Pocket Oncology (Pocket Notebook Series), 1st Ed.

COLON CANCER

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