Association of Coffee Intake With Survival in Patients With Advanced or Metastatic Colorectal Cancer.

IMPORTANCE: Several compounds found in coffee possess antioxidant, anti-inflammatory, and insulin-sensitizing effects, which may contribute to anticancer activity. Epidemiological studies have identified associations between increased coffee consumption and decreased recurrence and mortality of colorectal cancer. The association between coffee consumption and survival in patients with advanced or metastatic colorectal cancer is unknown. OBJECTIVE: To evaluate the association of coffee consumption with disease progression and death in patients with advanced or metastatic colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational cohort study included 1171 patients with previously untreated locally advanced or metastatic colorectal cancer who were enrolled in Cancer and Leukemia Group B (Alliance)/SWOG 80405, a completed phase 3 clinical trial comparing the addition of cetuximab and/or bevacizumab to standard chemotherapy. Patients reported dietary intake using a semiquantitative food frequency questionnaire at the time of enrollment. Data were collected from October 27, 2005, to January 18, 2018, and analyzed from May 1 to August 31, 2018. EXPOSURES: Consumption of total, decaffeinated, and caffeinated coffee measured in cups per day. MAIN OUTCOMES AND MEASURES: Overall survival (OS) and progression-free survival (PFS). RESULTS: Among the 1171 patients included in the analysis (694 men [59%]; median age, 59 [interquartile range, 51-67] years). The median follow-up time among living patients was 5.4 years (10th percentile, 1.3 years; IQR, 3.2-6.3 years). A total of 1092 patients (93%) had died or had disease progression. Increased consumption of coffee was associated with decreased risk of cancer progression (hazard ratio [HR] for 1-cup/d increment, 0.95; 95% CI, 0.91-1.00; P = .04 for trend) and death (HR for 1-cup/d increment, 0.93; 95% CI, 0.89-0.98; P = .004 for trend). Participants who consumed 2 to 3 cups of coffee per day had a multivariable HR for OS of 0.82 (95% CI, 0.67-1.00) and for PFS of 0.82 (95% CI, 0.68-0.99), compared with those who did not drink coffee. Participants who consumed at least 4 cups of coffee per day had a multivariable HR for OS of 0.64 (95% CI, 0.46-0.87) and for PFS of 0.78 (95% CI, 0.59-1.05). Significant associations were noted for both caffeinated and decaffeinated coffee. CONCLUSIONS AND RELEVANCE: Coffee consumption may be associated with reduced risk of disease progression and death in patients with advanced or metastatic colorectal cancer. Further research is warranted to elucidate underlying biological mechanisms.

Plasma 25-Hydroxyvitamin D Levels and Survival in Patients with Advanced or Metastatic Colorectal Cancer: Findings from CALGB/SWOG 80405 (Alliance).

PURPOSE: Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic colorectal cancer. EXPERIMENTAL DESIGN: We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic colorectal cancer participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders. RESULTS: At study entry, 63% of patients were vitamin D deficient (<20 ng/mL) and 31% were vitamin D insufficient (20-<30 ng/mL). Higher 25(OH)D levels were associated with an improvement in OS and PFS (P trend = 0.0009 and 0.03, respectively). Compared with patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53-0.83) for OS and 0.81 (95% CI, 0.66-1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics. CONCLUSIONS: In this large cohort of patients with advanced or metastatic colorectal cancer, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in patients with colorectal cancer are warranted.

Germline and Somatic DNA Damage Repair Gene Mutations and Overall Survival in Metastatic Pancreatic Adenocarcinoma Patients Treated with FOLFIRINOX.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. EXPERIMENTAL DESIGN: Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan-Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. RESULTS: Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (N = 7), BRCA2 (N = 5), PALB2 (N = 3), MSH2 (N = 1), and FANCF (N = 1) of all the DDR genes sequenced. Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent [14 vs. 5 months; HR, 0.58; 95% confidence interval (CI), 0.29-1.14; log-rank P = 0.08]. Multivariate logistic (OR, 1.47; 95% CI, 1.04-2.06; P = 0.04) and Cox regression (HR, 0.37; 95% CI, 0.15-0.94; P = 0.04) showed presence of DDR gene mutations was associated with improved OS. CONCLUSIONS: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.

Examining the effect of peer helping in a coping skills intervention: a randomized controlled trial for advanced gastrointestinal cancer patients and their family caregivers.

PURPOSE: At the end of life, spiritual well-being is a central aspect of quality of life for many patients and their family caregivers. A prevalent spiritual value in advanced cancer patients is the need to actively give. To address this need, the current randomized trial examined whether adding a peer helping component to a coping skills intervention leads to improved meaning in life and peace for advanced gastrointestinal cancer patients and their caregivers. Feasibility and acceptability outcomes were also assessed. METHODS: Advanced gastrointestinal cancer patients and caregivers (n = 50 dyads) were randomly assigned to a 5-session, telephone-based coping skills intervention or a peer helping + coping skills intervention. One or both dyad members had moderate-severe distress. Peer helping involved contributing to handouts on coping skills for other families coping with cancer. Patients and caregivers completed measures of meaning in life/peace, fatigue, psychological symptoms, coping self-efficacy, and emotional support. Patient pain and caregiver burden were also assessed. RESULTS: Small effects in favor of the coping skills group were found regarding meaning in life/peace at 1 and 5 weeks post-intervention. Other outcomes did not vary as a function of group assignment, with both groups showing small decreases in patient and caregiver fatigue and caregiver distress and burden. High recruitment and retention rates supported feasibility, and high participant satisfaction ratings supported acceptability. CONCLUSIONS: Although a telephone-based intervention is feasible and acceptable for this population, peer helping in the context of a coping skills intervention does not enhance spiritual well-being relative to coping skills alone.

Clinical Pathways: Management of Quality and Cost in Oncology Networks in the Metastatic Colorectal Cancer Setting.

PURPOSE: Via Pathways (clinical pathways for cancer) provide evidence-based guidance for specific patient presentations based on the merit of efficacy, then toxicity, and finally cost (if efficacy and toxicity are comparable). We evaluated the impact of a change to the guidance in the metastatic colorectal cancer (mCRC) setting across two large, integrated health networks. METHODS: Cetuximab and panitumumab were determined to have equal efficacy in the treatment of mCRC with no significant difference in toxicity based on recent data from key clinical studies. A cost analysis using Centers for Medicare and Medicaid Services average sales data determined a cost advantage for panitumumab. A substitution of panitumumab for cetuximab in the clinical pathway for all mCRC lines of therapy was initiated as of August 2014. RESULTS: In the preimplementation period, 86 (93.5%) and six (6.5%) treatment selections were for cetuximab and panitumumab, respectively. After the pathway change was implemented, 13 (18.1%) and 59 (81.9%) treatment selections were for cetuximab and panitumumab, respectively. The change in prescribing habits was rapidly altered by the pathway change. The estimated annualized cost savings for the two health networks resulting from the response to the pathway change was $711,021. CONCLUSION: This study demonstrates that clinical pathways can act as a tool to assist oncology practices in decreasing costs and quickly responding to changing treatment paradigms by providing clinicians with consensus-driven treatment recommendations that incorporate the most up-to-date clinical trial results, toxicity considerations, and regimen cost information.

Pathological complete response with anti-PD-1 therapy in a patient with microsatellite instable high, BRAF mutant metastatic colon cancer: a case report and review of literature.

IMPORTANCE: Mismatch repair (MMR) and BRAF mutation status are established independent prognostic factors for colorectal cancer (CRC). MMR deficient tumors are considered to have better prognosis whereas BRAF mutation is associated with poor prognosis. Studies evaluating the combined effect of BRAF and MMR status suggest MSI-high and BRAF mutant patients have a poorer prognosis as compared to MSI-high and BRAF wild type patients. Emerging evidence suggests MMR status predicts the immune response to anti-PD-1 therapy in CRC patients; however little is known about combined MMR and BRAF mutation status in this context. Therefore, it is important to identify whether there is a differential response to anti-PD-1 therapy based on BRAF status in the subset of MSI-high CRC patients. OBSERVATIONS: We report the first case of MSI-high, BRAF mutant metastatic CRC that had an excellent response (pathologic complete response) to anti-PD-1 therapy. We take this opportunity to review the similar cases in literature and discuss combined MMR and BRAF status as a potential biomarker for anti-PD-1 therapy. CONCLUSION AND RELEVANCE: The case presented illustrates that anti-PD-1 therapy can be effectively used to treat CRC patients with MSI-high and BRAF mutant status which is usually considered a poor prognostic category as opposed to MSI-high and BRAF wild type tumors. Future studies with anti-PD-1 therapy distinguishing these molecular subgroups will improve our knowledge of whether BRAF status can add to MMR status as a predictive biomarker for anti-PD-1 therapy in patients with metastatic CRC.

Randomized phase II open-label study of mFOLFOX6 in combination with linifanib or bevacizumab for metastatic colorectal cancer.

BACKGROUND: Although CRC is the third most commonly diagnosed cancer in the United States, second-line CRC treatment is limited. In this trial we examined the efficacy and safety of linifanib, an oral, potent, selective tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor families, with mFOLFOX6, compared with bevacizumab and mFOLFOX6, in previously treated metastatic CRC. PATIENTS AND METHODS: One hundred forty-eight patients with advanced CRC previously treated with fluoropyrimidine or irinotecan received bevacizumab (10 mg/kg, intravenous), low-dose linifanib (7.5 mg), or high-dose linifanib (12.5 mg), with mFOLFOX6. The primary end point was progression-free survival (PFS). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety. RESULTS: No statistically significant differences in PFS occurred between bevacizumab and linifanib doses (low, hazard ratio [HR], 1.453 [95% confidence interval [CI], 0.830-2.539]; high, HR, 1.257 [95% CI, 0.672-2.351]). Median OS values were similar for bevacizumab and high-dose linifanib (bevacizumab, 16.5 months [95% CI, 13.0-not available]; high-dose linifanib, 16.4 months [95% CI, 11.9-21.7]; low-dose linifanib, 12.0 months [95% CI, 10.1-13.0]). ORRs were similar (bevacizumab, 34.7% [95% CI, 21.7-49.6]; low-dose linifanib, 24.0% [95% CI, 13.1-38.2]; high-dose linifanib, 22.4% [95% CI, 11.8-36.6]). Median cycles of 5-fluorouracil were reduced in the linifanib arms, versus the bevacizumab arm. Grade 3/4 adverse event occurrences were more frequent with linifanib. Palmar-plantar erythrodysesthesia, hypothyroidism, and thrombocytopenia were more common with high-dose linifanib than bevacizumab. CONCLUSION: Combining linifanib with mFOLFOX6 as a second-line treatment for metastatic CRC did not improve PFS, radiographic findings, or duration of response versus bevacizumab and mFOLFOX6.

Stage III Colon Cancer: What Works, What Doesn't and Why, and What's Next.

Adjuvant treatment for patients with stage III colon cancer, one of the most common malignancies, is an important issue in oncology. The use of adjuvant chemotherapy in this setting has undoubtedly improved prognosis. This article describes the development of adjuvant therapy and progress in the past decade as well as failures in multiple agents that have demonstrated efficacy in the metastatic setting. Finally, the current clinical trials will be reviewed, as well as complementary therapies including diet and exercise for survivors of colorectal cancer.

Current options for the management of rectal cancer.

Patients diagnosed with rectal cancer should undergo locoregional staging with transrectal endoscopic ultrasound (EUS) or surface coil array MRI of the pelvis if that technique is available. Patients thought to have more than very early stage (T1 or T2) disease should undergo abdominal imaging as well by CT or MRI, and chest imaging with either CXR or preferably CT. The care of rectal cancer patients should be coordinated amongst an experienced multidisciplinary team to maximize the chance of cure and to minimize both local recurrence and complications of therapy. For patients with very early stage disease (T1N0 or T2N0), local resection with or without chemoradiation may be adequate therapy, but these patients must be selected carefully and should be without any poor prognostic factors. For the majority of patients with T3N0 or greater rectal cancer, standard therapy consists of neoadjuvant continuous 5-FU and radiation followed by surgery and further chemotherapy (either with 5-FU, capecitabine, or FOLFOX). The use of capecitabine, irinotecan, and oxaliplatin during radiotherapy shows promise, but remains investigational pending results of phase III studies. Neoadjuvant therapy is preferred because it decreases local recurrence and appears to result in improved postoperative bowel function in comparison with postoperative therapy. Select patients with high (>10 cm from the anal verge) uT3N0 tumors may be at sufficiently low risk of local recurrence to justify omission of radiotherapy. Patients who experience pathologic complete response to radiotherapy should still receive postoperative adjuvant chemotherapy to reduce systemic recurrence risk until data demonstrate that this is not necessary. Patients with stage IV rectal cancer may still require local therapy with radiation, surgery, or both; however, care should be taken in these patients that chemotherapy is not excessively delayed as this is the one modality in this case that can result in improved survival.

Hepatocellular carcinoma: the role of the North American GI Steering Committee Hepatobiliary Task Force and the advent of effective drug therapy.

Hepatocellular carcinoma (HCC) is a disease that requires multidisciplinary management. There has been no widely accepted standard for systemic therapy for this disease until recently. This article briefly discusses the management of earlier stage HCC, then focuses on newer agents with promise, particularly sorafenib, a drug that appears to be the new standard of care for advanced disease.

Systemic therapy for colorectal cancer: focus on newer chemotherapy and novel agents.

Systemic therapy for metastatic colorectal cancer is evolving rapidly after many years without significant change. Standard adjuvant therapy for rectal cancer, on the other hand, remains much the same as it has been since the early 1990s. Recent additions to the colorectal cancer armamentarium include capecitabine, irinotecan, and oxaliplatin. Use of these agents in metastatic colorectal cancer and potential for use in localized rectal cancer are discussed. In addition to these "classical" chemotherapeutic agents, there are a number of exciting therapies designed to target specific molecular features of malignant cells. These agents are now being tested in colorectal cancer in addition to chemotherapy and to radiotherapy, with the hope that improvements in outcome will be made without substantial increases in treatment toxicity. The focus of the section on newer classes of agents will be on agents that are in phase II and III trials, with brief mention of other exciting treatment strategies.