Association between radiotherapy protocol variations and outcome in the CONVERT trial.

Background: Radiotherapy quality assurance (QA) is integral to radiotherapy delivery. Here we report comprehensive contouring, dosimetry, and treatment delivery QA, describe protocol compliance, and detail the impact of protocol variations on acute grade ≥3 toxicity, progression free survival (PFS), and overall survival (OS) in the phase III CONVERT trial. Materials/Methods: Radiotherapy planning data from one hundred randomly selected patients were requested. Members of the CONVERT Trial Management Group (TMG) recontoured the heart, lung, and spinal cord organs at risk (OAR) according to the trial guideline. The existing radiotherapy plan were re-applied to the new structures and the new dosimetric data were recollected. Compliance with radiotherapy QA components were recorded and radiotherapy QA components were pooled into protocol variations: acceptable, acceptable variation, and unacceptable variation. Univariable analysis with a Cox proportional hazards model established the relationship between protocol variations and patient outcome. Results: Ninety-three cases were submitted for retrospective radiotherapy QA review. Demographics of the radiotherapy QA cohort (n=93) matched the non-QA (n=450) cohort. 97.8% of gross tumour volume (GTV) contours were protocol compliant. OAR contours were non-compliant in 79.6% instances of the heart, 37.6% lung, and 75.3% spinal cord. Of the non-compliant heart contours, 86.5% and 2.7% had contours caudal and cranial to the protocol-defined heart borders. 10.8% did not include the pericardial sac and 2.7% did not include the anterior aspect of the pericardium. Eleven (11.8%) submissions exceeded protocol-defined dosimetric heart constraints; six of which were only noted on the application of protocol-compliant contours. Unacceptable variations were not associated with an increase in grade 3 toxicity (p=0.808), PFS (p=0.232), or OS (p=0.743). Conclusion: Non-protocol compliant heart contours were associated with increased dose delivered to the heart OAR, with 11.8 % of submitted heart structures exceeding protocol-defined constraints. In this QA cohort of patients with small cell lung cancer, unacceptable variations were not associated with acute grade ≥3 toxicity, PFS, or OS. Radiotherapy QA remains the cornerstone of high-quality radiotherapy delivery and should be embedded into clinical trial and non-clinical trial practice; clinical trials should report standardised radiotherapy QA parameters alongside trial outcomes.

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.

Risk factors for urethral stricture following external beam radiotherapy and HDR brachytherapy for prostate cancer.

PURPOSE: A potential late side effect of high-dose-rate (HDR) prostate brachytherapy combined with external beam radiotherapy (EBRT) is urethral stricture. The purpose of this study was to evaluate dosimetric parameters possibly contributing to stricture development, including dose to bladder base and D2cc(Gy) within 10 mm of prostatic urethra (D2cc 10 mm), which has, so far, not been reported in the literature. METHODS AND MATERIALS: Patients developing urethral stricture, and matched controls, were identified from a prospective database of those receiving 46 Gy in 23 fractions of EBRT, followed by a single 15 Gy HDR brachytherapy dose. Patients had locally advanced, high- and intermediate-risk prostate cancer. Brachytherapy treatment planning parameters (planning target volume (PTV) size (cm 3), V110(%) bladder base, D2cc 10mm, number of HDR catheters, number of source dwell positions, and total source dwell time within 10 mm of the prostatic urethra) were analyzed to determine potential risk factors for urethral stricture. RESULTS: Seventy-two patients were treated, 22 of whom developed a urethral stricture. Univariate logistic regression performed on the planning parameters identified increased PTV size and D2cc 10 mm, with decreased V110(%) bladder base as risk factors for stricture formation. CONCLUSIONS: It is suggested that PTV size, V110(%) bladder base, and D2cc 10mm are predictive of urethral stricture formation following EBRT and brachytherapy to the prostate. This study demonstrates the importance of minimizing high dwell times and hot spots close to organs at risk and also the correction of any craniocaudal movement of catheters to avoid potential hot spots in the bulbomembranous urethra where there may be increased dose sensitivity.

Focal boost to residual gross tumor volume in brachytherapy for cervical cancer-A feasibility study.

PURPOSE: Image-guided plan optimization with MRI and CT for interstitial and intracavitary brachytherapy is an established technique in treating cervical cancer. The purpose of this study was to assess the feasibility of boosting the dose to the residual gross tumor volume (GTV-Tres) to 140% of the high-risk clinical target volume (HR-CTV) prescription. METHODS AND MATERIALS: Brachytherapy plans from 50 consecutive patients were analyzed in this study. All received external beam radiotherapy followed by brachytherapy (6 Gy × 4 fraction or 7 Gy × 4 fraction to HR-CTV). The original treatment plans were reoptimized escalating the GTV-Tres dose 140% of the original HR-CTV prescription dose to 8.4 Gy and 9.8 Gy/ per fraction, respectively, with the aim of achieving GTV-TresV140 ≥ 90% and D98 ≥ 100 Gy. The HR-CTV coverage and organ at risk (OAR) dose-volume histogram values were kept within the tolerance, which had been accepted for the original clinical plans. RESULTS: A total of 24 patients (48%) achieved the planning goal after reoptimization. There was no significant difference between the D2cc of the OARs of the clinical plan and the study boost plan. The factors having greatest impact on the delivered dose to the GTV-Tres are proximity of the OAR, intrauterine positioned outside the GTV-Tres, and suboptimal interstitial placement for boosting GTV-Tres. CONCLUSIONS: It is possible to boost the prescription dose to the GTV-Tres achieving 140% increase, which equates to an EQD2α/ß=10 > 100 Gy. Plans without both interstitial catheters and/or intrauterine within the GTV-Tres are most likely to be suboptimal. This planning study demonstrates that dose escalation to the GTV-Tres is feasible and further work into clinical application should be considered.

Effect of accurate heart delineation on cardiac dose during the CONVERT trial.

OBJECTIVE: This study investigated the effect of deviation from protocol in heart delineation for the Concurrent Once-daily Versus twice-daily Radiotherapy (CONVERT) Trial ( ClinicalTrials.gov Identifier NCT00433563) quality assurance (QA) programme and the effect of that on mean cardiac dose and percentage of heart volume receiving ≥5 Gy (V5%) and percentage of heart volume receiving ≥30 Gy (V30%). METHODS: Patients with limited-stage small-cell lung cancer in the CONVERT trial were randomized to receive 45 Gy in 30# twice daily or 66 Gy in 33# once daily radiotherapy, with concurrent chemotherapy in both arms. Of the 100 trial patient cases reviewed by the QA team [for patient selection, disease/organs at risk (OARs) outlining and treatment planning], 50 patient cases were selected, and the heart was reoutlined according to the "gold standard" trial protocol. Dose-volume histogram (DVH) data were extracted. The impact of change in heart volume on cardiac DVH is presented. RESULTS: For gold standard cardiac outlines, an increase in V5% and V30% was seen in 77.3% and 81.8% of cases, respectively, in the control arm (45 Gy) and in 78.6% and 82.1% of cases, respectively, in the experimental arm (66 Gy). The median increase in V5% was 1.4% and in V30%, it was 3.4%. The average of the mean cardiac dose for the control arm increased by 2.1 Gy (from 15.2 Gy for the centres outline to 17.3 Gy for the gold standard outline) and for the experimental arm by 2.4 Gy (from 16.2 to 18.6 Gy). CONCLUSION: This study demonstrates the importance of having a robust QA programme in place to ensure accuracy of cardiac delineation to facilitate future studies investigating the impact of cardiac dose on toxicity. Advances in knowledge: This study highlights the importance of ensuring accurate delineation of OARs in clinical trials, where conclusions about normal tissue toxicity are to be drawn.

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.

Protocol for the CONVERT trial-Concurrent ONce-daily VErsus twice-daily RadioTherapy: an international 2-arm randomised controlled trial of concurrent chemoradiotherapy comparing twice-daily and once-daily radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good performance status.

INTRODUCTION: Concurrent ONce-daily VErsus twice-daily RadioTherapy (CONVERT) is the only multicentre, international, randomised, phase III trial open in Europe and Canada looking at optimisation of chemoradiotherapy (RT) in limited stage small cell lung cancer (LS-SCLC). Following on from the Turrisi trial of once-daily versus twice-daily (BD) concurrent chemoradiotherapy, there is a real need for a new phase III trial using modern conformal RT techniques and investigating higher once-daily radiation dose. This trial has the potential to define a new standard chemo-RT regimen for patients with LS-SCLC and good performance status. METHODS AND ANALYSIS: 447 patients with histologically or cytologically proven diagnosis of SCLC were recruited from 74 centres in eight countries between 2008 and 2013. Patients were randomised to receive either concurrent twice-daily RT(45 Gy in 30 twice-daily fractions over 3 weeks) or concurrent once-daily RT(66 Gy in 33 once-daily fractions over 6.5 weeks) both starting on day 22 of cycle 1. Patients are followed up until death. The primary end point of the study is overall survival and secondary end points include local progression-free survival, metastasis-free survival, acute and late toxicity based on the Common Terminology Criteria for Adverse Events V.3.0, chemotherapy and RTdose intensity. ETHICS AND DISSEMINATION: The trial received ethical approval from NRES Committee North West-Greater Manchester Central (07/H1008/229). There is a trial steering committee, including independent members and an independent data monitoring committee. Results will be published in a peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN91927162; Pre-results.

The evaluation of low dose hyper-radiosensitivity in normal human skin.

BACKGROUND AND PURPOSE: The laboratory phenomenon of low dose hyper-radiosensitivity (LDHRS) describes an excess of cell kill at doses below 1Gy relative to that predicted by the linear quadratic model. These data have stimulated clinical investigation into LDHRS in vivo. PATIENTS AND METHODS: Skin was used as a model of normal human tissue. Two studies were initiated investigating the response to low doses of radiation. Study 1 compared once daily skin doses of approximately 0.5 and >1.0Gy in 24 patients receiving pelvic radiotherapy. Skin biopsies before and during radiotherapy were analysed histologically to assess the basal cell density (BCD). Study 2 compared two regimens of equal dose/time intensity--an ultrafractionated regimen (0.5Gy TDS x 12 days) with a conventional regimen (1.5Gy OD x 12 days). Skin biopsies taken during treatment assessed BCD and proliferative index. In both studies the changes in BCD were compared using non-linear regression analysis. RESULTS: Study 1. The results show a significantly greater reduction in BCD in the low dose group when BCD is plotted against dose. This effect is lost when BCD is plotted against time Study 2. The results demonstrate a significantly greater reduction in BCD in the higher dose/fraction arm. The proliferative response was similar in both treatment groups. CONCLUSIONS: These data suggest that LDHRS does not occur in skin following doses of approximately 0.5Gy/fraction when regimens of equal dose/time intensity are compared. As only small volumes of normal tissue were irradiated it is difficult to predict the biological relevance of this with respect to larger field low dose per fraction irradiation regimens or risk of cancer induction. Equally we cannot extrapolate to effects resulting from exposure to doses <0.5Gy or to the effects of low doses on other endpoints.