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BackgroundPatients with high‐risk prostate cancer (HRPC) have multiple accepted treatment options. Because there is no overall survival benefit of one option over another, appropriate treatment must consider patient life expectancy, quality of life, and cost.MethodsThe authors compared quality‐adjusted life years (QALYs) and cost effectiveness among treatment options for HRPC using a Markov model with three treatment arms: (1) external‐beam radiotherapy (EBRT) delivered with 20 fractions, (2) EBRT with 23 fractions followed by low‐dose‐rate (LDR) brachytherapy boost, or (3) radical prostatectomy alone. An exploratory analysis considered a simultaneous integrated boost according to the FLAME trial (ClinicalTrials.gov identifier NCT01168479).ResultsTreatment strategies were compared using the incremental cost‐effectiveness ratio (ICER). EBRT with LDR brachytherapy boost was a cost‐effective strategy (ICER, $20,929 per QALY gained). These results were most sensitive to variations in the biochemical failure rate. However, the results still demonstrated cost effectiveness for the brachytherapy boost paradigm, regardless of any tested parameter ranges. Probabilistic sensitivity analysis demonstrated that EBRT with LDR brachytherapy was favored in 52% of 100,000 Monte Carlo iterations. In an exploratory analysis, EBRT with a simultaneous integrated boost was also a cost‐effective strategy, resulting in an ICER of $62,607 per QALY gained; however, it was not cost effective compared with EBRT plus LDR brachytherapy boost.ConclusionsEBRT with LDR brachytherapy boost may be a cost‐effective treatment strategy compared with EBRT alone and radical prostatectomy for HRPC, demonstrating high‐value care. The current analysis suggests that a reduction in biochemical failure alone can result in cost‐effective care, despite no change in overall survival.

AbstractBackgroundThe objective of this study was to report acute changes in patient‐reported quality of life (PRQOL) using the 26‐item Expanded Prostate Index Composite (EPIC‐26) questionnaire in a prospective study using hypofractionated intensity‐modulated proton beam therapy (H‐IMPT) targeting the prostate and the pelvic lymph nodes for high‐risk or unfavorable intermediate‐risk prostate cancer.MethodsFifty‐five patients were enrolled. H‐IMPT consisted of 45 GyE to the pelvic lymph nodes and 67.5 GyE to the prostate and seminal vesicles in 25 fractions. PRQOL was assessed with the urinary incontinence (UI), urinary irritative/obstructive symptoms (UO), and bowel function (BF) domains of EPIC‐26 questionnaire. Mean changes in domain scores were analyzed from pretreatment to the end of treatment and 3 months posttreatment. A clinically meaningful change (or minimum important change) was defined as a score change > 50% of the baseline standard deviation.ResultsThe mean scores of UO, UI, and BF at baseline were 84.6, 91.1, and 95.3, respectively. At the end of treatment, there were statistically significant and clinically meaningful declines in UO and BF scores (−13.5 and −2.3, respectively), while the decline in UI score was statistically significant but not clinically meaningful (−13.7). A clinically meaningful decline in UO, UI, and BF scores occurred in 53.5%, 22.7%, and 73.2% of the patients, respectively. At 3 months posttreatment, all three mean scores showed an improvement, with fewer patients having a clinically meaningful decline in UO, UI, and BF scores (18.4%, 20.5%, and 45.0%, respectively). There was no significant reduction in the mean UO and UI scores compared to baseline, although the mean BF score remained lower than baseline and the difference was clinically meaningful.ConclusionsUO, UI, and BF scores of PRQOL declined at the end of H‐IMPT. UO and UI scores showed improvement at 3 months posttreatment and were similar to the baseline scores. However, BF score remained lower at 3 months posttreatment with a clinically meaningful decline.

AbstractPurpose/ObjectivesHolmium laser enucleation of the prostate (HoLEP) is commonly performed in patients with significant bladder outlet obstruction. However, there are few reports on the toxicity of external beam irradiation (RT) for prostate cancer in patients after prior HoLEP. In this study, we evaluate the side effects and treatment outcomes of RT after HoLEP.Materials/MethodsEighteen patients who had HoLEP and subsequently received RT for prostate cancer were included. Data collected included patient and disease characteristics, urinary function, and radiation dose. Acute and late urinary (GU) and gastrointestinal (GI) side effects were evaluated. Disease control and survival rates were calculated using Kaplan–Meier method.ResultsMedian follow‐up was 18 months (range: 4–46 months). Median prostate volume was 107 ml before HoLEP and 24 ml after HoLEP. Median International Prostate Symptom Score (IPSS) was 17 (range: 5–32) before HoLEP. Median decline in IPSS score after HoLEP was 7 (range: −2–21). On uroflow study, peak flow rate, and post‐void residual were significantly improved after HoLEP. After radiation, peak flow rate and average flow rate showed a decline but remained significantly improved compared to pre‐HoLEP measurements. Maximum acute Common Terminology Criteria for Adverse Events (CTCAE) adverse events were 12 grade 1 and 3 grade 2 for GU, and 3 grade 1 for GI, respectively. Maximum late adverse events were 13 grade 1 and 2 grade 2 for GU, and all grade 0 for GI, respectively. At last follow‐up, there were 8 grade 1 and 1 grade 2 late GU, and 3 grade 1 late GI adverse events, respectively. There was no significant increase in urinary incontinence after RT compared to before RT. The 18‐month biochemical control, local control, distant control rates were 78%, 94%, and 80%, respectively.ConclusionsPatients who received RT as definitive treatment for prostate cancer after prior HoLEP had low risk of serious acute and late side effects. HoLEP can be safely performed and should be considered in patients with significant bladder outlet obstruction and large prostate volume before RT.

Abstract Background: Partial breast irradiation (PBI) is an established option for selected patients with early stage breast cancer. The optimal technique, target volume and dose/fractionation for PBI has yet to be defined. The most studied regimen in North America (38.5 Gy in 10 fractions twice daily) has been associated with cosmetic deterioration. We hypothesized that condensing treatment and reducing the total administered dose could improve the therapeutic ratio in luminal breast cancer and DCIS based on emerging evidence that breast cancer is more sensitive than surrounding normal tissues to high dose fractions. Herein, we report cosmetic, tolerability, disease control, and patient reported outcomes of a novel ultra-accelerated PBI regimen. Methods: We conducted a single arm, three cohort trial of photon, proton, and brachytherapy PBI. Technique was selected at physician and patient discretion. Eligible women were age ≥ 50 years with estrogen receptor positive (ER+), sentinel lymph node negative invasive or in-situ breast cancer measuring ≤ 2.5 cm. The regimen was designed to have comparable biologically equivalent effect as 40 Gy in 15 fractions, assuming an α/β ratio of 3.5. Intracavitary brachytherapy target volume was lumpectomy cavity plus 1 cm and prescribed 21 Gy in 3 fractions. Photon and proton target volumes were post-operative tumor bed plus 1 cm and a 3 mm setup uncertainty margin, prescribed 21.9 Gy (RBE) in 3 fractions, and delivered with image guidance. The primary outcome was the percentage difference in patients with adverse cosmesis (defined as fair or poor cosmesis) at 3 years compared to baseline pre-PBI, as assessed by trained nurses using the 4-point Harvard breast cosmesis scale. Patients also completed quality of life surveys and self-reported cosmesis using the 4-point scale. Locoregional and distant recurrence-free survival was determined using the Kaplan-Meier method. Adverse events were assessed using CTCAE, v 4.0. Results: Between 2015 and 2017, 163 patients were treated: photons in 58, protons in 48, and brachytherapy in 57. Median patient age was 66 years. 129 (79%) patients had invasive breast cancer (all ER+) and 34 (21%) had DCIS (83% ER+). Median tumor size was 1.1 cm. Grade was 2-3 in 102 (63%). The median mean heart/ipsilateral lung doses were photons 0.1/1.6 Gy, protons <0.001/0.1 Gy, and brachytherapy 0.5/0.9 Gy. Median follow-up was 4.1 years (IQR 3.9-5.0). The proportion of patients with adverse cosmesis (by RN assessment) was 14.3% at baseline and 3.8% at 3 years, with four patients (1 photon, 1 proton, 2 brachytherapy) experiencing cosmetic deterioration at 3 years from baseline. The proportion with adverse cosmesis by self-report at 3 years was 2.4%, with three patients (1 photon, 1 proton, 1 brachytherapy) reporting cosmetic deterioration. Four patients developed locoregional recurrence (1 photons, 2 protons, 1 brachytherapy); three were local only and one was local and distant. 4-year locoregional recurrence and distant metastasis-free survival were 97.9% and 97.4%, respectively. There were 2 treatment related ≥ grade 2 late events (grade 2 fibrosis and grade 2 seroma, both brachytherapy associated), and no evidence of deterioration in patient-reported pain, fatigue, breast related or overall quality of life, as assessed by the patient reported outcomes version of the CTCAE, 10-point linear analog scales, and the breast cancer treatment outcomes scale. Conclusions: Ultra-accelerated 3-fraction PBI exquisitely spared normal tissues and was associated with favorable cosmetic outcomes, disease control, and excellent long-term tolerability. This ‘precision-radiotherapy’ approach may optimize the therapeutic ratio over more aggressive radiotherapy options as well as radiotherapy omission, particularly in patients with long life expectancies. Citation Format: Robert Mutter, Tina Hieken, Todd DeWees, Arslan Afzal, Stephanie Kenison, Laura Vallow, Christopher Deufel, Nicholas Remmes, Kathryn Ruddy, Judy Boughey, Keith Furutani, Amy Degnim, James Jakub, Tamara Vern-Gross, Dean Shumway, William Wong, Samir Patel, Lisa McGee, Minetta Liu, Carlos Vargas, Daniel Visscher, Bradley Stish, Deanna Pafundi, Mark Waddle, Michael Golafshar, Michele Halyard, Kimberly Corbin, Sean Park. Ultra-accelerated photon, proton, and brachytherapy partial breast irradiation: Primary results of the Mayo 3-fraction 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 PD7-03.

248 Background: Hypofractionated prostate cancer radiation has showed similar results in several prior phase III studies (PCG GU 003, PACE-B, and Hypo PC RT). However, prospective phase II-III clinical trial data testing 5 tx after prostatectomy is scarce. Methods: Between 2018 and 2019, 41 patients were treated after postprostatectomy for high risk features. 5 patients were treated adjuvantly, 36 for salvage including 8 with oligometastatic disease. Indications for adjuvant RT included a PSA < 0.2 and +margins, SVI, or EPE. Salvage RT was offered for PSA ≥0.2. Oligometastatic RT for patients with ≤5 RT targets. Staging included C11 PET for all cases. Total dose to the prostate bed was 30-32 Gy in 5tx QOD with IMRT, conebeam IGRT, and MRI registration. All salvage patients received ADT for 6 months and oligometastatic patients for 18 months. Dose to the metastatic sites was 30 in 5tx QOD. Of the 41 patients 8 also received SBRT to the sites of oligometastatic disease. We looked at clinical outcomes defining biochemical failure as a PSA > 0.2 after treatment, baseline adjusted CTC AE V5.0, baseline adjusted patient reported toxicities (PRO CTC AE), QOL (EPIC, PROMIS), and AUA was used for all cases. Results: Median follow up was 23 months (range 10-37). Pre-RT T stage was T2-T3b, with 47% being T3a-b; Pre RT Median PSA of 0.4 (range < 0.1-1.9); Median GS 8 (6-9); and (+) margins in 48.8%. Sites of oligometastatic disease radiated included the LN and bone. Treatment related AE were grade 0-1 in all cases, except for one patient with G2 GU incontinence. Overall QOL remained high during follow including Promis 10 overall, mental, and physical scores; urinary bother, irritative/obstructive, and AUA scores; bowel overall, bowel bother, and bowel function scores; and overall sexual, sexual function, and sexual bother scores remained at baseline levels during follow up. Only hormonal overall, hormonal function, and hormonal bother had lower scores at 3 months that recovered by 12 months in patients treated with ADT for 6 months and by 24 months in patients treated with ADT for 18 months. A total of 3 clinical failure have been seen; 2 patients with regional failures alone; and one with axial skeleton bony failures for 93% clinical control at median follow up of 23 months. All 3 patients with clinical failure were salvaged successfully with SBRT and all patients remain disease free at last follow up. A total 5 patients with raising PSAs alone have been seen. All patients have been re-staged with C11 PET. No failures in the prostate bed or previously radiated sites have been seen. Conclusions: Toxicity for RT over 5tx is lower than expected with only one case of grade 2 urinary incontinence. QOL scores remained high during follow up, minor changes in hormonal scores were seen during ADT, but recovered after. 30-32 Gy over 5 tx provided 100% control in radiated targets and metastatic sites. Clinical trial information: NCT03570827.

PURPOSE BIM activation is essential for epidermal growth factor receptor ( EGFR)-tyrosine kinase inhibitor (TKI)–triggered apoptosis in EGFR-mutant non–small-cell lung cancer (NSCLC). A deletion in the intron two of the BIM gene results in generation of alternatively spliced isoforms that impairs their apoptotic response to TKIs, conferring the NSCLC cells intrinsic resistance to these medications. Patients with both alterations have poor clinical evolution. The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus bevacizumab (Bev) versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletions ( BIMdel). MATERIALS AND METHODS A retrospective analysis was conducted. BIMdel was detected using polymerase chain reaction analysis and direct sequencing of DNA. BIM protein expression was investigated by immunohistochemistry, and BIM mRNA levels by reverse transcriptase-polymerase chain reaction. Clinical characteristics, overall survival, progression-free survival (PFS), overall response rate (ORR), and treatment-related adverse events were compared between both groups. RESULTS Thirty-three patients were included; 15 received EGFR-TKIs, and 18 received EGFR-TKIs plus Bev. The median age was 63 years, with a majority of recruited female patients. All included individuals had an Eastern Cooperative Oncology Group performance score of 2 or less. The addition of Bev resulted in a significantly higher ORR (94.4% v 40%, P > .001). Median PFS was longer with the use of the combination therapy (11.12 v 7.87 months; P = .001). Median overall survival tended to be longer in the EGFR-TKIs plus Bev (30.9 v 25.4 months; P = .06) but failed to reach statistical significance. Response in terms of both partial and complete as well as overall favorably affected PFS. CONCLUSION EGFR-TKIs plus Bev conferred a significantly higher ORR and PFS in advanced NSCLC patients with EGFR mutation and BIMdel. Further prospective studies are needed to validate these findings.

Abstract Purpose: The optimal salvage treatment for malignant glioma after prior radiotherapy (RT) is not well established. Proton therapy (PT) is an attractive treatment modality for reirradiation (ReRT) of recurrent disease; however, data are limited.Methods: The prospective, multi-institutional Proton Collaborative Group (PCG) registry was queried for patients with malignant glioma who previously received RT and underwent PT-ReRT between 7/2011-10/2018. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method and Cox proportional hazards regression analysis. Results: 109 consecutive patients were identified. Median follow-up was 11.2 months and median time interval (TI) from prior RT (median 59.3 Gy) to PT-ReRT (median 49.6 Gy) was 45.7 months. Primary histology was glioblastoma (n=62), oligodendroglioma (n=26), and astrocytoma (n=20). Median PFS and OS was 6.1 and 11.1 months, respectively. On UVA, improved PFS was associated with oligodendroglioma (HR 0.39) and astrocytoma (HR 0.55) histologies, WHO Grade III (HR 0.36), TI (HR 0.989), surgical resection (HR 0.39), and PT-ReRT dose ≥50 Gy (HR 0.59) (all p<0.03), while improved OS was associated with oligodendroglioma histology (HR 0.35), WHO grade III (HR 0.33), ECOG 0 (HR 0.47), TI (HR 0.985), and PT-ReRT dose ≥50 Gy (HR 0.58) (all p<0.04). Late Grade 3 toxicities occurred in 5.6% of patients with no attributable acute or late Grade 4-5 events.Conclusion: In the largest series of glioma PT-ReRT reported to date, retreatment appears well tolerated with acceptable outcomes and favorable toxicities compared to photon historical controls. Dose escalation achievable with PT may improve outcomes for well-selected patients.

Purpose: As patients with mediastinal lymphoma are typically young with curable disease, advanced radiation techniques such as proton therapy are often considered to minimize subacute and late toxicity. However, it is unclear which mediastinal lymphoma patients are treated with proton therapy. Within a prospective, multi-institutional proton registry, we characterized mediastinal lymphoma patients treated with proton therapy and assessed concordance with consensus recommendations published in 2018 by the International Lymphoma Radiation Oncology Group (ILROG). Methods: Eligible patients included those with lymphoma of the mediastinum treated exclusively with proton therapy for whom digital imaging and communications in medicine (DICOM) treatment data were available for review. Given the challenge with reliably visualizing the left mainstem coronary artery, the inferior-most aspect of the left pulmonary artery (PA) was used as a surrogate. Extent of disease was characterized as upper mediastinum (above level of left PA), middle mediastinum (below left PA but at or above level of T8), or low mediastinum (below T8). Results: Between November 2012 and April 2019, 56 patients were treated and met inclusion criteria. Patients treated with proton therapy were young (median, 24 y; range: 12 to 88), with over half being female (55%). Patients were most commonly treated at initial diagnosis (86%) and had Hodgkin lymphoma (79%). Most patients (96%) had mediastinal disease that extended down to the level of the heart: 48% had middle and 48% had low mediastinal involvement. Nearly all patients (96%) met the ILROG consensus recommendations: 95% had lower mediastinal disease, 46% were young females, and 9% were heavily pretreated. Heart (mean) and lung dose (mean, V5, V20) were significantly associated with lowest extent of mediastinal disease. Conclusions: Mediastinal lymphoma patients treated with proton therapy are typically young with lower mediastinal involvement. Within a prospective, multi-institutional proton registry, nearly all treated patients fit the ILROG consensus recommendations regarding which mediastinal lymphoma patients may most benefit from proton therapy.

Abstract Background: Recent advances in radiotherapy techniques have allowed ablative doses to be safely delivered to inoperable liver tumors. In this setting, proton beam radiotherapy (PBT) provides the means to escalate radiation dose to the target volume while sparing the uninvolved liver. This study evaluated the safety and efficacy of hypofractionated PBT for liver tumors, predominantly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).Methods: We evaluated the prospective registry of the Proton Collaborative Group for patients undergoing definitive PBT for liver tumors. Demographic, clinicopathologic, toxicity, and dosimetry information were compiled.Results: To date, 63 patients have been treated at 9 institutions between 2013-2019. Thirty (48%) had HCC and 25 (40%) had ICC. The median dose and biological equivalent dose (BED) delivered was 58.05 GyE (range, 32.5-75) and 80.5 GyE (range, 53.6-100), respectively. The median mean liver BED was 13.9 GyE. Three (4.8%) patients experienced at least one grade ³3 toxicity. With median follow-up of 5.1 months (range, 0.1-40.8), the local control (LC) rate at 1 year was 91.2% for HCC and 90.9% for ICC. The 1-year LC was significantly higher (95.7%) for patients receiving BED greater than 75.2 GyE than for patients receiving BED of 75.2 GyE or lower (84.6%, p = 0.029). The overall survival rate at 1 year was 65.6% for HCC and 81.8% for ICC. Conclusions: Hypofractionated PBT results in excellent LC, sparing of the uninvolved liver, and low toxicity, even in the setting of dose-escalation. Higher dose correlates with improved LC, highlighting the importance of PBT especially in patients with recurrent or bulky disease.