Lindsay E. James

Randomized Phase II Placebo-Controlled Trial of Maintenance Therapy Using the Oral Triple Angiokinase Inhibitor BIBF 1120 After Chemotherapy for Relapsed Ovarian Cancer

PURPOSE Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease. PATIENTS AND METHODS We conducted a randomized, double-blind, controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer, with evidence of response, but at high risk of further early recurrence. The patients were randomly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo, twice per day, continuously for 36 weeks. End points were progression-free survival (PFS), toxicity, and overall survival. RESULTS Thirty-six-week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P = .06). Four patients continued on BIBF 1120, including two patients for another year or more. The proportion of patients with any grade 3 or 4 adverse events was similar between the groups (34.9% for BIBF 1120 v 27.5% for placebo; P = .49; mostly grade 3). However, more patients on BIBF 1120 experienced diarrhea, nausea, or vomiting (mainly grade 1 or 2 and no grade 4). There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 (51.2%) compared with patients on placebo (7.5%; P < .001), but this was rarely of clinical significance, and patients continued with the trial treatment. A single-level dose reduction to 150 mg was made in 15 patients, all on active drug. CONCLUSION BIBF 1120 is well tolerated and associated with a potential improvement in PFS. The observed treatment effect is sufficient to justify further study within a large phase III trial.

Gemcitabine Plus Carboplatin Versus Mitomycin, Ifosfamide, and Cisplatin in Patients With Stage IIIB or IV Non-Small-Cell Lung Cancer: A Phase III Randomized Study of the London Lung Cancer Group

PURPOSE This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life. PATIENTS AND METHODS Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m(2) on days 1 and 8 (GCa) or mitomycin 6 mg/m(2), ifosfamide 3g/m(2), and cisplatin 50 mg/m(2) on day 1 (MIC). RESULTS Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (hazard ratio, 0.76; 95% CI, 0.61 to 0. 93; P = .008). Median survival was 10 months with GCa and 7.6 months with MIC (difference, 2.4 months; 95% CI, 1.0 to 4.0), and 1-year survival was 40% with GCa and 30% with MIC (difference, 10%; 95% CI, 3% to 18%). Overall response rates were similar (42% for GCa v 41% for MIC; P = .84). More thrombocytopenia occurred with GCa (P = .03), but this was not associated with increased hospital admission or fatality. GCa caused less nausea, vomiting, constipation, and alopecia and was associated with fewer admissions for administration and better quality of life. CONCLUSION In patients with advanced NSCLC, GCa chemotherapy was shown to be a better-tolerated treatment that conferred a survival advantage over MIC.

Early Compared With Late Radiotherapy in Combined Modality Treatment for Limited Disease Small-Cell Lung Cancer: A London Lung Cancer Group Multicenter Randomized Clinical Trial and Meta-Analysis

PURPOSE To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC). PATIENTS AND METHODS Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks. RESULTS TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17). CONCLUSION This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT.

Anti-angiogenic Therapy Using Thalidomide Combined With Chemotherapy in Small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND Cancer cells rely on angiogenesis for growth and dissemination, and small cell lung cancer (SCLC) is a highly angiogenic tumor. We evaluated thalidomide, an anti-angiogenic agent, when combined with chemotherapy and as maintenance treatment. METHODS A total of 724 patients (51% with limited and 49% with extensive disease) were randomly assigned to receive placebo or thalidomide capsules, 100-200 mg daily for up to 2 years. All patients received etoposide and carboplatin every 3 weeks for up to six cycles. Endpoints were overall survival, progression-free survival, tumor response rate, toxicity, and quality of life (QoL). Hazard ratios (HRs) for comparing thalidomide against placebo were estimated using Cox regression modeling. Statistical tests were two-sided. RESULTS The median overall survival was 10.5 months (placebo) and 10.1 months (thalidomide) (HR for death = 1.09, 95% confidence interval [CI] = 0.93 to 1.27; P = .28). Among patients with limited-stage disease, there was no evidence of a survival difference (HR for death = 0.91, 95% CI = 0.73 to 1.15), but among patients with extensive disease, survival was worse in the thalidomide group (HR for death = 1.36, 95% CI = 1.10 to 1.68). Progression-free survival rates were also similar in the two groups (HR = 1.07, 95% CI = 0.92 to 1.24). Thalidomide was associated with an increased risk of having a thrombotic event, mainly pulmonary embolus and deep vein thrombosis (19% thalidomide vs 10% placebo; HR = 2.13, 95% CI = 1.41 to 3.20; P < .001). There were no statistically significant differences between treatments in hematological and nonhematological toxic effects, except more patients in the thalidomide group had rash, constipation, or neuropathy. Overall, QoL scores were similar in the two treatment groups, but thalidomide was associated with less insomnia and diarrhea and more constipation and peripheral neuropathy. CONCLUSIONS In this large randomized trial, thalidomide in combination with chemotherapy did not improve survival of patients with SCLC but was associated with an increased risk of thrombotic events.

Randomized trial comparing weekly versus 3-week chemotherapy in small-cell lung cancer: a Cancer Research Campaign trial.

PURPOSE A randomized trial of chemotherapy, given on either a 1-week or a 3-week schedule, was performed in small-cell lung cancer (SCLC) patients. The aim was to determine if weekly scheduling produced survival superior to conventional treatment. PATIENTS AND METHODS Four hundred thirty-eight patients with SCLC with either limited disease (LD; 276 patients) or good-prognosis extensive disease (ED; 162 patients) were randomized. Weekly chemotherapy was 12 alternating cycles of ifosfamide/doxorubicin and cis-platin/etoposide (PE), while 3-week treatment was six alternating cycles of cyclophosphamide/doxorubicin/vincristine (CAV) and PE. Thoracic irradiation was administered 3 weeks after completion of chemotherapy to LD patients who attained a complete response (CR) or partial response (PR). Patients were well matched for clinical characteristics and prognostic factors. RESULTS Overall response was the same in both arms: 82.3% (39.4% CR) with weekly and 81.1% (36.9% CR) with 3-week treatment. The median survival (MS) durations were 10.8 and 10.6 months for weekly and 3-week chemotherapy, respectively. The 2-year survival rates were 11.8% and 11.7% in the weekly and 3-week arms, respectively. Received dose-intensity (DI) was 73.9% of projected for weekly treatment and 92.7% for 3-week treatment. Hematologic toxicity was the major dose-limiting toxicity for the weekly treatment. CONCLUSION This trial excludes at 90% power a benefit of greater than 10% for 2-year survival for weekly treatment. The received DI was reduced to a greater extent with weekly treatment, mainly due to hematologic toxicity.

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.

Comparison of gemcitabine and carboplatin versus cisplatin and etoposide for patients with poor-prognosis small cell lung cancer

Background: The combination of cisplatin and etoposide (PE) has been a standard treatment for patients with poor-prognosis small cell lung cancer (SCLC). This non-inferiority design trial aimed to determine whether the combination of gemcitabine and carboplatin (GC) results in similar survival but is less toxic with better quality of life. Methods: Previously untreated patients with SCLC with extensive disease or limited stage with poor prognostic factors were randomly assigned to six 3-weekly cycles of GC or PE. Results: 241 patients (121 GC, 120 PE) were recruited, of which 216 (90%) had died. There was no difference in overall survival (HR 1.01, 95% CI 0.77 to 1.32). Median survival with GC and PE was 8.0 and 8.1 months, respectively. Median progression-free survival was 5.9 months with GC and 6.3 months with PE. Grade 3 or 4 myelosuppressions were more frequent with GC (anaemia: 14% GC vs 2% PE; leucopenia: 32% GC vs 13% PE; thrombocytopenia: 22% GC vs 4% PE), but these were not associated with increased hospital admissions, infections or fatalities. Grade 2–3 alopecia (68% PE vs 17% GC) and nausea (43% PE vs 26% GC) were more frequent with PE. Patients given GC received more chemotherapy as outpatients (89% GC vs 66% PE of treatment cycles). In QoL questionnaires, more patients receiving PE reported being upset by hair loss (p = 0.004) and impaired cognitive functioning (p = 0.04). Conclusions: GC is as effective as PE in terms of overall survival and progression-free survival and has a toxicity profile more acceptable to patients. Trial registration number: ISRCTN 39679215

A randomised, placebo-controlled trial of weekly paclitaxel and saracatinib (AZD0530) in platinum-resistant ovarian, fallopian tube or primary peritoneal cancer

BACKGROUND We investigated whether the Src inhibitor saracatinib (AZD0530) improved efficacy of weekly paclitaxel in platinum-resistant ovarian cancer. PATIENTS AND METHODS Patients with platinum-resistant ovarian, fallopian tube or primary peritoneal cancer were randomised 2 : 1 to receive 8-week cycles of weekly paclitaxel (wPxl; 80 mg/m(2)/week ×6 with 2-week break) plus saracatinib (S; 175 mg o.d.) or placebo (P) continuously, starting 1 week before wPxl, until disease progression. Patients were stratified by taxane-free interval (<6 versus ≥6 months/no prior taxane). The primary end point was progression-free survival (PFS) rate at 6 months. Secondary end points included overall survival (OS) and response rate (RR). RESULTS A total of 107 patients, median age 63 years, were randomised. Forty-three (40%) had received >2 lines of prior chemotherapy. The 6-month PFS rate was 29% (wPxl + S) versus 34% (wPxl + P) (P = 0.582). Median PFS was 4.7 versus 5.3 months (hazard ratio 1.00, 95% confidence interval 0.65-1.54; P = 0.99). RR (complete + partial) was 29% (wPxl + S) versus 43% (wPxl + P), P value = 0.158. Grade 3/4 adverse events were 36% versus 31% (P = 0.624); the most frequent G3/4 toxicities were vomiting (5.8% saracatinib versus 8.6% placebo), abdominal pain (5.8% versus 0%) and diarrhoea (4.3% versus 5.7%). Febrile neutropenia was more common in the saracatinib arm (4.3%) than placebo (0%). Response, PFS and OS were all significantly (P < 0.05) better in patients with taxane interval ≥6 months/no prior taxane (n = 85) than those <6 months (n = 22), regardless of randomisation. CONCLUSIONS Saracatinib does not improve activity of weekly paclitaxel in platinum-resistant ovarian cancer. Taxane-free interval of ≥6 months/no prior taxane was associated with better outcome in both groups. TRIALS REGISTRATION Clinicaltrials.gov NCT01196741; ISRCTN 32163062.

Inhibition of Carboplatin-Induced DNA Interstrand Cross-link Repair by Gemcitabine in Patients Receiving these Drugs for Platinum-Resistant Ovarian Cancer

Background: The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in platinum-resistant ovarian cancer. Peripheral blood lymphocytes were sampled after drug administration to measure DNA interstrand cross-link formation and repair. Patients and Methods: Forty patients received carboplatin target area under concentration-time curve (AUC 4) followed by gemcitabine 1,000 mg/m2 with a second dose of gemcitabine on day 8. Peripheral blood lymphocytes were obtained in 12 patients before and at intervals during the first cycle of chemotherapy. DNA cross-link formation and repair (unhooking) were measured by the single-cell gel electrophoresis (comet) assay following ex vivo incubation. Results: The global response rate was 47% (Response Evaluation Criteria in Solid Tumors rate, 29%; CA125 rate, 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA cross-linking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA cross-links following administration of gemcitabine. Conclusion: An enhanced activity of carboplatin in platinum-resistant ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA cross-links. Future studies should explore coadministration of these drugs, as this may be a more effective schedule. Clin Cancer Res; 16(19); 4899–905. ©2010 AACR.

A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer research Campaign trial.

We report the results of a randomised trial in extensive small-cell lung cancer (SCLC) of a novel approach to palliative chemotherapy. A widely used 3 weekly regimen was compared with the same drugs given at half the dose but twice the frequency with the same intended overall dose intensity (DI). A total of 167 patients defined as having extensive SCLC with adverse prognostic features were randomised to receive either a 3 weekly regimen of cisplatin 60 mg m-2 i.v. on day 1 and etoposide 120 mg m-2 i.v. on day 1 and 100 mg b.d. orally on days 2 and 3 alternating with cyclophosphamide 600 mg m-2 i.v., doxorubicin 50 mg m-2 i.v. and vincristine 2 mg i.v. all on day 1 for a maximum of six courses (3 weekly); or treatment with the same drugs but with each course consisting of half the 3 weekly dose given every 10 or 11 days for a maximum of 12 courses. In the 10/11 day regimen overall response rate was 58.9% (95% CI, 47.9-69.2%) with 12.8% complete responses (CR). For the 3 weekly treatment the overall response rate was 44.9% (95% CI, 35.0-55.5%) with 10.1% CR. Median survival was similar in the two arms at 6.4 months (95% CI, 4.9-7.3 months) and 5.8 months (95% CI, 4.0-6.6 months) respectively. Survival at 1 year was 9.9% (95% CI, 5.0-18.5%) and 8.9% (95% CI, 4.6-16.6%). The 95% CI for the difference in survival at 1 year is -7.09% to +9.09%. Haematological toxicity and treatment delays owing to infection were more frequent with the 10/11 day regimen but other toxicities were equal in both arms. Other aspects of quality of life were measured in a small representative cohort of patients using a daily diary card (DDC). There was a trend of improved quality of life on the 10/11 day arm, but there was little difference between the two treatments. The trial shows that a low-dose/high-frequency regimen with the same DI as conventionally scheduled chemotherapy gives similar response rates and survival. This and other modifications of the schedule may offer new approaches to palliative treatment of advanced cancer. However, in this trial there was no significant benefit in toxicity or other aspects of quality of life.