Sexual dysfunction among early-onset colorectal cancer survivors: Sex-specific correlates of sexual health discussions between patients and providers.

PURPOSE: To examine the prevalence of female sexual dysfunction (FSD), male erectile dysfunction (ED), and the prevalence and correlates of sexual health discussions between early-onset CRC survivors and their health care providers. METHODS: An online, cross-sectional survey was administered in partnership with a national CRC advocacy organization. Respondents (n = 234; diagnosed < 50 years, 6-36 months from diagnosis/relapse) were colon (36.8%) and rectal (63.3%) cancer survivors (62.5% male). The Female Sexual Function Index (FSFI-6) was used to measure FSD, and the International Index of Erectile Function (IIEF-5) was used to measure ED. Survivors reported whether a doctor communicated with them about sexual issues during/after treatment. RESULTS: Among females (n = 87), 81.6% had FSD (mean FSFI-6 score = 14.3 [SD±6.1]). Among males (n = 145), 94.5% had ED (mean IIEF-5 score = 13.6 [SD±3.4]). Overall, 59.4% of males and 45.4% of females reported a sexual health discussion. Among the total sample, older age of diagnosis and relapse were significantly associated with reporting a discussion, while female sex was negatively associated with reporting a sexual health discussion. Among males, older age at diagnosis and relapse, and among females, older age of diagnosis, were significantly associated with reporting a sexual health discussion. CONCLUSION: The prevalence of FSD and ED were high (8 in 10 females reporting FSD, almost all males reporting ED), while reported rates of sexual health discussion were suboptimal (half reported discussion). Interventions to increase CRC provider awareness of patients at risk for not being counseled are needed to optimize long-term health outcomes.

Colorectal cancer statistics, 2017.

Colorectal cancer (CRC) is one of the most common malignancies in the United States. Every 3 years, the American Cancer Society provides an update of CRC incidence, survival, and mortality rates and trends. Incidence data through 2013 were provided by the Surveillance, Epidemiology, and End Results program, the National Program of Cancer Registries, and the North American Association of Central Cancer Registries. Mortality data through 2014 were provided by the National Center for Health Statistics. CRC incidence rates are highest in Alaska Natives and blacks and lowest in Asian/Pacific Islanders, and they are 30% to 40% higher in men than in women. Recent temporal patterns are generally similar by race and sex, but differ by age. Between 2000 and 2013, incidence rates in adults aged ≥50 years declined by 32%, with the drop largest for distal tumors in people aged ≥65 years (incidence rate ratio [IRR], 0.50; 95% confidence interval [95% CI], 0.48-0.52) and smallest for rectal tumors in ages 50 to 64 years (male IRR, 0.91; 95% CI, 0.85-0.96; female IRR, 1.00; 95% CI, 0.93-1.08). Overall CRC incidence in individuals ages ≥50 years declined from 2009 to 2013 in every state except Arkansas, with the decrease exceeding 5% annually in 7 states; however, rectal tumor incidence in those ages 50 to 64 years was stable in most states. Among adults aged <50 years, CRC incidence rates increased by 22% from 2000 to 2013, driven solely by tumors in the distal colon (IRR, 1.24; 95% CI, 1.13-1.35) and rectum (IRR, 1.22; 95% CI, 1.13-1.31). Similar to incidence patterns, CRC death rates decreased by 34% among individuals aged ≥50 years during 2000 through 2014, but increased by 13% in those aged <50 years. Progress against CRC can be accelerated by increasing initiation of screening at age 50 years (average risk) or earlier (eg, family history of CRC/advanced adenomas) and eliminating disparities in high-quality treatment. In addition, research is needed to elucidate causes for increasing CRC in young adults. CA Cancer J Clin 2017. © 2017 American Cancer Society. CA Cancer J Clin 2017;67:177-193. © 2017 American Cancer Society.

Safety of pressurized intraperitoneal aerosolized chemotherapy in biliary cancer patients with peritoneal metastases.

Biliary tract cancers are a rare diagnosis with a rising incidence. Up to 20% of patients have peritoneal metastases, resulting in symptoms of ascites, abdominal pain and potential bowel obstruction. A standard of care systemic treatment comprises gemcitabine, cisplatin and durvalumab (gem/cis/durva). However, the clinical benefit among patients with peritoneal metastases remains unknown. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivers chemotherapy directly to the peritoneal space, which could potentially improve efficacy with minimal systemic toxicity. We describe the design of a Phase I study investigating PIPAC with nab-paclitaxel plus systemic gem/cis/durva among biliary tract cancer patients with peritoneal metastases who have not received prior systemic treatment. The primary end point is safety of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva.Clinical Trial Registration: NCT05285358 (ClinicalTrials.gov).

[Box: see text].

Racial and ethnic disparities in self-reported general and mental health status among colorectal cancer survivors: impact of sociodemographic factors and implications for mortality-a SEER-CAHPS study.

PURPOSE: Patient-reported outcomes are recognized as strong predictors of cancer prognosis. This study examines racial and ethnic differences in self-reported general health status (GHS) and mental health status (MHS) among patients with colorectal cancer (CRC). METHODS: A retrospective analysis of Medicare beneficiaries between 1998 and 2011 with non-distant CRC who underwent curative resection and completed a Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey within 6-36 months of CRC diagnosis. Analysis included a stepwise logistic regression to examine the relationship between race and ethnicity and fair or poor health status, and a proportional hazards model to determine the mortality risk associated with fair or poor health status. RESULTS: Of 1867 patients, Non-Hispanic Black (OR 1.56, 95% CI 1.06-2.28) and Hispanic (OR 1.48, 95% CI 1.04-2.11) patients had higher unadjusted odds for fair or poor GHS compared to Non-Hispanic White patients, also Hispanic patients had higher unadjusted odds for fair or poor MHS (OR 1.92, 95% CI 1.23-3.01). These relationships persisted after adjusting for clinical factors but were attenuated after subsequently adjusting for sociodemographic factors. Compared to those reporting good to excellent health status, patients reporting fair or poor GHS or MHS had an increased mortality risk (OR 1.52, 95% CI 1.31-1.76 and OR 1.63, 95% CI 1.34-1.99, respectively). CONCLUSION: Racial and ethnic differences in GHS and MHS reported after CRC diagnosis are mainly driven by sociodemographic factors and reflect a higher risk of mortality. Identifying unmet biopsychosocial needs is necessary to promote equitable care.

Improving survival in metastatic colorectal cancer through optimized patient selection.

The systemic treatment options for patients with metastatic colorectal cancer have recently expanded with the US Food and Drug Administration approval of fruquintinib being added to previously approved trifluridine/tipiracil with or without bevacizumab and regorafenib. These therapies are recommended for use based on the initial clinical trials that focused on their safety and efficacy in extending overall survival of patients with refractory metastatic disease, as well as later studies, including the ReDOS study that confirmed the dose-escalation strategy of regorafenib to be key in optimizing duration of therapy and preventing side effects. Although more research is needed on how to sequence third-line therapies, data from real-world studies showed that switching from regorafenib to trifluridine/tipiracil with or without bevacizumab allowed patients to have a chemotherapy-free break and led to improved survival, suggesting that there may be a benefit for using regorafenib first. Current treatment guidelines state that each therapy can be given before or after the others. Generally, sequencing considerations in the refractory setting include multiple variables such as tumor characteristics, toxicities, factors that are important to the patient, response to prior lines of therapy, and extent of disease.

Associations Between Patient Experience With Care, Race and Ethnicity, and Receipt of CRC Treatment Among SEER-CAHPS Patients With Multiple Comorbidities.

BACKGROUND: Patients with colorectal cancer (CRC) and multiple comorbidities are less likely to receive guideline-concordant treatment (GCT), a disparity exacerbated by racial and ethnic disparities in GCT. Yet, positive patient experiences with care are associated with more appropriate care use. We investigated associations between patient experiences with care, race and ethnicity, and receipt of GCT for CRC among older adults with multiple comorbidities. METHODS: We used SEER-Consumer Assessment of Healthcare Providers and Systems (CAHPS) data to identify participants diagnosed with CRC from 2001 to 2017 at age ≥67 years with additional chronic conditions. Stage-specific GCT was identified following recommendations in the NCCN Guidelines for Colon and Rectal Cancer. Patient experiences with care were identified from CAHPS surveys. Multivariable log-binomial regression estimated associations between race and ethnicity and receipt of GCT by experiences with care. RESULTS: A total of 2,612 patients were included. Those reporting excellent experience with getting care quickly were 5% more likely to receive GCT than those reporting less-than-excellent experience (relative risk [RR], 1.05; 95% CI, 1.04-1.05). When reporting less-than-excellent experience with getting care quickly, non-Hispanic Black (NHB) patients were less likely than non-Hispanic White (NHW) patients to receive GCT (RR, 0.80; 99.38% CI, 0.78-0.82), yet NHB patients were more likely to receive GCT than NHW patients when reporting excellent experience (RR, 1.05; 99.38% CI, 1.02-1.09). When reporting less-than-excellent experience with getting needed care, Hispanic patients were less likely than NHW patients to receive GCT (RR, 0.91; 99.38% CI, 0.88-0.94), yet Hispanic patients were more likely to receive GCT than NHW patients when reporting excellent experience (RR, 1.06; 99.38% CI, 1.03-1.08). CONCLUSIONS: Although excellent patient experience among those with multiple comorbidities may not be strongly associated with receipt of GCT for CRC overall, improvements in experiences of accessing care among NHB and Hispanic patients with CRC and additional comorbidities may aid in mitigating racial and ethnic disparities in receipt of GCT.

Fertility Preservation Discussions Between Young Adult Rectal Cancer Survivors and Their Providers: Sex-Specific Prevalence and Correlates.

BACKGROUND: Young adults (YA) diagnosed with rectal cancer are disproportionately impacted by the gonadotoxic effects of treatment and potential subsequent infertility. OBJECTIVE: The purpose of this study was to characterize the prevalence of fertility preservation measures used, reasons why such measures were not used, and correlates of discussion between providers and YA rectal cancer survivors. DESIGN: An online, cross-sectional survey was administered on the Facebook page of a national colorectal cancer (CRC) advocacy organization. Eligible participants were rectal cancer survivors diagnosed before age 50, between 6 and 36 months from diagnosis or relapse, and based in the US. RESULTS: Participants were 148 rectal cancer survivors. Over half of the survivors reported that their doctor did not talk to them about potential therapy-related fertility complications. Only one-fifth of survivors banked sperm (males) or eggs/embryos (females) prior to their cancer therapy. Older age at diagnosis and greater quality of life were significantly associated with a higher likelihood of fertility discussions among males. Greater quality of life was significantly associated with a higher likelihood of fertility discussion among females. CONCLUSIONS: These findings indicate that the majority of YA rectal cancer survivors do not receive, or cannot recall, comprehensive cancer care, and help to identify patients with rectal cancer who may be at risk for inadequate fertility counseling. Clinicians should provide proper counseling to mitigate this late effect and to ensure optimal quality of life for YA rectal cancer survivors.

Telemedicine in Cancer Care Beyond the COVID-19 Pandemic: Oncology 2.0?

PURPOSE OF REVIEW: This paper summarizes early experiences of telemedicine during the COVID-19 pandemic, the patient and physician experience, limitations in accessibility introduced by telemedicine, and the opportunities and anticipated sustained role of telemedicine for cancer care. RECENT FINDINGS: Research from a wide range of oncology facilities consistently demonstrates the feasibility of delivering telemedicine services over audio (telephone) and/or video platforms. Emerging work highlights that telemedicine is well suited for a subset of patients and clinical settings and that there are methods by which current disparities could potentially be ameliorated. Several current uncertainties limit the broad applicability of telemedicine longitudinally. Early responses to the pandemic that included rapid introduction of telemedicine demonstrated the feasibility of audio- and video-based platforms that achieved promising utility, while simultaneously demonstrating disparities based on patient characteristics and infrastructural support. Its long-term role will likely depend greatly on reimbursement and regulatory reform.

Temporal trends in self-reported general and mental health status among colorectal cancer patients: racial/ethnic disparities in a population-based analysis.

PURPOSE: Patient-reported outcomes are essential to patient-centered cancer care. We sought to determine the relationships between colorectal cancer (CRC) diagnosis and trends in self-reported general health status (GHS) and mental health status (MHS) among racial/ethnic groups. METHODS: We used population-based Surveillance, Epidemiology, and End Results (SEER)-Consumer Assessment of Healthcare Providers and Systems (CAHPS) data to identify CRC patients diagnosed from 1996 to 2011 who reported GHS and/or MHS on a CAHPS survey within 6 years before or after diagnosis and were 65 or older at survey completion. Multivariable logistic regression assessed relationships of patient race/ethnicity and CRC diagnosis with the odds of reporting fair or poor GHS or MHS. RESULTS: Five thousand five hundred forty-five patients reported GHS and/or MHS within 6 years before CRC diagnosis and 4,604 reported GHS and/or MHS within 6 years after diagnosis. 80.9% were non-Hispanic white (NHW), 7.1% were non-Hispanic black (NHB), 6.7% were Hispanic, and 5.3% were non-Hispanic Asian. Being diagnosed with CRC was associated with increased odds of reporting fair or poor GHS (OR = 1.55, 95% CI = 1.40-1.72) and MHS (OR = 1.33, 95% CI = 1.13-1.58). For GHS, this trend held for all race/ethnicities except NHBs, and for MHS, this trend held for NHWs and Hispanics only. CONCLUSION: CRC diagnosis is an important driver of increased likelihood of fair and poor GHS and MHS, but the relationship is complicated by effect modification by race/ethnicity. Efforts to further understand the race/ethnicity-specific relationships between CRC diagnosis and declines in GHS and MHS are necessary to promote equitable care for all patients.

Understanding the patient experience in hepatocellular carcinoma: a qualitative patient interview study.

PURPOSE: This study aimed to elucidate the patient experience of hepatocellular carcinoma (HCC) to guide patient-centered outcome measurement in drug development. METHODS: Patients with HCC participated in qualitative interviews to elicit disease-related signs/symptoms and impacts, using discussion guides developed from literature searches and discussions with oncologists. Interview participants rated the disturbance of their experiences (0-10 scale). A conceptual model was developed and mapped against patient-reported outcome (PRO) instruments identified from database reviews. RESULTS: Interviews were conducted with 25 individuals with HCC (68% were men; median age: 63 years; 12% Barcelona clinic liver cancer (BCLC) stage A; 32% stage B; and 56% stage C) in the USA. Fifty-one HCC-related concepts were identified from the interviews and were grouped into eight sign/symptom categories (eating behavior/weight changes; extremities [arms, legs]; fatigue and strength; gastrointestinal; pain; sensory; skin; other) and four impact categories (emotional; physical; cognitive function; other) for the conceptual model. The most prevalent and disturbing experiences across the disease stages were fatigue/lack of energy and emotional impacts such as frustration, fear, and depression. Abdominal pain and skin-related issues were particularly common and disturbing in individuals with HCC stage C. The EORTC QLQ-C30 and HCC18 were identified as commonly used PRO instruments in HCC studies and captured the relevant signs/symptoms associated with the patient experience. CONCLUSION: Patients with HCC reported a range of signs/symptoms and impacts that negatively affect daily functioning and quality of life. Including PRO measures in HCC clinical trials can provide meaningful patient perspectives during drug development.

Role of enterocyte-specific gene polymorphisms in response to adjuvant treatment for stage III colorectal cancer.

OBJECTIVES: The enterocyte subtype of colorectal cancer (CRC) responds favorably to oxaliplatin-based adjuvant treatment for stage III CRC. We examined the clinical significance of single-nucleotide polymorphisms (SNPs) in enterocyte-related genes MS4A12 and CDX2 in response to adjuvant treatment for stage III CRC. PATIENTS AND METHODS: A total of 350 patients with stage III CRC were included: 274 received adjuvant treatment with surgical resection (discovery cohort) and 76 received surgery alone (control cohort). In the discovery cohort, 68 patients received FOLFOX and 206 received oral fluoropyrimidine. SNPs were analyzed by PCR-based direct sequencing. RESULTS: In the discovery cohort, the MS4A12 rs4939378 G/G variant was associated with lower 5-year survival than any A allele [70% vs. 90%, univariate: hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.03-5.06, P = 0.035; multivariate: HR 2.58, 95% CI 1.15-5.76, P = 0.021]. Patients with the CDX2 rs3812863 G/G variant had better overall survival than those with any A allele, although this was not significant in multivariate analysis (5 year-survival: 95% vs. 82%, univariate: HR 0.34, 95% CI 0.12-0.97, P = 0.034; multivariate: HR 0.39, 95% CI 0.13-1.11, P = 0.078). The SNPs did not show significant association with overall survival in the control cohort, and significant interaction was observed between MS4A12 genotypes and groups (P = 0.007). CONCLUSIONS: Our findings suggest that MS4A12 and CDX2 gene polymorphisms may predict outcome in stage III CRC. However, the clinical significance of SNPs for response to oxaliplatin may differ by tumor stage.

Preemptive Versus Reactive Topical Clobetasol for Regorafenib-Induced Hand-Foot Reactions: A Preplanned Analysis of the ReDOS Trial.

BACKGROUND: Hand-foot skin reaction (HFSR) is the most common regorafenib-induced adverse event and is in need of effective prevention and palliation. MATERIALS AND METHODS: The Regorafenib Dose Optimization Study (ReDOS), a four-arm, previously published trial with a 1:1:1:1 randomization scheme, was analyzed in a manner in keeping with the original protocol to assess whether clobetasol 0.05% cream (a corticosteroid) applied to the palms and soles twice per day for 8 weeks was more effective when prescribed preemptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the first two cycles of regorafenib. RESULTS: Sixty-one patients received preemptive clobetasol, and 55 received reactive clobetasol. Groups were balanced on demographics. Over the first two cycles, no evidence of HFSR occurred in 30% with preemptive clobetasol versus 13% with reactive clobetasol (p = .03). During the first cycle, 54% and 45% of patients had no HFSR with preemptive and reactive clobetasol, respectively (p = .35). During the second cycle, 33% and 15% had no HFSR with preemptive and reactive clobetasol, respectively (p = .02). During the second cycle, rates of grade 1, 2, and 3 HFSR were 30%, 8%, and 3%, respectively, with preemptive clobetasol and 43%, 18%, and 7%, respectively, with reactive clobetasol (p = .12). Patient-reported outcomes showed HFSR compromised nearly all activities of daily living with worse quality of life in patients who received reactive versus preemptive clobetasol. No clobetasol-induced adverse events were reported. CONCLUSION: Preemptive clobetasol might lessen regorafenib-induced hand-foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort. IMPLICATIONS FOR PRACTICE: Regorafenib causes hand-foot skin reactions. Preemptive clobetasol, a high-potency topical corticosteroid, appears to lessen the severity of this adverse event. Although further study is needed, the favorable adverse event profile of this intervention might prompt clinicians to discuss this option with their patients.

Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer.

Colorectal cancer (CRC) can be classified into subtypes based on gene expression signatures. Patients with stage III enterocyte subtype of the CRC Assigner classifier have been shown to benefit from oxaliplatin adjuvant therapy. Here, we investigated whether single nucleotide polymorphisms (SNPs) in two enterocyte subtype-related genes, MS4A12 and CDX2, could predict the efficacy of oxaliplatin in first-line treatment for patients with metastatic CRC (mCRC). Three cohorts of patients were included: a discovery cohort receiving FOLFOX ± bevacizumab (BEV) (n = 146), a validation cohort receiving FOLFOXIRI + BEV (n = 230), and a control cohort receiving FOLFIRI + BEV (n = 228). SNPs were analyzed by PCR-based direct sequencing. In the discovery cohort, MS4A12 rs4939378 and CDX2 rs3812863 were identified as potential markers of efficacy. In the validation cohort, any G allele of MS4A12 rs4939378 was associated with longer progression-free survival (PFS) than the A/A variant in both univariate analysis (12.4 vs. 10.9 months, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49-0.99, P = 0.033) and multivariable analysis (HR 0.65, 95%CI 0.44-0.97, P = 0.035) in patients expressing wild-type KRAS, but not mutant KRAS. In contrast, longer PFS was observed for patients expressing the CDX2 rs3812863 G/G variant than any A allele in univariate analysis (32.3 vs. 10.3 months, HR 0.39, 95%CI 0.19-0.81, P = 0.004) only in patients expressing mutant KRAS. These findings were not observed in the control cohort. Thus, MS4A12 and CDX2 SNPs may have utility as predictive biomarkers of response to oxaliplatin-based treatment in mCRC patients.

Phase II Trial of Neoadjuvant Bevacizumab with Modified FOLFOX7 in Patients with Stage II and III Rectal Cancer.

LESSONS LEARNED: Neoadjuvant bevacizumab with modified FOLFOX7 without radiation failed to meet the goal of pathological complete response rate; however, the low number of recurrence and disease-free survival in this population, with predominantly stage III, is encouraging and worth further exploration. The racial distribution of the patient population, as well as a wait time of more than 4 weeks after last chemotherapy, may have contributed to the findings. BACKGROUND: Combination chemotherapy in lieu of radiation in rectal adenocarcinoma is under exploration in multiple trials. We evaluated the efficacy of neoadjuvant FOLFOX + bevacizumab in patients (pts) with clinical stage II and III disease. METHODS: Pts received six cycles of bevacizumab (5 mg/kg) and modified FOLFOX7 (oxaliplatin 85 mg/m2 , leucovorin 20 mg/m2 , and fluorouracil [5-FU] 2,400 mg/m2 ). Surgical resection was performed 6-8 weeks after completion of treatment and upon confirmation of nonmetastatic disease. We employed a Simon two-stage design and required three pathological complete responses (pCR) in the first 18 pts, with a prespecified pCR rate of 25% before moving to the next stage. RESULTS: Seventeen pts enrolled; 65% at stage III. Median age was 57 (35-79), 65% were male, 47% were Hispanic, 35% were white, and 18% were Asian. All pts but one completed six cycles of therapy. One pCR was observed (6%), and 11 of 17 (65%) pts had pathological downstaging. One patient experienced systemic recurrence and remains on treatment. Probability of disease-free survival (DFS) at 5 years is 0.94 (SE, 0.06). CONCLUSION: The study failed to meet the required three pCRs in the first 18 pts. The DFS in this population is encouraging and supports the hypothesis that select pts with rectal cancer may be spared from radiation.

Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study.

BACKGROUND: Regorafenib confers an overall survival benefit in patients with refractory metastatic colorectal cancer; however, the adverse event profile of regorafenib has limited its use. Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. This study evaluated the safety and activity of two regorafenib dosing schedules. METHODS: In this randomised, multicentre, open-label, phase 2 study done in 39 outpatient cancer centres in the USA, adults aged 18 years or older with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy, including EGFR inhibitors if KRAS wild-type, were enrolled. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had no previous treatment with regorafenib. Patients were randomly assigned (1:1:1:1) into four groups with two distinct regorafenib dosing strategies and two clobetasol usage plans, stratified by hospital. Regorafenib dosing strategies were a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib) if no significant drug-related adverse events occurred and a standard-dose strategy (160 mg/day orally) for 21 days of a 28-day cycle. Clobetasol usage plans (0·05% clobetasol cream twice daily applied to palms and soles) were either pre-emptive or reactive. After randomisation to the four preplanned groups, using the Pocock and Simon dynamic allocation procedures stratified by the treating hospitals, we formally tested the interaction between the two interventions, dosing strategy and clobetasol usage. Given the absence of a significant interaction (p=0·74), we decided to pool the data for the pre-emptive and reactive treatment with clobetasol and compared the two dosing strategies (dose escalation vs standard dose). The primary endpoint was the proportion of evaluable patients (defined as those who were eligible, consented, and received any protocol treatment) initiating cycle 3 and was analysed per protocol. Superiority for dose escalation was declared if the one-sided p value with Fisher's exact test was less than 0·2. This trial is registered with ClinicalTrials.gov, number NCT02368886. This study is fully accrued but remains active. FINDINGS: Between June 2, 2015, and June 22, 2017, 123 patients were randomly assigned to treatment, of whom 116 (94%) were evaluable. The per-protocol population consisted of 54 patients in the dose-escalation group and 62 in the standard-dose group. At data cutoff on July 24, 2018, median follow-up was 1·18 years (IQR 0·98-1·57). The primary endpoint was met: 23 (43%, 95% CI 29-56) of 54 patients in the dose-escalation group initiated cycle 3 versus 16 (26%, 15-37) of 62 patients in the standard-dose group (one-sided p=0·043). The most common grade 3-4 adverse events were fatigue (seven [13%] patients in the dose-escalation group vs 11 [18%] in the standard-dose group), hand-foot skin reaction (eight [15%] patients vs ten [16%] patients), abdominal pain (nine [17%] patients vs four [6%] patients), and hypertension (four [7%] patients vs nine [15%] patients). 14 patients had at least one drug-related serious adverse event: six patients in the dose-escalation group and eight patients in the standard-dose group. There was one probable treatment-related death in the standard-dose group (myocardial infarction). INTERPRETATION: The dose-escalation dosing strategy represents an alternative approach for optimising regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data. FUNDING: Bayer HealthCare Pharmaceuticals.

Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients.

Early VEGF-A reduction (EVR) by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BEV). The CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first-line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n = 48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF-A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24-0.83, p = 0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26-0.95, p = 0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF-A levels at baseline and a greater decrease in VEGF-A levels at day 14 compared to the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first-line treatment for mCRC.

Influence of the facility caseload on the subsequent survival of men with localized prostate cancer undergoing radical prostatectomy.

BACKGROUND: Several studies have investigated the relationship between experience measured by caseload and oncological outcomes, economics, and access to care for prostate cancer care. Oncological outcomes have been limited to biochemical failure after radical prostatectomy. Questions remain regarding the more definitive measures of outcomes and their relationship with caseload. METHODS: The National Cancer Database was used to investigate the outcomes of radical prostatectomy in the United States. With overall survival (OS) as the primary outcome, the relationship between the facility annual caseload (FAC) for all prostate cancer encounters and the facility annual surgical caseload (FASC) for those requiring radical prostatectomy was examined with a Cox proportional hazards model. Four volume groups were defined by caseload: <50th percentile (volume group 1 [VG1]), 50th to 74th percentiles (volume group 2 [VG2]), 75th to 89th percentiles (volume group 3 [VG3]), and ≥90th percentile (volume group 4 [VG4]). By FAC/FASC, 11%/8%, 17%/18%, 25%/26%, and 47%/49% of patients were treated in VG1 through VG4, respectively. RESULTS: Between 2004 and 2014, 488,389 patients underwent radical prostatectomy. At a median follow-up of 60.75 months, the median OS was not reached. There was a significant OS benefit as the caseload increased. For FAC, the adjusted OS difference between VG1 and VG4 at 90th percentile survivorship reached 13.2 months (hazard ratio [HR], 1.30; 95% CI, 1.23-1.36; P < .0001). For FASC, this was 11.3 months (HR, 1.25; 95% CI, 1.192-1.321; P < .0001). CONCLUSIONS: There is a statistically significant OS advantage from performing radical prostatectomy at a facility with a high annual caseload. Caseload measured by all prostate cancer encounters is a better predictor of favorable outcomes than the number of surgeries performed at a facility. LAY SUMMARY: An in-depth analysis of 488,389 cases of radical prostatectomy performed in more than 1000 facilities over a 10-year period showed better survival when surgery was performed in facilities with more experience and greater caseload. A survival difference of up to 13 months was observed when comparing patients treated at less experienced versus more experienced centers.   Experience across all stages of prostate cancer was a stronger predictor of survival outcome than just the number of surgeries performed.

Real-World Outcomes and Factors Associated With the Second-Line Treatment of Patients With Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma.

This retrospective observational study was designed to evaluate overall survival in a real-world patient population and to identify predictive factors associated with receipt of second-line therapy. A retrospective analysis of electronic medical records (Flatiron Health, New York) was conducted among patients initiating first-line therapy from January 1, 2013, through April 30, 2018. Eligible patients were diagnosed with advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma and ≥18 years of age at the time of treatment initiation. Patients alive 45 days after discontinuation of first-line therapy were considered potentially eligible for continued therapy and were categorized into those who received and those who did not receive second-line therapy. Survival analyses were conducted using Kaplan-Meier method and log-rank test without adjusting for any baseline covariates. Factors associated with further treatment were evaluated using logistic regression. A total of 3850 patients met eligibility criteria. Among the 2516 patients available to receive second-line therapy, 1515 (60.2%) received second-line therapy and 1001 (39.8%) did not receive further therapy. Among those potentially eligible to receive second-line therapy, median survival was 15.4 months (95% confidence interval [CI]: 14.6-16.0) from initiation of first-line therapy for those who received second-line therapy and 10.0 months (95% CI: 9.3-10.7) for those who did not. Longer duration of first-line therapy (≥169 vs ≤84 days), HER2-positive tumors, initially diagnosed with stage IV disease, less weight loss during first-line therapy, and younger age were associated with receipt of second-line therapy (all P < .001). Longer survival was associated with multiple lines of therapy; however, these results should be interpreted with caution, and no causal relationship can be inferred.