Late Toxicity Research Articles

Dosimetry Predictors of Late Skin Reactions after Whole Breast Radiotherapy on a Large Mono-Institutional Cohort of Patients

To develop an NTCP model predicting late skin toxicity using dosimetric parameters from the breast dermis to identify possible RT constraints on such a structure. The skin structure was defined as the 5 mm inner isotropic expansion from the outer CT body contour. It was retrospectively segmented on a large mono-Institutional cohort of early-stage breast cancer patients enrolled between 2009 and 2017 (n = 1066). Patients were treated with tangential-field RT, delivering 40 Gy in 15 fractions without a RT boost. Toxicity was reported during FU using SOMA/LENT scoring. The study endpoint was moderate-severe late toxicity consisting of Fibrosis-Atrophy-Telangiectasia-Pain (FATP G2+) developed within 42 months after RT completion. Automatic delineation of skin and DVH extraction were accomplished by scripting using the MIM_assistant software. Also, the impact of changes in the dose calculation algorithms during enrolment time was quantified. A logistic model was created by combining multifactorial variables, considering both clinical factors and the absolute skin DVH (cc). Variance Inflation Factor (VIF) was performed to reduce the multicollinearity. Repeated 5-fold cross-validation with SMOTE approach to overcome the class unbalance was applied for model feature selection. The predictive model was then developed on the entire population due to the limited G2+ events. The FATP G2+ rate was 3.8% with 40/1066 experiencing late toxicity. Among them, a 40% had already developed acute symptoms after RT completion showing a consequential effect. The multicollinearity analysis selected 27 clinical-treatment-dosimetric factors. After repeated (20 times) 5-fold cross-validation, the best-performing model included Post-Surgery Cosmetic alterations, Aromatase Inhibitors (as a protective factor), V20 Gy (50% of the prescribed dose - DVH plateau region) and V42 Gy (105% of the prescribed dose - DVH high-dose tail). Accuracy and f1-score were 0.76 and 0.58 in both training and test sets, providing good reliability for selected variables. AUC for the final model on the entire population was 0.76+/-0.04. We quantified the association between fibrosis and skin DVH when delivering 40 Gy in 15fr. The model suggested an independent role of V20 and V42 Gy and a heavy risk modulation by surgical effects and aromatase inhibitors. This last factor could interfere with adipose tissue and water-content distribution within the breast. For this purpose, a CT-based densitometry characterization of toxicity patients is ongoing.

Acute and Late Toxicities in Patients with Collagen Vascular Disease Receiving Curative-Intent Intensity-Modulated Radiotherapy to the Head and Neck Region

Historically, collagen vascular disease (CVD) was considered at least a relative contraindication to radiotherapy (RT). However, more recent meta-analyses suggest that for patients with certain CVDs such as rheumatoid arthritis (RA), there may not be an increased risk for severe toxicities, while for patients with CVDs such as systemic lupus erythematosus (SLE), dermatomyositis (DM) and scleroderma, there may be as high as a 2- to 4-fold risk for severe toxicities compared to patients without CVD. There are also data to suggest that patients with head and neck cancer (HNC) and comorbid CVD are at especially high risk of severe toxicities from RT. This study evaluated the hypothesis that among patients with HNC treated with curative-intent intensity-modulated radiation therapy (IMRT), patients with SLE or DM were more likely to have had late grade ≥3 toxicity rates compared to patients with other CVDs. A total of 23 patients who had HNC with comorbid CVD and received IMRT between 2005-2022 were included. Acute (≤90 days after completion of RT) and late (>90 days) toxicities were retrospectively classified using CTCAE v5.0. Toxicity rates were compared across CVD groups using Chi-squared tests. Median follow-up was 56.3 months. The most common CVDs were RA (9 patients, 39%), SLE (4 patients, 17%), and DM (4 patients, 17%). Median total RT dose was 66 Gy (range: 48-70 Gy), in 1.8-2.4 Gy fractions. Nine (39%) patients received concurrent chemotherapy. 14 (61%) patients had mucosal squamous cell carcinoma (SCC), 3 (13%) had cutaneous SCC, 2 (9%) had nasal cavity/paranasal sinus tumors, 2 (9%) had salivary gland tumors, 1 (4%) had cutaneous melanoma, and 1 (4%) had mucosal melanoma. Eight (35%) patients experienced acute grade ≥3 toxicities, and 3 (13%) patients experienced late grade ≥3 toxicities (Table 1). No patients had grade≥4 toxicities. Patients with SLE or DM did not have significantly higher risk of late grade ≥3 toxicities compared to those with other CVDs (25% vs. 7%, p = 0.21). In this small sample size of patients with HNC and comorbid CVD, definitive or post-operative IMRT was associated with approximately 35% acute and 15% late severe toxicity rates. While SLE/DM were associated with >3-fold late grade ≥3 toxicities, this association needs to be confirmed with larger data sets.

5-Year Results from a Prospective Phase II Trial of Ten-Fractions Hypofractionated Radiotherapy in Locally Advanced Breast Cancer

There is a growing interest for adjuvant loco-regional hypofractionated radiotherapy (Hypo-RT) regimens in patients (pts) undergoing surgery for locally advanced breast cancer (LABC). We report the 5-year results of a phase II study on Hypo-RT targeting the primary and regional lymph nodes in ten fractions (fxs). A schedule of 34 Gy/10 fxs/2 wks to the whole breast/chest wall and to the draining lymph nodes was used; an optional single fraction 8 Gy boost was administered with electrons to the tumor bed in patients who had undergone conservative surgery. Both acute (CTCAE 4.0) and late (LENT/SOMA) toxicities were collected. All pts but those who underwent mastectomy without reconstruction or with temporary expander were also asked to rate their cosmetic outcome according to the Harvard scale. Toxicity was assessed weekly during RT and then at each follow-up (fup) examination (1, 3, 6 months and then yearly). Late toxicity was assessed starting from 3 months after the end of Hypo-RT and loco-regional toxicity was prospectively collected. Cancer related endpoints in terms of loco-regional (LR) recurrence, distant metastasis, specific disease- free survival and overall survival (OS) were evaluated from the date of RT start to the diagnosis of local relapse/distant metastases or the last fup respectively. From February 2015 to March 2019, 59 women (median age 60 yrs, IQR: 48.3-68.8 yrs) with stage II to IIIA breast cancer who underwent axillary dissection and conservative surgery (83%) or mastectomy (17%) were accrued. One patient was lost to fup immediately after the end of RT. Of the 58 evaluable pts, 56 underwent neo-adjuvant (27.5%) or adjuvant (57%) chemotherapy and 15.5% exclusive hormone therapy as well. Trastuzumab was administered concomitant to RT in HER2 positive pts (25%). All pts completed treatment as planned. No grade 2+ acute toxicity was recorded. At the median fup of 63 months (range: 25-92 mths), the cumulative incidence of any grade locoregional late toxicity estimated with the Kaplan-Meier method is 43.4% (95% CI) (30.0% and 46.1% for patients undergone mastectomy and lumpectomy, respectively). Peak 2 events have been observed for fibrosis (1 pt, 1.7%), telangiectasia (1 pts, 1.7%) and lymphoedema (1 pt, 1.7%). One patient (1.7%) experienced grade 3 breast retraction. Of all eligible patients (N = 51), patient reported cosmetic outcome was excellent, good, fair and poor in 51.7%, 22.4%, 10.3% and 3.4%, respectively. No late lung toxicity was observed. The actuarial LR control rate at 5 years is 98%; for distant metastasis-free survival, specific disease-free survival and OS rates are 89.2%, 80.8% and 93.7% respectively. Our results support the activity of a 10-fxs Hypo-RT schedule targeting the primary site as well as the draining lymph node stations after surgery for LABC.

Multi-Institutional Phase II Trial Using Dose Escalated Five Fraction Stereotactic Partial Breast Irradiation (S-PBI) with GammaPodTM for Early-Stage Breast Cancer

We report on our early experience of a multi-institutional phase II study of dose escalated five fraction stereotactic partial breast irradiation (S-PBI) for early-stage breast cancer after partial mastectomy using the GammaPodTM stereotactic radiation system. Patient eligibility included DCIS or invasive epithelial histologies, AJCC clinical stage 0, I, or II with tumor size < 3 cm, and negative margins. Prior safety of Phase I dose escalation has been reported. Dose was 40 Gy delivered in 5 fractions to the CTV, and minimum dose 30 Gy in 5 fractions to the PTV. CTV margin was 1 cm and PTV margin 3 mm. For PTV cavities larger than 100cc, dose was reduced to 35Gy in 5 fractions to the CTV and 30 Gy in 5 fractions to the PTV. Primary endpoint of the study is to determine the 3-year patient global cosmesis score (4-point scale excellent, good, fair, or poor) and adverse cosmesis using a dose escalated approach with smaller PTV margins than conventional methods. Both patients and physicians completed baseline and subsequent cosmesis outcome questionnaires. Treatment related toxicity was graded using the NCI version 4.0 and RTOG/EORTC late radiation scale. From 3/2019-10/2021, 74 patients were treated respectively. Of these, 38 were treated to 40Gy and 36 were treated to 35 Gy. Median follow up (f/u) was 24 months (mo), range (r) 3-39mo. Median age was 63 years (r 43-77). Histology included 28 DCIS, and 46 invasive carcinomas. 45/46 invasive tumors were ER+. 60/74 (81%) patients received endocrine therapy, and 7/74 patient received chemotherapy. There were 221 acute grade 1 toxicities, and 28 Grade 2 toxicities. No grade 3 or higher acute toxicities were reported (< 90 days). The most common Grade 2 toxicities were radiation dermatitis (10), breast pain (8), blister (4), skin infection (2), nipple discharge (2), and fatigue (2). In the late period, there were 54 Grade 1 late toxicities, 4 Grade 2 late toxicities, and no Grade 3 or higher late toxicities. Grade 2 toxicities included fibrosis (2), and pain (2). Two patients developed grade 1 asymptomatic nonpalpable fat necrosis both diagnosed at 12 months after radiation treatments. The most common grade 1 late toxicities were breast pain (14), hyperpigmentation (8), fibrosis (10), and fatigue (5). Physicians scored cosmesis excellent or good 70/73 (95.8%), 58/60 (96.7%), 36/36 (100%),17/17(100%) respectively at baseline, 12 months, 24 months, and 36months post SBRT, while patients scored the same periods 62/71 (83.7%), 53/59 (89.8%), 33/36 (91.6%), 17/18 (94.4%). There have been no reports of disease recurrences. Results at 24-month median follow-up, of our dose escalated stereotactic partial breast 5 fraction regimen, has low acute and late toxicity, while maintaining high proportion of excellent/good cosmetic outcomes. Continued analysis of all cohorts is in progress. gov identifier is NCT03581136.

Phase I-II Study of Prone Hypofractionated Accelerated Breast and Nodal Intensity Modulated Radiation Therapy

In patients (pts) with breast cancer, prone radiation therapy (RT) has been shown to reduce heart and lung dose which may decrease late toxicity. Routinely used for whole breast irradiation, its use to treat regional lymph nodes (LNs) is not widespread. In this phase I-II study, pts treated with partial mastectomy or mastectomy with 1-5 pathologically involved LNs underwent whole breast or post-mastectomy RT plus regional nodal irradiation using IMRT to the supraclavicular and level III axillary LNs. Pts who underwent sentinel LN biopsy (SLNB) alone (no axillary dissection) had the level I and II axillary LNs included in the RT field. 40.5Gy in 15 daily 2.7Gy fractions with daily concomitant 0.5Gy tumor bed boost was prescribed. Normal tissue dose constraints included heart V5Gy<5%, ipsilateral lung V10Gy<20%, contralateral lung V5Gy<15%, ipsilateral brachial plexus (BP) maximal dose (Dmax)<43Gy, spinal cord Dmax≤37.5Gy, spinal cord + 0.5cm Dmax<41Gy, thyroid contralateral lobe Dmax<16Gy, esophagus V30Gy<50% and Dmax≤40.5Gy. The primary endpoints were dosimetric feasibility and incidence of >grade 2 acute toxicity according to CTCAE, v3.0. The secondary endpoint was late toxicity. Exploratory outcomes were local recurrence, disease free survival (DFS), and overall survival (OS). Between January 2011 to December 2016, 97 pts with stage IB-IIA breast cancer were enrolled. 66 pts underwent partial mastectomy and 31 pts underwent mastectomy. 16 pts had SLNB alone. 33% (95% CI: 23.8%, 43.3%) met all protocol dose constraints. Heart, contralateral lung, spinal cord and esophagus V30Gy constraints were met by all pts. The ipsilateral lung constraint was met in 95% (95% CI: 88.6%, 98.4%) of plans with a mean V10Gy of 9.44% (SD: 6.08). The BP Dmax constraint was exceeded in 31.6% (95% CI: 22.4%, 41.9%) of plans with a mean increase of 2.86 Gy (SD: 7.92 Gy) over target. The esophageal Dmax<40.5Gy constraint was exceeded in 6 plans with an increase in 0.74 Gy (SD: 0.46 Gy) over target. There were no grade 3 acute toxicities meeting the primary toxicity endpoint. Common acute low-grade toxicities by pt included fatigue (grade 1: 54 [56%]; grade 2: 2 [2%]), esophagitis (grade 1: 8 [8%]; grade 2: 2 [2%]), dermatitis (grade 1: 81 [84%]; grade 2: 6 [6%]). At median and maximum follow up of 8.02 (IQR: 3.31) and 13.3 years, respectively, there were 2 local recurrences (2.1%). DFS and OS were 86.6% (95% CI: 78.2%, 92.7%) and 90.7% (95% CI: 83.1%, 95.7%), respectively. The incidence of pts with maximum grade 1, 2 and 3 late toxicities were 39 (40%), 14 (14%), and 2 (2%), respectively. The maximum grade late toxicities included 1 grade 3 retraction and 2 grade 3 asymmetries. There was no brachial plexopathy or pneumonitis. Patients treated with prone hypofractionated hybrid breast/chest wall tangents and IMRT to the regional LNs demonstrate excellent dosimetry to the heart, lungs and spinal cord, minimal acute and late toxicity and excellent clinical outcomes. PMID: 26723552.

Late Toxicity and Patient Satisfaction in Hypofractionated Post-Mastectomy Radiotherapy after Immediate-Autologous Reconstruction

Immediate autologous reconstruction (IAR) is increasingly being used in the context of breast cancer patients (BCP) treated with mastectomy with the need for subsequent radiotherapy treatment. Currently in clinical practice, despite the fact that conventional fractionated RT (CFRT) has been the standard schedule, hypofractionation schemes are becoming increasingly common. Although no results have been reported on tolerance, late toxicity and satisfaction with treatment in this setting. Our aim was to evaluate late side-effects and patient´s satisfaction receiving PMRT after IAR, comparing CFRT vs HFRT. Between June 2015 and February 2020, 47 patients received either CF or HF PMRT after IAR in a tertiary hospital. IAR was performed with latissimus dorsi (LD) or deep inferior epigastric perforator (DIEP) flaps at the time of mastectomy. The prescribed dose was 50 Gy over 25 fractions in the CF schedule and 40.05 Gy over 15 fractions in the HF schedule. The target volume to be treated was the reconstructed chest-wall and the axillary-supraclavicular nodes if indicated, using intensity-modulated radiotherapy treatment technique. Late toxicity was evaluated using CTCAE v.5.0 criteria, and patient´s global satisfaction was assessed using a self-evaluation questionnaire, in which patients answered a series of selected questions related to radiation therapy from the BREAST-Q questionnaire, from 1-5 points. Median age was 48 years (28-77) and median follow-up was 51 months (27-99). 25 patients received HFRT and 22 CFRT. Late side effects after PMRT and tolerance until 3 years with both schedules are shown in Table 1. No relationship was found between incidence of late side effects and RT fractionation. Mean patient´s satisfaction was 3.8 in the CFRT schedule and 4 in the HFRT schedule. According to our findings, HFRT after IAR in post-mastectomy setting seems to be safe and well tolerated, with no high rates of severe late toxicity and with a good level of satisfaction of the treated patients. Table 1. Three years side effects of CRFT and HFRT radiotherapy after mastectomy and immediate autologous reconstruction in 47 patients.

Safety of Radiation Therapy for Treatment of Malignancy in Patients with Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) has been considered a relative contraindication to radiation therapy (RT) due to the potential greater risk of RT-induced toxicities, however, there is limited toxicity data using modern RT techniques. This study aims to assess toxicity outcomes in patients with IBD treated with abdominal or pelvic RT. After institutional review board approval, patients with IBD who received RT to the abdomen or pelvis were filtered from an institutional research repository and their electronic medical records were reviewed. Acute toxicity was defined as that occurring within 3 months of RT. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Univariable Cox proportional hazards regression was used to assess rates of grade ≥2 toxicity-free survival. We identified 62 patients with median age of 69 years (interquartile range [IQR] 62-77) who received RT from 2006-2022. Median follow up was 15 months (IQR 4-33). Most patients were male (42; 68%) and had a diagnosis of ulcerative colitis (44; 71%). The most common primary malignancy was colorectal/anal (26; 42%). Intensity-modulated RT (IMRT) was most frequently used (38; 61%) followed by 3-dimensional conformal RT (3D-CRT) (12; 19%) and stereotactic body RT (SBRT)/brachytherapy (12; 19%). For IMRT/3D-CRT, median dose delivered was 50 Gy (IQR 49-59) in 25 fractions (IQR 25-30), and median maximum dose (Dmax) to bowel was 48 Gy (IQR 43-52); whereas for SBRT/brachytherapy, the median dose was 32 Gy (IQR 27-40) in 3 fractions (IQR 2-5) and median bowel Dmax was 32 Gy (IQR 20-37). The median biologically effective dose delivered with an assumed alpha/beta ratio of 10 (BED10) across all RT modalities was 63 Gy (IQR 60-72). After initiation of RT, 31 patients (50%) and 14 patients (23%) experienced grade ≥2 acute and late toxicity, respectively. Thirteen patients (21%) and 7 patients (11%) experienced grade 3 acute and late toxicity, respectively. No patients experienced grade >3 toxicity. Acute toxicity resulted in interruption to RT for 5 patients (8%), 2 of which did not resume RT. Four patients (6%) required adjustment to chemotherapy or IBD medication dosage as a result of their acute toxicity. Median time from RT start to acute toxicity onset was 41 days (IQR 32-46), whereas median time to onset of late toxicity was 9 months (IQR 5-15). The most common acute and late toxicities were diarrhea (21; 34%) and bowel obstruction/perforation/fistula (4; 6%), respectively. Rates of grade ≥2 toxicity-free survival overtime were not significantly associated with IBD status (active vs quiescent), delivered BED10, or bowel Dmax BED3. In patients with IBD treated with abdominal or pelvic RT for malignancy, RT was feasible with acceptable rates of toxicity and active versus quiescent IBD status did not impact toxicity outcomes. Future research is needed to elucidate specific dose constraints when treating patients with IBD.

A Multicenter Study of Clinician and Patient Reported Acute and Late Toxicity after Radical (Chemo)Radiotherapy for Non-Endemic Nasopharyngeal Cancer

Curative (chemo)radiotherapy ((CT)RT) for Nasopharyngeal cancers (NPC) achieves excellent disease control but is associated with significant late toxicities despite modern treatment delivery. Contemporary late toxicity data, including patient reported outcomes (PROs), is limited in the non-endemic population; we present a large contemporary series of toxicity outcomes and late PROs following treatment of non-endemic NPC. Adult patients completing radical (CT)RT for primary NPC between February 2016 and 2020 at 7 large UK cancer centers were identified on institutional databases. Patients were excluded if they had prior head and neck cancer or prior therapeutic head and neck surgery (except neck dissection). Patients with an active other cancer were excluded from PRO assessment. Demographic, treatment, acute toxicity and outcome data were collected retrospectively from patient records. Disease-free patients were invited to complete an M.D. Anderson Dysphagia Index (MDADI) and University of Washington (UoW) Quality of Life (QoL) PROs questionnaires. A total of 180 eligible patients were identified: 68% male, median age 54 years, 11% ≥70 years. EBV status was positive in 61% (unknown 12%). Patients had stage I (5%), II (22%), III (37%), IV (36%) disease; 95% were performance status ≤1 at baseline. Median follow-up was 31.2 months (range 0-68). A total of 54% received 70Gy in 33-35# and 43% received 65-66 Gy in 30-33#. 66% received induction and 65% received concurrent chemotherapy. 9.5% had residual disease at the first follow-up scan. Subsequent locoregional or distant recurrence occurred in 5% and 12% respectively. At last assessment, 84% patients were alive, 16% had died (of which 70% had active disease). Acute treatment toxicity included: 63% of patients required enteral support (median duration 98 days) with 9% a feeding tube at 1 year post treatment. 18% G3 dermatitis, 53% G3 mucositis. 82% requiring opioids and 40% admitted for symptom management. 90 patients completed the PROs (76% response rate) at a median of 37.8 months post treatment (Table 1). These demonstrate significant QoL detriment: 28% report significant pain, 24% require regular analgesia, and 59% report significant impact on daily activity. This was found to persist at different timepoints (not shown). Excellent cancer survival outcomes are seen in a non-selected, non-endemic NPC population. However significant acute and late toxicity following radical treatment is identified which can profoundly negatively impact QoL in a relatively young cohort. This highlights the importance of ongoing efforts to reduce toxicity and supports the prospective evaluation of potential toxicity sparing technologies, such as proton beam radiotherapy.

Late Urinary Toxicity and QoL with Curative Radiotherapy for High-Risk Prostate Cancer: Dose-Effect Relations in the POP-RT Randomized Phase III Trial

Whole pelvic radiotherapy (WPRT) showed better biochemical failure-free survival and metastasis-free survival than prostate-only radiotherapy (PORT) in the phase III randomized POP-RT trial for high and very high-risk prostate cancer, albeit with higher RTOG grade 2 late urinary toxicity. We report updated long term, symptom-wise comparison and dose-effect relations from this trial. Late urinary toxicity, and cumulative severity of each symptom over the follow-up period was graded using CTCAE v5.0. Grade 2+ toxicities were compared between the trial arms by chi square test. Bladder dosimetry in 5-Gy increments (V5, V10, V15...V65 Gy, V68 Gy) from the trial database of approved radiotherapy plans, was compared for each urinary symptom and overall late gr2+ toxicity by student t-test. Observed differences in dosimetric parameters were tested using multivariable logistic regression analysis, including age at diagnosis, known diabetes, tumor stage, trial arm, and prior transurethral resection of prostate (TURP). Urinary QOL scores were compared between arms using generalised linear mixed model. Combined late symptom-wise toxicity and dose-volume data were available for analysis for 193/224 patients. At a median follow-up of 75 months, cumulative CTCAE gr2+ late urinary toxicity remained higher with WPRT than PORT, though not statistically significant (36.5% vs 26.8%, p = 0.15). Grade 3 toxicity was low and similar in both arms. Symptom-wise cumulative rates showed no significant difference between arms (Table 1). Dosimetric comparison showed significantly higher bladder V5-V15 in patients with gr2+ toxicity over those with <gr2 urinary toxicity. On symptom-wise analysis, V5-V40 range was significantly higher for presence of dysuria, hematuria, and urgency. No significant differences were observed over higher dose range for any urinary symptom. On multivariable analysis, no significant association was identifiable between bladder dosimetry and urinary symptoms. Urinary QOL scores was similar between both the arms for all the symptoms. Compared to prostate-only radiotherapy, whole pelvic radiotherapy resulted similar Grade 3 urinary toxicity of about 5% with about 10% higher cumulative grade 2+ urinary toxicity over long term follow up. This difference was not reflected in patient-reported QOL. WPRT particularly increased urgency and hematuria. Larger bladder volume being irradiated with 5Gy to 15Gy dose range could contribute to increase in urinary symptoms.

Clinical Outcomes with Triple Tandem Brachytherapy for Medically Inoperable Endometrial Cancer in a Predominantly Black Patient Population

Radiation outcomes for Black patients with medically inoperable endometrial cancer (MIEC) is limited, despite this demographic comprising a higher proportion of the MIEC patient population. We report clinical outcomes and toxicities using triple tandem brachytherapy (TTB) with or without external beam radiation therapy (EBRT) for MIEC in predominantly Black patients. An IRB approved retrospective review was performed of all MIEC patients treated definitively with TTB ± EBRT from 2014-2021 at a single institution. Patients were divided based on stage. Group 1 = FIGO stage 1A/1B and Group 2 = FIGO stage 2-4B. Patients with cervical involvement were treated with TTB + ovoids. The Kaplan-Meier estimates were generated to estimate overall survival (OS) and local failure-free survival (LFFS). Local control (LC) was evaluated clinically. Acute and late toxicities were evaluated. Planning parameters for target volume(s) and OARs (organs at risk) were per ABS guidelines. Statistics reported are median values and ranges. Of 30 patients, 93.3% received TTB + EBRT. Mean age at diagnosis was 65.3 years (40.5-88.7 years). 70% of patients were Black. Median prescribed doses were 45 Gy (range: 21-50.4 Gy) for EBRT and 22.25 Gy (range: 16.5-49.1 Gy) for brachytherapy. Median BMI was 48.1 (27.8- 69) and Charlson Comorbidity Index was 4 (1-11). Patient stages were FIGO 1A/B (n = 19), 2 (n = 1), 3 (n = 1), 3b (n = 1), 3C1 (n = 3), 3C2 (n = 2), and 4B (n = 2) due to inguinal lymphadenopathy. 90% had endometrioid histology while 6.7% and 3.3% had clear cell and serous carcinoma, respectively. Median follow up was 32.1 months (1.7-93.6). Median OS for Group 1 was 50.9 months and 43.5 months for Group 2, while 1-/4-year OS was 84.2%/54.4% and 90.9%/17.5% for Group 1 and 2, respectively (p = 0.616). 53.3% of patients died of non-EC causes. The 1-/4-year LFFS was 100%/93.3% for Group 1 and 90%/70.5% for Group 2 (p = 0.113). Four patients (13.3%) developed recurrence (stage 1A/B, 2, 3C1, and 4B), but only 1 died of disease (Stage 2 with clear cell histology). After EBRT but pre-TTB, 50% (n = 15) and 16.6% (n = 5) had acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicities, respectively. After TTB treatment, 2 more patients developed acute grade 2 GU toxicity. Late toxicities were Grade 2: GU (n = 1) and GI (n = 1) and Grade 4 GI bleed (n = 1) treated with argon plasma coagulation. TTB ± EBRT for MIEC in predominantly Black patients was associated with excellent LFFS and acceptable toxicity rates, especially in early-stage MIEC with endometrioid histology. Furthermore, even in patients at high risk of death from other causes, LC may help preserve quality of life. Additional studies are needed to evaluate and optimize outcomes for Black patients with MIEC.

The KRAS-Variant and Cetuximab in HPV-Positive Oropharyngeal Cancer in NRG/RTOG 1016

NRG/RTOG 1016 was a non-inferiority phase III trial comparing radiation with cisplatin versus cetuximab monotherapy for patients with HPV-positive oropharyngeal squamous cell carcinoma (SCC). The trial did not meet the non-inferiority criteria for overall survival (OS) and had significantly worse progression-free survival (PFS) and locoregional failure (LRF) in patients treated with cetuximab. Based on prior evidence that HNSCC patients with a germ-line mutation in KRAS (the KRAS-variant) had a positive response to radiation with cisplatin plus cetuximab without increased toxicity, samples from RTOG 1016 were used to test the protocol-specified hypothesis that KRAS-variant patients will have better outcomes when receiving IMRT + cetuximab monotherapy compared to IMRT + cisplatin. The KRAS-variant was tested in 562 samples at MiraDx, a CLIA-certified laboratory. OS, PFS, LRF, and distant metastases (DM) were as defined per the RTOG 1016 protocol, and hazard ratios (HRs) were estimated by (cause-specific) Cox models. Negative binomial regression was used to model the number of treatment-related acute and late (≤ and > 180 days from end of treatment, respectively) grade 3-5 adverse events. To assess the predictive role of the KRAS-variant, all models included KRAS, assigned treatment, and their interaction, with the interaction tested at two-sided 0.05. HRs and toxicity ratios are expressed as IMRT + cetuximab / IMRT + cisplatin. The prevalence of the KRAS-variant was 16% with similar patient and tumor characteristics and well-balanced treatment arms for variant and non-variant patients. Median follow-up was 8.6 years. There was no significant interaction between KRAS and treatment for OS (p = 0.99), PFS (p = 0.56), LRF (p = 0.09), or DM (p = 0.19) (Table 1). In KRAS-variant patients the mean acute and late toxicity ratios were 0.53 (95% CI 0.36, 0.80) and 1.62 (95% CI 0.57, 4.62). In non-variant patients, the mean acute and late toxicity ratios were 0.80 (95% CI 0.67, 0.95) and 0.55 (95% CI 0.35, 0.87), respectively. The interaction of KRAS and treatment was not significant for acute (p = 0.07) or late toxicity (p = 0.07). While this study does not directly refute prior evidence that KRAS-variant patients benefit from radiation + cisplatin and cetuximab, this study does not support the hypothesis that the KRAS-variant is a predictive biomarker of improved outcome in HPV+ oropharyngeal SCC patients treated with IMRT + cetuximab alone, and suggests that for KRAS-variant patients, potential benefits in LRF and acute toxicity with cetuximab may be offset by worse DM and worse late toxicity.

Effectiveness and Toxicity of Five Fraction Prone Accelerated Partial Breast Irradiation

Accelerated partial breast irradiation (APBI) after breast conserving therapy (BCT) is increasingly used to treat women with early stage breast cancer. Our institution was an early adopter of 5-fraction ABPI and delivers APBI primarily to patients in the prone position. This study reports long term oncologic and cosmetic outcome in a large cohort of women treated with 5-fraction external beam APBI. We included patients receiving APBI 600 cGy × 5 fx delivered every other day or every day between 2010 and 2022. Late toxicities and clinician and patient rated cosmesis were evaluated for patients with > 6 month follow up. Univariate and multivariate logistic regression models were used to identify clinical and dosimetric factors associated with development of acute and late toxicities, clinician and patient rated cosmesis. All statistical tests were two-sided, and the null hypothesis was rejected for p<0.05. Kaplan Meier methodology was used to calculate overall survival (OS), disease-free survival (DFS) and locoregional recurrence-free survival (LR-RFS). Four hundred and forty-two patients received APBI either daily (56%) or every other day (44%). Most of the patients (92%) were treated in the prone position. Average mean heart dose was 23 cGy for left-sided and 11 cGy for right-sided breast cancers. Ipsilateral lung V30% ≤ 30%. At a median follow up of 48 months (range: 5.96 - 155 months), 12 (2.7%) patients developed a local recurrence, 14 (3.2%) patients developed a contralateral breast primary, 10 patients (2.3%) developed a distant metastasis and one patient (0.2%) developed a local recurrence followed by a distant metastasis 1 month later. Out of 258 patients with > 6 month follow up, rates of late grade 1-2 telangiectasia, fibrosis, edema, atrophy and hyperpigmentation were 4%, 18%, 1%, 19% and 7% respectively. There was only one late grade 3 event in a patient who developed significant breast atrophy. The rate of good-excellent physician and patient rated cosmesis was 95% and 89% respectively (N = 256 at median follow up of 80 months). On multivariate logistic regression, patients who did not receive any adjuvant endocrine or chemotherapy were at increased risk of developing a local recurrence. Patients with PR negative disease were at increased risk of distant metastasis. Patient who experienced any grade of acute dermatitis during treatment were at increased risk of any high grade (grade ≥ 2) late adverse event and worse physician rated cosmesis. Daily or every other day treatment did not correlate with worse toxicity or clinical outcomes. Plastic surgery involvement, LVI, EIC, lobular histology, and ER negativity did not correlate with an increased risk of recurrence. Five-year LR-RFS, DFS and OS were 98%, 92.5% and 98.6% respectively. Five- fraction APBI delivered primarily in the prone position either daily or every other day was effective with low rates of local recurrence, minimal toxicity and excellent cosmetic scores at long term follow up.

Pancreatic Cancer Outcome: Local Treatment with Radiation Using MRI-Linac

Stereotactic MR-guided on-table adaptive radiotherapy (SMART) is a surging modality in radiotherapy, delivering high dose radiation to the tumor in great proximity to susceptible organs. The aim of this study is to evaluate the clinical outcome in locally advanced or recurrent pancreatic tumors with or without prior irradiation. All consecutive patients were treated in our center for pancreatic cancer (PC) using SMART technology to a prescription of 50Gy (BED10 100 Gy1o) in 5 fractions, with daily on-table adaptation of treatment plan. Endpoints for this retrospective, single center, IRB approved study were local control, overall survival, local disease-free period, acute and late toxicities. Fifty-four PC patients were treated between 8.2019-9.2022, with median follow-up of 8.9 months from SMART (0.8-34 months). Forty patients had upfront inoperable PC (45% were metastatic at RT, five treated to liver metastatic lesions concomitantly) and fourteen patients had local recurrence following prior pancreatectomy, six of them had prior adjuvant RT. 87% received at least one round of chemotherapy (Oxaliplatin based- 72%), 25% received ≥2 regimens. Mean age was 68.9 (45-86) years. There was no significant difference in baseline parameters between prior pancreatectomy and inoperable groups. On-table adaptive replanning was performed for 100% of all (269) fractions (one patient received 4 fractions). No patient reported grade ≥2 acute GI toxicity. Six patients reported fatigue at the end of RT, four of them had prior radiation. Forty-eight patients were available for evaluation. Complete local control was achieved in 21.7% (10 patients) for median of 9 months (2.8-28.8 months), three had later local progression. Eight patients had regional or marginal recurrence following treatment. 6-months and 12-months OS was 75% and 52%, respectively. There was no significant difference in toxicity and outcome between post-pancreatectomy and inoperable groups. Pancreatic cancer local ablative SMART is safe, with minimal treatment-related toxicity, even in previously irradiated patients. Local control with complete response was achieved by 20% of patients. Further studies are needed to evaluate long-term outcome and late toxicity.

Largest Real-World Data of Regional Nodal Irradiation Using Ultra-Hypofractionated 5-Fraction Adjuvant Radiation Therapy for Breast Cancer from a Single Institute in India

Safety data for ultra-hypofractionated (UHFRT) 5-daily fractions of the supraclavicular fossa (SCF) radiation therapy (RT) have been reported only on 384 patients treated in trial setting in UK-FAST-Forward (n = 286) and HYPORT study (n = 98). Internal Mammary nodal (IMN) RT has been reported only in 6 patients from HYPORT study. We report acute and late toxicities in largest real world regional nodal irradiation (RNI) cohort of not only with 5-daily but also with 5-weekly once RT regimen. Of 1435 patients (1463 breasts) who received 5-fraction RT in an IEC approved registry and prospectively followed, we report 999 consecutive cases receiving RNI with a median age of 49 years (IQR:42-56years). During pandemic all patients were treated with 5-fr regimens only to limit hospital visits whereas prior to and subsequently only in patients with advanced age or with issues precluding daily 15-20 treatments. Of these, 431 (43.1%) had locally advanced BC, and 280 (28%) patients presented with ≥cN2 disease. Median cT and pT sizes were 4cm (IQR:3-6cm) and 2.8cm (IQR:1.5-4cm) respectively. Tumor was Her2 positive in 290(29%) and TNBC in 220(22%). Of these 999 cases, 611 received NACT, 647 had mastectomy and 351 had breast conserving surgery (BCS). Simultaneous integrated tumor bed boost (SIB) was given in 341 (97.1%) of BCS cases. The fractionation used was 26 Gy/5-daily fractions (SIB = 32 Gy) in 762 and 28.5 Gy/ 5 once weekly fractionation (SIB = 33 Gy) in 232 cases. RNI included SCF in all 999 and IMN in 168 patients. Of the 831 cases not requiring IMN RT, 573 (70.4%) had 3D conformal RT (n = 573/831,70.4%) whereas Inverse-planned intensity modulated RT was used in 152/168 (90.4%) patients requiring IMN RT. All Mono-isocentric technique was used for all RNI cases treated with 3D CRT. Nearly half of the patients treated with SIB received additional boost dose with electrons (50.5%) and the remaining with IMRT. In these 999 patients treated with UHFRT the peak RTOG grade ≥II skin and pharyngeal toxicity was 7.2% and 8.1% respectively. Among the 341 BCS cases who received SIB with UHFRT, the RTOG acute grade II and III skin toxicity was seen in 6.6% and 0.3% cases respectively. The maximum skin toxicity at 2 weeks after completion of RT of grade ≥II was significantly higher with 5-weekly compared to daily regimen (16.1 vs 4.6, p<0.01). In contrast, the maximum pharyngeal toxicity of grade ≥II was significantly higher with 5-daily compared to weekly fractionation (8.8% vs 5.2%, p = 0.04). At median follow-up of 25 months (CI:23.6-26.3 months), none of our patients had developed symptomatic radiation pneumonitis, brachial plexopathy or any major cardiac event. Five-fraction adjuvant breast cancer RT is well tolerated with low acute toxicity burden even among patients requiring regional nodal irradiation. No brachial plexopathy was observed in cases treated with mono-isocentric RNI but longer follow-up is required to inform about the late toxicities and locoregional control rates.

Meta-Analysis of Five Fraction Preoperative Radiotherapy for Soft Tissue Sarcoma

There is increasing interest in shorter courses of radiation therapy (RT) in the management of soft tissue sarcoma (STS). Studies investigating preoperative ultra-hypofractionated 5-fraction RT for STS are few and often limited to single institution experiences with less than 50 patients. We therefore performed a meta-analysis to determine the efficacy and safety of preoperative 5-fraction RT for STS based on currently published literature, with an analysis evaluating effects of dose delivered. This study level meta-analysis was conducted using Bayesian methods. Statistical estimation for risk of outcome rates were conducted by posterior mean and 95% highest posterior density (HPD) intervals. Studies with two-year local control (LC) and description of major wound complications (MWC) per the CAN-NCIC-SR2 study were included in this meta-analysis, and these served as the primary endpoints. Secondary endpoints included rates of acute and late toxicity. A total of ten studies were identified; seven met inclusion criteria (Kalbasi 2020, Kubicek 2021, Leite 2021, Spalek 2021, Gobo Silva 2021, Bedi 2022, Mayo 2022). Three studies (Kosela-Paterczyk 2014, Kosela-Paterczyk 2021, Potkrajcic 2021) did not include adequate information to accurately determine 2-year LC or MWC. Subgroup analyses were performed for ≥30 Gy vs <30 Gy as the EQD2 of 30 Gy in 5 fractions for an α/β of 3-4 is 50-54 Gy, equivalent to standard preoperative RT fractionation. A total of 208 patients were included from seven studies. Five studies used ≥30 Gy (n = 144) and 2 studies <30 Gy (n = 64). The median follow-up was 29 months (range: 21-57). Primary tumor location was lower extremity in 68%, upper extremity in 22%, and trunk in 10%. In studies with available information, most tumors were intermediate (27%, 46/169) or high grade (67%, 114/169) and 50% (79/158) were >10 cm. Two-year LC for the entire cohort was 96.9% (95% HPD: 0.9374-0.9889) and the rate of MWC was 30.6% (95% HPD: 0.2106-0.4149). Acute grade 2 and 3 dermatitis was seen in 12.7% and 2.2%, respectively. Late grade 2 toxicities included fibrosis (11.1%), stiffness (6.0%), and lymphedema (4.0%) and late grade 3 toxicities included fibrosis (1.8%) and stiffness (0.4%). Grade 4 toxicity was rare and included fibrosis (0.6%) and stiffness (0.6%). There was a trend toward improved LC with ≥ 30 Gy (95% HPD: 0.949-0.997 vs 0.838-0.986). There was no difference in MWC (95% HPD: 0.185-0.420 vs 0.172-0.553) or late toxicity between the two groups. Acute grade 3 dermatitis was seen less frequently with regimens <30 Gy (95% HPD: 0-0 vs 0.009-0.072), however rare overall. Preoperative 5-fraction RT for STS demonstrates excellent 2-year LC with MWC and toxicity similar to standard fractionation preoperative RT. Multi-institutional trials with a universal RT protocol and larger sample size are warranted to assess this novel treatment paradigm.

Long-Term Anorectal Function in Rectal Cancer Patients Managed by a Watch-and-Wait Strategy after Neoadjuvant Therapy: A Cross-Sectional Study

Rectal cancer patients reaching complete clinical response (cCR) after neoadjuvant chemoradiotherapy can be offered a nonoperative watch-and-wait (W&W) strategy. As evidence of good oncological outcomes accumulates, the functional outcomes remain less explored. The aim of this study is to comprehensively assess the long-term rectal toxicity and anorectal function in patients managed by a W&W strategy and to investigate the clinical risk factors for anorectal dysfunction. Seventy W&W patients who were disease-free at the moment of recruitment were included. A minimum 2-year follow-up was considered. We graded late rectal toxicity according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale and the Late Effects of Normal Tissue/Subjective Objective Management Analytic (LENT/SOMA) system. Long-term anorectal function was assessed with the Wexner score, the Low Anterior Resection Syndrome score (LARS score), and the Memorial Sloan Kettering Bowel Function Instrument (MSK BFI). All patients received standard chemoradiotherapy consisting of a total dose of 5000 cGy in 25 fractions. The median tumor distance from the anal verge was 3 (IQR 2-4) cm. After a median follow-up of 43 (IQR 28-66) months, less than half of patients developed Grade 1 (40.0%) or Grade 2 (1.4%) late rectal toxicity, and no patients complained of higher grades. LENT/SOMA criteria also identified more patients with mild symptoms. The most frequent symptoms were sphincter control problems, mainly manifested as fecal urgency, reported by 60.0% of patients. For long-term anorectal function, the median LARS score was 16 (IQR 4-25). 17.1% of patients reported minor LARS and 15.7% reported major LARS. The median Wexner score was 2 (IQR 0-3). The median MSK BFI total score was 82 (IQR 77-86). Smoking history was an independent risk factor for anorectal dysfunction in multivariate analyses (OR = 6.491, 95% CI 1.536-27.432). Rectal cancer patients managed by a watch-and-wait strategy after neoadjuvant chemoradiotherapy have retained satisfactory anorectal function. However, fecal urgency might be a common problem. Smoking history was an independent risk factor for long-term anorectal dysfunction. Prospective studies with emphasis on bowel function outcomes containing a larger number of patients are needed.

Hypofractionated Radiotherapy for Prostate Cancer (HRT20) Trial: Results

Radiotherapy is a definitive standard treatment for men with localized prostate cancer. Improvements in technology allow higher doses of radiation delivered to the prostate in less days, with lower doses to surrounding healthy tissues trying to reduce side effects. Several studies demonstrated that hypofractionated radiotherapy of 60 Gy is non-inferior to conventional radiotherapy fractionation. To report the first results in toxicity and biochemical relapse free survival of HRT20 trial after 5 years of recruitment. The HRT20 trial is registered (NCT03851926). A prospective observational study enrolled 298 men with localized prostate cancer (pT1b-T3aN0M0) started in October 2016. Median age was 75 (53-91). Median PSA was 14.5ng/ml. Using NCCN classification: 12,6% were low risk, 50.5% were intermediate and 36.9 % were high risk patients. The median duration of the treatment was 30 days (23-41) The clinical target volume (CTV) consisted of the prostate and seminal vesicles when affected. The CTV-planning target volume (PTV) margin was 0.8 cm. The primary end point evaluated assessed by CTCAE 4.0 was related later adverse events and the second end point was biochemical relapse free survival by Phoenix definition. WMAT plans calculations were carried out using the Monaco TPS version 5.10 based on a single arc arrangement. Univariate and multivariate logistic analyses were carried out. After median follow up of 56 months. The 5-year incidence rates of grade 2 and 3 late gastrointestinal toxicities were 6.3% and 3.1%, respectively, and those of grade 2 and 3 late genitourinary toxicities were 7.9% and 1%, respectively. PTV volume was found to be correlated with late rectal bleeding (p = 0.02). Also, urinary tract obstruction was correlated with PTV volume. The proportion of patients who were biochemical failure free at 5 years was 88·3% (95% CI 86·0-90·2) Multivariate analysis indicated that risk stage (p = 0.03) and number of positive needles biopsy cores (p = 0.02) were prognostic factor for biochemical relapse-free survival rates. The findings of this study indicate that hypofractionated is well tolerated and it is associated with good 5-years tumor-control outcomes in patients with localized prostate cancer. Long-term follow-up continues.

Outcomes for Patients with Head and Neck Sarcoma Treated Curatively with Radiation Therapy and Surgery

Soft tissue sarcomas (STS) of the head and neck are rare and diverse entities that are challenging to manage. Definitive treatment requires surgery, often with radiation therapy (RT). We sought to describe the outcomes of patients treated curatively with surgery and RT for head and neck STS. We performed a retrospective review of patients treated at a tertiary cancer center for non-metastatic STS of the head and neck between 1968 and 2020; over half were treated in the modern era defined as 2005 or after. Patients with rhabdomyosarcomas or cutaneous angiosarcoma were excluded. The Kaplan-Meier method was used to estimate actuarial overall survival (OS), disease-specific survival (DSS) and local control (LC). Multivariable analyses (MVA) were conducted using Cox proportional hazards model. Median follow-up was 82 months. Of the 192 patients, the majority were male (n = 111, 58%), White (n = 158, 82%), and median age was 49.5 [IQR 32.5-64]. The highest proportion of tumors were in the neck (n = 50, 26%), paranasal sinuses (n = 36, 19%), or face (n = 23, 12%). The most common histology was sarcoma, not otherwise specified (n = 44, 23%), followed by undifferentiated pleomorphic sarcoma (n = 32, 17%), and neurogenic sarcoma (n = 15, 8%). Most patients were treated with postoperative RT (n = 134, 70%). Patients treated with preoperative RT were older (median 56.5 yrs vs post-op 44 yrs, p = 0.009). Post-op RT doses were higher (median 60 Gy, pre-op 50 Gy, p<0.001), and margins were more likely to be negative in those treated with pre-op RT (n = 39, 67%, post-op 69, 51%, p = 0.02). 5-year LC, DSS, and OS for the entire cohort was 76% (95% CI 69-82), 74% (67-80), and 71% (64-77), respectively. LC was not affected by treatment sequence (pre-op RT 78% (63-88), post-op RT 75% (66-82), p = 0.48). Patients with negative margins had improved 5-yr LC (86% (77-92), positive/uncertain 65% (53-74), p = 0.003). On MVA, positive/uncertain margin was the only variable associated with LC (HR 2.54 (1.34-4.82), p = 0.004). Poorer 5-yr DSS was associated with higher grade (grade 3 75% (63-84), grade 1-2 89% (75-94), p = 0.02), and treatment era (pre-2005 68% (57-76), on/after 2005 80% (70-87), p = 0.04). These both remained significant on MVA (grade 3 HR 2.39 (1.07-5.36), p = 0.034; pre-2005 HR 2.31 (1.03-5.21), p = 0.043). Sixteen patients (8%) developed a late RT toxicity, including fibrosis (n = 4, 2%), necrosis (osteoradionecrosis n = 2, brain necrosis n = 1, soft tissue necrosis n = 1), and eye dryness (n = 2, 1%). Neither the timing of RT nor dose was found to be associated with developing a late RT toxicity. Head and neck STS continues to have relatively poorer local control than STS of the trunk or extremities. Timing of RT did not impact oncologic or long-term RT-related toxicity outcomes. However, more data are needed to ascertain whether preoperative RT may impact acute surgical toxicities. These data contribute to multidisciplinary care planning for patients with STS in these challenging anatomic locations.

Proton Re-Irradiation with Concurrent Hyperthermia in Patients with Recurrent Breast Cancer

The aim of this study is to evaluate the safety and effectiveness of proton re-irradiation with concurrent hyperthermia in the treatment of recurrent breast cancer. We retrospectively identified patients previously treated with photon whole breast or chest wall irradiation for a primary breast cancer at our institution, who subsequently developed a histologically-confirmed locoregional recurrence or new ipsilateral primary breast cancer and underwent proton chest wall re-irradiation with concurrent hyperthermia as part of definitive treatment. Acute toxicity was evaluated once weekly while on-treatment and at 2 weeks and 3 months post-treatment. Toxicities were graded according to CTCAE v4.0. Fifteen patients received proton re-irradiation with concurrent superficial hyperthermia at our institution from August 2018 to December 2022. Median interval between radiation treatment courses was 7.7 years (range 1-30 years). Four patients (26%) had gross, unresected disease at the time of re-treatment. The median initial radiation dose, re-irradiation dose, and cumulative EQD2 was 60.4 Gy (50.6-61.2 Gy), 60 Gy (RBE) (45-66 Gy (RBE)), and 120 Gy (RBE) (103-126 Gy (RBE)), respectively. Patients received a median of 9 (3-14) concurrent hyperthermia treatments delivered twice weekly, and 13 patients (87%) received seven or more hyperthermia treatments. Median toxicity follow-up was 9 months (0-36 months). Acute grade 3 toxicities included two patients (13%) with grade 3 dermatitis, both of which resolved with conservative management within 3 months of treatment completion. Chronic grade 2 or higher toxicities included two grade 2 hyperpigmentation, one grade 3 induration, one grade 2 telangiectasia, and one grade 2 rib fracture. There were no grade 4-5 acute or late toxicities. There was one in-field local recurrence and one regional recurrence outside of the re-irradiation field. Both patients had gross, unresected disease at the time of re-irradiation. Two patients (13%) developed distant disease. Proton re-irradiation with concurrent hyperthermia is feasible and well-tolerated in the re-treatment of breast cancer. Further studies are warranted to determine long-term toxicity and oncologic outcomes.

Disease Control and Toxicity Outcomes after Intraoperative HDR Brachytherapy for Neck Recurrences in Patients Previously Irradiated Head and Neck Cancer

Despite recent advances in local and systemic therapies for head and neck squamous cell carcinomas (HNSCC), the most common types of treatment failure remain local and regional. Patients with HNSCC also have a higher risk of developing secondary head and neck tumors due to a field cancerization phenomenon. Treatment of these recurrences poses a challenge, particularly in patients having previously received full dose external beam radiotherapy (EBRT) to the head and neck region. This study evaluates the clinical outcomes of intraoperative Harrison-Anderson-Mick applicator (HAM) HDR brachytherapy (BT) after salvage neck dissection for neck recurrences in patients previously irradiated for HNSCC. All patients having received HAM BT for HNSCC neck recurrences at a single institution were identified. Demographic, treatment, disease control and toxicity data were collected retrospectively. Toxicity was graded as per Common Terminology Criteria for Adverse events version 5. The Kaplan Meier method was used to assess overall survival (OS) and ipsilateral regional control (IRC) from the time of HAM BT. Nineteen patients with regional recurrence of HNSCC were treated with HAM BT Ir-192 between July 2006 and June 2022, with a median follow-up for survival of 51.4 months (range: 2.5-186.7). The median BT dose was 12.5 Gy delivered intraoperatively at 5 mm tissue depth/1 cm from source. Fifteen patients (78.9%) also received postoperative EBRT to a median dose of 46 Gy in 23 fractions and 13 (68.4%) received systemic therapy. Six patients (31.6%) developed ipsilateral neck recurrences (4 who had adjuvant EBRT and 2 who did not), 2 patients had primary site recurrences and 5 patients developed distant metastases. In terms of acute toxicity, 4 patients had grade 3 dysphagia requiring feeding tube (FT) placement and one patient required surgical intervention for wound necrosis. In terms of late toxicity, 2 additional patients required FT placement and 1 was able to have it removed. No grade 4+ late toxicities were noted. The IRC at the site of HAM BT at 1 year was 71.5% and 63.6% at 5 years. The 1-year OS was 81.3% and 5-year OS was 40.9%. Intraoperative HAM BT resulted in favorable rates of IRC with acceptable toxicity in the reirradiation setting for HNSCC.