Dmitriy Zamarin and Leonard Saltz
Epidemiology
• 143460 annual new cases of CRC in US: 103170 colon, 40290 rectal
• 51690 annual death, accounting for 9% of all CA death
• Highest incidence in Australia & New Zealand, Europe & North America
Risk Factors
• Age, increasing incidence between 40–50 & in each succeeding decade
• Familial syn (FAP, HNPCC, MUTYH-associated polyposis, Peutz–Jeghers, Juvenile polyposis)
• Personal or FHx of CRC or adenomatous polyps
• IBD: UC > CD, increasing risk 8–10 y after initial dx
• Other associations: Abdominal radiation, race/ethnicity (higher incidence in AA), acromegaly, long-term immunosuppression, DM, EtOH, obesity & lack of physical activity, cholecystectomy, androgen deprivation therapy (ADT), tobacco, low-fiber diet
Prevention
• ASA & NSAIDs: Potential protective effect of ASA & NSAIDs on development of colonic adenomas & CRC
• Diet: Potential protective benefit of avoidance of red meat, limited caloric intake
Genetics
• FAP (Mts in APC tumor suppressor): Less than 1%. Colon CA incidence 90% by age 45. Variants: Attenuated FAP, Gardner syn (+bone & soft tissue tumors), Turcot syn (+brain tumors)
• HNPCC (Mts in DNA MMR genes): Mean age of dx 48, penetrance of 40–80% depending on the affected gene. Other extracolonic tumors common: Endometrial CA, stomach, ovarian, small bowel, hepatobiliary, renal pelvis, & ureter
Pathology
• Adenoma-CA sequence: Most common pathway, adenomas on avg take 10 y to develop (Cell 1990;61:759). Accumulation of genetic Mts (eg, APC:53) leads to tumorigenesis. Risk of CRC ↑ w/adenoma size, #, & histology (villous > tubular)
• Serrated polyp pathway (CpG Island Methylation Phenotype or CIMP): Alternative route for CRC development through serrated adenomas
Molecular Classification
• Chromosomal instability (hereditary & sporadic): Gain of function Mts in oncogenes (eg, KRAS, & loss of function Mts in tumor suppressor genes (eg, APC, p53, DCC, SMAD4, SMAD2), no MSI
• CIMP (serrated polyp pathway):
• Hypermethylation of promoters of MMR genes such as MLH1, high incidence of BRAF Mts, MSI-high tumors
• Lynch/HNPCC (hereditary, 2° to Mt in MMR genes MLH1, MSH2, MSH6, PMS1): MSI-high, (-)chromosomal instability, (-)BRAF Mt
Clinical Presentation
• Distal colon: Hematochezia, abdominal pain, obstruction, overflow diarrhea
• Proximal colon: Iron deficiency anemia, melena, hematochezia, obstruction (rare)
• Met disease: RUQ pain, ascites, wt loss, fatigue
• Other sx: Sx from local invasion (bladder, small bowel); may mimic diverticulitis; FUO; S. bovis bacteremia & C. septicum sepsis
Screening in Average Risk Populations
• Preferred by most guidelines: Colonoscopy every 5–10 y starting at 50, highest Se & Sp, ↓ mortality in RCT (NEJM 2012;366:687)
• Other options: CT colonography every 5 y; flexible sigmoidoscopy every 5 y; FOBT annually; fecal immunochemical test (FIT) annually; stool DNA (uncertain)
Screening in Increased Risk Populations
• Lynch Syndrome (LS): Genetic counseling, colonoscopy at age 25 or 2–5 y prior to earliest colon CA & every 1–2 y; consider total abdominal colectomy
• Inherited polyposis syn (FAP, MUTYH, Peutz–Jeghers, Juvenile polyposis)—genetic counseling, colonoscopy in teens & then every 1–3 y, depending on clinical findings & syn; early total abdominal colectomy
• Personal h/o adenomatous polyps: Colonoscopy w/in 5 y (3 y for adv or >2 polyps)
• IBD—colonoscopy 8–10 y after onset of sx, then every 1–2 y
• FHx: If CRC or adenoma in 1 FDR <60, colonoscopy beginning at age 40 or 10 y earlier than the age of youngest at dx, whichever comes 1st
Diagnostic Evaluation
• Colonoscopy
• CT of chest abdomen & pelvis
• Hepatic function panel, CEA
• KRAS Mt status in pts w/met disease
• MSI testing or IHC for MMR proteins for pts <50
• Liver MRI for pts w/questionable liver mets
Staging & Prognosis
Surveillance After Initial Therapy
• Hx & physical every 6 mos for 5 y
• CEA every 6 mos for 5 y
• CT of chest/abdomen/pelvis annually for 5 y
• Colonoscopy in 1 y; if no adv adenoma repeat in 3 y, then every 5 y
Chemotherapy for Advanced & Metastatic Disease
• Definitions: FOLFOX: Infusional 5-FU/LV + OX; FOLFIRI: Infusional 5-FU/LV + irinotecan, CapeOX: Cap + OX
• 1st line: Infusional 5-FU/LV; Cap; FOLFOX (J Clin Oncol 2004;22:23); CapeOX; FOLFIRI (J Clin Oncol 2007;25:4779) ± Bev (J Clin Oncol 2007; 25:1539; J Clin Oncol 2007;25:4779) or FOLFOX ± panitumumab or FOLFIRI ± cetuximab/panitumumab (CRYSTAL NEJM 2009;360:1408; J Clin Oncol 2010;28:4697)
• 2nd line: FOLFIRI or irinotecan for pts who received prior FOLFOX; FOLFOX/CapeOX for pts w/prior FOLFIRI; FOLFOX/CapeOX, or FOLFIRI for prior 5-FU/LV or Cap. All regimens ± Bev/ziv-aflibercept, irinotecan-based regimens ± panitumumab/cetuximab
• 3rd line: Irinotecan ± panitumumab/cetuximab (BOND NEJM; 351:337) or single agent panitumumab/cetuximab, or single-agent regorafenib
• For FOLFOX, OX can be discontinued after 3–4 mos of Rx till progression to avoid neurotoxicity (OPTIMOX1 J Clin Oncol 2007;25:3224)
• No role for dual Ab (anti-EGFR & anti-VEGF) Rx
• No role for anti-EGFR Rx in KRAS mutant CAs