Tag: Colon Cancer

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.

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)

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

SUMMARY: Approximately 32 million Americans take a statin in the United States. Statins (3-Hydroxy-3-MethylGlutaryl coenzyme A reductase inhibitors) are usually prescribed to lower LDL cholesterol. Cholesterol is a structural component of cell membranes and a reduction in the availability of cholesterol can result in decreased proliferation and migration of cancer cells. The six statin drugs available in the United States include LIPITOR® (Atorvastatin), ZOCOR® (Simvastatin), CRESTOR® (Rosuvastatin), MEVACOR® (Lovastatin), PRAVACHOL® (Pravastatin) and LESCOL® (Fluvastatin). Statin use in cancer patients has been associated with a reduction in cancer related mortality in several clinical studies. This benefit has been attributed to the inhibition of HMG-CoA reductase, which is a rate limiting enzyme in the mevalonate and cholesterol synthesis pathway. The mevalonate pathway is upregulated by mutated p53 (tumor suppressor gene) which is often expressed in cancer cells. By inhibiting the mevalonate pathway, statins can reduce isoprenoid levels such as farnesylpyrophosphate (F-PP) and geranylgeranylpyrophosphate (GG-PP). These isoprenoids are essential for the posttranslational modification of several proteins involved in important intracellular signaling pathways and therefore play a crucial role in cell growth, proliferation, survival and migration. Statins also inhibit angiogenic pathways and proteasomes, thereby negatively impacting cell proliferation and survival. Survival benefit with statin use after colorectal cancer diagnosis has been unclear. To answer this question, the authors identified a cohort of patients (N=7657) diagnosed with stage I to III colorectal cancer from 1998 to 2009, in the National Cancer Data Repository (English Cancer Registry). Information on statin use was obtained from medical records of patients and in this cohort of patients 35% were identified to have used statin drugs following diagnosis of colorectal cancer. Twenty percent of these patients had stage I disease, 43% had stage II disease and 37% had stage III disease. Patients were followed up for 14 years following their diagnosis of colorectal cancer. Statin use after a diagnosis of colorectal cancer was associated with a 29% reduction in colorectal cancer-specific mortality (HR= 0.71). There was a dose-response association with a 36% reduction in colorectal cancer-specific mortality with statin use for more than 1 year (HR=0.64). Statin users after colorectal cancer diagnosis also had a 25% reduction in all-cause mortality (HR=0.75). The authors concluded that based on this large population based colorectal cancer cohort, statin use following diagnosis of colorectal cancer was associated with longer rates of survival. Cardwell CR, Hicks BM, Hughes C, et al. J Clin Oncol 2014;32:3177-3183

SUMMARY: The American Cancer Society estimates that approximately 137,000 new cases of colorectal cancer will be diagnosed in the United States in 2014 and over 50,000 are expected to die of the disease. It is the third leading cause of cancer death in the U.S. and the lifetime risk of developing colorectal cancer is 1 in 20. Implementation of screening programs in the U.S. has resulted in a 46% decrease in the rate of death from colorectal cancer, from its peak. The U.S. Preventive Services Task Force recommends annual screening with high sensitivity Fecal Occult Blood Testing (FOBT), sigmoidoscopy every 5 years with high-sensitivity FOBT every 3 years and screening colonoscopy every 10 years. Fecal Immunochemical testing (FIT) measures intact human globin protein as opposed to heme. Animal heme from meat will not trigger a false positive test with FIT and as such dietary restrictions are not necessary. Further, FIT is superior to FOBT in detecting advanced adenomas and only requires one stool specimen, as opposed to three specimens for FOBT. COLOGUARD® is highly sensitive, noninvasive, multitarget, stool based DNA test, for colorectal cancer screening ie.early detection of colorectal cancer and precancerous lesions. This test takes advantage of the genetic and epigenetic alterations that leads to the development of colorectal cancer and analyzes the altered DNA signatures of cancerous and precancerous cells that exfoliate into the colon. In addition, this test includes an immunochemical assay for human hemoglobin. The stool samples can be easily collected, mailed from home, and requires no bowel preparation, medication restrictions or dietary change. The purpose of this study was to determine the sensitivity of COLOGUARD® as compared with FIT, for the detection of screening-relevant colorectal cancer. The study was conducted at 90 medical centers throughout the United States and Canada and evaluable patients (N=9989) were asymptomatic individuals between ages 50 and 84 years who were required to provide a stool sample and undergo screening colonoscopy within 90 days. Enrollment was weighted toward those aged 65 years or older. The primary outcome was the ability of COLOGUARD® to detect colorectal cancer and secondary outcomes were the ability of COLOGUARD® to detect advanced precancerous lesions, polyps with high grade dysplasia and serrated sessile polyps measuring 1 cm or more, when compared to FIT. (Sensitivity is defined as the proportion of persons with disease who have a positive test and Specificity is defined as proportion of persons without disease who have a negative test.) The sensitivity for detecting colorectal cancer was 92% with COLOGUARD® and 74% with FIT (P=0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% vs 23.8% (P<0.001), polyps with high-grade dysplasia was 69.2% vs 46.2% (P=0.004) and serrated sessile polyps measuring 1 cm or more were 42.4% vs 5.1%, (P<0.001) with COLOGUARD® and FIT respectively. Specificities with COLOGUARD® were lower compared to FIT (P<0.001). The authors concluded that COLOGUARD® can detect significantly more colorectal cancers and precancerous lesions than FIT. The high sensitivity of this non-invasive, stool DNA test, to detect curable stage of colorectal cancer, may increase the number of people, who will choose to be screened for colorectal cancer. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. N Engl J Med 2014; 370:1287-1297

SUMMARY: It is estimated that approximately 97,000 new cases of colon cancer will be diagnosed in 2014 and over 50,000 will die of the disease. The lifetime risk of developing colorectal cancer is about 1 in 20. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Multi agent chemotherapy in combination with monoclonal antibodies, targeted against Epidermal Growth Factor Receptor (EGFR) such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab), have demonstrated survival benefit, for patients with metastatic colon cancer, whose tumors do not harbor KRAS mutations in exon 2. The authors in this study evaluated the benefit of testing metastatic colorectal cancer tumors for RAS mutations beyond the mutations in the KRAS gene at exon 2. The most common RAS oncogenes in human cancer are HRAS, KRAS, and NRAS. Mutations in HRAS are not common in colon cancer whereas KRAS and NRAS mutations are seen in colon cancer and tend to be mutually exclusive. Activating mutations in exon 2 of the KRAS gene is seen in about 40% of colon cancer patients and predicts resistance to EGFR therapy. Mutational analysis is therefore usually performed to look for mutations in exon 2 of the KRAS gene. It appears however that a broader assessment of the RAS genes may more accurately predict resistance to EGFR therapy. It is also known that mutations in BRAF gene, which is downstream from RAS, may confer poor prognosis in colon cancer, regardless of therapy. The authors in a previous publication showed that in a phase III study involving 1,186 patients, the addition of VECTIBIX®, a fully human, EGFR targeted, monoclonal antibody, when combined with FOLFIRI (Folinic acid, Fluorouracil and Irinotecan), significantly improved Progression Free Survival, when compared to FOLFIRI alone (HR=0.73; P=0.004), with a trend towards improved Overall Survival (HR=0.85; P=0.12). Evolving data has suggested that testing for additional mutations in the RAS genes may help better understand the efficacy of/resistance to VECTIBIX®. In this present analysis, tumor samples of patients from the authors previous study, that were already known to be Wild Type KRAS – unmutated at KRAS exon 2 (N=597), were assessed for additional RAS mutations, specifically in KRAS exons 3 and 4 and NRAS exons 2, 3 and 4. Eighteen percent (18%) of the Wild Type KRAS exon 2 patients harbored additional RAS mutations. It was noted that patients receiving VECTIBIX® along with FOLFIRI had an improvement in both the median OS and PFS when they had wild-type (unmutated) RAS tumors compared to those, whose tumors harbored RAS mutations (median OS: 16.2 vs 11.8 months; median PFS: 6.4 vs 4.8 months). More importantly, amongst patients with mutated RAS tumors, the addition of VECTIBIX® to FOLFIRI resulted in no significant survival benefit compared to FOLFIRI alone (median OS: 11.8 vs 11.1 months; median PFS: 4.8 vs 4.0 months). The authors concluded that comprehensive RAS mutational analysis rather than KRAS testing alone, gives more relevant information for proper selection of patients with metastatic colorectal cancer, who would benefit from EGFR targeted monoclonal antibodies such as VECTIBIX®. In addition patients with RAS mutations could be spared from the associated cost and toxicites of EGFR targeted monoclonal antibodies that will not improve their outcomes. Peeters M, Oliner KS, Price TJ, et al. J Clin Oncol 32, 2014 (suppl 3; abstr LBA387)