Nonsurgical Management




Chemoprevention of Colorectal Cancer



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Principle



Primary cancer prevention: prophylactic measures to intercept tumor development.



Chemoprevention: pharmacologic blocking of intrinsic oncogene- or carcinogen-induced cell proliferation and transformation.




Alternatives



Secondary/tertiary prevention: screening, surveillance.




Indications




  • • General population at risk.
  • • High-risk population (eg, status post polypectomy or cancer resection).




Positive Effect Documented



COX Inhibitors



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.



Calcium (3 g/Day)



Decreased incidence of recurrent colorectal adenomata.



Mechanism: intraluminal binding of bile and fatty acids, direct antiproliferative effect in colonic mucosa.



Vitamin D



Decreased incidence of colorectal cancer.



Mechanism: through calcium effect, direct antiproliferative effect of Vitamin D?




Positive Effect Controversial or Awaiting Further Confirmation




  • • 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.




Positive Effect Not Documented




  • • Vitamins C and E.
  • • β-Carotenes.





Chemotherapy—Commonly Used Drugs



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Principle



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.




Mechanism of Action Categories




  • • 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.




Specific Drugs



5-Fluorouracil (+ Leucovorin)



Antimetabolite (pyrimidine analogue).



Mechanism of Action


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.



Protocols


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.



Toxicity and Adverse Effects


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).



Dose Adjustments


Plasma half-life 10–20 minutes, hepatic catabolism into carbon dioxide and metabolite → urinary excretion. Perioperative discontinuation 3–4 weeks.



Complications


Familial dihydropyrimidine dehydrogenase (DPD) deficiency → risk of severe toxicity.



Capecitabine (Xeloda)



Antimetabolite (pyrimidine analogue).



Mechanism of Action


Oral prodrug of 5-FU: intestinal absorption → accumulation in tumor cells → intracellular three-step metabolism to active 5-FU → cytotoxic effect as 5-FU.



Protocols


Setting: adjuvant and metastatic CRC. Dosing convenience: oral administration alone or as part of combination regimens.



Toxicity and Adverse Effects


Like 5-FU but generally improved tolerance.



Dose Adjustments


Renal dysfunction. Perioperative discontinuation 3–4 weeks.



Complications


Familial DPD deficiency → risk of severe toxicity.



Oxaliplatin (Eloxatin)



Platin-based alkylating agent.



Mechanism of Action


Exact details unknown: unspecific cytotoxic effect, synergistic with 5-FU.



Protocols


Setting: adjuvant and metastatic CRC. IV administration: FOLFOX4, FOLFOX6, FOLFOX7, CAPEOX, IROX.



Toxicity and Adverse Effects


Neuropathy (acute/reversible and chronic/irreversible), neutropenia, nausea/vomiting, diarrhea, fatigue. Less ototoxicity and nephrotoxicity than cisplatin and carboplatin.



Dose Adjustments


Half-life 15–30 minutes. Discontinuation 4 weeks before/after elective surgery.



Complications


Febrile neutropenia. Increased toxicity in combination with bolus 5-FU.



Irinotecan (Camptosar, CPT-11)



Topoisomerase I inhibitor.



Mechanism of Action


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.



Protocols


Setting: metastatic CRC, not established for adjuvant. FOLFIRI, IFL.



Toxicity and Adverse Effects


Diarrhea, dehydration, myelosuppression, alopecia.



Dose Adjustments


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.



Complications


Severe diarrhea-induced dehydration, neutropenia.



Bevacizumab (Avastin)



Monoclonal antibody → targeted immunotherapy.



Mechanism of Action


Monoclonal antibody against vascular endothelial growth factor (VEGF) → blocking tumor angiogenesis. For adequate tumor response: combination with cytotoxic chemotherapy drug needed (eg, 5-FU).



Protocols


Setting: metastatic CRC, not (yet) established for adjuvant. IV administration every 14 days in combination chemotherapy protocols (with 5-FU/LV, oxaliplatin, irinotecan).



Toxicity and Adverse Effects


Increased risk of grade 3–4 bleeding, thromboembolism, hypertension. Bowel perforation. Negative impact on anastomotic and wound healing.



Dose Adjustments


Half-life ~20 days (range 10–50 days) → discontinuation 4–6 weeks before/after elective surgery.



Complications


GI perforation (1–2%), bleeding 3%, arterial emboli 2–3%, reversible posterior leukoencephalopathy syndrome < 1%.



Cetuximab (Erbitux)



Monoclonal antibody → targeted immunotherapy.



Mechanism of Action


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.



Protocols


Setting: metastatic CRC. Metastatic CRC, combination with irinotecan.



Toxicity and Adverse Effects


Dermatologic: acne-like rash, xerosis (dry skin), fissures/rhagades.



Dose Adjustments


Half-life ~4–5 days → discontinuation 2–3 weeks prior/after elective surgery.



Complications


Severe skin eruptions → pain, superinfection.



Panitumumab (Vectibix)



Monoclonal antibody → targeted immunotherapy.



Mechanism of Action


Entirely human monoclonal antibody against EGFR.



Protocols


Setting: metastatic CRC. IV treatment of EGFR-expressing metastatic CRC with disease progression despite conventional chemotherapy.



Imatinib (Gleevec) and Sunitinib



Tyrosine kinase inhibitors → see separate discussion later in chapter.



Mitomycin C



Antitumor antibiotic.



Mechanism of Action


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.



Protocols


Setting: anal cancer. IV administration.



Toxicity and Adverse Effects


Myelosuppression, cardiac and pulmonary toxicity, nephrotoxicity.



Dose Adjustments


Half-life 15–20 minutes, elimination by hepatic metabolism.



Complications


Myelosuppression (cumulative effect), renal failure and hemolytic uremic syndrome (10%), pulmonary toxicity (40% mortality).



Gemcitabine (Gemzar)



Pyrimidine antimetabolite.



Mechanism of Action


Antimetabolite related to cytarabine: intracellular metabolism to active di-/triphosphate nucleosides → S-phase/G1-phase–specific inhibition of DNA synthesis → apoptosis.



Protocols


Setting: metastatic CRC. IV administration.



Toxicity and Adverse Effects


Myelosuppression, rashes, flulike symptoms, edema, hemolytic uremic syndrome.



Dose Adjustments


Half-life 1–10 hours (50% urinary excretion) → discontinuation 4–6 weeks before/after elective surgery.



Cisplatin (Platinol)



Alkylating agent.



Mechanism of Action


Exact details unknown: DNA crosslinking resulting in unspecific cytotoxic effect.



Protocols


Alternate protocol to Nigro standard protocol for anal squamous cell cancer.



Toxicity and Adverse Effects


Dose-dependent cumulative nephrotoxicity, neuro- and ototoxicity, bone marrow suppression.



Dose Adjustments


Half-life up to 3 days (!).



Complications


Acute nephrotoxicity. Increased toxicity in combination with radiation therapy.



Raltitrexed (Tomudex)



Antimetabolite.



Mechanism of Action


Inhibitor of thymidylate synthase: depletion of cellular thymidine triphosphate (needed for DNA/RNA synthesis) → DNA/RNA fragmentation → cell death.



Protocols


Setting: metastatic CRC. IV administration.



Toxicity and Adverse Effects


GI toxicity (nausea, vomiting, anorexia), myelosuppression (neutropenia, anemia, thrombocytopenia), dermatologic, fever, etc.



Dose Adjustments


Half-life ~8 days (50% urinary excretion) → discontinuation 4–6 weeks before/after elective surgery. Dose reduction for GI or hematologic side effects.



Complications


Life-threatening or fatal combination of leukopenia/thrombocytopenia with GI toxicity.



Experimental Drugs (in the Pipeline)




  • • PTK787: multi-inhibitor of vascular endothelial growth factor receptor (VEGFR).
  • • BAY 43-9006: dual inhibitor of RAF kinase and VEGFR.





Chemotherapy Protocols—Curative Intent (Colorectal Cancer)



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Principle



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.




Indications




  • • 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.




Summary of Evidence



Stage III Colorectal Cancer (CRC)




  • • 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.



Stage II CRC




  • • 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.




Alternatives



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.




Adjuvant Chemotherapy Protocols with Curative Intent



Weekly Bolus 5-FU + Leucovorin (Roswell Park)



Bolus of 5-FU + leucovorin weekly for 6 weeks, 2 weeks of rest → total of three cycles every 8 weeks.



Indication


Standard protocol if oxaliplatin is contraindicated or not tolerated.



Contraindications


Ongoing sepsis, neutropenia, liver failure, kidney failure.



Toxicity and Adverse Effects


Grade III or IV: diarrhea 40%, stomatitis 1%, neutropenia 4%.



Monthly Bolus 5-FU + Leucovorin (Mayo Clinic)



Bolus of 5-FU + leucovorin on days 1–5, followed by 3 weeks of rest → total of six cycles every 4 weeks.



Indication


Standard protocol if oxaliplatin is contraindicated or not tolerated.



Contraindications


Ongoing sepsis, neutropenia, liver failure, kidney failure.



Toxicity and Adverse Effects


More toxic than other 5-FU/LV regimens → grade III or IV: diarrhea 13–21%, stomatitis 14–18%, neutropenia 16–55%.



Capecitabine (Xeloda)



Capecitabine: two oral doses twice daily for 14 days + 7 days of rest → total of eight cycles every 3 weeks.



Indication


Alternative/new protocol if oxaliplatin is contraindicated or not tolerated.



Contraindications


Ongoing sepsis, neutropenia, liver failure, kidney failure.



Toxicity and Adverse Effects


Better tolerated than IV 5-FU/LV regimens.



FOLinic acid + Fluorouracil + OXaliplatin (FOLFOX 4)



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.



Indication


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).



Contraindications


Allergic reactions. Preexisting neuropathy.



Toxicity and Adverse Effects


Neutropenia (> 40%), febrile neutropenia, peripheral neuropathy (grade 3: 12% immediate, 1% persistent long-term).



FOLinic acid + Fluorouracil + OXaliplatin (FOLFOX 6)



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.



Indication


Same as FOLFOX4, but higher dose of oxaliplatin and more convenient for patient: need for treatment only on day 1 of each cycle.



Contraindications


Allergic reactions. Preexisting neuropathy.



Toxicity and Adverse Effects


Neutropenia (> 40%), febrile neutropenia, peripheral neuropathy (grade 3: 12% immediate, 1% persistent long-term).



CAPEcitabine (XELoda) + OXaliplatin (CAPEOX, XELOX)



Oxaliplatin IV day 1; capecitabine PO bid days 1–14 + 7 days of rest → every 21 days.



Indication


Alternative protocol to FOLFOX with increased dosing convenience.



Contraindications


Ongoing sepsis, neutropenia, liver failure, kidney failure.



Toxicity and Adverse Effects


Comparable or slightly better toxicity profile than FOLFOX.





Chemotherapy Protocols—Metastatic Colorectal Cancer



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Principle



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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Jan 14, 2019 | Posted by in GASTOINESTINAL SURGERY | Comments Off on Nonsurgical Management
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