Primary cancer prevention: prophylactic measures to intercept tumor development.
Chemoprevention: pharmacologic blocking of intrinsic oncogene- or carcinogen-induced cell proliferation and transformation.
- • General population at risk.
- • High-risk population (eg, status post polypectomy or cancer resection).
Reduced endogenous prostaglandin: COX-2 not elevated in normal colon epithelium, overexpressed in 40–50% of colorectal adenomas, 90% of colorectal cancers.
- • Long-term use of ASA: reduction in incidence of colorectal polyps.
- • Sulindac: delay of polyp formation and regression of large bowel polyps in FAP.
- • Selective COX-2 inhibitors (celecoxib, rofecoxib): same benefits plus presumed less ulcerogenic, but increased cardiac risk.
Decreased incidence of recurrent colorectal adenomata.
Mechanism: intraluminal binding of bile and fatty acids, direct antiproliferative effect in colonic mucosa.
Decreased incidence of colorectal cancer.
Mechanism: through calcium effect, direct antiproliferative effect of Vitamin D?
- • Fiber: benefit is supported by epidemiologic association and “gut feeling” but has not been confirmed by prospective trials.
- • Folate.
- • Ursodeoxycholic acid.
- • Hormone replacement therapy → reduction in incidence of colorectal cancer and cancer-specific mortality.
- • Selenium.
Chemotherapy has evolved as a cornerstone in the treatment of various cancers. There is a large number of known chemotherapy agents overall with a wide range of mechanisms of action, but a limited number of drugs are commonly used in the realm of colorectal surgery patients. Selection of specific drugs, protocol, routes of administration, timing, and duration depend on several patient- and tumor-related factors.
- • Antimetabolites: 5-fluorouracil (+ leucovorin), capecitabine, gemcitabine.
- • Platin-based alkylating agents: oxaliplatin, carboplatin, cisplatin.
- • Topoisomerase inhibitors: irinotecan.
- • Targeted immunotherapy (monoclonal antibodies): bevacizumab, cetuximab, panitumumab.
- • Cytotoxic/antitumor antibiotics: mitomycin C.
- • Tyrosine kinase inhibitors: imatinib, sunitinib.
Antimetabolite (pyrimidine analogue).
Intracellular conversion to active metabolites → combined cytotoxic effect from inhibition of thymidylate synthase and incorporation into cellular RNA and DNA.
Leucovorin (LV; folinic acid): increase in cellular levels of reduced folates → modulation of 5-FU.
Setting: adjuvant and metastatic colorectal cancer (CRC). 5-FU/LV remains the baseline of current chemotherapy protocols: continuous infusion generally is more effective and better tolerated than bolus administration.
Bone marrow suppression (maximum after 9–14 days), GI toxicity (anorexia, nausea/vomiting, diarrhea, stomatitis = signs of impending toxicity → need to interrupt treatment), dermatologic (reversible maculopapular rash, hand-and-foot syndrome, alopecia, sensitivity to sunlight, hyperpigmentations), neurologic (headache, visual disturbances, cerebellar ataxia).
Plasma half-life 10–20 minutes, hepatic catabolism into carbon dioxide and metabolite → urinary excretion. Perioperative discontinuation 3–4 weeks.
Familial dihydropyrimidine dehydrogenase (DPD) deficiency → risk of severe toxicity.
Antimetabolite (pyrimidine analogue).
Oral prodrug of 5-FU: intestinal absorption → accumulation in tumor cells → intracellular three-step metabolism to active 5-FU → cytotoxic effect as 5-FU.
Setting: adjuvant and metastatic CRC. Dosing convenience: oral administration alone or as part of combination regimens.
Like 5-FU but generally improved tolerance.
Renal dysfunction. Perioperative discontinuation 3–4 weeks.
Familial DPD deficiency → risk of severe toxicity.
Platin-based alkylating agent.
Exact details unknown: unspecific cytotoxic effect, synergistic with 5-FU.
Setting: adjuvant and metastatic CRC. IV administration: FOLFOX4, FOLFOX6, FOLFOX7, CAPEOX, IROX.
Neuropathy (acute/reversible and chronic/irreversible), neutropenia, nausea/vomiting, diarrhea, fatigue. Less ototoxicity and nephrotoxicity than cisplatin and carboplatin.
Half-life 15–30 minutes. Discontinuation 4 weeks before/after elective surgery.
Febrile neutropenia. Increased toxicity in combination with bolus 5-FU.
Topoisomerase I inhibitor.
Intracellular conversion into active metabolite SN-38 → inhibition of intracellular topoisomerase-controlled topology/cleavage of supercoiled DNA double helix during transcription/replication → inhibition of DNA relaxation and unwinding necessary for replication and transcription → cell death.
Setting: metastatic CRC, not established for adjuvant. FOLFIRI, IFL.
Diarrhea, dehydration, myelosuppression, alopecia.
Half-life ~6–12 hours (inactivation by enzyme UGT1A1), but longer lasting biologic effect → discontinuation 4 weeks before/after elective surgery.
Patients with polymorphisms in UGT1A1 gene → higher effective dose (decreased inactivation) → need for dose reduction.
Severe diarrhea-induced dehydration, neutropenia.
Monoclonal antibody → targeted immunotherapy.
Monoclonal antibody against vascular endothelial growth factor (VEGF) → blocking tumor angiogenesis. For adequate tumor response: combination with cytotoxic chemotherapy drug needed (eg, 5-FU).
Setting: metastatic CRC, not (yet) established for adjuvant. IV administration every 14 days in combination chemotherapy protocols (with 5-FU/LV, oxaliplatin, irinotecan).
Increased risk of grade 3–4 bleeding, thromboembolism, hypertension. Bowel perforation. Negative impact on anastomotic and wound healing.
Half-life ~20 days (range 10–50 days) → discontinuation 4–6 weeks before/after elective surgery.
GI perforation (1–2%), bleeding 3%, arterial emboli 2–3%, reversible posterior leukoencephalopathy syndrome < 1%.
Monoclonal antibody → targeted immunotherapy.
Chimeric monoclonal antibody against epidermal growth factor receptor (EGFR): high-affinity binding specifically to extracellular domain of human EGFR → blocks EGF/transforming growth factor-α binding to EGFR, which prevents activation of intracellular tyrosine kinase and EGFR signaling cascade → impaired cell growth and proliferation. Synergistic antitumor activity with conventional anticancer drugs and radiation.
Setting: metastatic CRC. Metastatic CRC, combination with irinotecan.
Dermatologic: acne-like rash, xerosis (dry skin), fissures/rhagades.
Half-life ~4–5 days → discontinuation 2–3 weeks prior/after elective surgery.
Severe skin eruptions → pain, superinfection.
Monoclonal antibody → targeted immunotherapy.
Entirely human monoclonal antibody against EGFR.
Setting: metastatic CRC. IV treatment of EGFR-expressing metastatic CRC with disease progression despite conventional chemotherapy.
Tyrosine kinase inhibitors → see separate discussion later in chapter.
Antitumor antibiotic.
Isolated from Streptomyces caespitosus: in vivo activation to alkylating agent → binding to DNA with cross-linking → dysfunction resulting in cell-cycle–independent DNA synthesis and transcription.
Setting: anal cancer. IV administration.
Myelosuppression, cardiac and pulmonary toxicity, nephrotoxicity.
Half-life 15–20 minutes, elimination by hepatic metabolism.
Myelosuppression (cumulative effect), renal failure and hemolytic uremic syndrome (10%), pulmonary toxicity (40% mortality).
Pyrimidine antimetabolite.
Antimetabolite related to cytarabine: intracellular metabolism to active di-/triphosphate nucleosides → S-phase/G1-phase–specific inhibition of DNA synthesis → apoptosis.
Setting: metastatic CRC. IV administration.
Myelosuppression, rashes, flulike symptoms, edema, hemolytic uremic syndrome.
Half-life 1–10 hours (50% urinary excretion) → discontinuation 4–6 weeks before/after elective surgery.
Alkylating agent.
Exact details unknown: DNA crosslinking resulting in unspecific cytotoxic effect.
Alternate protocol to Nigro standard protocol for anal squamous cell cancer.
Dose-dependent cumulative nephrotoxicity, neuro- and ototoxicity, bone marrow suppression.
Half-life up to 3 days (!).
Acute nephrotoxicity. Increased toxicity in combination with radiation therapy.
Antimetabolite.
Inhibitor of thymidylate synthase: depletion of cellular thymidine triphosphate (needed for DNA/RNA synthesis) → DNA/RNA fragmentation → cell death.
Setting: metastatic CRC. IV administration.
GI toxicity (nausea, vomiting, anorexia), myelosuppression (neutropenia, anemia, thrombocytopenia), dermatologic, fever, etc.
Half-life ~8 days (50% urinary excretion) → discontinuation 4–6 weeks before/after elective surgery. Dose reduction for GI or hematologic side effects.
Life-threatening or fatal combination of leukopenia/thrombocytopenia with GI toxicity.
- • PTK787: multi-inhibitor of vascular endothelial growth factor receptor (VEGFR).
- • BAY 43-9006: dual inhibitor of RAF kinase and VEGFR.
Probability of recurrent cancer 40–50% after “curative” radical resection of stage II and III without residual disease (R0 resection). With better understanding of tumor pathophysiology, availability of different chemotherapy drugs, and more sophisticated protocols, adjuvant or neoadjuvant chemotherapy has secured a role beyond just acceptance, demonstrating superiority over the surgery-only approach for a large number of cancer patients with increased response and survival rates.
Selection of specific drugs, protocol, route of administration, timing, and duration depend on several factors: histopathology, stage, primary and secondary tumor sites, patient performance status, response to treatment, side effects, and performed or planned surgery. Evidence is subject to continuous change or updates as results from trials come in.
- • Colon cancer stage III (pTxN1–2).
- • Colon cancer stage IIB (pT4N0), particularly if perforation.
- • Colon cancer stage IIA (pT3) with unfavorable features: peritumoral lymphovascular involvement, inadequately sampled nodes, poorly differentiated histology.
- • Rectal cancer stage II (u/pT3–4N0) and III (u/pTxN1–2).
- • Rectal cancer stage pT2 post transanal local excision.
- • Postoperative chemotherapy for 6 months is sufficient (no benefit from longer course).
- • IV 5-FU/LV is superior to bolus 5-FU/LV.
- • Levamisole is not necessary.
- • Combination of 5-FU/LV and oxaliplatin is superior to 5-FU/LV alone.
- • Capecitabine is similarly effective or even modestly better than IV 5-FU/LV.
- • Effectiveness of adjuvant chemotherapy is independent of patient age.
- • No documented role in adjuvant setting for the use of irinotecan, cetuximab, or bevacizumab, but subject to ongoing trials.
- • No documented survival benefit of adjuvant therapy for patients with standard risk stage II disease.
- • Chemotherapy in high-risk stage II disease appears logical but remains controversial because of lack of objective validation → needs further studies.
Surgery alone: colon cancer—stage I (pT1–2N0), stage IIA (pT3N0); in medically fit patients routine use of adjuvant chemotherapy is not recommended for stage II colon cancer without poor prognostic indicators.
Radiation alone or radiation + surgery: increasingly unusual approach for GI/anorectal tumors.
Bolus of 5-FU + leucovorin weekly for 6 weeks, 2 weeks of rest → total of three cycles every 8 weeks.
Standard protocol if oxaliplatin is contraindicated or not tolerated.
Ongoing sepsis, neutropenia, liver failure, kidney failure.
Grade III or IV: diarrhea 40%, stomatitis 1%, neutropenia 4%.
Bolus of 5-FU + leucovorin on days 1–5, followed by 3 weeks of rest → total of six cycles every 4 weeks.
Standard protocol if oxaliplatin is contraindicated or not tolerated.
Ongoing sepsis, neutropenia, liver failure, kidney failure.
More toxic than other 5-FU/LV regimens → grade III or IV: diarrhea 13–21%, stomatitis 14–18%, neutropenia 16–55%.
Capecitabine: two oral doses twice daily for 14 days + 7 days of rest → total of eight cycles every 3 weeks.
Alternative/new protocol if oxaliplatin is contraindicated or not tolerated.
Ongoing sepsis, neutropenia, liver failure, kidney failure.
Better tolerated than IV 5-FU/LV regimens.
Oxaliplatin IV day 1; leucovorin IV days 1 and 2; 5-FU IV bolus, followed by continuous infusion over days 1 and 2 → total of 12 cycles every 14 days.
Standard intensive chemotherapy of choice if tolerated, particularly for tumors with aggressive features and younger patients; 18–25% risk reduction compared with bolus 5-FU/LV (78% vs 73% disease-free survival).
Allergic reactions. Preexisting neuropathy.
Neutropenia (> 40%), febrile neutropenia, peripheral neuropathy (grade 3: 12% immediate, 1% persistent long-term).
Oxaliplatin IV day 1; leucovorin IV day 1 only; 5-FU IV bolus, followed by continuous infusion (higher dose than FOLFOX4) over days 1 and 2 → total of 12 cycles every 14 days.
Same as FOLFOX4, but higher dose of oxaliplatin and more convenient for patient: need for treatment only on day 1 of each cycle.
Allergic reactions. Preexisting neuropathy.
Neutropenia (> 40%), febrile neutropenia, peripheral neuropathy (grade 3: 12% immediate, 1% persistent long-term).
Oxaliplatin IV day 1; capecitabine PO bid days 1–14 + 7 days of rest → every 21 days.
Alternative protocol to FOLFOX with increased dosing convenience.
Ongoing sepsis, neutropenia, liver failure, kidney failure.
Comparable or slightly better toxicity profile than FOLFOX.
Availability of new drugs, introduction of biologic agents, and refinement of drug combinations and sequences has resulted in improved prospects for patients with metastatic colorectal cancer (CRC), prolonging overall survival from 6 months to currently > 22 months.
Treatment goals in the metastatic setting are:
- • Cessation of tumor progression, tumor shrinkage (→ potential for future resection of metastatic foci).
- • Maintenance/improvement of overall quality of life.
- • Acceptable profile of adverse effects.
- • Prolonged survival.
Presence of limited metastatic disease is still consistent with possibility of resection with curative intent: combination chemotherapy is increasingly established. Route of drug administration: systemic administration (IV/oral) = standard. Regional treatment (hepatic arterial infusion, intraperitoneal chemotherapy) in the majority of situations is of no benefit.
All common regimens of advanced chemotherapy are based on 5-FU/LV (continuous infusion) or its oral prodrug capecitabine (Xeloda) in combination with either oxaliplatin or irinotecan.
Addition of targeted therapies bevacizumab or cetuximab (against vascular endothelial growth factor [VEGF], endothelial growth factor receptor [EGFR]) increases efficacy of chemotherapy with irinotecan and oxaliplatin: → FOLFIRI, FOLFOX, or XELOX plus bevacizumab have evolved as similarly effective first-line regimens for metastatic disease with regard to response and progression-free survival. Potentially even better response from combination of irinotecan and oxaliplatin (FOLFOXIRI).
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