RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases - results and lessons learnt.

BACKGROUND: Brain metastases occur in up to 75% of patients with advanced melanoma. Most are treated with whole-brain radiotherapy (WBRT), with limited effectiveness. Vandetanib, an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and rearranged during transfection tyrosine kinases, is a potent radiosensitiser in xenograft models. We compared WBRT with WBRT plus vandetanib in the treatment of patients with melanoma brain metastases. METHODS: In this double-blind, multi-centre, phase 2 trial patients with melanoma brain metastases were randomised to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo. The primary endpoint was progression-free survival in brain (PFS brain). The main study was preceded by a safety run-in phase to confirm tolerability of the combination. A post-hoc analysis and literature review considered barriers to recruiting patients with melanoma brain metastases to clinical trials. RESULTS: Twenty-four patients were recruited, six to the safety phase and 18 to the randomised phase. The study closed early due to poor recruitment. Median PFS brain was 3.3 months (90% confidence interval (CI): 1.6-5.6) in the vandetanib group and 2.5 months (90% CI: 0.2-4.8) in the placebo group (P=0.34). Median overall survival (OS) was 4.6 months (90% CI: 1.6-6.3) and 2.5 months (90% CI: 0.2-7.2), respectively (P=0.54). The most frequent adverse events were fatigue, alopecia, confusion and nausea. The most common barrier to study recruitment was availability of alternative treatments. CONCLUSIONS: The combination of WBRT plus vandetanib was well tolerated. Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we are unable to provide a definitive result due to poor accrual. A review of barriers to trial accrual identified several factors that affect study recruitment in this difficult disease area.

A Phase II study of high-dose-rate afterloading brachytherapy as monotherapy for the treatment of localized prostate cancer.

PURPOSE: A Phase II dose escalation study has been undertaken to evaluate high-dose-rate brachytherapy (HDRBT) monotherapy for prostate cancer. METHODS AND MATERIALS: A total of 110 patients have been entered, all with locally advanced cancer. Three dose levels have been used; 34 Gy in four fractions, 36 Gy in four fractions, and 31.5 Gy in three fractions. These equate to 226Gy(1.5), 252Gy(1.5), and 252Gy(1.5), respectively. Thirty patients have received 34 Gy, 25 received 36 Gy, and 55 patients received 31.5 Gy. Acute and late toxicity was analyzed using the International Prostate Symptom Score, and urologic and rectal events were scored using the Radiation Therapy Oncology Group/Common Terminology Criteria scoring systems. RESULTS: Seven patients required urethral catheterization at 2 weeks; 3 receiving 34 Gy, 1 receiving 36 Gy, and 3 receiving 31.5 Gy. Only 3 patients remained catheterized at 12 weeks. Radiation Therapy Oncology Group 1 and 2 gastrointestinal toxicity at 2 weeks was seen in 61%, 68%, and 77%, respectively. Grade 3 bladder toxicity was seen in 2 patients at 6 months, 1 each from the 36 Gy and 31.5 Gy arms. One patient from the 31.5-Gy cohort reported Grade 2 bowel toxicity at 6 months. Prostate-specific antigen (PSA), stratified for androgen deprivation therapy (ADT) and no-ADT patients ranged from 16.1-22.9 microg/L and 11.1-12.5 microg/L, respectively. This fell at 12 months to 0.2-0.6 microg/L and 0.5-1.4 microg/L, respectively. No PSA relapses have yet been seen with a median follow-up of 30 months (34 Gy), 18 months (36 Gy), and 11.8 months (31.5 Gy). CONCLUSIONS: Early results suggest an excellent biochemical response with no differences seen in acute and late toxicity between doses of 34 Gy/four fractions, 36 Gy/four fractions, or 31.5 Gy/three fractions.

High-dose-rate afterloading intraluminal brachytherapy for advanced inoperable rectal carcinoma.

PURPOSE: High-dose-rate (HDR) intraluminal brachytherapy for advanced or inoperable tumors of the rectum has been used both palliatively and to dose escalate after chemoradiation for curative treatment. METHODS: Between 1993 and 2007, 79 patients were treated with HDR afterloading brachytherapy for rectal cancer; 70 patients had adenocarcinoma of the rectum; and 9 patients had squamous cell carcinoma of the anal canal. Fifty-two patients had localized disease but were unfit for major surgery and received radiotherapy with radical intent. Twenty-seven patients with advanced or metastatic disease received palliative treatment. The median age was 82 years (range, 33-97). Radical treatment comprised either chemoradiation followed by intraluminal brachytherapy delivering 12 Gy at 1 cm in two fractions or radical monotherapy delivering up to 36 Gy at 1 cm in six fractions two to three times weekly. Palliative HDR brachytherapy schedules were predominantly 10 Gy at 1 cm single dose. RESULTS: Objective local tumor response was seen in 41 of 48 assessable patients (85%); of whom, 28 patients (58%) had a complete response and 13 (27%) had a partial response. The most common symptom was rectal bleeding, which was controlled with a complete response rate of 63%. The median duration of the symptom response was 3 months (range, 1-73), and the median survival of the palliative patients was 6 months (range, 1 week-37 months). The median survival for patients treated with radical intent was 18.5 months (range, 2-119). Six patients reported late toxicity with three cases of rectal ulcer, two strictures, and one fistula. CONCLUSIONS: Intraluminal HDR brachytherapy is effective as local treatment in both the radical and palliative setting, with high tumor and symptom response rates, and acceptable late toxicity.