Basal cell carcinoma (BCC) is a common malignancy with a good prognosis in the majority of cases. However, some BCC patients develop a more advanced disease that poses significant management challenges. Such cases include locally advanced, recurrent or metastatic BCC, or tumours that occur in anatomical sites where surgical treatment would result in significant deformity. Until recently, treatment options for these patients have been limited, but increased understanding of the molecular basis of BCC has enabled potential therapies, such as hedgehog signalling pathway inhibitors, to be developed. A clear definition of advanced BCC as a distinct disease entity and formal management guidelines have not previously been published, presumably because of the rarity, heterogeneity and lack of treatment options available for the disease. Here we provide a UK perspective from a multidisciplinary group of experts involved in the treatment of complex cases of BCC, addressing the key challenges associated with the perceived definition and management of the disease. With new treatments on the horizon, we further propose a definition for advanced BCC that may be used as a guide for healthcare professionals involved in disease diagnosis and management.

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Objectives:We assessed the impact of three-dimensional (3D) conformal planning vs conventional planning of preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) on small bowel and bladder sparing and in optimising coverage of tumour target volume. Methods: Conformal and conventional plans were created for 50 consecutive patients. The conformal plan delineated a gross tumour volume (GTV), a clinical target volume (CTV) 1 to cover potential subclinical disease spread, a CTV2 to outline the mesorectum and lymph node areas at risk, and a planning target volume (PTV) to cover set-up error and organ movement. The conventional plan was created using digitally reconstructed radiographs (DRRs). Patients were treated with a dose of 45 Gy in 25 fractions with concurrent chemotherapy over 5 weeks. Dose-volume histograms (DVHs) were created and compared for GTV, PTV, small bowel and bladder. The GTV was covered by the conventional plan in all patients. Results: Significant differences were shown for median PTV coverage with conformal planning compared with conventional planning: 99.2% vs 94.2% (range 95.9-100% vs 75.5-100%); p,0.05. The median volume of irradiated small bowel was significantly lower for CT plans at all DVH levels. Median bladder doses did not differ significantly. Conclusion: 3D conformal CT planning is superior to conventional planning in terms of coverage of the tumour volume. It significantly reduces the volume of small bowel irradiated with no decrease in the rate of R0 resection compared with published data, and at the present time should be considered as the standard of care for rectal cancer planning. Chemoradiotherapy (CRT) followed by total mesorectal excision is the standard for care when MRI staging demonstrates threatened surgical margins in locally advanced rectal cancer (LARC) [1,2]. Radiotherapy planning for rectal cancer uses conventional orthogonal simulation with standardised radiation fields based on patterns of loco-regional relapse in relation to pelvic bony anatomy [3]. Three-field conventional orthogonal planning is considered an acceptable technique for planning preoperative CRT and major trials evaluating long-course chemoradiation for rectal cancer have permitted the use of conventional planning within their protocols [4,5]. In recent years, the treatment of rectal cancer has improved through advances in the planning and delivery of radiotherapy as well as improved preoperative imaging with MRI, the development of surgical techniques using total mesorectal excision (TME) and more accurate histopathological reporting [6]. Radiotherapy planning must ensure all clinically and radiologically identifiable disease is encompassed while still minimising the dose to the surrounding organs at risk, particularly the small bowel and bladder. Potential areas of microscopic spread and the appropriate pelvic lymph nodes should also be treated.Preoperative MRI has improved the knowledge of pelvic anatomy and identification of pelvic lymph nodes at risk according to tumour l...

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.

e21010 Background: Despite significant gains from systemic immunotherapy, prompt recognition and management of immune related adverse events (irAEs) remains key to minimising acute and chronic morbidity, and can sometimes allow treatment to be re-initiated. Active management of irAEs is corticosteroid based, with additional immunosuppressants used for steroid-refractory toxicity. Although the majority of irAEs resolve promptly, prolonged steroid exposure is required to maintain irAE control. Patients are therefore frequently exposed to cumulative high doses of steroids that in turn can be associated with significant long-term morbidity. Methods: Melanoma patients treated at Mount Vernon Cancer Centre (UK) with ipilimumab, pembrolizumab or combination ipilimumab and nivolumab; who were managed for checkpoint inhibitor-induced colitis had their corticosteroid exposure calculated. Data was collected on patient characteristics, onset of colitis and the subsequent use of corticosteroids, immunosuppressant and anti-TNFα agents until complete resolution of symptoms. Results: Of 137 patients, 18 (13.1%) had grade 3-4 colitis. Median time to onset of colitic symptoms was 13 days (IQR 7-20) with 8 (44%) requiring intravenous corticosteroid. Median time from commencement of steroid treatment to grade 1 colitis was 11.5 days (IQR 6.75-25.25), with resolution of symptoms seen at a median of 43 days. Median total corticosteroid exposure was 3000mg oral prednisolone equivalent (range 540-7580mg) with median duration of corticosteroid exposure being 103.5 days (IQR 67-136). 8 patients experienced flare of colitis during corticosteroid dose reduction. In all cases of colitis flare, the anti-TNFα agent infliximab resulted in improvement to grade 1 toxicity within 48 hours. Conclusions: Patients requiring treatment with corticosteroids for checkpoint inhibitor induced colitis are exposed to high doses of corticosteroids for prolonged periods of time, with the potential for significant steroid-associated sequelae. Alternative steroid-sparing regimens to manage checkpoint inhibitor induced autoimmune toxicities are required.

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