Analysis of the association between salivary proteins and oral mucositis in patients with head and neck cancer undergoing IMRT: a longitudinal study.

INTRODUCTION: This longitudinal study assessed the association between salivary protein composition and the clinical onset/severity of oral mucositis (OM) in patients with head and neck tumours treated with intensity-modulated-radiotherapy (IMRT). METHODS: Saliva samples/clinical data were obtained from 40 head and neck cancer patients treated at Guy's Hospital before -IMRT(T0) and after-IMRT (T1 = 6 m, T2 = 12 m) (ethics approval/consent). Salivary flow rate, total protein concentration, and secretion rate were determined from saliva samples and compared with pre-treatment values. OM was assessed, total/specific salivary proteins, including mucin 5B and 7, IgA, cystatin-S, albumin, and α-amylase, were quantified. RESULTS: 95% patients experienced OM during IMRT, with 33 subjects reaching grade 2&3. At T1, there was a significant reduction in salivary flow rate, total protein secretion rate, α-amylase and cystatin-S compared to baseline. Remarkably IMRT did not significantly alter mucin 5B and 7, or the IgA secretion rate at any time point. At T1, all the analyzed proteins were associated with the OM outcomes. In addition, there was a significant inverse correlation between IgA concentration at T0 and the severity of OM during IMRT. CONCLUSION: This study revealed significant associations between several salivary proteins and OM in patients with head and neck cancer undergoing IMRT. Further longitudinal studies are needed to confirm these results. CLINICAL SIGNIFICANCE: The study contributes to the understanding of certain salivary proteins association with OM. This could be the first step towards identifying potential salivary markers that could offer perspectives for personalized medicine approaches to improve their quality of life (QoL). RESEARCH QUESTION: What is the association between salivary proteins and the occurrence and severity of OM in head and neck cancer patients? AIM: To assess the association between salivary protein composition with the clinical onset/severity of oral mucositis (OM) in head and neck cancer patients treated with intensity modulated radiotherapy. NULL HYPOTHESIS: There is no association between salivary proteins and onset/severity of OM in HNC patients.

Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma.

PURPOSE: To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). METHOD AND MATERIALS: All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8 years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. RESULTS: ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5 days, P = 0.042) than in the MF group. CONCLUSION: The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC.

The effect of primary tumor volume on the prognosis of nasopharyngeal carcinoma in era of volumetric modulated arc therapy: a propensity score matched cohort study.

OBJECTIVE: The role of Primary Tumor Volume (PTV) in Nasopharyngeal Carcinoma (NPC) treated with Volumetric Modulated Arc Therapy (VMAT) is still unclear. The aim of this study was to access the effect of PTV in prognosis prediction of nasopharyngeal carcinoma in era of VMAT. METHODS: Between January 20 and November 2011, 498 consecutive NPC patients with stage I-IVA disease who received VMAT at a single center were retrospectively analyzed. Receiver Operating Characteristic (ROC) was performed to access the cut-off point of PTV. Univariate Kaplan-Meier and multivariate Cox regression analyses were used to evaluate prognostic value for PTV. The Propensity Score Matching (PSM) was used to adjust baseline potential confounders. RESULTS: The 5-year Locol-Regional Failure-Free (L-FFR), Distant Failure-Free Survival (D-FFR), Disease-Free Survival (DFS) and Overall Survival (OS) were 90.6%, 83.7%, 71.5% and 79.3%, respectively. Before PSM, the 5-year L-FFR, D-FFR, DFS, OS rates for NPC patients with PTV ≤ 38 mL vs. PTV > 38 mL were 94.1% vs. 90.4% (p = 0.063), 87.9% vs. 76.3% (p < 0.001), 78.5% vs. 58.5% (p < 0.001) and 86.3% vs. 66.7% (p < 0.001) respectively. Multivariate analysis showed PTV was an independent prognostic factor for D-FFS (p = 0.034), DFS (p = 0.002) and OS (p = 0.001). PTV classified was still an independent prognostic factor for OS after PSM (HR = 2.034, p = 0.025. CONCLUSIONS: PTV had a substantial impact on the prognosis of NPC patients treated with VMAT before and after PSM simultaneously. PTV > 38 mL may be considered as an indicator of the clinical stage of nasopharyngeal carcinoma. LEVEL OF EVIDENCE: III.

Predicted cardiac and second cancer risks for patients undergoing VMAT for mediastinal Hodgkin lymphoma.

BACKGROUND AND PURPOSE: To predict treatment-related cardiovascular disease (CVD) and second cancer 30-year absolute mortality risks (AMR30) for patients with mediastinal Hodgkin lymphoma in a large multicentre radiation oncology network in Ireland. MATERIAL AND METHODS: This study includes consecutive patients treated for mediastinal lymphoma using chemotherapy and involved site radiotherapy (RT) 2016-2019. Radiation doses to heart, left ventricle, cardiac valves, lungs, oesophagus, carotid arteries and female breasts were calculated. Individual CVD and second cancer AMR30 were predicted using Irish background population rates and dose-response relationships. RESULTS: Forty-four patients with Hodgkin lymphoma were identified, 23 females, median age 28 years. Ninety-eight percent received anthracycline, 80% received 4-6 cycles ABVD. Volumetric modulated arc therapy (VMAT) ± deep inspiration breath hold (DIBH) was delivered, median total prescribed dose 30 Gy. Average mean heart dose 9.8 Gy (range 0.2-23.8 Gy). Excess treatment-related mean AMR30 from CVD was 2.18% (0.79, 0.90, 0.01, 0.13 and 0.35% for coronary disease, heart failure, valvular disease, stroke and other cardiac diseases), 1.07% due to chemotherapy and a further 1.11% from RT. Excess mean AMR30 for second cancers following RT were: lung cancer 2.20%, breast cancer in females 0.34%, and oesophageal cancer 0.28%. CONCLUSION: For patients with mediastinal lymphoma excess mortality risks from CVD and second cancers remain clinically significant despite contemporary chemotherapy and photon-RT. Efforts to reduce the toxicity of combined modality treatment, for example, using DIBH, reduced margins and advanced RT, e.g. proton beam therapy, should be continued to further reduce potentially fatal treatment effects.

Radiation Therapy for Prostate Cancer Using HYpofractionation Directed by UltraSound (RAPHYDUS): A Brazilian Public Health Care System Study.

PURPOSE: This study evaluated the toxicity associated with a short course dose-escalated hypofractionated radiation therapy (HFRT) using image guided RT with or without androgen suppression therapy in patients with prostate cancer. METHODS AND MATERIALS: This single-center prospective observational study included 132 patients with prostate cancer from 2016 to 2020. Patients received HFRT using image guided RT (84%) with 3-dimensional (91%) or intensity modulated RT (9%). Total prescribed doses were 66 Gy (63%), 63 Gy (12%), and 60 Gy (24%) in 22, 21, or 20 daily fractions depending on organ-at-risk dose constraints. Acute toxicity was scored using Radiation Therapy Oncology Group criteria and the international prostate symptom index. The expanded prostate cancer index composite questionnaire was used to collect quality of life data (ranging from 0-100). RESULTS: The study population consisted of 111 patients who completed RT during a period of 3 years. The risk groups were as follows: low risk (12%), intermediate (32%), and high (56%). None of the patients had suspicious lymph nodes. Ninety percent received androgen suppression therapy. Maximum acute genitourinary and gastrointestinal toxicity peaked at grade 3 in 4 of 111 evaluated patients (4%) and at grade 2 in 7 of 111 evaluated patients (8%), respectively. The average international prostate symptom score increased from 4.8 at pretreatment to 14.0 during week 4 and normalized (5.7) 3 months after treatment completion. CONCLUSIONS: The current HFRT dose-escalation trial has demonstrated the feasibility of administering 66 Gy in 22 fractions with low acute gastrointestinal and genitourinary toxicities. Further follow-up will report late toxicities and outcomes.

High dose image-guided, intensity modulated radiation therapy (IG-IMRT) for chordomas of the sacrum, mobile spine and skull base: preliminary outcomes.

PURPOSE: To report preliminary outcomes of high dose image-guided intensity modulated radiotherapy (IG-IMRT) in the treatment of chordomas of the sacrum, mobile spine and skull base. METHODS: Retrospective analysis of chordoma patients treated with surgery and/or radiotherapy (RT) in a single tertiary cancer center. Initial treatment was categorized as (A) Adjuvant or definitive high-dose RT (78 Gy/39fx or 24 Gy/1fx) vs (B) surgery-only or low dose RT. The primary endpoint was the cumulative incidence of local failure. RESULTS: A total of 31 patients were treated from 2010 through 2020. Median age was 55 years, tumor location was 64% sacrum, 13% lumbar, 16% cervical and 6% clivus. Median tumor volume was 148 cc (8.3 cm in largest diameter), 42% of patients received curative-intent surgery and 65% received primary RT (adjuvant or definitive). 5-year cumulative incidence of local failure was 48% in group A vs 83% in group B (p = 0.041). Tumor size > 330 cc was associated with local failure (SHR 2.2, 95% CI 1.12 to 7.45; p = 0.028). Eight patients developed distant metastases, with a median metastases-free survival of 56.1 months. 5-year survival for patients that received high dose RT was 72% vs 76% in patients that received no or low dose RT (p = 0.63). CONCLUSION: Our study suggests high-dose photon IG-IMRT improves local control in the initial management of chordomas. Health systems should promote reference centers with clinical expertise and technical capabilities to improve outcomes for this complex disease.

Radiotherapy-related toxicity for localized prostate cancer: meta-analysis comparing conventional or moderately hypofractionated vs. ultrahypofractionated protocols.

BACKGROUND: To compare toxicities in relation to standard radiation treatments [conventional fractionation RT (CRT) and moderate hypofractionated RT (MRT)] with ultrahypofractionated RT (URT) in the treatment of patients with localized PCa. METHODS: A searched was performed in Medline, Embase, Cochrane CENTRAL, and LILACS to January 2020 for studies comparing URT to CRT and/or MRT in relation to genitourinary (GU) and gastrointestinal (GI) toxicity in the treatment of patients with localized PCa. URT, MRT and CRT were defined as protocols delivering a daily dose of ≥5 Gy, 2.4-4.9 Gy, and <2.4 Gy per fractions regardless total dose, respectively. RESULTS: Eight studies with 2929 patients with localized PCa were included in the analysis. These eight studies did not find any difference between URT and MRT/CRT groups in relation to acute GU toxicity (21.0% × 23.8%, RD -0.04; 95% CI -0.13, 0.06; p = 0.46; I2 = 89%) and acute GI toxicity (4.9% × 6.9%, RD -0.03; 95% CI -0.07, 0.01; p = 0.21; I2 = 79%). Six studies did not find any difference between URT and MRT/CRT groups in relation to late GU toxicity (3.9% × 4.7%, RD -0.01; 95% CI -0.03, 0.00; p = 0.16; I2 = 19%) and late GI toxicity (2.1% × 3.5%, RD -0.01; 95% CI -0.03, 0.00; p = 0.05; I2 = 22%). CONCLUSION: The present study suggests that acute GU/GI and late GU/GI toxicity are similar between URT and standard protocols. More studies with longer follow-ups directed to oncology outcomes are warranted before any recommendation on this topic.

Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311).

PURPOSE: Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC. METHODS: E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index. RESULTS: Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6]) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented. CONCLUSION: Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC.

Synchronous bilateral breast cancer treated with a 3-week hypofractionated radiotherapy schedule: clinical and dosimetric outcomes.

BACKGROUND AND PURPOSE: Synchronous bilateral breast cancer (SBBC) accounts for 1-3.5% of breast cancer patients. The aim of this study was to evaluate dosimetric issues, clinical outcomes, and acute toxicities for SBBC patients receiving synchronous bilateral hypofractionated radiotherapy (SBHRT) and to compare them with patients treated with synchronous bilateral normofractionated RT schedule (SBNRT). MATERIALS AND METHODS: From April 2016 to March 2020, 39 SBBC patients were referred to our institution. Patients were divided according to their prescription dose: Group A: 50 Gy/25fx (fractions), B: 60-64 Gy/25fx, C: 40.05 Gy/15fx; D: 48 Gy/15fx. Toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE)v.5.0. RESULTS: 34 patients were finally evaluated. Median follow-up was 24 months for NF schedule and 9 months for HF schedule. In the HF schedule, no acute side-effects > G2 were observed and no dermatitis was reported in 6th month´s assessments. 95% of patients have no evidence of disease and only 1 patient presented local relapse in the first mammography after RT. No distant failures or deaths were observed. Regarding dosimetric issues, the inter-patient average Dmean for the heart was: Group A: 5.0 Gy (4.6-5.5), Group B: 4.4 Gy (4.1-5.4), Group C: 4.8 Gy (4.5-5.1) and Group D: 5.3 Gy (4.4-5.6). For the lungs, the inter-patient average Dmean was: Group A: 10.8 Gy (9.8-12.2), Group B: 11.5 Gy (11.3-12), Group C: 9.8 Gy (9.3-10.5) and Group D: 10.5 Gy (10-11.3). CONCLUSIONS: This is the first study reporting the safety, feasibility, and tolerability of 40.05 Gy/15fx over 3 weeks for the treatment of SBBC patients. Further study with larger accrual is mandatory.

Acute and intermediate toxicity of 3-week radiotherapy with simultaneous integrated boost using TomoDirect: prospective series of 287 early breast cancer patients.

AIMS: To report toxicity of a hypofractionated scheme of whole-breast (WB) intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) to the tumor bed (TB) using Tomotherapy® with Direct modality. METHODS: Patients with early breast cancer, undergoing radiotherapy (RT) in 15 daily fractions to WB (prescription dose 40.05 Gy) and SIB to the TB (48 Gy), between 2013 and 2017, was analyzed. Primary endpoint was acute and intermediate toxicity assessed at the end and within 6 months from RT, according to Radiation Therapy Oncology Group (RTOG) scale. Secondary endpoints included early chronic toxicity at 12-months follow-up, using the Late Effects Normal Tissue Task Subjective, Objective, Management, and Analytic (LENT-SOMA) scale, and cosmesis using Harvard criteria. RESULTS: The study population was of 287 patients. Acute and intermediate toxicity was collected among 183 patients with data available at the end of RT and within 6 months, 85 (46%) experienced G2 toxicity and 84 (46%) G1 toxicity, while 14 (8%) did not report toxicity at any time. A significant reduction of any grade toxicity was observed between the two time points, with the majority of patients reporting no clinically relevant toxicity at 6 months. At univariate analysis, age < 40 years, breast volume > 1000 cm3 and Dmax ≤ 115% of prescription dose were predictive factors of clinically relevant acute toxicity (G ≥ 2) at any time. At multivariable analysis, only age and breast volume were confirmed as predictive factors, with Relative Risks (95% Confidence Intervals): 2.02 (1.13-3.63) and 1.84 (1.26-2.67), respectively. At 12-month follow-up, 113 patients had complete information on any toxicity with 53% of toxicity G < 2, while cosmetic evaluation, available for 102 patients, reported a good-excellent result for 86% of patients. CONCLUSIONS: Hypofractionated WB IMRT with a SIB to the TB, delivered with TomoDirect modality, is safe and well-tolerated. Most patients reported no toxicity after 6 months and good-excellent cosmesis. Predictive factors of clinically relevant toxicity might be considered during treatment planning in order to further reduce side effects.

Evaluation of the correlation between side effects to oral mucosa, salivary glands, and general health status with quality of life during intensity-modulated radiotherapy for head and neck cancer.

PURPOSE: The aim of this study was to evaluate the distribution of acute clinical complications that involve the oral cavity (oral mucositis and salivary flow), general health status (Karnofsky performance status scale (KPS) and weight), and quality of life using the worst performance throughout radiotherapy treatment by intensity-modulated radiation therapy (IMRT) in the head and neck region and to evaluate the correlation between these variables. METHODS: This prospective, longitudinal study evaluated 32 patients who were undergoing IMRT for head and neck tumors. The measures were collected weekly through standardized protocols and a quality of life questionnaire (UW-QOL version 4). RESULTS: The worst performance for all variables was concentrated in treatment weeks 2 and 5. Regarding quality of life, the emotional dimensions were the most affected (pain 62.86; activity 55; recreation 43.57; mood 49.97; shoulder 57.06; anxiety 42.91). There were a higher number of moderate mucositis correlations with quality of life (mucositis × KPS 0.002; mucositis × weight loss 0.03; mucositis × pain 0.001; mucositis × activity 0.002; mucositis × recreation 0.001; mucositis × swallowing 0.002; mucositis × saliva 0.006; mucositis × mood 0.007; mucositis × anxiety 0.002). CONCLUSIONS: IMRT treatment severely deteriorated the patients' quality of life. There were important correlations between the clinical variables and quality of life, especially mucositis.

Intensity-modulated radiation therapy administered to a previously irradiated spine is effective and well-tolerated.

PURPOSE: This study sought to discern the clinical outcomes of intensity-modulated radiation therapy (IMRT) administered to the spine in patients who had undergone previous radiotherapy. METHODS: A total of 81 sites of 74 patients who underwent previous radiotherapy administered to the spine or peri-spine and subsequently received IMRT for the spine were analyzed in this study. The prescribed dose of 80 Gy in a biologically effective dose (BED) of α/ß = 10 (BED10) was set as the planning target volume. The constraint for the spinal cord and cauda equine was D0.1 cc ≤ 100 Gy and ≤ 150 Gy of BED for re-irradiation alone and the total irradiation dose, respectively. RESULTS: The median follow-up period was 10.1 (0.9-92.1) months after re-irradiation, while the median interval from the last day of the previous radiotherapy to the time of re-irradiation was 15.6 (0.4-210.1) months. Separately, the median prescript dose of re-irradiation was 78.0 (28.0-104.9) of BED10. The median survival time in this study was 13.9 months, with 1-, 3-, and 5-year overall survival rates of 53.7%, 29.3%, and 26.6%, respectively. The 1-, 3-, and 5-year local control rates were 90.8%, 84.0%, and 84.0%, respectively. Neurotoxicity was observed in two of 72 treatments (2.8%) assessed after re-irradiation. CONCLUSION: Re-irradiation for the spine using IMRT seems well-tolerated. Definitive re-irradiation can be a feasible treatment option in patients with the potential for a good prognosis.

Decrease in treatment intensity predicts worse outcome in patients with locally advanced head and neck squamous cell carcinoma undergoing radiochemotherapy.

PURPOSE: Radiochemotherapy (RCT) is an effective standard therapy for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Nonetheless, toxicity is common, with patients often requiring dose modifications. METHODS: To investigate associations of RCT toxicities according to CTCAE version 5.0 and subsequent therapy modifications with short- and long-term treatment outcomes, we studied all 193 patients with HNSCC who received RCT (70 Gy + platinum agent) at an academic center between 03/2010 and 04/2018. RESULTS: During RCT, 77 (41%, 95% CI 34-49) patients developed at least one ≥ grade 3 toxicity, including seven grade 4 and 3 fatal grade 5 toxicities. The most frequent any-grade toxicities were xerostomia (n = 187), stomatitis (n = 181), dermatitis (n = 174), and leucopenia (n = 98). Eleven patients (6%) had their radiotherapy schedule modified (mean radiotherapy dose reduction = 12 Gy), and 120 patients (64%) had chemotherapy modifications (permanent discontinuation: n = 67, pause: n = 34, dose reduction: n = 7, change to other chemotherapy: n = 10). Objective response rates to RCT were 55% and 88% in patients with and without radiotherapy modifications (p = 0.003), and 84% and 88% in patients with and without chemotherapy modifications (p = 0.468), respectively. Five-year progression-free survival estimates were 20% and 50% in patients with and without radiotherapy modifications (p = < 0.001), and 53% and 40% in patients with and without chemotherapy modifications (p = 0.88), respectively. CONCLUSIONS: Reductions of radiotherapy dose were associated with impaired long-term outcomes, whereas reductions in chemotherapy intensity were not. This suggests that toxicities during RCT should be primarily managed by modifying chemotherapy rather than radiotherapy.

Salvage radiation therapy in prostate cancer: relationship between rectal dose and long-term, self-reported rectal bleeding.

PURPOSE: To quantify the relationship between the rectal dose distribution and the prevalence of self-reported rectal bleeding among men treated with salvage radiotherapy (ST) delivered by three-dimensional conformal radiotherapy (3DCRT) for prostate cancer. To use this relationship to estimate the risk of rectal bleeding for a contemporary cohort of patients treated with volumetric modulated arc therapy (VMAT) ST. METHODS AND PATIENTS: Rectal bleeding of any grade was reported by 56 (22%) of 255 men in a PROM-survey at a median follow-up of 6.7 years after 3DCRT ST. Treatment plan data were extracted and dose-response relationships for the rectal volumes receiving at least 35 Gy (V35Gy) or 63 Gy (V63Gy) were calculated with logistic regression. These relationships were used to estimate the risk of rectal bleeding for a cohort of 253 patients treated with VMAT ST. RESULTS: In the dose-response analysis of patients in the 3DCRT ST cohort, both rectal V35Gy and V63Gy were statistically significant parameters in univariable analysis (p = 0.005 and 0.003, respectively). For the dose-response models using either rectal V35Gy or V63Gy, the average calculated risk of rectal bleeding was 14% among men treated with VMAT ST compared to a reported prevalence of 22% for men treated with 3DCRT ST. CONCLUSIONS: We identified dose-response relationships between the rectal dose distribution and the risk of self-reported rectal bleeding of any grade in a long-term perspective for men treated with 3DCRT ST. Furthermore, VMAT ST may have the potential to decrease the prevalence of late rectal bleeding.

Patterns of treatment failure in patients with prostate cancer treated with 76-80 Gy radiotherapy to the prostate and seminal vesicles ± hormonotherapy.

PURPOSE: To assess the pattern of treatment failure in patients with prostate cancer (PCa) treated with radiotherapy (76-80 Gy) ± hormone therapy (HT). We also evaluated the influence of treatment failure on survival outcomes. METHODS: Retrospective study of patients with PCa (n = 302) treated with radiotherapy (RT) ± HT at our centre between November 1999 and July 2007. The mean patient age was 70.2 years (range 51-87). Distribution by NCCN risk group was low (n = 80, 26.5%), intermediate (n = 86, 28.5%), high (n = 77, 25.5%), and very high (n = 49, 16.2%). Most patients (n = 273, 90.4%) received IMRT at a dose of 76-80 Gy. HT was administered in 237 patients (78.5%), in most cases (n = 167, 55.3%) for < 7 months RESULTS: Survival rates at 10 years were: overall survival (OS), 64.3%; biochemical disease-free survival, 83.9%; disease-free survival, 92.5%; and metastasis-free survival (MFS), 94.3%. Biochemical failure (BF) was observed in 55 cases (18.2%), 32 of whom subsequently developed clinical recurrence: metastasis (n = 17, 5.6%), local failure (n = 11, 3.6%), and regional failure (n = 4, 1.3%). The cause of death (n = 159) was intercurrent disease in 115 cases (72.3%), second cancer in 27 (17.0%), and PCa in 17 (10.7%). Biochemical failure-free survival ≤ 24 months was significantly associated with worse OS and MFS (p = 0.0001). Late genitourinary and gastrointestinal toxicity grade ≥ 3 (RTOG) was observed in 18 (6.0%) and 7 (2.3%) patients, respectively. CONCLUSIONS: The main type of treatment failure after 76-80 Gy of radiotherapy ± HT is local or metastatic. In all cases, biochemical failure occurred prior to treatment failure. BF within 24 months of treatment completion was significantly associated with worse OS and MFS.

VMAT partial-breast irradiation: acute toxicity of hypofractionated schedules of 30 Gy in five daily fractions.

PURPOSE: To report acute toxicities in breast cancer (BC) patients (pts) recruited in a prospective trial and treated with accelerated partial-breast irradiation (APBI) using Volumetric Modulated Arc Therapy (VMAT) delivered with a hypofractionated schedule. METHODS: From March 2014 to June 2019, pts with early-stage BC (Stage I), who underwent breast conservative surgery (BCS), were recruited in a prospective study started at the National Cancer Institute of Milan. Pts received APBI with a hypofractionated schedule of 30 Gy in five daily fractions. Radiotherapy treatment (RT) was delivered using VMAT. Acute toxicity was assessed according to RTOG/EORTC criteria at the end of RT. RESULTS: Between March 2014 and June 2019, 151 pts were enrolled in this study. 79 Pts had right-side and 72 had left-side breast cancer. Median age was 69 (range 43-92). All pts presented with pathological stage IA BC, molecular classification was Luminal A in 128/151 (85%) and Luminal B in 23/151 (15%) cases. Acute toxicity, assessed at the end of RT, consisted of G1 erythema in 37/151 (24. 5%) pts and skin toxicities higher than G1, did not occur. Fibrosis G1 and G2 were reported in 41/151 (27. 1%) pts and in 2/151 pts (1. 3%), respectively. Edema G1 occurred in 8/151 (5. 3%) pts and asthenia G1 occurred in 1/151 (0. 6%) pts. CONCLUSIONS: APBI with VMAT proved to be feasible and can be a valid alternative treatment option after BCS in selected early breast cancer pts according to ASTRO guidelines. A longer follow-up is needed to assess late toxicity.

Pelvic fractures and changes in bone mineral density after radiotherapy for cervical, endometrial, and vaginal cancer: A prospective study of 239 women.

BACKGROUND: Advances in radiotherapy (RT) have led to improved oncologic outcomes for women with gynecologic cancers; however, the long-term effects and survivorship implications need further evaluation. The purpose of this study was to determine the incidence of pelvic fractures and changes in bone mineral density (BMD) after pelvic RT. METHODS: Two hundred thirty-nine women who had pelvic RT for cervical, endometrial, or vaginal cancer between 2008 and 2015 were prospectively studied. BMD scans and biomarkers of bone turnover were obtained at the baseline and 3 months, 1 year, and 2 years after RT. Imaging studies were assessed for pelvic fractures for up to 5 years. Patients with osteopenia, osteoporosis, or pelvic fractures at any point were referred to the endocrinology service for evaluation and treatment. RESULTS: The median age at diagnosis was 51 years; 132 patients (56%) were menopausal. The primary diagnoses were cervical (63.6%), endometrial (30.5%), and vaginal cancer (5.9%). Sixteen patients (7.8%; 95% confidence interval, 4.5%-12.4%) had pelvic fractures with actuarial rates of 3.6%, 12.7%, and 15.7% at 1, 2, and 3 years, respectively. Fractures were associated with baseline osteoporosis (P < .001), higher baseline bone-specific alkaline phosphatase (P < .001), and older age (P = .007). The proportion of patients with osteopenia/osteoporosis increased from 50% at the baseline to 58%, 59%, and 70% at 3 months, 1 year, and 2 years, respectively. CONCLUSIONS: A high proportion of women had significant decreases in BMD after pelvic RT, with 7.8% diagnosed with a pelvic fracture. BMD screening and pharmacologic intervention should be strongly considered for these high-risk women.

Influence of the technique and comorbidities in hypofractionated radiotherapy for prostate cancer.

PURPOSE: To analyze the differences in toxicity and biochemical relapse-free survival with hypofractionated radiotherapy with three-dimensional radiotherapy (3D-CRT) or volumetric arc therapy (VMAT) for prostate cancer taking into account comorbidity measured using the Charlson Comorbidity Index (CCI). METHODS: From January 2011 to June 2016, 451 patients with prostate cancer were treated with 60 Gy (20 daily fractions). VMAT or 3D-CRT was used. Distribution by stage: 17% low-risk, 27.2% intermediate-risk; 39.2% high-risk, 16.6% very high-risk. Mean CCI was 3.4. RESULTS: With a median follow up of 51 months, most patients did not experience any degree of acute GI toxicity (80.9%) compared to 19.1%, who experienced some degree, mainly G-I /II. In the multivariate analysis, only technique was associated with acute GI toxicity ≥ G2. Patients treated with VMAT had greater acute GI toxicity compared with those who received 3D-CRT (23.9% vs. 13.5%, p = 0.005). With respect to acute GU toxicity, 72.7% of patients experienced some degree, fundamentally G-I/II. Neither age, CCI, nor androgen deprivation therapy (ADT) were associated with greater toxicity. Overall survival at 2, 5 and 7 years was 97%, 88% and 83% respectively. The only factor with statistical significance was CCI, with a greater number of events in individuals with a CCI ≥ 4 (p < 0.03). CONCLUSIONS: Hypofractionated radiotherapy for prostate cancer is an effective, well-tolerated treatment even for elderly patients with no associated comorbidity. Longer follow up is needed in order to report data on late toxicity.

Estudo randomizado duplo-cego e placebo controlado do substituto salivar com sistema enzimático para xerostomia em pacientes irradiados em região de cabeça e pescoço / Randomized double-blind, placebo-controlled study of salivary substitute with enzymatic system for xerostomia in patients irradiated in the head and neck region

Xerostomia e/ou hipossalivação é uma das mais frequentes complicações orais em pacientes irradiados em região de cabeça e pescoço, com importante impacto na qualidade de vida ao longo do tempo. O objetivo do estudo, foi avaliar a eficácia do Bioxtra Spray® na redução da intensidade de xerostomia e seu impacto na qualidade de vida em pacientes que foram irradiados em região de cabeça e pescoço pela técnica de Radioterapia de Intensidade Modulada (IMRT) ou Radioterapia Conformada Tridimensional (RTC3D), em um período de 8 a 9 meses após o término do tratamento. Foi realizado um estudo prospectivo, randomizado, duplo cego e placebo controlado, com um total de 40 pacientes alocados no Grupo Placebo (n=19) ou Bioxtra Spray® (n=21). Os pacientes utilizaram ambos os produtos três vezes ao dia durante 30 dias. Para as análises, foram realizadas a avaliação da intensidade da xerostomia, avaliação da taxa de fluxo salivar não estimulada e estimulada através da sialometria e a avaliação da qualidade de vida através do Questionário de Qualidade de Vida da Universidade de Washington, validado em português (QQV-UW) em 2 fases: Fase 1 (antes do uso de ambos os produtos); Fase 2 (após 30 dias de uso dos produtos). Em relação à intensidade da xerostomia, não foram observadas melhoras significativas da queixa de boca seca após 30 dias de uso do Bioxtra Spray®( p>0,05). Analisando os exames de sialometria, foi observado que, após 30 dias de uso, o Grupo Bioxtra Spray® apresentou saliva não estimulada e estimulada significativamente maior quando comparado ao Grupo Placebo (p<0,05). Em relação à qualidade de vida, de maneira geral o Grupo Placebo apresentou melhores escores gerais dos domínios do QQV-UW quando comparados ao Grupo Bioxtra Spray® nas duas fases do estudo (p<0,05). Não foram observadas diferenças significativas em relação ao domínio saliva do QQV-UW entre os grupos nas duas fases do estudo. Interessante observar que os pacientes de ambos os Grupos que foram submetidos à técnica IMRT apresentaram índices tanto na taxa de fluxo salivar quanto na qualidade de vida significativamente melhores em ambas as fases do estudo quando comparados à técnica RTC3D. Por fim, concluímos que o Bioxtra Spray®, na metodologia estudada, não apresentou resultados positivos na lubrificação oral e na qualidade de vida dos pacientes. Contudo, estudos em longo prazo que avaliam seu efeito enzimático na proteção dos tecidos orais são recomendados

Xerostomia and/or hyposalivation are common oral complication in patients irradiated in the head and neck region with an important impact on quality of life over time. The aim of this study was to evaluate the effectiveness of Bioxtra Spray® in reducing xerostomia intensity and its impact on the quality of life of patients who were irradiated in the head and neck region by the Intensity Modulated Radiation Therapy (IMRT) or Three Dimensional Conformal Radiotherapy (RTC3D) over a period of 6 months to 1 year after the end of treatment. A prospective, randomized, double-blind, placebo-controlled study was performed, with a total of 40 patients allocated to the Placebo Arm (n= 19) or Bioxtra Spray® (n = 21). Patients used both products three times a day for 30 days and for the analyzes, the evaluation of xerostomia grade, evaluation of the unstimulated and stimulated salivary flow rate through sialometry and the evaluation of quality of life through the University of Washington Quality of Life Questionnaire, validated in Portuguese (UW-QoL) were performed in 2 phases: Phase 1 (before the use of both products); Phase 2 (after 30 days of using both products). Regarding xerostomia grade, no significant improvement in dry mouth complaints was observed after 30 days of use (p> 0.05). Analyzing the sialometry exams, it was observed that after 30 days of use, the Bioxtra Spray® Group showed unstimulated and stimulated salivary flow rate significantly higher when compared to the Placebo Arm (p <0.05). Regarding quality of life, in general, the Placebo Arm had better overall scores than in the UW-QoL domains when compared to the Bioxtra Spray® Group in the two phases of the study (p <0.05). No significant differences were observed in relation to the UW-QoL saliva domain between the groups in the two phases of the study. It is interesting to note that patients from both Groups who underwent the IMRT technique showed significantly better rates of salivary flow and quality of life in both phases of the study when compared to the RTC3D technique. In conclusion, we observed that Bioxtra Spray® did not present positive results in oral lubrication and in patients' quality of life. However, studies evaluating its enzymatic effect in protecting oral tissues are recommended