Quantitative assessments of late radiation-induced skin and soft tissue toxicity and correlation with RTOG scales and biological equivalent dose in breast cancer

Purpose Radiation-induced toxicity (RIT) is usually assessed by inspection and palpation. Due to their subjective and unquantitative nature, objective methods are required. This study aimed to determine whether a quantitative tool is able to assess RIT and establish an underlying BED-response relationship in breast cancer. Methods Patients following seven different breast radiation protocols were recruited to this study for RIT assessment with qualitative and quantitative examination. The biologically equivalent dose (BED) was used to directly compare different radiation regimens. RIT was subjectively evaluated by physicians using the Radiation Therapy Oncology Group (RTOG) late toxicity scores. Simultaneously an objective multiprobe device was also used to quantitatively assess late RIT in terms of erythema, hyperpigmentation, elasticity and skin hydration. Results In 194 patients, in terms of the objective measurements, treated breasts showed higher erythema and hyperpigmentation and lower elasticity and hydration than untreated breasts (p < 0.001, p < 0.001, p < 0.001, p = 0.019, respectively). As the BED increased, Δerythema and Δpigmentation gradually increased as well (p = 0.006 and p = 0.002, respectively). Regarding the clinical assessment, the increase in BED resulted in a higher RTOG toxicity grade (p < 0.001). Quantitative assessments were consistent with RTOG scores. As the RTOG toxicity grade increased, the erythema and pigmentation values increased, and the elasticity index decreased (p < 0.001, p = 0.016, p = 0.005, respectively). Conclusions The multiprobe device can be a sensitive and simple tool for research purpose and quantitatively assessing RIT in patients undergoing radiotherapy for breast cancer. Physician-assessed toxicity scores and objective measurements revealed that the BED was positively associated with the severity of RIT.

QOLP-15. FEASIBILITY OF AN ELECTRONIC PATIENT REPORTED STEROID TOXICITY MONITORING PROGRAM IN PATIENTS WITH MALIGNANT GLIOMAS

OBJECTIVE To determine the feasibility of a longitudinal, electronic, patient-reported survey of steroid toxicity in patients with malignant glioma (MG). BACKGROUND Corticosteroids are frequently used for management of cerebral edema in MG, with side effects resulting from prolonged use or high dosage. Corticosteroid use is common and may negatively impact quality of life (QOL) and survival in MG. DESIGN/METHODS We prospectively enrolled patients with MG receiving neuro-oncologic care at the University of Rochester with or without their caregivers on an IRB-approved study. Subjects received 12 weekly electronic questionnaires through a secure health portal focused on symptoms of corticosteroid toxicities, dosing and functional status. Weekly toxicity scores were calculated based on the number of reported toxicities (0-17). Completed questionnaires were reviewed by a care team member to inform clinical management. Corticosteroid dosing adjustments were documented in the medical record. Feasibility was defined as an overall questionnaire completion rate of 70%. RESULTS 11 patient/caregiver pairs were enrolled (11 patients, including 9 with caregivers). Median patient age was 58. Patient tumors were glioblastoma (82%), anaplastic astrocytoma (9%) and anaplastic oligodendroglioma (9%). Phase of treatment was concurrent (55%), adjuvant (36%) and recurrence (9%). Median dexamethasone does at study start and conclusion were 4mg/day and 3mg/day. Median weekly toxicity score was 5/17 (range: 0-14). The most common toxicities were muscle weakness, sleep disturbance and weight gain and were reported by 82% of participants. Overall questionnaire completion rate was 81%. Ten percent of questionnaires resulted in clinically significant symptoms requiring follow-up from a provider. CONCLUSION Patients with MG experience frequent corticosteroid toxicities. Electronic corticosteroid toxicity monitoring is feasible in patients with MG and may lead to changes in management. Future studies are needed to assess utility of this tool and impact on QOL and survival.

Morbidity associated with the use of oxaliplatin versus mitomycin C in hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis of colorectal or appendiceal origin: a multi-institutional comparative study

Background: The raw costs of mitomycin C (MMC) and oxaliplatin for hyperthermic intraperitoneal chemotherapy (HIPEC) differ substantially. We sought to compare the morbidity and toxicity profiles associated with the use of oxaliplatin and MMC in patients undergoing cytoreductive surgery (CRS) and HIPEC for peritoneal carcinomatosis (PC) of colorectal or appendiceal origin, to evaluate whether the costeffectiveness of these 2 agents should dictate drug choice. Methods: We conducted a retrospective multi-institutional study of all patients with PC of colorectal or appendiceal origin treated with CRS-HIPEC using MMC or oxaliplatin from 2010 to 2015. Demographic, perioperative, morbidity, toxicity and cost data were compared between the 2 treatment groups and between cancer-origin subgroups. Results: Forty-two patients treated with MMC and 76 treated with oxaliplatin were included in the study. Baseline demographic and tumour characteristics were comparable in the 2 groups, except that the patients treated with MMC had higher Charlson Comorbidity Index scores. The MMC group had a higher rate of cancer of colorectal origin (76.2% v. 57.9%, p = 0.047) and longer operative times (553 v. 320 min, p < 0.001). In the subgroup of patients whose cancer was of colorectal origin, patients treated with MMC had a higher transfusion rate (50.0% v. 28.6%, p = 0.023) and lower postoperative baseline hemoglobin level (100 v. 119 g/L, p = 0.002) than those treated with oxaliplatin. There was no difference in hematologic toxicity scores after controlling for postoperative anemia. There was no difference in the rates of major complications and 90-day mortality. However, MMC was less costly than oxaliplatin ($724 v. $8928). Conclusion: MMC and oxaliplatin are both suitable agents for HIPEC and are associated with comparable morbidity and toxicity profiles, regardless of cancer origin. Thus, we propose that cost-effectiveness should ultimately dictate drug selection.

Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin

Purpose The aim was to explore the correlation between increasing doses of [6R]-5,10-methylenetetrahydrofolate (arfolitixorin) and plasma concentrations of deoxyuridine (dUr) in patients with metastatic colorectal cancer (mCRC), subjected to 5-fluorouracil (5-FU)-based chemotherapy. The aim was further to investigate the possibility to predict toxicity and clinical response during treatment using gender, age, and plasma dUr as explanatory variables. Methods Thirty-three patients from the ISO-CC-005 phase I/IIa study, which investigated safety and tolerability of arfolitixorin at four dose levels, were included. Toxicity and clinical response were evaluated after 4 cycles of chemotherapy. Plasma dUr was quantified before (0 h) and 24 h after 5-FU administration at the first (C1) and fourth (C4) cycle using LC–MS/MS. Fit modelling was used to predict toxicity and clinical response. Results The dUr levels increased with increasing arfolitixorin dose. Females had higher total and haematological toxicity scores (p = 0.0004 and 0.0089, respectively), and needed dose reduction more often than males (p = 0.012). Fit modeling showed that gender and the dUr levels at C1-0 h and C4-24 h predicted total toxicity (p = 0.0011), whereas dUr C4-0 h alone was associated with gastrointestinal toxicity (p = 0.026). Haematological toxicity was predicted by gender and age (p = 0.0071). The haematological toxicity score in combination with the dUr levels at C1-24 h and C4-24 h predicted early clinical response (p = 0.018). Conclusion The dUr level before and during administration of 5-FU and arfolitixorin was predictive for toxicity and early clinical response and could be a potential surrogate marker for thymidylate synthase inhibition in patients with mCRC. Trial registration NCT02244632, first posted on ClinicalTrials.gov on September 19, 2014

A tailored predication model to improve outcomes and mortality in geriatric indigenous women with breast cancer of western Australia.

e14000 Background: Indigenous women with breast cancer (BrCa) have higher mortality than Non-Indigenous women. Remoteness, aggressive tumour biology, treatment acceptance and compliance are all contributory factors. A retrospective study of geriatric indigenous women (aged 55 years more) with BrCa has shown high co-morbidity and treatment-related toxicity scores translating to high mortality comparing to the non-indigenous geriatric population (aged 65 years or more). An algorithm allowing prediction of risk of morbidity and mortality to enable optimisation of care for this patient group, catering to needs, values, beliefs and resources of geriatric Indigenous patients is warranted. Methods: To create a predictive algorithm and model of care based on the demographics, social environment, biology, co-morbidity burden and predicted chemotherapy toxicity scores of Indigenous women with BrCa to then be applied to a validatory prospective study.A cohort of 132 indigenous geriatric patients was identified from the Western Australian Cancer Registry from 2001 to 2010 along with remoteness matched geriatric non-Indigenous women in a 1:1 ratio. Data was collated on cancer biology, chemotherapy toxicity, mortality, co-morbidity burden (by the Charlson Co-Morbidity Index -CCI) and predicted chemotherapy toxicity (by CARG toxicity score). An algorithm was created based on these factors to identify patients at greatest risk of morbidity and mortality. Results: Elements identified as predicting morbidity and mortality were; remoteness based on distance from Perth (scored 0-3), lymph node status (scored 0-1), social isolation (scored 0-1), the Carg score (scored 0-3), and the CCI (scored 0-4). The KR Geri-Indigenous Rx Model was created using these components and scored out of 12. Conclusions: The score has been used to create three risk categories, low (1-3) intermediate (4-8) and high risk (9-12). A model of care was designed with staged increases in service elements and intensity for increasing risk category. These include the addition of Indigenous health worker review initially in clinic as well as at home during chemotherapy, initial geriatric assessment and potential geriatrician review, optimization of co-morbidities and medications, consideration of dose adjustments, social worker visits to increase services, increased surveillance, with telehealth contact and GP update with treatment planning as well as on treatment completion. A prospective study based on this model is planned.

Comparison of toxicity and effectiveness between fixed-dose and body surface area-based dose capecitabine

Background: Capecitabine is generally dosed based on body surface area (BSA). This dosing strategy has several limitations; however, evidence for alternative strategies is lacking. Therefore, we analyzed the toxicity and effectiveness of fixed-dose capecitabine and compared this strategy with a BSA-based dose of capecitabine in a large set of patients. Methods: Patients treated with fixed-dose capecitabine between 2003 and 2015 were studied. A comparable group of patients, dosed based on BSA, was chosen as a control cohort. A total of two combined scores were used: capecitabine-specific toxicity (diarrhea, National Cancer Institute Common Toxicity Criteria grade ⩾3, hand-foot syndrome ⩾2, or neutropenia ⩾2), and clinically relevant events due to toxicity, that is, hospital admission, dose reduction, or discontinuation. Per treatment regimen, patients were divided into three BSA groups based on BSA quartiles corrected for sex. Toxicity scores were compared by a Chi-square test between cohorts, and within cohorts using BSA groups. Progression-free survival (PFS) was estimated by the Kaplan–Meier method. Results: A total of 2319 patients were included (fixed dosed, n = 1126 and BSA-based dose, n = 1193). Overall, four regimens were evaluated: capecitabine-radiotherapy ( n = 1178), capecitabine-oxaliplatin ( n = 519), capecitabine triplet ( n = 181) and capecitabine monotherapy ( n = 441). The incidence of capecitabine-specific toxicity and clinically relevant events was comparable between fixed-dose and BSA-dosed patients, while a small difference (7.1%) in absolute dose was found. Both cohorts showed only a higher incidence of both toxicity scores in the lowest BSA group of the capecitabine-radiotherapy group ( p < 0.05). Subgroups of the fixed-dose cohort analyzed for PFS, showed no differences between BSA groups. Conclusions: Fixed-dose capecitabine is as comparably well tolerated and effective as BSA-based dosing and could be considered as a reasonable alternative for BSA-based dosing.

Challenges in the Clinical Application of the American Society of Clinical Oncology Value Framework: A Medicare Cost-Benefit Analysis in Chronic Lymphocytic Leukemia

Purpose: The ASCO Value Framework calculates the value of cancer therapies. Given costly novel therapeutics for chronic lymphocytic leukemia, we used the framework to compare net health benefit (NHB) and cost within Medicare of all regimens listed in the National Comprehensive Cancer Network (NCCN) guidelines. Methods: The current NCCN guidelines for chronic lymphocytic leukemia were reviewed. All referenced studies were screened, and only randomized controlled prospective trials were included. The revised ASCO Value Framework was used to calculate NHB. Medicare drug pricing was used to calculate the cost of therapies. Results: Forty-nine studies were screened. The following observations were made: only 10 studies (20%) could be evaluated; when comparing regimens studied against the same control arm, ranking NHB scores were comparable to their preference in guidelines; NHB scores varied depending on which variables were used, and there were no clinically validated thresholds for low or high values; treatment-related deaths were not weighted in the toxicity scores; and six of the 10 studies used less potent control arms, ranked as the least-preferred NCCN-recommended regimens. Conclusion: The ASCO Value Framework is an important initial step to quantify value of therapies. Essential limitations include the lack of clinically relevant validated thresholds for NHB scores and lack of incorporation of grade 5 toxicities/treatment-related mortality into its methodology. To optimize its application for clinical practice, we urge investigators/sponsors to incorporate and report the required variables to calculate the NHB of regimens and encourage trials with stronger comparator arms to properly quantify the relative value of therapies.