needs to be achieved.