Colon Cancer Statistics in the US

Colorectal cancer is fourth most frequently diagnosed cancer in US

Second leading cause of cancer deaths

In 2013, estimated 96,830 new cases of colon cancer and approx. 40,000 cases of rectal cancer will occur.

Incidence of colon and rectal cancer has decreased from 60.5 per 100,000 people in 1976 to 46.4 in 2005.

Mortality decreased by 35% from 1990 to 2007.

Risk Assessment

• Approx 20% cases of colon cancer are associated with familial clustering.

• Genetic susceptibility to colorectal cancer includes Lynch syndrome (also known as HNPCC) and FAP (familial adomatous polyposis).

• Important to review family history.

Lynch Syndrome

• It is the most common form of genetically determined colon cancer predisposition.

• Accounts for 2-4% of all cases.

• Results from germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2).

• Patients to be sequenced have to undergo one of 2 tests: 1)immunohistochemical analysis for MMR protein expression, which is diminished due to mutation or 2) analysis of MSI, which results from MMR deficiency and is detected as changes in length of repetitive DNA elements in tumor tissue caused by insertion or deletion of repeated units.

Lynch Syndrome

• Testing BRAF gene for mutation is indiacted when IHC analysis shows MLH1 protein expression to be absent in the tumor.

• Presence of BRAF mutation indicates that MLH1 gene expression is downregulated through somatic hypermethykation of promoter region of the gene and not through germline mutation.

• Cost effectiveness of Universal or reflex testing has been confirmed

• It is recommended that universal genetic testing should be done on tumors of all patients with newly diagnosed CRC.

• Alternative approach is to test patients diagnosed before 70 years plus patients diagnosed at older ages who meet Bethesda guidelines.

• This has a sensitivity of 95.1% and specificity of 95.5%.

• While this strategy failed to detect 4.9% of Lynch cases, it resulted in approx. 35% fewer tumors undergoing MMR testing than a universal approach.

• NCCN recommends the selective approach.

• MMR testing should be done in Stage II tumors.

Staging

Pathologic Review

Pathologic Review

Pathologic Review

Pathologic Review

FOLFOX

• The Phase III EORTC 40983 study, evaluated use of perioperative FOLFOX (6 cycles before and 6 cycles after surgery) for patients with resectable liver metastases.

• It showed absolute improvements in 3 year PFS of 8.1% (P=0.041) and 9.2% (P=0.025) for all eligible and resected patients when chemo with surgery was compared with surgery alone.

• No difference in OS was seen.

• Oxaliplatin is associated with increased risk of peripheral sensory neuropathy.

FOLFOX

• Results of OPTIMOX1 study showed that a “stop-and-go” approach using oxaliplatin free intervals resulted in decreased neurotoxicity and did not affect OS in patients receiving FOLFOX as initial therapy for metastatic disease.

• Discontinuation of oxaliplatin from FOLFOX or CapeOx should be considered after 3 months of therapy, while maintaining the other drugs in the regimen for 6 months or till tumor progression.

• Patients with oxaliplatin induced neurotoxicity should not receive it again until near complete resolution.

• No role of calcium/magnesium infusions in preventing oxaliplatininduced neurotoxicity.

CapeOx

• It is an active first line therapy for patients with metastatic CRC.• CapeOx and FOLFOX have similar median PFS.• Toxicities associated with Capecitabine include the following:• 1)Patients with diminished creatinine clearance may accumulate levels of

the drug requiring dose modification.• 2) The incidence of hand-foot syndrome was increased in patients receiving

Capecitabine based regimens as compared to 5FU/LV based regimens.• 3) North American patients may have increased risk of adverse events at

doses tolerated by their European counterparts.• Recent studies have shown that capecitabine induced hand-foot skin

reactions are associated with an improved OS.• Bevacizumab may be added to Capecitabine as first line therapy.

FOLFIRI

• FOLFOX and FOLFIRI have comparable efficacy in terms of response rate, PFS and OS.

• Toxicities associated with irinotecan include both early and late forms of diarrhea, dehydration and severe neutropenia.

• Irinotecan is inactivated by the enzyme uridine diphosphate glucuronyltransferase 1A1, which is also involved in converting bilirubin into more soluble forms through conjugation.

• Deficiencies in UGT1A1 can be caused by genetic polymorphism and can result in conditions associated with unconjugated hyperbilirubinemias such as types I and II Crigler-Najjar and Gilbert syndromes.

FOLFIRI

• Irinotecan should be used with caution and at a decreased rate in patients with Gilbert syndrome or elevated serum bilirubin.

• Certain polymorphism can decrease level of glucuronidation of the active metabolite of irinotecan and result in toxic levels of the drug.

• Dosing of irinotecan should be individualized based on UGT1A1 genotype.

• Commercial tests for detecting UGT1A1 allele which is associated with decreased gene expression and reduced levels of UIGT1A1 expression.

• No role of testing for UGT1A1 allele in patients who develop irinotecanrelated toxicity since these patients require a dose reduction regardless.

• Avastin as well as Cetuximab/Panitumumab may be added to FOLFIRI.