Common Terminology Criteria For Adverse Events V4 Research Articles

Clinical outcome data of anxiety patients treated with cannabis-based medicinal products in the United Kingdom: a cohort study from the UK Medical Cannabis Registry

RationaleCannabis-based medicinal products (CBMPs) have been identified as novel therapeutics for generalised anxiety disorder (GAD) based on pre-clinical models; however, there is a paucity of high-quality evidence on their effectiveness and safety.ObjectivesThis study aimed to evaluate the clinical outcomes of patients with GAD treated with dried flower, oil-based preparations, or a combination of both CBMPs.MethodsA prospective cohort study of patients with GAD (n = 302) enrolled in the UK Medical Cannabis Registry prescribed oil or flower-based CBMPs was performed. Primary outcomes were changes in generalised anxiety disorder-7 (GAD-7) questionnaires at 1, 3, and 6 months compared to baseline. Secondary outcomes were single-item sleep quality scale (SQS) and health-related quality of life index (EQ-5D-5L) questionnaires at the same time points. These changes were assessed by paired t-tests. Adverse events were assessed in line with CTCAE (Common Terminology Criteria for Adverse Events) v4.0.ResultsImprovements in anxiety, sleep quality and quality of life were observed at each time point (p < 0.001). Patients receiving CBMPs had improvements in GAD-7 at all time points (1 month: difference −5.3 (95% CI −4.6 to −6.1), 3 months: difference −5.5 (95% CI −4.7 to −6.4), 6 months: difference −4.5 (95% CI −3.2 to −5.7)). Thirty-nine participants (12.9%) reported 269 adverse events in the follow-up period.ConclusionsPrescription of CBMPs in those with GAD is associated with clinically significant improvements in anxiety with an acceptable safety profile in a real-world setting. Randomised trials are required as a next step to investigate the efficacy of CBMPs.

P01.07.A Neurocognitive outcomes after proton beam therapy for skull base tumours

Abstract Background Evidence suggests that Proton Beam Therapy (PBT) may lessen the risk of neurocognitive decline (NCD) by reducing the dose to the normal brain as compared to conventional photon radiotherapy (XRT). We report the incidence of moderate-severe (Grade ≥3) NCD in adults treated for skull base chordomas and chondrosarcomas within the United Kingdom’s Proton Overseas Programme (POP). Material and Methods Baseline (pre-PBT) and follow-up clinical outcomes data were prospectively collected as part of a national PBT-outcomes registry, which started in 2008 . This registry is curated by a dedicated Proton Clinical Outcomes Unit. Specifically, late toxicities ≥G3 as per CTCAE (Common Terminology Criteria for Adverse Events) v4.0 definition, occurring later than 90 days after treatment completion, were recorded. This study focuses on the incidence of memory impairment (MI) in the adult (≥25 y) cohort. Results Between 2008-2018, 141 adult patients were treated for skull base chordomas (77 patients, 54.6%) and chondrosarcomas (64 patients, 45.4%) via the POP (the majority -62.8%- treated at the University of Florida PBT Institute). Median age at treatment was 51 years (range 26-77). Median prescription dose was 73.8 GyRBE (70-75.6), with a median dose per fraction of 1.8 Gy (1.2-2.1). Of note, the median dose for chondrosarcomas was 70.2 GyRBE (70-75.6), whereas the median dose for chordomas was 73.8 GyRBE (72-75.6). Median follow up was 39 months (0-138). On clinical assessment, 4 patients (2 chordomas, 2 chondrosarcomas) were reported with G3 MI after a median time of 43 months (27-49). None of them had impaired memory at baseline, nor relevant neurological comorbidities. Median age of those who developed G3 MI was 63 y (39-70). Median prescription dose was 72.9 GyRBE (70-73.8). Plans were available for 3 of these 4 patients. Relevant dose statistics to hippocampi and temporal lobes were extracted. Dmean to the omo- and contralateral hippocampi in these 3 patient plans were: patient 1) 33.7 and 11.6 GyRBE; patient 2) 28.1 and 24.4 Gy; patient 3) 8.7 and 8.2 GyRBE, respectively. V20 to the omo- and contralateral temporal lobes in the same patients were: patient 1) 47% and 10%; patient 2) 29% and 28.7%; patient 3) 30% and 28%, respectively. Suggested constraints for these structures are: Dmean &amp;lt; 20 Gy to the hippocampi and V20Gy &amp;lt;10% to the temporal lobes. Conclusion Our results indicate that adult patients undergoing high dose radiation for radioresistant tumours may experience detrimental effects on memory. Neurocognitive baseline and follow-up assessment is not routinely performed in this age group but might be appropriate to explore which domains of cognitive function are mainly affected. Larger cohorts are warranted to establish predictive factors and better understand dose volume effect of brain structures and neurocognitive sequelae.

Concordance of the WHO, RTOG, and CTCAE v4.0 grading scales for the evaluation of oral mucositis associated with chemoradiation therapy for the treatment of oral and oropharyngeal cancers.

The ability to consistently and accurately assess oral mucositis (OM) is critical to descriptions of its incidence and severity and in evaluating the effectiveness of potential interventions. The lack of a single grading scale compounds outcome interpretation. Consequently, we assessed the concordance of three of the most commonly used OM grading criteria (World Health Organization (WHO), Radiation Therapy Oncology Group (RTOG), and the common terminology criteria for adverse events (CTCAE). Data was evaluated from two hundred patients with oropharyngeal or oral cavity cancers who underwent chemoradiation therapy and were enrolled in a double-blind, randomized, placebo-controlled trial in which trained assessors evaluated patients twice weekly. WHO, RTOG, and CTCAE scores were assigned centrally by independent evaluators blinded to the study group. Concordance among the three scales for all OM scores and severe OM scores (score ≥ 3) was defined as the percentage agreement and measured using Cohen's weighted Kappa. Of 3,578 OM assessments, 57% had identical scores for all three scales. When any score was considered, the concordance between WHO and RTOG scales was 71% (kappa 0.58; 95%CI: 0.56-0.60), 62% for the WHO and CTCAE scales (kappa 0.46; 95%CI: 0.44-0.48) and 78% for the CTCAE and RTOG scales (kappa 0.69; 95%CI: 0.68-0.71). When patients had severe OM (WHO score ≥ 3), 99.6% (521/523) of the CTCAE OM assessments had scores of 3 or 4 (kappa 0.98; 95%CI: 0.98-0.999) and 97.7% of the RTOG ones (511/523) had scores of 3 or 4 (kappa 0.69; 95%CI: 0.62-0.75). Among patients who had a WHO score of 4, 31.7% (63/199) and 96.0% (196/199) of patients had RTOG or CTCAE scores of 2 or 3, respectively. Discordance was seen with patients who exhibited mild to moderate OM or most severe OM (grade 4) as described by WHO criteria. Whereas scale selection seems less critical in studies in which general "severe mucositis" is the primary outcome, it is particularly important in accurately describing OM's clinical trajectory and the frequency and impact in its most severe forms.

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

454P - Predictors of severity and comparison of CTCAE V3.0 vs V4.3 in assessing chemotherapy induced extravasation injuries

BackgroundExtravasation is an important Adverse Event in chemotherapy, which is evaluated using CTCAE (Common Terminology Criteria for Adverse Events) grading scale. This study focuses on predicting risk factors and comparing CTCAE v3.0 and 4.3 in assessing chemotherapy-induced extravasation. MethodsAn observational study was conducted in medical oncology wards of a tertiary care hospital among adult patients receiving parenteral chemotherapy. European society of medical oncology – European oncology nursing society (ESMO-EONS) guidelines was used to classify chemotherapeutic agents. Significant risk factors were determined using binary logistic analysis. Spearman’s rank correlation coefficient and Wilcoxon’s sign rank test was applied to evaluate the difference between CTCAE v3.0 and v4.3. ResultsA total of 46 patients were enrolled in the study. According to CTCAE v4.3, amongst the 46 patients who experienced extravasation 30 presented with Grade II and the rest 16 with Grade III severity. Patients aged above 60 years showed significance (OR: 2.236, p = 0.007), and females were prone to severe extravasation injury (OR: 2.713, p = 0.010). Ambulation was found to be a major risk factor (OR: 4.66, p = 0.001). Patients with comorbidities had higher chances of getting severe extravasation (OR: 3.009, p = 0.029) and irritants were found to be predominant in worsening it (OR: 2.24, p = 0.007). The Spearman’s rank correlation coefficient established a good association in EV grades between both versions of CTCAE (rho=0.877, p = 0.000). Wilcoxon’s Rank test revealed a significant difference between the two. (p = 0.0003). ConclusionsThe severity of EV depends on early identification of symptoms, patient related factors and nature of drug. This information is pivotal to work towards a scenario of better-prevented and managed events of EV. The updated versions of CTCAE (v4.3 and v5) are better fit to use for accurate scoring of severity. Legal entity responsible for the studyAll Authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Platinum based chemotherapy in elderly patients with non-small cell lung carcinoma (NSCLC): Experience from an Indian tertiary cancer center.

e20528 Background: Instituting platinum based chemotherapy in elderly population is often associated with poor tolerance and attending toxicities. We present our limited center experience of chemotherapy in the geriatric population group. Methods: This is a retrospective single center experience of all registered patients in lung cancer clinic (LCC) in the department of medical oncology, Dr. B.R.A. IRCH, AIIMS. All histopathologically proven cases of NSCLC with age more than 70 years who received platinum based chemotherapy (single/doublet) with complete patient records were analysed. The study was carried out between November 2016 and August 2018.Data was analysed using STATA v13. Results: The cohort consisted of 25 patients who satisfied the inclusion criteria. Males comprised 84%(n = 21) of the cohort. Median age of study population was 72.7 years years (Range 70-84). 36%(n = 9) of the study population had one comorbidity while 8% (n = 2) had multiple comorbidities. 68% (n = 17) of the cohort were smokers. ECOG(Eastern cooperative oncology group) PS (performance status) 1 was seen in 48% (n = 12) and PS 2 in 32% (n = 8) and PS 3 in 16% (n = 4) respectively of the patients. Histopathologically, 48% (n = 12) of the population constituted squamous cell carcinoma while 40%(n = 10) had adenocarcinoma. 76%(n = 19) patients had Stage 4 NSCLC. Most common chemotherapy regimes used were weekly Paclitaxel carboplatin (n = 11, 44%), three weekly paclitaxel carboplatin (n = 8 , 32%) Pemetrexed carboplatin (n = 5, 20%) and gemcitabine carboplatin (n = 1, 4%). Only 12% (n = 3) could complete more than 4 cycles of chemotherapy and 3 could receive maintenance chemotherapy. Best responses according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria v1.1 achieved were complete response in 12%(n = 3), partial response in 16% (n = 4), stable disease 24%(n = 6) and progressive disease in 48%(n = 12). Most common grade 3 and 4 adverse events according to CTCAE (common terminology criteria for adverse events) v4.03 were mucositis 29.17%(n = 7), diarrhea 12% (n = 3), peripheral neuropathy 12.5 (n = 3) and hematological toxicity 16%(n = 4). Conclusions: The patient number in this study cohort is limited.However, our experience demonstrates that abbreviated therapy in elderly subgroup is fairly well tolerated. Various tools like comprehensive geriatric assessment need to be utilized to provided tailored therapy in the elderly subgroup. A prospective study is required to address the efficacy and toxicity profile of chemotherapy in this select population.

Outcome Definition Influences the Relationship Between Genetic Polymorphisms of ERCC1, ERCC2, SLC22A2 and Cisplatin Nephrotoxicity in Adult Testicular Cancer Patients.

Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009–2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (ORadj = 0.24; 95% CI: 0.08–0.70; p = 0.009) compared to genotype CC. In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (ORadj = 4.41; 95% CI: 1.96–9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (ORadj = 5.06; 95% CI: 1.69–15.16; p = 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed.

Self-evaluation of duration of adjuvant chemotherapy side effects in breast cancer patients: A prospective study.

BackgroundWe recently reported that self‐evaluation of the incidence and severity of treatment‐related side effects (TSEs) using a National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0‐based questionnaire was feasible and more informative than doctor reports in patients undergoing standard adjuvant chemotherapy for operable breast cancer. Here, we compare self‐ and doctor‐evaluated day of onset and duration of TSEs in the same population.Patients and methodsSix hundred and four patients were enrolled at 11 sites in Italy. CTCAE v4.0 definitions of grade of severity of nausea, vomiting, constipation, anorexia, dysgeusia, diarrhea, fatigue, pain, paresthesia, and dyspnea were translated into Italian and rephrased. Questionnaires were administered after the first and third chemotherapy cycles. At each time‐point, information on TSEs was extracted from the medical charts and compared to patient questionnaires.ResultsA total of 594 and 573 paired patient and doctor questionnaires were collected after cycles one and three, respectively. TSE duration was significantly longer when reported by patients compared to doctors for six and seven of ten items after cycles one and three, respectively. Due to the combined effect of doctor underreporting of TSE incidence and duration, the mean percentages of cycle days with TSEs were significantly higher for all ten items when based on patient reports. Day of onset could not be evaluated because of insufficient numbers of complete records.ConclusionsSelf‐reporting TSE duration is feasible using a CTCAE‐derived questionnaire. As doctors tend to underestimate TSE incidence and duration, patient‐reported outcomes should be incorporated into clinical practice, perhaps using eHealth technologies, to harness their potential to better estimate total TSE burden.

Abstract P2-11-20: Tolerability and outcomes of radiation therapy for breast cancer in older women: A retrospective study in 817 patients

Abstract Background: Breast cancer (BC) management in older women requires an individual approach and is becoming increasingly topical given the aging population. Postoperative radiation therapy (RT) is a standard treatment of BC after breast-conserving-surgery in most patients but its relative benefit may be counteracted by potential side-effects, especially in elderly. The aim of this study was to assess acute and long-term radiation-induced toxicities and the impact of comorbidities on outcomes in the older women treated by RT for non-metastatic breast cancer. Materials and Methods: Women aged ≥ 70 years at diagnosis, who received exclusive or postoperative RT for primary non-metastatic breast cancer, including carcinoma in situ, between 2003 and 2009 were retrieved from the Institut Curie registry. We calculated the Charlson Comorbidity Index (CCI) for each patient and collected the cardiovascular risk factors other than age (hypertension, dyslipidemia, smoking status). We analyzed overall survival (OS), progression free survival (PFS) and acute and late toxicities according to the CTCAE (Common Terminology Criteria for Adverse Events) v3.0. Results: A total of 817 patients was included in this study. Median age at diagnosis was 76.6 years [70 – 93.3]. Most patients had HR+ (hormone-receptor positive) HER2- breast cancer (83.9 %). 517 patients (62.7%) had at least one cardiovascular risk factor. With a median follow-up of 6.7 years [0.5 - 13], OS at 5 years was 86.3% CI95%[83.8 - 88.8], and PFS was 84.5% CI95%[81.9 – 87.1]. OS at 5 years was statistically different according to the Charlson index: 90.2% CI95%[87.2 – 93.3] for a CCI of 0, 84.6 % CI95%[80.5 – 88.8] for a CCI of 1, and 78% CI95%[70.5 – 86.2] for a CCI ≥ 2 (p &amp;lt; 0.001, log-rank test), respectively. Similar results were found for PFS (p &amp;lt; 0.001, log-rank test). 22.6% of patients had no toxicity; of those who experienced toxicity, most was limited to grade I or II. Only five cases (0.6%) of radiation – induced pneumonitis were reported after a median time of 16.4 months (grade I, n = 1; grade II, n = 2). One case (0.1%) of myocardial ischemia was described 14.5 months after RT. Women older than 80 years were less likely to have acute dermatitis (OR = 0.62; CI95%[0.45 - 0.85]), long-term breast pain (OR = 0.31; CI95%[0.14 - 0.62]), and long-term breast deformation (OR = 0.63; CI95%[0.42 - 0.93]) compared to patients younger than 80 years. There was no significant association found between other cardiovascular risk factors and toxicities. Conclusion: Radiation therapy for breast cancer in the older women is well-tolerated. An extended follow-up is planned in order to assess toxicities at a longer time horizon. Further studies could be envisaged to assess the quality-of-life during and after RT for breast cancer in the older patient population. Citation Format: Cao KI, Salviat F, Fourquet A, Falcou M-C, Laki F, Beuzeboc P, Savignoni A, Bazire L, Poortmans P, Kirova YM. Tolerability and outcomes of radiation therapy for breast cancer in older women: A retrospective study in 817 patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-20.

Approach for Classification and Severity Grading of Long-term and Late-Onset Health Events among Childhood Cancer Survivors in the St. Jude Lifetime Cohort.

Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAE v4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAE v4.03. This article describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained. Cancer Epidemiol Biomarkers Prev; 26(5); 666-74. ©2016 AACR.

Five-year outcomes from a prospective trial of image-guided accelerated hypofractionated proton therapy for prostate cancer

Purpose: To report 5-year outcomes of a prospective trial of image-guided accelerated hypofractionated proton therapy (AHPT) for prostate cancer.Patients and methods: 215 prostate cancer patients accrued to a prospective institutional review board-approved trial of 70Gy(RBE) in 28 fractions for low-risk disease (n = 120) and 72.5Gy(RBE) in 29 fractions for intermediate-risk disease (n = 95). This trial excluded patients with prostate volumes of ≥60 cm3 or International Prostate Symptom Scores (IPSS) of ≥15, patients on anticoagulants or alpha-blockers, and patients in whom dose-constraint goals for organs at risk (OAR) could not be met. Toxicities were graded prospectively according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. This trial can be found on ClinicalTrials.gov (NCT00693238).Results: Median follow-up was 5.2 years. Five-year rates of freedom from biochemical and clinical disease progression were 95.9%, 98.3%, and 92.7% in the overall group and the low- and intermediate-risk subsets, respectively. Actuarial 5-year rates of late radiation-related CTCAE v3.0 grade 3 or higher gastrointestinal and urologic toxicities were 0.5% and 1.7%, respectively. Median IPSS before treatment and at 4+ years after treatment were 6 and 5 for low-risk patients and 4 and 6 for intermediate-risk patients.Conclusions: Image-guided AHPT 5-year outcomes show high efficacy and minimal physician-assessed toxicity in selected patients. These results are comparable to the 5-year results of our prospective trials of standard fractionated proton therapy for patients with low-risk and intermediate-risk prostate cancer. Longer follow-up and a larger cohort are necessary to confirm these findings.

Abstract P5-11-01: Self-evaluation of duration of adjuvant chemotherapy side effects in breast cancer patients: A prospective study

Abstract Background: Collection and analysis of chemotherapy-related side-effects (CSE) is critical in the management of cancer patients (pts) both in experimental trials and in the clinical practice. Usually, most of the available conventional systems like the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) capture CSE severity but not their duration. Recently we observed that self-evaluation of CSE incidence and severity by a CTCAE v4.0-based questionnaire was feasible and potentially more informative than doctor reports in pts undergoing standard adjuvant chemotherapy (ACT) for operable breast cancer (Montemurro et al., JAMA Oncol 2; 445-452, 2016). Our questionnaire had also a section for reporting, for each of the considered CSE, day of onset, duration and whether it was still present at the time of the visit. Here we report the analysis of patient self-evaluation of CSE duration. Methods: The study prospectively enrolled 604 pts receiving ACT for operable breast cancer between January 2011 and October 2013 at 11 sites in Italy. CTCAE v4.0 definitions of grade of severity for nausea, vomiting, constipation, anorexia, dysgeusia, diarrhea, fatigue, pain, paresthesia, and dyspnea were translated into Italian and rephrased. Questionnaires were administered after the first and third cycle of chemotherapy. At each time-point, information on CSE was extracted from the medical charts and compared to patient questionnaires. Results: Overall 1177 questionnaires were collected, 596 after cycle 1 and 581 after cycle 3 of ACT. A median of 82% of the fields was completely filled-in. 594 and 573 pts-questionnaires had a corresponding MD-questionnaire. Comparison of CSE duration after cycle 1 of chemotherapy as self-assessed by pts versus that reported by doctors is summarized in the table. For all CSE, patient reported longer duration than doctors did. Comparisons of reports after cycle 3 were similar. PatientsDoctors Item (available paried data)Incidence (%)Mean duration* (SD)Incidence 8%)Mean Duration* (SD)P**Nausea (538)673.7 (3.6)401.6 (2.6)&amp;lt;0.01Vomiting (571)221.8 (1.7)111.2 (1.8)&amp;lt;0.01Constipation (546)492.7 (3.4)121.0 (2.9)&amp;lt;0.01Anorexia (563)533.8 (4.2)71.0 (1.9)&amp;lt;0.01Dysgeusia (556)505.0 (5.7)81.0 (4.1)&amp;lt;0.01Diarrhea (568)152.4 (2.8)40.9 (1.8)&amp;lt;0.01Fatigue (533)756.7 (5.2)250.9 (2.5)&amp;lt;0.01Pain (518)323.6 (4.4)100.5 (2.4)&amp;lt;0.01Paresthesia (582)232.9 (5.2)35.2 (0.8)&amp;lt;0.01Dyspnea (574)256.2 (5.6)25.0 (1.8)&amp;lt;0.01 *5% trimmed mean, ** Student T test for paired samples Conclusions: self-reporting of CSE duration is feasible in patients receiving ACT after breast cancer surgery by using a CTCAE-derived questionnaire. Because doctors tend to underestimate both incidence and duration of CSE, patient-reported outcomes should be incorporated into the clinical practice because of the potential to provide a better estimate of the total burden of CSE. Supporte by a grant of the Rete Oncologica Del Piemonte e della Valle d'Aosta. Citation Format: Galizia D, Martinello R, Cagnazzo C, Foresto M, Gallizioli S, Longo V, Berchialla P, Solinas G, Calori A, Volpone C, Parola G, Tealdi G, Ballari A, Montemurro F. Self-evaluation of duration of adjuvant chemotherapy side effects in breast cancer patients: A prospective study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-01.

Refined Hepatic Grading System Improves Risk Stratification of Long-Term Outcomes in the Patients Developing Chronic Gvhd

Background: Chronic GVHD (cGVHD) is a syndrome with diverse clinical features resembling autoimmune disorders. cGVHD affects long-term outcomes of allogeneic HCT, resulting in significant morbidity and mortality. Scoring the severity of cGVHD has been proposed with recent changes in the grading system of cGVHD based on the NIH consensus criteria (NCC) in 2015. Grading of liver GVHD is based on the severity of liver enzyme elevation both in NCC in 2005 and 2015. The cutoff of liver enzyme profiles for liver GVHD grading is arbitrarily determined but never been validated. In this study we attempted to evaluate 3 grading systems of hepatic parameters used in 1) NCC 2005, 2) NCC 2015, and 3) the common terminology criteria for adverse events (CTCAE) version 4.0. We also have adopted binary recursive partitioning (rpart) to define the optimal cut-off that provides the best risk stratification to overall survival (OS) after development of cGVHD.Methods: A retrospective review was conducted to compare the hepatic grading systems using liver enzyme parameters used in NCC 2005, NCC2015 and CTCAE v4.0. We reviewed 336 patients who developed cGVHD after allogeneic HCT performed between 2002 and 2014. Long-term outcomes including OS and non-relapse mortality (NRM) after the occurrence of cGVHD were analyzed using the 3 hepatic grading systems. Using rpart, we determined the optimal value for each component of the liver enzyme profile (i.e. AST, ALT, ALP and bilirubin level) was which could identify the best risk stratification of OS. A refined hepatic grading system was generated based on the cut off of ALP and bilirubin level proposed by rpart method, which divided the patients into three groups: low (bilirubin <14 mmol/L and ALP < 146 IU/L), intermediate (bilirubin level ≥14 mmol/L or ALP ≥ 146 IU/L) and high risk (both) . OS and NRM were also compared according to the refined hepatic grading system.Results: Out of 336 patients, 181 had liver involvement of cGVHD. The 3 year OS rate was 74.9% (66.7-81.3%) in the group developing liver GVHD, while that was 67.0% (57.7-74.7%) in the group without liver GVHD (p=0.629). There is no difference of non-relapse mortality (NRM) between patients with or without liver GVHD (14.4% vs. 17.2%; p= 0.661).In the patients developing liver GVHD, 3 hepatic grading systems were evaluated with respect to OS and NRM after onset of cGVHD. None of the 3 grading systems could stratify the patients statistically according to OS (p=0.211 for NCC 2005; p=0.423 for NCC 2015; p=0.461 for CTCAE4.0) or to NRM (p=0.615 for NCC 2005; p=0.327 for NCC 2015; p=0.941 for CTCAE v4.0). Using rpart, we found that 1) bilirubin level ≥14 mmol/L (p=0.01) and 2) ALP ≥ 146 IU/L (p=0.059) are associated with shorter OS, 2) AST and ALT levels were not associated with OS or NRM.A refined hepatic grading system was generated with assignment of a score to each risk factor. A score of 1 was assigned to bilirubin ≥14 mmol/L and ALP ≥ 146 IU/L, each. Total score was calculated with risk score 0 (n=54, 30.0%), risk score 1 (n=85, 57.2%) and risk score 2 (n=41, 22.8%). This hepatic grading system could stratify the patients according to their OS (p=0.015): 89.6% in low vs. 71.8% in intermediate vs. 58.0% in high risk group after onset of cGVHD.Then, we have applied the refined hepatic grading system into all 336 patients developing cGVHD regardless of organ involvement. As expected, the hepatic grading system can stratify 336 patients according to OS: 79.6% in low vs. 65.4% in intermediate vs. 53.9% in high risk group after onset of cGVHD (p=0.001); according to NRM: 11.9% in low vs. 17.2% in intermediate vs. 26.1% in high risk group after onset of cGVHD (p=0.089).Multivariate analysis was performed including 9 covariates including refined hepatic grading system, liver involvement of cGVHD, cGVHD subtype, cGVHD onset < 5 months, age (by decade), platelet counts, HLA match, gender mismatch, and T cell depletion, and confirmed that the refined hepatic grading system is an independent prognostic factor for OS (p=0.003, HR 0.491) in addition to cGVHD onset <5 months and HLA match.Conclusions: None of hepatic grading systems could stratify the patients according to OS/NRM after development of cGVHD. The refined hepatic grading system using bilirubin ≥14 mmol/L and ALP ≥ 146 IU/L at onset of cGVHD defined by the rpart method, could improve risk stratification of the patients developing cGVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Adverse event grading following CTCAE v3.0 underestimates hypertensive side effects in patients with glioma treated with Bevacizumab.

Anti-VEGF therapy with Bevacizumab (BEV) is widely used in cases of relapsed high-grade glioma (HGG). Arterial hypertension is a known side effect of anti-VEGF therapy. 42 Patients with relapsed HGG were treated with BEV 10mg/kg on days 1 and 15 of 28-day cycles in addition to treatment with 40mg TMZ daily until disease progression, based on magnetic resonance imaging and/or worsening of clinical status. In a retrospective analysis, hypertensive side effects were evaluated as the primary endpoint, while survival information in addition to toxicity was analyzed as secondary endpoint. Grading which employs the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 detected hypertensive events with a significantly higher sensitivity than CTCAE version 3.0. The rate of severe hypertensive events observed as CTCAE≥°3 were 9.5% in version 3.0 and 45.2% in version 4.0. The results presented here indicate that CTCAE version 3.0 may underreport the incidence and grade of BEV-induced hypertension within clinical trials. As hypertension has not only long-term, but also severe short-term side effects, we suggest that arterial hypertension under BEV should be scored according to CTCAE version 4.0 to avoid clinically relevant hypertension-related adverse events in these patients.

Stereotactic Body Radiotherapy for Elderly Patients With Medically Inoperable Pancreatic Cancer.

People over the age of 75 years account for approximately 40% of patients diagnosed with pancreatic cancer, many with comorbidities that may limit their treatment options. This study reports on the use of stereotactic body radiation therapy (SBRT) in this population. Twenty consecutively treated patients over the age of 75 with pathologically proven localized pancreatic cancer were included in this retrospective review. All had been evaluated by a multidisciplinary team as unable to tolerate surgery or combined chemoradiation therapy. Patient outcomes were analyzed to determine the safety and efficacy of SBRT in this elderly cohort. The median age was 83.2 years (minimum 77 y, maximum 90 y). Eighteen patients were treated at time of initial diagnosis, and 2 for recurrence after surgery. Eleven (55%) of the patients had an Adult Comorbidity Evaluation-27 comorbidity index score of 3 (severe) and 6 (30%) had a score of 2 (moderate). Fourteen patients were treated with 35 Gy in 5 fractions, 5 with 30 Gy in 5 fractions, and 1 patient with 36 Gy in 3 fractions. Seven (35%) patients had common terminology criteria for adverse events (CTCAE) V4.0 toxicity grade of 1-2, and 3 patients had a CTCAE V4.0 toxicity grade of 3-4, 2 with dehydration, and 1 had episodes of gastrointestinal bleeding. Three patients recurred locally, 10 had distant metastases, 4 of whom were found on the first posttreatment scan. Median overall survival was 6.4 months (95% confidence interval, 3.5-10.8 mo). Median recurrence-free survival was 6.8 months (95% confidence interval, 1.3-23.5 mo). Two patients survived >23 months. SBRT for pancreatic cancer appears to be a safe and effective method for treatment of elderly patients, even in the setting of severe comorbidities.

Quantitative tool to evaluate the somatic burden due to chemotherapy-induced adverse events: the somatic burden score.

Although there are several established methods like the Common Terminology Criteria for Adverse Events (CTCAE), heretofore, no objective, quantitative measurement exists for the somatic burden due to chemotherapy-induced adverse events (SB-CHINAE). We developed the Somatic Burden Score (SBS-AE) that combines the severity grade and duration of an AE. This paper describes the development and validation of the SBS-AE. SBS-AE's calculation was based on the number of days of CTCAE grades of a particular AE. The target value was the weighted, relative duration of an AE grade using CTCAE v3.0. We applied the SBS-AE in 64 patients with hematological malignancies and high-dose chemotherapy (HDC). The ratio measurement scale of the SBS-AE allows all statistical measures using SBS-AE, as all necessary mathematical operations are defined for it. We calculated an overall-SBS-HDC, defined as the total SB-CHINAE of HDC. To determine SBS-AE's criterion and construct validity, three self-rating scales and one clinician rating scale were used (German Clinical Trials Register, Main ID: DRKS00003453). The SBS-AE's criterion validity could be verified both with statistical significance and at least medium-to-large effects (p < 0.05, Cohen's d > 0.79, f (2) > 0.18). The quantitative measured SB-CHINAE was equally associated with subjectively assessed physical health-related quality of life (0.15 ≤ R (2) ≤ 0.49), objectively evaluated toxicities (0.48 ≤ R (2) ≤ 0.67), transfusion-dependent thrombocytopenia, and anemia (Cohen's d > 0.89). Patients' somatic burden of HDC was 5.8-fold greater compared with standard chemotherapy regimens. The SBS-AE indicates psychometric and clinical properties and may prove useful in the future design of cancer clinical trials and supportive care interventions inside of the inpatient setting.

Attention must be paid: adverse event reporting needs improvement

The insightful review by Russell and Colevas discusses various tools used in the reporting of adverse events, highlighting the need for consistent adverse event reporting guidelines [1]. With clinical trial data being larger and more complex than ever, accurate toxicity reporting is necessary to assess a drug’s efficacy and safety profile – the two factors that serve as an integral base for regulatory decision making. Both in and out of clinical trial settings, reporting rates are low and adverse event reports are often incomplete. To date there is no standard approach for adverse event reporting. The Common Terminology Criteria for Adverse Events (CTCAE) serves as a lexicon used to define an adverse event and its severity. In clinical trials, reports are graded in terms of the CTCAE v4.0 terminology – this system uses definitions from the Medical Dictionary for Regulatory Activities (MedDRA). To improve medication safety initiatives, established reporting guidelines are needed. In oncology trials, adverse events may arise from iatrogenic causes or from an underlying disease. The CTCAE v4.0 defines an adverse event as “any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medical treatment or procedure.” Adverse events can be symptoms, exam finding, abnormal laboratory values, or irregular radiology reports. A serious adverse event is life threatening, requires hospitalization, results in disability, or results in an abnormality or birth defect. In the CTCAE v4.0, adverse events are organized into System Organ Classes. These groups are based on anatomical, physiological or etiological criteria and are easily mapable to the MedDRA. The terminology was agreed upon by the National Cancer Institute and the European Medicines Agency. The severity of the adverse event is ranked on a 1–5 scale; one being the least severe and five resulting in death. This scale is not included in the MedDRA definitions – as it is unique to the CTCAE. Adverse event categories cover a wide array of laboratory values and clinical findings. Russell et al. examine adverse event reporting in clinical trials and provided eight recommendations for clinical investigators [1]: ■ Collect all serious adverse events without regard to causality;

Effect of CTCAE v4 grading of hypertension on reported toxicity in advanced cancer patients receiving vascular endothelial growth factor (VEGF)-targeting agents.

e15600 Background: The NCI Common Terminology Criteria for Adverse Events (CTCAE) system changed to version 4 in 2009, and several AE categories underwent changes in grading (Gr), including HTN. As many anti-neoplastic agents, particularly those targeting VEGF are associated with HTN, changing in the grading system may result in changes to maximum tolerated or recommended phase II doses in early dose-escalation studies or overall HTN AE reporting across all studies. Methods: We initially reviewed individual patient data of a multicenter phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC), which graded AE’s using CTCAE v3. Individual patient (pt) data was reviewed and HTN AE’s were re-graded using CTCAE v4 criteria for up to 12 cycles of therapy on study. A separate (confirmatory) data set in pts with metastatic colorectal cancer (CRC) treated on a phase IIIb study of regorafenib was subsequently analyzed. Results: In the RCC study, only 1 of 23 pts with complete source documents available had stable highest HTN Gr across both CTCAE versions. In the CRC study, 0 of 8 pts had stable Gr. Table 1 compares each individual’s highest CTCAE v3 versus v4 grading of HTN in each study. Across both studies, all pts had HTN AE’s using CTCAE v4. Only 1 pt maintained grading using both versions (Gr 3), with 30 (96.8%) changing grades. Four (12.9%) moved from Gr 0 to Gr 1, fifteen (48.4%) from Gr 0 to Gr 2, five (16.1%) from Gr 1 to Gr 2, one from Gr 1 to Gr 3, and six (19.4%) from Gr 2 to Gr 3. Conclusions: Re-classification of grading in this study demonstrates that only 3.2% maintained stable grading of HTN across systems, with 51.6% increasing by 2 grades. The change in AE reporting criteria has the potential to significantly impact results of clinical trials. This may be particularly important with VEGF-targeted agents, with emerging data pointing towards HTN as a pharmacodynamic marker in pts with RCC, and may affect dosing and AE reporting of other drugs with blood pressure effects. Clinical trial information: NCT00121251, NCT01538680. [Table: see text]

Association of CTCAE v4 grading of hypertension with toxicity in patients with renal cancer receiving vascular endothelial growth factor (VEGF)-targeting agents.

447 Background: The NCI Common Terminology Criteria for Adverse Events (CTCAE) system underwent a change to version 4 in May 2009. In addition to system re-organization, several AE categories underwent changes in grading, including hypertension (HTN). As many anti-neoplastic agents, particularly those targeting VEGF are associated with HTN, changing in the grading system may result in changes to maximum tolerated or recommended phase II doses (MTD or RP2D) in dose-escalation studies using classic trial schemas (such as 3+3 design). Methods: We reviewed individual patient data of a phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC). The phase I portion of the study was conducted to define the dose-limiting toxicity and RP2D of the combination (Am J Clin Oncol, 2011). The phase II portion further assessed efficacy as defined by objective response rate. Initial grading of AE’s during this study used CTCAE v3. Individual patient data was reviewed and HTN AE’s were re-graded using CTCAE v4 criteria for up to 12 cycles of therapy on study. Results: Of 28 pts enrolled, 23 (82.1%) had complete source documents available for the complete evaluation of HTN. The table compares each individual’s highest CTCAE v3 versus v4 grading of HTN on study. All pts had HTN AE’s using CTCAE v4. Only 1 pt maintained grading using both versions (Gr 3), with 22 (95.7%) changing grades. Two (8.7%) moved from Gr 0 to Gr 1, fourteen 60.9(%) from Gr 0 to Gr 2, four (17.4%) from Gr 1 to Gr 2, one from Gr 1 to Gr 3, and two (8.7%) from Gr 2 to Gr 3. Conclusions: Re-classification of grading in this study demonstrates that only 4.3% maintained stable grading of HTN across systems, with 65.2% increasing by 2 grades. The change in AE reporting criteria has the potential significantly impact results of clinical trials. This may be particularly important with VEGF-targeted agents, with emerging data pointing towards HTN as a pharmacodynamic marker in pts with RCC, and may affect dosing of other drugs with blood pressure effects, including CYP17 inhibitors for prostate cancer. Clinical trial information: NCT00121251. [Table: see text]

Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Based Hybrid Patient and Physician Questionnaire for Head and Neck (HN) Radiotherapy Symptom Reporting

HN patients often experience multiple worsening symptoms during radiotherapy (RT), and some are unable to speak or have hoarseness. Physician driven systematic patient symptom questioning and obtaining comprehensible answers from the HN cancer patient can be challenging. To more efficiently monitor patient symptoms, a CTCAE v4.0 based hybrid patient and physician weekly questionnaire was created.