Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study.

OBJECTIVE: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl). METHODS: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event. RESULTS: AUC statistics (range, 0.52-0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively. CONCLUSION: The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.

Palliative Medical Management of Inoperable Malignant Bowel Obstruction With "Triple Therapy": Dexamethasone, Octreotide, and Metoclopramide.

CONTEXT: Malignant bowel obstruction (MBO) is a complication of advanced malignancy. For inoperable patients, symptoms are often treated using analgesics, anticholinergics, and anti-emetics. There are, however, few published guidelines for the medical management of MBO. OBJECTIVE: To measure the effect of the combination of dexamethasone, octreotide, and metoclopramide ("triple therapy") in patients with MBO, compared to patients who received none of the 3 medications ("no drug therapy"). METHODS: A retrospective cohort study of patients with MBO admitted in a single-center comprehensive cancer center. Patients who received dexamethasone, octreotide, and metoclopramide during their hospitalization for treatment of inoperable MBO were selected for analysis. Patients were excluded if they received a venting gastric tube. Rate of de-obstruction as well as time to de-obstruction were measured. RESULTS: There were 20 patients identified who received all 3 drugs of interest, and 29 patients identified who received none of the 3 medications. There was no statistically significant difference in rates of de-obstruction between the 2 groups, though there was a non-significant trend toward patients who received triple therapy were more likely to reach de-obstruction, compared to patients who had no drug therapy (95% vs. 83%, p = 0.379); there was no significant difference in adjusted analysis. CONCLUSION: In patients with inoperable MBO, there was no statistically significant difference in rates of de-obstruction with triple drug therapy compared to patients who received none of the 3 drugs, though the study may not have been powered to detect a difference and further investigation is warranted.

Daily Time of Radiation Treatment Is Associated with Subsequent Oral Mucositis Severity during Radiotherapy in Head and Neck Cancer Patients.

BACKGROUND: Limited treatment options are available for oral mucositis, a common, debilitating complication of cancer therapy. We examined the association between daily delivery time of radiotherapy and the severity of oral mucositis in patients with head and neck cancer. METHODS: We used electronic medical records of 190 patients with head and neck squamous cell carcinoma who completed radiotherapy, with or without concurrent chemotherapy, at Roswell Park Comprehensive Cancer Center (Buffalo, NY) between 2015 and 2017. Throughout a 7-week treatment course, patient mouth and throat soreness (MTS) was self-reported weekly using a validated oral mucositis questionnaire, with responses 0 (no) to 4 (extreme). Average treatment times from day 1 until the day before each mucositis survey were categorized into seven groups. Multivariable-adjusted marginal average scores (LSmeans) were estimated for the repeated- and maximum-MTS, using a linear-mixed model and generalized-linear model, respectively. RESULTS: Radiation treatment time was significantly associated with oral mucositis severity using both repeated-MTS (n = 1,156; P = 0.02) and maximum-MTS (n = 190; P = 0.04), with consistent patterns. The severity was lowest for patients treated during 8:30 to <9:30 am (LSmeans for maximum-MTS = 2.24; SE = 0.15), increased at later treatment times and peaked at early afternoon (11:30 am to <3:00 pm, LSmeans = 2.66-2.71; SEs = 0.16/0.17), and then decreased substantially after 3 pm. CONCLUSIONS: We report a significant association between radiation treatment time and oral mucositis severity in patients with head and neck cancer. IMPACT: Although additional studies are needed, these data suggest a potential simple treatment time solution to limit severity of oral mucositis during radiotherapy without increasing cost.

Two- Versus Four-Times Weekly Acupuncture-Like Transcutaneous Electrical Nerve Stimulation for Treatment of Radiation-Induced Xerostomia: A Pilot Study.

Background: Xerostomia occurs in the majority of patients undergoing chemoradiation therapy for head and neck cancer (HNC). Acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) treatment has been studied as an encouraging modality to improve salivary function and related symptoms. The purpose of this study was to compare ALTENS treatment by using a four-times weekly schedule for 6 weeks versus a twice-weekly schedule for 12 weeks with a validated xerostomia scale at 15 months from the start of ALTENS treatment. Materials and Methods: This single-center randomized study was conducted in 30 patients treated with radiotherapy with or without chemotherapy for HNC between 2014 and 2017, who had at least grade 1 or 2 symptomatic dry mouth (xerostomia) according to CTEP NCI Common Terminology Criteria for Adverse Events (CTCAE version 4.0). These patients were randomly assigned to receive ALTENS four-times weekly for 6 weeks or two-times weekly for 12 weeks. The University of Michigan 15-item Xerostomia-related Quality of Life Scale (XeQoLS) was administered at 6, 9, 15, and 21 months from the start of ALTENS treatment. A random-effects generalized linear model was used to model the overall XeQoLS score at the 15-month endpoint; adjusted for a random time effect, a fixed treatment arm, and interaction of time and treatment. Comparison between arms was based on a 0.05 nominal significance level. Results: XeQoLS decreased for all patients (although not statistically for each arm) from a mean of 22 and 21 at baseline (in the four times per week and twice weekly arms) to 12 in both arms at 15 months, with no difference between arms (p = 0.68). There were no attributable grade 1-3 adverse events. Arms were balanced for age, gender, race, and baseline xerostomia. Conclusions: This study demonstrates that both ALTENS regimens are safe, well tolerated, and appear to be equally effective. We now routinely make ALTENS units available for home use.

Buprenorphine for Cancer Pain in Patients With Nonmedical Opioid Use: A Retrospective Study at a Comprehensive Cancer Center.

BACKGROUND: Outpatients with cancer commonly have nonmedical opioid use (NMOU) behaviors and use opioids to dull emotional and existential suffering. Buprenorphine is often used for cancer pain due to less reported euphoria when compared to other opioids. METHODS: A retrospective review was done in patients who were prescribed buprenorphine for cancer pain. Pain scores were reported on a Likert pain scale of 1 to 10. Nonmedical opioid use was defined as patients taking opioids for emotional pain at or above the maximum prescribed amount. RESULTS: For 16 patients, the mean pain score prior to buprenorphine (pain pre) was 8.3 (Standard deviation (Std) 1.6), and the mean pain score on follow-up post-buprenorphine (pain post) was 6.1 (Std 2.3) with a reduction in mean pain score (pain change) of -2.0 (Std 2.9, P = .059). Those patients without NMOU had a pain prescore of 9.5 (Std 1.0) and pain post of 4.3 (Std 2.5) with a mean pain change of -5.0 (Std 1.7, P = .20). The mean pain change in those with chemical coping (-1.3/Std 2.7), illicit drug use (-2.8/Std 1.0), or psychiatric comorbidity (-2.4/Std 2.7) were reduced after buprenorphine, however, not statistically significant. Outpatient rotation to buprenorphine was well tolerated. CONCLUSIONS: The pain score in those patients without NMOU was significantly lower after rotation to buprenorphine than those with NMOU. We deduce that in those with NMOU, it is more challenging to achieve pain relief with buprenorphine. Overall, for all patients, rotation to buprenorphine resulted in a marginally significantly reduced pain score.

The Trials (and Tribulations) of Complementary and Alternative Medicine in Oncology.

Two decades following the creation of the Office of Cancer Complementary and Alternative Medicine at the National Cancer Institute, the status of complementary and alternative medicine (CAM) research within oncology remains opaque. To better understand the landscape of CAM studies in oncology, we identified CAM-related phase III randomized controlled trials (RCTs) through ClinicalTrials.gov and compared these CAM trials to all non-CAM oncologic RCTs. Pearson χ2 testing was used to compare proportions across groups; all tests were two-sided. Comparing the 25 identified CAM RCTs with 739 non-CAM RCTs, CAM studies were more likely to be sponsored by a cooperative group (64.0% vs 28.6%, P < .001) and less likely to be industry funded (8.0% vs 76.5%, P < .001). CAM trials disproportionately excluded disease-related outcomes as endpoints (8.0% vs 84.6%, P < .001), were unsupported by prior early-phase data (55.0% vs 96.1%, P < .001), and did not meet the primary endpoint (8.7% vs 53.0%, P < .001). Given the observed relationship between encouraging pilot data and subsequent phase III trial success, we contend that future CAM RCTs may yield more promising findings if better supported by appropriately designed and well-characterized early-phase signals.

TP53 Status as a Determinant of Pro- vs Anti-Tumorigenic Effects of Estrogen Receptor-Beta in Breast Cancer.

BACKGROUND: Anti-tumorigenic vs pro-tumorigenic roles of estrogen receptor-beta (ESR2) in breast cancer remain unsettled. We investigated the potential of TP53 status to be a determinant of the bi-faceted role of ESR2 and associated therapeutic implications for triple negative breast cancer (TNBC). METHODS: ESR2-TP53 interaction was analyzed with multiple assays including the in situ proximity ligation assay. Transcriptional effects on TP53-target genes and cell proliferation in response to knocking down or overexpressing ESR2 were determined. Patient survival according to ESR2 expression levels and TP53 mutation status was analyzed in the basal-like TNBC subgroup in the Molecular Taxonomy of Breast Cancer International Consortium (n = 308) and Roswell Park Comprehensive Cancer Center (n = 46) patient cohorts by univariate Cox regression and log-rank test. All statistical tests are two-sided. RESULTS: ESR2 interaction with wild-type and mutant TP53 caused pro-proliferative and anti-proliferative effects, respectively. Depleting ESR2 in cells expressing wild-type TP53 resulted in increased expression of TP53-target genes CDKN1A (control group mean [SD] = 1 [0.13] vs ESR2 depletion group mean [SD] = 2.08 [0.24], P = .003) and BBC3 (control group mean [SD] = 1 [0.06] vs ESR2 depleted group mean [SD] = 1.92 [0.25], P = .003); however, expression of CDKN1A (control group mean [SD] = 1 [0.21] vs ESR2 depleted group mean [SD] = 0.56 [0.12], P = .02) and BBC3 (control group mean [SD] = 1 [0.03] vs ESR2 depleted group mean [SD] = 0.55 [0.09], P = .008) was decreased in cells expressing mutant TP53. Overexpressing ESR2 had opposite effects. Tamoxifen increased ESR2-mutant TP53 interaction, leading to reactivation of TP73 and apoptosis. High levels of ESR2 expression in mutant TP53-expressing basal-like tumors is associated with better prognosis (Molecular Taxonomy of Breast Cancer International Consortium cohort: log-rank P = .001; hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.84, univariate Cox P = .02). CONCLUSIONS: TP53 status is a determinant of the functional duality of ESR2. Our study suggests that ESR2-mutant TP53 combination prognosticates survival in TNBC revealing a novel strategy to stratify TNBC for therapeutic intervention potentially by repurposing tamoxifen.

Accuracy of American College of Surgeons National Surgical Quality Improvement Program Universal Surgical Risk Calculator in Predicting Complications Following Robot-Assisted Radical Cystectomy at a National Comprehensive Cancer Center.

Introduction: There is paucity of literature about the validation of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP®) surgical risk calculator for prediction of outcomes after robot-assisted radical cystectomy (RARC). We sought to evaluate the accuracy of the ACS NSQIP surgical risk calculator in the patients who underwent RARC at our institute. Methods: We retrospectively reviewed our prospectively maintained database for patients who underwent RARC between 2005 and 2017. Accuracy of the ACS NSQIP surgical risk calculator was assessed, by comparing the rate of actual complication events after surgery with the receiver operating characteristics curve analysis by calculating the fractional area under the curve (AUC) and the Brier score (BS). We utilized the code number 51595 and 51596 in the ACS NSQIP calculator for the patients undergoing radical cystectomy and reconstructed with the ileal conduit and neobladder, respectively. Results: A total of 462 patients were included in this study: 99 (22%) had diabetes, 302 (66%) had hypertension requiring medication, and 241 (52%) were classified as high American Society of Anesthesiologists (≥3) class. The actual observed rates of any complication and serious complications were 48% and 11%, vs 29% and 25% predicted by the ACS NSQIP, respectively. The actual mean length of hospital stay (10.6 ± 7.8 days) was longer compared with the predicted length (8.5 ± 1.6 days). AUC values were low and the BSs were high for any complication (AUC: 0.50 and BS: 0.29), serious complication (AUC: 0.53 and BS: 0.12), urinary tract infection (AUC: 0.61 and BS: 0.14), renal insufficiency (AUC: 0.64 and BS: 0.08), return to operation room (AUC: 0.58 and BS: 0.07), and early readmission (AUC: 0.55 and BS: 0.11, respectively). Conclusions: The ACS NSQIP calculator demonstrated low accuracy in predicting postoperative outcomes after RARC. These findings highlight the need for development of procedure- and technique-specific RARC calculators.

Factors influencing patient pathways for receipt of cancer care at an NCI-designated comprehensive cancer center.

BACKGROUND: Within the field of oncology, increasing access to high quality care has been identified as a priority to reduce cancer disparities. Previous research reveals that the facilities where patients receive their cancer care have implications for cancer outcomes. However, there is little understanding of how patients decide where to seek cancer care. This study examined the factors that shape patients' pathways to seek their cancer care at a National Cancer Institute-designated comprehensive cancer center (NCI-CCC), and differences in these factors by race, income and education. METHODS: In-depth interviews and survey questionnaires were administered to a random sample of 124 patients at one NCI-CCC in the Northeast US. In-depth interview data was first analyzed qualitatively to identify themes and patterns in patients' pathways to receive their cancer care at an NCI-CCC. Logistic Regression was used to examine if these pathways varied by patient race, income, and education. RESULTS: Two themes emerged: following the recommendation of a physician and following advice from social network members. Quantitative data analysis shows that patient pathways to care at an NCI-CCC varied by education and income. Patients with lower income and education most commonly sought their cancer care at an NCI-CCC due to the recommendation of a physician. Patients with higher income and education most commonly cited referral by a specialist physician or the advice of a social network member. There were no statistically significant differences in pathways to care by race. CONCLUSIONS: Our findings show that most patients relied on physician recommendations or advice from a social network member in deciding to seek their cancer care at an NCI-CCC. Due to the role of physicians in shaping patients' pathways to the NCI-CCC, initiatives that strengthen partnerships between NCI-CCCs and community physicians who serve underserved communities may improve access to NCI-CCCs.