A phase I study of mTOR inhibitor everolimus in association with cisplatin and radiotherapy for the treatment of locally advanced cervix cancer: PHOENIX I.

BACKGROUND: Cervix cancer (CC) represents the fourth most common cancer in women. Treatment involving cisplatin and radiotherapy has been the standard for locally advanced disease. Everolimus inhibits the aberrant activity of mTOR that is part of carcinogenesis in CC. Further everolimus inactivates the HPV E7 oncoprotein and inhibits its proliferation. Preclinical models have suggested that everolimus sensitizes tumoral cells and vasculature to cisplatin and radiotherapy. METHODS: In a 3 + 3 design, the trial aimed to treat three dose levels of at least three patients with daily doses of everolimus (2.5, 5 and 10 mg/day), cisplatin and radiotherapy delivered in a 9-week interval in CC patients, stage IIB, IIIA or IIIB. Patients received everolimus from day -7 up to the last day of brachytherapy. Primary objective was to evaluate safety, toxicity and the maximum-tolerated dose (MTD) of everolimus in association with cisplatin and radiotherapy. Pharmacokinetic (PK) parameters and response rates were analyzed as secondary objectives. RESULTS: Thirteen patients were enrolled, 6 at 2.5 mg, 3 at 5 mg and 4 at 10 mg. Four patients did not complete the planned schedule, 1 at 2.5 mg presented grade 4 acute renal failure interpreted as dose-limiting toxicity (DLT) and 3 at 10 mg: 1 with disease progression, and 2 with DLTs-1 grade 3 rash and 1 grade 4 neutropenia. PK results were characterized by dose-dependent increases in AUC and C max. CONCLUSIONS: The MTD of everolimus in combination with cisplatin and radiotherapy has been defined as 5 mg/day. The data regarding safety and response rates support further studies.

Measuring relief of dysphagia in locally advanced esophageal carcinoma patients submitted to high-dose-rate brachytherapy.

BACKGROUND AND PURPOSE: Esophageal neoplasm has a poor prognosis, and palliative care remains an important goal of treatment. The purpose of this study was to assess the ability of high-dose-rate brachytherapy (HDRB) to improve dysphagia in 115 patients treated at our institution. METHODS AND MATERIALS: Patients previously submitted to external beam radiotherapy that at least, 1 month after, presented with residual disease and persistent dysphagia, were given HDRB as palliative treatment. Patients with tumors extending to the level of cardia and those with cervical esophageal lesions were also eligible. HDRB consisted of three fractions of 500 cGy given weekly. Dysphagia was assessed using a food texture-based scale classified according to the type of food patients were able to swallow (absent, solid, pasty, or liquid). At the end of treatment, a single-category shift in dysphagia classification was scored as +1 (e.g., liquid to pasty) or -1 (e.g., solid to pasty), and a dual-category shift was scored as +2 (e.g., liquid to solid) or -2 (e.g., absent to pasty). RESULTS: Most patients (51.1%) had improvement of dysphagia, and 55.3% of this group experienced one-point improvement. Procedural complications included stricture (38.2%), bleeding (7%), and fistula (8.7%). In the present study, 13 patients with cervical esophageal lesions underwent HDRB without fistula formation. CONCLUSIONS: Esophageal HDRB effectively reduces dysphagia. Tumor location was not related to development of complications.