Transforming the oncology data paradigm by creating, capturing, and retrieving structured cancer data at the point of care: A Mayo Clinic pilot.

INTRODUCTION: Structured data capture requires defined languages such as minimal Common Oncology Data Elements (mCODE). This pilot assessed the feasibility of capturing 5 mCODE categories (stage, disease status, performance status (PS), intent of therapy and intent to change therapy). METHODS: A tool (SmartPhrase) using existing and custom structured data elements was Built to capture 4 data categories (disease status, PS, intent of therapy and intent to change therapy) typically documented as free-text within notes. Existing functionality for stage was supported by the Build. Participant survey data, presence of data (per encounter), and time in chart were collected prior to go-live and repeat timepoints. The anticipated outcome was capture of >50% sustained over time without undue burden. RESULTS: Pre-intervention (5-weeks before go-live), participants had 1390 encounters (1207 patients). The median percent capture across all participants was 32% for stage; no structured data was available for other categories pre-intervention. During a 6-month pilot with 14 participants across three sites, 4995 encounters (3071 patients) occurred. The median percent capture across all participants and all post-intervention months increased to 64% for stage and 81%-82% for the other data categories post-intervention. No increase in participant time in chart was noted. Participants reported that data were meaningful to capture. CONCLUSIONS: Structured data can be captured (1) in real-time, (2) sustained over time without (3) undue provider burden using note-based tools. Our system is expanding the pilot, with integration of these data into clinical decision support, practice dashboards and potential for clinical trial matching.

Phase 1 trial of navitoclax and sorafenib in patients with relapsed or refractory solid tumors with hepatocellular carcinoma expansion cohort.

Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051.

Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study.

BACKGROUND: HER2 is an actionable target in metastatic colorectal cancer. We assessed the activity of tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer. METHODS: MOUNTAINEER is a global, open-label, phase 2 study that enrolled patients aged 18 years and older with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer at 34 sites (clinics and hospitals) in five countries (Belgium, France, Italy, Spain, and the USA). Initially, the study was designed as a single-cohort study, which was expanded following an interim analysis to include more patients. Initially, patients were given tucatinib (300 mg orally twice daily) plus intravenous trastuzumab (8 mg/kg as an initial loading dose, then 6 mg/kg every 21 days; cohort A) for the duration of treatment (until progression), and after expansion, patients were randomly assigned (4:3), using an interactive web response system and stratified by primary tumour location, to either tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C). The primary endpoint was confirmed objective response rate per blinded independent central review (BICR) for cohorts A and B combined and was assessed in patients in the full analysis set (ie, patients with HER2-positive disease who received at least one dose of study treatment). Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03043313, and is ongoing. FINDINGS: Between Aug 8, 2017, and Sept 22, 2021, 117 patients were enrolled (45 in cohort A, 41 in cohort B, and 31 in cohort C), of whom 114 patients had locally assessed HER2-positive disease and received treatment (45 in cohort A, 39 in cohort B, and 30 in cohort C; full analysis set), and 116 patients received at least one dose of study treatment (45 in cohort A, 41 in cohort B, and 30 in cohort C; safety population). In the full analysis set, median age was 56·0 years (IQR 47-64), 66 (58%) were male, 48 (42%) were female, 88 (77%) were White, and six (5%) were Black or African American. As of data cutoff (March 28, 2022), in 84 patients from cohorts A and B in the full analysis set, the confirmed objective response rate per BICR was 38·1% (95% CI 27·7-49·3; three patients had a complete response and 29 had a partial response). In cohorts A and B, the most common adverse event was diarrhoea (55 [64%] of 86), the most common grade 3 or worse adverse event was hypertension (six [7%] of 86), and three (3%) patients had tucatinib-related serious adverse events (acute kidney injury, colitis, and fatigue). In cohort C, the most common adverse event was diarrhoea (ten [33%] of 30), the most common grade 3 or worse adverse events were increased alanine aminotransferase and aspartate aminotransferase (both two [7%]), and one (3%) patient had a tucatinib-related serious adverse event (overdose). No deaths were attributed to adverse events. All deaths in treated patients were due to disease progression. INTERPRETATION: Tucatinib plus trastuzumab had clinically meaningful anti-tumour activity and favourable tolerability. This treatment is the first US Food and Drug Administration-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer. FUNDING: Seagen and Merck & Co.

Patient-reported Adverse Events During Neoadjuvant Therapy in a Phase 2 Borderline Resectable Pancreatic Cancer Clinical Trial (Alliance A021501).

OBJECTIVE: We sought to evaluate symptomatic adverse event (AE) rates among patients with pancreatic cancer receiving neoadjuvant therapy on clinical trial (A021501) using the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE). BACKGROUND: To date, pancreatic cancer clinical trials have measured AEs using standard physician reporting [Common Terminology Criteria for Adverse Events (CTCAE)]. Patient-reported symptomatic AEs have been incompletely characterized. METHODS: A021501 (December 31, 2016-January 1, 2019) randomized patients with borderline resectable pancreatic ductal adenocarcinoma to 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX+hypofractionated radiotherapy (Arm 2), followed by pancreatectomy and adjuvant FOLFOX6. Patients completed PRO-CTCAE assessments at baseline, on day 1 of each chemotherapy cycle, and daily during radiotherapy. RESULTS: Of 126 patients, 96 (76%) initiated treatment and completed a baseline plus at least 1 postbaseline PRO-CTCAE assessment. Diarrhea and fatigue were the only symptomatic grade 3 or higher AEs identified in at least 10% of patients using CTCAE. At least 10% of all patients reported an adjusted PRO-CTCAE composite grade 3 AE during neoadjuvant treatment for 10 of 15 items: anxiety (10%), bloating of abdomen (16%), decreased appetite (18%), diarrhea (13%), dry mouth (21%), fatigue (36%), nausea (18%), generalized pain (16%), abdominal pain (21%), and problems tasting (32%). Decreased appetite was higher in Arm 2 than in Arm 1 ( P =0.0497); no other differences between study arms were observed. CONCLUSION: Symptomatic AEs during neoadjuvant therapy were common and were reported more frequently by patients using PRO-CTCAE than were recorded by clinicians using standard CTCAE.

Selecting Optimal First-Line Treatment for Microsatellite Stable and Non-Mutated RAS/BRAF Metastatic Colorectal Cancer.

OPINION STATEMENT: Standard frontline treatment of metastatic colorectal cancer (CRC) is cytotoxic chemotherapy plus a biologic agent such as an anti-EGFR monoclonal antibody (cetuximab or panitumumab) or anti-VEGF antibody (bevacizumab). Predictive biomarkers include mismatch repair (MMR) status, and RAS and BRAF mutation status; and important factors in treatment selection include primary tumor location, intent of therapy, and potential toxicity, as well as patient age, comorbidities, and patient preference. To date, single-, double-, or triple-agent cytotoxic chemotherapy all have important roles in appropriately selected patients, with the addition of anti-VEGF or anti-EGFR antibody therapy based on the relevant predictive biomarker. Data indicate that patients with proficient MMR, RAS/BRAF wt mCRC are candidates for an anti-EGFR antibody plus doublet chemotherapy if they have a left-sided primary tumor, or for anti-VEGF (bevacizumab) plus doublet or triplet chemotherapy if they have a right-sided primary tumor. Future studies may provide more predictive biomarkers to further personalize therapy for this heterogeneous disease.

Pancreatic cancer risk to siblings of probands in bilineal cancer settings.

PURPOSE: Pancreatic cancer (PC) risk is increased in families, but PC risk and risk perception have been understudied when both parents have cancer. METHODS: An unbiased method defining cancer triads (proband with PC and both parents with cancer) in a prospective registry estimated risk of PC to probands' siblings in triad group 1 (no parent with PC), group 2 (1 parent with PC), and group 3 (both parents with PC). We estimated standardized incidence ratios (SIRs) using a Surveillance, Epidemiology, and End Results (SEER) reference. We also estimated the risk when triad probands carried germline pathogenic/likely pathogenic variants in any of the 6 PC-associated genes (ATM, BRCA1, BRCA2, CDKN2A, MLH1, and TP53). PC risk perception/concern was surveyed in siblings and controls. RESULTS: Risk of PC was higher (SIR = 3.5; 95% CI = 2.2-5.2) in 933 at-risk siblings from 297 triads. Risk increased by triad group: 2.8 (95% CI = 1.5-4.5); 4.5 (95% CI = 1.6-9.7); and 21.2 (95% CI = 4.3-62.0). SIR in variant-negative triads was 3.0 (95% CI = 1.6-5.0), whereas SIR in variant-positive triads was 10.0 (95% CI = 3.2-23.4). Siblings' perceived risk/concern of developing PC increased by triad group. CONCLUSION: Sibling risks were 2.8- to 21.2-fold higher than that of the general population. Positive variant status increased the risk in triads. Increasing number of PC cases in a triad was associated with increased concern and perceived PC risk.

A pilot study of Pan-FGFR inhibitor ponatinib in patients with FGFR-altered advanced cholangiocarcinoma.

Background Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations. Methods This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results Twelve patients were enrolled prior to early termination of the trial. Partial responses were observed in 1 from 12 patients. Median PFS was 2.4 months and median OS was 15.7 months. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed. Conclusions Ponatinib as a single agent in FGFR altered BTC is tolerable with limited clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies.

PURPOSE: Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. METHODS: Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. RESULTS: Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. CONCLUSIONS: Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.

A feasibility study of virtual group therapy to improve quality of life of cancer caregivers.

BACKGROUND: Cancer caregiving can negatively impact the quality of life (QOL) of the caregiver. In-person interventions for improving coping skills have been shown to be effective in improving QOL for caregivers. OBJECTIVES: This pilot project explored the feasibility and acceptability of a virtual group therapy intervention to improve short-term cancer caregiver QOL. METHODS: Caregivers of cancer patients were enrolled in a structured multidisciplinary intervention of eight virtual group therapy sessions provided over four weeks between September 9, 2013 and November 17, 2014. Group sessions were led by trained facilitators and included components of physical therapy, occupational therapy, psychosocial education, cognitive-behavioral intervention, supportive discussion, spiritual reflection, and mindfulness therapy. Feasibility was based on acceptable number of recruited participants per session; acceptability was defined using attendance and 80% QOL completion rates. QOL domains and symptom burden were assessed using validated single items. RESULTS: The 20 cancer caregivers who enrolled were mostly older (80% were ≥ 65 years), female (76.5%), married to the patient (88.2%), Caucasian (100%), and highly educated (100%). 60% attended one to five sessions, 15% attended six to eight sessions, and 25% attended no sessions. Thirty percent completed pre- and post- intervention ratings of QOL items. SIGNIFICANCE OF RESULTS: Findings suggested that a virtual group therapy intervention is feasible for the cancer caregivers in this study. Although not statistically significant, the caregivers reported higher QOL and less symptom burden in multiple domains after participating in the virtual group therapy intervention.

Considerations in the management of younger patients with colorectal cancer.

The incidence of colorectal cancer in patients ages 18 to 49 years has increased by 51% throughout the past 3 decades. In the United States, recent guidelines lowered the initial screening age to 45 years. More than 75% of colorectal tumors in younger patients are diagnosed based on the onset of symptoms, such as rectal bleeding, abdominal pain, weight loss, or anemia. In most cases, these individuals do not have a family history of colorectal cancer. On average, the diagnosis of colorectal cancer in younger patients occurs from 6 months to several years after symptoms first arise. As a result, younger patients diagnosed with colorectal cancer tend to present with advanced disease. If a younger patient does not have any contraindications, it is appropriate to consider treatment with a triplet chemotherapy combined with a biologic. The impact of treatment can be greater for younger patients than for older individuals. Even mild or moderate toxicities can strongly impact their daily lives. Younger patients with colorectal cancer are likely to have a higher risk for long-term treatment-related sequelae, particularly because they tend to present with advanced disease and will receive therapy for a prolonged period.

Role of Surgery and Perioperative Therapy in Older Patients with Resectable Pancreatic Ductal Adenocarcinoma.

BACKGROUND: It is unclear whether results from recent trials of resectable pancreatic ductal adenocarcinoma (PDAC) are generalizable to older patients, who are underrepresented. We aimed to evaluate outcomes of surgery and of neoadjuvant and adjuvant therapy in older patients with resectable PDAC. PATIENTS AND METHODS: We included patients aged ≥65 years with upfront resectable PDAC from a prospectively maintained pancreatic cancer registry from 2007 to 2016. Patients were stratified into ages 65-75 and 75+ years. Overall survival (OS) was assessed in treatment comparisons: (A) surgery (n = 636) versus nonsurgical (n = 178), (B) neoadjuvant therapy (n = 139) versus upfront surgery (n = 497), and (C) adjuvant therapy (n = 379) versus surgery alone (n = 118). We compared neoadjuvant (n = 139) versus adjuvant therapy (n = 379) in an exploratory analysis. RESULTS: Nine hundred and three patients had a median age of 73.7 (range, 65-96.6) years. Median OS was 26.6 versus 11.9 months (adjusted hazard ratio [HRadj ], 0.4; 95% confidence interval [CI], 0.31-0.52; p < .001) in Comparison A groups, 30.7 versus 25.8 months (HRadj , 0.69; 95% CI, 0.49-0.96; p = .03) in Comparison B groups, and 26.9 versus 17.4 months (HRadj , 0.62; 95% CI, 0.44-0.88; p = .008) in Comparison C groups, respectively. OS benefit in these treatment comparisons was present in age group 75+ with HRadj 0.24 (95% CI, 0.16-0.36; p < .001) in Comparison A and HRadj 0.52 (95% CI, 0.27-1; p = .049) in Comparison B, but not in Comparison C with HRadj 0.68 (95% CI, 0.43-1.08; p = .1). Statistically comparable median OS of patients who received neoadjuvant or adjuvant therapy stratified by age groups was observed. CONCLUSION: Older patients with resectable PDAC who received surgery, neoadjuvant therapy, or adjuvant therapy appeared to have improved survival outcomes compared with those who did not receive such treatment. IMPLICATIONS FOR PRACTICE: Older patients with resectable pancreatic ductal adenocarcinoma (PDAC) in general are underrepresented in large clinical trials and less well studied in terms of the role of surgery, neoadjuvant therapy, and adjuvant therapy. This study collected data on older patients with resectable PDAC from a prospectively maintained single-institutional pancreatic cancer registry of a tertiary referral center from 2007 to 2016. It was found that, with multidisciplinary evaluation, older patients with resectable PDAC who received surgery, neoadjuvant therapy, or adjuvant therapy appeared to have improved survival outcomes compared with those who did not receive such treatment. These results are of substantial importance to practitioners who treat older patients, who are traditionally underrepresented in most clinical trials.

A Systematic Review and Network Meta-Analysis of Regorafenib and TAS-102 in Refractory Metastatic Colorectal Cancer.

BACKGROUND: Regorafenib at different dosing strategies and TAS-102 are treatment options for refractory metastatic colorectal cancer (mCRC). We aimed to evaluate the comparative effectiveness evidence supporting these different strategies. MATERIALS AND METHODS: We searched different databases for randomized controlled trials evaluating TAS-102 or regorafenib in patients with refractory mCRC who failed prior oxaliplatin, irinotecan, and fluoropyrimidine. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White's multivariate meta-regression to pool evidence from direct and indirect comparisons. RESULTS: Six trials at low risk of bias (2,445 patients) were included. Direct comparisons showed that Rego 160 and TAS-102 as monotherapy were superior to best-supportive care (BSC) in terms of PFS (Rego 160: hazard ratio [HR], 0.4; 95% confidence ratio [CI], 0.26-0.63; TAS-102: HR, 0.46 CI, 0.40-0.52) and OS (Rego 160: HR, 0.67; CI, 0.48-0.93; TAS-102: HR, 0.67; CI, 0.57-0.80). Network analysis showed no statistically difference in PFS or OS between Rego 160 and TAS-102. Rego 80+ was superior to BSC in terms of OS (HR, 0.44; CI, 0.23-0.84) and PFS (HR, 0.37; CI, 0.21-0.66). Rego 80+ was associated with statistically nonsignificant improvement in OS and PFS compared with TAS-102 and Rego 160. CONCLUSION: Regorafenib 160 and TAS-102 appear to have similar efficacy. Rego 80+ is shown to be superior to BSC. A trend for improved OS was observed with Rego 80+ versus Rego 160 or TAS 102. IMPLICATIONS FOR PRACTICE: Regorafenib at a dose of 160 mg and TAS-102 appear to have similar efficacy in patients with refractory metastatic colorectal cancer. Regorafenib with a dose escalation strategy is superior to best-supportive care. Given its tolerability and the observed trend in survival benefit compared with regorafenib 160, dose escalation strategy of regorafenib (80+) may be the preferred option in this setting.

Characterization of Comorbidities Limiting the Recruitment of Patients in Early Phase Clinical Trials.

BACKGROUND: Early phase clinical trials evaluate the safety and efficacy of new treatments. The exclusion/inclusion criteria in these trials are usually rigorous and may exclude many patients seen in clinical practice. Our objective was to study the comorbidities limiting the participation of patients with breast, colorectal, or lung cancer in clinical trials. MATERIALS AND METHODS: We queried ClinicalTrials.gov on December 31, 2016. We reviewed the eligibility criteria of 1,103 trials. Logistic regression analyses were completed, and exclusion was studied as a binary variable. RESULTS: Out of 1,103 trials, 70 trials (6%) excluded patients >75 years of age, and 45% made no reference to age. Eighty-six percent of trials placed restrictions on patients with history of prior malignancies. Regarding central nervous system (CNS) metastasis, 416 trials (38%) excluded all patients with CNS metastasis, and 373 (34%) only allowed asymptomatic CNS metastasis. Regarding chronic viral infections, 347 trials (31%) excluded all patients with human immunodeficiency virus, and 228 trials (21%) excluded all patients with hepatitis B or C infection. On univariate analysis, chemotherapy trials were more likely to exclude patients with CNS metastasis and history of other malignancies than targeted therapy trials. Multivariate analysis demonstrated that industry-sponsored trials had higher odds of excluding patients with compromised liver function. CONCLUSION: Many clinical trials excluded large segments of the population of patients with cancer. Frequent exclusion criteria included patients with CNS metastasis, history of prior malignancies, and chronic viral infections. The criteria for participation in some clinical trials may be overly restrictive and limit enrollment. IMPLICATIONS FOR PRACTICE: The results of this study revealed that most early phase clinic trials contain strict exclusion criteria, potentially excluding the patients who may be more likely to represent the population treated in clinical settings, leaving patients susceptible to unintended harm from inappropriate generalization of trial results. Careful liberalization of the inclusion/exclusion criteria in clinical trials will allow investigators to understand the benefits and drawbacks of the experimental drug for a broader population, and possibly improve recruitment of patients with cancer into clinical trials.

Association between treatment facility volume, therapy types and overall survival in patients with intrahepatic cholangiocarcinoma.

BACKGROUND: To determine the association between the number of patients with intra-hepatic cholangiocarcinoma (IHCC) treated annually at a treatment facility (volume) and overall survival (outcome). METHODS: Patients with IHCC reported to the National Cancer Database (years 2004-2015) were included. We classified facilities by tertiles (T; mean IHCC patients treated/year): T1: <2.56; T2: 2.57-5.39 and T3: ≥5.40. Volume-outcome relationship was determined by using Cox regression adjusting for patient demographics, comorbidities, tumor characteristics, insurance type and therapy received. RESULTS: There were 11,344 IHCC patients treated at 1106 facilities. On multivariable analysis, facility volume was independently associated with all-cause mortality (p < 0.001). The unadjusted median OS by facility volume was: T1: 5 months (m), T2: 8.1 m, and T3: 13.1 m (p < 0.001). Compared with patients treated at T3 facilities, patients treated at lower-tertile facilities had significantly higher risk of death [T2 hazard ratio (HR), 1.12 [95% CI, 1.05-1.23]; T1 HR, 1.21 [95% CI, 1.11-1.33]. Patients treated at high-volume centers were more likely to get surgery (34.6 vs 13.1%) and adjuvant therapy. CONCLUSION: IHCC patients treated at high-volume facilities had a significant improvement in OS and were more likely to receive surgery and adjuvant therapy as compared to that of patients at low-volume facilities.

Outcome of Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Mayo Clinic Experience.

BACKGROUND: Deficiencies in the DNA mismatch repair system cause errors during DNA replication, which in turn give rise to microsatellite instability (MSI). The impact of MSI on survival in metastatic colorectal cancer (mCRC) is unclear. This cohort study aims to investigate the prognostic and predictive value of MSI in mCRC prior to the immune therapy era. MATERIALS AND METHODS: A total of 75 MSI-high (MSI-H) mCRC patients (pts) and 75 matched (age, gender, disease sidedness, metachronous/synchronous) microsatellite-stable (MSS) mCRC pts were identified from 1,268 mCRC pts who had MSI/mismatch repair test results at Mayo Clinic Rochester between January 1992 and July 2016. A retrospective review was conducted by using data from electronic medical records. Statistical analyses utilized the Kaplan-Meier method, log-rank test, and Cox proportional hazards models. RESULTS: The MSS group was well matched to the MSI-H group based on age, gender, location, and chronicity of metastatic disease. MSI-H mCRC pts had earlier disease recurrence (median time from initial diagnosis to metastatic disease diagnosis, MSI-H group 12.9 vs. MSS group 20.9 months, p = .034). Median overall survival (OS) was 28.1 and 37.4 months for MSI-H and MSS pts, respectively (p = .99). In total, 94.7% of MSI-H pts and 98.7% of MSS pts had fluoropyrimidine-based chemotherapy for metastatic disease, and there was no difference in OS between these two groups (32.3 vs. 37.4 months, p = .91). Forty-three MSI-H and thirty-nine MSS pts had metastasectomy and/or ablation of metastases (p = .51) with longer median OS compared with pts without metastasectomy (MSI-H: 82.0 vs. 13.9, p < .001; MSS: 69.9 vs. 19.7, p < .001). Age <65 years, BRAF wild type, and metastasectomy were associated with better OS in univariate analysis. Only metastasectomy remained statistically significant in multivariate analysis (p < .001). CONCLUSION: In mCRC, patients with MSI-H tumors have similar, but numerically shorter, median overall survival compared with those with MSS tumors. In both groups, metastasectomy and ablation of metastatic disease should be considered to optimize OS. IMPLICATIONS FOR PRACTICE: This study clearly demonstrated the survival benefits that aggressive metastasectomy provides in selected microsatellite instability-high metastatic colorectal cancer patients. This could be meaningful practice-changing information that has been long awaited.

Alliance for clinical trials in oncology (ALLIANCE) trial A021501: preoperative extended chemotherapy vs. chemotherapy plus hypofractionated radiation therapy for borderline resectable adenocarcinoma of the head of the pancreas.

BACKGROUND: Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and 64% of operations achieved an R0 resection. However, the individual contributions of preoperative chemotherapy and radiation therapy to therapeutic outcome remain poorly defined. METHODS: In Alliance for Clinical Oncology Trial A021501, a recently activated randomized phase II trial, patients (N = 134) with a CT or MRI showing a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed anatomic criteria for borderline resectable disease will be randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 2 days for 4 cycles) or to 7 cycles of modified FOLFIRINOX followed by stereotactic body radiation therapy (33-40 Gy in 5 fractions). Patients without evidence of disease progression following preoperative therapy will undergo pancreatectomy and will subsequently receive 4 cycles of postoperative modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, bolus 5-fluorouracil 400 mg/m2, and infusional 5-fluorouracil 2400 mg/m2 over 2 days for 4 cycles). The primary endpoint is the 18-month overall survival rate of patients enrolled into each of the two treatment arms. An interim analysis of the R0 resection rate within each arm will be conducted to assess treatment futility after accrual of 30 patients. Secondary endpoints include rates of margin-negative resection and event-free survival. The primary analysis will compare the 18-month overall survival rate of each arm to a historical control rate of 50%. The trial is activated nationwide and eligible to be opened for accrual at any National Clinical Trials Network cooperative group member site. DISCUSSION: This study will help define standard preoperative treatment regimens for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02839343 , registered July 14, 2016.

Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies.

BACKGROUND: A previous phase II trial in patients with chemorefractory metastatic colorectal cancer demonstrated a 63 % disease control rate with a combination of bevacizumab and sorafenib. This phase I trial sought to determine the maximum tolerable dose (MTD) of bevacizumab and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. METHODS: A standard 3 + 3 trial design utilized 3 escalating sorafenib dose levels: (1) 200 mg daily, days 3-7, 10-14; (2) 200 mg twice daily, days 3-6, 10-13; and (3) 200 mg twice daily, days 3-7, 10-14 combined with standard dose FOLFIRI (5-fluouracil, leucovorin, and irinotecan) and bevacizumab (5 mg/kg), repeated every 14 days. RESULTS: Fifteen patients were evaluable for safety and response assessment. There were no dose limiting toxicities (DLTs) at dose level 1 or 2. At dose level 3, two patients experienced DLTs (asymptomatic grade 3 hypophosphatemia, grade 3 dehydration and diarrhea). The MTD was determined to be dose level 2: sorafenib 200 mg twice daily, days 3-6, 10-13 combined with FOLFIRI and bevacizumab at standard doses. Four patients had a partial response and 8 had stable disease as best response (disease control rate of 80 %). Three patients with CRC had disease control >12 months. CONCLUSIONS: The MTD of this regimen is sorafenib 200 mg twice daily, days 3-6, 10-13 combined with standard doses of FOLFIRI and bevacizumab. Dual antiangiogenic treatment combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies.