Risk Factors For Late Toxicity Research Articles

A multicenter cooperative group study of late effects after high-risk neuroblastoma: COG ALTE15N2—LEAHRN study.

10002 Background: Aggressive therapies for high-risk neuroblastoma (HRNBL) have resulted in increased survival, but late effects have not been well-characterized. Methods: Comprehensive cross-sectional evaluation of health outcomes in HRNBL survivors enrolled on the COG Neuroblastoma Biology Study after 1/1/2000 and ≥ 5 years from primary diagnosis, using medical record abstraction and in-person clinical assessments. Descriptive and multivariable analyses identified extent of and risk factors for late toxicity. Results: There were 375 participants from 88 COG centers, 205 (55%) male; 92 (26%) non-white; 45 (13%) Hispanic. Median age at neuroblastoma diagnosis was 2.5 years (range: 0.2-15.8), at enrollment was 12.0 years (range: 5.0-24.0). All had received chemotherapy; 94% received cisplatin (median dose: 398 mg/m2). Other exposures included: radiation (95%), isotretinoin (91%), anti-GD2 antibody therapy (64%), MIBG (7%), single (79%) or tandem autologous transplantation (ASCT; 20%). ASCT conditioning included: Busulfan/Melphalan (BuMel) (18%), Carboplatin/Etoposide/Melphalan (CEM) (73%), Thiotepa/Cytoxan (19%), and total body irradiation (5%). Severe ototoxicity (requiring hearing aids) was observed in 58% of participants. Physician-reported late effects included hypothyroidism (17%), pulmonary hypertension (1%), congestive heart failure (2%), and hypertension (6%). Pulmonary Function Studies revealed restrictive lung disease [RLD - Total Lung Capacity < 70% predicted] in 8% of subjects. Laboratory study showed elevated creatinine in 7% and Hemoglobin A1c in 7%. Growth failure (height Z-score < -1.7) was observed in 34%. Subsequent malignant neoplasms (SMN) developed in 15 participants (4%; 4 sarcomas, 3 MDS/t-AML, single instance of 8 other malignancies). Adjusting for sex, follow-up time, age, and race, there were no differences in risk of SMN, severe ototoxicity, growth failure, or RLD for participants who received BuMel vs. CEM-based condtioning, or among those who received anti-GD2 antibody therapy vs. those who did not. Use of carboplatin during ASCT was not assocoiated with increased ototoxicity risk for any category of cisplatin induction dose. Comparing subjects who received CEM as a component of tandem ASCT (vs. single CEM), there was increased risk of growth failure [OR (95%CI) = 4.2(2.1, 8.4); p < 0.0001], but not RLD. Exposure to isotretinoin was not associated with increased risk of growth failure. Further multivariable analyses will be presented, exploring risks for late toxicity associated with conditioning regimens, radiation therapy, surgical approaches, and acute and chronic complications of therapy. Conclusions: The burden of late toxicity in HRNBL survivors is substantial. Anti-GD2 immunotherapy and isotretinoin do not appear to be associated with SMN, ototoxicity, growth failure, or RLD.

A Comparison between Patient- and Physician-Reported Late Radiation Toxicity in Long-Term Prostate Cancer Survivors.

Simple SummaryRadiotherapy is widely used as treatment for localized prostate cancer. Due to a high incidence and a good survival after treatment, a large number of prostate cancer survivors are at risk of developing late radiation toxicity. Symptoms may significantly affect quality of life; therefore, the monitoring of toxicities and evaluating their impact are increasingly important matters. Toxicities have always been assessed by physicians, but there is a growing interest in the use of questionnaires to be completed by patients themselves, so-called patient-reported outcome measures. The aim of this study was to compare both outcomes in long-term prostate cancer survivors, and to determine which outcome correlates best with a biological predictor of late radiation toxicity. In symptomatic patients, we found a low agreement; patients assigned greater severity to symptoms than the trial physician assistant did. Neither outcome correlated with the biological predictor. Consideration of both perspectives seems warranted to provide the best care.Patient-reported outcome measures (PROMs) are advocated for the monitoring of toxicity after radiotherapy. However, studies comparing physician- and patient-reported toxicity show low concordance. In this study, we compared physician- and patient-reported toxicity in long-term prostate cancer survivors after radiotherapy, and we determined the correlation with a presumable risk factor for late toxicity: γ-H2AX foci decay ratio (FDR). Patients formerly included in a prospective study were invited to participate in this new study, comprising one questionnaire and one call with a trial physician assistant. Concordance was calculated for seven symptoms. Gamma-H2AX FDRs were determined in ex vivo irradiated lymphocytes in a previous analysis. Associations between FDR and long-term prevalence of toxicity were assessed using univariable logistic regression analyses. The 101 participants had a median follow-up period of 9 years. Outcomes were discordant in 71% of symptomatic patients; in 21%, the physician-assessed toxicity (using CTCAE) was higher, and, in 50%, the patients reported higher toxicity. We did not find a correlation between presence of toxicity at long-term follow-up and FDR. In conclusion, patients assigned greater severity to symptoms than the trial physician assistant did. Consideration of both perspectives may be warranted to provide the best care.

A Deep Learning Approach Validates Genetic Risk Factors for Late Toxicity After Prostate Cancer Radiotherapy in a REQUITE Multi-National Cohort.

Background: REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side effects and improve QUalITy of lifE in cancer survivors) is an international prospective cohort study. The purpose of this project was to analyse a cohort of patients recruited into REQUITE using a deep learning algorithm to identify patient-specific features associated with the development of toxicity, and test the approach by attempting to validate previously published genetic risk factors.Methods: The study involved REQUITE prostate cancer patients treated with external beam radiotherapy who had complete 2-year follow-up. We used five separate late toxicity endpoints: ≥grade 1 late rectal bleeding, ≥grade 2 urinary frequency, ≥grade 1 haematuria, ≥ grade 2 nocturia, ≥ grade 1 decreased urinary stream. Forty-three single nucleotide polymorphisms (SNPs) already reported in the literature to be associated with the toxicity endpoints were included in the analysis. No SNP had been studied before in the REQUITE cohort. Deep Sparse AutoEncoders (DSAE) were trained to recognize features (SNPs) identifying patients with no toxicity and tested on a different independent mixed population including patients without and with toxicity.Results: One thousand, four hundred and one patients were included, and toxicity rates were: rectal bleeding 11.7%, urinary frequency 4%, haematuria 5.5%, nocturia 7.8%, decreased urinary stream 17.1%. Twenty-four of the 43 SNPs that were associated with the toxicity endpoints were validated as identifying patients with toxicity. Twenty of the 24 SNPs were associated with the same toxicity endpoint as reported in the literature: 9 SNPs for urinary symptoms and 11 SNPs for overall toxicity. The other 4 SNPs were associated with a different endpoint.Conclusion: Deep learning algorithms can validate SNPs associated with toxicity after radiotherapy for prostate cancer. The method should be studied further to identify polygenic SNP risk signatures for radiotherapy toxicity. The signatures could then be included in integrated normal tissue complication probability models and tested for their ability to personalize radiotherapy treatment planning.

Hypofractionated whole breast radiotherapy with or without hypofractionated boost in early stage breast cancer patients: a mono-institutional analysis of skin and subcutaneous toxicity.

Our study evaluated skin and subcutaneous toxicity analyzing its correlation with patient- and treatment-related factors in a large mono-institutional series of women with early stage breast cancer treated with adjuvant hypofractionated whole breast radiotherapy (WBRT) with or without a sequential hypofractionated boost (HB). Two hundred and nineteen patients, median age 62years, received adjuvant hypofractionated WBRT in 16 fractions to a total dose of 42.4Gy. Patients with negative prognostic factors received a HB of 2.65Gy for 4 or 5 (patients with focal positive surgical margins) fractions. Systemic adjuvant treatments were hormonal therapy (HT) and/or chemotherapy (CHT) and/or Trastuzumab. Toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE 4.03) scale at 5th, 10th, 16th, 20th day from the start of radiotherapy (RT) and 1, 6 and 12months after the end of RT. Univariate and multivariate analysis estimated toxicity predictive factors. No case of treatment interruption and no acute or late G3 toxicities occurred. In the univariate analysis HB administration resulted a risk factor for acute toxicity, while CHT administration and number of excised lymph nodes ≥ 10 resulted a risk factor for late toxicity. In the multivariate analysis none of the evaluated factors emerged a risk factor for acute and/or late toxicity. Our results confirmed that hypofractionated WBRT even followed by a HB resulted safe and well tolerated. Longer follow-up is warranted to estimate late toxicity and treatment outcomes.

Long-term complications of definitive chemoradiotherapy for esophageal cancer using the classical method.

Chemoradiation therapy is widely used to treat both inoperable and operable patients, and is less invasive than surgery. Although the number of long-term survivors who have received chemoradiation therapy is increasing, the long-term toxicity pattern and cumulative incidence of toxicity regarding this modality are poorly understood. Classically, chemoradiation therapy for esophageal cancer consists of an anterior–posterior field and a subsequent oblique boost field. We retrospectively analyzed patients who were treated with definitive chemoradiation therapy for esophageal cancer using this classical method from 1999 to 2008. For the assessment of toxicity, the National Cancer Institute Common Toxicity Criteria Version 3.0 was adopted. A total of 101 patients were analyzed. The median follow-up time was 16 months for all patients and 62 months for the surviving patients. Eleven patients experienced late toxicities of ≥Grade 3. Two patients died of late toxicities. The 3- and 5-year cumulative incidences for the first late cardiopulmonary toxicities of ≥Grade 3 were 17.4% and 20.8%, respectively. Cardiopulmonary effusions were observed within the first 3 years of completion of the initial treatment in seven out of eight patients. Sudden death and cardiac ischemia were observed over a 10-year period. Older age was found to be a risk factor for late toxicity after definitive chemoradiation therapy for esophageal cancer. Substantial toxicities were observed in patients who had received chemoradiation therapy for esophageal cancer using the classical method. To minimize the incidence of late toxicity, more sophisticated radiation techniques may be useful.

Radiotherapy for early-stage prostate cancer in men under 70 years of age.

To demonstrate that radiotherapy (RT) is a valid alternative to surgery in men ≤70 years old with localized prostate cancer. From 1988 to 2009, 214 patients with T1-2 N0 M0 prostate cancer were treated with RT. The effects of patient- and treatment-related risk factors on toxicity were investigated. Median follow-up was 105 months (range 14.2-180). The 5-, 10-, and 15-year biochemical relapse-free survival for all 214 patients was 80%, 61.9%, and 57.5%, respectively. In bivariate analysis, age (≤65 vs 65-70 years) was not a significant factor for biochemical relapse, while radiation dose was (p = 0.05) in multivariate analysis. Cancer-specific survival rates at 5, 10, and 15 years were 98.4%, 93.2%, and 69.7%, respectively. Median overall survival (OS) was 167 months (95% confidence interval 147.3-186.7). The OS rates at 5, 10, and 15 years were 91.8%, 75.8%, and 42.5%, respectively. Acute genitourinary (GU) and gastrointestinal (GI) toxicities occurred in 105 (49%) and 98 patients (45.8%), respectively, with only 2 cases of grade III GI toxicity. Late GU and GI toxicities occurred in 17 (7.9%) and 20 (9.3%) patients, respectively, with 1 grade III GI toxicity and 2 grade III GU toxicities. Risk factors for late toxicity were age and RT dose and technique, which were unrelated to acute toxicity. Age ≤70 years does not consistently confer a negative prognosis for localized prostate cancer. Radiotherapy appears to be a viable alternative to surgery, offering excellent long-term cancer control.

Renal impairment and late toxicity in germ-cell cancer survivors

BackgroundTreatment with bleomycin–etoposide–cisplatin (BEP) impairs renal function and increases the risk of late cardiovascular disease (CVD) and death. We investigated the influence of BEP on glomerular filtration rate (GFR) and assessed the importance of GFR changes on CVD and death in a large cohort of germ-cell cancer survivors. Patients and methodsBEP-treated patients (N = 1206) were identified in the Danish DaTeCa database, and merged with national registers to identify late toxicity. GFR were measured (51Cr-EDTA clearance) before and after treatment and at 1, 3 and 5-year follow-up. The influence of BEP on GFR was evaluated with a linear mixed model. Risk factors for late toxicity were identified by a landmark analysis adjusting for covariates. The cohort was compared with the background population with standardized hospitalization/mortality rates. ResultsGFR changed (ΔGFR) -11.3%, -15.4% and -25.9% after three, four and five+ cycles of BEP. For patients with impaired renal function before treatment the changes were 4.3%, 0.0% and -12.8%, respectively. During follow-up a significant rebound of GFR was documented. Compared with the background population, all patients, irrespective of renal function, had an increased risk of CVD and death. This risk depended on chronic kidney disease stage before treatment but not after treatment. ΔGFR had no influence on risk of late toxicity [death: hazard ratio (HR) 1.06, P = 0.50; CVD: HR 0.97, P = 0.61]. ConclusionsRenal function after BEP is closely related to number of cycles, but the changes in GFR are partly reversible and have no impact on risk of CVD or death.

Esophageal Dose Tolerance to Hypofractionated Stereotactic Body Radiation Therapy: Risk Factors for Late Toxicity

To identify factors associated with grade ≥3 treatment related late esophageal toxicity after lung or liver stereotactic body radiation therapy (SBRT). This was a retrospective review of 52 patients with a planning target volume within 2 cm of the esophagus from a prospective registry of 607 lung and liver SBRT patients treated between 2005 and 2011. Patients were treated using a risk-adapted dose regimen to a median dose of 50 Gy in 5 fractions (range, 37.5-60 Gy in 3-10 fractions). Normal structures were contoured using Radiation Therapy Oncology Group (RTOG) defined criteria. The median esophageal point dose and 1-cc dose were 32.3 Gy (range, 8.9-55.4 Gy) and 24.0 Gy (range, 7.8-50.9 Gy), respectively. Two patients had an esophageal fistula at a median of 8.4 months after SBRT, with maximum esophageal point doses of 51.5 and 52 Gy, and 1-cc doses of 48.1 and 50 Gy, respectively. These point and 1-cc doses were exceeded by 9 and 2 patients, respectively, without a fistula. The risk of a fistula for point doses exceeding 40, 45, and 50 Gy was 9.5% (n=2/21), 10.5% (n=2/19), and 12.5% (n=2/16), respectively. The risk of fistula for 1-cc doses exceeding 40, 45, and 50 Gy was 25% (n=2/9), 50% (n=2/4), and 50% (n=2/4), respectively. Eighteen patients received systemic therapy after SBRT (11 systemic chemotherapy, and 6 biologic agents, and 1 both). Both patients with fistulas had received adjuvant anti-angiogenic (vascular endothelial growth factor) agents within 2 months of completing SBRT. No patient had a fistula in the absence of adjuvant VEGF-modulating agents. Esophageal fistula is a rare complication of SBRT. In this series, fistula was seen with esophageal point doses exceeding 51 Gy and 1-cc doses greater than 48 Gy. Notably, however, fistula was seen only in those patients who also received adjuvant VEGF-modulating agents after SBRT. The potential interaction of dose and adjuvant therapy should be considered when delivering SBRT near the esophagus.

Outcome of a phase II prospective study on partial breast irradiation with interstitial multi-catheter high-dose-rate brachytherapy

Background and purposePartial breast irradiation (PBI) is an alternative to whole-breast irradiation after breast-conserving surgery in selected patients. Until the results of randomized phase III studies are available, phase II studies inform about PBI. We report the 5year results of a phase II prospective study with PBI using interstitial multi-catheter high-dose-rate brachytherapy (ClinicalTrials.gov Identifier: NCT00499057). MethodsHundred patients received PBI (4Gy, twice a day for 4days, until 32Gy). Inclusion criteria were: age ⩾40years, infiltrating carcinoma without lobular histology, ductal in situ carcinoma, tumor size ⩽2.5cm, negative surgical margins and axillary lymph nodes. ResultsAt a median follow-up of 60months late toxicity occurred in 25 patients; the 5-year probability of freedom from late toxicity was 72.6% (95% CI: 63.7–81.7). Tamoxifen was the only significant risk factor for late toxicity. Cosmetic results, judged by physicians and patients, were good/excellent in 98 patients. Three local relapses (1 true, 2 elsewhere) and 1 regional relapse occurred. The 5-year probability of local or regional relapse-free survival was 97.7% (95% CI: 91.1–99.4) and 99.0% (95% CI: 92.9–99.8), respectively. ConclusionPBI with interstitial multi-catheter brachytherapy is associated with low relapse and late toxicity rates.

Impact of neoadjuvant androgen ablation and other factors on late toxicity after external beam prostate radiotherapy

Purpose To evaluate the late toxicity profile of prostate cancer patients treated with external beam radiotherapy, to investigate the possible risk factors for late toxicity, and to determine whether neoadjuvant androgen ablation (NAA) is a factor. Methods and materials The study population consisted of 1192 patients with ≥24 months' follow-up. Late GI and GU toxicities were scored with a modified Radiation Therapy Oncology Group/Subjective, Objective, Management, and Analytic scale. All patients were treated with external beam radiotherapy (52.5 Gy in 20 fractions to 72 Gy in 36 fractions), using either conventional or three-dimensional conformal techniques. Of the 1192 patients, 40% received NAA (median 5 months). Risk factors investigated on multivariate analysis were age, past medical history, use of pelvic fields, dose, fractionation, use and duration of neo- and adjuvant androgen ablation, and acute toxicity (Grade 2 or greater). Results The median follow-up for the group was 49 months (range 24–105). The incidence of late Grade 2-3 GI or GU toxicity was 30% at 5 years (GI 12% and GU 20%). The incidence of late Grade 3 GI or GU toxicity was 8% at 5 years (GI 2.7% and GU 5.5%). No Grade 4 toxicity occurred. The risk factors of significance in relation to the development of late Grade 3 GU toxicity were coexisting GU disease ( p = 0.02), prior transurethral resection of the prostate or transurethral resection of bladder tumor ( p <0.0001), and presence of acute GU toxicity ( p = 0.012). For late Grade 3 GI toxicity, short-term (≤2 months) NAA ( p = 0.0002) and coexisting GI disease ( p = 0.017) were risk factors. Conclusion Short-term (≤2 months) NAA, but not longer durations of NAA, increases the risk of developing Grade 3 GI late toxicity. The possible mechanism of this phenomenon is unclear.

Impact of neoadjuvant androgen ablation and other factors on late toxicity following external beam prostate radiation

Purpose/Objective: 1.To evaluate the late toxicity profile of prostate cancer patients treated with external beam radiotherapy (EBRT).2.To investigate possible risk factors for late toxicity, and to determine if neoadjuvant androgen ablation (NAA) was a factor.