Isotoxic Intensity Modulated Radiation Therapy in Stage III Non-Small Cell Lung Cancer: A Feasibility Study.

PURPOSE: Not all patients with stage III non-small cell lung cancer (NSCLC) are suitable for concurrent chemoradiation therapy (CRT). Local failure rate is high for sequential concurrent CRT. As such, there is a rationale for treatment intensification. METHODS AND MATERIALS: Isotoxic intensity modulated radiation therapy (IMRT) is a multicenter feasibility study that combines different intensification strategies including hyperfractionation, acceleration, and dose escalation facilitated by IMRT. Patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and unsuitable for concurrent CRT were recruited. A minimum of 2 cycles of platinum-based chemotherapy was compulsory before starting radiation therapy (RT). Radiation dose was increased until a maximum dose of 79.2 Gy was reached or 1 or more of the organs at risk met predefined constraints. RT was delivered in 1.8-Gy fractions twice daily, and an RT quality assurance program was implemented. The primary objective was the delivery of isotoxic IMRT to a dose >60 Gy equivalent dose in 2-Gy fractions (EQD2 assuming an α/ß ratio of 10 Gy for acute reacting tissues). RESULTS: Thirty-seven patients were recruited from 7 UK centers. Median age was 69.9 years (range, 46-86 years). The male-to-female ratio was 17:18. ECOG PS was 0 to 5 in 14.2% of patients; PS was 1 to 27 in 77.1% of patients; PS was 2 to 3 in 8.6% of patients. Stage IIIA:IIIB ratio was 22:13 (62.9%:37.1%). Of 37 patients, 2 (5.4%) failed to achieve EQD2 > 60 Gy. Median prescribed tumor dose was 77.4 Gy (range, 61.2-79.2 Gy). A maximum dose of 79.2Gy was achieved in 14 patients (37.8%). Grade 3 esophagitis was reported in 2 patients, and no patients developed grade 3 to 4 pneumonitis. There were 3 grade 5 events: acute radiation pneumonitis, bronchopulmonary hemorrhage, and acute lung infection. Median follow-up at time of analysis was 25.4 months (range, 8.0-44.2) months for 11 of 35 survivors. The median survival was 18.1 months (95% confidence interval [CI], 13.9-30.6), 2-year overall survival was 33.6% (95% CI, 17.9-50.1), and progression-free survival was 23.9% (95% CI, 11.3-39.1). CONCLUSIONS: Isotoxic IMRT is a well-tolerated and feasible approach to treatment intensification.

Experiences and impact of mistreatment and obstetric violence on women during childbearing: a systematic review protocol.

REVIEW QUESTION/OBJECTIVE: The aim of this review is to synthesize the best available evidence on the experiences of mistreatment and/or obstetric violence in women. Specifically, the objective is to explore, from a woman's point of view, the impacts and consequences of mistreatment and/or obstetric violence during childbearing. The review question is: "What are the experiences and impact of mistreatment and obstetric violence on women during the active period of childbearing?"

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.

Predicting Radiation Esophagitis Using 18F-FDG PET During Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Treatment of locally advanced non-small cell lung cancer with chemoradiotherapy (CRT) is limited by development of toxicity in normal tissue, including radiation esophagitis (RE). Increasingly, (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is being used for adaptive planning. Our aim was to assess changes in esophageal FDG uptake during CRT and relate the changes to the onset and severity of RE. METHODS: This prospective study in patients with stage II-III non-small cell lung cancer involved serial four-dimensional computed tomography and PET scans during CRT (60-74Gy). RE was recorded weekly using the Common Terminology Criteria for Adverse Events (v4.0), and imaging was performed at weeks 0, 2, 4, and 7. Changes in the esophagus's peak standard uptake value (SUVpeak) were analyzed for each time point and correlated with grade of RE using the Wilcoxon rank-sum test. The volume of esophagus receiving 50 Gy (V50) and volume of esophagus receiving 60 Gy (V60) were correlated with the development of RE, and the C-statistic (area under the curve [AUC]) was calculated to measure predictivity of grade 3 RE. RESULTS: RE developed in 20 of 27 patients (74%), with grade 3 reached in 6 (22%). A significant percentage increase in SUVpeak in the patients with RE was noted at week 4 (p = 0.01) and week 7 (p = 0.03). For grade 3 RE, a significant percentage increase in SUVpeak was noted at week 2 (p = 0.01) and week 7 (p = 0.03) compared with that for less than grade 3 RE. Median V50 (46.3%) and V60 (33.4%) were significantly higher in patients with RE (p = 0.04). The AUC measurements suggested that the percentage change in SUVpeak at week 2 (AUC = 0.69) and V50 (AUC = 0.67) and V60 (AUC = 0.66) were similarly predictive of grade 3 RE. CONCLUSIONS: Serial FDG-PET images during CRT show significant increases in SUVpeak for patients in whom RE develops. The changes at week 2 may predict those at risk for the development of grade 3 RE and may be informative for adaptive planning and early intervention.

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.

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.

Investigation of a Patient Reported Outcome tool to assess radiotherapy-related toxicity prospectively in patients with lung cancer.

BACKGROUND AND PURPOSE: There is a paucity of data regarding the feasibility and relevance of Patient Reported Outcome (PRO) tools to assess radiotherapy-related toxicity in lung cancer. MATERIAL AND METHODS: From January to June 2013, lung cancer patients undergoing thoracic radiotherapy/chemo-radiotherapy completed nine patient-adapted Common Terminology Criteria for Adverse Events (CTCAE), the European Organisation for Research and Treatment of Cancer Quality of Life (QoL) questionnaire and the Hospital Anxiety and Depression Scale (HADS) at baseline, the end of radiotherapy and at follow-up. Clinicians completed the same CTCAE items and agreement between patients' and clinicians' reporting was assessed using weighted kappa coefficients. QoL and HADS scores were correlated with the patients' and clinicians' reported toxicity. RESULTS: 70/116 patients completed the questionnaires for at least one time point excluding baseline. Agreement between patients' and clinicians' reported toxicity ranged from slight to substantial. Most discrepancies were within one grade and patients reported greater severity than clinicians for most symptoms. QoL and HADS scores were more strongly correlated with the patients' compared to clinicians' matching toxicity reports. The PRO tool was found to be statistically reliable. CONCLUSIONS: The use of a PRO tool in lung cancer radiotherapy is feasible, reliable and acceptable to patients. PROs should be integrated in future clinical trials evaluating new radiotherapy approaches to assess toxicity.

Radical treatment of non-small cell lung cancer during the last 5 years.

The management of non-small cell lung cancer (NSCLC) has continued to improve over the last 5 years due to advances in surgery, radiological staging, combined modality therapies and advances in radiation technology. We have an updated staging classification (7th Edition American Joint Committee on Cancer staging) and now in 2011, a new histology classification introducing the concepts of adenocarcinoma in situ and minimally invasive adenocarcinoma. This classification has profound surgical implications as the role of limited resection is reconsidered for early stage lesions. Surgery is curative in early stage disease. The role of surgery in locally advanced NSCLC remains controversial. The principal aim is a complete resection as this will determine long-term prognosis. Intraoperative staging of lung cancer is extremely important to determine the extent of resection according to the tumour and nodal status. Systematic nodal dissection is generally advocated to obtain accurate intraoperative staging and to help decide on adjuvant therapy. Radiotherapy currently plays a major role in the management of lung cancer as most patients are not surgical candidates due to disease stage, fitness and co-morbidities. In the last 5 years we have seen continuing optimisation of chemo-radiotherapy combinations and technological advances including the development of image guided radiotherapy (IGRT), stereotactic ablative body radiotherapy (SABR) and intensity modulated radiotherapy (IMRT). Quality of life evaluation is becoming increasingly important and should be considered when deciding on a specific treatment, especially in a multimodality setting.