Post radiation mucosal ulcer risk after a hypofractionated stereotactic boost and conventional fractionated radiotherapy for oropharyngeal carcinoma.

BACKGROUND/PURPOSE: Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients' quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC. MATERIAL AND METHODS: We performed a retrospective cohort study (N = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) (N = 180), or 24 Gy IMRT (2 Gy fractions) (N = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT. RESULTS: All cases of PRMU (N = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% (N = 46) vs. 12% (N = 18) for conventional fractionation (p = 0.003). Most PRMU developed within nine months (N = 48). PRMU occurring > nine months (N = 16) were mainly observed in the SBRT boost group (N = 15). Sex (p = 0.048), acute tube feeding (p = < 0.001), tumor subsite tonsil (p = 0.001), and N stage (p = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions. CONCLUSION: The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.

Bladder-sparing (chemo)radiotherapy in elderly patients with muscle-invasive bladder cancer: a retrospective cohort study.

BACKGROUND: Organ-sparing treatment for muscle-invasive bladder cancer by maximal transurethral removal of the tumor (TURB) followed by chemoradiation (CRT) has shown promising results in recent studies, and is therefore considered to be an acceptable alternative for the standard of radical cystectomy (RC) in selected patients. We report on outcomes in a single-center, retrospective CRT cohort in comparison to a RC and radiotherapy only (RT) cohort. PATIENTS AND METHODS: The patient population included n = 84 CRT patients, n = 93 RC patients, and n = 95 RT patients. Primary endpoints were local control (LC) up to 2 years and overall survival (OS) up to 5 years. Cox regression was performed to determine risk factors for LC and OS in the CRT group. Acute genito-urinary (GU) and gastro-intestinal (GI) toxicity were scored with CTCAE version 4 for the RT and CRT cohort. Logistic regression was used to determine risk factors for toxicity. We followed the EQUATOR guidelines for reporting, using the STROBE checklist for observational research. RESULTS: Baseline characteristics were different between the treatment groups with in particular worse comorbidity scores and higher age in the RT cohort. The CRT schedule was completed by 96% of the patients. LC at 2 years was 83.4% (90% CI 76.0-90.8) for CRT vs. 70.9% (62.2-79.6) for RC and 67.0% (56.8-77.2) for RT. OS at 5 years was 48.9% (38.4-59.4) for CRT vs. 46.6% (36.4-56.8) for RC, and 27.6% (19.4-35.8) for RT. High T stage was significantly associated with worse LC and OS in the CRT group. GU/GI toxicity grade ≥2 occurred in 43 (48.3%) RT patients and 38 (45.2%) CRT patients. CONCLUSIONS: The organ-preserving strategy with CRT was feasible and tolerable in this patient population, and the achieved LC and OS were satisfactory in comparison to the RC cohort and literature.

Internal Mammary Chain Sentinel Nodes in Early-Stage Breast Cancer Patients: Toward Selective Removal.

BACKGROUND: Removal of internal mammary chain sentinel nodes (IMCSNs) affects prognosis and treatment of breast cancer, and internal mammary chain radiotherapy (IMCRT) can improve survival for selected patients. This study aimed to determine the effect of IMCSN biopsy on recurrence-free survival (RFS) and overall survival (OS) and to identify predictive factors for IMCSN and distant metastasis. METHODS: Patients with IMCSNs were selected from a prospective database for the period 1999-2007. Lymphoscintigraphy was performed after intratumoral technetium-99 m injection, and all sentinel nodes were removed. Both RFS and OS were calculated for subgroups with tumor-positive, tumor-negative, or non-removed IMCSNs. Predictive factors were identified for tumor-positive IMCSNs and distant metastasis by regression analysis. RESULTS: For 287 (85%) of 336 patients, IMCSN biopsy was performed, and metastasis was detected in 38 patients (13%). The patients with tumor-positive IMCSNs had poorer OS than the patients with no IMCSN metastasis or non-removed IMCSNs (p = 0.002). These patients also had worse RFS due to distant metastasis (p = 0.002). Axillary metastasis was predictive for tumor-positive IMCSNs (positive predictive value, 38.5%). The predictive factors for distant metastasis were tumor-positive IMCSNs (hazard ratio [HR], 2.5), non-removed IMCSNs (HR, 2.3), tumor diameter greater than 1.5 cm (HR, 3.5), and age older than 65 years (HR, 3.1; reference, < 50 years). CONCLUSIONS: Patients with IMCSNs have worse survival due to distant metastasis. The clinically relevant predictive factor for distant metastasis is tumor larger than 1.5 cm. According to the authors' current protocol, IMCSN biopsy is performed for patients younger than 70 years who have a tumor larger than 1.5 cm, with the cardiotoxicity of the adjuvant IMCRT weighed against the survival benefit.

Prediction of early mortality following stereotactic body radiotherapy for peripheral early-stage lung cancer.

BACKGROUND/PURPOSE: To investigate prognostic factors for death within 6 months of stereotactic body radiotherapy (SBRT) for patients with peripheral early-stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This analysis included 586 NSCLC patients with peripheral tumors treated with SBRT. Potential patient and tumor prognostic factors, including the Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale (CIRS), were analyzed by logistic regression analysis for association with early mortality (death <6 months after SBRT). Additionally, CCI and CIRS were compared with respect to their predictive ability for early mortality by comparing multivariate models with each comorbidity index, and assessing their respective discriminatory abilities (C-index). RESULTS: A total of 36 patients (6.1%) died within 6 months of the start of SBRT. With a median follow-up of 25 months, 3-year overall survival was 54%. CIRS and tumor diameter were significant predictors of early mortality on multivariate analysis (p = .001). Patients with a CIRS score of 8 or higher and a tumor diameter over 3 cm had a 6-month survival of 70% versus 97% for those lacking these two features (p < .001). CCI was not predictive for early mortality on univariate nor multivariate analysis; the model containing CCI had a C-index of 0.65 versus 0.70 for the model containing CIRS. CONCLUSION: CIRS and tumor diameter predict for early-mortality in peripheral early-stage NSCLC treated with SBRT. CIRS may be a more useful comorbidity index than CCI in this population when assessing short-term life expectancy.

Long-term outcomes following stereotactic body radiotherapy boost for oropharyngeal squamous cell carcinoma.

Background/purpose: To determine the efficacy and toxicity profile of a stereotactic body radiotherapy (SBRT) boost as a first line treatment in patients with oropharyngeal squamous cell carcinoma (OPSCC). Materials and methods: We performed a retrospective cohort study in 195 consecutive OPSCC patients with T1-small T3 disease, treated at Erasmus MC between 2009 and 2016 with a SBRT (3 × 5.5 Gy) boost after 46 Gy IMRT. Primary endpoints were disease-specific survival (DSS) and Grade ≥3 toxicity (Common Terminology Criteria). The Kaplan-Meier method and Cox regression model were applied to determine rates and risk factors. Results: The median follow-up was 4.3 years. Treatment compliance was high (100%). Rates of 5-year DSS and late grade ≥3 toxicity were 85% and 28%, respectively. Five-year overall survival was 67%. The most frequently observed toxicities were mucosal ulceration or soft tissue necrosis (n = 30, 5 year 18%), dysphagia or weight loss (n = 18, 5 year 12%) and osteoradionecrosis (n = 11, 5 year 9%). Current smoker status (hazard ratio [HR] = 2.9, p = .001) and Charlson Comorbidity Index ≥2 (HR = 1.9, p = .03) were was associated with increased toxicity risk. Tooth extraction prior to RT was associated with increased osteoradionecrosis risk (HR = 6.4, p = .006). Conclusion: We reported on outcomes in the largest patient series to date treated with a hypofractionated boost for OPSCC. Efficacy was good with survival rates comparable to conventionally fractionated (chemo)radiotherapy. Grade ≥3 toxicity profiles showed high rates of soft tissue necrosis and osteoradionecrosis. Strategies to mitigate severe toxicity risks are under investigation to improve the tolerability of the SBRT boost.

Hyoid bone displacement as parameter for swallowing impairment in patients treated for advanced head and neck cancer.

Reduced hyoid displacement is thought to contribute to aspiration and pharyngeal residues in head and neck cancer (HNC) patients with dysphagia. To further study hyoid elevation and anterior excursion in HNC patients, this study reports on temporal/kinematic measures of hyoid displacement, with the additional goal to investigate correlations with clinical swallowing impairment. A single-blind analysis of data collected as part of a larger prospective study was performed at three time points before and after chemoradiotherapy. Twenty-five patients had undergone clinical swallowing assessments at baseline, 10-weeks, and 1-year post-treatment. Analysis of videofluoroscopic studies was done on different swallowing consistencies of varying amounts. The studies were independently reviewed frame-by-frame by two clinicians to assess temporal (onset and duration) and kinematic (anterior/superior movement) measures of hyoid displacement (ImageJ), laryngeal penetration/aspiration, and presence of vallecula/pyriform sinus residues. Patient-reported oral intake and swallowing function were also evaluated. Mean maximum hyoid displacement ranged from 9.4 mm (23 % of C2-4 distance) to 12.6 mm (27 %) anteriorly, and from 18.9 mm (41 %) to 24.9 mm (54 %) superiorly, depending on bolus volume and consistency. Patients with reduced superior hyoid displacement perceived significantly more swallowing impairment. No correlation between delayed or reduced hyoid excursion and aspiration or residue scores could be demonstrated. Hyoid displacement is subject to variability from a number of sources. Based on the results, this parameter seems not very valuable for clinical use in HNC patients with dysphagia.

Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial.

BACKGROUND: Several studies have reported a low α to ß ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. We tested this theory in the phase 3 HYPRO trial for patients with intermediate-risk and high-risk prostate cancer. We have previously reported acute incidence of genitourinary and gastrointestinal toxicity; here we report data for late genitourinary and gastrointestinal toxicity. METHODS: In this randomised non-inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a prostate-specific antigen concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks (three fractions per week). Randomisation was done with the minimisation procedure, stratified by treatment centre and risk group. The primary endpoint was to detect a 10% enhancement in 5-year relapse-free survival with hypofractionation. A key additional endpoint was non-inferiority of hypofractionation in cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. We planned to reject inferiority of hypofractionation for late genitourinary toxicity if the estimated hazard ratio (HR) was less than 1·11 and for gastrointestinal toxicity was less than 1·13. We scored toxicity with the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer (RTOG/EORTC) criteria from both physicians' records (clinical record form) and patients' self-assessment questionnaires. Analyses were done in the intention-to-treat population. Patient recruitment for the HYPRO trial was completed in 2010. The trial was registered with www.controlled-trials.com, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients (410 in both groups) were randomly assigned. Analyses for late toxicity included 387 assessable patients in the standard fractionation group and 395 in the hypofractionation group. The median follow-up was 60 months (IQR 51·2-67·3). The database for all analyses (both groups and both genitourinary and gastrointestinal toxicities) was locked on March 26, 2015. The incidence of grade 2 or worse genitourinary toxicity at 3 years was 39·0% (95% CI 34·2-44·1) in the standard fractionation group and 41·3% (36·6-46·4) in the hypofractionation group. The estimated HR for the cumulative incidence of grade 2 or worse late genitourinary toxicity was 1·16 (90% CI 0·98-1·38), suggesting that non-inferiority could not be shown. The incidence of grade 2 or worse gastrointestinal toxicity at 3 years was 17·7% (14·1-21·9) in standard fractionation and 21·9% (18·1-26·4) hypofractionation. With an estimated HR of 1·19 (90% CI 0·93-1·52) for the cumulative incidence of grade 2 or worse late gastrointestinal toxicity, we could not confirm non-inferiority of hypofractionation for cumulative late gastrointestinal toxicity. Cumulative grade 3 or worse late genitourinary toxicity was significantly higher in the hypofractionation group than in the standard fractionation group (19·0% [95% CI 15·2-23·2] vs 12·9% [9·7-16·7], respectively; p=0·021), but there was no significant difference between cumulative grade 3 or worse late gastrointestinal toxicity (2·6% [95% CI 1·2-4·7]) in the standard fractionation group and 3·3% [1·7-5·6] in the hypofractionation group; p=0·55). INTERPRETATION: Our data could not confirm that hypofractionation was non-inferior for cumulative late genitourinary and gastrointestinal toxicity compared with standard fractionation. Before final conclusions can be made about the utility of hypofractionation, efficacy outcomes need to be reported. FUNDING: The Dutch Cancer Society.

Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Studies have reported a low α/ß ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. In the multicentre phase 3, HYpofractionated irradiation for PROstate cancer (HYPRO) trial, hypofractionated radiotherapy was compared with conventionally fractionated radiotherapy for treatment of prostate cancer. We have previously reported acute and late incidence of genitourinary and gastrointestinal toxicity; here we report protocol-defined 5-year relapse-free survival outcomes. METHODS: We did an open-label, randomised, phase 3 trial at seven Dutch radiotherapy centres. We enrolled patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localised prostate cancer, a prostate-specific antigen concentration of 60 µg/L or less, and a WHO performance status of 0-2. We used a web-based application to randomly assign (1:1) patients to either hypofractionated radiotherapy of 64·6 Gy (19 fractions of 3·4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78·0 Gy (39 fractions of 2·0 Gy, five fractions per week). Based on an estimated α/ß ratio for prostate cancer of 1·5 Gy, the equivalent total dose in fractions of 2·0 Gy was 90·4 Gy for hypofractionation compared with 78·0 Gy for conventional fractionation. The primary endpoint was relapse-free survival. All analyses were done on an intention-to-treat basis in all eligible patients. The HYPRO trial completed recruitment in 2010 and follow-up is ongoing. This trial is registered with ISRCTN, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients were enrolled, of whom 804 were eligible and assessable for intention-to-treat analyses. Of these, 407 were assigned hypofractionated radiotherapy and 397 were allocated conventionally fractionated radiotherapy. 537 (67%) of 804 patients received concomitant androgen deprivation therapy for a median duration of 32 months (IQR 10-44). Median follow-up was 60 months (IQR 51-69). Treatment failure was reported in 169 (21%) of 804 patients, 80 (20%) in the hypofractionation group and 89 (22%) in the conventional fractionation group. 5-year relapse-free survival was 80·5% (95% CI 75·7-84·4) for patients assigned hypofractionation and 77·1% (71·9-81·5) for those allocated conventional fractionation (adjusted hazard radio 0·86, 95% CI 0·63-1·16; log-rank p=0·36). There were no treatment-related deaths. INTERPRETATION: Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer. FUNDING: Dutch Cancer Society.

Sexual Function After Hypofractionated Versus Conventionally Fractionated Radiotherapy for Prostate Cancer: Results From the Randomized Phase III HYPRO Trial.

INTRODUCTION: Hypofractionated radiotherapy could increase the radiobiological tumor dose for localized prostate cancer. The effects of hypofractionation on sexual function are not well known. AIM: To compare sexual function in patients with prostate cancer treated with 78 Gy in 39 fractions of 2 Gy or 64.6 Gy in 19 fractions of 3.4 Gy. METHODS: In total, 820 men with intermediate- to high-risk T1b-T4NX-0MX-0 prostate cancer were enrolled in the phase III HYPRO trial (2007-2010) and randomized to conventional fractionation (39 × 2 Gy) or hypofractionation (19 × 3.4 Gy). Sexual function was assessed at baseline and at 6, 12, 24, and 36 months after treatment using the International Index of Erectile Function (IIEF). For this analysis, patients (n = 322) with a baseline assessment, at least one follow-up assessment, and no or short-term (6-month) androgen-deprivation therapy were included. MAIN OUTCOME MEASURES: Mean IIEF domain scores were compared between treatments in the total population and the hormone-naïve population (n = 197) using the independent t-test. Incidences of severe erectile dysfunction (domain score < 11) at last follow-up were calculated in patients with partial or full baseline function. Binary logistic regression analyses were applied to calculate the odds ratio of hypofractionation vs conventional fractionation and to adjust for clinical factors. RESULTS: Median age was 71 years (interquartile range = 67-71) and median follow-up was 37 months (interquartile range = 25-38). Androgen-deprivation therapy was prescribed in 125 (39%). IIEF domain scores decreased after treatment but were comparable between treatment arms at baseline and during follow-up. Orgasmic function scores in hormone-naïve patients were significantly higher at 3 years after hypofractionation (4.08 vs 2.65, P = .031). In patients (n = 120) with partial or full baseline erectile function, the incidence of erectile dysfunction at last follow-up was 34.4% for hypofractionated treatment vs 39.3% for conventional treatment (adjusted odds ratio = 0.84, 95% CI = 0.37-1.90, P = .67). CONCLUSION: No significant differences in erectile functioning between conventional and hypofractionated radiotherapy were found. Hormone-naïve patients reported significantly higher orgasmic function scores at 3 years after hypofractionation.

Radiation dose to the tongue and velopharynx predicts acoustic-articulatory changes after chemo-IMRT treatment for advanced head and neck cancer.

The aim of this study was to investigate to what extent changes in speech after C-IMRT treatment are related to mean doses to the tongue and velopharynx (VP). In 34 patients with advanced hypopharyngeal, nasopharyngeal, or oropharyngeal cancer, changes in speech from pretreatment to 10 weeks and 1 year posttreatment were correlated with mean doses to the base of tongue (BOT), oral cavity (OC) and tonsillar fossa/soft palate (VP). Differences in anteroposterior tongue position, dorsoventral degree of tongue to palate or pharynx constriction, grooving, strength, nasality, and laryngeal rise, were assessed by acoustic changes in three speech sounds that depend on a (post-) alveolar closure or narrowing (/t/, /s/, /z/), three with a tongue to palate/pharyngeal narrowing (/l/, /r/, /u/), and in vowel /a/ at comfortable and highest pitch. Acoustically assessed changes in tongue positioning, shape, velopharyngeal constriction, and laryngeal elevation were significantly related to mean doses to the tongue and velopharynx. The mean dose to BOT predicted changes in anteroposterior tongue positioning from pre- to 10-weeks posttreatment. From pretreatment to 1-year, mean doses to BOT, OC, and VP were related to changes in grooving, strength, laryngeal height, nasality, palatalization, and degree of pharyngeal constriction. Changes in speech are related to mean doses to the base of tongue and velopharynx. The outcome indicates that strength, motility, and the balance between agonist and antagonist muscle forces change significantly after radiotherapy.

Implementation of a standardized HIPEC protocol improves outcome for peritoneal malignancy.

BACKGROUND: Experience with Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in a pioneer hospital resulted in a treatment protocol that has become the standard in the Netherlands. Outcome of CRS and HIPEC was reviewed to assure differences between the pioneer phase and the period wherein the Dutch HIPEC protocol was clinically implemented. METHODS: The first consecutive 100 CRS and HIPEC procedures performed in the Netherlands were included as pioneer cohort (1995-1999). Two-hundred and seventy-two procedures that were performed in three participating HIPEC centres after the implementation of the Dutch HIPEC protocol were included as the implementation cohort (2005-2012). Another 100 recent patients of the first centre were included as a control group (2009-2011). Indications for the CRS and HIPEC treatment were peritoneal carcinomatosis (PC) from colorectal carcinoma and pseudomyxoma peritonei (PMP). RESULTS: Of the 472 included procedures, 327 (69 %) procedures were performed for PC from colorectal carcinoma and 145 for PMP (31 %). Compared with the implementation phase, the pioneer phase was characterized by more affected abdominal regions (mean 4.3 vs. 3.5, p < 0.001), more resections (mean 3.8 vs. 3.4, p < 0.001), less macroscopic radical cytoreductions (66 vs. 86 %, p < 0.001) and more patients with major morbidity (grade III-V) (64 vs. 32 %, p < 0.001). Other determinants of morbidity were high tumour load and multiple organ resections. Outcome of the implementation phase was similar to the control group. CONCLUSIONS: This study determined that outcome had improved ever since the Dutch HIPEC protocol has been implemented based on completeness of cytoreduction and decreasing morbidity.

Predictive Factors for Toxicity After Primary Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review.

PURPOSE: Women with locally advanced cervical cancer (LACC) undergoing primary platinum-based chemoradiotherapy and brachytherapy often experience toxicities. Normal-tissue complication probability (NTCP) models quantify toxicity risk and aid in optimizing radiation therapy to minimize side effects. However, it is unclear which predictors to include in an NTCP model. The aim of this systematic review was to provide an overview of the identified predictors contributing to gastrointestinal (GI), genitourinary (GU), and vaginal toxicities and insufficiency fractures for LACC. METHODS AND MATERIALS: A systematic search was performed and articles evaluating the relationship between predictors and toxicities in women with LACC treated with primary chemoradiation were included. The Quality In Prognosis Studies tool was used to assess risk of bias, with high-risk studies being excluded from further analysis. Relationships between dose-volume parameters, patient and treatment characteristics, and toxicity endpoints were analyzed. RESULTS: Seventy-three studies were identified. Twenty-six had a low or moderate risk of bias and were therefore included. Brachytherapy-related dose-volume parameters of the GI tract, including rectum and bowel equivalent dose in 2 Gy fractions (EQD2) D2 cm3, were frequently related to toxicities, unlike GU dose-volume parameters. Furthermore, (recto)vaginal point doses predicted toxicities. Few studies evaluated external beam radiation therapy dose-volume parameters and identified rectum EQD2 V30 Gy, V40 Gy, and V55 Gy, bowel and bladder EQD2 V40 Gy as toxicity predictors. Also, total reference air kerma and vaginal reference length were associated with toxicities. Relationships between patient characteristics and GI toxicity were inconsistent. The extent of vaginal involvement at diagnosis, baseline symptoms, and obesity predicted GU or vaginal toxicities. Only 1 study evaluated insufficiency fractures and demonstrated lower pretreatment bone densities to be associated. CONCLUSIONS: This review detected multiple candidate predictors of toxicity. Larger studies should consider insufficiency fractures, assess dose levels from external beam radiation therapy, and quantify the relationship between the predictors and treatment-related toxicities in women with LACC to further facilitate NTCP model development for clinical use.

Personalizing dental screening and prevention protocols in dentulous patients with oropharyngeal cancer undergoing radiotherapy: A retrospective cohort study.

Objectives: Patients with head and neck cancer are routinely screened for dental foci prior to radiotherapy (RT) to prevent post- RT tooth extractions associated with an increased risk of osteoradionecrosis. We evaluated the risk factors for post-RT tooth extraction to personalise dental screening and prevention protocols prior to RT. Materials and methods: This retrospective cohort study included dentulous patients diagnosed with oropharyngeal cancer who had undergone radiation therapy at doses 60-70 Gy and achieved a disease-free survival of ≥ 1 year (N = 174). Risk factors were assessed using Cox regression models. Results: The cumulative incidence of post-RT tooth extraction was 30.7 % at 5 years. Main indications for extraction (n = 62) were radiation caries (n = 20) and periodontal disease (n = 27). Risk factors associated (p < 0.05) with radiation caries-related extractions included active smoking, alcohol abuse, poor oral hygiene, parotid gland irradiation, and mandibular irradiation. A high-dose volume in the mandible was associated with periodontal disease events. Conclusion: Post-RT extractions due to radiation caries were influenced by lifestyle factors and RT dose in the mandible and parotid glands. Periodontal disease-related extractions were primarily associated with the mandibular dose. During dental screening these post-RT risk factors should be taken into account to prevent osteoradionecrosis.

Accounting for fractionation and heterogeneous dose distributions in the modelling of osteoradionecrosis in oropharyngeal carcinoma treatment.

BACKGROUND AND PURPOSE: Osteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy (RT). With a renewed interest in hypofractionation for head and neck radiotherapy, more information concerning ORN development after high fraction doses is important. The aim of this explorative study was to develop a model for ORN risk prediction applicable across different fractionation schemes using Equivalent Uniform Doses (EUD). MATERIAL AND METHODS: We performed a retrospective cohort study in 334 oropharyngeal squamous cell carcinoma (OPSCC) patients treated with either a hypofractionated Stereotactic Body Radiation Therapy (HF-SBRT) boost or conventional Intensity Modulated Radiation Therapy (IMRT). ORN was scored with the CTCAE v5.0. HF-SBRT and IMRT dose distributions were converted into equivalent dose in 2 Gy fractions (α/ß = 0.85 Gy) and analyzed using EUD. The parameter a that led to an EUD that best discriminated patients with and without grade ≥ 2 ORN was selected. Patient and treatment-related risk factors of ORN were analyzed with uni- and multivariable regression analysis. RESULTS: A total of 32 patients (9.6%) developed ORN grade ≥ 2. An EUD(a = 8) best discriminated between ORN and non-ORN (AUC = 0.71). In multivariable regression, pre-RT extractions (SHR = 2.34; p = 0.012), mandibular volume (SHR = 1.04; p = 0.003), and the EUD(a = 8) (SHR = 1.14; p < 0.001) were significantly associated with ORN. CONCLUSION: Risk models for ORN based on conventional DVH parameters cannot be directly applied to HF-SBRT fractionation schemes and dose distributions. However, after correcting for fractionation and non-uniform dose distributions using EUD, a single model can distinguish between ORN and non-ORN after conventionally fractionated radiotherapy and hypofractionated boost treatments.

Advances in radiotherapy and its impact on second primary cancer risk: A multi-center cohort study in prostate cancer patients.

BACKGROUND: Modelling studies suggest that advanced intensity-modulated radiotherapy may increase second primary cancer (SPC) risks, due to increased radiation exposure of tissues located outside the treatment fields. In the current study we investigated the association between SPC risks and characteristics of applied external beam radiotherapy (EBRT) protocols for localized prostate cancer (PCa). METHODS: We collected EBRT protocol characteristics (2000-2016) from five Dutch RT institutes for the 3D-CRT and advanced EBRT era (N = 7908). From the Netherlands Cancer Registry we obtained patient/tumour characteristics, SPC data, and survival information. Standardized incidence ratios (SIR) were calculated for pelvis and non-pelvis SPC. Nationwide SIRs were calculated as a reference, using calendar period as a proxy to label 3D-CRT/advanced EBRT. RESULTS: From 2000-2006, 3D-CRT with 68-78 Gy in 2 Gy fractions, delivered with 10-23 MV and weekly portal imaging was the most dominant protocol. By the year 2010 all institutes routinely used advanced EBRT (IMRT, VMAT, tomotherapy), mainly delivering 78 Gy in 2 Gy fractions, using various kV/MV imaging protocols. Sixteen percent (N = 1268) developed ≥ 1 SPC. SIRs for pelvis and non-pelvis SPC (all institutes, advanced EBRT vs 3D-CRT) were 1.17 (1.00-1.36) vs 1.39 (1.21-1.59), and 1.01 (0.89-1.07) vs 1.03 (0.94-1.13), respectively. Nationwide non-pelvis SIR was 1.07 (1.01-1.13) vs 1.02 (0.98-1.07). Other RT protocol characteristics did not correlate with SPC endpoints. CONCLUSION: None of the studied RT characteristics of advanced EBRT was associated with increased out-of-field SPC risks. With constantly evolving EBRT protocols, evaluation of associated SPC risks remains important.

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

Patient-Reported Outcomes in the Acute Phase of the Randomized Hypofractionated Irradiation for Prostate Cancer (HYPRO) Trial.

PURPOSE: Many patients experience bowel and bladder toxicity during the acute phase of radiation therapy for prostate cancer. Recent literature indicates that hypofractionation (HF) might increase this acute response but little is known on patient-reported outcome during this phase with HF. We evaluated the course of patient-reported acute symptoms during HF versus standard fractionated (SF) radiation therapy within the hypofractionated irradiation for prostate cancer (HYPRO) trial. METHODS AND MATERIALS: In the HYPRO trial patients were treated with either 64.4 Gy (HF) in 19 fractions (3 times per week) or 78 Gy (SF) in 39 fractions (5 times per week). Normalized total dose for 2 Gy/fractions (NTD2Gy)for acute toxicity (α/ß ratio of 10) for HF was 72.1 Gy with a similar dose rate of 10.2 Gy per week. Among the 794 patients who were previously eligible for acute grade ≥2 toxicity assessment, 717 had filled out ≥1 symptom questionnaires. For each maximum symptom, we scored "any complaint" and "moderate-severe complaint." Differences were tested by χ2 test, and associations with clinical factors were tested using logistic regression. Significance was set at P ≤ .008 to adjust for multiple testing. RESULTS: We observed significantly higher rates of moderate-severe painful defecation (HF 10.8%, SF 5.3%), any mucus discharge (HF 47.1%, SF 37.4%), any rectal blood loss (HF 16.1%, SF 9.3%), increased daily stool frequency ≥4 and ≥6 (HF 34.6%/13.8%, SF 25.6%/7.0%), and any urinary straining (HF 69.9%, SF 58.0%). At 3 months postradiation therapy, rates dropped considerably with similar levels for HF and SF. Hormonal treatment was associated with less acute gastrointestinal symptoms. CONCLUSION: The increased patient-reported acute rectal symptoms with HF confirmed the previously reported results on acute grade ≥2 rectal toxicity. The increase in bladder symptoms with HF was not identified previously. These observations contradict the NTD2Gy calculations. We observed no patterns of persisting complaints with HF after the acute period; therefore, HF is well tolerated and only associated with a temporary increase of symptoms.

Single vocal cord irradiation for early-stage glottic cancer: Excellent local control and favorable toxicity profile.

OBJECTIVE: To validate the earlier reported promising oncologic outcomes and favorable toxicity profile following single vocal cord irradiation (SVCI) in an expanded cohort of patients with early-stage glottic cancer treated at our institute with longer follow-up time. MATERIALS AND METHODS: Between February 2011 and January 2020, 111 consecutive patients with early-stage glottic cancer were treated with SVCI to the whole involved vocal cord (58.08 Gy, given in 16 fractions of 3.63 Gy). Setup verification was done using cone-beam CT, prior to each fraction. The endpoints were local control (LC), overall survival (OS), grade ≥ 3 toxicity and voice quality assessment using voice-handicap index (VHI) questionnaires. RESULTS: Median follow-up was 41 months (range; 8-84). Two patients developed in-field local failure (LF). The 3- and 5-year LC rates were 99.1% and 97.1%, respectively. As both patients with LF were successfully salvaged with total laryngectomy, the 5-year ultimate LC-rates was 99%. The 5-years OS was 80.6%. All patients finished treatment without any interruption. No patients developed acute grade ≥ 3 toxicity. Late grade 3 toxicity was reported in 7 patients (6.5%) out of 108 patients evaluable for late toxicity; 2 because of severe hoarseness and 5 because of laryngeal radionecrosis (4.5%). The 5-years laryngectomy-free survival was 98.1%. The VHI-scores improved over time, only 22% of patients had VHI > 30 at 3-years post-radiotherapy, compared to 38% at baseline. CONCLUSIONS: Local control rate and laryngectomy-free survival of SVCI are excellent with favorable toxicity profile and good VHI-score. These results validate our early results.

Osteoradionecrosis after postoperative radiotherapy for oral cavity cancer: A retrospective cohort study.

OBJECTIVE: Osteoradionecrosis (ORN) is a severe late complication after radiotherapy but current knowledge on ORN risks in the setting of postoperative radiotherapy (PORT) is limited. We studied the incidence and risk factors of ORN in patients with oral cavity cancers (OCC, treated with PORT. PATIENTS AND METHODS: A retrospective cohort study was conducted including OCC patients (mainly squamous cell) treated with postoperative intensity modulated radiotherapy between 2010 and 2018 with > 1 year disease-free survival. Cumulative incidences of ORN were computed using the Kaplan Meier method. Clinical and dosimetric risk factors for mandibular ORN were evaluated using Cox regression models. RESULTS: Within our cohort (N = 227, median follow-up 49 months) we observed 46 cases of ORN, mainly in the mandible (n = 41). The cumulative incidence of mandibular ORN was 15.9 % (SE 2.5 %) at three years and 19.8 % (SE 3.0 %) at five years. At univariable analysis, smoking, mandibular mandibulotomy or segment resection, mean dose to the mandible, and mandible volume (%) ≥ 60 Gy (V60) were significantly associated with increased ORN risks. At multivariable analysis, smoking (HR 2.13, 95 %CI 1.12-4.06) and V60 (HR 1.02 per 1 % increase, 95 %CI 1.01-1.04) remained predictive factors. For active smokers with a high V60 ≥ 40 % we observed rapid ORN development with a 1-year incidence of 29 % vs 6 % for others (p < 0.01). CONCLUSION: OCC Patients treated with PORT are at high risk for mandibular ORN. We identified the mandibular volume receiving ≥ 60 Gy as the dominant risk factor, especially in active smokers. Limiting high-dose volumes at treatment planning may decrease ORN risks.

The COMPLETE trial: HolistiC early respOnse assessMent for oroPharyngeaL cancEr paTiEnts; Protocol for an observational study.

INTRODUCTION: The locoregional failure (LRF) rate in human papilloma virus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) remains disappointingly high and toxicity is substantial. Response prediction prior to or early during treatment would provide opportunities for personalised treatment. Currently, there are no accurate predictive models available for correct OPSCC patient selection. Apparently, the pivotal driving forces that determine how a OPSCC responds to treatment, have yet to be elucidated. Therefore, the holistiC early respOnse assessMent for oroPharyngeaL cancer paTiEnts study focuses on a holistic approach to gain insight in novel potential prognostic biomarkers, acquired before and early during treatment, to predict response to treatment in HPV-negative patients with OPSCC. METHODS AND ANALYSIS: This single-centre prospective observational study investigates 60 HPV-negative patients with OPSCC scheduled for primary radiotherapy (RT) with cisplatin or cetuximab, according to current clinical practice. A holistic approach will be used that aims to map the macroscopic (with Intra Voxel Incoherent Motion Diffusion Kurtosis Imaging (IVIM-DKI); before, during, and 3 months after RT), microscopic (with biopsies of the primary tumour acquired before treatment and irradiated ex vivo to assess radiosensitivity), and molecular landscape (with circulating tumour DNA (ctDNA) analysed before, during and 3 months after treatment). The main end point is locoregional control (LRC) 2 years after treatment. The primary objective is to determine whether a relative change in the mean of the diffusion coefficient D (an IVIM-DKI parameter) in the primary tumour early during treatment, improves the performance of a predictive model consisting of tumour volume only, for 2 years LRC after treatment. The secondary objectives investigate the potential of other IVIM-DKI parameters, ex vivo sensitivity characteristics, ctDNA, and combinations thereof as potential novel prognostic markers. ETHICS AND DISSEMINATION: The study was approved by the Medical Ethical Committee of Erasmus Medical Center. The main results of the trial will be presented in international meetings and medical journals. TRIAL REGISTRATION NUMBER: NL8458.