Tag: Colon Cancer

FDA Approves LONSURF®, A Novel Oral Agent for Refractory Colorectal Cancer

RR

SUMMARY: The FDA on September 22, 2015 approved LONSURF® (Trifluridine/Tipiracil) for the treatment of patients with metastatic ColoRectal Cancer (CRC), who have been previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy and if RAS wild-type, an anti-EGFR therapy. The American Cancer Society estimates that approximately 133,000 new cases of ColoRectal Cancer (CRC) will be diagnosed in the United States in 2015 and close to 50,000 are expected to die of the disease. Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. Patients with metastatic CRC, whose disease has progressed after treatment with standard therapies, have limited therapeutic options available, to treat their disease.

LONSURF® is a combination of two agents – a novel oral nucleoside, Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil hydrochloride. This combination has a unique mechanism of action. Trifluridine, the active ingredient of LONSURF® incorporates into DNA resulting in DNA damage. Degradation of Trifluridine which occurs when taken orally is prevented by Tipiracil hydrochloride.

The RECOURSE study is a pivotal, global, phase III trial, in which 800 patients with metastatic ColoRectal Cancer, refractory to all standard therapies were randomly assigned in a 2:1 ratio to receive either LONSURF® (N=534) or placebo (N=266). Patients received LONSURF® 35mg/m2 or matching placebo orally, twice daily after meals, on Days 1-5 and 8-12 of each 28 day cycle. Treatment was continued until disease progression or unacceptable toxicity. Eligible patients had metastatic ColoRectal Cancer (mCRC), previously treated with chemotherapy and biological therapy, which included Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy and if RAS wild-type, an anti-EGFR therapy. The primary endpoint of this study was overall survival and the secondary endpoint was progression-free survival.

It was noted that LONSURF® significantly improved Overall Survival compared to placebo (7.1 months vs 5.3 months; HR=0.68; P<0.001), with a 32% reduction in the risk of death. LONSURF® also significantly improved Progression Free Survival compared to placebo (HR = 0.47; P<0.001). The most common grade 3 or more adverse events were leukopenia (21%), anemia (18%) and febrile neutropenia (4%), noted in patients receiving LONSURF®. The authors concluded that LONSURF® significantly improved Overall Survival in patients with refractory metastatic ColoRectal Cancer, providing a novel oral therapeutic option for this patient group. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. Mayer RJ, Van Cutsem E, Falcone A, et al. N Engl J Med 2015; 372:1909-1919

LONSURF® (Trifluridine/Tipiracil)

RR

The FDA on September 22, 2015 approved LONSURF® for the treatment of patients with metastatic colorectal cancer, who have been previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biologic product, and an anti-EGFR monoclonal antibody, if RAS wild-type. LONSURF® is a product of Taiho Oncology, Inc.

NCCN Recommends Universal Screening for Lynch Syndrome in Patients with Newly Diagnosed Colorectal Cancer

RR

SUMMARY: The American Cancer Society estimates that in the United States, for the year 2015, approximately 140,000 new cases of ColoRectal Cancer (CRC) will be diagnosed and close to 50,000 patients will die of the disease. The lifetime risk of developing ColoRectal Cancer is about 1 in 20 (5%). Lynch Syndrome (Hereditary NonPolyposis Colorectal Cancer – HNPCC), is an Autosomal Dominant, inherited disorder, associated with an increased risk of colorectal, endometrial, ovary, gastric, small bowel, pancreatic, brain, ureter or renal pelvis cancer. Approximately 3 to 5 percent of all cases of ColoRectal Cancer, are caused by Lynch Syndrome (LS) and 1 in 35 patients with newly diagnosed ColoRectal Cancer is related to Lynch Syndrome. Four MMR genes (MisMatch Repair genes), MLH1, MSH2, MSH6, and PMS2 are involved in the repair of mistakes that occur during DNA replication. When any of these genes are mutated, repair of DNA replication mistakes is prevented resulting in continuous division of abnormal cells and possibly cancer. The EPCAM gene lies next to the MSH2 gene on chromosome 2 and mutations in the EPCAM gene can cause the MSH2 gene to be inactivated, interrupting DNA repair and leading to accumulation of DNA replication errors and possible malignancy. Germline mutations in the MMR genes, is classically seen in Lynch Syndrome and results in microsatellite instability in tumors. Tumors are described as MSI-High when they have changes in 2 or more, of the 5 microsatellite markers. So, high levels of MSI within a tumor are suggestive of defective DNA mismatch repair. MSI-H is a hallmark of Lynch syndrome. However MSI-H is present in approximately 15% of patients with sporadic CRC. This is secondary to epigenetic silencing of MLH1 through promoter hypermethylation, rather than germline mutations in the MMR genes.

A Clinical Diagnosis of Lynch Syndrome can be made based on personal and family history if at least three relatives have a malignancy associated with Lynch Syndrome such as colorectal, endometrial, small bowel, ureter or renal pelvis cancer. In addition the following criteria should be met: • One relative must be a first-degree relative of the other two. • At least two successive generations must be affected. • At least one relative with a Lynch syndrome associated cancer should be diagnosed before 50 years of age. • Familial Adenomatous Polyposis should be excluded. • Tumors should be verified whenever possible. Because family history can sometimes be difficult to obtain or confirm, NCCN in those circumstances has recommended screening all newly diagnosed colorectal cancer patients for Lynch syndrome.

ImmunoHistoChemistry (IHC) staining can be performed on the tumor tissue for protein expression of the four MMR genes. IHC test is described as normal when all 4 mismatch repair proteins are normally expressed suggesting that an underlying mismatch repair gene mutation is unlikely. When IHC test is abnormal, it means that that at least one of the 4 mismatch repair proteins is not expressed and an inherited mutation may be present in the gene related to that protein. This can be further confirmed by mutation analysis of the corresponding gene. However, the lack of expression of MMR proteins by IHC is highly concordant with molecular MSI testing and IHC is therefore more practical and cost-effective. Tumors with loss of MMR protein expression or MSI-H are classified as MMR deficient (dMMR). Patients with sporadic tumors with MSI-H or MMR deficiency (dMMR) generally are older women with stage II disease and present with tumors in the proximal colon and the tumors are poor differentiated with increased number of tumor-infiltrating lymphocytes. These patients in retrospective studies had superior stage-adjusted survival compared to MMR proficient tumors. Further, single agent 5-Fluorouracil when given in an adjuvant setting was not beneficial in this patient group.

It should also be noted that a majority of colon cancer tumors that lack protein expression on IHC staining of MLH1 (often coexisting with loss of PMS2) are often due to an acquired genetic defect. If the IHC indicates absence of MLH1 protein expression, tumor should be tested for BRAF mutation V600E, which can be seen in sporadic colorectal cancers, but rarely found in patients who have Lynch Syndrome. Once a diagnosis of Lynch Syndrome is made, at risk family members should undergo colonoscopic evaluation at 20-25 years of age or 2-5 years prior to the earliest colon cancer, if it is diagnosed before age 25 and is repeated every 1-2 years. Prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) should be considered by women who have completed childbearing. NCCN Guidelines Version 1.2014 Lynch Syndrome

Late Breaking Abstract-ASCO 2015 Treating Cancer Based on Genomics Regardless of Tumor Type

RR

SUMMARY: KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti–PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The treatment paradigm for solid tumors has been rapidly evolving with a better understanding of the Immune checkpoints. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent, related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, PD-1(Programmed cell Death-1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic respons

ASCO 2015 Selective Internal Radiation Therapy with Y-90 Improves Outcomes in Metastatic Colorectal Cancer

RR

SUMMARY:The American Cancer Society estimates that approximately 133,000 new cases of ColoRectal Cancer (CRC) will be diagnosed in the United States in 2015 and close to 50,000 are expected to die of the disease. Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. About 10-20% of the patients with liver metastases have resectable disease, which may translate into long term survival. CRC patients with synchronous metastases tend to have more extensive disease with bilobar liver involvement. With the availability of more effective chemotherapy regimens and targeted systemic interventions, the median survival of CRC patients with metastatic disease has increased from 6 months in the 1990’s to 24 months. Selective Internal Radiation Therapy (SIRT) or RadioEmbolization using radioisotope Yttrium-90 (Y-90) coated resin particles, a pure beta emitter, has demonstrated significant benefit for patients with unresectable liver metastases, in previously published studies. Y-90 resin microspheres are no bigger in diameter than a human hair and are introduced into the hepatic artery by initially accessing the femoral artery. The blood supply to the liver tumors is via the hepatic artery and these tumors tend to be hypervascular. The Y-90 resin microspheres become preferentially lodged in the narrow capillaries that surround liver tumors and selectively deliver a high dose of short-range beta radiation to the liver tumors. The physical properties of Y-90 resin microspheres facilitate even distribution of radioactivity within and around the liver metastases.SIRFLOX is an International, multi-center, open-label, randomized phase III study, which evaluated the efficacy and safety of combining modified FOLFOX6 (Oxaliplatin, 5-FU and Leucovorin) chemotherapy regimen with or without AVASTIN® (Bevacizumab) with SIRT, using Y-90 resin microspheres, as first line treatment in patients with unresectable liver only or liver dominant metastatic ColoRectal Cancer (mCRC). The randomization included 530 patients of whom 263 patients received mFOLFOX6 with or without AVASTIN® (Group A) and 267 patients received mFOLFOX6 + SIRT administered once with cycle 1, with or without AVASTIN® (Group B), with the treatment given until disease progression. Patients were stratified based on the extent of liver involvement (25% or less versus more than 25%), presence of extra hepatic disease (liver only versus liver dominant disease) and treatment with AVASTIN®, which was at the discretion of the attending physician. Forty percent of the patients had extra hepatic disease. The primary endpoint was Progression Free Survival (PFS). With a median follow up of 36.1 months, the median PFS in the liver was 12.6 months versus 20.5 months in Group A versus Group B respectively (HR=0.69; P=0.002). The hepatic Response Rate was 68.8% versus 78.7% (P=0.042), with a Complete Response Rate of 1.9% versus 6.0% (P=0.02) in Groups A and B respectively. Even though hematologic and gastrointestinal adverse events were higher in the SIRT group, the toxicity levels were acceptable. The authors concluded that the addition of SIRT to chemotherapy resulted in a 7.9 month improvement in Progression Free Survival in the liver, for patients with unresectable metastatic ColoRectal cancer (mCRC), with a 31% reduction in the risk of tumor progression in the liver. With the liver being the most common site of spread in patients with metastatic CRC, this study provides Level One evidence to support the use of SIRT in combination with chemotherapy in this patient group. SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 ± bevacizumab (bev) versus mFOLFOX6 + selective internal radiation therapy (SIRT) ± bev in patients (pts) with metastatic colorectal cancer (mCRC). Gibbs P, Heinemann V, Sharma NK, et al. J Clin Oncol 33, 2015 (suppl; abstr 3502)</s

Daily Aspirin May Improve Survival after Diagnosis of Colorectal Cancer

RR

SUMMARY:The American Cancer Society estimates that approximately 133,000 new cases of ColoRectal Cancer (CRC) will be diagnosed in the United States in 2015 and close to 50,000 are expected to die of the disease. Several epidemiological studies as well as randomized controlled trials have shown that Aspirin reduces the incidence of ColoRectal Cancer (CRC) and CRC associated mortality. Platelets have long been implicated in the mechanism of tumor metastases. More recent data suggests that platelets may play a role in tumorigenesis as well, through the release of angiogenic and growth factors due to overexpression of COX-2. Daily low dose Aspirin inhibits COX-1 and COX-2. It is postulated that Aspirin also works by COX-independent mechanisms such as, the inhibition of NF-kB and Wnt/ β-catenin signaling, which may play a role in its chemopreventive properties. Even though the benefits of Aspirin in the primary prevention of CRC remains well established, the role of Aspirin in secondary prevention in patients with CRC is unclear. The authors conducted this trial to evaluate the association between Aspirin use after diagnosis of CRC with CRC-Specific Survival (CSS) and Overall Survival (OS) in the largest group of patients ever studied. The study authors in this retrospective study identified 25,644 patients in the Cancer Registry of Norway, diagnosed with ColoRectal Cancer (CRC) from 2004 through 2011. Using the Norwegian Prescription Database, the authors were then able to establish that 6,109 patients in this large cohort had documented exposure to Aspirin. Exposure to Aspirin was defined as a prescription for more than 6 months of Aspirin following a diagnosis of CRC. The median follow up was 2.2 years. The authors performed a multivariate regression analysis controlling for age, gender, tumor stage, tumor differentiation and noted that exposure to Aspirin post-diagnosis, independently improved ColoRectal Cancer (CRC) -Specific Survival (HR=0.75; P<0.001) and Overall Survival (HR=0.86; P<0.001). The authors concluded that in this large group of unselected ColoRectal Cancer (CRC) patients, exposure to Aspirin after the diagnosis of CRC is independently associated with improved Colorectal Cancer-Specific Survival and Overall Survival. They added that because of the risk of bleeding, the risk–benefit should be assessed before Aspirin is routinely recommended to this patient population. Impact of aspirin as secondary prevention in an unselected cohort of 25,644 patients with colorectal cancer: A population-based study. Bains S, Mahic M, Cvancarova M, et al. J Clin Oncol 33, 2015 (suppl; abstr 3504)

CYRAMZA® (Ramucirumab)

RR

The FDA on April 24, 2015 approved CYRAMZA® for use in combination with FOLFIRI for the treatment of patients with metastatic ColoRectal Cancer (mCRC), whose disease has progressed on a first line Bevacizumab, Oxaliplatin and Fluoropyrimidine containing regimen. CYRAMZA® is a recombinant human monoclonal IgG1 antibody that binds to the human vascular endothelial growth factor- receptor 2 (VEGF-R2), preventing the interaction of VEGF-R2 to its ligands. CYRAMZA® was approved earlier in 2014 for the treatment of patients with advanced Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma and in December 2014, for use in combination with TAXOTERE® (Docetaxel) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC). CYRAMZA® injection for intravenous infusion, is a product of Eli Lilly and Company.

FDA Approves CYRAMZA® for Metastatic ColoRectal Cancer

RR

SUMMARY: The FDA on April 24, 2015 approved CYRAMZA® for use in combination with FOLFIRI for the treatment of patients with metastatic ColoRectal Cancer (mCRC), whose disease has progressed on a first line AVASTIN® (Bevacizumab), ELOXATIN® (Oxaliplatin) and Fluoropyrimidine containing regimen. The American Cancer Society estimates that approximately 133,000 new cases of ColoRectal Cancer (CRC) will be diagnosed in the United States in 2015 and close to 50,000 are expected to die of the disease. With the availability of new active agents for the treatment of CRC, improving Overall Survival for patients with advanced disease, by prudently planning a treatment strategy and properly sequencing these agents, has become increasing relevant. CYRAMZA® (Ramucirumab) is a recombinant human IgG1 monoclonal antibody that binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D and thus inhibits ligand-induced proliferation and migration of endothelial cells. This is unlike AVASTIN®, which inhibits VEGF-A. Several studies have demonstrated that continuing VEGF inhibition along with standard second-line chemotherapy beyond disease progression has a significant advantage, in patients with mCRC. Two observational studies (BRiTE and ARIES) as well as an open label phase III study have all shown improvement in median Overall Survival (OS) when AVASTIN® was continued beyond first progression and given along with second line chemotherapy. In the VELOUR trial, FOLFIRI in combination with ZALTRAP® (Aflibercept), a VEGF-A, VEGF-B and Placental Growth Factor inhibitor, when given as second line therapy for those patients with mCRC who had progressed on AVASTIN® plus ELOXATIN® containing regimen, resulted in a significant improvement in the median PFS and OS.

The RAISE trial is a double-blind, phase III study in which 1072 patients with mCRC who progressed on or after first-line treatment with AVASTIN®, ELOXATIN® and a Fluoropyrimidine were randomized to receive FOLFIRI given along with antiangiogenic agent CYRAMZA® (N = 536) or placebo (N = 536), every 2 weeks. The FOLFIRI regimen consisted of CAMPTOSAR® (Irinotecan) 180 mg/m2 IV, Folinic Acid 400 mg/m2 IV and 5-FU 400 mg/m2 IV bolus followed by 5-FU 2400 mg/m2 continuous IV infusion over 46 to 48 hours. CYRAMZA® was administered at a dose of 8 mg/kg IV every 2 weeks. The median age of patients was 62 years, about 50% harbored KRAS mutations and 99% of the patients had an ECOG performance status of 0 or 1. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of the study was Overall Survival (OS) and secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR) and toxicity. There was a statistically significant Overall Survival improvement in patients receiving FOLFIRI plus CYRAMZA® compared to those receiving FOLFIRI plus placebo with a median OS of 13.3 and 11.7 months for patients on the FOLFIRI plus CYRAMZA® and FOLFIRI plus placebo arms, respectively (HR=0.85; P=0.023). The median PFS with FOLFIRI and CYRAMZA® was 5.7 months versus 4.5 months with FOLFIRI and placebo (HR= 0.79; P=0.001). There was no statistically significant difference in Objective Response Rate noted in the two treatment groups. Compared to the placebo group, more patients receiving CYRAMZA®, experienced grade 3 or more adverse events such as neutropenia (38.4% vs 23.3%) and hypertension (10.8% vs 2.8%). Other adverse events associated with CYRAMZA® included hemorrhage (43.9% vs 22.7% with placebo) and proteinuria (17% vs 4.5% with placebo). The authors concluded that CYRAMZA® is a new treatment option for second line treatment of patients with metastatic ColoRectal Cancer, including those with KRAS mutations. Tabernero J, Cohn AL, Obermannova R, et al. RAISE: A randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab (RAM) or placebo (PBO) in patients (pts) with metastatic colorectal carcinoma (CRC) progressive during or following first-line combination therapy with bevacizumab (bev), oxaliplatin (ox), and a fluoropyrimidine (fp). 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 512.

Higher Serum Vitamin D Levels May Improve Survival in Patients with Advanced Colon Cancer

RR

SUMMARY: The American Cancer Society estimates that approximately 133,000 new cases of colorectal cancer will be diagnosed in the United States in 2015 and close to 50,000 are expected to die of the disease. There is a growing body of evidence suggesting that Vitamin D has colon cancer preventing properties and may induce antitumor immunity. A recent study by Song and colleagues (Gut. 2015;64:260-271) showed that high plasma level 25-Hydroxy Vitamin D [25(OH)D] was associated with lower risk of colorectal cancer with intense immune reaction, supporting that vitamin D through tumor-host interaction may play a role in cancer immunoprevention. There appears to be a strong association between plasma 25(OH)D level and colorectal cancer (CRC) specific mortality, with better outcomes in patients with Stage I-III CRC, who had higher plasma levels of 25(OH)D (Zgaga L, et al. J Clin Oncol 2014;32:2430-2439). The researchers in this present study conducted a prospective analysis of data from CALGB 80405 trial and evaluated the relationship between plasma 25(OH)D level and patient outcomes, which included Overall Survival and Progression Free Survival (PFS). CALGB 80405 is a phase III trial in which patients with newly diagnosed, advanced colorectal cancer were initially randomized to three groups- 1) Chemotherapy (FOLFIRI or mFOLFOX6) with ERBITUX® (Cetuximab) 2) Chemotherapy with AVASTIN® (Bevacizumab) 3) Chemotherapy with ERBITUX® and AVASTIN®. The protocol was later amended to only include patients with KRAS Wild Type tumors and the chemotherapy with ERBITUX® and AVASTIN® group was deleted. This trial was not designed to compare chemotherapy regimens. The Overall Survival (OS) in both the treatment groups were similar at 29+ months.

In the present study, plasma 25(OH)D level were measured at baseline in 1,043 patients at the time of their enrollment in CALGB 80405, and dietary and lifestyle behaviors were collected from self-administered questionnaires. The median plasma 25(OH)D level was 17.2 ng/mL, with the range varying from 2.2 to 72.7 ng/mL (recommended range is 20-30 ng/mL). Factors associated with lower 25(OH)D level included older age, black race, lower dietary and supplemental vitamin D intake, higher Body Mass Index (BMI), ECOG performance status of 1 versus 0 and lower physical activity. Additionally, patients whose blood specimens were drawn in the winter and spring months had significantly lower 25(OH)D level, as did patients who were from the Northern and Northeastern parts of the United States. Vitamin D supplement use was uncommon in this patient population. After adjusting for pathologic and clinical prognostic factors, patients in the group with the highest level of 25(OH)D had significantly improved median OS compared to those in the group with the lowest level (32.6 vs 24.5 months; HR=0.67, P trend 0.002). Higher level of 25(OH)D was also associated with improved PFS (median 12.2 vs 10.1 months; HR 0.80, P trend = 0.02). These results were consistent across all subgroups of patients. The authors concluded that higher plasma level of 25(OH)D was associated with significantly improved survival in metastatic CRC patients treated with a combination of chemotherapy and biologic agents. With 30-35% of the malignancies attributed to dietary habits, the onus is therefore on the treating physicians to provide nutrition counseling during and after cancer treatment. Recommending vitamin D supplements for those patients with colon cancer with low vitamin D levels, may therefore not be unreasonable. Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405 (Alliance). Ng K, Venook AP, Sato K, et al. J Clin Oncol 33, 2015 (suppl 3; abstr 507)

Pre- and Post-diagnosis Physical Activity, Television Viewing, and Mortality Among Patients With Colorectal Cancer in the National Institutes of Health–AARP Diet and Health Study

RR

SUMMARY:The American Cancer Society estimates that approximately 137,000 new cases of colorectal cancer were diagnosed in the United States in 2014 and over 50,000 died of the disease. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival and Overall Survival. Reducing risk of death and improving survival even further with leisure time physical activity is the topic of this discussion. The most prevalent sedentary behavior, watching TV, has been associated with poorer survival in the general population. Several studies have suggested protective effects of physical activity on cancer recurrence although this has not been conclusive. Pooled data from other studies have shown that lack of physical activity among survivors of ColoRectal Cancer (CRC) has been associated with higher mortality risk. However, the independent effects of physical activity before and after colorectal cancer diagnosis, has remained unclear and the association between watching TV and mortality in survivors of CRC has not been defined. There are several biologic mechanisms that explain the association between sedentary life style, physical activity, and mortality. The adipose tissue in the body in addition to serving as the storage site for energy also releases adipokines, which have pro-inflammatory and anti-inflammatory properties. Physical activity decreases inflammatory adipocytokines and increases anti-inflammatory cytokines and thereby could affect cancer incidence and mortality. Also, physical activity has been shown to increase insulin sensitivity. Several studies have shown increased risk of CRC, increased angiogenesis, tumor growth, and anti-apoptotic activity with higher circulating insulin and insulin-like growth factor-1 and lower insulin-binding protein levels. Physical activity also improves cardiovascular health by lowering blood pressure. The authors in this study explored the impact of lifestyle such as moderate to vigorous intensity physical activity level and TV viewing time (sedentary life style) on ColoRectal Cancer mortality among CRC survivors, with particular attention to pre and post cancer diagnosis contributing factors. Data was collected from a large cohort of patients enrolled in the National Institutes of Health Diet and Health Study and the associations were analyzed between pre CRC diagnosis (N=3797) and post CRC diagnosis (N= 1759) life styles (physical activity and TV watching) and overall and disease-specific mortality. It was noted that patients who had 7 or more hours of weekly leisure physical activity before their diagnosis of CRC had a 20% lower risk of all-cause mortality compared to those who had a sedentary life style and were not engaged in any leisure time activity (HR=0.80; P=0.02). Patients who were engaged in 7 or more hours of weekly leisure physical activity post CRC diagnosis had a 31% lower risk of all-cause mortality compared to those who reported no activity (HR=0.69; P=0.006). This benefit was noted independent of pre-diagnosis activity. Amongst those who reported sedentary lifestyle, patients who spent 5 or more TV hours per day before CRC diagnosis had a 22% increased risk in all-cause mortality compared to those who watched no more than 2 hours of TV per day (HR=1.22; P=0.002). A similar trend of increased risk of all-cause mortality was seen in those who spent more TV hours, post diagnosis although this was not statistically significant. The authors concluded that in patients with CRC, leisure time physical activity was inversely associated with all-cause mortality, whereas more TV hours was associated with increased mortality risk. Health Care providers should therefore proactively promote increasing physical activity and minimizing TV hours, among survivors of ColoRectal Cancer. Arem H, Pfeiffer RM, Engels EA, et al. J Clin Oncol 2015; 33:180-188