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In this study, irradiation of the internal mammary and medial supraclavicular nodes plus whole breast or thoracic-wall radiation therapy in women with localized breast cancer was linked to increased disease-free survival but only a marginal gain in overall survival. The first filter stations for the lymphatic drainage of the breast are the axillary and internal mammary lymph nodes. 1 Surgical studies have shown that the incidence of metastatic involvement of the internal mammary nodes varies between 4% and 9% in patients with axillary node–negative breast cancer and between 16% and 65% in patients with axillary node–positive breast cancer. 2 – 4 As a consequence, surgical dissection of the internal mammary nodes was attempted but abandoned in the 1970s, since no improvement in survival was observed. 4 , 5 Elective irradiation of the regional nodes remained widely used until the late 1980s, when it became . . .

In a prospective, randomized trial involving patients with urothelial carcinoma who had undergone radical surgery, adjuvant nivolumab was compared with placebo. The median disease-free survival was 20.8 months with nivolumab and 10.8 months with placebo. Treatment-related adverse events of grade 3 or higher were noted in 17.9% of patients in the nivolumab group.

Assessment of tumour burden has become an integral part of most oncology clinical trials, and enables the evaluation of the activity and efficacy of new cancer therapeutics in solid tumours. Although RECIST was developed to assess treatment activity in early phase II trials with tumour response as the primary end point, it is now applied across the spectrum from early phase I trials through to confirmatory phase III trials. Several questions regarding the role of RECIST in the rapidly changing landscape of oncology therapeutics, and the challenges faced in its evaluation, are highlighted. Response Evaluation Criteria In Solid Tumours (RECIST) remain an integral part of the assessment of tumour burden in many clinical trials in oncology; these criteria are used to evaluate the activity and efficacy of new cancer therapeutics in solid tumours. We aim to define the purpose of RECIST, and reflect on the level of documentation needed to enable changes for these criteria to develop a new RECIST. Maintaining the applicability of RECIST as a standard evaluation approach is associated with many challenges, in particular with maintaining a balance between the specificity and generalizability, continued validation and innovation, and use of RECIST in early phase versus late-phase drug development, as well as its relevance in clinical trials versus clinical practice. Key questions relate to different modes of actions of new classes of treatments and new imaging modalities; thus, the RECIST Working Group remains committed to maintain RECIST as a standard for the oncology community.

BackgroundNivolumab has demonstrated antitumor activity and manageable safety in the single-arm, phase II CheckMate 275 study in patients with unresectable locally advanced or metastatic platinum-resistant urothelial carcinoma. We report updated results of the global population and a subanalysis of Japanese patients from this study.MethodsPatients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) confirmed by blinded independent review committee (BIRC) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS) by BIRC and overall survival (OS). Safety was also reported. The minimum follow-up was 21 months.ResultsOverall, 270 patients were treated with nivolumab globally; 23 patients were Japanese. In the global and Japanese populations, respectively, ORR per BIRC was 20.4% and 21.7%; median PFS was 1.9 (95% confidence interval [CI] 1.9–2.3) and 3.8 months (95% CI 1.9–7.2); and median OS was 8.6 (95% CI 6.1–11.3) and 21.0 months (95% CI 7.2–not reached). The most common any grade treatment-related adverse events were fatigue (18.1%) and diarrhea (12.2%) in the global population; the most common in the Japanese population were diarrhea (26.1%) and pyrexia (13.0%). Grade 3 or 4 treatment-related adverse events occurred in 61 (22.6%) and seven (30.4%) of the global and Japanese patients, respectively.ConclusionsNivolumab continues to show antitumor activity and survival in the global population of CheckMate 275. Meaningful clinical benefit was also observed in Japanese patients. No new safety signals were identified.

Beam Output Auditing (BOA) is one key process of the EORTC radiation therapy quality assurance program. Here the results obtained between 2005 and 2014 are presented and compared to previous results. For all BOA reports the following parameters were scored: centre, country, date of audit, beam energies and treatment machines audited, auditing organisation, percentage of agreement between stated and measured dose. Four-hundred and sixty-one BOA reports were analyzed containing the results of 1790 photon and 1366 electron beams, delivered by 755 different treatment machines. The majority of beams (91.1%) were within the optimal limit of ≤ 3%. Only 13 beams (0.4%; n  = 9 electrons; n  = 4 photons), were out of the range of acceptance of ≤ 5%. Previous reviews reported a much higher percentage of 2.5% or more of the BOAs with >5% deviation. The majority of EORTC centres present beam output variations within the 3% tolerance cutoff value and only 0.4% of audited beams presented with variations of more than 5%. This is an important improvement compared to previous BOA results.

Purpose 18 F-Labelled fluorodeoxyglucose (FDG) can detect early changes in tumour metabolism and may be a useful quantitative imaging biomarker (QIB) for prediction of disease stabilization, response and duration of progression-free survival (PFS). Standardization of imaging procedures is a prerequisite, especially in multicentre clinical trials. In this study we reviewed the quality of FDG scans and compliance with the imaging guideline (IG) in a phase III clinical trial. Methods Forty-four cancer patients were enroled in an imaging sub-study of a randomized international multicentre trial. FDG scan had to be performed at baseline and 10–14 days after treatment start. The image transmittal forms (ITFs) and Digital Imaging and Communications in Medicine (DICOM) [ 1 ] standard headers were analysed for compliance with the IG. Mean liver standardized uptake values (LSUV mean ) were measured as recommended by positron emission tomography (PET) Response Criteria in Solid Tumors 1.0 (PERCIST) [ 2 ]. Results Of 88 scans, 81 were received (44 patients); 36 were properly anonymized; 77/81 serum glucose values submitted, all but one within the IG. In 35/44 patients both scans were of sufficient visual quality. In 22/70 ITFs the reported UT differed by >1 min from the DICOM headers (max. difference 1 h 4 min). Based on the DICOM, UT compliance for both scans was 31.4 %. LSUV mean was fairly constant for the 11 patients with UT compliance: 2.30 ± 0.33 at baseline and 2.27 ± 0.48 at follow-up (FU). Variability substantially increased for the subjects with unacceptable UT (11 patients): 2.27 ± 1.04 at baseline and 2.18 ± 0.83 at FU. Conclusion The high attrition number of patients due to low compliance with the IG compromised the quantitative assessment of the predictive value for early response monitoring. This emphasizes the need for better regulated procedures in imaging departments, which may be achieved by education of involved personnel or efforts towards regulations. LSUV mean could be monitored to assess quality and compliance in an FDG PET/CT study.

Imaging has steadily evolved in clinical cancer research as a result of improved conventional imaging methods and the innovation of new functional and molecular imaging techniques. Despite this evolution, the design and data quality derived from imaging within clinical trials are not ideal and gaps exist with paucity of optimised methods, constraints of trial operational support, and scarce resources. Difficulties associated with integrating imaging biomarkers into trials have been neglected compared with inclusion of tissue and blood biomarkers, largely because of inherent challenges in the complexity of imaging technologies, safety issues related to new imaging contrast media, standardisation of image acquisition across multivendor platforms, and various postprocessing options available with advanced software. Ignorance of these pitfalls directly affects the quality of the imaging read-out, leading to trial failure, particularly when imaging is a primary endpoint. Therefore, we propose a practical risk-based framework and recommendations for trials driven by imaging biomarkers, which allow identification of risks at trial initiation to better allocate resources and prioritise key tasks.

Background The ongoing EORTC 22042–26042 trial evaluates the efficacy of high-dose radiotherapy (RT) in atypical/malignant meningioma. The results of the Dummy Run (DR) and prospective Individual Case Review (ICR) were analyzed in this Quality Assurance (QA) study. Material/methods Institutions were requested to submit a protocol compliant treatment plan for the DR and ICR, respectively. DR-plans ( n =12) and ICR-plans ( n =50) were uploaded to the Image-Guided Therapy QA Center of Advanced Technology Consortium server ( http://atc.wustl.edu/ ) and were assessed prospectively. Results Major deviations were observed in 25% ( n =3) of DR-plans while no minor deviations were observed. Major and minor deviations were observed in 22% ( n =11) and 10% ( n =5) of the ICR-plans, respectively. Eighteen% of ICRs could not be analyzed prospectively, as a result of corrupted or late data submission. CTV to PTV margins were respected in all cases. Deviations were negatively associated with the number of submitted cases per institution (p=0.0013), with a cutoff of 5 patients per institutions. No association (p=0.12) was observed between DR and ICR results, suggesting that DR’s results did not predict for an improved QA process in accrued brain tumor patients. Conclusions A substantial number of protocol deviations were observed in this prospective QA study. The number of cases accrued per institution was a significant determinant for protocol deviation. These data suggest that successful DR is not a guarantee for protocol compliance for accrued patients. Prospective ICRs should be performed to prevent protocol deviations.

To the Editor: The benefit of nivolumab maintenance therapy in the study by Bajorin et al. (June 3 issue) 1 appears to have been driven mainly by the 308 patients who received cisplatin as neoadjuvant therapy and reflects cross-sensitivity (hazard ratio, 0.52; 95% confidence interval [CI] 0.38 to 0.71) rather than by the 401 patients who did not (hazard ratio, 0.92; 95% CI, 0.69 to 1.21). This also explains the lack of benefit in the 309 patients with a creatinine clearance of less than 60 ml per minute (hazard ratio, 0.87; 95% CI, 0.64 to 1.18) and by those with primary . . .