Pierre Lavertu

BACKGROUND: The current study presents mature results from a Phase III randomized trial comparing radiation therapy and concurrent chemoradiotherapy in patients with resectable American Joint Committee on Cancer Stage III and IV disease. METHODS: One hundred patients were randomized to receive either radiation therapy alone (Arm A) (at a dose of between 66-72 grays [Gy] at 1.8-2 Gy per day) and the identical radiation therapy with concurrent chemotherapy (Arm B) (5-fluorouracil, 1000 mg/m(2)/day, and cisplatin, 20 mg/m(2)/day, both given as continuous intravenous infusions over 4 days beginning on Days 1 and 22 of the radiation therapy). Primary site resection was planned for patients with residual or recurrent local disease. Cervical lymph node dissection was performed for regional persistent disease or recurrence, or if N2-3 disease was present at the time of presentation. RESULTS: After completing all therapy including surgery, 82% of the patients in Arm A and 98% of the patients in Arm B had been rendered disease free (P = 0.02). At a median follow-up of 5 years (range, 3-8 years), the 5-year Kaplan-Meier projections for overall survival for Arm A versus Arm B were 48% versus 50% (P = 0.55). Kaplan-Meier projections for the recurrence free interval were 51% versus 62% (P = 0.04), projections for a distant metastasis free interval were 75% versus 84% (P = 0. 09), projections for overall survival with primary site preservation were 34% versus 42% (P = 0.004), and projections for local control without surgical resection were 45% versus 77% (P < 0.001). Salvage surgery proved to be successful in 63% and 73%, respectively, of the Arm A and Arm B patients with primary site failure. Unrelated death while free of disease occurred in 22% and 32%, respectively, of Arm A and Arm B patients (P = 0.26). CONCLUSIONS: The addition of concurrent chemotherapy to definitive radiation in patients with resectable Stage III and IV squamous cell carcinoma of the head and neck improves the likelihood of disease clearance, a recurrence free interval, and primary site preservation. However, overall survival does not appear to be improved, reflecting both effective surgical salvage after local recurrence and competing causes of death.

BACKGROUND: Multimodality treatments for patients with squamous cell head and neck carcinoma often produce significant mucositis and dysphagia, mandating enteral nutritional support. Patient preference has resulted in the increasing use of percutaneous endoscopic gastrostomy (PEG) tubes rather than nasogastric (NG) tubes. Anecdotal observations of prolonged PEG dependence and of a need for pharyngoesophageal dilatation in PEG patients prompted a retrospective review of the use of both types of feeding tubes. METHODS: Patients who were treated on clinical trials of radiotherapy or chemoradiotherapy for squamous cell head and neck carcinoma between 1989 and 1997 were reviewed retrospectively. Data were gathered regarding demographics, primary tumor site, T and N classifications, and the need for feeding tube placement. In patients requiring feeding tubes, the type and duration of the feeding tube, the need for tracheostomy, the need for pharyngoesophageal dilatation, and the degree of mucositis and dysphagia at baseline and at 1 month, 3 months, 6 months, and 12 months after beginning treatment were recorded. Comparisons were then made between the NG and the PEG groups. RESULTS: Ninety-one feeding tubes were placed in 158 patients over the 8-year interval. A hypopharyngeal primary site, female gender, a T4 primary tumor, and treatment with chemoradiotherapy were predictive of a need for feeding tube placement. NG tubes were placed in 29 patients, and PEG tubes were placed in 62 patients. PEG patients had more dysphagia at 3 months (59% vs. 30%, respectively; P = 0.015) and at 6 months (30% vs. 8%, respectively; P = 0.029) than NG patients. The median tube duration was 28 weeks for PEG patients compared with 8 weeks for NG patients, (P < 0.001). Twenty-three percent of PEG patients needed pharyngoesophageal dilatation compared with 4% of NG patients (P = 0.022). These end points could not be correlated with age, stage, primary tumor site, or tracheostomy placement. CONCLUSIONS: Although patients treated for head and neck carcinoma find that the PEG tube is a more acceptable route for enteral nutrition than the NG tube, in the authors' experience, a PEG tube was required for longer periods of time and was associated with more persistent dysphagia and an increased need for pharyngoesophageal dilatation. A randomized prospective trial is needed to test these observations.

BACKGROUND Multimodality treatments for patients with squamous cell head and neck carcinoma often produce significant mucositis and dysphagia, mandating enteral nutritional support. Patient preference has resulted in the increasing use of percutaneous endoscopic gastrostomy (PEG) tubes rather than nasogastric (NG) tubes. Anecdotal observations of prolonged PEG dependence and of a need for pharyngoesophageal dilatation in PEG patients prompted a retrospective review of the use of both types of feeding tubes. METHODS Patients who were treated on clinical trials of radiotherapy or chemoradiotherapy for squamous cell head and neck carcinoma between 1989 and 1997 were reviewed retrospectively. Data were gathered regarding demographics, primary tumor site, T and N classifications, and the need for feeding tube placement. In patients requiring feeding tubes, the type and duration of the feeding tube, the need for tracheostomy, the need for pharyngoesophageal dilatation, and the degree of mucositis and dysphagia at baseline and at 1 month, 3 months, 6 months, and 12 months after beginning treatment were recorded. Comparisons were then made between the NG and the PEG groups. RESULTS Ninety-one feeding tubes were placed in 158 patients over the 8-year interval. A hypopharyngeal primary site, female gender, a T4 primary tumor, and treatment with chemoradiotherapy were predictive of a need for feeding tube placement. NG tubes were placed in 29 patients, and PEG tubes were placed in 62 patients. PEG patients had more dysphagia at 3 months (59% vs. 30%, respectively; P = 0.015) and at 6 months (30% vs. 8%, respectively; P = 0.029) than NG patients. The median tube duration was 28 weeks for PEG patients compared with 8 weeks for NG patients, (P < 0.001). Twenty-three percent of PEG patients needed pharyngoesophageal dilatation compared with 4% of NG patients (P = 0.022). These end points could not be correlated with age, stage, primary tumor site, or tracheostomy placement. CONCLUSIONS Although patients treated for head and neck carcinoma find that the PEG tube is a more acceptable route for enteral nutrition than the NG tube, in the authors' experience, a PEG tube was required for longer periods of time and was associated with more persistent dysphagia and an increased need for pharyngoesophageal dilatation. A randomized prospective trial is needed to test these observations. Cancer 2001;91:1785–90. © 2001 American Cancer Society.

BACKGROUND: A phase III randomized comparison of radiotherapy alone versus combination chemotherapy and concurrent continuous-course radiotherapy was performed at the Cleveland Clinic Foundation. METHODS: Between March 1990 and June 1995, 100 patients with resectable stage III and IV squamous cell head and neck cancer were randomized to either Arm A: radiotherapy alone, 68-72 Gy at 1.8-2.0 Gy per day; or to Arm B: the identical radiotherapy with concurrent chemotherapy. Chemotherapy consisted of 5-fluorouracil, 1000 mg/m2/day, and cisplatin 20 mg/m2/ day, both given as continuous intravenous infusions over 4 days beginning on day 1 and day 22 of the radiotherapy. At 50-55 Gy, patients were clinically reassessed. If a response was evident, radiotherapy was completed. In non-responding patients, however, radiotherapy was terminated and surgery recommended. After completion of all treatment, salvage surgery was performed, if possible, for any residual primary or nodal disease or for any subsequent locoregional recurrence. RESULTS: Except for an overrepresentation of T1 patients on Arm A, the treatment arms were equivalent. Toxicity was greater in the patients on Arm B with a higher incidence of grade III and IV neutropenia, thrombocytopenia, cutaneous reaction, and mucositis. Feeding tubes were also required more often, and weight loss was greater on the chemotherapy arm. No toxic deaths occurred. With a median follow-up of 36 months, the Kaplan-Meier 3-year projections of relapse-free survival are 52% for Arm A and 67% for Arm B (p = .03), and the likelihood of developing hematogenous metastases is 21% for Arm A and 10% for Arm B (p = .04). Although overall survival is not significantly different, overall survival with successful primary site preservation was 35% for Arm A and 57% for Arm B (p = .02). This difference remains statistically significant in the subsets of patients with laryngeal and hypopharyngeal primaries but not in patients with oropharyngeal primaries. CONCLUSIONS: Continuous-course radiotherapy and concurrent combination chemotherapy is an intensive, toxic but tolerable treatment regimen, which, when compared with radio therapy alone, can produce an improvement in relapse-free survival, a decrease in distant metastases, and an improvement in overall survival with successful primary site preservation.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogene is mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor that acts on the RAF-1 serine/threonine kinase. In preclinical mouse models, sorafenib inhibits the growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with ATC who had failed up to two previous therapies. METHODS: The primary endpoint of the trial was the Response Evaluation Criteria In Solid Tumors (RECIST)-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. RESULTS: Two of the 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months, respectively. For the patients with stable disease, the median duration was 4 months (range 3-11 months). The overall median progression-free survival was 1.9 months with a median and a 1-year survival of 3.9 months and 20%, respectively. Toxicity was manageable and as previously described for sorafenib, including hypertension and skin rash. CONCLUSION: Sorafenib has activity in ATC, but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.