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The development of normal tissue radiation dose-response models for children with cancer has been challenged by many factors, including small sample sizes; the long length of follow-up needed to observe some toxicities; the continuing occurrence of events beyond the time of assessment; the often complex relationship between age at treatment, normal tissue developmental dynamics, and age at assessment; and the need to use retrospective dosimetry. Meta-analyses of published pediatric outcome studies face additional obstacles of incomplete reporting of critical dosimetric, clinical, and statistical information. This report describes general methods used to address some of the pediatric modeling issues. It highlights previous single- and multi-institutional pediatric dose-response studies and summarizes how each PENTEC taskforce addressed the challenges and limitations of the reviewed publications in constructing, when possible, organ-specific dose-effect models. [ABSTRACT FROM AUTHOR]

At its very core, radiation oncology involves a trade-off between the benefits and risks of exposing tumors and normal tissue to relatively high doses of ionizing radiation. This trade-off is particularly critical in childhood cancer survivors (CCS), in whom both benefits and risks can be hugely consequential due to the long life expectancy if the primary cancer is controlled. Estimating the normal tissue–related risks of a specific radiation therapy plan in an individual patient relies on predictive mathematical modeling of empirical data on adverse events. The Pediatric Normal-Tissue Effects in the Clinic (PENTEC) collaborative network was formed to summarize and, when possible, to synthesize dose-volume-response relationships for a range of adverse events incident in CCS based on the literature. Normal-tissue clinical radiation biology in children is particularly challenging for many reasons: (1) Childhood malignancies are relatively uncommon—constituting approximately 1% of new incident cancers in the United States—and biologically heterogeneous, leading to many small series in the literature and large variability within and between series. This creates challenges in synthesizing data across series. (2) CCS are at an elevated risk for a range of adverse health events that are not specific to radiation therapy. Thus, excess relative or absolute risk compared with a reference population becomes the appropriate metric. (3) Various study designs and quantities to express risk are found in the literature, and these are summarized. (4) Adverse effects in CCS often occur 30, 50, or more years after therapy. This limits the information content of series with even very extended follow-up, and lifetime risk estimates are typically extrapolations that become dependent on the mathematical model used. (5) The long latent period means that retrospective dosimetry is required, as individual computed tomography–based radiation therapy plans gradually became available after 1980. (6) Many individual patient-level factors affect outcomes, including age at exposure, attained age, lifestyle exposures, health behaviors, other treatment modalities, dose, fractionation, and dose distribution. (7) Prospective databases with individual patient-level data and radiation dosimetry are being built and will facilitate advances in dose-volume-response modeling. We discuss these challenges and attempts to overcome them in the setting of PENTEC. [ABSTRACT FROM AUTHOR]

TARGIT-A was a pragmatic randomized noninferiority trial including women with early-stage breast cancer treated postlumpectomy with either external beam radiation therapy (EBRT) or 50 kV x-rays delivered intraoperatively with or without EBRT, as indicated. The long-term update of the pre-pathology cohort did not include a 10-year estimate of the primary endpoint of local failure (although tabular 5-year data was provided). Here, we used the data from the pre-pathology manuscript to estimate the cumulative incidence of local failure. Using digitizer software and the published survival curves, we extracted the Kaplan-Meier rate of local recurrence-free survival and overall survival. The extracted data were calibrated to the published point-estimates to within ±0.5%. The data were then fit to parametric survival models, and overall survival and local recurrence-free survival curves were subtracted to give the estimate of local failure in the presence of the competing risk of death. Bootstrap resampling was used to assess for parameter uncertainty in the modeling process. Our analysis estimated that the risk of local failure at 10 years in the TARGIT-A pre-pathology cohort is approximately 1.7% with EBRT (95% confidence interval [CI], 0%-4.3%) and 5.5% in the pragmatic risk-adapted TARGIT strategy (95% CI, 2.9%-8.0%). A weighted average estimate suggests that the risk of local failure in low-risk women treated with TARGIT alone is approximately 6.6% at 10 years (95% CI, 3.3%-10.0%), with an estimated difference of 4.9% (95% CI, 0.6%-9.2%) compared with EBRT. These data allow for contextualization and informed decisions when considering megavoltage EBRT, kilovoltage intraoperatively, or omission of radiation therapy entirely. [ABSTRACT FROM AUTHOR]

Purpose: More than a decade of randomized controlled trials in prostate cancer has established a positive radiation dose response at moderate doses and a consistently low α/β ratio in the linear quadratic model for moderate hypofractionation. The recently published large randomized trial of ultrahypofractionated prostate cancer radiation therapy adds substantially to our current knowledge of dose response and fractionation sensitivity.Methods and Materials: Randomized trials of dose escalation and hypofractionation of radiation therapy were meta-analyzed to yield the overall best estimate of the α/β ratio. Additionally, a putative saturation of dose effect previously reported at approximately 80 Gy EQD2 was investigated by mapping the relative effectiveness assessed at 5 years onto a single reference dose-response curve.Results: Meta-analysis of 14 randomized trials including 13,384 patients yielded a best estimate of α/β = 1.6 Gy (95% confidence interval, 1.3-2.0 Gy) but with highly significant heterogeneity (I2 = 70%, P = .0005). Further analysis indicated an association between increasing dose per fraction in the experimental arm and increasing α/β ratio (slope, 0.6 Gy increase in α/β per Gy increase in fraction size; P = .017). This deviation from the linear quadratic model could, however, also be explained by biochemical control maxing out at doses above approximately 80 Gy.Conclusions: Biochemical control data from randomized controlled trials of dose-per-fraction escalation in prostate cancer radiation therapy are inconsistent with the presence of a constant fractionation sensitivity in the linear-quadratic model and/or a monotonic dose response for biochemical control beyond 80 Gy equivalent dose. These observations have a potential effect on the optimal doses in future trials and the interpretation of ongoing trials of ultrahypofractionation. [ABSTRACT FROM AUTHOR]

To quantify the effects of opening a proton center (PC) on an academic medical center (AMC)/radiation oncology department. Radiation treatment volume and relative value units from fiscal year 2015 (FY15) to FY17 were retrospectively analyzed at the AMC and 2 community-based centers. To quantify new patient referrals to the AMC, we reviewed the electronic medical record for all patients seen at the PC since consults were initiated in November 2015 (n = 1173). Patients were excluded if the date of entry into the AMC electronic medical record predated their PC consultation. Hospital resource use and professional and technical charges were obtained for these patients. Academic growth, philanthropy, and resident education were evaluated based on grant submissions, clinical trial enrollment, philanthropy, and pediatric case exposure, respectively, from PC opening through FY17. From FY15 to FY17, radiation fractions at the AMC and the 2 community sites decreased by 14% (95% confidence interval [CI], 12%-16%, P <.001) and increased by 19% (95% CI, 16%-23%, P <.001) and 2% (95% CI, –1.1 to 4.3%, P = NS), respectively; the number of new starts decreased by 3% (95% CI, –13% to 7%, P = NS) and 2% (95% CI, –20% to 16%, P = NS) and increased by 13% (95% CI –2% to 27%, P = NS), respectively. At the AMC, technical and professional relative value units decreased by 5% and 14%, respectively. The PC made 561 external referrals to the AMC, which resulted in $2.38 million technical and $2.13 million professional charges at the AMC. Fifteen grant submissions ($12.83 million) resulted in 6 awards ($3.26 million). Twenty-two clinical trials involving proton therapy were opened, on which a total of 5% (n = 54) of patients enrolled during calendar years 2017 and 2018. The PC was involved in gift donations of $1.6 million. There was a nonsignificant 37% increase in number of pediatric cases. Despite a slight decline in AMC photon patient volumes and relative value units, a positive downstream effect was associated with the addition of a PC, which benefited the AMC. [ABSTRACT FROM AUTHOR]

Purpose: Randomized trials of altered dose/fractionation for external beam radiation therapy are meta-analyzed with the aim of establishing the dose response and fractionation sensitivity.Methods and Materials: Studies were identified through PubMed through April 1, 2017. Studies of any-risk prostate cancer patients and any modification of external beam radiation therapy were included. The outcomes and comparisons collected were hazard ratios for biochemical no evidence of disease (bNED) and overall survival (OS). Trial-by-trial estimates of the steepness of the dose-response curve for bNED were performed for dose-escalation trials, followed by inverse variance weighting. The steepness was used to extract estimates of α/β, which were subsequently synthesized. Both analyses were performed assuming no effect of overall treatment time and were repeated assuming a loss of 0.31 Gy/d for a protracted treatment time. Finally, all trials were included in the analyses of the dose response for fractionation-corrected doses. This analysis was repeated for OS. Finally, the per-trial effect on OS was compared to the effect on bNED.Results: We identified 13 randomized trials involving 10,184 patients. The dose response for bNED from dose-escalation trials was γ50 = 0.62 (95% confidence interval [CI] 0.37-0.87) and γ50 = 0.87 (95% CI 0.53-1.21) without and with the overall treatment time effect, respectively. The corresponding estimates of α/β from 8 fractionation trials (7946 patients) were 1.2 Gy (95% CI 0.8-1.7) and 2.7 Gy (95% CI 1.6-3.8). The heterogeneity in the data can be explained by the shallower dose response for bNED in trials with effective doses in the experimental arm >80 Gy equivalent dose in 2-Gy fractions (EQD2) (P = .04). No indication was found of a dose response for OS or a correlation with improvement in bNED.Conclusions: The reported data of moderate hypofractionation are consistent with a low α/β value with narrow CIs. Dose-escalation trials have demonstrated a dose response for bNED. Escalating doses to >80 Gy EQD2 might not improve bNED. A correlation between benefit in bNED and OS was not found. [ABSTRACT FROM AUTHOR]

: PurposeTo analyze some of the limitations to improvement of the outcome of radiotherapy (RT) expected from the introduction of sophisticated treatment planning and delivery technology.: Methods and materialsSeveral recent examples from the literature were analyzed in some detail. Mathematical modeling techniques were used to assess the likely clinical impact of new technologies or biologic principles. The findings of recent randomized controlled trials of RT for prostate, breast, and rectal cancer were analyzed from the perspective of cost-effectiveness and therapeutic gain.: ResultsThe main findings of the analyses may be summarized as follows. Dosimetric precision should aim for a <2% patient-to-patient variability in the delivered dose. Imprecision in clinical target volume definition remains an obstacle for high-precision RT. Functional imaging and novel biologic assays may facilitate a move from a clinical target volume to the real target volume. Improved target volume coverage is mainly important if RT has high effectiveness. Radiation oncology is increasingly becoming evidence based. However, there is still a long way to go. Hypofractionation in adjuvant RT for breast cancer may represent a favorable balance between cost and benefit. Treatment complications are potentially associated with both suffering and high cost. The identification of high-risk patients would improve the cost-effectiveness of high-tech RT aimed at avoiding complications. Conformal RT may allow the introduction of hypofractionation, which, again, could potentially save resources. With improvement in surgery and more screening-detected cancer cases, the number needed to treat increases, and this will directly affect the cost-effectiveness of high-tech RT unless efficient patient selection can be developed.: ConclusionSustained technological refinement is only likely to be cost-effective if the clinical and biologic understanding of patient-to-patient variability in the risk of specific types of failure and the optimal multimodality approach to handle these risks is developed at the same time. Mathematical modeling together with methods from health technology assessment and health economics are useful complements to standard methods from evidence-based medicine. Progress in functional imaging and in basic and clinical cancer biology is likely to provide the tools required for individualized risk-adapted RT. [Copyright &y& Elsevier]

Purpose: To investigate compliance to the prescribed dose-fractionation schedule in five randomized controlled trials of altered fractionation in radiotherapy for head-and-neck carcinoma.Methods and Materials: Individual patient data from 2566 patients participating in the European Organization for Research and Treatment of Cancer (EORTC) 22791, EORTC 22811, EORTC 22851, Princess Margaret Hospital (PMH), and continuous hyperfractionated accelerated radiotherapy (CHART) head-and-neck trials were merged in the fractionation IMPACT (Intergroup Merger of Patient data from Altered or Conventional Treatment schedules) study database. The ideal treatment time was defined as the minimum time required to deliver a prescribed schedule. Compliance to the prescribed overall treatment time was quantified as the difference between the actual and the ideal overall time. An overall measure of compliance in an individual patient, the total dose lost (TDL), was calculated as the dose lost due to prolongation of therapy (assuming a D(prolif) of 0.64 Gy/day) plus the difference between the prescribed and the actual dose given.Results: The time in excess of the ideal ranged up to 97 days (average 3.9 days), and 25% of the patients had delays of 6 days or more. World Health Organization (WHO) performance status and nodal stage had a significant effect on TDL. TDL was significantly higher in the conventional than in the altered arm of the EORTC 22851 and CHART trials. In the PMH trial, TDL was significantly higher in the hyperfractionation than in the conventional arm. Centers participating in the three EORTC trials varied significantly in their compliance. There was a significant improvement in compliance in patients treated more recently.Conclusions: Even in randomized controlled trials, compliance to the prescribed radiation therapy schedule may be relatively poor, especially after conventional fractionation. This affects the interpretation of the outcome of these trials. [ABSTRACT FROM AUTHOR]

Purpose: To present a novel method for meta-analysis of the fractionation sensitivity of tumors as applied to prostate cancer in the presence of an overall time factor. Methods and Materials: A systematic search for radiation dose-fractionation trials in prostate cancer was performed using PubMed and by manual search. Published trials comparing standard fractionated external beam radiation therapy with alternative fractionation were eligible. For each trial the α/β ratio and its 95% confidence interval (CI) were extracted, and the data were synthesized with each study weighted by the inverse variance. An overall time factor was included in the analysis, and its influence on α/β was investigated. Results: Five studies involving 1965 patients were included in the meta-analysis of α/β. The synthesized α/β assuming no effect of overall treatment time was −0.07 Gy (95% CI −0.73-0.59), which was increased to 0.47 Gy (95% CI −0.55-1.50) if a single highly weighted study was excluded. In a separate analysis, 2 studies based on 10,808 patients in total allowed extraction of a synthesized estimate of a time factor of 0.31 Gy/d (95% CI 0.20-0.42). The time factor increased the α/β estimate to 0.58 Gy (95% CI −0.53-1.69)/1.93 Gy (95% CI −0.27-4.14) with/without the heavily weighted study. An analysis of the uncertainty of the α/β estimate showed a loss of information when the hypofractionated arm was underdosed compared with the normo-fractionated arm. Conclusions: The current external beam fractionation studies are consistent with a very low α/β ratio for prostate cancer, although the CIs include α/β ratios up to 4.14 Gy in the presence of a time factor. Details of the dose fractionation in the 2 trial arms have critical influence on the information that can be extracted from a study. Studies with unfortunate designs will supply little or no information about α/β regardless of the number of subjects enrolled. [Copyright &y& Elsevier]

Purpose: To compare rates of severe late toxicities following concomitant chemoradiotherapy and radiotherapy alone for cervical cancer. Methods and Materials: Patients with cervical cancer were treated at a single institution with radiotherapy alone or concomitant chemoradiotherapy for curative intent. Severe late toxicity was defined as grade ≥3 vaginal, urologic, or gastrointestinal toxicity or any pelvic fracture, using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE), occurring ≥6 months from treatment completion and predating any salvage therapy. Severe late toxicity rates were compared after adjusting for pertinent covariates. Results: At 3 years, probability of vaginal severe late toxicity was 20.2% for radiotherapy alone and 35.1% for concomitant chemoradiotherapy (P=.026). At 3 years, probability of skeletal severe late toxicity was 1.6% for radiotherapy alone and 7.5% for concomitant chemoradiotherapy (P=.010). After adjustment for case mix, concomitant chemoradiotherapy was associated with higher vaginal (hazard ratio [HR] 3.0, 95% confidence interval [CI], 1.7-5.2, P<.001), and skeletal (HR 7.0, 95% CI 1.4-34.1, P=.016) severe late toxicity. Compared to high dilator compliance, moderate (HR 3.6, 95% CI 2.0-6.5, P<.001) and poor (HR 8.5, 95% CI 4.3-16.9, P<.001) dilator compliance was associated with higher vaginal severe late toxicity. Age >50 was associated with higher vaginal (HR 1.8, 95% CI 1.1-3.0, P=.013) and skeletal (HR 5.7, 95% CI 1.2-27.0, P=.028) severe late toxicity. Concomitant chemoradiotherapy was not associated with higher gastrointestinal (P=.886) or urologic (unadjusted, P=.053; adjusted, P=.063) severe late toxicity. Conclusion: Compared to radiotherapy alone, concomitant chemoradiotherapy is associated with higher rates of severe vaginal and skeletal late toxicities. Other predictive factors include dilator compliance for severe vaginal late toxicity and age for severe vaginal and skeletal late toxicities. [Copyright &y& Elsevier]

Purpose: To analyze the outcome in all oropharynx cancer patients treated at the University of Wisconsin during 1995–2005 and highlight the methodologic challenge in comparing outcome after intensity-modulated radiotherapy (IMRT) with that of historical controls. Methods and Materials: Outcomes were compared in 195 oropharynx cancer patients after definitive radiotherapy with curative intent in the pre-IMRT era (pre-IMRT, n = 105), after IMRT (IMRT+, n = 52) or after non-IMRT techniques during the IMRT era (IMRT−, n = 38). Results: With a median follow-up of 30.4 months, the 3-year overall survival rate in IMRT+, IMRT−, and pre-IMRT patients was 88.2%, 81.1%, and 67.7%, respectively; and for locoregional control was 96.1%, 78.1%, and 81.1%. Patients from the IMRT era more frequently received concurrent chemotherapy (67% vs. 6%, p < 0.001) and underwent adjuvant neck dissection (52% vs. 29%, p = 0.002). Patients with T3–4 disease and bilateral neck disease were significantly less likely to receive IMRT. Cox regression analysis identified IMRT as a significant prognostic factor (p = 0.04); however, after including T stage in the model, IMRT lost independent significance (p = 0.2). Analysis of a potential effect of IMRT on Grade 3+ mucositis or skin reaction was also hampered by the change in other treatment characteristics. Conclusions: Outcomes in oropharynx cancer have improved at our institution since the introduction of IMRT. However, multiple factors have contributed to this improvement, and presentation of IMRT outcomes without the full context of historical and contemporary controls may yield data that overstate outcome after IMRT. [Copyright &y& Elsevier]

Purpose: To establish whether a relationship exists between improvement in locoregional control (LRC) and improvement in overall survival (OS) in trials of modified radiotherapy for head-and-neck cancer and to attempt to quantify the relationship.Methods and materials: A systematic review of the literature was performed for randomized controlled trials of radiotherapy for head-and-neck cancer involving the use of altered fractionation or hypoxic sensitizers. The changes in LRC at 2 years and OS at 5 years were recorded for each trial. Regression analysis was used to investigate the relationship between the two variables.Results: Nineteen relevant trials were identified. Fourteen reported sufficient data for analysis. Linear regression analysis showed a statistically significant correlation between LRC and OS with a slope of 0.67 (95% confidence interval, 0.38–0.96, p = 0.00017).Conclusions: We have demonstrated a relationship between a change in LRC and a change in OS in randomized trials of modified radiotherapy for head-and-neck cancer. A 10% improvement in the 2-year LRC is predicted to lead to a 6.7% improvement in the 5-year OS. This type of analysis may have applications in other tumor sites. [Copyright &y& Elsevier]

Black women with breast cancer often present with more aggressive disease compared with other races, contributing to an increased risk of cancer mortality. Despite this inequity, Black women remain severely underrepresented in breast cancer clinical trials. We aim to characterize factors that influence a woman's decision to enroll in a clinical trial, with the goal of identifying clinical interventions to aid in the recruitment of vulnerable groups. A cross-sectional, descriptive study was conducted using a questionnaire adapted from 2 prevalidated surveys investigating factors influencing clinical trial enrollment. The survey was administered to women with curable breast cancer during a single follow-up visit at 4 different sites within a university medical system where all patients are screened for clinical trial eligibility. Chi-square tests and Mann-Whitney U tests were used to assess associations or differences between the populations. One hundred ninety-four out of 209 women completed the survey, giving a compliance rate of 93%. Twenty-six percent of women self-identified as Black, most women were located at community sites (67.1%), most women had diagnoses of early-stage disease (I: 57.7%, II: 29.4%), and 81% of women had some collegiate-level education. Black women were younger at diagnosis (P =.005) and less likely to be married (P =.012) but more often lived with family members (P =.003) and had a lower median income (P <.001). According to the survey, Black women were less likely to trust their care team (P =.032), more likely to believe that research ultimately harms minorities (P <.001), and had a stronger belief in God's will determining illness and wellness (P <.001). Recurring themes of trust in the health care team, patient education, and advancement of cancer treatments were discussed in the focus groups. Failure to offer clinical trials and mistrust in research institutions may pose the greatest hindrances to the enrollment of Black women in clinical trials. Empowering women through education and fostering trustworthy relationships can encourage greater clinical trial participation. [ABSTRACT FROM AUTHOR]

In this Pediatric Normal Tissue Effects in the Clinic (PENTEC) vision paper, challenges and opportunities in the assessment of subsequent neoplasms (SNs) from radiation therapy (RT) are presented and discussed in the context of technology advancement. The paper discusses the current knowledge of SN risks associated with historic, contemporary, and future RT technologies. Opportunities for research and SN mitigation strategies in pediatric patients with cancer are reviewed. Present experience with radiation carcinogenesis is from populations exposed during widely different scenarios. Knowledge gaps exist within clinical cohorts and follow-up; dose-response and volume effects; dose-rate and fractionation effects; radiation quality and proton/particle therapy; age considerations; susceptibility of specific tissues; and risks related to genetic predisposition. The biological mechanisms associated with local and patient-level risks are largely unknown. Future cancer care is expected to involve several available RT technologies, necessitating evidence and strategies to assess the performance of competing treatments. It is essential to maximize the utilization of existing follow-up while planning for prospective data collection, including standardized registration of individual treatment information with linkage across patient databases. [ABSTRACT FROM AUTHOR]

Pediatric Normal Tissue Effects in the Clinic (PENTEC) seeks to refine quantitative radiation dose-volume relationships for normal-tissue complication probabilities (NTCPs) in survivors of pediatric cancer. This article summarizes the evolution of PENTEC and compares it with similar adult-focused efforts (eg, Quantitative Analysis of Normal Tissue Effects in the Clinic [QUANTEC] and Hypofractionated Treatment Effects in the Clinic [HyTEC]) with respect to content, oversight, support, scope, and methodology of literature review. It then summarizes key organ-specific findings from PENTEC in an attempt to compare NTCP estimates in children versus adults. In brief, select normal-tissue risks within developing organs and tissues (eg, maldevelopment of musculoskeletal tissue, teeth, breasts, and reproductive organs) are primarily relevant only in children. For some organs and tissues, children appear to have similar (eg, brain for necrosis, optic apparatus, parotid gland, liver), greater (eg, brain for neurocognition, cerebrovascular, breast for lactation), less (ovary), or perhaps slightly less (eg, lung) risks of toxicity versus adults. Similarly, even within the broad pediatric age range (including adolescence), for some endpoints, younger children have greater (eg, hearing and brain for neurocognition) or lesser (eg, ovary, thyroid) risks of radiation-associated toxicities. NTCP comparisons in adults versus children are often confounded by marked differences in treatment paradigms that expose normal tissues to radiation (ie, cancer types, prescribed radiation therapy dose and fields, and chemotherapy agents used). To add to the complexity, it is unclear if age is best analyzed as a continuous variable versus with age groupings (eg, infants, young children, adolescents, young adults, middle-aged adults, older adults). Further work is needed to better understand the complex manner in which age and developmental status affect risk. [ABSTRACT FROM AUTHOR]

From the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative, a systematic review and meta-analysis of publications reporting on radiation dose-volume effects for risk of primary hypothyroidism after radiation therapy for pediatric malignancies was performed. All studies included childhood cancer survivors, diagnosed at age <21 years, whose radiation therapy fields exposed the thyroid gland and who were followed for primary hypothyroidism. Children who received pituitary-hypothalamic or total-body irradiation were excluded. PubMed and the Cochrane Library were searched for studies published from 1970 to 2017. Data on age at treatment, patient sex, radiation dose to neck or thyroid gland, specific endpoints for hypothyroidism that were used in the studies, and reported risks of hypothyroidism were collected. Radiation dose-volume effects were modeled using logistic dose response. Relative excess risk of hypothyroidism as a function of age at treatment and sex was assessed by meta-analysis of reported relative risks (RR) and odds ratios. Fifteen publications (of 1709 identified) were included for systematic review. Eight studies reported data amenable for dose-response analysis. At mean thyroid doses of 10, 20, and 30 Gy, predicted rates of uncompensated (clinical) hypothyroidism were 4%, 7%, and 13%, respectively. Predicted rates of compensated (subclinical) hypothyroidism were 12%, 25%, and 44% after thyroid doses of 10, 20, and 30 Gy, respectively. Female sex (RR = 1.7, P <.0001) and age >15 years at radiation therapy (RR = 1.3, P =.005) were associated with higher risks of hypothyroidism. After a mean thyroid dose of 20 Gy, predicted risks of hypothyroidism were 13% for males <14 years of age, increasing to 29% for females >15 years of age. A radiation dose response for risk of hypothyroidism is evident; a threshold radiation dose associated with no risk is not observed. Thyroid dose exposure should be minimized when feasible. Data on hypothyroidism after radiation therapy should be better reported to facilitate pooled analyses. [ABSTRACT FROM AUTHOR]

Purpose: This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer (LACC).Methods and Materials: Patient-reported symptoms (European Organization for Research and Treatment of Cancer [EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up (baseline and ≥3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition (treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was evaluated.Results: Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (interquartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event.Conclusions: Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of distinguishing between transient and persisting symptoms in the aftercare of LACC survivors. [ABSTRACT FROM AUTHOR]

Clinical studies of the dependence of normal tissue response on dose-volume factors are often confusingly inconsistent, as the QUANTEC reviews demonstrate. A key opportunity to accelerate progress is to begin storing high-quality datasets in repositories. Using available technology, multiple repositories could be conveniently queried, without divulging protected health information, to identify relevant sources of data for further analysis. After obtaining institutional approvals, data could then be pooled, greatly enhancing the capability to construct predictive models that are more widely applicable and better powered to accurately identify key predictive factors (whether dosimetric, image-based, clinical, socioeconomic, or biological). Data pooling has already been carried out effectively in a few normal tissue complication probability studies and should become a common strategy. [Copyright &y& Elsevier]

Biomarkers are of interest for predicting or monitoring normal tissue toxicity of radiation therapy. Advances in molecular radiobiology provide novel leads in the search for normal tissue biomarkers with sufficient sensitivity and specificity to become clinically useful. This article reviews examples of studies of biomarkers as predictive markers, as response markers, or as surrogate endpoints for radiation side effects. Single nucleotide polymorphisms are briefly discussed in the context of candidate gene and genomewide association studies. The importance of adjusting for radiation dose distribution in normal tissue biomarker studies is underlined. Finally, research priorities in this field are identified and discussed. [Copyright &y& Elsevier]

Advances in dose–volume/outcome (or normal tissue complication probability, NTCP) modeling since the seminal Emami paper from 1991 are reviewed. There has been some progress with an increasing number of studies on large patient samples with three-dimensional dosimetry. Nevertheless, NTCP models are not ideal. Issues related to the grading of side effects, selection of appropriate statistical methods, testing of internal and external model validity, and quantification of predictive power and statistical uncertainty, all limit the usefulness of much of the published literature. Synthesis (meta-analysis) of data from multiple studies is often impossible because of suboptimal primary analysis, insufficient reporting and variations in the models and predictors analyzed. Clinical limitations to the current knowledge base include the need for more data on the effect of patient-related cofactors, interactions between dose distribution and cytotoxic or molecular targeted agents, and the effect of dose fractions and overall treatment time in relation to nonuniform dose distributions. Research priorities for the next 5–10 years are proposed. [Copyright &y& Elsevier]

Purpose: There are little data quantifying the psychosocial needs of patients with cancer undergoing definitive radiation therapy. These needs significantly affect patients' access to care and treatment outcomes. Thus, our study aimed to characterize the socioeconomic needs of patients with cancer treated at an academic institution in urban and suburban radiation clinics.Methods and Materials: A prospective, cross-sectional analysis was performed of patients undergoing curative radiation therapy for head and neck, lung/thoracic, gynecologic, or gastrointestinal malignancies using a questionnaire consolidated from prevalidated surveys. Main outcomes were differences in psychosocial needs stratified by race (Black vs non-Black) and time point (pretreatment, 1 month, 6 months, and 1 year after completion of radiation treatment). χ2 and Mann-Whitney U testing determined statistical differences between selected variables. Binary logistic regression analysis identified predictors of certain socioeconomic needs.Results: Two hundred twenty-one of 266 patients completed the survey, giving a compliance rate of 83%. Black patients were more likely to be single (79% vs 37%; P < .001), reside in zip codes with a lower median income (74% vs 42%; P < .001), and be seen at our inner-city photon location (60% vs 25%; P < .001) compared with non-Black patients. Significantly higher proportions of Black compared with non-Black patients had unmet needs regarding pain (67% vs 39%; P = .005), stress management (64.7% vs 43.3%; P = .009), transportation (64% vs 19%; P < .001), and smoking cessation (35% vs 8.7%; P < .001) when all time points were considered. On multivariate analysis, Black patients were 2.6, 2.2, 7.2, and 3.4 times more likely than non-Black patients to request assistance with pain, stress, transportation, and financial aid, respectively.Conclusions: We identified disparate psychosocial needs of our cancer population, where Black patients had greater unmet needs than non-Black patients. By doing so, we plan to develop pragmatic, targeted interventions that, when combined with guideline-concordant cancer care, can lead to improvements in cancer outcomes and quality of life before, during, and after radiation therapy. [ABSTRACT FROM AUTHOR]

Purpose To compare hyperfractionation versus standard fractionation for T2N0 vocal cord carcinoma in a randomized controlled trial. Methods and Materials Patients with T2 vocal cord cancer were stratified by substage (T2a vs T2b) and randomly assigned to receive either hyperfractionation (HFX) to 79.2 Gy in 66 fractions of 1.2 Gy given twice a day, or standard fractionation (SFX) to 70 Gy in 35 fractions given once a day. The trial was designed to detect a 55% reduction in the local failure hazard rate with 80% statistical power. Results Between April 1996 and July 2003, a total of 250 patients were enrolled. Of 239 patients analyzable for outcomes, 94% were male, 83% had a Karnofsky performance status of 90-100, and 62% had T2a tumor. Median follow-up for all surviving patients was 7.9 years (range, 0.6-13.1 years). The 5-year local control (LC) rate was 8 points higher but not statistically significant (P=.14 for HFX [78%] vs SFX [70%]), corresponding to a 30% hazard rate reduction. The 5-year disease-free survival (DFS) was 49% versus 40% (P=.13) and overall survival (OS) was 72% versus 63% (P=.29). HFX was associated with higher rates of acute skin, mucosal, and laryngeal toxicity. Grade 3-4 late effects were similar with a 5-year cumulative incidence of 8.5% (3.4%-13.6%) after SFX and 8.5% (3.4%-13.5%) after HFX. Conclusions The 5-year local control was modestly higher with HFX compared to SFX for T2 glottic carcinoma, but the difference was not statistically significant. These results are consistent with prior studies of hyperfractionation showing a benefit in local control. Substaging by T2a versus T2b carries prognostic value for DFS and OS. For cost and convenience reasons other altered fractionation schedules have been adopted in routine practice. [ABSTRACT FROM AUTHOR]

Purpose: Toxicity concerns have limited pelvic nodal prescriptions to doses that may be suboptimal for controlling microscopic disease. In a prospective trial, we tested whether image-guided intensity-modulated radiation therapy (IMRT) can safely deliver escalated nodal doses while treating the prostate with hypofractionated radiotherapy in 5½ weeks. Methods and Materials: Pelvic nodal and prostatic image-guided IMRT was delivered to 53 National Comprehensive Cancer Network (NCCN) high-risk patients to a nodal dose of 56 Gy in 2-Gy fractions with concomitant treatment of the prostate to 70 Gy in 28 fractions of 2.5 Gy, and 50 of 53 patients received androgen deprivation for a median duration of 12 months. Results: The median follow-up time was 25.4 months (range, 4.2–57.2). No early Grade 3 Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events v.3.0 genitourinary (GU) or gastrointestinal (GI) toxicities were seen. The cumulative actuarial incidence of Grade 2 early GU toxicity (primarily alpha blocker initiation) was 38%. The rate was 32% for Grade 2 early GI toxicity. None of the dose–volume descriptors correlated with GU toxicity, and only the volume of bowel receiving ≥30 Gy correlated with early GI toxicity (p = 0.029). Maximum late Grades 1, 2, and 3 GU toxicities were seen in 30%, 25%, and 2% of patients, respectively. Maximum late Grades 1 and 2 GI toxicities were seen in 30% and 8% (rectal bleeding requiring cautery) of patients, respectively. The estimated 3-year biochemical control (nadir + 2) was 81.2 ± 6.6%. No patient manifested pelvic nodal failure, whereas 2 experienced paraaortic nodal failure outside the field. The six other clinical failures were distant only. Conclusions: Pelvic IMRT nodal dose escalation to 56 Gy was delivered concurrently with 70 Gy of hypofractionated prostate radiotherapy in a convenient, resource-efficient, and well-tolerated 28-fraction schedule. Pelvic nodal dose escalation may be an option in any future exploration of potential benefits of pelvic radiation therapy in high-risk prostate cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high). Methods and Materials: Nine published prostate cancer dose escalation studies including 6,539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, γ50, is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies. Results: Nonrandomized studies produced a statistically significantly higher γ50 than randomized studies for intermediate- to high-risk patients (γ50 = 1.63 vs. γ50 = 0.93, p = 0.03) and a borderline significantly higher (γ50 = 1.78 vs. γ50 = 0.56, p = 0.08) for low-risk patients. No statistically significant difference in γ50 was found between low- and intermediate- to high-risk patients (p = 0.31). From the pooled data of low and intermediate- to high-risk patients in randomized trials, we obtain the overall best estimate of γ50 = 0.84 with 95% confidence interval 0.54–1.15. Conclusions: Nonrandomized studies overestimate the steepness of the dose–response curve as compared with randomized trials. This is probably the result of stage migration, improved treatment techniques, and a shorter follow-up in higher dose patients that were typically entered more recently. This overestimation leads to inflated expectations regarding the benefit from dose-escalation and could lead to underpowered clinical trials. There is no evidence of a steeper dose response for intermediate- to high-risk compared with low-risk patients. [Copyright &y& Elsevier]

Purpose: Local tumor recurrence remains a major problem in patients with inoperable non–small-cell lung cancer undergoing radiotherapy. We investigated the theoretical gain in the estimated tumor control probability (TCP) using an individualized maximal tolerable dose (MTD) prescription, for both conventional and accelerated fractionation schemes. Methods and Materials: For 64 non–small-cell lung cancer patients, five treatment plans were compared, dependent on the normal tissue dose constraints for the lung and spinal cord. The first two used a classic fractionation (2 Gy/d, 5 d/wk) to a total dose of 60 Gy (QDclassic) or determined by the individualized MTD (QDMTD). The third scheme assumed a hypofractionated schedule of 2.75-Gy fractions (QDhypofr). The fourth and fifth assumed hyperfractionation and acceleration (1.8 Gy twice daily, either BIDclassic or BIDMTD). The TCPs for the groups of patients were estimated. Results: The mean biologic equivalent dose in 2-Gy fractions for tumor, corrected for accelerated repopulation was significantly greater for the BIDMTD scheme (62.1 Gy) than for any other scheme (QDclassic, 47.5 Gy; QDMTD, 52.0 Gy; QDhypofr, 56.9 Gy; and BIDclassic, 56.9 Gy; p < 0.001). Although both dose-escalation (QDMTD) and hypofractionation (QDhypofr) resulted in an increase in the mean estimated TCP of 5.6% (p < 0.001) and 14.6% (p < 0.001), respectively, compared with QDclassic, the combination of escalation and acceleration (BIDMTD) improved the mean estimated TCP by 26.4% (p < 0.001). Conclusion: The results of this planning study showed a large gain in the estimated TCP using an MTD scheme with 1.8-Gy fractions BID compared with other fractionation schedules. Clinical studies implementing this concept are ongoing. [Copyright &y& Elsevier]

Purpose: To evaluate the feasibility of using tomotherapy to deliver whole brain radiotherapy with hippocampal avoidance, hypothesized to reduce the risk of memory function decline, and simultaneously integrated boost to brain metastases to improve intracranial tumor control. Methods and Materials: Ten patients treated with radiosurgery and whole brain radiotherapy underwent repeat planning using tomotherapy with the original computed tomography scans and magnetic resonance imaging–computed tomography fusion-defined target and normal structure contours. The individually contoured hippocampus was used as a dose-limiting structure (<6 Gy); the whole brain dose was prescribed at 32.25 Gy to 95% in 15 fractions, and the simultaneous boost doses to individual brain metastases were 63 Gy to lesions ≥2.0 cm in the maximal diameter and 70.8 Gy to lesions <2.0 cm. The plans were generated with a field width (FW) of 2.5 cm and, in 5 patients, with a FW of 1.0 cm. The plans were compared regarding conformation number, prescription isodose/target volume ratio, target coverage, homogeneity index, and mean normalized total dose. Results: A 1.0-cm FW compared with a 2.5-cm FW significantly improved the dose distribution. The mean conformation number improved from 0.55 ± 0.16 to 0.60 ± 0.13. Whole brain homogeneity improved by 32% (p <0.001). The mean normalized total dose to the hippocampus was 5.9 ± 1.3 Gy2 and 5.8 ± 1.9 Gy2 for 2.5- and 1.0-cm FW, respectively. The mean treatment delivery time for the 2.5- and 1.0-cm FW plans was 10.2 ± 1.0 and 21.8 ± 1.8 min, respectively. Conclusion: Composite tomotherapy plans achieved three objectives: homogeneous whole brain dose distribution equivalent to conventional whole brain radiotherapy; conformal hippocampal avoidance; and radiosurgically equivalent dose distributions to individual metastases. [Copyright &y& Elsevier]

Purpose: There is increasing interest in radiogenomics and the characterization of molecular profiles that predict normal tissue and tumor radioresponse. A meeting in Amsterdam was organized by the International Atomic Energy Agency to discuss this topic on an international basis.Methods and Materials: This report is not completely exhaustive, but highlights some of the ongoing studies and new initiatives being carried out worldwide in the banking of tumor and normal tissue samples underpinning the development of molecular marker profiles for predicting patient response to radiotherapy. It is generally considered that these profiles will more accurately define individual or group radiosensitivities compared with the nondefinitive findings from the previous era of cellular-based techniques. However, so far there are only a few robust reports of molecular markers predicting normal tissue or tumor response.Results: Many centers in different countries have initiated tissue and tumor banks to store samples from clinical trials for future molecular profiling analysis, to identify profiles that predict for radiotherapy response. The European Society for Therapeutic Radiology and Oncology GENEtic pathways for the Prediction of the effects of Irradiation (GENEPI) project, to store, document, and analyze sample characteristics vs. response, is the most comprehensive in this regard.Conclusions: The next 5-10 years are likely to see the results of these and other correlative studies, and promising associations of profiles with response should be validated in larger definitive trials. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the patterns of recurrence when selective mediastinal node irradiation based on FDG-PET scan data is used in patients with non-small-cell lung cancer (NSCLC). Methods and Materials: A prospective Phase I/II study was undertaken on 44 patients with NSCLC without detectable distant metastases on CT and FDG-PET scan, delivering either 61.2 Gy in 34 fractions over 23 days or 64.8 Gy in 36 fractions over 24 days (1.8 Gy b.i.d. with 8-h interval). Only the primary tumor and the positive mediastinal areas on the pretreatment FDG-PET scan were irradiated. Isolated nodal failure was defined as recurrence in the regional nodes outside of the clinical target volume, in the absence of in-field failure. Results: The CT and FDG-PET stage distribution was as follows: Stage I: 8 patients (18%) and 13 patients (29%); Stage II: 6 patients (14%) and 10 patients (23%); Stage IIIA: 15 patients (34%) and 7 patients (16%); Stage IIIB: 15 patients (34%) and 14 patients (32%), respectively. After a median follow-up time of 16 months (95% confidence interval [CI], 11-21 months) postradiotherapy, 11 patients (25%) developed a local recurrence. Only 1 patient (crude rate, 2.3%; upper bound of 95% CI, 10.3%), with a Stage II tumor on both CT and PET, developed an isolated nodal failure. The median actuarial overall survival was 21 months (95% CI, 14-28 months), and the median actuarial progression-free survival was 18 months (95% CI, 12-24 months). Conclusions: Selective mediastinal node irradiation based on FDG-PET scan data in patients with NSCLC results in low isolated nodal failure rates. In the Phase I component of this trial, radiation dose escalation up to 64.8 Gy in 36 fractions over 24 days is feasible. [ABSTRACT FROM AUTHOR]

Purpose: With this modeling study, we wanted to estimate the potential gain from incorporating fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning in the radiotherapy treatment planning of CT Stage N2-N3M0 non–small-cell lung cancer (NSCLC) patients. Methods and materials: Twenty-one consecutive patients with clinical CT Stage N2-N3M0 NSCLC were studied. For each patient, two three-dimensional conformal treatment plans were made: one with a CT-based planning target volume (PTV) and one with a PET-CT–based PTV, both to deliver 60 Gy in 30 fractions. From the dose–volume histograms and dose distributions on each plan, the dosimetric factors predicting esophageal and lung toxicity were analyzed and compared. For each patient, the maximal tolerable prescribed radiation dose for the CT PTV vs. PET-CT PTV was calculated according to the constraints for the lung, esophagus, and spinal cord. From these results, the tumor control probability (TCP) was estimated, assuming a clinical dose–response curve with a median toxic dose of 84.5 Gy and a γ50 of 2.0. Dose–response curves were modeled, taking into account geographic misses according to the accuracy of CT and PET in our institutions. Results: The gross tumor volume of the nodes decreased from 13.7 ± 3.8 cm3 on the CT scan to 9.9 ± 4.0 cm3 on the PET-CT scan (p = 0.011). All dose–volume characteristics for the esophagus and lungs decreased in favor of PET-CT. The esophageal V45 (the volume of the esophagus receiving 45 Gy) decreased from 45.2% ± 4.9% to 34.0% ± 5.8% (p = 0.003), esophageal V55 (the volume of the esophagus receiving 55 Gy) from 30.6% ± 3.2% to 21.9% ± 3.8% (p = 0.004), mean esophageal dose from 29.8 ± 2.5 Gy to 23.7 ± 3.1 Gy (p = 0.004), lung V20 (the volume of the lungs minus the PTV receiving 20 Gy) from 24.9% ± 2.3% to 22.3% ± 2.2% (p = 0.012), and mean lung dose from 14.7 ± 1.3 Gy to 13.6 ± 1.3 Gy (p = 0.004). For the same toxicity levels of the lung, esophagus, and spinal cord, the dose could be increased from 56.0 ± 5.4 Gy with CT planning to 71.0 ± 13.7 Gy with PET planning (p = 0.038). The TCP corresponding to these doses was estimated to be 14.2% ± 5.6% for CT and 22.8% ± 7.1% for PET-CT planning (p = 0.026). Adjusting for geographic misses by PET-CT vs. CT planning yielded TCP estimates of 12.5% and 18.3% (p = 0.009) for CT and PET-CT planning, respectively. Conclusion: In this group of clinical CT Stage N2-N3 NSCLC patients, use of FDG-PET scanning information in radiotherapy planning reduced the radiation exposure of the esophagus and lung, and thus allowed significant radiation dose escalation while respecting all relevant normal tissue constraints. This, together with a reduced risk of geographic misses using PET-CT, led to an estimated increase in TCP from 13% to 18%. The results of this modeling study support clinical trials investigating incorporation of FDG-PET information in CT-based radiotherapy planning. [Copyright &y& Elsevier]

The National Cancer Institute's Radiation Research Program, in collaboration with the Radiosurgery Society, hosted a workshop called Understanding High-Dose, Ultra-High Dose Rate and Spatially Fractionated Radiotherapy on August 20 and 21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically based clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Current incidence methods for reporting mild or moderate symptoms capture the (first) occurrence of an event and do not allow distinguishing between patients who suffer from long-lasting versus transient morbidity. This paper introduces a new methodological approach that identifies cancer survivors who have clinically relevant, long-lasting symptoms (patients with late, persistent, substantial and treatment-related symptoms, [LAPERS]).Methods and Materials: LAPERS can be evaluated in patients with baseline information and at least 3 late follow-up assessments after treatment. LAPERS identifies individual patients with a given symptom that is substantial (above a predefined clinically relevant threshold) and must be present in at least half of the follow-ups. Baseline morbidity is accounted for by requiring the median of the late symptom score to be worse than the baseline condition. The LAPERS approach was applied to 4 relevant patient-reported genito-urinary/gastrointestinal symptoms within the prospective, longitudinal EMBRACE study (An intErnational study on MRI-guided BRachytherapy in locally Advanced CErvical cancer, www.embracestudy.dk). LAPERS was compared with crude incidence and prevalence rates.Results: Within the EMBRACE cohort, 651/1044 patients (62%) had baseline and long-term follow-up available (median follow-up: 42 months). There was a considerable gap between LAPERS, crude incidence, and prevalence rates. The proportion of patients with LAPERS events was 3.8-4.8 times lower than crude incidences. The highest prevalence rates across follow-up times were 1.8-2.6 times lower than crude incidences.Conclusions: These findings indicate limitations of incidence methods for reporting substantial patient-reported symptoms because a considerable proportion of patients with symptoms do not experience them persistently over time, as they may fluctuate or get successfully treated. In contrast, the LAPERS method for longitudinal analysis identifies patients with clinically relevant, long-lasting symptoms. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this review was to evaluate the current status of reporting prospectively assessed late morbidity after curative radiation therapy in large clinical studies.Methods and Materials: A descriptive review on publications from 10 high-impact journals with a primary or partial focus on radiation therapy published between December 1, 2015, and November 30, 2017, was conducted. Publications were considered eligible if they reported prospectively assessed late morbidity after curative radiation therapy and included ≥200 patients with cancer of any type. Full text publication and supplementary material were analyzed according to items based on extensions to the Consolidated Standards of Reporting Trials (CONSORT) statement regarding reporting of harms and patient reported outcomes.Results: Overall, 802 publications were identified in PubMed; of these, 69 met the eligibility criteria. Mild and moderate morbidity were reported in 40% and 57% of publications; aggregated endpoints instead of individual endpoints were reported in 23%. In 43% of publications, crude incidence of worst grade of morbidity was used as the only statistical method for summarizing physician-assessed morbidity. Duration of morbidity or recurrent events were not reported in any of the publications.Conclusions: Comprehensive, quantitative reporting of late morbidity after radiation therapy is challenging because of the high dimensionality and time evolution of the range of normal tissue effects. The following suggestions and recommendations are proposed: (1) report on individual severity grades, including moderate and mild; (2) use patient reported outcomes in complement to physician-assessed morbidity; (3) report on individual symptoms/endpoints on top of aggregated endpoints; (4) report on duration of morbidity or recurrent events; (5) take steps toward a consensus on severity grading scales/patient questionnaires; (6) use time to event analysis and prevalence rates; (7) report or use statistical methods accounting for pretreatment morbidity when relevant. [ABSTRACT FROM AUTHOR]

Purpose: The study aims to perform joint estimation of the risk of recurrence caused by inadequate radiation dose coverage of lymph node targets and the risk of cardiac toxicity caused by radiation exposure to the heart. Delivered photon plans are compared with realistic proton plans, thereby providing evidence-based estimates of the heterogeneity of treatment effects in consecutive cases for the 2 radiation treatment modalities.Methods and Materials: Forty-one patients referred for postlumpectomy comprehensive nodal photon irradiation for left-sided breast cancer were included. Comparative proton plans were optimized by a spot scanning technique with single-field optimization from 2 en face beams. Cardiotoxicity risk was estimated with the model of Darby et al, and risk of recurrence following a compromise of lymph node coverage was estimated by a linear dose-response model fitted to the recurrence data from the recently published EORTC (European Organisation for Research and Treatment of Cancer) 22922/10925 and NCIC-CTG (National Cancer Institute of Canada Clinical Trials Group) MA.20 randomized controlled trials.Results: Excess absolute risk of cardiac morbidity was small with photon therapy at an attained age of 80 years, with median values of 1.0% (range, 0.2%-2.9%) and 0.5% (range, 0.03%-1.0%) with and without cardiac risk factors, respectively, but even lower with proton therapy (0.13% [range, 0.02%-0.5%] and 0.06% [range, 0.004%-0.3%], respectively). The median estimated excess absolute risk of breast cancer recurrence after 10 years was 0.10% (range, 0.0%-0.9%) with photons and 0.02% (range, 0.0%-0.07%) with protons. The association between age of the patient and benefit from proton therapy was weak, almost non-existing (Spearman rank correlations of -0.15 and -0.30 with and without cardiac risk factors, respectively).Conclusions: Modern photon therapy yields limited risk of cardiac toxicity in most patients, but proton therapy can reduce the predicted risk of cardiac toxicity by up to 2.9% and the risk of breast cancer recurrence by 0.9% in individual patients. Predicted benefit correlates weakly with age. Combined assessment of the risk from cardiac exposure and inadequate target coverage is desirable for rational consideration of competing photon and proton therapy plans. [ABSTRACT FROM AUTHOR]