A Phase I Study of Dasatinib with Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer.

OBJECTIVES: Src family kinases (SFKs) are expressed in non-small cell lung cancer (NSCLC) and may be involved in tumor growth and metastases. Inhibition of SFK may also enhance radiation. The purpose of this study was to evaluate if a maximum dose of 100 mg of dasatinib could be safely administered with concurrent chemoradiation and then continued as maintenance for patients with newly diagnosed stage III NSCLC. METHODS: Patients with stage III locally advanced NSCLC received paclitaxel, 50 mg/m(2)/week, with carboplatin area under the curve (AUC) = 2, weekly for 7 weeks, and concurrent radiotherapy, 64.8 Gy. Three dose levels of dasatinib 50, 70, and 100 mg/day were planned. RESULTS: 11 patients with locally advanced NSCLC were entered. At the 70 mg dose level 1 patient had grade 5 pneumonitis not responsive to therapy, and one patient had reversible grade 3 pneumonitis and grade 3 pericardial effusion. Due to these toxicities the Brown University Oncology Group Data Safety Monitoring Board terminated the study. CONCLUSION: Dasatinib could not be safely combined with concurrent chemoradiation for stage 3 lung cancer due to pneumonitis.

Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation for rectal cancer.

PURPOSE: To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen followed by concurrent bevacizumab, oxaliplatin, continuous infusion 5-fluorouracil (5-FU), and radiation for patients with rectal cancer. METHODS AND MATERIALS: Eligible patients received 1 month of induction bevacizumab and mFOLFOX6. Patients then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m(2)/week for 6 weeks), and continuous infusion 5-FU (200 mg/m(2)/day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m(2)/week. Resection was performed 4-8 weeks after the completion of chemoradiation. RESULTS: The trial was terminated early because of toxicity after 26 eligible patients were treated. Only 1 patient had significant toxicity (arrhythmia) during induction treatment and was removed from the study. During chemoradiation, Grade 3/4 toxicity was experienced by 19 of 25 patients (76%). The most common Grade 3/4 toxicities were diarrhea, neutropenia, and pain. Five of 25 patients (20%) had a complete pathologic response. Nine of 25 patients (36%) developed postoperative complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). CONCLUSIONS: Concurrent oxaliplatin, bevacizumab, continuous infusion 5-FU, and radiation causes significant gastrointestinal toxicity. The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens. The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections.

Weekly paclitaxel and carboplatin induction chemotherapy followed by concurrent chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: To perform a phase II trial evaluating dose dense induction chemotherapy for locally advanced head and neck cancer. PATIENTS AND METHODS: Thirty-five patients received 6 weekly doses of carboplatin (area under the curve=2) and paclitaxel (135 mg/m) followed by concurrent weekly paclitaxel (40 mg/m) and carboplatin (area under the curve=1) and daily radiation (66-72 Gy). RESULTS: There was 1 induction death from neutropenic sepsis and 1 sudden death during chemoradiotherapy. The overall response rate with induction was 79%. With >40 months of follow-up, the 36-month overall survival was 67% and squamous cell carcinoma of the head and neck survival 84%. Patients undergoing biopsy of the primary tumor site after the therapies had 17/18 (94%) pathologic complete response rate. The locoregional relapse rate was 40% (24 mo 28%) and distant relapse rate was 8% with only 1 distant site. CONCLUSIONS: Therapy was active but patients must be carefully selected and monitored. Compared with the historical controls, dose dense and intense induction chemotherapy decreased distant failure rate without compromising the locoregional control.

Selective organ preservation in operable locally advanced head and neck squamous cell carcinomas guided by primary site restaging biopsy: long-term results of two sequential brown university oncology group chemoradiotherapy studies.

OBJECTIVES: The long-term outcomes of selective organ preservation in operable, locally advanced head and neck cancers in two sequential chemoradiotherapy (CRT) protocols (HN-53, HN-67) are reported. METHODS: A total of 65 patients were treated with CRT consisting of carboplatin (AUC=1/week) and paclitaxel (60 or 40 mg/m2/week) with radiation (1.8 Gy/day). After 5 weeks of CRT, if primary site biopsies were pathologically negative, then completion CRT to 67-72 Gy was done with neck dissection in node-positive cases. Alternatively, a positive rebiopsy required primary site resection and neck dissection followed by radiotherapy boost as deemed necessary. RESULTS: Pathologic complete responses occurred in 71% patients who then completed CRT; the remaining 29% patients underwent primary site surgery. The 5-year and median overall survival were 47% and 57 months with no statistically significant differences between the two groups. Overall long-term failure rates were: 6% local, 6% regional, and 32% distant. CONCLUSIONS: This strategy of selective organ preservation was effective in 71% patients with CRT, whereas salvage surgery was required in the remainder. Long-term survival was equivalent in both treatment groups.

Changing patterns of failure of head and neck cancer.

BACKGROUND: With the increased use of neoadjuvant therapy for advanced stage squamous cell carcinoma of the head and neck, we have observed an apparent change in the pattern of failure from predominantly locoregional sites to distant metastases. We reviewed the patterns of failure in cancers of the oral cavity, oropharynx, and larynx at our institution during the last decade. OBJECTIVE: To determine whether there has been a significant change in the patterns of recurrence from the historical locoregional failure to distant sites, and whether this change is associated with the increased use of multimodality therapy. METHODS: We reviewed cancer registry data on patients with squamous cell carcinoma of the head and neck diagnosed between January 1, 1988, and December 31, 1999. Sites included the oral cavity and oropharynx (including the tongue, floor of mouth, retromolar trigone, gingiva, tonsil, and lip) and larynx. RESULTS: Among 432 patients with squamous cell carcinoma of the head and neck, 280 (65%) had oral cavity and oropharyngeal cancers, and 152 (35%) had laryngeal cancers. Overall, 19% developed locoregional recurrence, and 8% developed distant failure. Although locoregional failure for oral cavity and oropharyngeal squamous cell carcinoma decreased from 26% to 16% from 1988-1993 to 1994-1999, distant failure increased significantly from 3% to 8%. During these periods, multimodality therapy was used in 62% of oral cavity and oropharyngeal cancers, and this rate remained essentially unchanged. For laryngeal cancer, locoregional and distant failure remained stable at 18% and 9%, respectively. In these laryngeal cancers, the use of multimodality therapy decreased from 60% to 46%, but this difference was not statistically significant (P =.43). CONCLUSIONS: Although locoregional control in oral cavity and oropharyngeal cancers has improved significantly with the use of multimodality therapy, the incidence of distant failure has doubled. In laryngeal squamous cell carcinoma, the patterns of failure have not changed significantly.