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.

Colorectal%20cancer Treatment

Pharmacotherapy

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

Chemotherapy for Colon Cancer

Nonmetastatic Colon Cancer

  • Choice of adjuvant therapy for resected, nonmetastatic colon cancer depends on the stage of the disease
  • Stage I and 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)
    • Addition of Oxaliplatin to 5-FU/LV did not show additional survival benefit among stage II colon CA patients and in patients ≥70 years of age
  • 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
  • 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
    • Neoadjuvant or adjuvant chemoradiation therapy (FU-based chemotherapy + RT) may be considered in highly-selected patients if T4 tumor is penetrating to a fixed structure or during recurrent disease
  • FOLFOX is superior to 5-FU/LV for stage III colon CA
  • 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

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
    • Bolus 5-FU/LV/RT may be given as an alternative
  • Resectable T3 or node-positive lesions should be given preoperative chemoradiotherapy, unless contraindicated
    • Preoperative Capecitabine/radiotherapy and 5-FU/radiotherapy are the preferred treatment options

Total Neoadjuvant Therapy (TNT)

  • Neoadjuvant chemotherapy precedes chemoradiotherapy and surgery
  • Benefits include improved tolerance and completion rates of chemotherapy, early prevention or eradication of micrometastases, facilitate resection, increased rates of pathologic complete response and minimized duration of ileostomy

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 risk 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 and 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 and clear margins
  • Those with pathologic stage I disease (T1-T2, N0, M0), following resection, may be managed with observation only

Locally Unresectable Rectal Cancer and/or T4 Lesions

  • Treatment approach can be chemoradiotherapy or TNT consisting of 12-16 weeks of chemotherapy followed by chemoradiotherapy
  • 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, mutational profile of the tumor, toxicity profiles, type and 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, Encorafenib, Ipilimumab, Irinotecan, Lapatinib, Oxaliplatin, Panitumumab, Pembrolizumab, Pertuzumab, Nivolumab, Ziv-Aflibercept, Ramucirumab, Regorafenib, Trastuzumab and Trifluridine-Tipiracil
  • As part of pretreatment work-up, it is recommended for all metastatic colorectal cancer patients to undergo KRAS/NRAS and BRAF gene status testing at diagnosis of stage IV disease
    • For purposes of planning treatment continuum
    • Testing for HER2 amplification is also recommended for patients with metastatic colorectal cancer
      • Not required if KRAS/NRAS/BRAF mutation in the tumor is already known
    • 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:2
    • FOLFOX with or without Bevacizumab
    • CapeOx with or without Bevacizumab
    • FOLFOX or FOLFIRI + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type1 and left-sided tumors
    • FOLFIRI with or without Bevacizumab
    • FOLFOXIRI 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/BRAF wild-type and left-sided tumors
    • Nivolumab or Pembrolizumab or Nivolumab + Ipilimumab for dMMR/MSI-H
    • Trastuzumab with Pertuzumab or Lapatinib for HER2-amplified and RAS/BRAF wild-type gene tumors
  • 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 + Bevacizumab3 or Ziv-Aflibercept or Ramucirumab
      • Irinotecan + Bevacizumab3 or Ziv-Aflibercept or Ramucirumab
      • FOLFIRI + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type1 and left-sided tumors
      • Irinotecan + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type1 and left-sided tumors
      • Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation
      • (Nivolumab with or without Ipilimumab) or Pembrolizumab for dMMR/MSI-H
      • Trastuzumab + Pertuzumab or Lapatinib for HER2-amplified and RAS/BRAF wild-type gene tumors
    • For patients previously given Irinotecan-based regimens without Oxaliplatin:
      • FOLFOX with or without Bevacizumab
      • CapeOx with or without Bevacizumab
      • FOLFOX + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type1 tumors
      • Irinotecan + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type1 tumors
      • Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation
      • (Nivolumab with or without Ipilimumab) or Pembrolizumab for dMMR/MSI-H
      • Trastuzumab + Pertuzumab or Lapatinib for HER2-amplified and RAS/BRAF wild-type gene tumors
    • For patients previously given Oxaliplatin and Irinotecan:
      • Irinotecan + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type1 tumors
      • Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation
      • Regorafenib
      • Trifluridine + Tipiracil
      • (Nivolumab with or without Ipilimumab) or Pembrolizumab for dMMR/MSI-H
      • Trastuzumab + Pertuzumab or Lapatinib for HER2-amplified and RAS/BRAF wild-type gene tumors
    • For patients previously given fluoropyrimidine-based therapy without Irinotecan or Oxaliplatin:
      • FOLFOX or CapeOx with or without Bevacizumab
      • FOLFIRI or Irinotecan ± Bevacizumab3 or Ziv-Aflibercept or Ramucirumab
      • Irinotecan + Oxaliplatin ± Bevacizumab
      • Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation 
      • (Nivolumab with or without Ipilimumab) or Pembrolizumab for dMMR/MSI-H
      • Trastuzumab + Pertuzumab or Lapatinib for HER2-amplified and RAS/BRAF wild-type gene tumors
  • Regorafenib is a treatment option for those who still progressed despite using available regimens 
  • Trifluridine-Tipiracil is an oral combination drug and 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
    • A TNT approach is recommended
  • The most effective sequencing of chemotherapy remains unclear
  • Has been shown to improve disease-free survival and progression-free survival
  • Choice of therapy depends on the following:
    • Patient’s history of chemotherapy
    • Clear or involved circumferential resection margin (CRM) as per MRI evaluation
    • Safety and toxicity profile of the regimens

Preoperative Chemotherapy

  • To reduce possibility of developing hepatotoxicity, preoperative chemotherapy is limited to about 2-3 months, while carefully monitored by a multidisciplinary team
  • Treatment approach differ between colon and rectal cancer with resectable synchronous metastasis
    • Colon cancer: Chemotherapy
    • Rectal cancer: Chemotherapy with or without radiotherapy
  • Choice of regimen include:
    • FOLFOX3 or CapeOX1 or 5-FU/LV or Capecitabine
    • Infusional 5-FU + pelvic RT or Capecitabine + RT or bolus 5-FU/LV + pelvic RT
    • FOLFIRI

Postoperative Chemotherapy

  • Choice of regimen include FOLFOX3 or CapeOX3 or 5-FU/LV or Capecitabine

Unresectable Synchronous Metastatic Colorectal Cancer

  • Patients are given intensive systemic chemotherapy to attempt conversion to resectable status
    • May evaluate patients for resection after 2 months of chemotherapy and every 2 months thereafter while under chemotherapy

Preoperative Chemotherapy

  • 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) and against vascular endothelial growth factor (VEGF) to cytotoxics should be considered in mCRC 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 and elective surgery is currently recommended-
      • Improves progression-free survival when combined with Fluoropyrimidine and 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 and Panitumumab, anti-EGFR antibodies, are active as single agent in metastatic CRC that are chemorefractory
      • However, activity of anti-EGFRs is confined to KRAS/NRAS wild-type1 tumors
    • Choice of regimen include:
      • FOLFOX or CapeOX or FOLFIRI or FOLFOXIRI with or without Bevacizumab
      • FOLFOX or FOLFIRI or FOLFOXIRI with or without Panitumumab or Cetuximab (for KRAS/NRAS/BRAF wild-type tumors1 only)

Postoperative Chemotherapy

  • A total of 6 months perioperative therapy is required
  • Recommended treatment options for adjuvant therapy are systemic treatment regimens for advanced or metastatic disease

Metachronous Metastases

  • KRAS/NRAS genotyping test should be done to determine whether anti-EGFR agents (Cetuximab, Panitumumab) can be considered
  • Testing for BRAF mutation and HER2 amplification as well as MSI/MMR is also recommended to determine if targeted therapy 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/BRAF wild-type tumors
    • (Nivolumab with or without Ipilimumab) or Pembrolizumab for dMMR/MSI-H
    • Encorafenib + (Cetuximab or Panitumumab) 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
1KRAS/NRAS/BRAF wild-type tumors are those negative for KRAS/BRAF mutation. 
2Patients who can tolerate intensive therapy with a high response rate.
3Preferred agent as recommended by NCCN clinical practice guidelines on colon cancer. Version 2.2020 and NCCN clinical practice guidelines on rectal cancer. Version 2.2020.

Local Therapies for Metastatic Colorectal Cancer

  • Option for select patients with liver-only or liver-dominant metastatic disease which cannot be resected or ablated with clear margins
  • Studies have demonstrated similar efficacy of hepatic arterial infusion chemotherapy (HAIC) and transcatheterarterial chemoembolization in patients with unresectable colorectal hepatic metastases

Hepatic Arterial Infusion Chemotherapy (HAIC)

  • Involves placement of a hepatic arterial port or implantable pump during liver resection
    • Where subsequent infusion of chemotherapy directed to the liver metastases will be given
    • Limited by its potential for biliary toxicity and required technical expertise
  • Should be considered selectively and in institutions capable of this procedure

Transhepatic Arterial Chemoembolization (TACE)

  • Involves catheterization of hepatic artery, causing vessel occlusion with local chemotherapy
  • Use is still limited to clinical trials

Tumor Ablation

  • Eg cryoablation, electro-coagulation, microwave ablation, percutaneous ethanol injection, radiofrequency ablation (RFA) 
  • May be considered in those who cannot undergo resection due to comorbidity, location of metastases or an estimate inadequate organ volume post-resection
  • Is not a substitute for resection in those patients with resectable diseases

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