colorectal%20cancer
COLORECTAL CANCER
Colorectal cancer is a carcinoma arising from the luminal surface of the colon.
It is the 2nd most common cancer in women and third most common cancer in male worldwide. It commonly arises from adenomatous polyps.
It is strongly linked to age with 83% occurring in people ≥60 years old.
Rectal cancer is defined as cancerous lesions located within 12 cm of the anal verge.

Pharmacotherapy

  • Choice of therapeutic agents for colorectal cancers is based on factors such as goals of therapy, type & timing of prior therapy, efficacy & toxicity profiles of the drugs

Chemotherapy for Colon Cancer

Nonmetastatic Colon Cancer

  • Choice of adjuvant therapy for resected, nonmetastatic colon cancerdepends on the stage of the disease
  • Stage I & low-risk stage II disease does not require adjuvant therapy
  • Management for stage II disease depends on the presence or absence of high-risk features such as T4 tumors (stage IIB/IIC), lymphovascular invasion, poorly differentiated histology (except those that are MSI-H), perineural invasion (PNI), lesions with localized perforation or positive margins, bowel obstruction, inadequately sampled nodes (<12 lymph nodes)
    • Low-risk stage II disease can managed with clinical trial or observed without adjuvant therapy or considered for Capecitabine or 5-Fluorouracil/Leucovorin (5-FU/LV)
    • High-risk stage II disease can be managed with clinical trial or observation without adjuvant therapy or with chemotherapy with the following regimens:
      • Capecitabine or 5-FU/LV or infusional 5 FU/LV/Oxaliplatin (FOLFOX) or Capecitabine/Oxaliplatin (CapeOx) or bolus 5 FU/LV/Oxaliplatin (FLOX)
  • MSI-H or Microsatellite Instability-High refers to those with stage II disease colon cancer having high favorable outcome & are less likely to benefit from adjuvant therapy with Fluoropyrimidine alone
  • Stage III disease is managed with 6 months of adjuvant chemotherapy after primary surgical treatment; chemotherapeutic options include:
    • FOLFOX (preferred)
    • Single-agent Capecitabine
    • CapeOx (preferred)
    • 5-FU/LV in those whom Oxaliplatin is inappropriate
    • FLOX
  • Consider neoadjuvant chemotherapy for patients with resectable clinical T4b colon CA
    • 1st-line regimens for advanced/metastatic disease (FOLFOX, CapeOX, FOLFOX + Bevacizumab, CapeOX  + Bevacizumab) are recommended
  • Capecitabine appears to be equivalent to 5-FU/LV/Oxaliplatin combination in patients with stage III colon cancer 
  • Capecitabine in combination with Oxaliplatin (CapeOx) is superior to 5-FU/LV/Oxaliplatin combination
  • 5-FU/LV/Oxaliplatin combination is an alternative to FOLFOX
    • Studies show grade 3-4 diarrhea is higher with 5-FU/LV/Oxaliplatin combination than FOLFOX
  • Addition of Oxaliplatin to 5-FU/LV did not show additional survival benefit among stage II colon cancer patients & in patients ≥70 years of age

Chemotherapy for Rectal Cancer

  • Often includes locoregional treatment due to relatively high risk of recurrence
  • For patients treated with preoperative chemoradiotherapy, a 5 to 12-week interval is recommended prior to surgical resection to allow recovery from toxicities

Resectable Local/Nonmetastatic Rectal Cancer

Neoadjuvant Chemoradiotherapy

  • Preoperative chemoradiotherapy is recommended for stage II/III rectal cancer 
  • Standard preoperative chemoradiotherapy involves either infusional 5-FU or bolus 5-FU/LV or oral Capecitabine
    • Recent studies have shown Capecitabine to be equivalent to 5-FU in perioperative chemoradiotherapy
  • Resectable T3 or node-positive lesions should be given preoperative chemoradiotherapy, unless contraindicated
    • Preoperative Capecitabine/radiotherapy & 5-FU/radiotherapy are the preferred treatment options
    • 5-FU/LV/radiotherapy may be given as an alternative

Adjuvant Chemotherapy

  • Recommended for all stage II/III rectal cancer patients post-neoadjuvant chemoradiotherapy/surgery regardless of pathology results
    • Studies show that adjuvant chemotherapy should be given as soon as patient is medically able
    • Preferred regimen for higher risks patients are FOLFOX or CapeOx
    • Alternative regimens include 5-FU/LV or Capecitabine
    • Believed to be important to be given to patients even following a complete response
  • Postoperative chemoradiotherapy is recommended when stage I rectal cancer is upstaged to stage II or III after pathologic review of the surgical specimen
  • Often uses a “sandwich” approach - chemotherapy is administered before & after the chemoradiotherapy regimen
    • Recommended “sandwich” regimen consists of the following:
      • An optional 1st round of adjuvant chemotherapy with 5-FU with or without LV or FOLFOX or Capecitabine with or without Oxaliplatin; followed by
      • Concurrent Capecitabine/radiotherapy (preferred) or 5-FU/radiotherapy (preferably, infusional or bolus infusion with LV); followed by
      • 5-FU with or without LV or FOLFOX or Capecitabine with or without Oxaliplatin
  • A total of approximately 6 months of perioperative therapy is recommended
  • Chemotherapy alone can be given for patients with pathologic evidence of proximal T3, N0, M0 disease with favorable features & clear margins
  • Those with pathologic stage I disease (T1-T2, N0, M0), following resection, may be managed with observation only

Locally Unresectable Rectal Cancer &/or T4 Lesions

  • Patients with locally unresectable disease or those medically inoperable may be treated with:
    • Capecitabine/radiotherapy or
    • Infusional 5-FU/radiotherapy or
    • Bolus 5-FU/LV/radiotherapy
  • When resection is contraindicated following primary treatment (combination chemoradiotherapy or chemotherapy), patients should receive a systemic regimen for advanced/metastatic disease

Metastatic Colorectal Cancer

  • For patients undergoing resection for liver or lung colorectal metastasis, consider approximately 6 months of perioperative chemotherapy to increase chance of eradicating residual microscopic disease
  • Decision to initiate chemotherapy prior or after surgery depends on several factors:
    • Potential advantages of preoperative chemotherapy include earlier treatment of micrometastatic disease, responsiveness to chemotherapy can be determined, avoidance of local therapy for those with early disease progression
    • Potential risks associated with preoperative chemotherapy include possible development of liver steatohepatitis (with Irinotecan-based regimen), sinusoidal liver injury (Oxaliplatin-based), missing out on the “window of opportunity” for resection
  • Choice of agents depends on therapeutic goals, toxicity profiles, type & timing of prior therapy

Chemotherapeutic Regimens for Advanced/Metastatic Colorectal Cancer

  • Chemotherapeutic options include the following, either as single agents or in combination: 5 FU/LV, Bevacizumab, Capecitabine, Cetuximab, Irinotecan, Oxaliplatin, Panitumumab, Pembrolizumab, Nivolumab, Ziv-Aflibercept, Ramucirumab, Regorafenib, Trifluridine-Tipiracil & Vemurafinib
  • As part of pretreatment work-up, it is recommended for all metastatic colorectal cancer patients to undergo KRAS/NRAS gene status testing at diagnosis of stage IV disease
    • For purposes of planning treatment continuum
    • If KRAS/NRAS wild-type, BRAF testing can be done
    • KRAS/NRAS wild-type tumors are those negative for KRAS mutation
    • Patients with any known KRAS mutation or NRAS mutation should not be treated with Cetuximab or Panitumumab
  • Recommended initial regimens in those appropriate for intensive therapy:
    • FOLFOX with or without Bevacizumab
    • CapeOx with or without Bevacizumab
    • FOLFOX or FOLFIRI + (Cetuximab or Panitumumab) for KRAS/NRAS wild-type & left-sided tumors
    • FOLFIRI with or without Bevacizumab
    • FOLFOXIRI with or without Bevacizumab
    • Infusional 5-FU/LV with or without Bevacizumab
    • Capecitabine with or without Bevacizumab
  • Recommended initial regimens for patients who cannot tolerate intense initial therapy:
    • Infusional 5-FU/LV with or without Bevacizumab
    • Capecitabine with or without Bevacizumab
    • Cetuximab or Panitumumab for KRAS/NRAS wild-type & left-sided tumors
    • Nivolumab or Pembrolizumab or Nivolumab + Ipilimumab for dMMR/MSI-H
  • Oxaliplatin should be discontinued from CapeOx or FOLFOX after 3-4 months of therapy (or sooner, should ≥ grade 2 neurotoxicity develops)
  • 5-FU in combination with Irinotecan or Oxaliplatin should be given through an infusional biweekly regimen 
  • Recommended subsequent therapy regimens include:-
    • For patients previously given Oxaliplatin-based regimens without Irinotecan:
      • FOLFIRI or Irinotecan
      • FOLFIRI + Bevacizumab1 or Ziv-Aflibercept or Ramucirumab
      • Irinotecan + Bevacizumab1 or Ziv-Aflibercept or Ramucirumab
      • FOLFIRI + (Cetuximab or Panitumumab) for KRAS/NRAS wild-type & left-sided tumors
      • Irinotecan + (Cetuximab or Panitumumab) for KRAS/NRAS wild-type & left-sided tumors
      • Irinotecan + (Cetuximab or Panitumumab) + Vemurafenib for BRAF V600E mutation
      • (Nivolumab with or without Ipilimumab) or Pembrolizumab for dMMR/MSI-H
    • For patients previously given Irinotecan-based regimens without Oxaliplatin:
      • FOLFOX with or without Bevacizumab
      • CapeOx with Bevacizumab
      • Irinotecan + (Cetuximab or Panitumumab) for KRAS/NRAS wild-type tumors
      • Irinotecan + (Cetuximab or Panitumumab) + Vemurafenib for BRAF V600E mutation
      • (Nivolumab with or without Ipilimumab) or Pembrolizumab for dMMR/MSI-H
    • For patients previously given FOLFOXIRI:
      • Irinotecan + (Cetuximab or Panitumumab) for KRAS/NRAS wild-type tumors
      • Irinotecan + (Cetuximab or Panitumumab) + Vemurafenib for BRAF V600E mutation
      • Regorafenib
      • Trifluridine + Tipiracil
      • (Nivolumab with or without Ipilimumab) or Pembrolizumab for dMMR/MSI-H
    • For patients previously given fluoropyrimidine-based therapy without Irinotecan or Oxaliplatin:
      • FOLFOX or CapeOx with or without Bevacizumab
      • FOLFIRI or Irinotecan ± Bevacizumab1 or Ziv-Aflibercept or Ramucirumab
      • Irinotecan + Oxaliplatin ± Bevacizumab
      • (Nivolumab with or without Ipilimumab) or Pembrolizumab for dMMR/MSI-H
  • Regorafenib is a treatment option for those who still progressed despite using available regimens 
  • Trifluridine-Tipiracil is an oral combination drug & an additional option for patients who still progressed on standard therapies)

Resectable Synchronous Metastases

  • A total of approximately 6 months of perioperative therapy is recommended for most patients undergoing liver or lung resection
  • The most effective sequencing of chemotherapy remains unclear

Preoperative Chemotherapy

  • To reduce possibility of developing hepatotoxicity, preoperative chemotherapy is limited to about 2-3 months, while carefully monitored by a multidisciplinary team
  • Considered in highly selected cases in an attempt to convert to resectable status by reducing the size of the metastases
  • Limit development of hepatotoxicity by performing the surgery as soon as patient becomes resectable
  • Any active chemotherapeutic regimen for metastases can be used in attempting to convert to resectable status
    • Addition of monoclonal antibodies against epidermal growth factor receptors (EGFR) & against vascular endothelial growth factor (VEGF) to cytotoxics should be considered in metastatic colorectal cancer patients
    • Bevacizumab, an anti-VEGF antibody, increases the activity of an active cytotoxic regimen
      • To avoid potential surgical complications, an interval of ≥6 weeks between the last dose of Bevacizumab & elective surgery is currently recommended 
      • Improves progression-free survival when combined with Fluoropyrimidine & Oxaliplatin
      • Studies suggest that Bevacizumab modestly improves response rate to Irinotecan-based regimens
      • Usually continued in combination with a cytotoxic agent until toxicity, progression or until metastases are resectable
    • Cetuximab & Panitumumab, anti-EGFR antibodies, are active as single agent in metastatic colorectal cancer that are chemorefractory
      • However, activity of anti-EGFRs is confined to KRAS/NRAS wild-type tumors
      • KRAS/NRAS wild-type tumors are those negative for KRAS mutation
    • Choice of regimen include:
      • FOLFOX or CapeOX or FOLFIRI with or without Bevacizumab
      • FOLFOX or FOLFIRI with Panitumumab (for KRAS/NRAS wild-type tumors only)
      • FOLFIRI with Cetuximab (for KRAS/NRAS wild-type tumors only) with or without subsequent chemoradiotherapy (infusional 5-FU/pelvic radiotherapy or bolus FU/LV/pelvic radiotherapy or Capecitabine/radiotherapy)
      • KRAS/NRAS wild-type tumors are those negative for KRAS mutation

Adjuvant Chemotherapy

  • Postoperative adjuvant chemotherapy is recommended in patients who underwent liver or lung resection & who have received preoperative chemoradiotherapy
  • Postoperative chemoradiotherapy is recommended for those with synchronous metastases who have not received prior chemoradiotherapy & who are at higher risk for pelvic recurrence after resection
    • Consists of infusional 5-FU/pelvic radiotherapy or bolus FU/LV/pelvic radiotherapy or Capecitabine/radiotherapy

Unresectable Synchronous Metastatic Colorectal Cancer

  • Management is based on presence or absence of symptoms
  • Aside from surgery, symptomatic patients are managed with chemotherapy alone or with chemoradiotherapy (5-FU/radiotherapy or Capecitabine/radiotherapy)
  • Asymptomatic patients are given chemotherapy to attempt conversion to resectable status
    • May evaluate patients for resection after 2 months of chemotherapy & every 2 months thereafter while under chemotherapy

Metachronous Metastases

  • KRAS/NRAS genotyping test should be done to determine whether anti-EGFR agents (Cetuximab, Panitumumab) can be considered
  • Assess patient’s chemotherapy history
  • Patients with resectable disease, treatment is resection with 6 months of perioperative chemotherapy (pre-operative, postoperative, or both)
    • Choice of regimen is based on previous therapy
    • For those without history of chemotherapy use, CapeOx or FOLFOX are preferred
      • Capecitabine, 5-FU/LV, FLOX can also be considered
    • Observation is preferred if Oxaliplatin-based therapy was previously given
  • The following chemotherapeutic regimens may be considered in patients with unresectable disease given adjuvant FOLFOX/CapeOx within the past 12 months:
    • (FOLFIRI or Irinotecan) with or without Bevacizumab1 or Ziv-Aflibercept or Ramucirumab
    • (FOLFIRI or Irinotecan) with or without (Cetuximab or Panitumumab) for KRAS/NRAS wild-type tumors
    • (Nivolumab with or without Ipilimumab) or Pembrolizumab for dMMR/MSI-H
    • Irinotecan + (Cetuximab or Panitumumab) + Vemurafenib for BRAF V600E mutation
  • For patients who received adjuvant FOLFOX/CapeOx >1 year before diagnosis of metachronous metastasis, or received 5-FU/LV or Capecitabine, or no previous history of chemotherapy, general regimens for advanced or metastatic colorectal cancer is recommended
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