Late Normal Tissue Effects Research Articles

Disease and Toxicity Outcomes after Salvage Radiotherapy (SRT) for Biochemically Recurrent Prostate Cancer (PC) for Patients Enrolled in a Phase II, Open Label Trial Investigating Neoadjuvant Chemohormonal Therapy Followed by Radical Prostatectomy (RP)

Men with metastatic hormone sensitive prostate cancer have improved progression free and overall survival (PFS/OS) when treated with docetaxel and androgen deprivation therapy (ADT). Our institution conducted a phase II trial (UW17009) investigating the addition of three cycles of neoadjuvant docetaxel and ADT to RP in men with high-risk prostate cancer. Here we report toxicity and freedom from biochemical recurrence (FFBCR) for patients treated with SRT following participation in this trial. Between January 17, 2018 and August 10, 2021, 28 patients enrolled on UW17009. Patients who had a recurrence and received SRT were identified. Toxicity was assessed using modified LENT (Late Effects of Normal Tissues)/RTOG (Radiation Therapy Oncology Group) criteria, and time to recurrence following SRT was determined for each patient. Additionally, the months of ADT received by each patient was recorded. FFBCR was then determined for this cohort using the method of Kaplan and Meier. Of 28 patients enrolled on UW17009, 20 (71%) had BCR after RP. Of these, 19 received SRT, representing 68% of the patients enrolled on the trial. The rates of acute grade 1 and grade 2 GU toxicity with SRT were 37% (7) and 53% (10), respectively. The rates of acute grade 1 and grade 2 GI toxicity with SRT were 32% (6) and 37% (7), respectively. On patient experienced a grade 4 genitourinary toxicity during SRT. There were no acute grade 3 or grade 5 toxicities. The rates of late grade 1 and grade 2 GU toxicity were 16% (3) and 11% (2), respectively. The rates of late grade 1 and grade 2 GI toxicity were 11% (2) and 5% (1), respectively. There was 1 (5%) late grade 3 GU toxicity. There were no late grade 3-5 GI toxicities, or late grade 4-5 GU toxicities. The average duration of ADT after prostatectomy was 15 months (range: 0-37 months). According to the method of Kaplan and Meier, mean FFBCR after SRT was 34.0 months at a median of 37.8 months. Median FFBCR had not yet been reached. At the time of analysis, 13 patients remained free from biochemical recurrence after SRT. Rates of biochemical recurrence and SRT following neoadjuvant docetaxel and ADT and then RP were consistent with historical data, as was the rate of successful SRT. Toxicities were also consistent with historical data, though there was notably one acute grade 4 GU toxicity.

Noninferiority of Local Control and Comparable Toxicity of Intensity Modulated Radiation Therapy With Simultaneous Integrated Boost in Breast Cancer: 5-Year Results of the IMRT-MC2 Phase III Trial

The IMRT-MC2 trial was conducted to demonstrate the noninferiority of conventionally fractionated intensity modulated radiation therapy with a simultaneous integrated boost to 3-dimensional conformal radiation therapy with a sequential boost for adjuvant breast radiation therapy. A total of 502 patients were randomized between 2011 and 2015 for the prospective, multicenter, phase III trial (NCT01322854). Five-year results of late toxicity (late effects normal tissue task force-subjective, objective, management, and analytical), overall survival, disease-free survival, distant disease-free survival, cosmesis (Harvard scale), and local control (noninferiority margin at hazard ratio [HR] of 3.5) were analyzed after a median follow-up of 62 months. The 5-year local control rate for the intensity modulated radiation therapy with simultaneous integrated boost arm was non-inferior to the control arm (98.7% vs 98.3%, respectively; HR, 0.582; 95% CI, 0.119-2.375; P=.4595). Furthermore, there was no significant difference in overall survival (97.1% vs 98.3%, respectively; HR, 1.235; 95% CI, 0.472-3.413; P=.6697), disease-free survival (95.8% vs 96.1%, respectively; HR, 1.130; 95% CI, 0.487-2.679; P=.7758), and distant disease-free survival (97.0% vs 97.8%, respectively; HR, 1.667; 95% CI, 0.575-5.434; P=.3601). After 5 years, late toxicity evaluation and cosmetic assessment further showed no significant differences between treatment arms. The 5-year results of the IMRT-MC2 trial provide strong evidence that the application of conventionally fractionated simultaneous integrated boost irradiation for patients with breast cancer is both safe and effective, with noninferior local control compared with 3-dimensional conformal radiation therapy with sequential boost.

Single-centre Experience Comparing PBI to WBRT and the Effects on Volume of Breast Tissue Treated, Heart and Lung Dosimetry

Purpose: The IMPORT-LOW trial demonstrated non-inferiority of partial-breast radiotherapy (PBI) compared with standard whole breast radiotherapy (WBRT) with regards to local relapse in patients with early breast cancer with equivalent or fewer late normal tissue effects at 5 years [1]. This led to UK practice change, with selected low-risk patients offered PBI [2]. We aim to evaluate our single-centre experience by comparing volume of breast tissue treated, heart and lung dosimetry in patients treated with PBI compared to WBRT.

Stray neutron radiation exposures from proton therapy: physics-based analytical models of neutron spectral fluence, kerma and absorbed dose

Objective. Patients who receive proton beam therapy are exposed to unwanted stray neutrons. Stray radiations increase the risk of late effects in normal tissues, such as second cancers and cataracts, and may cause implanted devices such as pacemakers to malfunction. Compared to therapeutic beams, little attention has been paid to modeling stray neutron exposures. In the past decade, substantial progress was made to develop semiempirical models of stray neutron dose equivalent, but models to routinely calculate neutron absorbed dose and kerma are still lacking. The objective of this work was to develop a new physics based analytical model to calculate neutron spectral fluence, kerma, and absorbed dose in a water phantom. Approach. We developed the model using dosimetric data from Monte Carlo simulations and neutron kerma coefficients from the literature. The model explicitly considers the production, divergence, scattering, and attenuation of neutrons. Neutron production was modeled for 120–250 MeV proton beams impinging on a variety of materials. Fluence, kerma and dose calculations were performed in a 30 × 180 × 44 cm3 phantom at points up to 43 cm in depth and 80 cm laterally. Main Results. Predictions of the analytical model agreed reasonably with corresponding values from Monte Carlo simulations, with a mean difference in average energy deposited of 20%, average kerma coefficient of 21%, and absorbed dose to water of 49%. Significance. The analytical model is simple to implement and use, requires less configuration data that previously reported models, and is computationally fast. This model appears potentially suitable for integration in treatment planning system, which would enable risk calculations in prospective and retrospective cases, providing a powerful tool for epidemiological studies and clinical trials.

Implementation of External Beam Five-Fraction Adjuvant Breast Irradiation in a US Center.

Simple SummaryRadiation therapy to the whole breast is standard of care following breast-conserving surgery for early breast cancer. Previously this treatment was delivered daily over 3–5 weeks. Clinical trials of shorter treatment protocols completing radiation in five treatments have been completed showing similar outcomes to longer protocols; however, there remains a lack of international consensus as to which patients are best treated with shorter regimens. Here we describe how we developed a consensus in our department for using a five-fraction regimen, using a survey of physicians and a review of the most relevant literature.Five-fraction adjuvant whole breast radiation has been shown to be a safe and effective alternative to longer fractionation regimens. Given the lack of international consensus on patient selection for the protocol, we developed a consensus protocol to guide patient selection and facilitate safe and efficient five-fraction radiation in our radiation medicine department. In developing the directive, we surveyed departmental physicians about their choice of adjuvant breast regimen for various clinical scenarios. Patient travel burden was the factor most strongly impacting radiation oncologists’ decision-making when considering prescribing a five-fraction course of adjuvant breast radiation; the length of clinical trial follow-up data and acute and late normal tissue effects also impacted it, along with personal clinical experience and experience of dosimetry and physics personnel. Relative value unit (RVU) reimbursement and financial toxicity to the patient were reported to be less important in decision-making. Physicians were most comfortable using five-fraction radiation in women >50 years of age with low-risk cancer and for patients unable to attend for longer treatment courses. Eight months after implementation, the protocol accounts for 4.7% of breast irradiation delivered in our department.

Interventions for Radiation-Induced Fibrosis in Patients With Breast Cancer: Systematic Review and Meta-analyses

PurposeRadiation therapy can affect normal tissues in patients with breast cancer, causing adverse effects such as fibrosis. Although there are several interventions for radiation-induced fibrosis, the efficacy of these procedures is still unclear. The purpose of this review is to evaluate the efficacy of interventions for radiation-induced fibrosis in patients with breast cancer. Methods and MaterialsThis is a systematic review of randomized clinical trials. Studies that compared any intervention for fibrosis to another intervention, placebo, or no intervention were included. Outcomes assessed were fibrosis, adverse events, quality of life, treatment adherence, pain, and functionality. ResultsA total of 2501 publications were found, and 7 studies were selected because they met the inclusion criteria. The interventions for fibrosis were pentoxifylline and vitamin E, grape seed extract, kinesiotherapy, and endermotherapy. The results showed great heterogeneity in the treatment protocols for radiation-induced fibrosis in patients with breast cancer and in their evaluation metrics. The meta-analyses showed no benefit in using pentoxifylline and vitamin E compared with placebo or no intervention (standardized mean difference: −0.30; 95% confidence interval, −0.79 to 0.20; P = .24 [very low evidence]) compared with placebo and vitamin E (standardized mean difference: −0.09; 95% confidence interval, −0.66 to 0.49; P = .77 [moderate evidence]), respectively, assessed by the Late Effects Normal Tissue Task Force–Subjective, Objective, Management, and Analytic (LENT-SOMA) scoring scale. ConclusionsThe effectiveness of these interventions for the treatment of radiation-induced fibrosis in patients with breast cancer could not be determined. Although isolated studies show significant results favorable to the experimental groups, caution should be exercised in these findings because of the small number, small sample size, and high risk of bias presented by some of the included studies, which makes the recommendation for clinical practice still weak.

Five-fraction Radiotherapy for Breast Cancer: FAST-Forward to Implementation

IntroductionThe phase 3 FAST-Forward trial reported outcomes for 26 and 27 Gy schedules delivered in 5 fractions over 1 week versus 40 Gy in 15 fractions over 3 weeks in 4000 patients. We discuss concerns raised by the radiotherapy community in relation to implementing this schedule. Ipsilateral Breast Tumour Relapse (IBTR)Published estimated 5-year IBTR with 95% CI after 40 Gy in 15 fractions was 2.1% (95% CI 1.4–3.1), 1.7% (1.2–1.6) after 27 Gy and 1.4% (0.2–2.2) after 26 Gy, emphatically showing non-inferiority of the 5-fraction regimens. Subgroup analyses comparing IBTR in 26 Gy versus 40 Gy show no evidence of differential effect regarding age, grade, pathological tumour size, nodal status, tumour bed boost, adjuvant chemotherapy, HER2 status and triple negative status. The number of events in these analyses is small and results should be interpreted with caution. There was only 1 IBTR event post-mastectomy. Normal tissue effectsThe 26 Gy schedule, on the basis of similar NTE to 40 Gy in 15 fractions, is the recommended regimen for clinical implementation. There is a low absolute rate of moderate/marked NTE, these are predominantly moderate not severe change. Subgroup analyses comparing clinician-assessed moderate or marked adverse effect for 26 Gy versus 40 Gy show no evidence of differential effects according to age, breast size, surgical deficit, tumour bed boost, or adjuvant chemotherapy. Radiobiological considerationsThe design of the FAST-Forward trial does not control for time-related effects, and the ability to interpret clinical outcomes in terms of underlying biology is limited. There could conceivably be a time-effect for tumour control. A slight reduction in α/β estimate for the late normal tissue effects of test regimens might be a chance effect, but if real could reflect fewer consequential late effects due to lower rates of moist desquamation. ConclusionThe 26 Gy 5-fraction daily regimen for breast radiotherapy can be implemented now.

Late effects of radiation therapy in pediatric patients and survivorship.

Advances in multimodality therapy have led to childhood cancer cure rates over 80%. However, surgery, chemotherapy, and radiotherapy may lead to debilitating or even fatal long-term effects among childhood survivors beyond those inflicted by the primary disease process. It is critical to understand, mitigate, and prevent these late effects of cancer therapy to improve the quality of life of childhood cancer survivors. This review summarizes the various late effects of radiotherapy and acknowledges the Pediatric Normal Tissue Effects in the Clinic (PENTEC), an international collaboration that is systematically analyzing the association between radiation treatment dose/volume and consequential organ toxicities, in developing children as a basis to formulate recommendations for clinical practice of pediatric radiation oncology. We also summarize initiatives for survivorship and surveillance of late normal tissue effects related to radiation therapy among long-term survivors of childhood cancer treated in the past.

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

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. Patients with early breast cancer, undergoing radiotherapy (RT) in 15 daily fractions to WB (prescription dose 40.05Gy) and SIB to the TB (48Gy), between 2013 and 2017, was analyzed. Primary endpoint was acute and intermediate toxicity assessed at the end and within 6months 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. 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 6months, 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 6months. At univariate analysis, age < 40years, breast volume > 1000cm3 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. Hypofractionated WB IMRT with a SIB to the TB, delivered with TomoDirect modality, is safe and well-tolerated. Most patients reported no toxicity after 6months and good-excellent cosmesis. Predictive factors of clinically relevant toxicity might be considered during treatment planning in order to further reduce side effects.

Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and BCON trials.

SummaryBackgroundTwo radiotherapy fractionation schedules are used to treat locally advanced bladder cancer: 64 Gy in 32 fractions over 6·5 weeks and a hypofractionated schedule of 55 Gy in 20 fractions over 4 weeks. Long-term outcomes of these schedules in several cohort studies and case series suggest that response, survival, and toxicity are similar, but no direct comparison has been published. The present study aimed to assess the non-inferiority of 55 Gy in 20 fractions to 64 Gy in 32 fractions in terms of invasive locoregional control and late toxicity in patients with locally advanced bladder cancer.MethodsWe did a meta-analysis of individual patient data from patients (age ≥18 years) with locally advanced bladder cancer (T1G3 [high-grade non-muscle invasive] or T2–T4, N0M0) enrolled in two multicentre, randomised, controlled, phase 3 trials done in the UK: BC2001 (NCT00024349; assessing addition of chemotherapy to radiotherapy) and BCON (NCT00033436; assessing hypoxia-modifying therapy combined with radiotherapy). In each trial, the fractionation schedule was chosen according to local standard practice. Co-primary endpoints were invasive locoregional control (non-inferiority margin hazard ratio [HR]=1·25); and late bladder or rectum toxicity, assessed with the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic tool (non-inferiority margin for absolute risk difference [RD]=10%). If non-inferiority was met for invasive locoregional control, superiority could be considered if the 95% CI for the treatment effect excluded the null effect (HR=1). One-stage individual patient data meta-analysis models for the time-to-event and binary outcomes were used, accounting for trial differences, within-centre correlation, randomised treatment received, baseline variable imbalances, and potential confounding from relevant prognostic factors.Findings782 patients with known fractionation schedules (456 from the BC2001 trial and 326 from the BCON trial; 376 (48%) received 64 Gy in 32 fractions and 406 (52%) received 55 Gy in 20 fractions) were included in our meta-analysis. Median follow-up was 120 months (IQR 99–159). Patients who received 55 Gy in 20 fractions had a lower risk of invasive locoregional recurrence than those who received 64 Gy in 32 fractions (adjusted HR 0·71 [95% CI 0·52–0·96]). Both schedules had similar toxicity profiles (adjusted RD −3·37% [95% CI −11·85 to 5·10]).InterpretationA hypofractionated schedule of 55 Gy in 20 fractions is non-inferior to 64 Gy in 32 fractions with regard to both invasive locoregional control and toxicity, and is superior with regard to invasive locoregional control. 55 Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer.FundingCancer Research UK.

Intensity Modulated Radiation Therapy (IMRT) With Simultaneously Integrated Boost Shortens Treatment Time and Is Noninferior to Conventional Radiation Therapy Followed by Sequential Boost in Adjuvant Breast Cancer Treatment: Results of a Large Randomized Phase III Trial (IMRT-MC2 Trial)

In the modern era, improvements in radiation therapy techniques have paved the way for simultaneous integrated boost irradiation in adjuvant breast radiation therapy after breast conservation surgery. Nevertheless, randomized trials supporting the noninferiority of this treatment to historical standards of care approach are lacking. A prospective, multicenter, randomized phase 3 trial (NCT01322854) was performed to analyze noninferiority of conventional fractionated intensity modulated radiation therapy with simultaneous integrated boost (IMRT-SIB) to 3-D conformal radiation therapy with sequential boost (3-D-CRT-seqB) for breast cancer patients. Primary outcomes were local control (LC) rates at 2 and 5 years (noninferiority margin at hazard ratio [HR] of 3.5) as well as cosmetic results 6 weeks and 2 years after radiation therapy (evaluated via photo documentation calculating the relative breast retraction assessment [pBRA] score [noninferiority margin of 1.25]). A total of 502 patients were randomly assigned from 2011 to 2015. After a median follow-up of 5.1 years, the 2-year LC for the IMRT-SIB arm was noninferior to the 3-D-CRT-seqB arm (99.6% vs 99.6%, respectively; HR, 0.602; 95% CI, 0.123-2.452; P = .487). In addition, noninferiority was also shown for cosmesis after IMRT-SIB and 3-D-CRT-seqB at both 6 weeks (median pBRA, 9.1% vs 9.1%) and 2 years (median pBRA, 10.4% vs 9.8%) after radiation therapy (95% CI, -0.317 to 0.107 %; P = .332). Cosmetic assessment according to the Harvard scale by both the patient and the treating physician as well as late-toxicity evaluation with the late effects normal tissues- subjective, objective, management, analytic criteria, a score for the evaluation of long-term adverse effects in normal tissue, revealed no significant differences between treatment arms. In addition, there was no difference in overall survival rates (99.6% vs 99.6%; HR, 3.281; 95% CI: -0.748 to 22.585; P = .148) for IMRT-SIB and 3-D-CRT-seqB, respectively. To our knowledge, this is the first prospective trial reporting the noninferiority of IMRT-SIB versus 3-D-CRT-seqB with respect to cosmesis and LC at 2 years of follow-up. This treatment regimen considerably shortens adjuvant radiation therapy times without compromising clinical outcomes.

A Comparison of the Prognosis Between Juvenile and Adult Nasopharyngeal Carcinoma: A Propensity Score Matching Study

To investigate whether the juvenile patients with nasopharyngeal carcinoma (NPC) in China have better prognosis than the adult patients under the control of multiple variables, so as to provide a reference for the clinical treatment of juvenile NPC. 1139 newly diagnosed NPC patients without metastasis in our hospital were retrospectively collected. All patients were treated with intensity-modulated radiation therapy (IMRT), of which 60 cases were the juvenile (≤ 18 years old) between January 2003 and December 2018, and the remaining 1079 cases were the adult (≤ 65 years old) between January 2013 and December 2014. The median follow-up time was 83.6 months (6.8-190.2 months) and 61.1 months (4.5-84.3 months), respectively. To reduce selection and confounding bias, 1:2 propensity score matching (PSM) was used. Overall Survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and local relapse-free survival (LRFS) were estimated by Kaplan-Meier method and compared by the Log-rank test. The long-term toxicity of children and adolescents was evaluated according to the criteria of the Radiation Therapy Oncology Group (RTOG), the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and Late Effects Normal Tissue Task Force-Subjective, Objective, Management and Analytic (LENT-SOMA) scoring systems. The 5-year OS of the juvenile and adults were 88.07% and 85.08%, respectively. Before matching, the LRFS of the juvenile was significantly better than that of the adult (P = 0.039), but no significant difference was found in OS, DFS and DMFS, respectively (all P>0.05). After using a PSM, the DMFS was still found to be of no significant difference between the two groups, whereas the OS, DFS, and LRFS of the juvenile were markedly higher than that of the adult (P = 0.005, P = 0.035, and P = 0.023), respectively. With regard to the long-term toxicity of 53 alive juvenile patients, the common sequelae were cervix fibrosis, ototoxicity and xerostomia (20.75%, 20.75% and 18.87%). However, except for two patients developing grade 3 ototoxicity, all of the sequelae were within grade 2, and no degree 4 sequelae occurred. Using a PSM method, the juvenile with NPC had better 5-year OS, DFS and LRFS than the adult patients, which provides the first Chinese data with positive results in the IMRT era. In addition, as the sole grade 3 complication among the common late toxicities, ototoxicity was the most concerning problem which could have a negative impact on the quality of life. Therefore, how to reasonably lower the radiation dose to protect adjacent organs in juvenile NPC was deserved to be further explored.

EQD2 Analyses of Vaginal Complications in Exclusive Brachytherapy for Postoperative Endometrial Carcinoma.

Simple SummaryVaginal complications in exclusive vaginal-cuff brachytherapy (EVCBT) have not been analyzed in terms of the dose received by a vaginal volume of 2 cm3. The aim of this work was to analyze the vaginal dose and complications in EVCBT. In the present analysis, we found that all the patients receiving < 68Gy equivalent dose 2Gy/day at 2 cm3 of the most exposed area to the dose of the vagina only developed G0–G1 and 1G2 without vaginal stenosis complications and without relapses. This dose limit could eliminate G2 vaginal stenosis and is the hypothesis of a new analysis in our center.Background: To evaluate whether EQD2(α/β = 3Gy) at 2 cm3 of the most exposed area of the vagina is related to late vaginal toxicity in postoperative endometrial cancer (PEC) patients (p) treated with exclusive brachytherapy (BT). Methods: From 2014 to 2017, 43p were included in this study. BT was administered: 3-fractions of 6Gy in 37p and 2-fractions of 7.5Gy in 6p. The dose was prescribed at a depth of 5 mm from the applicator surface with dose-point optimization based on distance. The active treatment length was 2.5 cm. CTV-D90 and the dose to the most exposed 2 cm3 of the vagina was calculated for each patient. Late toxicity of the bladder and rectum was assessed using Radiation Therapy Oncology Group (RTOG) criteria, and vaginal toxicity by objective Late Effects Normal Tissue Task Force (LENT)-Subjective, Objective, Management, Analytic (SOMA) (LENT-SOMA) criteria. Statistics: frequency tables, mean, median, range, standard deviation, and box plot. Results: The median follow-up was 51 months (12–68). 20 p (46.5%) and 2 p (4.7%) developed G1 and G2 vaginal complications, respectively. Only 1/2 p-G2 receiving EQD2(α/β = 3Gy) at 2 cm3 >68Gy presented vaginal shortening and 18/20 p-G1 received doses < 68Gy. Conclusions: PECp receiving exclusive brachytherapy with doses < 68Gy EQD2(α/β = 3Gy) at 2 cm2 of the vagina presented only G0–G1 vaginal toxicity, except for one with bleeding telangiectasias. Larger prospective studies are necessary to confirm the present results.

An observational trial to establish the effect of hyperbaric oxygen treatment on pelvic late radiation tissue injury due to radiotherapy.

Rates of pelvic cancer are growing globally with around half of these patients receiving radiotherapy. In a small proportion, radiotherapy results in significant late radiation tissue injury (LRTI) to surrounding tissue, most commonly affecting the bladder and bowel mucosa. We conducted a combined prospective and retrospective observational trial to establish the effectiveness of hyperbaric oxygen treatment (HBOT) in improving the symptoms and signs of LRTI in these patients. Fifty-two patients were included after receiving radiotherapy for cancers of the bowel, bladder, cervix, prostate or vulva. They received HBOT at 203-243 kPa (2.0-2.4 atmospheres absolute (atm abs)) for 90 minutes with the median number of treatments being 30 (IQR 1). Late effects normal tissues - subjective, objective, management, analytic (LENT-SOMA) scores were recorded before and after treatment. The mean LENT-SOMA scores before and after HBOT were 11.7 (SD 5.3) and 8.1 (5.1) respectively. This reduction in score of 3.7 (95% CI 2.6 to 4.8) was statistically significant (P < 0.001). For radiation cystitis the mean reduction was 3.7 (95% CI 2.4 to 5.0, P < 0.001) and for radiation proctitis was 3.8 (95% CI 1.4 to 6.1, P = 0.004). There were no significant adverse effects recorded. Hyperbaric oxygen treatment may be an effective and safe treatment for pelvic late tissue radiation injury.

The effect of hyperbaric oxygen treatment on late radiation tissue injury after breast cancer: A case-series of 67 patients.

Late radiation tissue injury (LRTI) after breast cancer may benefit from hyperbaric oxygen treatment (HBOT). This study aimed to report the LRTI symptom scores up to 12 months after HBOT and identify risk factors for poor scores. A case-series of 67 patients who underwent a mean of 44 sessions of HBOT was analysed. LRTI symptoms were scored at four time points using the LENT-SOMA scale (Late Effects in Normal Tissues - Subjective, Objective, Management, and Analytic), a visual analog scale for pain, and the range of shoulder motion. Between starting HBOT and 12 months after HBOT 57 patients (85%) reported at least one point improvement in their LENT-SOMA score. Median pain and fibrosis scores improved significantly between the start and end of HBOT (P < 0.001), and remained stable three and 12 months after HBOT. The median breast oedema score improved significantly 12 months after HBOT (P = 0.003). Median shoulder abduction increased significantly from 90 to 165 degrees (P = 0.001) and median shoulder anteflexion increased significantly from 115 to 150 degrees (P = 0.004). Various risk factors were identified for poor scores despite HBOT; the most common risk factor was a poor score at start of HBOT. In this case-series, patients who underwent HBOT for LRTI after breast cancer reported significant improvement in pain, fibrosis, oedema, and shoulder movement. The improvement persisted up to 12 months after HBOT. A poor score at the start of HBOT was predictive for a poor score 12 months after HBOT.

Effect of Tumor Size and Tumor Location in the Breast on Late Cosmetic Outcomes in Patients with Early-Stage Breast Cancer Who Underwent Breast-Conserving Surgery and Intraoperative Boost Radiotherapy

This study aimed to investigate whether tumor size and tumor location in the breast affected cosmetic outcomes and late radiation toxicity in early-stage breast cancer patients who underwent breast conserving surgery and intraoperative radiotherapy as boost. This case series analysis study was based on records in the patient files and included 103 patients with breast cancer. Patients were scored using the Late Effects Normal Tissue Task Force (LENT)-Subjective, Objective, Management, Analytic (SOMA) scale. The effect of tumor size and tumor location on cosmetic outcomes was analyzed using one-way analysis of variance. The median duration of follow-up was 51 (24–78) months. Based on the LENT-SOMA scale, 40 (38.8%) women were grade 0, 42 (40.7%) grade 1, 18 (17.5%) grade 2, and 3 (2.9%) grade 3. The median tumor diameter of the patients was 16 for grade 0, 19 for grade 1, 23, for grade 2, and 25 for grade 3, respectively. Tumor locations in patients scored as grades 2 and 3 were mostly in inner quadrants, whereas those scored as grades 0 and 1 were similar in all quadrants. The effect of tumor size on cosmetic outcomes was statistically significant (p = 0.0001), whereas that of tumor location was no effect on result (p > 0.05). Radiotoxicity and cosmetic outcome in the late period may be related to tumor size and applicator diameter. Although patients with tumors located in the upper outer quadrant had better cosmetic outcomes, tumor location in the breast on the cosmesis was insignificant.

Radiation-Induced Brachial Plexopathy in Breast Cancer and the Role of Surgical Treatment

Abstract Objective We aimed to evaluate improvement in the pain, motor, and sensory functions after neurosurgical intervention, by objective methods in patients with radiation-induced brachial plexopathy (RIBP), as a complication of radiotherapy (RT). Materials and Methods In our study, 11 patients, who experienced grade 3 or 4 brachial plexopathy according to the LENT-SOMA (late effects of normal tissue—subjective, objective, management, analytic) side-effect index, as a complication of RT which was performed after being operated for breast cancer, were included. In the postoperative period pain, sensation, and motor function loss were followed. Results There was apparent regression in the pain. The mean visual analogue scale (VAS) value decreased to 4 from the preoperative VAS value of 9.4. However, no significant improvement was observed in either sensory and motor functions. Conclusion RIBP is a progressive disease in breast cancer patients after radiotherapy. Evaluation of the results of applied surgical treatments and changes in the results with time is important to direct the treatment. Neurolysis should only be considered when other treatment methods fail and should be considered as an irreversible and potentially permanent procedure.

Late-term effects of hypofractionated chest wall and regional nodal radiotherapy with two-dimensional technique in patients with breast cancer

PurposeHypofractionated radiotherapy (RT) is becoming a new standard in postoperative treatment of patients with early stage breast cancer after breast conservation surgery. However, data on hypofractionation in patients with advanced stage disease who undergo mastectomy followed by local and regional nodal irradiation (RNI) is lacking. In this retrospective study, we report late-term effects of 3 weeks post-mastectomy hypofractionated local and RNI with two-dimensional (2D) technique in patients with stage II and III breast cancer. MethodsBetween January 1990 and December 2007, 1,770 women with breast cancer who were given radical treatment with mastectomy, systemic therapy and RT at least 10 years ago were included. RT dose was 35 Gy/15 fractions/3 weeks to chest wall by two tangential fields and 40 Gy in same fractions to supraclavicular fossa (SCF) and internal mammary nodes (IMNs). SCF and IMNs dose was prescribed at dmax and 3 cm depth, respectively. Chemotherapy and hormonal therapy was given in 64% and 74% patients, respectively. Late-term toxicities were assessed with the Radiation Therapy Oncology Group (RTOG) scores and LENT-SOMA scales (the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic scales). ResultsMean age was 48 years (range, 19 to 75 years). Median follow-up was 12 years (range, 10 to 27 years). Moderate/marked arm/shoulder pain was reported by 254 (14.3%) patients. Moderate/marked shoulder stiffness was reported by 219 (12.3%) patients. Moderate/marked arm edema was seen in 131 (7.4%) patients. Brachial plexopathy was not seen in any patient. Rib fractures were noted in 6 (0.3%) patients. Late cardiac and lung toxicity was seen in 29 (1.6%) and 23 (1.3%) patients, respectively. Second malignancy developed in 105 (5.9%) patients.ConclusionRNI with 40 Gy/15 fractions/3 weeks hypofractionation with 2D technique seems safe and comparable to historical data of conventional fractionation (ClinicalTrial.gov Registration No. NCT04175821).

Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial

SummaryBackgroundWe aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial.MethodsFAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1–3, pN0–1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132.FindingsBetween Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were −0·3% (−1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and −0·7% (−1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1–5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy.Interpretation26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer.FundingNational Institute for Health Research Health Technology Assessment Programme.

FAST-Forward Phase III Randomised Controlled Trial of 1-Week Hypofractionated Breast Radiotherapy: 5-Year Results for Efficacy and Late Normal Tissue Effects

Background: FAST-Forward aims to identify a 5-fraction (Fr) schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week which is non-inferior for local cancer control and as safe as an international standard 15Fr regimen after primary surgery for early breast cancer. Five-year results are presented. Methods: FAST-Forward (ISRCTN19906132) randomised (1:1:1) patients with invasive carcinoma of the breast (pT1-3 pN0-1 M0) after breast conservation surgery or mastectomy to 40Gy in 15Fr (3 weeks), 27Gy or 26Gy in 5Fr (1 week) to whole breast/chest wall. Primary endpoint was ipsilateral breast tumour relapse (IBTR); assuming 2% 5-year incidence for 40Gy, non-inferiority was pre-defined as < 1.6% excess for 5Fr schedules (critical hazard ratio HR=1.81). Normal tissue effects (NTE) were assessed by clinicians, patients and photographs. Findings: 4096 consenting patients (1361 40Gy, 1367 27Gy, 1368 26Gy) were recruited November 2011-June 2014 from 97 UK centres. At 71 months median follow-up, 79 IBTR events were reported (40Gy: 31, 27Gy: 27, 26Gy: 21); HRs (95%CI) versus 40Gy/15Fr were 27Gy/5Fr: 0.86 (0.51,1.44), 26Gy/5Fr: 0.67 (0.38,1.16). Five-year incidence of IBTR after 40Gy was 2.1% (1.4,3.1); estimated absolute differences versus 40Gy/15Fr were -0.3% (-1.0,0.9) for 27Gy/5Fr (p=0.0022 for non-inferiority) and -0.7% (-1.3,0.3) for 26Gy/5Fr (p=0.00019). 5-year prevalence of any clinician-assessed moderate/marked breast NTE after 40Gy: 98/986 (9.9%), 27Gy: 155/1005 (15.4%), 26Gy: 121/1020 (11.9%). Across all clinician assessments from 1-5 years, odds ratios versus 40Gy/15Fr were 1.55 (1.32,1.83, p<0.0001) for 27Gy/5Fr and 1.12 (0.94,1.34, p=0.20) for 26Gy/5Fr. Patient and photographic assessments showed higher NTE risk for 27Gy versus 40Gy but not for 26Gy. Interpretation: 5-year local tumour incidence and NTE prevalence show 26Gy/5Fr in 1 week to be an effective and safe alternative to 40Gy/15Fr in 3 weeks for patients prescribed adjuvant local radiotherapy after primary surgery for early stage breast cancer. Trial Registration: ISRCTN19906132. Funding Statement: The FAST-Forward trial is funded by the National Institute for Health Research (NIHR) Health Technology Assessment Programme - HTA (UK) (09/01/47), with programme grants from Cancer Research UK to support the work of ICRCTSU (C1491/A15955; C1491/A25351). We acknowledge NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research (London, UK). Declaration of Interests: JMB reports grants from NIHR HTA and grants from Cancer Research UK during the conduct of the study, and grants and non-financial support from Novartis (previously GSK), grants and non-financial support from Astra Zeneca, grants and non-financial support from Clovis Oncology, grants and non-financial support from Janssen-Cilag, grants and non-financial support from Merck Sharpe & Dohme, grants and non-financial support from Puma Biotechnology, grants and non-financial support from Pfizer, grants and non-financial support from Roche, grants from Medivation, outside the submitted work. DAW reports travel grants from Roche Pharmaceuticals, outside the submitted work. JSH, MAS and LS report grants from NIHR HTA and grants from Cancer Research UK, during the conduct of the study. CCK reports personal fees from Roche Pharmaceutical, outside the submitted work. AA, AMB, DJB, CC, CEC, MC, AG, PH, CM, ZN, NS, IS, JRY declare no competing interests. Ethics Approval Statement: FAST-Forward was approved by the national South East Coast Kent Research Ethics Committee (11/LO/0958) and local Research and Development offices of all participating centres.