The impact of contour variation on tumour control probability in anal cancer.

BACKGROUND: While intensity modulated radiotherapy (IMRT) has been widely adopted for the treatment of anal cancer (AC), the added contour complexity poses potential risks. This study investigates the impact of contour variation on tumour control probability (TCP) when using IMRT for AC. METHODS: Nine Australian centres contoured a single computed tomography dataset of a patient with AC. The same optimised template-based IMRT planning protocol was applied to each contour set to generate nine representative treatment plans and their corresponding dose volume histograms. A geometric analysis was performed on all contours. The TCP was calculated for each plan using the linear quadratic and logitEUD model. RESULTS: The median concordance index (CI) for the bladder, head and neck of femur, bone marrow, small bowel and external genitalia was 0.94, 0.88, 0.84, 0.65 and 0.65, respectively. The median CI for the involved nodal, primary tumour and elective clinical target volumes were 0.85, 0.77 and 0.71, respectively. Across the nine plans, the TCP was not significantly different. Variation in TCP between plans increased as tumour cell load increased or radiation dose decreased. CONCLUSIONS: When using IMRT for AC, contour variations generated from a common protocol within the limits of minor deviations do not appear to have a significant impact on TCP. Contouring variations may be more critical with increasing tumour cell load or reducing radiotherapy dose.

Results of the Australasian (Trans-Tasman Oncology Group) radiotherapy benchmarking exercise in preparation for participation in the PORTEC-3 trial.

INTRODUCTION: Protocol deviations in Randomised Controlled Trials have been found to result in a significant decrease in survival and local control. In some cases, the magnitude of the detrimental effect can be larger than the anticipated benefits of the interventions involved. The implementation of appropriate quality assurance of radiotherapy measures for clinical trials has been found to result in fewer deviations from protocol. This paper reports on a benchmarking study conducted in preparation for the PORTEC-3 trial in Australasia. METHODS: A benchmarking CT dataset was sent to each of the Australasian investigators, it was requested they contour and plan the case according to trial protocol using local treatment planning systems. These data was then sent back to Trans-Tasman Oncology Group for collation and analysis. RESULTS: Thirty three investigators from eighteen institutions across Australia and New Zealand took part in the study. The mean clinical target volume (CTV) volume was 383.4 (228.5-497.8) cm(3) and the mean dose to a reference gold standard CTV was 48.8 (46.4-50.3) Gy. CONCLUSIONS: Although there were some large differences in the contouring of the CTV and its constituent parts, these did not translate into large variations in dosimetry. Where individual investigators had deviations from the trial contouring protocol, feedback was provided. The results of this study will be used to compare with the international study QA for the PORTEC-3 trial.

Gastrointestinal dose-histogram effects in the context of dose-volume-constrained prostate radiation therapy: analysis of data from the RADAR prostate radiation therapy trial.

PURPOSE: To use a high-quality multicenter trial dataset to determine dose-volume effects for gastrointestinal (GI) toxicity following radiation therapy for prostate carcinoma. Influential dose-volume histogram regions were to be determined as functions of dose, anatomical location, toxicity, and clinical endpoint. METHODS AND MATERIALS: Planning datasets for 754 participants in the TROG 03.04 RADAR trial were available, with Late Effects of Normal Tissues (LENT) Subjective, Objective, Management, and Analytic (SOMA) toxicity assessment to a median of 72 months. A rank sum method was used to define dose-volume cut-points as near-continuous functions of dose to 3 GI anatomical regions, together with a comprehensive assessment of significance. Univariate and multivariate ordinal regression was used to assess the importance of cut-points at each dose. RESULTS: Dose ranges providing significant cut-points tended to be consistent with those showing significant univariate regression odds-ratios (representing the probability of a unitary increase in toxicity grade per percent relative volume). Ranges of significant cut-points for rectal bleeding validated previously published results. Separation of the lower GI anatomy into complete anorectum, rectum, and anal canal showed the impact of mid-low doses to the anal canal on urgency and tenesmus, completeness of evacuation and stool frequency, and mid-high doses to the anorectum on bleeding and stool frequency. Derived multivariate models emphasized the importance of the high-dose region of the anorectum and rectum for rectal bleeding and mid- to low-dose regions for diarrhea and urgency and tenesmus, and low-to-mid doses to the anal canal for stool frequency, diarrhea, evacuation, and bleeding. CONCLUSIONS: Results confirm anatomical dependence of specific GI toxicities. They provide an atlas summarizing dose-histogram effects and derived constraints as functions of anatomical region, dose, toxicity, and endpoint for informing future radiation therapy planning.

Impact of treatment planning and delivery factors on gastrointestinal toxicity: an analysis of data from the RADAR prostate radiotherapy trial.

BACKGROUND: To assess the impact of incremental modifications of treatment planning and delivery technique, as well as patient anatomical factors, on late gastrointestinal toxicity using data from the TROG 03.04 RADAR prostate radiotherapy trial. METHODS: The RADAR trial accrued 813 external beam radiotherapy participants during 2003-2008 from 23 centres. Following review and archive to a query-able database, digital treatment plans and data describing treatment technique for 754 patients were available for analysis. Treatment demographics, together with anatomical features, were assessed using uni- and multivariate regression models against late gastrointestinal toxicity at 18-, 36- and 54-month follow-up. Regression analyses were reviewed in the context of dose-volume data for the rectum and anal canal. RESULTS: A multivariate analysis at 36-month follow-up shows that patients planned using a more rigorous dose calculation algorithm (DCA) was associated with a lower risk of stool frequency (OR: 0.435, CI: 0.242-0.783, corrected p = 0.04). Patients using laxative as a method of bowel preparation had higher risk of having increased stool frequency compared to patients with no dietary intervention (OR: 3.639, CI: 1.502-8.818, corrected p = 0.04). Despite higher risks of toxicities, the anorectum, anal canal and rectum dose-volume histograms (DVH) indicate patients using laxative had unremarkably different planned dose distributions. Patients planned with a more rigorous DCA had lower median DVH values between EQD23 = 15 Gy and EQD23 = 35 Gy. Planning target volume (PTV), conformity index, rectal width and prescription dose were not significant when adjusted for false discovery rate. Number of beams, beam energy, treatment beam definition, positioning orientation, rectum-PTV separation, rectal length and mean cross sectional area did not affect the risk of toxicities. CONCLUSIONS: The RADAR study dataset has allowed an assessment of technical modifications on gastrointestinal toxicity. A number of interesting associations were subsequently found and some factors, previously hypothesised to influence toxicity, did not demonstrate any significant impact. We recommend trial registries be encouraged to record technical modifications introduced during the trial in order for more powerful evidence to be gathered regarding the impact of the interventions.

Prospective quality of life assessment between treatment groups for oral cavity squamous cell carcinoma.

BACKGROUND: Postoperative radiation therapy (PORT) is frequently recommended to improve survival outcome. The effect of PORT-associated morbidity on patients' quality of life (QOL) is, however, not well established. This study assessed the effect of PORT on medium-term (ie, at 6 months) QOL in patients with oral cavity squamous cell carcinoma (SCC). METHODS: Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Quality of Life Questionnaire Core Head and Neck 35 (QLQ-HN35) at initial presentation, and at 3-, 6-, and 12-month follow-up. Baseline QOL scores were adjusted for using analysis of covariance (ANCOVA). RESULTS: Global health status (mean difference = 13.3; p = .042) and xerostomia (mean difference = 35.4; p = .003) were significantly worse at 6 months in patients who received PORT compared to those treated with surgery alone. CONCLUSION: The survival advantage needs to be balanced against increased treatment toxicity. PORT is associated with reduced global health status, increased xerostomia, and marginally increased levels of fatigue at 6 months posttreatment for oral cavity cancer.

Constrained-beam inverse planning for intensity-modulated radiation therapy of prostate cancer patients with bilateral hip prostheses.

Hip prostheses present a technical challenge in the planning of curative external beam radiation treatment for patients with prostate cancer. Bilateral prostheses compel planners to compromise between target coverage and avoidance of beam entry through the prostheses. Inverse planning systems given objectives to avoid dose to prostheses are overly restricted from allowing exit dose to them. We report a novel inverse planning technique for intensity-modulated radiation therapy of patients with prostate cancer and bilateral hip prostheses, by constraining beam characteristics rather than dose in the inverse planning process.

Surface dosimetry for breast radiotherapy in the presence of immobilization cast material.

Curative breast radiotherapy typically leaves patients with varying degrees of cosmetic damage. One problem interfering with cosmetically acceptable breast radiotherapy is the external contour for large pendulous breasts which often results in high doses to skin folds. Thermoplastic casts are often employed to secure the breasts to maintain setup reproducibility and limit the presence of skin folds. This paper aims to determine changes in surface dose that can be attributed to the use of thermoplastic immobilization casts. Skin dose for a clinical hybrid conformal/IMRT breast plan was measured using radiochromic film and MOSFET detectors at a range of water equivalent depths representative of the different skin layers. The radiochromic film was used as an integrating dosimeter, while the MOSFETs were used for real-time dosimetry to isolate the contribution of skin dose from individual IMRT segments. Strips of film were placed at various locations on the breast and the MOSFETs were used to measure skin dose at 16 positions spaced along the film strips for comparison of data. The results showed an increase in skin dose in the presence of the immobilization cast of up to 45.7% and 62.3% of the skin dose without the immobilization cast present as measured with Gafchromic EBT film and MOSFETs, respectively. The increase in skin dose due to the immobilization cast varied with the angle of beam incidence and was greatest when the beam was normally incident on the phantom. The increase in surface dose with the immobilization cast was greater under entrance dose conditions compared to exit dose conditions.

Comparison of prostate IMRT and VMAT biologically optimised treatment plans.

Recently, a new radiotherapy delivery technique has become clinically available--volumetric modulated arc therapy (VMAT). VMAT is the delivery of IMRT while the gantry is in motion using dynamic leaf motion. The perceived benefit of VMAT over IMRT is a reduction in delivery time. In this study, VMAT was compared directly with IMRT for a series of prostate cases. For 10 patients, a biologically optimized seven-field IMRT plan was compared with a biologically optimized VMAT plan using the same planning objectives. The Pinnacle RTPS was used. The resultant target and organ-at-risk dose-volume histograms (DVHs) were compared. The normal tissue complication probability (NTCP) for the IMRT and VMAT plans was calculated for 3 model parameter sets. The delivery efficiency and time for the IMRT and VMAT plans was compared. The VMAT plans resulted in a statistically significant reduction in the rectal V25Gy parameter of 8.2% on average over the IMRT plans. For one of the NTCP parameter sets, the VMAT plans had a statistically significant lower rectal NTCP. These reductions in rectal dose were achieved using 18.6% fewer monitor units and a delivery time reduction of up to 69%. VMAT plans resulted in reductions in rectal doses for all 10 patients in the study. This was achieved with significant reductions in delivery time and monitor units. Given the target coverage was equivalent, the VMAT plans were superior.

Dose-volume constraints to reduce rectal side effects from prostate radiotherapy: evidence from MRC RT01 Trial ISRCTN 47772397.

PURPOSE: Radical radiotherapy for prostate cancer is effective but dose limited because of the proximity of normal tissues. Comprehensive dose-volume analysis of the incidence of clinically relevant late rectal toxicities could indicate how the dose to the rectum should be constrained. Previous emphasis has been on constraining the mid-to-high dose range (>/=50 Gy). Evidence is emerging that lower doses could also be important. METHODS AND MATERIALS: Data from a large multicenter randomized trial were used to investigate the correlation between seven clinically relevant rectal toxicity endpoints (including patient- and clinician-reported outcomes) and an absolute 5% increase in the volume of rectum receiving the specified doses. The results were quantified using odds ratios. Rectal dose-volume constraints were applied retrospectively to investigate the association of constraints with the incidence of late rectal toxicity. RESULTS: A statistically significant dose-volume response was observed for six of the seven endpoints for at least one of the dose levels tested in the range of 30-70 Gy. Statistically significant reductions in the incidence of these late rectal toxicities were observed for the group of patients whose treatment plans met specific proposed dose-volume constraints. The incidence of moderate/severe toxicity (any endpoint) decreased incrementally for patients whose treatment plans met increasing numbers of dose-volume constraints from the set of V30

Efficacy of palliative low-dose involved-field radiation therapy in advanced lymphoma: a phase II study.

PURPOSE: To confirm the efficacy of low-dose involved-field radiation therapy (LD-IFRT) as palliative treatment in patients symptomatic from advanced lymphoma. PATIENTS AND METHODS: A total of 36 patients (47 sites), received 4 Gy in 2 fractions to the lymphoma with a 1.5-2-cm margin. Pathology subtypes included 29 (62%) sites with indolent lymphoma and 18 (36%) sites with aggressive lymphoma histology. Bulky disease was seen in 22 (48%) sites and, of these, 6 sites had disease > 10 cm. A median of 3 previous chemotherapy regimens (range, 0 to 9 regimens) preceded LD-IFRT. The primary endpoint of the study was in-field lymphoma control. Patients completed the European Organization for the Research and Treatment of Cancer QLQ-C30 quality of life (QOL) questionnaire before RT and at 3-4 weeks after treatment. RESULTS: The overall response rate (RR) at 1-3 months after the RT was 75%. A complete remission (CR) was observed in 13 patients (36%) lasting up to a maximum of 31.3 months and ongoing at analysis. A partial remission (PR) was achieved in 14 patients (39%) lasting up to 10 months. The response rate for non-diffuse large B-cell lymphoma (DLBCL) sites was 86%, while it was 50% for sites with DLBCL histology. Median time to local progression for the entire group was 15 months. There was no statistical difference between the QOL before and after LD-IFRT. CONCLUSION: LD-IFRT is an effective and easy treatment for patients with advanced lymphoma that can be repeated at previously irradiated sites, a particularly useful attribute because of the relapsing nature, especially of advanced follicular subtypes.

Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis.

BACKGROUND: Resectable oesophageal cancer is often treated with surgery alone or with preoperative (neoadjuvant) chemoradiotherapy or chemotherapy. We aimed to clarify the benefits of neoadjuvant chemoradiotherapy or chemotherapy versus surgery alone by a meta-analysis of randomised trial data. METHODS: Eligible trials were identified first from earlier published meta-analyses and systematic reviews. We also used MEDLINE, Cancerlit, and EMBASE databases to identify additional studies and published abstracts from major scientific meetings since 1980. Only randomised studies with an analysis by an intention-to-treat principle were included, and searches were restricted to those databases citing articles in English. We used published hazard ratios if available or estimates from other survival data or survival curves. Treatment effects by type of tumour and treatment sequencing were also investigated. FINDINGS: Ten randomised comparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1209) and eight of neoadjuvant chemotherapy versus surgery alone (n=1724) in patients with local operable oesophageal carcinoma were identified. The hazard ratio for all-cause mortality with neoadjuvant chemoradiotherapy versus surgery alone was 0.81 (95% CI 0.70-0.93; p=0.002), corresponding to a 13% absolute difference in survival at 2 years, with similar results for different histological tumour types: 0.84 (0.71-0.99; p=0.04) for squamous-cell carcinoma (SCC), and 0.75 (0.59-0.95; p=0.02) for adenocarcinoma. The hazard ratio for neoadjuvant chemotherapy was 0.90 (0.81-1.00; p=0.05), which indicates a 2-year absolute survival benefit of 7%. There was no significant effect on all-cause mortality of chemotherapy for patients with SCC (hazard ratio 0.88 [0.75-1.03]; p=0.12), although there was a significant benefit for those with adenocarcinoma (0.78 [0.64-0.95]; p=0.014). INTERPRETATION: A significant survival benefit was evident for preoperative chemoradiotherapy and, to a lesser extent, for chemotherapy in patients with adenocarcinoma of the oesophagus. The findings provide an evidence-based framework for the use of neoadjuvant treatment in management decisions.