Intermittent erlotinib in combination with pemetrexed: phase I schedules designed to achieve pharmacodynamic separation.

INTRODUCTION: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). Pharmacodynamic separation by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors with chemotherapy may increase efficacy by overcoming hypothesized antagonism. METHODS: Two dose-escalating phase I trials (arm A and arm B) were conducted simultaneously. Pemetrexed was given every 21 days (500 mg/m intravenously). In arm A, erlotinib was given weekly on days 2, 9, and 16 (800-1400 mg). In arm B, erlotinib was given on days 2 to 16 (150-250 mg). Patients continued therapy until disease progression or unacceptable toxicity. RESULTS: Forty-two patients with advanced solid tumors, including 16 NSCLC, were treated. Patient characteristics included median age of 63 (range, 29-77), 19 males, and Karnofsky performance status >or=90/<90 = 27/15. The median number of cycles was 2. Treatment was well tolerated. Planned dose escalation was completed without reaching a maximum tolerated dose. Dose-limiting toxicities included grade 3 infection/fever (arm A: 500/1200) and grade 3 infection/neutropenia (arm B: 500/150). Rash frequency was 55% in arm A and 90% in arm B. There were six partial responses (four lung, one head and neck, one breast) and 16 stable diseases. Four patients with NSCLC remained on therapy for 9, 16, 16, and 22 cycles. CONCLUSIONS: We report the first clinical trial to test intermittent erlotinib plus pemetrexed. Pemetrexed 500 mg/m and weekly erlotinib 1400 mg (arm A) or pemetrexed 500 mg/m and erlotinib 250 mg on days 2 to 16 (arm B) are feasible and well tolerated. Arm B efficacy is being examined in a randomized phase II trial for second-line NSCLC.

Long-term results of maximally aggressive trimodality therapy in a high-risk subset of early-stage cervical cancer patients.

OBJECTIVE: To evaluate the long-term survival and treatment-related morbidity associated with treating patients who have early-stage cervical carcinoma metastatic to the paraaortic lymph nodes with radical hysterectomy, pelvic and paraaortic lymphadenectomy, and adjuvant, extended field chemoradiation with cisplatin and 5-fluorouracil (5-FU). STUDY DESIGN: From 1988 to 1997, 14 consecutive patients referred to Radiological Associates of Sacramento following radical hysterectomy and pelvic and paraaortic lymphadenectomy with findings of clinical stage IB or IIA cervical cancer and histologically confirmed lymph node metastasis to the common iliac or paraaortic distributions were treated with adjuvant, extended field chemoradiation utilizing prolonged infusion 5-FU and bolus cisplatin. Retrospective chart review was performed, and survival and morbidity information were analyzed. Recurrence was assessed among patients based on age, race, total number of nodes involved, gross vs. microscopic nodal involvement, squamous vs. nonsquamous tumor histology, time to initiation of adjuvant treatment and time required to complete that treatment. Calculated 5-year survival, mean survival, morbidity type and incidence are reported for the group as a whole. RESULTS: Calculated 5-year survival of patients in this series was 38% by life table analysis. Median survival was 4.4 years; 50% of patients had a recurrence. None of the examined parameters were significant predictors of recurrence. There was 1 treatment-related death and a second case of severe treatment-related morbidity (radiation enteritis requiring colostomy and bilateral ureteral stenosis requiring bilateral nephrostomies). There were 6 cases of minor treatment-related toxicity occurring in 5 of 14 (36%) treated patients. CONCLUSION: In general, survival in the current series of patients was akin to that in clinically similar patients treated with chemoradiation alone. Morbidity among our patients was significant. In the presence of positive paraaortic lymph nodes there were no independent predictors of recurrence among the pathologic or treatment parameters examined.

Paclitaxel and carboplatin with amifostine in advanced, recurrent, or refractory endometrial adenocarcinoma: a phase II study of the Southwest Oncology Group.

OBJECTIVES: To evaluate the response rate and progression free and overall survival of patients with advanced endometrial cancer treated with paclitaxel, carboplatin and amifostine. To evaluate the toxicity of amifostine when used in combination with carboplatin and paclitaxel. METHODS: Forty-seven eligible patients (median age: 66; range 45-82) with bidimensionally measurable advanced, recurrent, or refractory endometrial cancer were treated with carboplatin (AUC = 6), paclitaxel (175 mg/M2) and amifostine (740 mg/M2) every 4 weeks for 6 cycles or until disease progression or unacceptable toxicity. RESULTS: There were 4 CRs (8%) (2 confirmed, 2 unconfirmed) and 15 PRs (32%) (9 confirmed, 6 unconfirmed) for a total response rate of 40% (95% confidence interval [CI], 26% to 56%). The median progression-free survival (PFS) was 7 months (95% CI, 6-9 months) and a 6-month PFS rate of 64% (95% CI, 50% to 78%). The median overall survival was 14 months (95% CI, 12 to 17 months). Toxicity was tolerable. While 79% of patients developed Grade 3/4 neutropenia (30% Grade 3, 49% Grade 4), there were no episodes of Grade 4 febrile neutropenia and one episode of infection with grades 3-4 neutropenia. CONCLUSION: The combination of paclitaxel and carboplatin with amifostine was well reasonably tolerated in this cohort. The regimen demonstrated significant activity in endometrial cancer, comparable to other multi-agent chemotherapy programs in terms of response rate and survival, and with a favorable toxicity profile.

Randomized Phase II trial of two high-dose chemotherapy regimens with stem cell transplantation for the treatment of advanced ovarian cancer in first remission or chemosensitive relapse: a Southwest Oncology Group study.

OBJECTIVES: To evaluate response rates, progression-free survival (PFS), overall survival (OS), and toxicity of two high-dose chemotherapy regimens with stem cell rescue used to treat patients with recurrent or persistent stage III/IV ovarian cancer, with the goal of taking one forward into a Phase III comparison with conventional therapy. METHODS: Patients under 65 with clinically or pathologically persistent disease after initial chemotherapy or those relapsing >6 months after a complete remission (CR) were randomized to CMC carboplatin (1500 mg/m(2)), mitoxantrone (75 mg/m(2)), and cyclophosphamide (120 mg/kg)], or CTC: [cisplatin (165 mg/m(2)), thiotepa (600 mg/m(2)), and cyclophosphamide (5625 mg/m(2))] with stem cell rescue. RESULTS: Of 67 randomized, the 32 and 26 eligible in the CMC and CTC arms were matched including age (median 49), maximum tumor diameter, and disease status at transplant. Low-risk disease (maximum diameter disease

Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin.

BACKGROUND: Because studies have suggested that anemia has an adverse effect on outcome for patients with cervical carcinoma who are treated with radiation, recombinant human erythropoietin (rHuEpo) has been used increasingly to maintain hemoglobin levels in these patients. Erythropoietin may increase the risk of thrombosis. The authors performed a retrospective analysis to determine whether there was an increased rate of symptomatic venous thrombosis associated with the use of rHuEpo in patients with carcinoma of the uterine cervix and vagina. METHODS: A retrospective, case-control study was performed on consecutive patients with localized carcinoma of the uterine cervix or vagina who were treated with chemotherapy and radiation (chemoradiotherapy). The primary outcome was symptomatic venous thrombosis. RESULTS: One hundred forty-seven patients were reviewed. When they were divided into women who received rHuEpo (n = 75 patients) and women who did not receive rHuEpo (n = 72 patients), there were no significant differences in age, height, weight, disease stage, or body mass index. Fewer patients in the rHuEpo group required transfusions. In the rHuEpo group, 17 of 75 patients had either an upper extremity thrombosis (n = 12 patients) or a lower extremity thrombosis (n = 7 patients): 2 patients had both, and 2 patients had more than 1 event. Two of 72 patients who did not receive rHuEpo had symptomatic thrombosis. Patients who received rHuEpo had an odds ratio (OR) of developing thrombosis of 10.3 (95% confidence interval [95% CI], 2.3-46.2). Multiple logistic regression revealed that only the use of rHuEpo was associated with an increased risk of thrombosis (OR, 15.3; 95% CI, 3.1-76.7). CONCLUSIONS: Patients with cervical carcinoma who received chemoradiotherapy and rHuEpo had an increased risk of symptomatic venous thrombosis.