Gy Arm Research Articles

Erectile function preservation after salvage radiation therapy for biochemically recurrent prostate cancer after prostatectomy: Five-year results of the SAKK 09/10 randomized phase 3 trial

ObjectivesTo evaluate effects of dose intensified salvage radiotherapy (sRT) on erectile function in biochemically recurrent prostate cancer (PC) after radical prostatectomy (RP). Materials and methodsEligible patients had evidence of biochemical failure after RP and a PSA at randomization of ≤ 2 ng/ml. Erectile dysfunction (ED) was investigated as secondary endpoint within the multicentre randomized trial (February 2011 to April 2014) in patients receiving either 64 Gy or 70 Gy sRT. ED and quality of life (QoL) were assessed using CTCAE v4.0 and the EORTC QoL questionnaires C30 and PR25 at baseline and up to 5 years after sRT. Results344 patients were evaluable. After RP 197 (57.3 %) patients had G0-2 ED while G3 ED was recorded in 147 (42.7 %) patients. Subsequently, sexual activity and functioning was impaired. 5 years after sRT, 101 (29.4 %) patients noted G0-2 ED. During follow-up, 44.2 % of patients with baseline G3 ED showed any improvement and 61.4 % of patients with baseline G0-2 ED showed worsening. Shorter time interval between RP and start of sRT (p = 0.007) and older age at randomization (p = 0.005) were significant predictors to more baseline ED and low sexual activity in the long-term. Age (p = 0.010) and RT technique (p = 0.031) had a significant impact on occurrence of long-term ED grade 3 and worse sexual functioning. During follow-up, no differences were found in erectile function, sexual activity, and sexual functioning between the 64 Gy and 70 Gy arm. ConclusionED after RP is a known long-term side effect with significant impact on patients’ QoL. ED was further affected by sRT, but dose intensification of sRT showed no significant impact on erectile function recovery or prevalence of de novo ED after sRT. Age, tumor stage, prostatectomy and RT-techniques, nerve-sparing and observation time were associated with long-term erectile function outcome.ClinicalTrials.gov. Identifier: NCT01272050.

The Impact of Dose Rate on the Tumor Microenvironment Using Flattening-filter-free Beams

AimsRecently, dose delivery technology has rapidly evolved with flattening filter-free beams (FFF), and the biological effects of high dose rates are a matter of interest. We hypothesized that FFF beams at different dose rates obtained with modern linear accelerators have different effects on the TME. Materials and methodsThe B16–F10 melanoma syngeneic tumor model was established, and mice were randomized to 2 different doses (2 Gy and 10 Gy) and 3 different dose rates (1 Gy/min, 6 Gy/min, and 14 Gy/min) along with the control group. Euthanasia was performed on the seventh day after RT, and intracardiac blood was collected for a comet assay. Tumors were harvested and examined histomorphologically and immunohistochemically. Statistical analyses were performed using SPSS software version 23 (SPSS Inc., Chicago, IL, USA). ResultsThe daily growth rate was uniform, and no difference was observed between tumor volumes across all three dose rates for each dose. Deoxyribonucleic acid (DNA) damage in blood mononuclear cells was not affected by dose or dose rate. In the TME histomorphological examination, the number of mitosis is less in the 10 Gy arm, whereas the pleomorphism score was greater. Nevertheless, varying dose rates had no effect on the number of mitosis or the pleomorphism score. The severity of the inflammation, cell densities in the TME, and expression of immunohistochemical markers were comparable across all doses and dose rates. ConclusionIn our study involving the B16–F10 syngeneic tumor model, varying dose rates obtained with FFF beams had no effect on tumor volume, blood mononuclear cell DNA damage, or TME parameters. However, in order to fully understand the biological impacts of novel techniques, our study should be validated with alternative preclinical setups.

Evaluation of Different Regimens of Palliative Radiation Therapy for Symptomatic Bone Metastases: An Audit From a Tertiary Care Hospital in Jharkhand, India.

Background This study aimed to assess the efficacy of different radiation therapy regimens in treating patients with symptomatic bone metastases. Methodology A retrospective study was conducted by assigning patients with symptomatic bone metastases from different primary cancers into three groups, namely, Arms A, B, and C. The radiation dose delivered in each arm was as follows: 8 Gray (Gy) in a single fraction for Arm A, 20 Gy in five fractions at the rate of 4 Gy per fraction for Arm B, and 30 Gy in 10 fractions at the rate of 3 Gy per fraction for Arm C. Each arm consisted of 15 patients. A comparison was conducted across all three arms to evaluate pain relief based on the Visual Analog Scale (VAS), performance score improvement based on the Eastern Cooperative Oncology Group (ECOG), and analgesic requirement based on the World Health Organization (WHO) step ladder at one week, one month, and three months. Results The pain relief was measured using the VAS in three different arms, i.e., Arm A, B, and C. After one week, the pain relief was 66.67%, 60%, and 60%, respectively. After one month, it was 73.33% in all three arms. At three months, it was 80%, 86.67%, and 86.67%, respectively. The study also measured the improvement in the ECOG performance score. The improvement in all three arms was 60% after one week and 66.67% in Arm A and 73.33% in Arms B and C after one month. After three months, the improvement was 73.33%, 80%, and 80% in Arms A, B, and C, respectively. The decrease in analgesic usage was also measured in all three arms. After one week, it was 60% in all three arms. After one month, it was 66.67%, 73.33%, and 73.33% in Arms A, B, and C, respectively. At three months, it was 73.33%, 80%, and 80% in Arms A, B, and C, respectively. No significant statistical difference was found between the three arms. Conclusions The efficacy of a single 8 Gy arm was almost equivalent to that of other arms of multifractionated regimens in terms of improvement in pain and performance score and decreased use of analgesics for a short duration of follow-up. For high-volume cancer centers and patients with economic constraints, a single-fraction regime provides effective palliation for painful bone metastases.

Long-Term Outcomes of NRG/RTOG 0126, a Randomized Trial of High Dose (79.2 Gy) vs. Standard Dose (70.2 Gy) Radiation Therapy (RT) for Men with Localized Prostate Cancer

NRG/RTOG 0126, a phase III trial for men with localized prostate cancer testing whether dose escalation to 79.2 Gy with 3DCRT/IMRT improved overall survival (OS). Long-term results of this trial are presented. Patients with clinical stage T1b-T2b and either Gleason Score (GS) 2-6 and 10 ≤ PSA < 20 or GS 7 and PSA < 15 were eligible and randomized to receive 79.2 Gy or 70.2 Gy. No previous or concurrent androgen withdrawal therapy was administered. Treatment was delivered with 3DCRT/IMRT to a dose of 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions to the PTV encompassing the prostate and seminal vesicles. Image guidance was not required. ASTRO and Phoenix definitions were used for biochemical failure (ABF and PBF, respectively). OS was estimated by the Kaplan-Meier method and arms compared with the log-rank test. ABF, PBF, local progression (LP), distant metastases (DM) and time to late GI/GU toxicities were estimated by the cumulative incidence method and arms compared with Gray's test. One thousand five hundred thirty-two men were randomized, 763 to 79.2 Gy and 769 to 70.2 Gy. 1499 were eligible, 748 and 751 in the 79.2 Gy and 70.2 Gy arms respectively. Median age was 71, 70% had PSA < 10 ng/ml, 84% with GS 7, 57% had T1 disease, and 66% treated with 3D-CRT. Outcomes are shown in the TABLE: . With a median follow up of 12 years, there was no significant difference in OS. There was a statistically significant decrease in the cumulative incidence of ABF, PBF, DM, LP, and salvage therapies in the 79.2 Gy arm. There were significantly higher rates of grade 2+ GI and GU toxicity in the 79.2 Gy arm. There were no statistically significant differences in the rates of grade 3+ GU or GI toxicity between either arm. Long term follow up confirms no improvement in OS with dose escalation in this study population. However, there are significant improvements in ABF, PBF, DM, LP, and need for salvage therapy. Despite the use of more salvage therapy in the low dose arm, dose escalated RT resulted in lower rates of DM, a clinically relevant endpoint. Patients receiving dose escalation do experience a higher rate of grade 2+ GU and GI toxicity but no worse grade 3+ toxicities.

The Effect of Dose Rate on Tumor Microenvironment in External Beam Radiotherapy

The fact that treatment can be given at a narrow dose rate range in external radiotherapy (ERT) applications with crude delivery techniques has caused the dose rate to be neglected for a long time. Recently dose delivery technology has rapidly evolved and with the re-introduction of FLASH-RT to the radiation oncology stage, dose rate studies escalated. It is also known that interactions within the tumor microenvironment (TME) play a significant role in tumor prognosis. Herein we aimed to investigate the effect of three different dose rates on TME. To generate the tumor model, 1 million B16-F10 malignant melanoma cells were subcutaneously injected into the right flank of C57BL/6 mice. RT time was estimated to be 0.5 cm in diameter. Forty-two mice were randomly assigned to the control group, 2 different doses (2 Gy and 10 Gy), and 3 different dose rates (1 Gy/min, 6 Gy/min, and 14 Gy/min). Vernier scale measurements were taken every day to monitor the mice's tumor size. Euthanasia is induced on the seventh day after ERT. Tumor and metastatic organs were harvested, and evaluated histomorphological, and immunohistochemically. Intracardiac blood was collected for the comet assay. After radiation, the 10 Gy arm's mean tumor size was lower than that of the 2 Gy and control arms (p = 0.01 and p = 0.007). Tumor size did not differ between the 2 Gy and control arms (p = 0.53). Additionally, there was no difference in tumor diameters between low and high doses at different dose rates (p = 0.12, p = 0.21). Blood mononuclear cells in the control arm had less DNA damage than those in the 10 Gy arm (p = 0.04). The 2 Gy and 10 Gy arms did not differ in terms of DNA damage (p = 0.65). Each dose arm was evaluated in terms of dose rates and no significant difference was found (p = 0.79, p = 0.24). The number of mitoses per 10 HPF was assessed during the histological analysis. The number of mitoses in the 10 Gy arm was less than the 2 Gy arm (p = 0.001). There was no difference at different dose rates in the 2 Gy and 10 Gy arms (p = 0.28, p = 0.97). Pleomorphism score was evaluated as mild-moderate and severe (score 1-2-3). In comparison to the 2 Gy and control arms, the 10 Gy arm had a higher pleomorphism score (p = 0.01). The 2 Gy arm and the control arm did not vary from one another (p = 0.04). Pleomorphism scores were comparable across low and high doses at different dose rates (p = 0.35, p = 0.58). Different dose rates resulted in the same staining pattern with aSMA and SOX-10. In our study involving the B16-F10 syngeneic tumor model, we could not find a significant effect of three different dose rates on TME. With constantly improving treatment techniques, larger dose rates are going to be achieved. Owing to this, protocols should also list dose rate as a treatment variable. This project was supported by the TÜBİTAK, Short Term R&D Funding Program.

Optimum Radiation Dose for Palliation in Head and Neck SCC: A Phase III Randomized Controlled Trial (OPRAH)

Palliative radiotherapy has been used to alleviate symptoms in locally advanced (T4b) head and neck Squamous cell carcinoma, but optimum dose is still debated. The trial has been designed to determine if high palliative radiation dose (30 Gy/ 5#/ 5 days) improves progression free survival compared to low palliative dose (20 Gy/ 5# 5 days). The secondary objective was to compare toxicity rates profile between the two radiation doses (CTCAE version 5) and compare Quality of life between the two arms with QOL - HN35 questionnaire. This is a prospective randomized phase III randomized controlled trial. We hypothesized that by increasing the dose per fraction and total dose there would be an improvement in PFS without difference in late toxicity and QOL. The present study will also perform an exploratory analysis of effect of palliative radiotherapy on immune function and its effect on survival. Considering median PFS 2.5 months in 20 Gy arm we assumed that PFS will improve by 1.25 months (total PFS 3.75 months) in 30 Gy arm. To reach the hypothesis with 90% power and alpha error of 0.05, attrition rate of 10% sample size calculated was 286. Patients with cT4b disease of larynx/ Hypopharynx/ Oropharynx/ Oral cavity not amenable to surgery, Carotid encasement > 180 degree, histologically proven squamous cell carcinoma, Age > 18 years and < 75 years ECOG PS 0-2 were eligible. Until December 2022, we completed accrual of 239 patients. Median age: 53 years (Range: 29-70 years); Gender: Male: Female = 9: 1 (214: 25). 145 patients had history of smoking, 87 had additional history of tobacco chewing. 67 patients had history of alcohol consumption, 13 patients had history of smoking, tobacco and alcoholism. All patients had stage IVA or Stage IVB disease. Primary site was oral cavity in 58%, Oropharynx in 19%, larynx in 10% and hypopharynx in 8% cases. 72.3% patients had a PS of 1, 21.7% had PS 2 at presentation. Prior to RT requirement of analgesic was: No pain medicine: 5; WHO step I:173, WHO step II: 52, WHO step III:14. All patients received conformal radiation with 6 MV linear accelerator. Target volume was GTV plus 1 cm margin to form CTV and 5 mm expansion to generate PTV. Out of 239 patients 67 patients had a disease progression. Mucositis is the commonest side effect affecting most of the patients and improve with best supportive care. High dose palliation appears to be equally well tolerated. However, the impact of such dose escalation will be established if final analysis reaches the pre-defined endpoint.

Gastrointestinal Toxicity Prediction Not Influenced by Rectal Contour or Dose-Volume Histogram Definition

Rectal dose delivered during prostate radiation therapy is associated with gastrointestinal toxicity. Treatment plans are commonly optimized using rectal dose-volume constraints, often whole-rectum relative-volumes (%). We investigated whether improved rectal contouring, use of absolute-volumes (cc), or rectal truncation might improve toxicity prediction. Patients from the CHHiP trial (receiving 74 Gy/37 fractions [Fr] vs 60 Gy/20 Fr vs 57 Gy/19 Fr) were included if radiation therapy plans were available (2350/3216 patients), plus toxicity data for relevant analyses (2170/3216 patients). Whole solid rectum relative-volumes (%) dose-volume-histogram (DVH), as submitted by treating center (original contour), was assumed standard-of-care. Three investigational rectal DVHs were generated: (1) reviewed contour per CHHiP protocol; (2) original contour absolute volumes (cc); and (3) truncated original contour (2 versions; ±0 and ±2 cm from planning target volume [PTV]). Dose levels of interest (V30, 40, 50, 60, 70, 74 Gy) in 74 Gy arm were converted by equivalent-dose-in-2 Gy-Fr (EQD2α/β= 3 Gy) for 60 Gy/57 Gy arms. Bootstrapped logistic models predicting late toxicities (frequency G1+/G2+, bleeding G1+/G2+, proctitis G1+/G2+, sphincter control G1+, stricture/ulcer G1+) were compared by area-undercurve (AUC) between standard of care and the 3 investigational rectal definitions. The alternative dose/volume parameters were compared with the original relative-volume (%) DVH of the whole rectal contour, itself fitted as a weak predictor of toxicity (AUC range, 0.57-0.65 across the 8 toxicity measures). There were no significant differences in toxicity prediction for: (1) original versus reviewed rectal contours (AUCs, 0.57-0.66; P=.21-.98); (2) relative- versus absolute-volumes (AUCs, 0.56-0.63; P=.07-.91); and (3) whole-rectum versus truncation at PTV ± 2 cm (AUCs, 0.57-0.65; P=.05-.99) or PTV ± 0 cm (AUCs, 0.57-0.66; P=.27-.98). We used whole-rectum relative-volume DVH, submitted by the treating center, as the standard-of-care dosimetric predictor for rectal toxicity. There were no statistically significant differences in prediction performance when using central rectal contour review, with the use of absolute-volume dosimetry, or with rectal truncation relative to PTV. Whole-rectum relative-volumes were not improved upon for toxicity prediction and should remain standard-of-care.

Comparison of two high dose rate intracavitary brachytherapy regimens in treatment of cervical cancer: a preliminary report

BackgroundTo assess and compare the local control and toxicities between HDR Intracavitary Brachytherapy with 7.5 Gy and 9 Gy per fraction after EBRT in treatment of carcinoma cervix.MethodologyA total of 180 patients were randomly assigned to 2 arms. Arm A received HDR intracavitary brachytherapy with a dose of 7.5 Gy per fraction, 1 fraction per week for 3 fractions and Arm B received 9 Gy per fraction, 1 fraction per week for 2 fractions. Patients were evaluated on follow up for assessment of local control and toxicities.ResultsThe median follow up was 12 months (6–18 months). In arm A 89% of the patient had complete response and 11% had recurrence or metastasis. In arm B 93% of the patient had complete response and 7% had recurrence or metastasis. Grade 2/3 diarrhoea was seen in 4.4% of patients in Arm A and in 7.7% in Arm B. Grade 2/3 proctitis was seen in 3.3% of patients in 7.5 Gy arm and in 6.6% in 9 Gy arm. One patient in each arm had grade 1 haematuria. The overall duration of treatment was significant lower in Arm B compared to Arm A (59 days vs 68 days, p = 0.01).ConclusionThe result of this clinical study shows that Intracavitary brachytherapy with a dose of 9 Gy per fraction is non inferior to other schedules in term of local control and does not result in increased toxicity.

A randomised phase II trial of radiotherapy dose escalation, facilitated by intensity-modulated arc therapy techniques, in high-risk neuroblastoma

<h3>Objectives</h3> This trial compared intensity modulated arc therapy (IMAT) with conventional techniques for high-risk neuroblastoma, to establish whether IMAT could enable a higher radiation dose than standard to be given without exceeding normal tissue dose objectives. The aim was to determine the radiotherapy dose for use in a subsequent international randomised phase III trial. <h3>Methods</h3> Patients were randomised to receive either 21 Gy in 14 fractions, or 36 Gy in 24 fractions. The tumour volume and organs at risk were delineated according to a standard protocol. All patients were dual planned with both conventional and IMAT techniques. A quality assurance team prospectively reviewed the contours and the plans. The better technique, based on planning target volume dose achieved and organ at risk sparing, was selected for use. <h3>Results</h3> From 2017 to 2020, fifty patients were recruited and randomised, 25 to each arm. All 50 patients underwent radiotherapy planning, but only 43 completed protocol treatment, all with the IMAT technique. The IMAT technique improved planning target volume conformity and heterogeneity indices significantly. In the 21 Gy arm, the dose delivered in all patients was 21 Gy. In the 36 Gy arm, the median dose delivered was 36 Gy (range 21 Gy to 36 Gy). Disease progression occurred in 18 patients and 16 patients have died. At two years, the overall survival was 70%, and the event free survival was 60%. This phase II trial was not powered to detect a difference between the arms, and no difference in event-free or overall survival was observed. <h3>Conclusion</h3> This trial confirms that delivery of 36 Gy is possible using an IMAT technique without exceeding normal tissue tolerance. The new SIOPEN High-Risk 2 trial contains a Phase III randomisation comparing 36 Gy with 21.6 Gy inpatients with residual disease after surgery.

Long-Term Results of Two Novel Weekly High Dose Palliative Radiotherapy Schedules in Un-Resectable or Metastatic Breast Cancers: Should We Clinically Chase Statistical Significance?

<h3>Purpose/Objective(s)</h3> In a developing country like India, large fungating breast cancers are not uncommon. This causes much deterioration in the quality of life attributed to the pain, growth of maggots, bleeding and discharge from the tumor. Surgery is often not feasible, and chemotherapy hardly brings any response in such aggressive lesions. Our initial results were presented in the last two consecutive ASTRO conferences. Our first paper showed the feasibility and safety of extreme hypo-fractionated radiotherapy (8 Gy weekly x 5 fractions) while the second one compared the toxicity and response outcomes of 40 Gy (8 Gy weekly x 5 fractions) versus 24 Gy (8 Gy x 3). This paper presents the long-term local control and survival rates between the two groups. <h3>Materials/Methods</h3> A total of 54 patients were enrolled in the study. 24 patients received 5 fractions of weekly 8 Gy to the involved breast, while 30 patients received 3 fractions of the same dose. Early and late toxicities were assessed using RTOG toxicity criteria and Harvard 4-point cosmesis respectively. All patients were planned with tangential photon beams, ensuring that the lungs and the heart are outside our treatment field. <h3>Results</h3> Out of the fifty-four patients, 45 (83%) patients were upfront metastatic, while the remaining were unresectable post-neoadjuvant chemotherapy. Thirty-eight (70%) of the patients were hormone receptor-negative, 23 (42%) patients were Her 2 Neu positive which were almost equally distributed between both arms. Overall, 44 patients (81%) had extensive skin involvement including ulcerations, fungating mass, extensive peud' orange and satellite nodules. All these patients were treated with bolus over the skin. The median largest size was 8cm (3.3cm-16cm). 25 patients (46%) succumbed to their disease, within a year of treatment, as expected in such an aggressive cohort. As reported earlier, 52% of the patients had greater than grade 2 dermatitis in the 40 Gy arm versus none of the patients who had dermatitis grade 2 or above in the 24 Gy arm (p=0.051). Again, as reported earlier, the cosmesis was significantly worse in the 40 Gy arm with 25 % of patients reporting fair or poor cosmesis as compared to none in the 24 Gy arm (p=0.052). Nine (37%) progressed in the 40 Gy arm, versus 16 (53%) in the 24 Gy arm with a median progression-free survival of 11.3months versus 13.6 months, favoring the arm with 40 Gy (p=0.04). There was a trend to increased overall survival in the 40 Gy arm (25 months versus 18 months), although this was not statistically significant (p=0.5). <h3>Conclusion</h3> This unique study compares two novel high doses of palliative radiotherapy for fungating, unresectable and chemo-resistant malignancies of the breast. The 24 Gy regimen can be safely used, with minimal concerns of toxicity and cosmesis. Although the toxicities and deterioration of cosmesis were higher for the 40 Gy arm, the statistically significant local disease control may warrant the use of this higher dose which may be individualized based on the size and nature of the lesion.

Abstract PD10-02: A randomised phase II trial of single fraction or multi-fraction SABR (stereotactic ablative body radiotherapy) with atezolizumab in patients with advanced triple negative breast cancer (AZTEC trial)

Abstract A randomised phase II trial of single fraction or multi-fraction SABR (stereotactic ablative body radiotherapy) with atezolizumab in patients with advanced triple negative breast cancer (AZTEC trial) Abstract: BACKGROUND: In patients with advanced triple negative breast cancer (TNBC), immunotherapy has shown acceptable safety and efficacy in a PD-L1 (programmed death-ligand 1) positive population. Pre-clinical evidence has demonstrated that SABR can prime a more effective systemic anti-tumor response in combination with checkpoint inhibition. It is currently unknown if single or multi-fraction SABR scheduling synergises best with atezolizumab therapy. METHODS: This was a multi-centre, open label, phase 2 randomised trial of patients with advanced TNBC, unselected for (PD-L1) status, who had recurred at least 6 months post completion of (neo) adjuvant chemotherapy and received less than 2 lines of treatment in the metastatic setting. Participants were randomised to 20Gy SABR in 1 fraction or 24Gy SABR in 3 fractions to 1-4 sites of disease, with at least one metastasis left unirradiated. Within 5 days following the final fraction of radiotherapy atezolizumab was commenced at a dose of 1200 mg every 21 days and continued for up to 24 months, or until progression or intolerable toxicity. The primary endpoint is progression- free survival (PFS). Secondary endpoints include efficacy according to PD-L1 IHC status (positive: SP142 ≥1%) and TIL (tumour infiltrating lymphocyte) quantity, response assessment, overall survival and safety. Results presented are from interim analysis performed 18 weeks after the last patient commenced treatment. RESULTS: Fifty evaluable patients were recruited and randomised between 20th November 2018 and 12thApril 2021 with a median age of 57 [35 - 79] yrs. Thirty (60%) and 20 (40%) patients had received none or one previous line of chemotherapy in the metastatic setting, respectively. 14/40 (35%) patients were PD-L1 positive at baseline and 26/42 (62%) had TIL≥5%. Median follow-up was 17 months. The median PFS for the 20 Gy arm was 2.5 (90% CI: 1.7-4.5) months, 3.1 (90% CI: 1.8-3.9) months for the 24 Gy arm. For both arms combined, the PFS was 3.1 (90% CI: 1.8-3.9) months, with no difference between the arms, HR 1.2 (95% CI: 0.6-2.1), p=0.64. PFS by PD-L1 IHC status and TIL&amp;lt;5% vs ≥5% was similar. There were 11 (22%) patients with clinical benefit (no PD within 24 weeks of C1D1), these were not significantly different by arm (p=0.74), nor by PD-L1 status (p=0.44) or TIL quantity (p=0.92) (Table 1). Overall survival is immature: estimated 12 months was 78% (95% CI:54-90) for the 20 Gy arm and 57% (95% CI: 33-75) for the 24 Gy arm.. In patients who were PD-L1 positive the ORR was 1/12 (8%) and DC was 3/14 (21%) compared with ORR of 1/14 (7%) and DC of 3/26 (12%) in patients who were PD-L1 negative. CONCLUSIONS: The efficacy between single and multi-fraction SABR in combination with Atezolizumab was similar and toxicity was acceptable. Efficacy was seen in PD-L1 positive and negative patients. Longer follow-up is required to assess the effect on OS.. (Research support and funding provided by the imCORE Network on behalf of F. Hoffmann-La Roche; AZTEC ClinicalTrials.gov Identifier: NCT03464942) Table 1.Response AssessmentResponse, n (%)All patients (n = 50)Patients with measurable disease (n = 32)Best objective response (non-SABR lesion)CR3 (6)2 (6)PR2 (4)2(6)NCR/NPD8 (16)0SD13 (26)13 (41)PD24 (48)15 (47)ORR (CR + PR)5 (10); 95% CI: 3-224 (12%); 95% CI: 4-29DCR (CR + PR + SD + non-CR/non-PD ≥24 weeks)a11 (22%); 95% CI: 12-377 (23%); 95% CI: 10-41aOne patient withdrew at 8 weeks and was not assessable for DCR. Citation Format: Steven David, Peter Savas, Shankar Siva, Michelle White, Michael W Neeson, Shane White, Gavin Marx, Robyn Cheuk, Michelle Grogan, Maria Farrell, Jessica Foudoulis, Annette Dempsey, Paul J Neeson, Mathias Bressel, Sherene Loi. A randomised phase II trial of single fraction or multi-fraction SABR (stereotactic ablative body radiotherapy) with atezolizumab in patients with advanced triple negative breast cancer (AZTEC trial) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-02.

Patient-reported health-related quality of life from a randomized phase II trial comparing standard-dose with high-dose twice daily thoracic radiotherapy in limited stage small-cell lung cancer

ObjectivesIn a randomized phase II trial, twice daily (BID) thoracic radiotherapy (TRT) of 60 Gy/40 fractions improved survival compared with 45 Gy/30 fractions in limited stage small-cell lung cancer (LS SCLC). Notably, the higher dose did not cause more toxicity. Here we present health related quality of life (HRQoL) reported by the trial participants during the first 2 years. Materials and methods170 patients were randomized 1:1 to TRT of 45 Gy or 60 Gy concurrently with cisplatin/etoposide chemotherapy. The 150 patients who commenced TRT and completed a minimum of one HRQoL-questionnaire were included in the present study. Patients reported HRQoL on the European Organization for Research and Treatment of Cancer Core 30 and Lung Cancer 13 Quality of Life Questionnaires. Questionnaires were completed weeks 0, 4 (before TRT), 8 (end of TRT), 12 (response evaluation after chemoradiotherapy) and 16 (end of prophylactic cranial irradiation), then every 10 weeks year one, and every 3 months year two. Primary HRQoL endpoints were dysphagia and dyspnea. A difference in mean score of ≥10 was defined as clinically significant. ResultsMaximum dysphagia was reported on week 8, with no significant difference between treatment arms (mean scores 45 Gy: 44.2, 60 Gy: 51.1). The 60 Gy arm had more dysphagia in the convalescence period, but dysphagia scores returned to baseline levels at week 16 in both arms. For dyspnea there were no significant changes, or differences between treatment arms, at any timepoint. There were no significant differences between treatment arms for any other HRQoL-scales. ConclusionTRT of 60 Gy did not cause significantly higher maximum dysphagia, though patients on the 60 Gy arm reported more dysphagia the first 8 weeks of convalescence. The higher dose was well tolerated and is an attractive alternative to current TRT schedules in LS SCLC.Trial reg Clinicaltrials.gov NCT0204184.

Hypofractionated Dose-Escalation for Elderly Patients With a Newly Diagnosed Glioblastoma Improves Survival

The standard of care for elderly glioblastoma patients (GBM) is 40 Gy in 15 fractions with temozolomide (TMZ). However, this regimen has a lower biologic equivalent dose (BED) compared to the Stupp regimen of 60 Gy in 30 fractions. We hypothesize that dose escalated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to 40 Gy in 15 fractions.Elderly patients (> 60 yo) who received hypofractionated radiation with TMZ were included in this analysis. Overall survival (OS) and progression free survival (PFS) were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Baseline characteristics were compared with pairwise tests. Univariate and multivariate analyses were performed.66 newly-diagnosed patients were eligible for this analysis. 39 patients were treated with 40 Gy in 15 fractions, and 27 patients were treated with 52.5 Gy in 15 fractions. The median follow up for this cohort was 8.8 months. Patients were well balanced with no significant differences in age, sex, MGMT, extent of resection, or KPS. The median OS was 7.9 months in the 40 Gy arm and 13.1 months in the 52.5 Gy arm (P = 0.035). For unmethylated patients, the median OS was 6.7 months in the 40 Gy arm and 11.3 months in the 52.5 Gy arm (P = 0.012). Increasing planning treatment volume (P = 0.007) was associated with decreased OS. On multivariate analysis, MGMT methylation (HR 0.45 [0.23-0.87] P = 0.018) and dose escalation (HR 0.45 [0.21-0.96] 0.04) remained independent prognostic factors for OS. In a multivariate model for PFS, only dose-escalation was significant (HR 0.49 [0.25-0.98] P = 0.045). No significant differences in toxicity were observed between treatment groups.Dose-escalation to 52.5 Gy in 15 fractions was associated with superior OS and PFS compared to standard of care 40 Gy in 15 fractions. This treatment regimen gives the elderly population an alternative to Stupp that is not de-escalating therapy. These hypothesis generating data support dose-escalated hypofractionation in future prospective trials.H.K. Perlow: None. M. Yang: None. B. Klamer: None. R. Raval: None. D.M. Blakaj: None. A.L. Arnett: None. S. Beyer: None. J.C. Grecula: None. M. Ammirati: None. J.B. Elder: None. R.R. Lonser: None. D. Hardesty: None. S.S. Ong: None. P. Giglio: None. C. Pillainayagam: None. J. Goranovich: None. A. Chakravarti: None. V. Gondi: Partner; Radiation Oncology Consultants, Ltd. Honoraria; UpToDate, RaySearch. Partnership; Radiation Oncology Consultants, Ltd. Co-Principal Investigator; NRG Oncology. P.D. Brown: None. J.D. Palmer: Research Grant; Varian Medical Systems, The Kroger Company. Consultant; Huron Consulting. Speaker's Bureau; Varian Medical Systems, Depuy Synthes. Advisory Board; Novocure. Member of panel; NCCN.

Therapeutic Radiation in Genetically Engineered Mouse Models of Cancer

Some drugs that target tumor metabolism are minimally effective in vitro but limit proliferation in vivo. Our goal was to develop a preclinical platform enabling us to test drugs that target cancer cell metabolism in combination with radiation therapy in vivo. Here we report the initial results of preclinical studies in autochthonous mouse models of prostate and colorectal cancer using radiation as monotherapy.A dose escalation study was performed in C57BL/6 wild-type mice using 1-5 fraction regimens with a BED of 90, 130, 180, and 250 (a/b = 3). Flank xenograft models of prostate cancer (22Rv1 and PC3 cells) were treated with 24 Gy in 4 fractions or sham irradiated (n = 10 animal per group, 40 animals total). Pb-Cre;Ptenfl/fl;p53fl/fl mice (autochthonous prostate cancer model) age 5 months were randomly assigned to two dose regimens (37.5 Gy in 5 fractions or 45 Gy in 5 fractions) or sham irradiation (n = 11-14 per group). Survival was estimated by Kaplan-Meier Analysis. Colorectal tumors were induced in male and female Villin-CreER;Apcfl/fl mice by intramucosal tamoxifen injection. Mice were assigned 2:1 to 37.5 Gy or sham irradiation (n = 10-15 per group). Treatment effect was measured as percent survival 6 months after tumor induction. In all cases pathologic response rate was determined using serial histologic sections and proliferation by Ki-67 immunohistochemistry.For a 2 cm field directed at the low abdomen and pelvis of mice, the maximum tolerated dose of radiation was 45 Gy delivered in 5 fractions. The intestinal tract was identified as the dose limiting organ for abdominopelvic radiation. In irradiated flank xenografts, growth delay was observed for all tumors compared with 100% progression in unirradiated controls. Pathologic complete response was observed in 1 of 10 (10%) 22Rv1 xenografts and 4 of 10 (40%) PC3 xenografts. In the autochthonous prostate cancer model, median survival was significantly improved in the 45 Gy (236 days, P < 0.0001) and 37.5 Gy (227 days, P = 0.0007) arms relative to control (206 days). Irradiated tumors were also smaller relative to control (mean difference -2.637 grams [95% CI -4.617 to -0.6563, P = 0.0153); however, all mice eventually died of local tumor progression. In the autochthonous colorectal cancer model, survival at 6 months was significantly improved in the radiation group relative to control (100% vs 40%, P = 0.0012). In both prostate and colorectal cancer autochthonous models the proliferation index at time of death (prostate) or 6 months after tumor induction (colorectal) was similar in irradiated and control cohorts.Hypofractionated radiation therapy can be safely administered to the abdominopelvic region in mice and improves survival in autochthonous mouse models of prostate and colorectal cancer. Radiation can induce pathologic complete responses in flank xenografts, but not autochthonous tumors, suggesting the presence of radioresistant persister cells in these models.

Demystifying Cardiac Dose in RTOG-0617

The RTOG-0617 trial presented worse overall survival for patients with lung cancer treated in the high-dose 74 Gy arm compared to those treated with 60Gy. In multi-variable models, whole heart volumetric dose parameters (volume of heart receiving at least 5Gy and 30Gy), and the high-dose treatment arm was found to be associated with survival, rescinding dose escalation. In this abstract, we repeat this survival analysis, but consider cardiac sub-regions to find an explanation for the counterintuitive survival difference observed between the treatment arms.Voxel-wise analysis was performed on dose distributions spatially normalized onto a template patient anatomy. Permutation testing assessed significance, identifying anatomical regions where dose was associated with overall survival. Dose to the identified cardiac sub-region was included in multi-variable modelling. Clinical and dosimetric variables were bootstrapped 500 times into an elastic-net variable selection model to identify variables associated with survival. Variable importance was assessed by (1) magnitude of model coefficients and (2) frequency of selection. Next, multi-variable Cox regression survival models were created to assess significance of dose to the identified cardiac region compared to v5 and v30 parameters used previously.A total of 488 patients, with accurate dose mapping, were included in the voxel-wise analysis. A significance region (P < 0.001) was identified in the base of the heart, centered over the origin of the left coronary artery and atrioventricular node, with median dose 9.5 Gy (high dose arm 10.2 Gy, low dose arm 9.1 Gy). Bootstrapping of clinical variables identified mean lung dose (selected 99%), treatment arm (65%), log tumor volume (66%) and heart region dose (62%) as most important factors associated with survival (v5 and v30 selected < 10%). Multi-variable models included mean lung dose, log tumor volume, age, gender, treatment arm, performance status, smoking history, PET staging and histology and either heart v5, v30 or the identified heart region dose. Heart v5 and v30 were not found to be associated with survival, with treatment arm (P < 0.05) and log tumor volume (P < 0.02) being significant. However, heart region dose was significant (P = 0.02), along with log tumor volume (P = 0.03). Other parameters, including treatment arm were not significant.These results show that dose to cardiac sub-regions is more strongly association with overall survival than whole heart dose parameters. Variable selection showed the importance to include mean lung dose, suggesting an interplay between lung and cardiac dose. The treatment arm effect observed in RTOG-0617 lost its significant once the identified base of heart region dose was included into the model. Our results suggest that the worse survival of the high dose arm in RTOG617 could be explained by the dose delivered to the base of the heart.

ES11.02 Advances in Thoracic Radiation in SCLC

ES11.02 Advances in Thoracic Radiation in SCLC

Dose-intensified Versus Conventional-dose Salvage Radiotherapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: The SAKK 09/10 Randomized Phase 3 Trial

BackgroundSalvage radiotherapy (SRT) is utilized for biochemical progression of prostate cancer after radical prostatectomy (RP). ObjectiveTo report the outcomes of the SAKK 09/10 trial comparing conventional and dose-intensified SRT. Design, setting, and participantsSAKK 09/10 was a randomized, multicenter, phase 3 trial that recruited men with biochemical progression after RP. InterventionPatients were randomly assigned to conventional-dose (64 Gy) or dose-intensified SRT (70 Gy) to the prostate bed without hormonal therapy. Outcome measurements and statistical analysisThe primary endpoint was freedom from biochemical progression (FFBP). Secondary endpoints included clinical progression-free survival (PFS), time to hormonal treatment, overall survival (OS), acute and late toxicity (Common Terminology Criteria for Adverse Events v4.0), and quality of life (QoL). Results and limitationsBetween February 2011 and April 2014, 350 patients were randomly assigned to 64 Gy (n = 175) or 70 Gy (n = 175). Median prostate-specific antigen at randomization was 0.3 ng/ml. After median follow-up of 6.2 yr, the median FFBP was 8.2 yr in the 64 Gy arm and 7.6 in the 70 Gy arm (log-rank p = 0.4), with a hazard ratio of 1.14 (95% confidence interval 0.82–1.60). The 6-year FFBP rates were 62% and 61%, respectively. No significant differences in clinical PFS, time to hormonal treatment, or OS were observed. Late grade 2 and 3 genitourinary toxicity was observed in 35 (21%) and 13 (7.9%) patients in the 64 Gy arm, and 46 (26%) and seven (4%) in the 70 Gy arm, respectively (p = 0.8). Late grade 2 and 3 gastrointestinal toxicity was observed in 12 (7.3%) and seven patients (4.2%) in the 64 Gy arm, and 35 (20%) and four (2.3%) in the 70 Gy arm, respectively (p = 0.009). There were no significant differences in QoL. ConclusionsConventional-dose SRT to the prostate bed is sufficient in patients with early biochemical progression of prostate cancer after RP. Patient summaryThe optimal radiation therapy dose for patients who have increased tumor markers after surgery for prostate cancer is unclear. We found that administering a higher dose only increased the gastrointestinal side effects without providing any benefits to the patient.This clinical trial is registered on ClinicalTrials.gov as NCT01272050.

Short Communication: Interim toxicity analysis for patients with limited stage small cell lung cancer (LSCLC) treated on CALGB 30610 (Alliance) / RTOG 0538

IntroductionThe CALGB 30610/RTOG 0538 randomized trial was designed to test whether high-dose thoracic radiotherapy (TRT) would improve survival compared with 45 Gy twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC). Two piloted experimental TRT regimens were of interest to study, 70 Gy daily (QD) and 61.2 Gy concomitant boost (CB). Driven by concerns about adequate patient accrual, a study design was employed that eliminated one experimental TRT arm based on early interim toxicity and tolerability, with the study then continuing as a traditional 2-arm phase III study. MethodsPatients with LSCLC were assigned to receive four cycles of cisplatin and etoposide chemotherapy with one of 3 TRT regimens starting with either the first or second cycle of chemotherapy. The interim endpoint was the cumulative highest toxicity calculated from a scoring system based on treatment-related grade 3 and higher toxicity and the ability to complete therapy in the experimental arms. ResultsThe final interim analysis was performed after 70 patients accrued to each experimental cohort, and a difference in treatment related toxicity scoring was not found (p = 0.739). Severe esophageal toxicity was comparable in both cohorts. Pulmonary toxicity was low overall, though 4 patients (5.7 %) on the 61.2 Gy arm developed grade 4 dyspnea, which was not observed in the 70 Gy arm. A protocol mandated decision was made to discontinue the 61.2 Gy arm following review of toxicity with the Data and Safety Monitoring Board. ConclusionA randomized trial design using a planned early interim toxicity analysis to discriminate between experimental treatment arms is feasible in a phase III setting. Refinement of the design could increase the likelihood of detecting clinically meaningful differences in toxicity in future studies.

Dose-intensified versus conventional dose-salvage radiotherapy for biochemically recurrent prostate cancer after prostatectomy: Six-year outcomes of the SAKK 09/10 randomized phase III trial.

194 Background: Salvage radiotherapy (RT) is often utilized in case of biochemical progression after radical prostatectomy (RP). Here we report the outcomes of the European SAKK 09/10 randomized phase 3 trial with the aim to compare effectiveness and tolerability of conventional vs. dose-intensified salvage RT. Methods: SAKK 09/10 is an open-label, multicenter, randomized phase 3 trial performed in 24 centers in Switzerland, Germany and Belgium. Men with biochemical progression (two consecutive rises with the final PSA &gt; 0.1 ng/mL or three consecutive rises) after RP with a PSA nadir of ≤ 0.4 ng/mL, with a PSA ≤ 2 ng/mL at randomization and without clinical evidence of macroscopic disease were recruited. Patients were randomly assigned to either conventional dose RT (64 Gy in 32 fractions) or dose-intensified RT (70 Gy in 35 fractions) directed to the prostate bed. Three-dimensional conformal RTor intensity-modulated RT/rotational techniques were used. The primary endpoint was freedom from biochemical progression (PSA ≥ 0.4 ng/mL and rising). Secondary endpoints included clinical progression-free survival, time to hormonal treatment, overall survival, acute and late toxicity (according to the NCI CTCAE v4.0) and quality of life (according to the EORTC QLQ-C30 and PR25). The trial was registered under NCT01272050 in clinicaltrials.gov. Results: Between 02/2011 and 04/2014, 350 patients were randomly assigned to 64 Gy (n = 175) or 70 Gy (n = 175), of whom 344 aged between 48 to 75 years were assessable for the intention-to-treat population. The median PSA at randomization was 0.3 ng/mL (range, 0.03-1.61 ng/mL). At the time of data cutoff (July 3, 2020), the median follow-up was 6.2 years (IQR 5.5-7.2) and a total of 138 biochemical progression events occurred. The estimated freedom from biochemical progression rate at 6 years was 62.3% (95% CI 54.2-69.4%) and 61.3% (95% CI 53.4-68.3%) for the 64 Gy and the 70 Gy arm, respectively, and the hazard ratio adjusted by stratification factors was 1.14 (95% CI 0.82-1.60; log-rank p = 0.44). No significant difference was found for clinical progression-free survival, time to hormonal treatment and overall survival between the two arms, respectively. Late grade 2 and 3 genitourinary toxicity was observed in 35 (21.2%) and 13 (7.9%) patients treated with 64 Gy, and in 46 (26.3%) and 7 (4%) patients with 70 Gy (p = 0.81). Lategrade 2 and 3 gastrointestinal toxicity was observed in 12 (7.3%) and 7 (4.2%) patients with 64 Gy, and in 35 (20%) and 4 (2.3%) patients with 70 Gy(p = 0.009). Quality of life data will be presented. Conclusions: Dose-intensified salvage RT to the prostate bed was not superior to conventional dose RT. However, dose-intensified salvage RT was associated with higher frequencies of late grade ≥ 2 gastrointestinal toxicity. Clinical trial information: NCT01272050.

RTOG0617 to Externally Validate Blood Cell ERCC1/2 Genotypic Signature as a Radiosensitivity Biomarker for Both Tumor and Normal Tissue for Individualized Dose Prescription

According to our previous finding of single Institutional data, a single nucleotide polymorphisms (SNPs) signature in DNA repair pathway genes ERCC1/ERCC2 may serve as a radiosensitivity biomarker for both tumor and normal tissue in patients with non-small cell lung cancer (NSCLC), and patients can be classified as sensitive or resistant accordingly for differential radiation dose interaction. Using patients enrolled in RTOG0617 a phase III randomized study on radiation dose, here we aimed to externally validate the above findings: i.e. patients with a sensitive genotype have better survival in the low-dose (60Gy) arm, while patients with a resistant genotype have better survival in the high-dose (74Gy) arm. Patients enrolled in RTOG0617 clinical trial with blood samples available for analysis were eligible to this study. DNA samples for genotyping were extracted from buffy-coat that were collected before commencement of treatment. A mass array system was used for genotyping. According to our previous finding, this study only analyzed rs11615 in ERCC1 and rs238406 in ERCC2 in the nucleotide excision repair (NER) pathway. Patients with CC-type in ERCC1-rs11615 and GG-type in ERCC2-rs238406 were classified as radio-resistant, and the remaining as radio-sensitive. Log rank test and Cox regression model were used for survival analysis. A total of 321 patients were eligible, with 275 of them had both ERCC1 and ERCC2 SNPs genotyped. The median follow-up was 68 (95% CI, 61-72) months. Among 163 assigned to 60 Gy arms, 67 patients carrying the resistant genotype had a median OS of 22 (16-29) months, comparing to a median OS of 31 (25-46) months for the sensitive genotype (P = 0.076, HR = 1.4 [95%CI: 0.96-2.01]). In 112 patients treated with 74 Gy, 36 patients carrying the resistant signature had a median survival of 31 (95% CI, 20-52) months, significantly better than a median OS of 20 (95% CI, 13-26) months in those carrying the sensitive signature (p = 0.025, HR = 0.59 [95% CI: 0.37-0.94]). The interaction between radio-sensitivity and RT dose group was significant (p = 0.004), suggesting that the ERCC1/2 SNP signature’s prognostic value significantly differed in 60Gy and 74Gy patients. This study of RTOG0617 phase III trial patients validated ERCC1/2 SNP signature as a radiosensitivity biomarker of both tumor and normal tissue, which explained the fact that high dose radiation decreased survival in patients treated with high dose radiation when they carry a radiation sensitive genotype in DNA repair pathway. While further prospective validation study with larger sample size may be needed, this study confirms the possibility of personalized dose prescription according to testing of genotypic signature of DNA repair pathway.