Sorafenib in platinum-treated patients with extensive stage small cell lung cancer: a Southwest Oncology Group (SWOG 0435) phase II trial.

INTRODUCTION: Sorafenib is a multikinase inhibitor affecting pathways involved in tumor progression and angiogenesis. We conducted a phase II trial of sorafenib in platinum-treated patients with extensive stage small cell lung cancer to determine the tumor response rate, toxicity, and overall survival. METHODS: Patients with histologically confirmed, measurable disease, Zubrod performance status 0 to 1, and no more than 1 prior platinum-based treatment were eligible. Patients were stratified by platinum-sensitivity status: sensitive (progression >90 days after platinum) or refractory (progression during or ≤90 days after platinum). Patients were treated with sorafenib 400 mg orally twice a day continuously on a 28-day cycle. RESULTS: Of 89 patients registered, 82 were evaluable for toxicity assessment, and 83 were evaluable for response. There were four partial responses seen among the 38 patients in the platinum-sensitive stratum, for an estimated response rate of 11% (95% confidence interval: 3-25%), and one partial response among the 45 patients in the platinum-refractory stratum, for an estimated response rate of 2% (95% confidence interval: 0-12%). The median overall survival estimates were 6.7 months (95% confidence interval: 6.1-9.1 months) for the platinum-sensitive stratum and 5.3 months (95% confidence interval: 3.3-7.5 months) in the platinum-refractory stratum. Nineteen patients discontinued treatment because of adverse events or side effects from therapy. CONCLUSIONS: Based on the lack of disease control seen in our trial, further investigation of single-agent sorafenib in the small cell lung cancer population is not recommended. Combination trials of sorafenib and chemotherapy are ongoing.

A phase I/II study of neoadjuvant chemotherapy followed by radiation with boost chemotherapy for advanced T-stage nasopharyngeal carcinoma.

PURPOSE: Local recurrence is the most common site of failure for locally advanced nasopharyngeal carcinoma (NPC) treated with neoadjuvant cisplatin/5-fluorouracil (PF) and definitive radiation at our center. Based on this, we studied the addition of chemotherapy during the boost phase of radiation after neoadjuvant PF for advanced T-stage (T3-T4) NPC. This strategy was based on theoretical radiosensitization with chemotherapy during accelerated repopulation of the tumor with relatively radioresistant clonogens. METHODS AND MATERIALS: Three cycles of neoadjuvant PF was followed by conventionally fractionated radiation with additional PF during the boost portion of the radiation course. An initial Phase I study was done to establish the maximum tolerated dose of concurrent PF. RESULTS: Forty-four patients were enrolled. Six patients in Phase I defined the MTD for concurrent PF as: cisplatin 10 mg/m2/day and PF 320 mg/m2/day, on Days 1-5 during Weeks 6 and 7 of radiation therapy based on dose-limiting toxicities of mucositis, neutropenia, and thrombocytopenia. Forty-one patients were treated with concurrent therapy per protocol: complete, partial, and minor responses were seen in 23, 16, and 2 patients, respectively. Progression-free and overall survival rates at 5 years were 55% (95% CI, 41-75%) and 66% (95% CI, 52-85%), respectively. Seven of 11 tumor-related deaths were due to local recurrence. Nine of 10 patients with local recurrence had T4-stage disease at presentation. Local control of T4 disease was achieved in 74% of patients overall, and in 25% (1/4) with World Health Organization (WHO) type 1, 76% (16/21) with WHO type 2, and 90% (9/10) with WHO type 3 histology. Common toxicities included mucositis, dermatitis, fatigue, vomiting, and weight loss. CONCLUSIONS: This regimen was feasible and associated with promising overall survival. Local recurrence remains the major reason for treatment failure in advanced T-stage NPC, especially WHO types 1 and 2. Other strategies to improve local control in these patients should be investigated.

Neoadjuvant chemotherapy for squamous cell carcinoma of the oral tongue in young adults: a case series.

BACKGROUND: Squamous cell carcinoma of the oral tongue (SCCOT) in the young population has emerged as a growing worldwide health problem. Standard therapies, consisting primarily of surgery with possible adjuvant radiotherapy, have resulted in only modest improvements in survival in recent decades, whereas the treatments for SCCOT continue to impair oral function. With the increased use and improved functional results of neoadjuvant chemotherapy in the treatment of squamous cell carcinoma of other upper aerodigestive tract sites, we have reviewed our experience with neoadjuvant chemotherapy in young patients with SCCOT. METHODS: A retrospective review was conducted of all patients younger than 45 years (N = 49) with previously untreated SCCOT evaluated at a comprehensive cancer center from July 1995 to August 2001. Charts were reviewed to obtain demographic data, comorbidities, nutritional status, tumor status, treatment and response information, and follow-up data. RESULTS: Fifteen patients were identified who received neoadjuvant chemotherapy with taxane-based regimens before undergoing glossectomy and neck dissection. Thirteen of these patients (87%) exhibited stage III or IV disease at presentation, and all exhibited at least a partial response at the primary site. Pathologically positive nodes were identified in only six patients (40%), although 13 (87%) had clinically or radiographically suspicious nodes at presentation. Adjuvant radiation therapy was administered to seven patients (47%). With a median follow-up of 39 months, no patient has had local or regional recurrence, although three patients (20%) have had distant metastases develop; one patient with an isolated distant metastasis was successfully salvaged with radiation. By comparison during the same period, 34 young adult patients with SCCOT were treated with surgery with or without postoperative radiotherapy but without the use of chemotherapy. Although these patients had lower T classifications (18% vs 67% T3/T4; p = .0007), incidence of nodal metastases (15% vs 87% N+; p < .0001), and overall disease stage (24% vs 87% stage III/IV; p < .0001) than the neoadjuvant chemotherapy group, the overall survival (82%), disease-specific survival (88%), and recurrence-free survival (82%) of the surgery-first group was similar to that of the neoadjuvant chemotherapy group (87%, 87%, and 80%, respectively). CONCLUSIONS: This retrospective investigation demonstrates that neoadjuvant chemotherapy with taxane-based regimens may play a role in the successful treatment of SCCOT in young adult patients. Ultimately, this treatment plan may lead to improved functional outcomes in young patients with SCCOT by allowing function-sparing surgery and avoiding postoperative radiotherapy, without sacrificing disease control and survival, but a prospective trial is needed. We have initiated a prospective clinical trial to further investigate the impact of neoadjuvant chemotherapy in patients younger than 50 with SCCOT.

The novel and effective nonplatinum, nontaxane combination of gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma: potential for decreased toxicity and combination with biological therapy.

BACKGROUND: Gemcitabine and vinorelbine are two of the most active third-generation agents for the treatment of advanced nonsmall cell lung carcinoma (NSCLC). The authors conducted a formal Phase II trial to evaluate the efficacy of this combination in both untreated and previously treated patients with Stage IIIB (with pleural effusion) or Stage IV NSCLC. METHODS: A total of 78 patients were treated on the current Phase II trial of front-line or second/third-line therapy with gemcitabine and vinorelbine in NSCLC. Eligible patients manifested either untreated disease (n = 42) or had received at least one but not more than two prior chemotherapy regimens (n = 36). The median age was 57.5 years (range, 33-79) with 57 men (73%) and 21 women (27%). The median performance status was one (range, one to two). The initial eight patients (four untreated and four previously treated) were treated at a previously established maximum tolerated dose of vinorelbine (30 mg/m(2)) and gemcitabine (1000 mg/m(2)) on Days 1, 8, and 15, with significant myelosuppression seen in five out of eight patients requiring dose omission in the first cycle. The next 70 patients received a reduced dose of vinorelbine (25 mg/m(2)) followed by gemcitabine (900 mg/m(2)) on Days 1, 8, and 15. RESULTS: Seventy eight patients were treated. Fifteen (36%) of the 42 evaluable patients who received front-line therapy had objective responses and 14 (33%) had stable disease. In the patients with prior treatment, 6 (17%) of 36 patients had partial response and 18 patients (50%) had stable disease. Median survival time for the previously untreated patient group was 10.1 months, with a one year survival of 43% and a two year survival rate of 32%. For the previously treated patients, the median survival time was 8.5 months, with a one year survival rate of 30%. Toxic effects were notable for significant myelosuppression, with > or =Grade 3 granulocytopenia seen in 55% of the patients on the untreated arm and 67% of the patients on the previously treated arm. Additionally, 9.5% and 13.9% (untreated and previously treated), respectively, of these patients experienced Grades 3 and 4 thrombocytopenia at some point in their treatment. A full dose delivery analysis showed that this myelosuppression resulted in Course 1, Day 15 skipped doses (even at the reduced dose level) in 42% of previously untreated patients and 47% of pretreated patients. Other side effects seen at Grades 3 and 4 in previously untreated and treated patients included anemia (9.5% and 2.8%), asthenia (4.8% and 5.5%), infection (14.3% and 5.6%), pain (9.5% and 19.4%), and pulmonary complications (4.8% and 13.8%). CONCLUSIONS: Gemcitabine/vinorelbine is an active, well-tolerated combination in both front-line and second/third-line therapy for Stage IIIB/IV NSCLC. The response rate, median survival rate, and one year survival rate compare favorably with platinum-based regimens. The toxicity profile of the gemcitabine/vinorelbine combination was quite favorable, with minimal Grade 3 and 4 toxic effects aside from granulocytopenia, which resulted in numerous Day 15 skipped doses but no significant febrile neutropenia or infection. The combination of gemcitabine and vinorelbine could be a useful regimen in standard clinical practice and has the potential for efficient combination with biologic/targeted therapy. Multiple randomized trials of this combination versus platinum combinations are now ongoing [corrected].