Late Grade Research Articles

Progression-Directed Therapy in Oligoprogressive Castration-Refractory Prostate Cancer: Results of the Prospective Single-Arm Phase II MEDCARE Trial

Next-line systemic treatment (NEST) for progressive metastatic castration-refractory prostate cancer (mCRPC) is associated with significant costs and non-negligible toxicity. For oligoprogressive (OP) disease, defined as the appearance of up to 3 progressive and/or new lesions and/or local recurrence on conventional imaging, progression-directed therapy (PDT) may prolong the efficacy of ongoing systemic therapy and delay initiation of NEST. To investigate whether PDT could postpone NEST in patients with OP mCRPC in the prospective, single-arm, monocentric MEDCARE trial. We enrolled patients with OP mCRPC while on ongoing treatment with androgen deprivation therapy (ADT), with or without an androgen receptor-targeted agent (ARTA). Progression was detected with conventional imaging (bone scan and CT of MRI). A history of docetaxel treatment was allowed. All progressive lesions had to be treatable with PDT, either (stereotactic body) radiation therapy ((SB)RT) or metastasectomy. Repeated PDT was allowed at the time of further oligoprogression. The primary endpoint was NEST-free survival. Secondary outcomes of the trial included clinical progression-free survival (cPFS), prostate cancer specific survival (PCSS), overall survival (OS) as well as acute and late toxicity. Between January 2020 and January 2021, 20 patients were included. Median age was 74 years. Median PSA level and PSA doubling at the time of inclusion were 4 ng/ml (IQR 2-11) and 4 months (IQR 3-5), respectively. Median follow-up was 28 months (IQR 5-33). A total of 31 lesions were treated with SBRT to 22.5-30 Gy in 3-5 fractions of 7.5-10 Gy. 11, 7 and 2 patients had one, two and three concurrent lesions respectively. At the time of inclusion, sixteen patients had bone metastases, two patients had only lymph node metastases, one patient a liver metastasis and one patient had local recurrence. If the primary tumor had not yet been treated, local radiotherapy to the prostate was given (n = 5). Five patients received repeated PDT for oligoprogression. Ongoing therapy at time of inclusion was ADT (n = 8) alone or ADT + ARTA (n = 12). The number of different systemic treatment lines received before inclusion was one, two and three for 5, 13 and 2 patients respectively. The median NEST-free survival was 17 months (95% CI: 9-25). The median cPFS was 6 months (95% CI: 5-7). The median PCSS was not reached while the median OS was 29 months (95% CI, 28-30). At last follow-up, 9 patients had died, of whom 6 due to progressive prostate cancer and 3 due to rapid progression of a second primary tumor (small cell lung cancer, leiomyosarcoma and acute myeloid leukemia). PDT was well tolerated with no acute nor late grade ≥3 toxicity. In OP mCRPC patients, PDT postpones the need for NEST for almost 1.5 years without inducing severe toxicity.

Is 80 the New 70? Octogenarians with Oropharyngeal Squamous Cell Carcinoma

As the human papilloma virus (HPV) pandemic evolves and life expectancy increases, the number of older adults with oropharyngeal squamous cell carcinoma (OPSCC) continues to increase. However, there is a paucity of data regarding the fastest growing subset of this population: octogenarians (OGs). We sought to understand differences in treatment tolerability and clinical outcomes between septuagenarians (SGs) and OGs with OPSCC. We identified SGs (age 70-79) and OGs (age 80-89) with OPSCC from a cohort of older adults with nonrecurrent, nonmetastatic head and neck squamous cell carcinoma (HNSCC) treated curatively from 2007-2020. We compared demographics, treatment characteristics and toxicities using Fischer's exact test. Time-to-event outcomes, overall survival (OS), locoregional control (LRC), and disease-specific survival (DSS), were evaluated using the Kaplan-Meier method. Of 293 patients (age 70-89) with HNSCC, 39% (n = 114) had OPSCC: 93 SGs (median age: 73; interquartile range [IQR]: 71-76), and 21 OGs (median age: 81, IQR: 80-84). The median follow-up for included patients was 2.4 years; 82% were male, 64% white, 48% > 20 pack year smoking history, 37% ECOG 1. Patients had AJCC 8th edition Stage: I (27%); II (33%); III (18%); IV (22%) OPSCC. Treatment consisted of adjuvant radiation (RT) (19%), adjuvant chemoradiation (CRT) (8%), surgery alone (6%), induction/concurrent CRT (27%), concurrent CRT (28%), or RT (12%), with no significant differences in stage or treatment modalities noted between SGs and OGs. Of note, 69% of SGs and 76% of OGs were HPV+. Among 107 patients who received any RT, 24% experienced a treatment interruption (19% of SGs vs. 48% of OGs, p = 0.001) and 2 patients (both HPV- SGs) died on treatment due to unrelated health conditions. Percutaneous endoscopic gastrostomy (PEG) tubes were placed prior to or during treatment in 43% of SGs and 62% of OGs, with OGs more likely to have a PEG placed during treatment (p = 0.025). There was no difference in the prevalence of late (> 6 months) CTCAE grade 2+ dysphagia (36%) or xerostomia (31%) between SGs and OGs. Estimated 3-year LRC, DSS, and OS were not significantly different between SGs (LRC:85%; DSS:87%; OS:76%) and OGs (LRC: 81%; DSS:94%; OS: 55%, p-values: 0.98, 0.42, 0.052, respectively). However, HPV+ disease significantly increased estimated 3-year OS for both SGs (HPV+: 84%; HPV-: 56%, p = 0.0006) and OGs (HPV+: 68%; HPV-: 20%, p = 0.008). In our cohort, OGs had a higher proportion of HPV+ OPSCC, which was associated with improved OS. This finding may provide insight into the latency of the virus. While there were similar amounts of toxicities among SGs and OGs, OGs more frequently underwent PEG tube placement and experienced more treatment interruptions. Given high rates of HPV+ OPSCC in OGs, our findings suggest that de-escalation strategies should be further investigated to improve tolerability and maximize outcomes for this neglected population.

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.

Single Institute Experience with MRI-Guided Adaptive Brachytherapy for Locally Advanced Cervix Cancer: Long Term Outcomes and Toxicity Analysis

We report over 10 years' experience of MRI-guided adaptive brachytherapy (MRIGABT) in locally advanced cervix cancer (LACC). A total of 162 patients with LACC FIGO stage IB-IVB were treated at our institute between 2010 and 2020. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m², 5 cycles, 1 day per cycle, 45-50.4 Gy external beam radiotherapy (EBRT) in 1·8-2 Gy fractions, followed by MRIGABT. Target volume definition and dose reporting for MRIGABT was according to GEC-ESTRO recommendations. MRIGABT dose prescription was according to our institutional practice. Overall survival (OS) and disease-free survival (DFS) were the primary endpoints. Kaplan-Meier estimates were calculated for OS and DFS at 2, 5 and 10-years. Organ-specific late toxicity grade ≥3 (≥G3) (CTCAEv5.0) was reported, alongside rates of bowel fistula, stricture, and perforation. Using logistic regression, we explored the relationship between EQD2 D2cc bladder and ≥G3 genitourinary (GU) toxicity. We compared patient proportions developing ≥ G3 GU toxicity in those who received EQD2 ≥85 Gy versus <85 Gy. We examined the following predictors of ≥G3 gastrointestinal (GI) toxicity: EQD2 dose (≥65 Gy versus <65 Gy), pre-existing bowel conditions, nodal boost, and extended field EBRT. Median follow up was 4.7 years (IQR 3.3-7.1 years). Median EBRT dose was 50.4 Gy (IQR 50.4-50.4 Gy); 91% received chemotherapy. Median high-risk clinical target volume (HRCTV) was 23.6 cm3 (IQR 16.6-31.3 cm3). Median doses were as follows; D90 HRCTV 88.9 Gy EQD210 (IQR 84.1-91.3 Gy), median D2cc bladder 81.6 (IQR 76.9-85.7 Gy), rectum 62.2 (IQR 57.9-65.3 Gy), sigmoid 67.4 (IQR 60.8-71.1 Gy), and bowel 55 (IQR 49.9-63.2 Gy), (all EQD23). The 2, 5 and-10-year OS were 98%, 80% and 75%. The 2, 5 and 10-year DFS were 98%, 75% and 60%. Late toxicity ≥G3 was 9% GU, 6% GI and 3% vaginal. There was a significant relationship between EQD2 and ≥G3 GU toxicity (OR: 1.11, 95% CI: 1.01-1.25; P = 0.04). When comparing those who received EQD2≥ 85Gy versus <85Gy, higher doses were associated with a greater proportion of ≥G3 GU toxicity (13% vs 6%). No significant predictors of ≥ G3 GI toxicity were observed. We observed excellent LC and OS. A significant relationship was found between EQD2 >85 Gy and bladder toxicity, although ≥G3 toxicity was low. We did not identify predictors of bowel toxicity. New predictors of bowel toxicity are required. Mean EBRT dose, D1.0 cc rectum, sigmoid and bowel are being investigated further.

Assessment of rectal toxicities after radiation therapy for localized prostate cancer: experience of the Akanda Cancer Institute in Gabon.

The purpose was to evaluate the incidence of acute and late rectal toxicities and their correlation with the clinical and dosimetric parameters of patients who underwent curative radiotherapy for localized prostate cancer at the Akanda Cancer Institute, Gabon. Between 2013 and 2021, a cohort of 46 patients with clinically localized stage cT1c-T4 prostate cancer was treated with three-dimensional conformal radiation therapy (3D-CRT) at the national cancer institute with doses ranging from 66 to 80 Gy. Post-radiation gastrointestinal (GI) toxicities were classified and graded according to the Common Terminology Criteria for Adverse Events CTCAE v4.0. In our study, 17.4% (8/46) developed acute GI. Grades 1 and 3 acute GI complications were seen in 13.0% (6/46) and 4.3% (2/46), respectively. No patient developed acute grade 2 or grade higher than 3 complications. Late GI side effects were limited. The median time to the development of late GI Grade ≥ 1 toxicities was 12 months (range: 9-19 months). 10.9% (5/46) had experience late GI. Among them, grade 1 and 2 were seen in 6.5% (3/46), and 4.3% (2/46), respectively. There was no grade 3 or higher complications. Statistically, we did not find any correlation between the presence of rectal toxicity and clinical factors or the presence of comorbidity. On the dosimetric level, the Mann-Whitney statistical test found a correlation between the presence of late GI toxicity and rectal volume irradiated at the prescribed dose (p = 0.02). Despite the high radiation doses involved, our results showed an acceptable complication rate.

Favorable Toxicity and Local Control with Ultrahypofractionated Radiation Therapy (UH-RT) for Melanoma of the Lower Genital Tract (LGT)

To report our experience using UH-RT +/- immunotherapy (IO) in women with melanoma of the LGT. We retrospectively identified 23 patients who received UH-RT to primary tumor for vulvovaginal melanoma from 2012 to 2022. Median age was 69 years (IQR: 62-76). Stage included localized, node positive, or metastatic. 18 (78%) had tumors involving the vagina/cervix and 5 (22%) had vulvar tumors. 6 patients had c-KIT mutations; 13 patients were wild-type; 4 patients were unknown. 12 (52%) were treated at initial presentation (cohort A) and 11 (48%) at local progression/recurrence following prior therapy (cohort B). In cohort A, most (n = 11) received concurrent IO. In cohort B, 3 recurred after surgery alone, 4 after systemic therapy alone and 4 after surgery and systemic therapy. RT consisted of 6 Gy x 6 (n = 11), 6 Gy x 5 (n = 10) and 5 Gy x 5-6 (n = 2) delivered to the primary tumor + 0.5 cm margin. Patients initiated IO either ≥3 months preRT (n = 8), concurrent with RT (n = 12) or ≥3 months following RT (n = 2). 1 patient in cohort B did not receive IO. Toxicity was graded using CTCAE v 5. Overall survival (OS) was measured from end of RT. Cumulative incidence of local progression was measured from end of RT. Kaplan-Meier method and Cox regression were used for survival analyses. Landmark method was used for timing of IO. Median follow-up as determined by reverse Kaplan-Meier method was 60 months (95% CI: 37-N/A). Overall incidence of acute/late grade 2+ toxicity for the entire cohort was 34%. Grade 2 acute toxicity included: dermatitis (n = 3), urinary (n = 2), vaginitis (n = 2) and diarrhea (n = 1). 3 patients experienced grade 3 acute dermatitis. 1 patient experienced late grade 2 vaginitis. No grade 3 or 4 toxicity was noted. No significant differences in toxicity were noted between RT regimens. Local disease control was achieved in 61% of patients. Local only, local and distant, and distant-only progression were seen in 17%, 22%, and 30% of patients respectively. 2-year cumulative incidence of local progression was 33% for the whole cohort, 28% for cohort A, and 36% for cohort B (p = 0.4). On UVA, factors associated with local progression were vulvar disease (p = 0.02) and c-KIT mutation (p = 0.011). No significant difference in local control was noted based on biologic effective dose (BED10 < = 48Gy vs >48Gy) (p = 0.06). Median OS for entire cohort, cohort A, and cohort B were 46, 72, and 30 months, respectively. 2-year survival (95% CI) was 67% (50%-91%), 73% (51%-100%), and 64% (41%-99%) respectively. On UVA, non-local disease at time of RT (p = 0.016) and receipt of IO ≥3 months prior to RT (p = 0.030) had worse OS. UH-RT+/- IO for melanoma of the LGT is well-tolerated with local disease control achieved in 61% of patients. Vulvar primary and c-Kit mutations were associated with worse local control. Additional follow-up may be necessary to determine the value of dose escalation.

A pilot study of stereotactic body radiotherapy combined with pelvic radiotherapy and GTVp boost based on multiparameter magnetic resonance image in patients with high-risk prostate cancer.

This pilot study aimed to explore the preliminary effects and safety of stereotactic body radiotherapy (SBRT) combined with preventive pelvic radiotherapy and primary gross tumor volumes (GTVp) boost in patients with high-risk prostate cancer based on multiparameter magnetic resonance image (mpMRI). Tumors were contoured as GTVp based on mpMRI. The prostate and proximal seminal vesicles were considered as the clinical target volume1. The pelvic lymphatic drainage area constituted clinical target volume 2. Radiation doses were 40Gy or 45Gy/5fractions to planning target volume of primary tumor, 37.5Gy/5f to prostate, seminal vesicle, and positive pelvic lymph nodes, and 25Gy/5f to pelvic synchronously. The treatment was delivered 3 times per week. Volumetric modulated arc radiotherapy and intensity-modulated radiotherapy were used to complete SBRT. The genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated. Quality of life data was also captured. A total of 15 patients were enrolled in this study with a median age of 78 (56-87) from 2017 to 2020. All patients received SBRT. At 3 months after radiotherapy, the proportion of PSA < 0.006 ng/mL was 66.7% (10/15). The 2-year biochemical relapse-free survival was 93.3%. The incidence of grade 1 acute GU side effects was 80% (12/15); the incidence of acute grade 1 GI toxicity was 66.7% (10/15); and no grade 2 or higher acute GU and GI side effects was observed. Two patients presented with temporary late grade 2 GI toxicity. International Prostatic System Score increased rapidly after a transient increase at 1 week (P = .001). There were no significant differences in EORTC quality of life scores in all domains except global health status. In this pilot study, it was revealed that SBRT combined with preventive pelvic radiotherapy and GTVp boost based on mpMRI image was effective and well tolerated for patients with high-risk prostate cancer.

Reduction of Late Urinary Toxicity from Prostate Cancer Radiotherapy via Intrafractional MV-kV Image Guidance

Prostate cancer localization during radiotherapy is difficult and introduces positional variability during treatment. Here we evaluate the impact on treatment toxicities of an in-house system that uses MV and kV imaging guidance (MKIG) to track implanted fiducials during stereotactic body radiotherapy (SBRT) for localized prostate cancer. A 3D MKIG platform that tracks prostate implanted fiducials in real-time was built and clinically translated to replace a prior commercial approach called intrafraction motion review (IMR), which tracks thefiducials in 2D kV view only. MKIG has been shown to correct both superior-inferior and anterior-posterior (AP) motions that are harmful to critical organs and is superior to IMR for intrafractional motion management, which is less sensitive to AP motions. From 2017 to 2019, 150 patients with localized prostate cancer were treated with SBRT to 40 Gy in 5 fractions. During the delivery of volumetric modulated arc therapy, orthogonal MV-kV pairs were simultaneously acquired at every 20° gantry rotation and rigidly registered to the reference image templates created from the planning CT. Calculated 3D translations of implanted fiducials were used to localize the prostate and alert the therapist to interrupt and reposition the prostate when exceeding a 1.5-2 mm threshold. A comparison cohort of 121 prostate patients was treated from 2015 to 2016 with the same prescription dose and treatment technique but instead managed by IMR, where the therapist interrupted treatment based on a 2mm expansion of the fiducial contours superimposed on the kV images. Statistics of intrafractional interruptions, patient shifts, and overall delivery time were collected to evaluate the efficacy of the clinical workflow. The incidence of late grade ≥2 toxicities was analyzed to assess clinical complications. The median follow-up time was 5.5 years (range of 3.6 to 8.0 years). The MKIG cohort had more interruptions per fraction (1.09 vs. 0.28) and longer average delivery time per fraction (579±205s vs. 357±117s) than IMR. 75% of shifts resulting from MKIG were less than 3mm, compared to 51% in IMR, indicating that MKIG tended to detect and correct smaller deviations (p<0.001). The baseline International Prostate Symptom Score was 7.9 in the MKIG cohort vs. 8.4 in IMR (p = 0.41). The incidence of late grade ≥2 urinary toxicity was lower in the MKIG than IMR cohort: 10.7% vs. 19.8% (p = 0.05). One grade ≥2 rectal toxicity was observed in the IMR cohort but none in MKIG. Wehave demonstrated that MKIG is a clinically practical and effective method for monitoring and correcting prostate positional deviations during SBRT of prostate cancer. MKIG is better suited than 2D IMR to localize the prostate and trigger patient repositioning during treatment. A statistically and clinically significant reduction in urinary toxicity was observed. The potential expansion of MKIG to other clinical sites and translation to other centers should be considered.

Utility of Stereotactic Body Radiation Therapy (SBRT) in Establishing Local Control for Invasive Breast Cancer Patients Not Undergoing Definitive Surgery

Breast cancer (BC) treatment involves a multi-modal approach where surgical resection is the backbone of therapy. However, due to medical comorbidities precluding surgery, unresectable disease, or patient preference, some patients do not undergo surgery. In the absence of resection, it is paramount to improve local control (LC) of the primary tumor. To that end, this study explored the role of ablative RT dose delivered with SBRT. Between 2015-2022, 21 patients (10 metastatic, 11 stage IA-IIIC) received 23 SBRT courses to primary BC lesions without planned surgery at our institution. One patient had undergone whole breast RT 20 years prior to SBRT. 7 patients were analyzed retrospectively; 15 are currently enrolled in a prospective study. SBRT dose was 40 Gy/5 fractions delivered every other day. Follow-up imaging (PET, CT, MRI, MMG/US) was reviewed to evaluate the response. CTCAE v.3 was used to document any acute (≤3 months) and late toxicities. Kaplan-Meier curves were used to estimate local control (LC) and overall survival (OS). Median age was 78.4 (45.9-97.3) years. Median follow-up was 14.7 (3.3-70.3) months after RT completion. Initial post-treatment imaging was available for all cases and was performed at a median of 4.0 (0.6-11.9) months after SBRT. The median pre-SBRT index lesion size was 3.1 (0.5-14.5) cm and PTV was 32.4 (11.5-522.4) cc. At a median 4 months post-SBRT, the median decrease in index lesion size was 20.8 (0-100) % and SUV reduction was 65.2 (20.8-100) %. Further improvement was seen on the 2nd follow-up scans at a median 7.8 months post-SBRT, with 62 (0-100) % and 88 (33.3-100) % median reduction in the tumor size and SUV, respectively, compared to pre-SBRT values. The estimated LC rate was 100% at 6 months and 93.3% at 12 months. The sole case of local progression occurred 9.5 months after SBRT, after an initial interval decrease in the primary lesion. Among the patients with available systemic follow-up scans, regional progression occurred in 4 (17.4%) cases at a median 18.6 (5.2-22.7) months post-SBRT. Six (37.5%) patients developed distant progression at a median 4.8 (0.9-16.2) months, all of whom had metastatic disease at diagnosis. The estimated OS was 85.7% at 6 months and 63.8% at 12 months. Most patients tolerated the treatment well. There was no grade 4 toxicity. Complete acute toxicity data is presented in Table 1. Only one patient experienced late grade 2 breast edema. Based on our preliminary results, definitive SBRT to the primary BC appears to have a role in providing LC in the treatment of non-surgical patients and is well-tolerated. Since the disease progression tends to occur outside the treated primary tumor, additional approaches to improve regional and distant control should be investigated.

Challenging the Role of Subtotal Resection Following Proton Radiotherapy for Adenoid Cystic Carcinoma of the Head and Neck

To report long-term outcomes of patients with adenoid cystic carcinoma (ACC) of the head and neck treated with proton radiotherapy. On this IRB-approved, single institutional prospective outcomes registry, 56 patients were included with de novo, nonmetastatic adenoid carcinoma of the head and neck treated with primary (n = 9) or adjuvant proton therapy from June 2007 to December 2021. The cohort had 30 women and 26 men with a median age of 57 years (range, 10-81 years). Twenty-nine percent (n = 16) had intracranial extension, 23% (n = 13) had orbital extension, and 55% (n = 31) had clinical cranial nerve involvement at the time of radiotherapy. Thirty patients underwent gross total resection (GTR), 26 had gross disease at the time of treatment undergoing a subtotal resection (STR) (n = 17) or biopsy alone (n = 9). The median dose to the primary site was 72.6 GyRBE (range, 64-74.4 GyRBE) delivered in either once (n = 19) or twice (n = 37) daily treatments. Thirty patients received either elective nodal irradiation (ENI) in a node negative neck or concurrent chemotherapy. With a median follow-up of 6.2 years (range, 0.9 - 14.7 years), the 5-year local-regional control (LRC), disease free survival (DFS), cause-specific survival (CCS) and overall survival (OS) were 88%, 85%, 89%, and 89%, respectively. Cranial extension (p = 0.003) and gross residual tumor (p = 0.0388) were factors associated with decreased LRC. While LRC for those with a GTR was 96%, those with STR or biopsy alone were 81% and 76%, respectively. T-stage (p = 0.0154), cranial extension (p = 0.0056), extent of resection (p = 0.0355), and gross residual tumor (p = 0.0094) were associated with decreased DFS. T-stage (p = 0.0099), extent of surgery (p = 0.029) and gross residual tumor (p.0071) were associated with decreased CCS. The 5-year cumulative incidence of clinically significant late grade ³3 toxicity was 15% and the crude incidence at most recent follow-up was 23% (n = 13). There was no LRC benefit with ENI (p = 0.94). Proton therapy provides excellent disease control for head and neck ACC with acceptable toxicity. Gross residual disease at the time of treatment and intracranial involvement were significant prognostic features for worse outcomes. STR did not confer benefit over biopsy only at 5-years and may question the role of extensive and morbid operations if GTR is not technically feasible.

Clinical Outcomes of Sidewall/Parametrial Simultaneous Integrated Boost for Patients with Cervical Cancer

In the treatment of cervical cancer, simultaneous integrated boost (SIB) is a common technique to deliver increased dose to gross disease in the para-aortic and pelvic nodal basins. However, SIB to the pelvic sidewall/parametria is not well characterized in the literature. We hypothesized that sidewall simultaneous integrated boost (SIB) in the treatment of cervical cancer is associated with acceptable levels of toxicity. From 1/2009-12/2018, patients who received concurrent chemoradiation with external beam radiation therapy, utilizing a sidewall SIB technique, followed by low dose rate or high dose rate brachytherapy treatment were retrospectively identified. Sidewall SIB was defined as treatment at 2.1-2.4Gy/fraction to the parametria-usually performed for those with disease width >4cm at time of treatment start. Acute and late toxicity grading was defined by the Common Terminology Criteria for Adverse Events Version 5.0. Overall survival (OS), local control, progression-free survival (PFS), and toxicity were analyzed utilizing the Kaplan Meier method. Potential associations between cumulative D2cc for bladder and rectum and time to toxicity were investigated using Cox regression. Fifty-six patients with IB2-IVB cervical cancer treated with sidewall SIB were identified, with a median follow up of 7.0 years (95% CI: 6.3, 8.3). Patients had a median age of 43 years (range: 26-68); 2 (3.6%) had FIGO stage I, 7 (12.5%) stage II, 46 (82.1%) stage III, and 1 (1.8%) stage IV disease. A majority had squamous cell histology (83.9%). Nearly all patients (96.4%) received concurrent cisplatin chemotherapy. Rates of acute grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal, and hematologic toxicity were 1.8%, 1.8%, 0%, and 15.9% respectively. Rates of late grade ≥3 GI, GU, and vaginal toxicity were 11.3%, 18.5%, and 11.1% respectively. OS and local control rates at five years were 0.61 (95% CI: 0.46, 0.73) and 0.95 (95% CI: 0.84, 0.98), respectively. Median PFS was 7.8 years (95% CI: 2.4, Not reached). Cumulative D2cc bladder was not significantly associated with time to Grade 2 or greater (HR 1.04, p = 0.33) or Grade 3 or greater (HR 1.02; p = 0.64) GU toxicity. Cumulative D2cc rectum was not significantly associated with time to Grade 2 or greater (HR 1.06, p = 0.06) or Grade 3 or greater (HR 1.08; p = 0.09) GI toxicity. Sidewall SIB is a feasible technique for dose escalation in the treatment of cervical cancer with rates of acute and late toxicity consistent with other reports.

Conditional Risk and Predictive Factors Associated with Late Toxicity for Prostate Cancer Patients Treated with External Beam Radiotherapy Alone on Randomized Trial RTOG 0126

Patients with localized prostate cancer (PCA) treated with RT alone have excellent outcomes, making quality of life and minimization of toxicities of great concern. The risk of developing toxicity may evolve with time from treatment which is of interest to patients seen in follow up. The primary objective of this study is to determine the conditional risk of grade 2+ GI or GU toxicity for patients treated with RT. A secondary objective is to determine risk factors associated with the development of late toxicities. We performed a post-hoc analysis of RTOG 0126, which enrolled patients with intermediate risk PCa who were randomized to receive standard dose RT of 70.2 Gy in 39 fractions vs dose escalated dose RT (DE-RT) of 79.2 Gy in 44 fractions. Cumulative incidence was used to calculate risk of grade 2+ GU and grade 2+ GI toxicity at initial time points, as well as for patients who survived 2 years and 5 years without respective grade 2+ toxicity. Risk factors of age, race, urinary incontinence, baseline urinary frequency, acute GU toxicity, treatment arm, RT method (3DCRT vs IMRT), and OAR contouring protocol violation were analyzed using univariate and multivariate Cox proportional hazards modeling for late GU toxicity. Risk factors of age, race, RT method, acute GI toxicity, DE-RT, RT method, and OAR contouring protocol violation were analyzed for late GI toxicity. One thousand four hundred ninety-nine patients with a median follow up of 8.4 years (range 0.02-13 years) were included for analysis. The conditional cumulative 5-year risk of late grade 2+ GI toxicity at enrollment, 2-, and 5-years of grade 2+GI toxicity free survivorship was 14.7%, 6.2%, and 1.8% respectively. The cumulative 5-year risk of late grade 2+ GU toxicity at enrollment, 2-, and 5-years of late grade 2+ GU toxicity free survivorship was 7.9%, 4.7%, and 2.7% respectively. Initially DE-RT (HR 1.401, 95% CI 1.099-1.787; p = 0.0066), acute GI toxicity (HR 1.962, 95% CI 1.271-2.616; P<0.0001), and black race (HR 0.630, 95% CI 0.4-0.993; p<0.0463) were predictive of late GI toxicity. After two years of 2+ GI toxicity free survivorship, only acute GI toxicity (HR 2.015, 95% CI 1.238-3.279, p<0.0048) remained predictive of late GI toxicity on MVA. DE-RT (HR 1.616, 95% CI 1.187-2.2, p<0.0023), IMRT (HR 0.559, 95% CI 0.389-0.804, p = 0.0017), and urinary frequency at baseline (HR 1.377, 95% CI 1-1.895 p<0.0498) were predictive of late GU toxicity at enrollment. This data suggests that as patients proceed further from completion of EBRT, the conditional risk of late toxicity decreases. The majority of grade 2+ GI and GU toxicities occur in the first two years of treatment and patients who have not had a grade 2+ GU or GI toxicity within the first five years are likely to remain toxicity free. Factors such as presence of baseline urinary dysfunction, presence of acute toxicities, DE-RT, and radiation modality predict for late toxicity. These findings are of relevance for clinicians and patients in the post treatment setting.

Complications after proton radiotherapy in children, focusing on severe late complications. A complete Swedish cohort 2008–2019

Background Proton radiotherapy (RT) is an attractive tool to deliver local therapy with minimal dose to uninvolved tissue, however, not suitable for all patients. The aim was to explore complications, especially severe late complications (grades 3–4), following proton RT delivered to a complete Swedish cohort of paediatric patients aged <18 years treated 2008–2019. Material and Methods Data was downloaded from a national registry. Complications with a possible causation with RT are reported. Proton treatments until July 2015 was performed with a fixed horizontal 172 MeV beam (The Svedberg Laboratory (TSL), Uppsala) in a sitting position and thereafter with gantry-based pencil-beam scanning technique (Skandion Clinic, Uppsala) in a supine position. Results 219 courses of proton RT (77 at TSL and 142 at Skandion) were delivered to 212 patients (mean age 9.2 years) with various tumour types (CNS tumours 58%, sarcomas 26%, germ cell tumours 7%). Twenty-five patients had severe acute complications (skin, mucous membrane, pharynx/oesophagus, larynx, upper gastrointestinal canal, lower gastrointestinal canal, eyes, ears). Fifteen patients had severe late complications; with increased proportion over time: 4% at 1-year follow-up (FU), 5% at 3-year, 11% at 5-year. Organs affected were skin (1 patient), subcutaneous tissue (4), salivary glands (1), upper GI (1), bone (7), joints (2), CNS (2), PNS (1), eyes (1) and ears (5). Twenty-one of the 28 patients with 10-year FU had at least one late complication grades 1–4 and fourteen of them had more than one (2–5 each). Conclusion The most important result of our study is the relatively low proportion of severe late complications, comparable with other proton studies on various tumours. Furthermore, the numbers of late complications are lower than our own data set on a mixed population of photon and proton treated paediatric patients, assuring the safety of using proton therapy also in the clinical practice.

Impact of Chronic Kidney Disease on Clinical Outcomes during Hospitalization and Five-Year Follow-Up after Coronary Artery Bypass Grafting.

Chronic kidney disease (CKD) is often associated with multiple comorbidities including diabetes mellitus, and each has its own complications and impact after cardiac surgery including coronary revascularization. The objective of this work was to study the impact of CKD on clinical outcomes after coronary artery bypass grafting (CABG) and to compare outcomes in patients with different grades of renal functions. We retrospectively reviewed all patients who underwent CABG from January 2016 to August 2020 at our tertiary care hospital using electronic medical records. The study included 410 patients with a median age of 60 years, and 28.6% of them had CKD and hospital mortality of 2.7%. About 71.4% of the patients had GFR > 60 mL/min per 1.73 m2, 18.1% had early CKD (GFR 30-60), 2.7% had late CKD (GFR < 30), and 7.8% of them had end-stage renal disease (ESRD) requiring dialysis. The CKD group had significantly more frequent hospital mortality (p = 0.04), acute cerebrovascular stroke (p = 0.03), acute kidney injury (AKI) (p < 0.001), longer ICU stay (p = 0.002), post-ICU stay (p = 0.001), and sternotomy wound debridement (p = 0.03) compared to the non-CKD group. The frequencies of new need for dialysis were 2.4% vs. 14.9% vs. 45.5% (p < 0.001) in the patients with GFR > 60 mL/min per 1.73 m2, early CKD, and late CKD, respectively. Acute cerebral stroke (OR: 10.29, 95% CI: 1.82-58.08, and p = 0.008), new need for dialysis (OR: 25.617, 95% CI: 13.78-85.47, and p < 0.001), and emergency surgery (OR: 3.1, 95% CI: 1.82-12.37, and p = 0.036) were the independent predictors of hospital mortality after CABG. The patients with CKD had an increased risk of strokes (HR: 2.14, 95% CI: 1.20-3.81, and p = 0.01) but insignificant mortality increase (HR: 1.44, 95% CI: 0.42-4.92, and p = 0.56) during follow-up. The patients with CKD, especially the late grade, had worse postoperative early and late outcomes compared to non-CKD patients after CABG. Patients with dialysis-independent CKD had increased risks of needing dialysis, hospital mortality, and permanent dialysis after CABG.

Anlotinib combined with whole-brain radiotherapy in non-small cell lung cancer with multiple brain metastases that progressed or developed after at least one lines of prior treatment.

Intracranial metastasis that failed standard systematic treatment is common in advanced non-small cell lung cancer (NSCLC), contributing significantly to morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of anlotinib combined with whole-brain radiotherapy (WBRT) for NSCLC with brain metastases (BMs) that progressed or developed after at least one line of prior treatment and compare the outcomes with that of the contemporary institutional control. NSCLC patients with multiple BMs that progressed or developed after at least one line of prior systematic treatment and treated with WBRT subsequently between 2019 and 2021 were selected retrospectively for analysis. Based on whether concurrent anlotinib had been used in combination with WBRT, the cases were divided into the anlotinib group and control group. The primary endpoints were intracranial progression-free survival (iPFS) and safety. A total of 76 patients met the inclusion criteria of the study. Of the 76 patients, 34 received concurrent WBRT and anlotinib followed by anlotinib maintenance and 42 were treated with WBRT alone or in combination with other systemic agents at the physicians' discretion. The median follow-up for the entire cohort was 21 months. The median iPFS for the anlotinib and control group was 6.7 months (95% CI, 4.6-9.9) and 5.3 months (95% CI, 4.0-6.5), respectively (log-rank P = 0.04). There was no difference in overall survival between the two groups (log-rank P = 0.38). In the anlotinib group, treatment-related adverse events were reported in 15 patients (44.1%), with acute or late grade 3-5 adverse events identified in 14.7% of patients (n = 5). WBRT plus anlotinib, as a convenient chemo-free regimen, may represent an overall safe and effective procedure in advanced NSCLC with multiple BMs that progressed or developed after standard systematic treatment.

Tolerance and Oncological Outcomes of In-Field Reirradiation for Locally Recurrent Breast Cancer: A Long-Term Single-Center Experience.

The management of cancer relapse in previously irradiated tissues is a challenging therapeutic issue. The aim of this work was to report our experience with breast reirradiation for locoregionally recurrent breast cancer. All patients who underwent breast or chest wall in-field reirradiation at the Institut Curie, Paris, France, between 2003 and 2019, were identified. Efficacy outcomes and physician-reported toxicities were retrospectively assessed. A total of 21,372 patients underwent breast irradiation in our institution. Of these, 28 received a second course of radiotherapy to the homolateral breast/chest wall. A total of 18 (64%) patients were treated with a curative intent, and 10 (36%) were treated for palliative purposes. Only one acute and one late grade 3 adverse events were reported. One patient with major cardiovascular risk factors died of myocardial infarction 13 months after left breast reirradiation. The 2-year LRFS, OS, DSS, PFS and MFS were 59%, 79%, 82%, 46% and 75%, respectively, in the whole cohort. The 2-year LRFS (72% vs. 31%, p = 0.02), OS (94% vs. 50%, p < 0.01), DSS (94% vs. 56%, p < 0.01) and PFS (61% vs. 20%, p = 0.02) differed significantly between patients treated with curative or palliative intent but not the MFS (78% vs. 69%, p = 0.77). Among the patients, eight (29%) remained relapse-free 5 years after reirradiation. Breast/chest wall reirradiation appears to be feasible with good disease control, especially in patients treated with a curative intent, and presents acceptable toxicity rates.

State of the art and future challenges of urethra-sparing stereotactic body radiotherapy for prostate cancer: a systematic review of literature

PurposeDoses delivered to the urethra have been associated with an increased risk to develop long-term urinary toxicity in patients undergoing stereotactic body radiotherapy (SBRT) for prostate cancer (PCa). Aim of the present systematic review is to report on the role of urethra-sparing SBRT (US-SBRT) techniques for prostate cancer, with a focus on outcome and urinary toxicity.MethodA systematic review of the literature was performed on the PubMed database on May 2023. Based on the urethra-sparing technique, 13 studies were selected for the analysis and classified in the two following categories: “urethra-steering” SBRT (restriction of hotspots to the urethra) and “urethra dose-reduction” SBRT (dose reduction to urethra below the prescribed dose).ResultsBy limiting the urethra Dmax to 90GyEQD2 (α/β = 3 Gy) with urethra-steering SBRT techniques, late genitourinary (GU) grade 2 toxicity remains mild, ranging between 12.1% and 14%. With dose-reduction strategies decreasing the urethral dose below 70 GyEQD2, the risk of late GU toxicity was further reduced (< 8% at 5 years), while maintaining biochemical relapse-free survival rates up to 93% at 5 years.ConclusionUS-SBRT techniques limiting maximum doses to urethra below a 90GyEQD2 (α/β = 3 Gy) threshold result in a low rate of acute and late grade ≥ 2 GU toxicity. A better understanding of clinical factors and anatomical substructures involved in the development of GU toxicity, as well as the development and use of adapted dose constraints, is expected to further reduce the long-term GU toxicity of prostate cancer patients treated with SBRT.

Management of chordoma and chondrosarcoma with definitive dose-escalated single-fraction spine stereotactic radiosurgery.

The management of chordoma or chondrosarcoma involving the spine is often challenging due to adjacent critical structures and tumor radioresistance. Spine stereotactic radiosurgery (SSRS) has radiobiologic advantages compared with conventional radiotherapy, though there is limited evidence on SSRS in this population. We sought to characterize the long-term local control (LC) of patients treated with SSRS. We retrospectively reviewed patients with chordoma or chondrosarcoma treated with dose-escalated SSRS, defined as 24Gy in 1 fraction to the gross tumor volume. Overall survival (OS) was calculated by Kaplan-Meier functions. Competing risk analysis using the cause-specific hazard function estimated LC time. Fifteen patients, including 12 with chordoma and 3 with chondrosarcoma, with 22 lesions were included. SSRS intent was definitive, single-modality in 95% of cases (N = 21) and post-operative in 1 case (5%). After a median censored follow-up time of 5 years (IQR 4 to 8 years), median LC time was not reached (IQR 8 years to not reached), with LC rates of 100%, 100%, and 90% at 1 year, 2 years, and 5 years. The median OS was 8 years (IQR 3 years to not reached). Late grade 3 toxicity occurred after 23% of treatments (N = 5, fracture), all of which were managed successfully with stabilization. Definitive dose-escalated SSRS to 24Gy in 1 fraction appears to be a safe and effective treatment for achieving durable local control in chordoma or chondrosarcoma involving the spine, and may hold particular importance as a low-morbidity alternative to surgery in selected cases.

Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer

Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. This was a phase 2, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to 12 weeks after completion of 60 to 70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 toxicity. Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range, 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n = 5; 2 were pembrolizumab-related), disease progression (n = 4), and completion of 1 year (n = 3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI, 4.2-23.7) and 22.8 months (95% CI, 6.9-not reached), respectively. There was only one isolated in-field failure after reRT. Grade ≥3 toxicities occurred in 10 patients (45%); 2 were pembrolizumab-related. There were 2 grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2 of 22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.

Impact of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcome in gynecological cancer

PurposeTo investigate the effect of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcomes in gynecological cancer. Materials and methodsThis retrospective study analyzed data of 590 patients who underwent hysterectomy and adjuvant pelvic radiotherapy between 2010 and 2020 at two tertiary centers. The pelvic nodal region was delineated based on a reduced margin definition or the Radiation Therapy Oncology Group (RTOG) guidelines. All patients were treated with intensity-modulated radiotherapy with imaging guidance. Gastrointestinal toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) and the Patient-Reported Outcome version (PRO-CTCAE). ResultsOverall, 352 (59.7%) and 238 (40.3%) patients underwent RTOG and reduced margin pelvic radiotherapy, respectively. Median follow-up was 6.4 years (IQR: 3.7–9.6). Reduced margin pelvic radiotherapy significantly lowered the radiation dose to the small bowel. For CTCAE grade ≥ 2 or 3, acute gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (16.4% vs. 33.5%, p < 0.001; 2.9% vs. 8.5%, p < 0.001). The reduced margin group reported less severe acute gastrointestinal toxicity (PRO-CTCAE score ≥ 3) than the RTOG group (12.5% vs. 28.7%, p < 0.001). Late grade 3 gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (0.8% vs. 4.8%, p = 0.006). The 5-year pelvic recurrence-free survival and disease-free survival in the RTOG and reduced margin pelvic radiotherapy groups were 97.4% and 97.9% (p = 0.55) and 80.7% and 83.5% (p = 0.18), respectively. ConclusionReduced margin pelvic radiotherapy decreased acute and late gastrointestinal toxicity and achieved favorable outcomes.