Trans-Tasman Radiation Oncology Group Research Articles

Multi-institutional investigation into the robustness of intra-cranial multi-target stereotactic radiosurgery plans to delivery errors.

The use of modulated techniques for intra-cranial stereotactic radiosurgery (SRS) results in highly modulated fields with small apertures, which may be susceptible to uncertainties in the delivery device. This study aimed to quantify the impact of simulated delivery errors on treatment plan dosimetry and how this is affected by treatment planning system (TPS), plan geometry, delivery technique, and plan complexity. A beam modelling error was also included as context to the dose uncertainties due to treatment delivery errors. Delivery errors were assessed for multiple-target brain SRS plans obtained through the Trans-Tasman Radiation Oncology Group (TROG) international treatment planning challenge (2018). The challenge dataset consisted of five intra-cranial targets, each with a prescription of 20Gy. Of the final dataset of 54 plans, 51 were created using the volumetric modulated arc therapy (VMAT) technique and three used intensity modulated arc therapy (IMRT). Thirty-five plans were from the Varian Eclipse TPS, 17 from Elekta Monaco TPS, and one plan each from RayStation and Philips Pinnacle TPS. The errors introduced included: monitor unit calibration errors, multi-leaf collimator (MLC) bank offset, single MLC leaf offset, couch rotations, and collimator rotations. Dosimetric leaf gap (DLG) error was also included as a beam modelling error. Dose to targets was assessed via dose covering 98% of planning target volume (PTV) (D98%), dose covering 2% of PTV (D2%), and dose covering 99% of gross tumor volume (GTV) (D99%). Dose to organs at risk (OARs) was assessed using the volume of normal brain receiving 12Gy (V12Gy), mean dose to normal brain, and maximum dose covering 0.03cc brainstem (D0.03cc). Plan complexity was also assessed via edge metric, modulation complexity score (MCS), mean MLC gap, mean MLC speed, and plan modulation (PM). PTV D98% showed high robustness on average to most errors with the exception of a bank shift of 1.0mm and large rotational errors ≥1.0° for either the couch or collimator. However, in some cases, errors close to or within generally accepted machine tolerances resulted in clinically relevant impacts. The greatest impact upon normal brain V12Gy, mean dose to normal brain, and D0.03cc brainstem was found for DLG error in alignment with other recent studies. All delivery errors had on average a minimal impact across these parameters. Comparing plans from the Monaco TPS and the Eclipse TPS, showed a lesser increase to V12Gy, mean dose to normal brain, and D0.03cc brainstem for Monaco plans (p<0.01) when DLG error was simulated. Monaco plans also correlated to lower plan complexity. Using Spearman's correlation coefficient (r) a strong negative correlation (r≤-0.8) was found between the mean MLC gap and dose to OARs for DLG errors. Reducing MLC complexity and using larger mean MLC gaps is recommended to improve plan robustness and reduce sensitivity to delivery and modelling errors. For cases in which the calculated dose distribution or dose indices are close to the clinically acceptable limits, this is especially important.

Long-Term Quality-of-Life Outcomes After Prostate Radiation Therapy With or Without High-Dose-Rate Brachytherapy Boost: Post Hoc Analysis of TROG 03.04 RADAR

Adding high-dose-rate brachytherapy (BT) boost to external beam radiation therapy (EBRT) improves biochemical control but may affect patient-reported quality of life (QOL). We sought to determine long-term QOL outcomes for EBRT+BT versus EBRT alone. This was a post hoc analysis of the Trans-Tasman Radiation Oncology Group 03.04 Randomized Androgen Deprivation and Radiotherapy (TROG 03.04 RADAR) trial. Only patients who received 74 Gy conventionally fractionated EBRT (n=260) or 46 Gy conventionally fractionated EBRT plus 19.5 Gy in 3 fractions high-dose-rate BT boost (n=237) were included in this analysis. The primary endpoint was patient-reported QOL measured using the European Organisation for Research and Treatment of Cancer QOL (EORTC QLQ-C30) and prostate-specific QOL module (EORTC QLQ-PR25) questionnaires. We evaluated temporal changes in QOL scores, rates of symptom resolution, and the proportion of men who had decrements from baseline of >2×the threshold for minimal clinically important change (2×MCIC) for each domain. At 5, 17, and 29 months after radiation therapy, the EBRT+BT group had 2.5 times (95% confidence interval [CI], 1.4-4.2; P < .001), 2.9 times (95% CI, 1.7-4.9; P < .001), and 2.6 times (95% CI, 1.4-4.6; P=.002) greater odds of reporting 2×MCIC in urinary QOL score compared with EBRT. There were no differences beyond 29 months. EBRT+BT led to a slower rate of urinary QOL symptom score resolution up to 17 months after radiation therapy compared with EBRT (P < .001) but not at later intervals. In contrast, at the end of the radiation therapy period and at 53 months after radiation therapy, the EBRT+BT group had 0.65 times (95% CI, 0.44-0.96; P=.03) and 0.51 times (95% CI, 0.32-0.79; P=.003) the odds of reporting 2×MCIC in bowel QOL symptom scores compared with EBRT. There were no significant differences in the rate of bowel QOL score resolution. There were no significant differences in global health status or sexual activity scores between the 2 groups. There were no persistent differences in patient-reported QOL measures between EBRT alone and EBRT+BT. BT boost does not appear to negatively affect long-term, patient-reported QOL.

TROG 15.03/ANZUP International Multicenter Phase II Trial of Focal Ablative STereotactic RAdiotherapy for Cancers of the Kidney (FASTRACK II)

Stereotactic body radiotherapy (SBRT) is an emerging non-invasive alternative for primary renal cell cancer (RCC) in patients unsuitable for surgery. The objective of the FASTRACK II clinical trial was to investigate the efficacy of SBRT for primary RCC. This non-randomized, intergroup multi-institutional phase II study was activated in 7 Australian centers and 1 Dutch center, through the Trans Tasman Radiation Oncology Group (TROG) and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Eligible patients had biopsy confirmed diagnosis of primary RCC with a single lesion within a kidney, ECOG performance ≤2 and were medically inoperable, high risk or declined surgery. For tumors ≤4 cm a single fraction of 26 Gy was prescribed, for tumors > 4 cm, 42 Gy in three fractions was prescribed. The primary outcome of the study was to estimate the efficacy of SBRT for primary RCC, defined as local control based on RECIST criteria. The study was powered assuming that 1-year local control would be 90%, with the null hypothesis of ≤80% considered undesirable and not worthy of proceeding to a future randomized controlled trial. Between July 2016 and February 2020, 70 patients were enrolled with a median follow-up of 42 months. Median age was 77 years. Forty-nine patients were male (70%), median BMI was 32 and median Charlson comorbidity score was 7. The median [IQR] RENAL complexity score was 8 [7-10]. Biopsy confirmation was 100%. Twenty-three patients (33%) had T1a disease. The median (interquartile range [IQR]) tumor size was 4.6cm [3.7-5.5]; it was 3.3cm [3.0-3.6] in those receiving single fraction (n = 23), and 5.3cm [4.6-6.0] in those receiving 3-fraction SBRT (n = 47). During real-time pre-treatment quality assurance review, 10 cases (14.3%) required resubmission for protocol deviation, 2119 variables were assessed at final review, and final protocol compliance was 99.3%. Seven (10%) patients experienced grade 3 treatment-related adverse events, with no grade 4 or 5 events observed. Eleven (16%) patients reported no adverse events. Local control was 100% throughout the lifetime of the trial (p<0.001). Cancer-specific survival was also 100% throughout the lifetime of the trial. Freedom from distant failure (95% CIs) at 1 and 3 years was 99% (90-100%). Overall survival (95% CIs) at 1 and 3 years was 99% (90-100%) and 82% (70-89%), respectively. Baseline mean eGFR (95% CI) was 61.1 mLs/min (56.6; 65.6) and reduced by -10.8 mLs/min (-13.0; -8.6) by 1-year, by -14.6 mLs/min (-17.0; -12.2) by 2-years and plateaued thereafter. In the first multicenter prospective trial of a non-surgical primary RCC cohort, enrolling mostly T1b+ disease, SBRT was an effective treatment strategy with no observed local failures. We observed an acceptable side effect profile and renal function after SBRT. These outcomes support the design of a future randomized clinical trial of SBRT versus surgery for primary RCC. The trial was registered with ID: NCT02613819.

Characteristics of chief investigators and principal investigators in Australian and New Zealand radiation oncology clinical trials.

Globally, the research community is coming to realise the need for diversity, equity and inclusion (DEI) amongst research teams and leadership. Diverse teams reduce homogeneous 'group think', propagate innovation, propound support for broader more representative research and facilitate the recruitment of patients from diverse backgrounds. Given the above, this study aims to retrospectively examine the characteristics of chief investigators (CI) and principal investigators (PI) in past and present Australian and New Zealand radiation oncology clinical trials. Data on CI and PI characteristics were attained from the Trans Tasman Radiation Oncology Group (TROG) website as well as archived master database files provided by the TROG Scientific Committee. Data included CI and PI discipline, clinical trial activation date, institution type (private vs. public) and geographical location if in Australia. Australian and New Zealand health practitioner registration agency websites were used to determine the registered sex of the CIs and PIs and their years of experience. One hundred and twenty TROG clinical trials have been initiated by 134 CIs from 1989 to 2022 and 463 TROG clinical trials have been opened by 465 PIs at their respective institutions from 2000 to 2022. Most TROG trial investigators have been radiation oncologists and those with over 10 years of experience. Only one in five trials and one in three trials have been led by female PIs and CIs, respectively. Investigators have largely been affiliated with public institutions, with only one in 100 CIs and one in eight PIs being affiliated with the private sector. TROG members from regional and rural areas in Australia have not been engaged as investigators, with all CIs and most PIs affiliated with metropolitan institutions. This study highlights the gaps in diversity amongst CIs and PIs in TROG clinical trials. Further unpacking and understanding of issues related to CI and PI diversity are important to inform initiatives to improve researcher, leadership and patient diversity in future TROG clinical trials.

Long-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.

Genitourinary Quality-of-Life Comparison Between Urethral Sparing Prostate Stereotactic Body Radiation Therapy Monotherapy and Virtual High-Dose-Rate Brachytherapy Boost

Although radiation dose escalation improves prostate cancer disease control, it can cause increased toxicity. Genitourinary (GU) symptoms after prostate radiation therapy affect patient health-related quality of life (QoL). We compared patient-reported GU QoL outcomes following 2 alternative urethral sparing stereotactic body radiation therapy regimens. Expanded Prostate Cancer Index Composite (EPIC)-26 GU scores were compared between 2 urethral sparing stereotactic body radiation therapy trials. The SPARK trial prescribed a "Monotherapy" dose of 36.25 Gy in 5 fractions to the prostate. The PROMETHEUS trial prescribed 2 phases: a 19- to 21-Gy in 2 fractions "Boost" to the prostate, followed by 46 Gy in 23 fractions or 36 Gy in 12 fractions. The biological effective dose (BED) for urethral toxicity was 123.9 Gy for Monotherapy and 155.8 to 171.2 Gy for Boost. Mixed effects logistic regression models were utilized to estimate the difference in the odds of a minimal clinically important change from baseline EPIC-26 GU score between regimens at each follow-up. 46 Monotherapy and 149 Boost patients completed baseline EPIC-26 scoring. Mean EPIC-26 GU scores revealed statistically superior urinary incontinence outcomes for Monotherapy at 12 months (mean difference, 6.9; 95% confidence interval [CI], 1.6-12.1; P=.01) and 36 months (mean difference, 9.6; 95% CI, 4.1-15.1; P < .01). Monotherapy also revealed superior mean urinary irritative/obstructive outcomes at 12 months (mean difference, 6.9; 95% CI, 2.0-12.9; P < .01) and 36 months (mean difference, 6.3; 95% CI, 1.9-10.8; P < .01). For both domains and at all time points, the absolute differences were <10%. There were no significant differences in the odds of reporting a minimal clinically important change between regimens at any time point. Even in the presence of urethral sparing, the higher BED delivered in the Boost schedule may have a small adverse effect on GU QoL compared with Monotherapy. However, this did not translate to statistically significant differences in minimal clinically important changes. Whether the higher BED of the boost arm offers an efficacy advantage is being investigated in the Trans Tasman Radiation Oncology Group 18.01 NINJA randomized trial.

Efficacy and toxicity of adjuvant radiotherapy in recurrent melanoma after adjuvant immunotherapy

BackgroundIn patients with stage III melanoma, despite surgical resection and adjuvant systemic therapy, locoregional recurrences still occur. The randomized, phase III Trans-Tasman Radiation Oncology Group (TROG) 02.01 trial demonstrated that...

Cost-Effectiveness of Single Versus Multifraction SABR for Pulmonary Oligometastases: The SAFRON II Trial

The use of stereotactic ablative body radiation therapy (SABR) in advanced cancer care is increasing, yet the cost-effectiveness of single-fraction (SF) versus multifraction (MF) SABR in pulmonary oligometastases is unknown. A prespecified cost-effectiveness analysis was conducted of the Trans Tasman Radiation Oncology Group 13.01 - SAFRON II - randomized trial comparing SF with MF SABR in 87 patients with 133 pulmonary oligometastases. A partitioned survival model assessed costs and quality-adjusted life-years (QALY) over the within-trial period (4 years) and longer-term (10 years). Costs reflected a societal perspective, expressed in Australian dollars (A$) using 2020 prices and were estimated using patient level data on health care utilization for radiation therapy (including patient time), post-radiation systemic therapy and treatment of adverse effects. Quality of life was assessed using the EuroQoL EQ-5D-5L. The incremental cost-effectiveness ratio (ICER) was expressed as the cost per QALY gained for SF versus MF SABR, with uncertainty assessed using deterministic and probabilistic sensitivity analyses. SF cost less than MF for initial therapy (difference of A$1194/patient). Mean time to initiation of systemic drug therapy did not differ between arms (P=.94). Numerical differences in survival favoring SF resulted in greater overall health care use for the within-trial period. The within-trial ICER was A$15,821/QALY and A$23,265/QALY over the longer term. Results were most sensitive to the cost of postprogression therapies and utility values. The sensitivity analysis indicated that SF SABR has a 97% probability of being cost-effective at a willingness-to-pay of A$50,000/QALY. SF has lower initial costs and is highly likely to be cost-effective. Time to initiation of systemic therapy associated with disease progression is highly patient relevant and is a major driver of cost-effectiveness. Comparisons for SF SABR with nonradiation therapy approaches to the treatment of pulmonary oligometastases warrant further investigation.

Radiotherapy Quality Assurance in the PORTEC-3 (TROG 08.04) Trial

AimsQuality assurance in radiotherapy (QART) is essential to ensure the scientific integrity of a clinical trial. This paper reports the findings of the retrospective QART assessment for all centres that participated in PORTEC-3; a randomised controlled trial that compared pelvic radiotherapy with concurrent chemoradiotherapy to the pelvis followed by adjuvant chemotherapy. The trial showed an overall survival benefit for the addition of the chemotherapy in the management of women with high-risk endometrial cancer. Materials and methodsClinicians were invited to upload a randomly selected case/s treated at each of the participating sites. Panel reviewers analysed the contours to certify that the target volumes and organ at risk structures were contoured according to guidelines. The results were categorised into acceptable, minor variation, major variation or unevaluable. The radiotherapy plans were dosimetrically evaluated using the well-established Trans-Tasman Radiation Oncology Group (TROG) protocol. ResultsBetween August 2010 and January 2018, data from 146 patients of 686 consecutively treated patients were retrospectively reviewed. All 16 Australia and New Zealand and 71 of 77 international centres uploaded data for evaluation. In total, 3514 dosimetric and contour variables were reviewed. Of these, 3136 variables were deemed acceptable (89.2%), with 335 minor (9.6%) and 43 major variations (1.2%). Major contour variations included the clinical target volume vaginal vault, clinical target volume parametria and differential planning target volume vault expansion. ConclusionThe results of the QART assessment confirmed high uniformity and low rates of both minor and major deviations in contouring and dosimetry in all sites. This supports the safe introduction of the PORTEC-3 treatment protocol into routine clinical practice.

Randomized trial of radiotherapy with weekly cisplatin or cetuximab in low risk HPV associated oropharyngeal cancer (TROG 12.01): A Trans-Tasman Radiation Oncology Group study.

6012 Background: The excellent prognosis of patients with low risk HPV associated oropharyngeal squamous cell carcinoma has led to concerns about overtreatment and excessive toxicity with radiotherapy and cisplatin, leading to interest in de-intensification trials. We investigated whether cetuximab, an EGFR targeting antibody, when combined with radiotherapy would result in a decrease in symptom burden and toxicity with similar efficacy when compared to weekly cisplatin. Methods: TROG 12.01, a randomised, multicentre trial involving 15 sites in Australia and New Zealand enrolled patients with HPV associated oropharyngeal squamous cell carcinoma, AJCC 7th edition Stage III (excluding T1-2N1) or stage IV (excluding T4 and/or N3 and/or N2b-c if smoking history &gt;10 pack years and/or distant metastases). Patients were randomised (1:1) to receive radiotherapy (70Gy in 35 fractions) with either weekly cisplatin, 7 doses of 40mg/m2 or cetuximab, loading dose of 400mg/m2 followed by 7 weekly doses of 250 mg/m2. The primary outcome was symptom severity assessed by the MD Anderson Symptom Inventory Head and Neck Symptom Severity Scale from baseline to 13 weeks post completion of radiotherapy using the area under the time-severity curve (AUC). Sample size was 170 evaluable patients to provide at least 90% power to detect an effect size of 0.5, using a 2-sided test at 0.05 level of significance. Trial was registered on ClinicalTrials.gov: NCT01855451. Results: Between 17th June 2013 and 7th June 2018, 189 patients were enrolled and 182 were evaluable, with 92 on cisplatin arm and 90 on cetuximab included in the main analysis. The median follow-up was 4.1 years (0.4 - 5.3). Analyses were performed in all eligible randomised patients that commenced treatment (modified intention-to-treat population). There was no difference in the primary endpoint of symptom severity; difference in AUC cetuximab – cisplatin was 0.05 (95%CI: -0.19, 0.30), p= 0.66. The T-score (mean number of &gt; grade 3 acute adverse events) was 4.35 (SD 2.48) in the cisplatin arm and 3.82 (SD 1.8) in the cetuximab arm, p= 0.108. The 3 -year failure-free survival rates were 93% (95% CI: 86-97%) in the cisplatin arm and 80% (95% CI: 70-87%) in the cetuximab arm (hazard ratio = 3.0 (95% CI: 1.2-7.7); p=0.015. The increase in failures in the cetuximab arm was evenly split between distant and locoregional failures. Conclusions: For patients with low risk HPV associated oropharyngeal cancer, radiotherapy and cetuximab had inferior failure-free survival without improvement in symptom burden or toxicity compared to radiotherapy and weekly cisplatin. Radiotherapy and cisplatin remains the standard of care. Clinical trial information: NCT01855451.

Stereotactic Body Radiotherapy (SBRT) Versus Conventional Palliative Radiotherapy (CRT) for Patients With Painful Spinal Metastases: A Phase 3, Randomized Controlled Trial

Background: Conventional external beam radiation (CRT) is standard palliative treatment for spinal metastases; however, complete response rates for pain are low. Stereotactic body radiotherapy (SBRT) delivers high dose ablative radiotherapy. We aimed to compare complete response rates (CR) for pain between SBRT and CRT to painful spinal metastases. Methods: We did this multicenter, phase 2/3, randomised controlled trial in 13 hospitals in Canada and 5 in Australia and New Zealand. Patients were eligible if they were aged 18 years and older, a spine MRI confirmed painful (pain measured as ≥2 points using the Brief Pain Inventory) site of spinal metastasis, no more than three consecutive vertebral segments to be included in the treatment volume, an Eastern Cooperative Oncology Group performance status of 0 to 2, and no frank instability or neurologically symptomatic spinal cord or cauda equina compression. Patients were randomized (1:1) to receive either 24Gy in 2 SBRT fractions or 20Gy in 5 CRT fractions using standard techniques. Treatment assignment was performed centrally using a minimization method to achieve balance for the stratification factors of radioresistant (gastrointestinal, sarcoma, melanoma and renal cell cancer metastases) vs. radiosensitive (all other histologies) histologic type, presence or absence of “Mass” on imaging (extra-osseous paraspinal and/or epidural disease extension), and center. Patients, caregivers and investigators were not masked to the treatment allocation. The primary endpoint was the CR rate for pain at 3 months post-radiation. Final analysis populations included the intent-to-treat (ITT) population for all efficacy endpoints, and the as-treated population for safety and quality assurance analyses. The trial is registered with ClinicalTrials.gov (NCT02512965). Findings: Patients were enrolled from January 2016 to September 2019. All 229 patients were included in the ITT analyses including 4 of the 114 patients randomized to SBRT who did not initiate the study intervention, 2 of the 115 in the CRT arm that initiated at least one fraction of radiation treatment but withdrew prior to completion, 22 (19%) patients in the CRT arm and 16 (14%) patients in the SBRT arm who were in-evaluable at the primary endpoint assessment at 3 months, and 39 (34%) patients in the CRT arm and 36 (32%) patients in the SBRT arm who were inevaluable at the 6 month endpoint. The median baseline worst pain score was 5 (range, 2-10) in both arms, and the median follow-up was 6.7 months (range, 0.2-8.9). At 3 months, 16/115 (14%) in the CRT arm vs. 40/114 (36%) in the SBRT arm (p=0.0002) achieved a CR for pain. Significance was retained on multivariable analyses (MVA, p=0.0003) and the risk ratio (RR) was 1.33 (95% C.I., 1.14 – 1.55) favoring SBRT. At 6 months, 18/115 (16%) in the CRT arm vs. 37/114 patients (33%) in the SBRT arm achieved a CR (p=0.004), significance was retained on MVA (p=0.007), and the RR was 1.24 (95% C.I., 1.07 – 1.44) favoring SBRT. The 3 month radiation site specific progression-free-survival rates for CRT vs. SBRT were 86% vs. 92% and, at 6 months, 69% vs. 75%, respectively. Quality-of-life outcomes were comparable with only financial perception at 1 month (p=0.03) favoring SBRT. Grade 2+ adverse events were observed in 12% and 11% in the CRT and SBRT arms, respectively. Interpretation: SBRT is superior to CRT in improving the CR rate for pain in selected patients with spinal metastases. Trial Registration: (NCT02512965). Funding: Canadian Cancer Society (CCS) and the National Health and Medical Research Council (NHMRC). Declaration of Interests: AS declares prior consulting services and/or honorarium for past educational seminars for Varian Medical Systems, Elekta AB, Astra Zeneca, Medtronic Kyphon, and BrainLAB, and research grants from Elekta AB and Varian Medical Systems. SS declares research grants from Varian Medical Systems, Merck-Sharp-Dohme and Bayer Pharmaceuticals and honorarium for past educational seminars and advisory board participation from Astra Zeneca and Reflexion. SDM declares grant support from Novartis/AAA and honorarium from Ipsen. MF declares grants from Elekta AB and honorarium for past educational seminars from Elekta AB and Varian Medical Systems. JG, IT, MK, MGF, ML, PJM, YL, MB, JB, KD, GLM, RKW, SKL, WRP, and ZG have no conflicts of interests to declare. Ethics Approval Statement: Each participating center obtained approval from their local research ethics board, and each patient provided written informed consent. All data were collected, maintained and analyzed by the Canadian Cancer Trials Group (CCTG) in Kingston, Ontario, Canada. The trial was sponsored in Canada by the CCTG and in Australia and New Zealand by the Trans Tasman Radiation Oncology Group (TROG), and independently monitored by the independent CCTG Data Safety Monitoring Board.

Abstract GS2-04: A randomized phase III study of radiation doses and fractionation schedules in non-low risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01)

Abstract Background: Wholebreast irradiation (WBI) after breast conserving surgery for DCIS reduces therisk of local recurrence including invasive recurrence. The objective of BIG3-07/TROG 07.01 is to test radiation dose escalation to the tumor bed (tumorbed boost) and fractionation sensitivity of whole breast irradiation (WBI) inpatients with non-low risk DCIS treated with breast conserving therapy. Methods: BIG3-07/TROG 07.01 is an international, multicenter, randomized, controlled, phase 3 trial. Eligible women were ≥18 years ofage with completely resected non-low risk DCIS defined as age &amp;lt;50 years orage ≥50 years plus at least one of the risk factors for local recurrence (palpable tumor,multifocal disease, tumor size ≥ 1.5cm, intermediate or high nuclear grade, central necrosis, comedo histologyand/or surgical margin &amp;lt;10 mm). Patients were randomized to have tumor bedboost (16 Gy in 8 daily fractions) or no boost following conventional WBI (50Gy in 25 daily fractions) or hypofractionated WBI (42.5 Gy in 16 dailyfractions) in one of three randomization categories selected by centers priorto study activation. Randomization A was a 4-arm randomization of no boost vs. boostfollowing conventional WBI vs. hypofractionated WBI. Patients in RandomizationB and Randomization C were assigned no boost or boost following conventional WBIand hypofractionated WBI, respectively. The primary endpoint was time to localrecurrence, analyzed by intention to treat. The trial was designed to detect a3% difference in 5-year free-from- local recurrence rates between the no boostand boost groups (93% vs 96%; hazard ratio, 0.56) with 90% power and 2-sidedalpha level of 5%. The primary effect of boost was assessed on all randomizedpatients. The secondary effect of WBI dose-fractionation and the interactionbetween boost and WBI dose-fractionation were assessed on patients in RandomizationA and additionally on all patients. Results: BetweenJune 2007 and June 2014, 1608 patients were randomized to have no boost (805patients) or boost (803 patients) after WBI. Conventional WBI was given in 831 patients(no boost in 416 patients; boost in 415 patients). Hypofractionated WBI wasgiven in 777 patients (no boost in 389 patients; boost in 388 patients). Adjuvantendocrine therapy was planned in 106 patients (13%) in the no boost group and105 patients (13%) in the boost group. Median follow-up was 6.6 years. The 5-yearfree-from- local recurrence rates were 93% in the no boost group and 97% in theboost group (hazard ratio, 0.47; 95% confidence interval [CI], 0.31 to 0.72;P&amp;lt;0.001). Forty-four percent and 45% of LRs were invasive in the no boostgroup and boost group, respectively. The effect of boost did not vary significantlyby age, tumor size, nuclear grade, surgical margin or endocrine therapy. Therewere no significant differences in the 5-year free-from- local recurrence ratesbetween the conventional WBI group and hypofractionated WBI group inRandomization A (94% vs. 94%, P=0.84) and in all randomized patients (95% vs.95%, P=0.89). The test for interaction between boost and dose-fractionation wasnot significant in Randomization A or in all randomized patients (both P=0.89).The rates of grade ≥2 breastpain (12% vs. 16%, P=0.84) and skin and subcutaneous tissue fibrosis (6% vs.15%, P=0.14) did not differ significantly between the groups. Conclusions: Inwomen with non-low risk DCIS treatedwith breast conserving surgery, the addition of tumor bed boost followingconventional or hypofractionated WBI reduced local recurrence rates. There wasno difference in local recurrence rates between conventional WBI andhypofractionated WBI. (Registered with ClinicalTrials.gov, NCT00470236.) Citation Format: Boon Hui Chua, Emma Link, Ian Kunkler, Ivo Olivotto, Antonia Helen Westenberg, Timothy Whelan, Guenther Gruber, Breast International Group (BIG)-aisbl, Trans Tasman Radiation Oncology Group, Scottish Cancer Trials Breast Group, Canadian Cancer Trials Group, European Organization for Research and Treatment of Cancer, International Breast Cancer Study Group, Cancer Trials Ireland. A randomized phase III study of radiation doses and fractionation schedules in non-low risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-04.

A Randomized Phase 3 Trial of Palliative Radiation Therapy Versus Concurrent Chemotherapy and Palliative Radiation Therapy in Patients With Good Performance Status, Locally Advanced, or Metastatic Non-Small Cell Lung Cancer With Symptoms due to Intrathoracic Disease Who are Not Suitable for Radical Chemo-radiation Therapy: Results of the Trans-Tasman Radiation Oncology Group 11.03 Trial

PurposeWe compared intrathoracic symptom response rate, quality of life (QOL) and toxicity in patients with non-small cell lung cancer (NSCLC) not suitable for radical chemo-radiation therapy, experiencing symptoms from intrathoracic disease, who were randomized to receive palliative radiation therapy (PRT36/12) or concurrent chemotherapy and PRT (C-PRT40/20). Methods and MaterialsWe included patients with stage III or IV NSCLC, with a Eastern Cooperative Oncology Group Performance status 0 to 1, who were experiencing at least one of the following: dyspnea, cough, hemoptysis, or chest pain. The primary outcome was a change in intrathoracic response rate from baseline to 6 weeks post completion of therapy using (1) a composite measure, the Intrathoracic Symptom Burden Index(ISBI), and (2) individual symptom scores measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and Quality of Life Questionnaire - Lung Cancer 13 item (QLQ-LC 13) instruments. ResultsSeventy-six patients were recruited with 68 eligible for analysis. In addition, 42.6% and 57.4% had stage III and IV disease, respectively. The Intrathoracic Symptom Burden Index was significantly lower at 6 weeks posttreatment than at baseline (adjusted mean difference −8.77, standard error 2.67; 95% confidence interval, −13.97% to −3.58%; P < .01) for the entire cohort with no difference between trial arms (P = .34). Both treatments provided effective palliation of individual symptoms with no significant difference between trial arms. QOL during treatment was significantly better for patients receiving C-PRT(40/20). There was no difference between arms in overall QOL between baseline and 6 weeks posttreatment. There was no difference in toxicity between treatment arms during treatment nor between baseline and 6 weeks posttreatment. There was no difference in progression-free survival. A nonstatistically significant 3-month improvement in median survival favored C-PRT(40/20). ConclusionPRT(36/12) and C-PRT(40/20) provide effective symptom palliation in patients with stage III NSCLC not suitable for radical chemo-radiation therapy and in patients with stage IV disease. Chemotherapy added to PRT(40/20) does not provide superior symptomatic relief in this patient cohort.

Validation of local p16 testing for determination of human papilloma virus status eligibility on a low risk oropharyngeal cancer trial - A Trans-Tasman Radiation Oncology Group study.

Accurate determination of human papilloma virus (HPV) status is critical when identifying patients with oropharyngeal squamous cell carcinoma (OPSCC) who may be candidates for de-escalation trials. In this study we investigated whether local p16 screening, by immunohistochemistry (IHC), has high positive predictive value (PPV) for HPV status in a good prognosis HPV positive OPSCC (HPVOPSCC) population treated on a clinical trial. Patients enrolled on the TROG 12.01 randomised trial for good prognosis HPVOPSCC were randomised based on local p16 IHC testing but subsequently had central p16 IHC and HPV RNA in situ hybridisation (HPV RNA ISH) testing. Correlations between the local and central p16 and central HPV RNA ISH were studied. The main outcome was the positive predictive value (PPV) of local pathology laboratory testing of p16. 176/182 patients had samples available for central testing. 172/176 were evaluable for central testing of p16, and all were confirmed to be p16 positive (172/172, 100%, 95% CI=[97.9%, 100%]). Similarly, 100% of those evaluable for HPV RNA ISH (155/155, 100%, 95% CI=[97.6%, 100%]) were confirmed HPV positive, indicating p16 overexpression driven by transcriptionally active HPV and a PPV of 100% for local p16 testing. Our results validate the suitability of local pathology laboratory p16 testing alone, in populations with a high attributable fraction of OPSCC due to HPV, to screen and enrol low risk HPVOPSCC patients onto de-intensification trials. This obviates the need for upfront more complex and expensive HPV assays and/or central laboratory testing.

Relationships between rectal and perirectal doses and rectal bleeding or tenesmus in pooled voxel-based analysis of 3 randomised phase III trials

Background and purposeThis study aimed to identify anatomically-localised regions where planned radiotherapy dose is associated with gastrointestinal toxicities in healthy tissues throughout the pelvic anatomy. Materials and methodsPlanned dose distributions for up to 657 patients of the Trans Tasman Radiation Oncology Group 03.04 RADAR trial were deformably registered onto a single exemplar computed tomography dataset. Voxel-based multiple comparison permutation dose difference testing, Cox regression modelling and LASSO feature selection were used to identify regions where dose-increase was associated with grade ≥2 rectal bleeding (RB) or tenesmus, according to the LENT/SOMA scale. This was externally validated by registering dose distributions from the RT01 (n = 388) and CHHiP (n = 241) trials onto the same exemplar and repeating the tests on each of these data sets, and on all three datasets combined. ResultsVoxel-based Cox regression and permutation dose difference testing revealed regions where increased dose was correlated with gastrointestinal toxicity. Grade ≥2 RB was associated with posteriorly extended lateral beams that manifested high doses (>55 Gy) in a small rectal volume adjacent to the clinical target volume. A correlation was found between grade ≥2 tenesmus and increased low-intermediate dose (∼25 Gy) at the posterior beam region, including the posterior rectum and perirectal fat space (PRFS). ConclusionsThe serial response of the rectum with respect to RB has been demonstrated in patients with posteriorly extended lateral beams. Similarly, the parallel response of the PRFS with respect to tenesmus has been demonstrated in patients treated with the posterior beam.

Reduced Dose Posterior to Prostate Correlates With Increased PSA Progression in Voxel-Based Analysis of 3 Randomized Phase 3 Trials

Reducing margins during treatment planning to decrease dose to healthy organs surrounding the prostate can risk inadequate treatment of subclinical disease. This study aimed to investigate whether lack of dose to subclinical disease is associated with increased disease progression by using high-quality prostate radiation therapy clinical trial data to identify anatomically localized regions where dose variation is associated with prostate-specific antigen progression (PSAP). Planned dose distributions for 683 patients of the Trans-Tasman Radiation Oncology Group 03.04 Randomized Androgen Deprivation and Radiotherapy (RADAR) trial were deformably registered onto a single exemplar computed tomography data set. These were divided into high-risk and intermediate-risk subgroups for analysis. Three independent voxel-based statistical tests, using permutation testing, Cox regression modeling, and least absolute shrinkage selection operator feature selection, were applied to identify regions where dose variation was associated with PSAP. Results from the intermediate-risk RADAR subgroup were externally validated by registering dose distributions from the RT01 (n = 388) and Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer Trial (CHHiP) (n = 253) trials onto the same exemplar and repeating the tests on each of these data sets. Voxel-based Cox regression revealed regions where reduced dose was correlated with increased prostate-specific androgen progression. Reduced dose in regions associated with coverage at the posterior prostate, in the immediate periphery of the posterior prostate, and in regions corresponding to the posterior oblique beams or posterior lateral beam boundary, was associated with increased PSAP for RADAR and RT01 patients, but not for CHHiP patients. Reduced dose to the seminal vesicle region was also associated with increased PSAP for RADAR intermediate-risk patients. Ensuring adequate dose coverage at the posterior prostate and immediately surrounding posterior region (including the seminal vesicles), where aggressive cancer spread may be occurring, may improve tumor control. It is recommended that particular care be taken when defining margins at the prostate posterior, acknowledging the trade-off between quality of life due to rectal dose and the preferences of clinicians and patients.

Increased Dose to Organs in Urinary Tract Associates With Measures of Genitourinary Toxicity in Pooled Voxel-Based Analysis of 3 Randomized Phase III Trials.

Purpose: Dose information from organ sub-regions has been shown to be more predictive of genitourinary toxicity than whole organ dose volume histogram information. This study aimed to identify anatomically-localized regions where 3D dose is associated with genitourinary toxicities in healthy tissues throughout the pelvic anatomy.Methods and Materials: Dose distributions for up to 656 patients of the Trans-Tasman Radiation Oncology Group 03.04 RADAR trial were deformably registered onto a single exemplar CT dataset. Voxel- based multiple comparison permutation dose difference testing, Cox regression modeling and LASSO feature selection were used to identify regions where 3D dose-increase was associated with late grade ≥ 2 genitourinary dysuria, incontinence and frequency, and late grade ≥ 1 haematuria. This was externally validated by registering dose distributions from the RT01 (up to n = 388) and CHHiP (up to n = 247) trials onto the same exemplar and repeating the voxel-based tests on each of these data sets. All three datasets were then combined, and the tests repeated.Results: Voxel-based Cox regression and multiple comparison permutation dose difference testing revealed regions where increased dose was correlated with genitourinary toxicity. Increased dose in the vicinity of the membranous and spongy urethra was associated with dysuria for all datasets. Haematuria was similarly correlated with increased dose at the membranous and spongy urethra, for the RADAR, CHHiP, and combined datasets. Some evidence was found for the association between incontinence and increased dose at the internal and external urethral sphincter for RADAR and the internal sphincter alone for the combined dataset. Incontinence was also strongly correlated with dose from posterior oblique beams. Patients with fields extending inferiorly and posteriorly to the CTV, adjacent to the membranous and spongy urethra, were found to experience increased frequency.Conclusions: Anatomically-localized dose-toxicity relationships were determined for late genitourinary symptoms in the urethra and urinary sphincters. Low-intermediate doses to the extraprostatic urethra were associated with risk of late dysuria and haematuria, while dose to the urinary sphincters was associated with incontinence.

External Validation of a Predictive Model of Urethral Strictures for Prostate Patients Treated With HDR Brachytherapy Boost.

Purpose: For prostate cancer treatment, comparable or superior biochemical control was reported when using External-Beam-Radiotherapy (EBRT) with High-Dose-Rate-Brachytherapy (HDRB)-boost, compared to dose-escalation with EBRT alone. The conformal doses produced by HDRB could allow further beneficial prostate dose-escalation, but increase in dose is limited by normal tissue toxicity. Previous works showed correlation between urethral dose and incidence of urinary toxicity, but there is a lack of established guidelines on the dose constraints to this organ. This work aimed at fitting a Normal-Tissue-Complication-Probability model to urethral stricture data collected at one institution and validating it with an external cohort, looking at neo-adjuvant androgen deprivation as dose-modifying factor.Materials and Methods: Clinical and dosimetric data of 258 patients, with a toxicity rate of 12.8%, treated at a single institution with a variety of prescription doses, were collected to fit the Lyman–Kutcher–Burman (LKB) model using the maximum likelihood method. Due to the different fractionations, doses were converted into 2 Gy-equivalent doses (α/β = 5 Gy), and urethral stricture was used as an end-point. For validation, an external cohort of 187 patients treated as part of the TROG (Trans Tasman Radiation Oncology Group) 03.04 RADAR trial with a toxicity rate of 8.7%, was used. The goodness of fit was assessed using calibration plots. The effect of neo-adjuvant androgen deprivation (AD) was analyzed separating patients who had received it prior to treatment from those who did not receive it.Results: The obtained LKB parameters were TD50 = 116.7 Gy and m = 0.23; n was fixed to 0.3, based on numerical optimization of the likelihood. The calibration plot showed a good agreement between the observed toxicity and the probability predicted by the model, confirmed by bootstrapping. For the external validation, the calibration plot showed that the observed toxicity obtained with the RADAR patients was well-represented by the fitted LKB model parameters. When patients were stratified by the use of AD TD50 decreased when AD was not present.Conclusions: Lyman–Kutcher–Burman model parameters were fitted to the risk of urethral stricture and externally validated with an independent cohort, to provide guidance on urethral tolerance doses for patients treated with a HDRB boost. For patients that did not receive AD, model fitting provided a lower TD50 suggesting a protective effect on urethra toxicity.

Contour variation is a primary source of error when delivering post prostatectomy radiotherapy: Results of the Trans-Tasman Radiation Oncology Group 08.03 Radiotherapy Adjuvant Versus Early Salvage (RAVES) benchmarking exercise.

Variation in target volume delineation from clinical trial protocols has been shown to contribute to poorer patient outcomes. A clinical trial quality assurance framework can support compliance with trial protocol. Results of the TROG 08.03 RAVES benchmarking exercise considering variation from protocol, inter-observer variability and impact on dosimetry are reported in this paper. Clinicians were required to contour and plan a benchmarking case according to trial protocol. Geometric pjmirometers including volume, Hausdorff Distance, Mean Distance to Agreement and DICE similarity coefficient were analysed for targets and organs at risk. Submitted volumes were compared to a STAPLE and consensus 'reference' volume for each structure. Dosimetric analysis was performed using dose volume histogram data. Benchmarking exercise submissions were received from 96 clinicians. In total 205 protocol variations were identified. The most common variation was inadequate contouring of the CTV in 84/205 (41%). The CTV volume ranged from 65.3 to 193.1cm3 with a median of 113.2cm3 . The most common dosimetric protocol variation related to rectal dosimetry. The mean submitted rectal volume receiving 40Gy and 60Gy, respectively, was 56.14%±5.55% and 30.25%±6.15%. When corrected to the protocol defined length the mean rectal volume receiving 40Gy was 60.8%±7.92%, while the volume receiving 60Gy was 33.86%±8.21%. Variations from protocol were found in the RAVES benchmarking exercise, most notably in CTV and rectum delineation. Inter-observer variability was evident. Incorrect delineation of the rectum impacted on dosimetric compliance with protocol.

453O - Quality of life in the CHISEL randomized trial of stereotactic ablative radiotherapy (SABR) versus standard radiotherapy for stage I non-small cell lung cancer (Trans-Tasman Radiation Oncology Group 09.02)

453O - Quality of life in the CHISEL randomized trial of stereotactic ablative radiotherapy (SABR) versus standard radiotherapy for stage I non-small cell lung cancer (Trans-Tasman Radiation Oncology Group 09.02)