N. Bayman

Prophylactic radiotherapy to intervention sites in mesothelioma: A systematic review and survey of UK practice

BACKGROUND AND PURPOSE Patients with malignant pleural mesothelioma (MPM), who undergo chest instrumentation, may develop seeding at the site of intervention, leading to subcutaneous tumour. This is believed to be reduced by the common practice of prophylactic irradiation to intervention tracts (PIT). However, evidence to support PIT is currently inadequate and contentious. MATERIALS AND METHODS We carried out a systematic search of published literature for articles relating to the incidence of chest wall intervention tract metastases and the use of PIT in mesothelioma. In addition, a survey of current practice was conducted in 54 UK oncology centres. RESULTS Fourteen studies revealed an incidence of chest wall intervention tract metastases of 0-48% with a trend toward a higher rate of metastases for more invasive procedures. Three randomised controlled trials (RCTs), two prospective non-randomised studies and five retrospective series met the eligibility criteria to evaluate the role of PIT in MPM. Of the three RCTs, two did not support the use of PIT. None of the RCTs included patients who had received systemic chemotherapy. Of the oncology centres responding to the survey, 75% practiced PIT, and 80% would be interested in a trial to determine the efficacy of PIT. CONCLUSIONS No consensus has been reached to support the use of PIT. However, most centres in the UK still offer PIT. There was widespread interest in a randomised controlled trial to establish PIT efficacy in the era of effective systemic chemotherapy for malignant pleural mesothelioma.

Radiotherapy for small-cell lung cancer—Where are we heading?

Radiotherapy has an established role in the management of limited-disease small-cell lung cancer. However, essential questions related to the optimisation of thoracic radiotherapy remain unanswered including (i) optimal total dose, (ii) fractionation, (iii) timing and sequencing of radiation, (iv) volume of irradiation, and (v) concurrent chemotherapy combinations. The role of thoracic radiotherapy for extensive-disease small-cell lung cancer is more poorly understood but evidence suggests radiotherapy may have an important role in this setting. This review highlights the need for well-designed multi-national trials aimed at the optimisation and standardisation of radiotherapy for SCLC.

The impact of lymphovascular invasion on survival in oral carcinoma.

Data was retrospectively analysed on 72 consecutive patients treated primarily with resection and concomitant neck dissection for intraoral carcinomas. Twenty prognostic variables were assessed by univariate analysis to assess their influence on survival. Seven variables were significant at the 5% level. Survival was negatively influenced by six tumour related factors, increasing T stage (P=0.039), increasing N stage (P=0.004), greater than two nodes histologically positive nodal disease (P=0.017), tumour size > 4 cm (P=0.022), residual disease at the primary site (P=0.012), extracapsular nodal spread (P=0.01) and the one treatment related factor analysed, adjuvant radiotherapy (P=0.039). Subsequent multivariate analysis was performed via the cox stepwise regression method to assess the influence on survival of all factors which achieved significance at the 20% level. There were only two variables which made a significant difference (P<0.05) to the multivariate model. The presence of lymphovascular invasion (P=0.015) and histological evidence of mandibular invasion (P=0.047). Lymphovascular invasion appeared in the final model despite not achieving statistical significance at the 5% level on univariate analysis. A final cox survival model was constructed. The relative risk of death for those with cervical metastases (N2 and above) at diagnosis was 3.74 (P=0.005). The addition of lymphovascular invasion to the cox model revealed an increase in the relative risk of death in the presence of lymphovascular invasion of 2.99 (P=0.015). Patients with nodal negative disease and one single node positive provided the baseline risk as there was no significant difference between these two groups. The presence of histological evidence of lymphovascular invasion in oral carcinoma surgical specimens has a significant impact on survival outcome in oral carcinoma patients.

Radiotherapy for lung cancer in the elderly.

Mortality from lung cancer is increasing in patients > or = 70 years. Radiotherapy has an important role in the treatment of lung cancer for this group. Despite this, there have been few elderly specific trials of radiotherapy in lung cancer and current treatment is often based on evidence extrapolated from studies treating younger patients. This review of the literature examines the impact of radiotherapy for the radical and palliative treatment of non-small-cell and small-cell lung cancer, on survival, treatment-related toxicity and quality of life in the elderly. We also comment on the need for validated, practical geriatric screening and assessment tools to help predict toxicity to treatment.

New radiotherapy approaches in locally advanced non-small cell lung cancer.

Radiotherapy plays a major role in the treatment of patients with locally advanced non-small cell lung cancer (NSCLC), particularly since most patients are not suitable for surgery due to the extent of their disease, advanced age and multiple co-morbidities. Despite advances in local and systemic therapies local control and survival remain poor and there is a sense that a therapeutic plateau has been reached with conventional approaches. Strategies for the intensification of radiotherapy such as dose escalation have shown encouraging results in phase I-II trials, but the outcome of the phase III Radiation Therapy Oncology Group 0617 trial was surprisingly disappointing. Hyperfractionated and/or accelerated fractionating schedules have demonstrated superior survival compared to conventional fractionation at the expense of greater oesophageal toxicity. Modern radiotherapy techniques such as the integration of 4-dimensional computed tomography for planning, intensity modulated radiotherapy and image-guided radiotherapy have substantially enhanced the accuracy of the radiotherapy delivery through improved target conformality and incorporation of tumour respiratory motion. A number of studies are evaluating personalised radiation treatment including the concept of isotoxic radiotherapy and the boosting of the primary tumour based on functional imaging. Proton beam therapy is currently under investigation in locally advanced NSCLC. These approaches, either alone or in combination could potentially allow for further dose escalation and improvement of the therapeutic ratio and survival for patients with NSCLC.

Management of unresectable stage III non-small-cell lung cancer with combined-modality therapy: a review of the current literature and recommendations for treatment.

Lung cancer remains the most common cause of cancer deaths in the United Kingdom, and long-term survival from lung cancer has hardly improved over the past 30 years. The benefit of combined-modality therapy with chemotherapy and radiation therapy in improving survival for patients with inoperable non-small-cell lung cancer (NSCLC) was discovered over 10 years ago. In this comprehensive literature review, we discuss the current status of combined-modality therapy for unresectable stage III NSCLC. The efficacy and toxicity of different chemoradiation therapy regimens are presented. The potential role of novel and targeted therapies and radiation dose escalation is also considered. Finally, recommendations are made for the treatment of unresectable stage III NSCLC.

How can we optimise concurrent chemoradiotherapy for inoperable stage III non-small cell lung cancer?

Latest evidence sets a clear mandate for concurrent chemoradiotherapy as the current standard of care for inoperable stage III non small cell lung cancer patients with good performance status and minimal co-morbidities. However, a survival plateau has been reached, with disappointing results from dose escalation studies using conventional fractionation and studies investigating the addition of systemic doses of chemotherapy delivered before or after concurrent chemoradiotherapy. A review was carried out to address three questions considered fundamental to improving outcome in patients with stage III non-small cell lung cancer: (1) Can radiotherapy regimens be optimised using advanced radiotherapy techniques to improve local control rate and overall survival? (2) Can systemic therapy regimens be optimised to reduce the risk of distant metastases? (3) Should concurrent chemoradiotherapy be considered standard of care for locally advanced non-small cell lung cancer in the elderly? It is clear that further improvement in outcome for these patients will be determined by better local control and by reducing the risk of distant recurrence. Given the technological advances in radiotherapy planning and delivery in recent years plus the abundance of novel targeted therapies exploiting critical oncogenic pathways, further advances in combined drug-radiation treatment for lung cancer seem highly possible.

Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention.

Introduction Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT-guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention site and patients can develop tumour nodules within the chest wall. In an effort to prevent nodules developing, it has been widespread practice across Europe to irradiate intervention sites postprocedure—a practice known as prophylactic irradiation of tracts (PIT). To date there has not been a suitably powered randomised trial to determine whether PIT is effective at reducing the risk of chest wall nodule development. Methods and analysis In this multicentre phase III randomised controlled superiority trial, 374 patients who can receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will be 21 Gy in three fractions. Subsequent chemotherapy is given at the clinicians’ discretion. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6 months after randomisation would be clinically significant. All patients will be followed up for up to 2 years with monthly telephone contact and at least four outpatient visits in the first year. Ethics and dissemination PIT was approved by NRES Committee North West—Greater Manchester West (REC reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to be randomised by the end of 2015. The analysis of the primary end point, incidence of chest wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer reviewed journal and results will also be presented at scientific meetings and summary results published online. A follow-up analysis is expected to be published in 2018. Trial registration number ISRCTN04240319; NCT01604005; Pre-results.

Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study

Introduction The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of ‘isotoxic’ radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable. Methods and analysis Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years. Ethics and dissemination The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West—Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally. Trial registration number NCT01836692; Pre-results.

Primary Radiotherapy for Carcinoma of the Retromolar Trigone: A Useful Alternative to Surgery

AIMS Squamous cell carcinoma of the retromolar trigone is uncommon. The standard initial treatment is primary surgery, which usually involves microvascular reconstruction with a composite flap. Some patients are considered unsuitable for this procedure. This retrospective study examined the outcome and toxicity for patients with squamous cell carcinoma of the retromolar trigone treated with definitive radiotherapy in a single centre. MATERIALS AND METHODS Between 1991 and 2000, 43 patients were treated with definitive radiotherapy with a median dose of 50Gy in 16 fractions over 21 days. Hospital case notes and radiotherapy records were analysed. RESULTS The median age was 66 years (range 39-84 years). Nodal disease was evident in 13 (30.2%) patients. Twenty-one patients (51.2%) had stage I/II disease and 20 patients (48.8%) had stage III/IV disease. After a median follow-up of 59 months, 13 (30.2%) patients were alive and well, nine (20.9%) patients had died of an intercurrent illness and 21 (48.8%) had died of their disease. Five-year locoregional control was 46.5% (95% confidence interval 29.7-61.7), cause-specific survival was 45.7% (95% confidence interval 29.1-60.8) and overall survival was 30.9% (95% confidence interval 17.5-46.3). Osteoradionecrosis was documented in two patients. DISCUSSION This hypofractionated regimen is convenient for this patient population and produced comparable outcomes to longer fractionation schedules without an increase in late toxicity.