Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial.

BACKGROUND: Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. METHODS: We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. FINDINGS: Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5-60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74-1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. CONCLUSION: DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375.

CyberKnife Radiosurgery of Skull-base Tumors: A UK Center Experience.

The study aim was to evaluate patient individualized Cyberknife® treatment for heterogeneous skull-base tumors. Patients treated between 2009 and 2013 at The Harley Street Clinic were studied. In total, 66 patients received 15-30 Gy in 1-5 fractions to a median planning target volume (PTV) of 6.4 cc, including patients with secondary, multiple, residual and recurrent tumors, and those with tumors of uncertain pathological type. Outcome analysis was pragmatically restricted to 35 patients who had single, primary tumors treated with curative intent, and sufficient diagnostic and outcome information. Sixteen vestibular schwannoma patients with median PTV 3.8 cc (range 0.81-19.6) received 18-25 Gy in 3-5 fractions: 81% showed no acute toxicity, 50% reported no late toxicity, 71% of symptoms were stable/improved and local control was 100% at 11.4 months median follow-up. Twelve meningioma patients with median PTV of 5.5 cc (range 0.68-22.3) received 17-30 Gy in 1-5 fractions: 83% experienced no acute toxicity, 33% reported no late toxicity, 88% of symptoms were stable/improved and local control was 100% at 22.1 months median follow-up. Seven patients with other tumor types with median PTV of 24.3 cc (range 7.6-100.5) received 15-28.5 Gy in 1-5 fractions: 57% experienced no acute toxicity, 57% reported no late toxicities, 66% of symptoms were stable and local control was 43% at 14.9 months median follow-up. When tumor types were considered together, smaller tumors (PTV < 6.4 cc) showed reduced acute toxicity (p = 0.01). Overall, smaller benign tumors showed low acute toxicity, excellent local control, and good symptom management: a focus on enhanced neurological preservation may refine outcomes. For other tumor types outcome was encouraging: a focus on optimal dose and fractionation scheduling may reduce toxicity and improve local control. Individual patient experiences are detailed where valuable lessons were gained for optimizing local control and minimizing toxicity.

Pineal and leptomeningeal metastases from a parotid carcinoma ex pleomorphic adenoma.

Carcinoma ex pleomorphic adenoma (CEPA) is an uncommon complication of an untreated pleomorphic adenoma (PA), but one that has a life-threatening significance. This case report documents the clinical, radiological and histopathological features of an extremely rare case of biopsy-proven pineal metastasis, with cerebellopontine and leptomeningeal spread, from CEPA of the parotid gland in spite of the patient having undergone parotidectomy, ipsilateral neck dissection and adjuvant radiotherapy. In spite of the current surgical and oncological treatment of CEPA, the rates of recurrence and distant metastases are high, with a subsequently poor prognostic outcome in most patients. Distant spread is usually to the bones and the lungs; however, more unusual locations have been documented. Our finding of pineal metastasis from CEPA has not previously been reported in the literature. Although this is a rare complication of an unusual condition, the aggressive behaviour of these malignancies warrants close clinical follow-up, with a low threshold for re-imaging and investigation if indicated.

The use of ionising radiation for the purpose of arresting external haemorrhage from an intracranial mass lesion.

External bleeding from any form of tumour of the central nervous system is unusual. We present a case where this difficult problem was controlled by the use of Gamma Irradiation from a focused delivery system.

Phase I/II study of oncolytic HSV GM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck.

PURPOSE: This study sought to define the recommended dose of JS1/34.5-/47-/GM-CSF, an oncolytic herpes simplex type-1 virus (HSV-1) encoding human granulocyte-macrophage colony-stimulating factor (GM-CSF), for future studies in combination with chemoradiotherapy in patients with squamous cell cancer of the head and neck (SCCHN). EXPERIMENTAL DESIGN: Patients with stage III/IVA/IVB SCCHN received chemoradiotherapy (70 Gy/35 fractions with concomitant cisplatin 100 mg/m(2) on days 1, 22, and 43) and dose-escalating (10(6), 10(6), 10(6), 10(6) pfu/mL for cohort 1; 10(6), 10(7), 10(7), 10(7) for cohort 2; 10(6), 10(8), 10(8), 10(8) for cohort 3) JS1/34.5-/47-/GM-CSF by intratumoral injection on days 1, 22, 43, and 64. Patients underwent neck dissection 6 to 10 weeks later. Primary end points were safety and recommended dose/schedule for future study. Secondary end points included antitumor activity (radiologic, pathologic). Relapse rates and survival were also monitored. RESULTS: Seventeen patients were treated without delays to chemoradiotherapy or dose-limiting toxicity. Fourteen patients (82.3%) showed tumor response by Response Evaluation Criteria in Solid Tumors, and pathologic complete remission was confirmed in 93% of patients at neck dissection. HSV was detected in injected and adjacent uninjected tumors at levels higher than the input dose, indicating viral replication. All patients were seropositive at the end of treatment. No patient developed locoregional recurrence, and disease-specific survival was 82.4% at a median follow-up of 29 months (range, 19-40 months). CONCLUSIONS: JS1/34.5-/47-/GM-CSF combined with cisplatin-based chemoradiotherapy is well tolerated in patients with SCCHN. The recommended phase II dose is 10(6), 10(8), 10(8), 10(8). Locoregional control was achieved in all patients, with a 76.5% relapse-free rate so far. Further study of this approach is warranted in locally advanced SCCHN.

The immunohistochemical assessment of hypoxia, vascularity and proliferation in bladder carcinoma.

BACKGROUND AND PURPOSE: Hypoxia and proliferation are important determinants of radiation responsiveness; prospective measures of these before radiotherapy may enable individualisation of treatment schedules. Immunohistochemical techniques offer a potential means of achieving this in routine biopsy material. MATERIAL AND METHODS: Cellular hypoxia as measured by pimonidazole fixation and immunohistochemistry has been evaluated in a series of human bladder cancers with dual staining of sections for pimonidazole and either the vascular markers, CD31/34, or proliferation markers, Ki-67 or cyclin A. Twenty one tumour specimens were examined suitable for the double staining technique. RESULTS: The median hypoxic fraction was 9% (range 0-38). Seven tumours did not stain for pimonidazole and 11 exhibited necrosis. The mean vascular density ranged from 16.7 to 160.6 vessels per mm2. The median hot spot count was 30 (range 16-43). There was a statistically significant increase in vessel density in hypoxic compared to oxic regions measured by both vessel density (P = 0.02) and hot spot count (P = 0.004). Proliferation indices decreased from oxic to hypoxic areas close to blood vessels. CONCLUSIONS: We have demonstrated that bladder cancer exhibits a range of hypoxia, proliferation and vascular density which may be used to form the basis for patient selection for hypoxia modification, accelerated radiotherapy and vascular targeting agents.

The modification of human tumour blood flow using pentoxifylline, nicotinamide and carbogen.

AIM: To assess the effect of combining oral nicotinamide, oral pentoxifylline and carbogen gas (2% CO2, 98% O2) breathing on human tumour red cell flux. METHODS AND MATERIALS: Microregional red blood cell flux was measured in accessible tumour nodules using laser Doppler microprobes in 11 patients with histologically proven malignancy. Patients received single oral doses of nicotinamide 40 mgkg-1 and pentoxifylline 1200 mg 2h before a 10-min period of carbogen gas breathing, corresponding to peak plasma concentrations of these drugs. Red cell flux in up to six microregions in each tumour was measured for 30 min, recording pre-, during and post-carbogen breathing for 10 min each. RESULTS: Data from ten of the 11 patients could be assessed. The red cell flux in 48 microregions was analysed and the mean red cell flux was calculated. A mean relative increase in red cell flux of 1.18 (+/-0.09, 95% confidence interval (CI)) was observed after 6 min of carbogen breathing, 2h after the administration of nicotinamide and pentoxifylline. This compares to relative increases of 1.4 (+/-0.39, 95%CI) after nicotinamide with carbogen and 1.15 (+/-0.10, 95%CI) after pentoxifylline with carbogen. These differences are not statistically significant (P>0.05). The increased red cell flux persisted after the cessation of carbogen gas breathing. CONCLUSIONS: A combination of pentoxifylline, nicotinamide and carbogen produces an increase in human tumour red cell flux, similar to that observed when each of the drugs are used alone with carbogen breathing.