Late Normal Tissue Effects Research Articles

One-week vaginal brachytherapy schedule as exclusive adjuvant post-operative treatment in intermediate- and high-intermediate-risk endometrial cancer patients.

PurposeThe aim of the study was to report survival outcomes and toxicities incidence by using one-week vaginal brachytherapy (VBT) schedule in intermediate- and high-intermediate-risk endometrial cancer patients.Material and methodsOne hundred and eight patients were treated with exclusive high-dose-rate (HDR) brachytherapy short schedule (7 Gy/fraction/every other day/1 week). Acute and late rectal, urinary, and vaginal toxicities were recorded according to radiation therapy oncology group (RTOG) scores and late effects normal tissue task force – subjective, objective, management, analytic (LENT-SOMA) scores, respectively. Overall survival (OS), cause specific survival (CSS), and disease-free survival (DFS) were evaluated.ResultsMedian follow-up was 44 months (range, 6-117 months). The 5-year OS, CSS, and DFS rates were 92.7%, 96.4%, and 89.5%, respectively. Seven of 108 (6.5%) patients relapsed after a median time of 31 months (range, 5-56 months). Death occurred in 6 patients. Four patients died for intercurrent causes without an evidence of disease. Acute bladder toxicity G1-G2 was reported in 11 of 108 (10%) patients, vaginal toxicity G1-G2 in 6 of 108 (5.5%), and gastrointestinal toxicity was observed in 3 of 108 (3%) patients. Late bladder and gastrointestinal G1 toxicities were reported in 4 of 108 (4%) and 1 of 108 (1%) patients, respectively. Late vaginal toxicity (G1-G2) was recorded in 3 of 108 (3%) cases. No grade 3-4 bladder, vaginal, and gastrointestinal toxicities were noted.ConclusionsExclusive short course adjuvant VBT is an effective treatment in patients with early-stage endometrial cancer and provides good outcomes in terms of disease local control and DFS, with low rates of toxicity profile.

Comparison of Toxicity and Cosmetic Outcomes After Accelerated Partial Breast Irradiation or Whole Breast Irradiation Using 3-Dimensional Conformal External Beam Radiation Therapy

PurposeTo compare rates of acute and late skin toxicities and cosmetic outcomes after accelerated partial breast irradiation (APBI) or whole breast irradiation (WBI) using 3-dimensional conformal external beam radiation therapy in women with breast cancer after breast conservation surgery (BCS). Methods and MaterialsWomen >35 years of age with invasive or noninvasive breast cancer ≤4 cm treated by BCS were randomized to 3D-CRT APBI (34 Gy/10 fractions/5 days) or WBI (40 Gy/16 fractions/3 weeks ± boost irradiation). The primary outcome was ipsilateral breast tumor recurrence. Important secondary outcomes were skin toxicities using Radiation Therapy Oncology Group scores, Late Effects Normal Tissue Task Force and Subjective, Objective, Management, Analytic scales, and adverse cosmetic outcome. This interim analysis focuses on the secondary endpoints of radiation toxicities and cosmesis. Patient and tumor characteristics and rates of adverse cosmetic outcomes and skin toxicities were compared using Fisher exact tests. All statistical tests were 2 sided, with P < .05 considered statistically significant. ResultsBetween June 2011 and December 2015, 133 women with breast cancer were randomized to 3D-CRT APBI or WBI. Patient and tumor characteristics were balanced between the 2 arms. Median follow-up was 60 months (range, 12-93 months). Grade 4 late toxicity was not seen in either of the treatment arms, and grade 3 toxicity was very low for each endpoint assessed in both the groups. The rates of grade ≥2 acute dermatitis were 8% and 15%, respectively, for APBI and WBI (P = .18). Rates of grade ≥1 late radiation toxicities were higher in the WBI arm compared with the APBI arm for breast shrinkage (P = .008), pigmentation (P = .028), fibrosis (P = .040), induration (P = .048), and edema (P = .33). Adverse cosmesis at last follow-up was significantly higher in patients treated with WBI: 33% compared with 6% with APBI (P < .001). ConclusionsIn women with breast cancer after BCS, APBI was associated with better cosmetic outcome and fewer late radiation toxicities than WBI.

Quantitative Evaluation of Shear Wave Elastography on Radiation-Induced Neck Fibrosis in Patients With Nasopharyngeal Carcinoma.

The value of shear wave elastography (SWE) for quantitatively assessing neck fibrosis induced by radiotherapy (RT) in patients with nasopharyngeal carcinoma was evaluated over time. We prospectively observed 56 patients with nasopharyngeal carcinoma before and after therapeutic neck irradiation. The elasticity parameters including Emax and Emean were used to measure the stiffness of the bilateral sternocleidomastoid muscles. Twenty-seven patients completed a 1.5-year follow-up, with examinations beginning at 3, 6, 12, and 18 months after RT. Forty controls were recruited for reliability tests (along with the patients) and measurement comparisons. The consistency of SWE measurements with the Late Effects Normal Tissue Task Force-Subjective, Objective, Management and Analytic (LENT-SOMA) scale was tested. The intraclass correlation coefficients of elasticity indices for both patients and controls were higher than 0.75. The Emax and Emean of bilateral sternocleidomastoid muscles in the pre-RT patient group were comparable with those of the controls, and increased with increasing postirradiation duration (r = 0.514-0.555; P < 0.01). Significant increases in the Emax and Emean were observed 18 months after RT. The SWE correlated well with the LENT-SOMA score when assessing radiation-induced neck fibrosis 1.5 years after RT (r = 0.557-0.649; P < 0.01). Furthermore, both the Emax and Emean in the LENT-SOMA grade 0 subtype were higher 18 months after RT than before RT (P < 0.01). Because of its high reliability and good consistency with the LENT-SOMA score and better stiffness reflection at grade 0, SWE may be used to objectively and quantitatively evaluate the variation trend of radiation-induced neck fibrosis.

Comparison between high-dose and low-dose intravenous methylprednisolone therapy in patients with brain necrosis after radiotherapy for nasopharyngeal carcinoma

BackgroundRadiotherapy is the standard radical treatment for nasopharyngeal carcinoma (NPC) and may cause radiation-induced brain necrosis (RN). Intravenous steroids have been considered as an effective treatment for RN. However, evidence concerning the efficacy of different doses of intravenous steroid therapy remains insufficient to establish the optimal regimen for NPC patients with RN. MethodsWe retrospectively reviewed charts of 169 patients who were diagnosed with RN after radiotherapy for NPC, treated with low-dose or high-dose intravenous methylprednisolone (IVMP) and followed up for 12 months. We collected the clinical data, including the Late Effects of Normal Tissue (LENT)/Subjective, Objective, Management, Analytic (SOMA) scales score and Montreal Cognitive Assessment (MoCA) score. Magnetic resonance imaging (MRI) was performed pre- and post-treatment to define the radiographic response. ResultsThere were no significant differences in the treatment response based on MRI, or changes in clinical symptoms and cognitive function between low and high-dose groups. Thirty of 93 low-dose patients (32.3%) and 21 of 76 high-dose patients (27.6%) presented effective response in MRI, with no significant differences between groups (P = 0.515). Neither group showed a significant difference in the effective rate based on the MoCA total score and LENT/SOMA score. The most commonly reported grade 3 adverse events in the high-dose group (n = 76) were infections and infestations (3 [3.9%] vs. none for low-dose group). ConclusionsWe found low-dose IVMP was not inferior to high-dose IVMP for NPC patients with RN. In addition, treatment-related infections and infestations were likewise more common with high-dose steroid than low-dose steroid.

Can patient-reported outcomes be used instead of clinician-reported outcomes and photographs as primary endpoints of late normal tissue effects in breast radiotherapy trials? Results from the IMPORT LOW trial

BackgroundIn an era of low local relapse rates after adjuvant breast radiotherapy, risks of late normal-tissue effects (NTE) need to be balanced against risk of relapse. NTE are assessed using patient-reported outcome measures (PROMs), clinician-reported outcomes (CRO) and photographs. This analysis investigates whether PROMs can be used as primary NTE endpoints in breast radiotherapy trials. MethodsAnalyses were conducted within IMPORT LOW (ISRCTN12852634) at 2 and 5 years. NTE were recorded by CRO, photographs and PROMs. Measures of agreement tested concordance, risk ratios for radiotherapy groups were compared, and influence of baseline characteristics on concordance investigated. ResultsIn 1095 patients who consented to PROMS and photographs, PROMs were available at 2 and/or 5 years for 976 patients, of whom 909 had CRO and 844 had photographs. Few patients had moderate/marked NTE, irrespective of method used (eg. 19% patients and 9% clinicians reported breast shrinkage at year-5). Patients reported more NTE than assessed from CRO or photographs (p < 0.001 for most NTE). Concordance between assessments was poor on an individual patient level; eg. for year-5 breast shrinkage, % agreement = 48% and weighted kappa = 0.17. Risk ratios comparing radiotherapy schedules were consistent between PROMs and CRO or photographs. ConclusionsFew patients had moderate/marked NTE irrespective of method used. Patients reported more NTE than CRO and photographs, therefore NTE may be underestimated if PROMs are not used. Despite poor concordance between methods, effect sizes from PROMs were consistent with CRO and photographs, suggesting PROMs can be used as primary NTE endpoints in breast radiotherapy trials.

Comprehensive Validation Study of Quality-of-Life Questionnaire Using Objective Clinical Measures: Breast Cancer Treatment Outcome Scale (BCTOS), Brazilian Portuguese Version

IntroductionWhen evaluating a quality-of-life questionnaire (QLQ), many validation studies do not correlate quality-of-life scores with objective measurements of complications associated with treatment. Patients and MethodsWe performed a cross-sectional observational study with 300 patients submitted to breast-conserving therapy. The patients answered the European Organization for Research and Treatment of Cancer (EORTC) QLQs C-30 and BR23, as well as the Brazilian Portuguese version of the Breast Cancer Treatment Outcome Scale (BCTOS) questionnaire. Retest, internal consistency, factorial analysis, convergent/divergent analysis, and Rasch evaluation were performed. All patients underwent physical evaluations to assess lymphedema, handgrip strength, shoulder range of motion, breast cosmesis, and breast pain, and these groups were compared on the basis of BCTOS scores. Receiver operating characteristic curve determined the predictive value of BCTOS scores associated with clinical practice. ResultsThe internal consistencies of the BCTOS domains ranged from 0.785 to 0.895. Factor analysis grouped according to the original questionnaire. Convergent validation showed differences in the sexual functioning and sexual enjoyment domains of the EORTC BR23. Analysis of known groups found that in most domains, the scores were higher in patients with lymphedema, strength deficit, shoulder range-of-motion alteration, poor breast cosmesis, breast pain, and axillary lymphadenectomy. Using a cutoff of 1.26, lymphedema was associated with the edema domain; using a cutoff of 1.33, Late Effects Normal Tissue Task Force/Subjective, Objective, Management, Analytic pain was associated with the pain domain; and using a cutoff of 2.37, the cosmetic domain was associated with subjective cosmesis. ConclusionThe association of objective measurements in a validation study of quality of life qualified the study and allowed us to develop better parameters for comparisons of results of breast-conserving therapy between populations.

Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials

Background and purposeAdjuvant lymphatic radiotherapy (LNRT) is recommended for selected axillary node positive women with early breast cancer. We investigated whether hypofractionated LNRT is safe combined with similarly-hypofractionated breast/chest wall radiotherapy (RT). Material and methodsThe Standardisation of Breast Radiotherapy (START) pilot, A and B trials randomised women with early breast cancer to schedules of 2.67–3.3 Gy versus 2.0 Gy fractions (control). RT adverse effects were assessed by patients using the EORTC QLQ-BR23 and protocol-specific questions, and by physicians. Rates of arm/shoulder effects were compared between schedules for patients given LNRT. Results864/5861 (14.7%) patients received LNRT (385 START-pilot, 318 START-A, 161 START-B). Prevalences of moderate/marked arm/shoulder effects were low up to 10 years. There were no significant differences between the hypofractionated and control groups for patient- and physician-assessed symptoms in START-A or START-B. In START-pilot, adverse effect rates were higher after 13 fractions of 3.3 Gy, consistent with effects reported in the breast/chest wall (significant for shoulder stiffness, HR 3.07, 95%CI 1.62–5.83, p = 0.001). ConclusionsThe START trial results suggest that appropriately-dosed hypofractionated LNRT is safe in the long-term, according to patient and physician-assessed arm and shoulder symptoms. These findings are consistent with those reported after the same schedules delivered to the breast/chest wall.

Effect of Hypofractionation on Prostate Cancer Radiotherapy

Context: Prior research over the past few decades has shown that the hypofractionated external beam radiation therapy could be a valuable method with an outstanding potential to treat the prostate cancer. The alpha-beta ratio (α/β) is an indication of the fractionation sensitivity of a particular cell type. Values of α/β ≥ 10 Gy are responsible for early-responding normal tissues and most tumors, while values of α/β < 5 Gy are for late-responding normal tissues. The α/β ratio could be raised by either a local tumor control increase or a decrease of normal tissue late effects through the application of an unconventional fractionation schedules. Evidence Acquisition: This review article aimed to investigation the details of radiobiological and clinical trials which are reported to highlight the characteristics of hypofractionation for the prostate cancer treatment based on the investigation of clinical results from hypofractionated treatments. Results: With the sufficient radiobiological and physiological research studies, it may be claimed that if α/β value for prostate cancer is less than the adjacent surrounding organs at risk and by applying fewer and larger fractions; a better therapeutic ratio can be achieved for the patient. Conclusions: Radiobiological modeling can play a major role in the design of new protocols. Also, one should be aware that in modeling the hypofractionated treatment, normal tissue iso-effects are significantly important and some assumptions needed to be made regarding α/β values for the critical normal tissue complication endpoint.

Proton radiobiology and its clinical implications.

Denser ionisation clustering and complex DNA damage in proton Bragg peaks far exceeds that seen with conventional X-rays. This results in more efficient cell sterilisation, quantified by the relative biological effectiveness (RBE). Currently, a 1.1 RBE is used to determine the clinical proton doses by dividing the usual X-rays dose by this amount. This number, derived from short-term experiments, has been criticised as being irrelevant to late normal tissue (NT) effects following radiotherapy and included many control irradiations using lower voltage X-rays (with elevated RBE values) than those used in the clinic. In principle, an increased RBE could be used for each organ at risk, by using extensions of the clinically successful linear quadratic model.Protons undoubtedly reduce or eliminate NT radiation dose in tissues distantly located from a tumour, but the necessity to include NT margins around a tumour can result in a higher volume of NT than tumour being irradiated. Deleterious side-effects can follow if the NT RBE exceeds 1.1, including in tissue very close to these margins and which are only partially spared.Use of a constant 1.1 RBE can ‘overdose’ NT, which may require a greater dose reduction such as 1.2 in the brain; some tumours may be ‘under-dosed’ (since they might require a lesser or no reduction in dose). More sophisticated proton experiments show that RBE values of 1.1–1.5 and higher occur in some situations. There are now mathematical models of varying degrees of complexity that can estimate the RBE from the dose, LET and the low-LET radiosensitivities. True multidisciplinary cooperation is required to implement such new ideas in proton therapy in order to improve safety and effectiveness.

Comparative Analysis of Efficacy, Toxicity, and Patient-Reported Outcomes in Rectal Cancer Patients Undergoing Preoperative 3D Conformal Radiotherapy or VMAT.

Locally advanced rectal cancer (LARC) patients are usually treated within a multimodal therapy regime, in which the tumor resection plays the major role. This treatment ideally includes 5-fluorouracile (5FU)-based chemoradiation (CRT) leading to significantly improved local control rates. Local therapy as radiotherapy (RT) is required to be adapted referring to side effects and efficacy. Purpose of this study is the comparison of dosimetric parameters, acute and late toxicity, and quality of life in terms of patient-reported outcome (PRO) in patients treated with VMAT or 3D conformal radiotherapy (3DCRT) for LARC. Pelvic RT for LARC was performed with a prescription dose of 45 Gy in 1.8 Gy per fraction, 50.4 Gy in 1.8 Gy per fraction, or 50 Gy in 2 Gy per fraction. Chemotherapy included 5FU or 5FU/Oxaliplatin or Capecitabine-based RT. Acute and late toxicity were evaluated via National Institute Common Terminology Criteria for Adverse Events version (CTCAE) v4.03 and the Scoring System Late effects of Normal Tissue. Quality of life was established via EORTC QLQCR29. After a median follow-up of 38 months (VMAT) and 78 months (3DCRT) there was no significant difference in progression-free survival (p = 0,85) but a significant difference in overall survival (p = 0.032). Regarding dose-volume parameters, patients treated with VMAT plans had a lower V20 of the bladder than 3DCRT-treated patients (p = 0.004). VMAT plans can also reduce Dmean of the right (p = 0.002) and left (p < 0.001) femoral head. Acute side effects between the VMAT and 3DCRT patients showed no significant difference. But concerning long-term effects, VMAT-treated patients had a significant lower appearance of high grade anal incontinence (p = 0.032). Quality of life (PRO) showed no significant different between the patients except of hair loss and worrying about weight. VMAT treatment of LARC in preoperative CRT revealed a reduction of dose to organs at risk (OARs) as bladder and femoral heads. However, no changes in acute and long-term toxicity profiles were detectable. For late toxicity and quality of life data longer follow-up times are required.

Comparative results of three short brachytherapy schedules as exclusive treatment in postoperative endometrial carcinoma

PurposeTo compare vaginal control and treatment toxicity of three different high-dose-rate brachytherapy schedules as exclusive treatment in postoperative endometrial carcinoma. Methods and MaterialsFrom 2003 to 2015, three different schedules were used as postoperative treatment for 146 patients (p) with intermediate-risk endometrial carcinoma. Group 1 (41 p): six fractions of 4–6 Gy, 3–4 fractions per week; Group 2 (59 p): four fractions of 5–6 Gy administered daily; Group 3 (46 p): 6 Gy × 3 fractions in three consecutive days. The dose was prescribed at 5 mm of applicator surface using an active treatment length of 2.5 cm. Toxicity scores were evaluated using the Radiation Therapy Oncology Group scores for bladder and rectum and the objective criteria of late effects of normal tissues–subjective, objective, management, analytic for vagina. Statistics used were group descriptions calculating their means, medians, and ranges. Bivariate analysis was evaluated using variance models and χ2 tests. ResultsThe mean followup was as follows: Group 1: 88 months, Group 2: 75 months, and 41 months in Group 3. No vaginal relapses were found. Late toxicity ≥ G2: rectum: 0 p in the three groups (0%). Bladder: Group 1: 1 p (2.4%), Group 2: 0%, and Group 3: 0%. Vagina: Group 1: 4 p (9.5%); Group 2: 9 p (15.3%); and Group 3:10 p (21.8%). There were no differences in late toxicity among the three groups of patients for rectum (p = 0.83), bladder (p = 0.58), and vagina (p = 0.67); the expected global risk of complications for rectum, bladder, and vagina is 0.8%, 0.8%, and 28.8%, respectively. ConclusionsSimilar results in vaginal control and complications were achieved with the three schedules. The use of three fractions of 6 Gy administered daily is the best option for patient comfort and convenience and use of resources. Nonetheless, specific studies are needed to demonstrate the best cost-efficacy regime.

Comparing the RTOG/EORTC and LENT-SOMA scoring systems for the evaluation of late skin toxicity after 125I seed brachytherapy for parotid gland cancer

PurposeThe Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue Task Force-Subjective, Objective, Management and Analytic (LENT-SOMA) scoring systems were compared for grading late skin effects after iodine-125 seed brachytherapy in parotid gland cancer patients. Methods and MaterialsA total of 109 patients diagnosed with parotid gland carcinoma were treated postoperatively with iodine-125 seed brachytherapy at a dose of 100–120 Gy. After 6–24 months of followup, telangiectasia, skin pigmentation, atrophy, fibrosis, and ulceration were scored according to both RTOG and LENT-SOMA scale criteria. The strength of correlation between the scores and the interobserver variability were calculated. ResultsOf 109 patients, 22.9% had telangiectasia; 78.9%, pigmentation; 28.4%, fibrosis; 4.6%, edema; 0.9%, ulceration; 37.6%, retraction and/or atrophy; 22.9%, sensation change; and 11%, scaliness and/or roughness. Compared with RTOG, LENT-SOMA criteria resulted in the upgrading of pigmentation in 17% of cases, the downgrading of all instances of telangiectasia and the downgrading of one instance of Grade 4 ulceration to Grade 3. Between the two scales, fibrosis and atrophy correlated well (Spearman ρ, 0.992, 0.986). An additional 229 side effects were observed using LENT-SOMA criteria. ConclusionsThe LENT-SOMA scale was more accurate than the RTOG scale for the evaluation of late skin and subcutaneous toxicity. The downgrading of telangiectasia and upgrading of pigmentation with the LENT-SOMA scale reflected the patients' conditions better than the scores obtained with the RTOG scale. The assessment of fibrosis and atrophy correlated well between the two scales. The use of the sum of the individual scores of the LENT-SOMA is therefore advocated. The addition of decreased sweating and the removal of the alopecia (scalp) metric should be considered to standardize the reporting of late radiation morbidity.

Proteomics approaches to investigate cancer radiotherapy outcome: slow train coming

Radiotherapy represents an effective curative strategy that along with surgery and chemotherapy is traditionally used in cancer treatment. An optimal therapy delivers accurate radiation doses to tumour while protecting surrounding normal tissue. Although radiotherapy regimens have improved in recent years, tumour radioresistance and normal tissue toxicity remain major challenges that considerably contribute to the effectiveness of cancer therapy. These factors affect especially radiosensitive individuals in the treatment of whom the balance between effective tumour killing and adverse normal tissue late effects turns out to be problematic. Understanding molecular mechanisms involved in tumour and normal tissue response is essential in order to improve radiotherapy outcome in the field of personalised medicine. Alteration in the global proteome of cells and tissues truthfully reflects the changes in physiology and pathophysiology of biological samples. This makes proteomics analysis a powerful tool principally enabling identification of radioresistance biomarkers in cancer and sensitivity biomarkers in individuals. Yet, the use of proteomics in cancer therapy is still in its infancy and more research is needed to fulfil the great promise of this technique. The present review summarises recent proteomic-based studies searching for biomarkers for more accurate prediction of radiotherapeutic response in tumour and normal tissue.

The impact of active breathing control on internal mammary lymph node coverage and normal tissue exposure in breast cancer patients planned for left-sided postmastectomy radiation therapy

PurposeThe purpose of this study was to evaluate the impact of the active breathing control (ABC) technique on IMN coverage and organs at risk in patients planned for postmastectomy radiation therapy (PMRT), with the inclusion of the internal mammary lymph nodes (IMNs). The effect of body mass index (BMI) on recorded dosimetric parameters was examined in the same patient cohort. Methods and materialsFifty left-sided postmastectomy patients with breast cancer who underwent free-breathing (FB) and ABC-Elekta CT simulation scans were selected at random from an institutional breast cancer database between 2008 and 2014. The ABC plans were directly compared with FB plans from the same patient. ResultsThe IMN planning target volume coverage met dosimetric criteria for coverage of receiving more than 90% of the prescribed dose (V90) >90%, although it decreased with ABC compared with FB (94.5% vs 98%, P < .001). Overall, ABC significantly reduced doses to all measured heart and left anterior descending coronary artery parameters, ipsilateral lung V20, and mean lung dose compared with FB (P < .001). There was no difference seen between the ABC and FB plans with respect to the dose to contralateral lung or contralateral breast. There was no correlation identified between BMI and any of the dosimetric parameters recorded from the ABC and FB plans. ConclusionsOur results suggest that ABC reduces IMN coverage in left-sided breast cancer patients planned for PMRT; however, dosimetric criteria for IMN coverage were still met, suggesting that this is not likely to be clinically significant. ABC led to significant sparing of organs at risk compared with FB conditions and was not affected by BMI. Collectively, the results support the use of ABC for breast cancer patients undergoing left-sided PMRT requiring regional nodal irradiation that includes the IMNs. Further prospective clinical studies are required to determine the impact of these results on late normal tissue effects.

Prostate external beam radiotherapy combined with high-dose-rate brachytherapy: dose-volume parameters from deformably-registered plans correlate with late gastrointestinal complications.

BackgroundDerivation of dose-volume correlated with toxicity for multi-modal treatments can be difficult due to the perceived need for voxel-by-voxel dose accumulation. With data available for a single-institution cohort with long follow-up, an investigation was undertaken into rectal dose-volume effects for gastrointestinal toxicities after deformably-registering each phase of a combined external beam radiotherapy (EBRT)/high-dose-rate (HDR) brachytherapy prostate treatment.MethodsOne hundred and eighteen patients received EBRT in 23 fractions of 2 Gy and HDR (TG43 algorithm) in 3 fractions of 6.5 Gy. Results for the Late Effects of Normal Tissues — Subjective, Objective, Management and Analytic toxicity assessments were available with a median follow-up of 72 months. The HDR CT was deformably-registered to the EBRT CT. Doses were corrected for dose fractionation. Rectum dose-volume histogram (DVH) parameters were calculated in two ways. (1) Distribution-adding: parameters were calculated after the EBRT dose distribution was 3D-summed with the registered HDR dose distribution. (2) Parameter-adding: the EBRT DVH parameters were added to HDR DVH parameters. Logistic regressions and Mann-Whitney U-tests were used to correlate parameters with late peak toxicity (dichotomised at grade 1 or 2).ResultsThe 48–80, 40–63 and 49–55 Gy dose regions from distribution-adding were significantly correlated with rectal bleeding, urgency/tenesmus and stool frequency respectively. Additionally, urgency/tenesmus and anorectal pain were associated with the 25–26 Gy and 44–48 Gy dose regions from distribution-adding respectively. Parameter-adding also indicated the low-mid dose region was significantly correlated with stool frequency and proctitis.ConclusionsThis study confirms significant dose-histogram effects for gastrointestinal toxicities after including deformable registration to combine phases of EBRT/HDR prostate cancer treatment. The findings from distribution-adding were in most cases consistent with those from parameter-adding. The mid-high dose range and near maximum doses were important for rectal bleeding. The distribution-adding mid-high dose range was also important for stool frequency and urgency/tenesmus. We encourage additional studies in a variety of institutions using a variety of dose accumulation methods with appropriate inter-fraction motion management.Trial registrationNCT NCT00193856. Retrospectively registered 12 September 2005.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0719-2) contains supplementary material, which is available to authorized users.

Prolongation of overall treatment time as a cause of treatment failure in early breast cancer: An analysis of the UK START (Standardisation of Breast Radiotherapy) trials of radiotherapy fractionation

BackgroundTests of tumour treatment time effect in patients prescribed post-operative radiotherapy for early breast cancer have focussed on time to start of radiotherapy rather than overall treatment time. The START randomised trials of radiotherapy fractionation provide an opportunity to directly estimate the effect of treatment acceleration. MethodsBetween 1986 and 2002, a total of 5861 women with early breast cancer were recruited into the UK START pilot (START-P), START-A and START-B randomised trials. START-P and START-A tested 13 fractions of 3.0–3.3Gy against 25 fractions of 2.0Gy with a fixed treatment duration of 5weeks for all schedules; START-B tested 15 fractions of 2.67Gy in 3weeks against 25 fractions of 2.0Gy over 5weeks. Estimates of the effect of length of treatment for local–regional relapse and for a measure of late normal tissue effects (change in photographic breast appearance, for patients following breast conserving surgery) were obtained from Cox proportional hazards regression analyses stratified according to trial. ResultsAt a median follow-up of 10years, 444/5831 (7.6%) patients with data available had a local–regional relapse, and 1135/3185 (35.6%) had mild or marked change in photographic breast appearance by 5years. Adjusting for prognostic factors, the estimate of the overall treatment time effect for local–regional relapse was 0.60Gy/day (95%CI 0.10 to 1.18Gy/day, p=0.02), and 0.14Gy/day (95%CI −0.09 to 0.34Gy/day, p=0.29) for change in photographic breast appearance. ConclusionsCombined analysis of the START trials generates the hypothesis that overall treatment time is a significant determinant of local cancer control after adjuvant whole breast radiotherapy, with approximately 0.6Gy per day ‘wasted’ in compensating for tumour cell proliferation.

DNA Methyltransferase Gene Polymorphisms for Prediction of Radiation-Induced Skin Fibrosis after Treatment of Breast Cancer: A Multifactorial Genetic Approach.

PurposeThis study was conducted to investigate the role of four polymorphic variants of DNA methyltransferase genes as risk factors for radiation-induced fibrosis in breast cancer patients. We also assessed their ability to improve prediction accuracy when combined with mitochondrial haplogroup H, which we previously found to be independently associated with a lower hazard of radiation-induced fibrosis.Materials and MethodsDNMT1 rs2228611,DNMT3A rs1550117,DNMT3A rs7581217, and DNMT3B rs2424908 were genotyped by real-time polymerase chain reaction in 286 Italian breast cancer patients who received radiotherapy after breast conserving surgery. Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue–Subjective Objective Management Analytical (LENT-SOMA) scale. The discriminative accuracy of genetic models was assessed by the area under the receiver operating characteristic curves (AUC).ResultsKaplan-Meier curves showed significant differences among DNMT1 rs2228611 genotypes in the cumulative incidence of grade ≥ 2 subcutaneous fibrosis (log-rank test p-value= 0.018). Multivariate Cox regression analysis revealed DNMT1 rs2228611 as an independent protective factor for moderate to severe radiation-induced fibrosis (GG vs. AA; hazard ratio, 0.26; 95% confidence interval [CI], 0.10 to 0.71; p=0.009). Adding DNMT1 rs2228611 to haplogroup H increased the discrimination accuracy (AUC) of the model from 0.595 (95% CI, 0.536 to 0.653) to 0.655 (95% CI, 0.597 to 0.710).ConclusionDNMT1 rs2228611 may represent a determinant of radiation-induced fibrosis in breast cancer patients with promise for clinical usefulness in genetic-based predictive models.

Why RBE must be a variable and not a constant in proton therapy.

This article considered why the proton therapy (PT) relative biological effect (RBE) should be a variable rather than a constant. The reasons for a variable proton RBE are enumerated, with qualitative and quantitative arguments. The heterogeneous data sets collated by Paganetti et al (2002) and the more homogeneous data of Britten et al (2013) are further analyzed using linear regression fitting and RBE-inclusive adaptations of the linear-quadratic (LQ) radiation model. The in vitro data show RBE increasing as dose per fraction is lowered. In the Paganetti et al (2002) data sets, the differences between observed and expected effects are smaller when the LQ model is used, but with such data heterogeneity, firm statistical conclusions cannot be obtained. The more homogeneous data set shows an unequivocal variation in RBE with dose per faction. The in vivo data are inappropriate for assessments of late normal tissue effects in radiotherapy. Also, if there is the same degree of uncertainty in an RBE of 1.1 or in an RBE of 2-3 for C ions, the fractional and biological effective doses can vary considerably and be greater in the proton case. So, errors in RBE assignment are important for protons, just as with C ions. Further experimental programmes are proposed, including late normal tissue end points. Better RBE allocations might further improve PT outcomes. This study provides a rigorous critique of the 1.1 RBE used for protons, from theoretical and practical standpoints. Data analysis shows that the LQ model is more appropriate than simple linear regression. Comprehensive research programmes are suggested.

Recovery of Salivary Function: Contralateral Parotid-sparing Intensity-modulated Radiotherapy versus Bilateral Superficial Lobe Parotid-sparing Intensity-modulated Radiotherapy

AimsTo establish whether there is a difference in recovery of salivary function with bilateral superficial lobe parotid-sparing intensity-modulated radiotherapy (BSLPS-IMRT) versus contralateral parotid-sparing IMRT (CLPS-IMRT) in patients with locally advanced head and neck squamous cell cancers. Materials and methodsA dosimetric analysis was carried out on data from two studies in which patients received BSLPS-IMRT (PARSPORT II) or CLPS-IMRT (PARSPORT). Acute (National Cancer Institute, Common Terminology Criteria for adverse events – NCI CTCAEv3.0) and late (Late Effects of Normal Tissue- subjective, objective, management analytical – LENTSOMA and Radiation Therapy Oncology Group) xerostomia scores were dichotomised: recovery (grade 0–1) versus no recovery (≥grade 2). Incidence of recovery of salivary function was compared between the two techniques and dose-response relationships were determined by fitting dose-response curves to the data using non-linear logistic regression analysis. ResultsSeventy-one patients received BSLPS-IMRT and 35 received CLPS-IMRT. Patients received 65 Gy in 30 fractions to the primary site and involved nodal levels and 54 Gy in 30 fractions to elective nodal levels. There were significant differences in mean doses to contralateral parotid gland (29.4 Gy versus 24.9 Gy, P < 0.005) and superficial lobes (26.8 Gy versus 30.5 Gy, P = 0.02) for BSLPS and CLPS-IMRT, respectively. Lower risk of long-term ≥grade 2 subjective xerostomia (LENTSOMA) was reported with BSLPS-IMRT (odds ratio 0.50; 95% confidence interval 0.29–0.86; P = 0.012). The percentage of patients who reported recovery of parotid saliva flow at 1 year was higher with BSLPS-IMRT compared with CLPS-IMRT techniques (67.1% versus 52.8%), but the difference was not statistically significant (P = 0.12). For the whole parotid gland, the tolerance doses, D50, were 25.6 Gy (95% confidence interval 20.6–30.5), k = 2.7 (0.9–4.5) (CLPS-IMRT) and 28.9 Gy (26.1–31.9), k = 2.4 (1.4–3.4) (BSLPS-IMRT). For the superficial lobe, D50 were similar: BSLPS-IMRT 23.5 Gy (19.3–27.6), k = 1.9 (0.5–3.8); CLPS-IMRT 24.0 Gy (17.7–30.1), k = 2.1 (0.1–4.1). ConclusionBSLPS-IMRT reduces the risk of developing high-grade subjective xerostomia compared with CLPS-IMRT. The D50 of the superficial lobe may be a more reliable predictor of recovery of parotid function than the whole gland mean dose.

Radiation Therapy Did Not Induce Long-Term Changes in Rectal Mucosa: Results From the Randomized Scandinavian Prostate Cancer Group 7 Trial

To investigate long-term changes in the rectal mucosa after curative external beam radiation therapy in the treatment of prostate cancer. In the Scandinavian Prostate Cancer Group 7trial, 880 men with locally advanced prostate cancer were randomized to hormonal therapy alone versus hormonal therapy plus radiation therapy to 70Gy. A subcohort from this trial being randomized at our center (n=178) was invited to a study on late anorectal side effects during 2003-2005, approximately 5years after treatment, including measuring health-reported quality of life and physician-assessed toxicity score by the Late Effects Normal Tissue Task Force/Subjective, Objective, Management, Analytic (LENT/SOMA) and European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group score. Sixty-seven patients had a rectal mucosa biopsy. Sixty-four biopsies wereincluded in the final analysis, of which 33 patients were randomized to hormonal treatment and 31 to hormonal treatment plus radiation therapy. The presence of fibrosis, number of capillaries, and lymphocyte infiltration was then evaluated by light microscopy. The group receiving radiation therapy had significantly higher LENT/SOMA and function/bother scale scores than the group that only received hormonal treatment, but there was no significant difference in the presence of fibrosis, ectasia, number of capillaries in the lamina propria, or lymphocyte infiltration between the groups. Radiation therapy to 70Gy to the prostate does not induce long-term microscopic mucosal changes in the rectum 5years after treatment. This is in contrast to the general assumption that structural changes, including fibrosis, seen after radiation therapy include the mucosa. We speculate that the main late effects of radiation therapy on the structure of the rectum are located in the deeper layers of the rectal wall than the mucosa.