Colorectal%20cancer Treatment

Colon Cancer

Nonmetastatic Colon CA

• Consider neoadjuvant therapy for patients with resectable clinical T4b tumors or with bulky nodal disease
  • First-line regimens for advanced/metastatic disease (FOLFOX or CapeOx) are recommended
  • Checkpoint inhibitor immunotherapy (eg Nivolumab with or without Ipilimumab, Pembrolizumab) may be used for patients with dMMR/MSI-H disease
• Neoadjuvant chemoradiotherapy (chemoRT) (5-FU or Capecitabine or 5-FU/LV + radiation therapy [RT]) may be considered in patients with locally unresectable or medically inoperable disease

Metastatic Colon CA

• Neoadjuvant therapy for 2-3 months with FOLFOX or CapeOx is an option for resectable synchronous liver and/or lung pMMR/MSS-positive metastases
  • FOLFIRI or FOLFIRINOX may also be used if FOLFOX and CapeOx are unavailable or contraindicated
• Neoadjuvant therapy for 2-3 months with FOLFOX or CapeOx is an option for resectable metachronous pMMR/MSS- and dMMR/MSI-H-positive metastases
  • 5-FU/LV or Capecitabine may also be used
• Please see further details of synchronous and metachronous metastases in Systemic Therapy discussion
• Pembrolizumab, Dostarlimab-gxly or Nivolumab with or without Ipilimumab, as preferred options for neoadjuvant therapy of resectable dMMR/MSI-H metastatic CRC

Rectal Cancer

Resectable Nonmetastatic or Locally Unsectable Rectal CA

Neoadjuvant Therapy

• FOLFOX or CapeOx are preferred neoadjuvant treatment options for resectable synchronous and metachronous pMMR/MSS metastases
  • 5-FU/LV or Capecitabine may also be used
• Infusional 5-FU with pelvic RT or Capecitabine with RT are treatment options for resectable synchronous and metachronous pMMR/MSS metastases with involved circumferential resection margin (CRM)
  • Please see further details of synchronous and metachronous metastases in Systemic Therapy discussion
• Checkpoint inhibitor immunotherapy agents Pembrolizumab, Dostarlimab-gxly or Nivolumab with or without Ipilimumab, are preferred options for neoadjuvant therapy of resectable dMMR/MSI-H metastatic CRC
  • Also used in resectable synchronous liver only and/or lung only dMMR/MSI-H metastases

Total Neoadjuvant Therapy (TNT)

• For patients w/ nonmetastatic, locally unresectable or medically inoperable rectal cancer
• Neoadjuvant therapy precedes chemoRT and surgery, composed of FOLFOX or CapeOx, infusional 5-FU or oral Capecitabine, or bolus 5-FU/LV
  • FOLFIRINOX may be considered
  • Treatment duration of 12-16 weeks is recommended
• 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

Neoadjuvant Chemoradiotherapy

• Preoperative chemoRT is recommended for stage II/III rectal cancer
• Standard preoperative chemoRT involves either infusional 5-FU or bolus 5-FU/LV or oral Capecitabine
  • Bolus 5-FU/LV/RT may be given as an alternative for patients unable to tolerate Capecitabine or infusional 5-FU

• 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

Systemic Therapy 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)
  • Microsatellite Instability-High (MSI-H) refers to those with stage II disease colon cancer having high favorable outcome and are less likely to benefit from adjuvant therapy with Fluoropyrimidine alone. 
  • Low-risk stage II disease can managed with clinical trial or observed without adjuvant therapy in patients with dMMR/MSI-H colon CA or considered for Capecitabine or 5-Fluorouracil/Leucovorin (5-FU/LV) in patients with pMMR/MSS colon CA
  • 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 3-6 months of adjuvant chemotherapy after primary surgical treatment; chemotherapeutic options include:
  • FOLFOX (preferred): 3-6 months in low-risk stage III patients & 6 months in high-risk stage III patients
  • CapeOx (preferred): 3 months in low-risk stage III patients & 3-6 months in high-risk stage III patients
  • Single-agent Capecitabine
  • 5-FU/LV in those whom Oxaliplatin is inappropriate

• FOLFOX or CapeOx is superior to 5-FU/LV for stage III colon CA
• FOLFOX may be considered in stage II colon CA with multiple high-risk factors
• Capecitabine appears to be equivalent to bolus-5-FU/LV combination in patients with stage III colon cancer 
• 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

Systemic Therapy 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

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 first 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
• A total of approximately 6 months of perioperative therapy is recommended
• 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

Systemic Therapy Regimens for Advanced/Metastatic Colorectal Cancer

• Chemotherapeutic options include the following, either as single agents or in combination: 5-FU/LV, Bevacizumab, Capecitabine, Cetuximab, Dostarlimab-gxly, Encorafenib, Entrectinib, Ipilimumab, Irinotecan, Lapatinib, Larotrectinib, Oxaliplatin, Panitumumab, Pembrolizumab, Pertuzumab, Nivolumab, Ramucirumab, Regorafenib, Selpercatinib, Trastuzumab, Trifluridine-Tipiracil, Tucatinib and Ziv-aflibercept
• 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

• The addition of a biologic agent (eg Bevacizumab, Cetuximab, Panitumumab) to first-line therapy regimens FOLFIRI and FOLFOX is an option for patients with RAS wild-type tumor
• Recommended initial regimens in those appropriate for intensive therapy:²
  • FOLFOX with or without Bevacizumab
  • CapeOx with or without Bevacizumab
  • FOLFOX or FOLFIRI or CapeOx + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type¹ and left-sided tumors
  • FOLFIRI with or without Bevacizumab
  • FOLFIRINOX with or without Bevacizumab
  • (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H
    •  Response to treatment should be closely monitored for 10 weeks
• Recommended initial regimens for patients who cannot tolerate intense initial therapy:
  • Infusional 5-FU with or without LV with or without Bevacizumab
  • Capecitabine with or without Bevacizumab
  • Cetuximab or Panitumumab for KRAS/NRAS/BRAF wild-type¹ and left-sided tumors
  • (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H
  • Trastuzumab with (Pertuzumab or Lapatinib or Tucatinib) 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
    • (Cetuximab or Panitumumab) with or without Irinotecan for KRAS/NRAS/BRAF wild-type¹ and left-sided tumors
    • Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation; addition of Binimetinib to Encorafenib + Cetuximab may be considered
    • (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H without prior immunotherapy
    • Trastuzumab with (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki 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 or CapeOx + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type¹ and left-sided tumors
    • (Cetuximab or Panitumumab) with or without Irinotecan for KRAS/NRAS/BRAF wild-type¹ and left-sided tumors
    • Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation; addition of Binimetinib to Encorafenib + Cetuximab may be considered
    • (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H without prior immunotherapy
    • Trastuzumab with (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2-amplified and RAS/BRAF wild-type gene tumors
  • For patients previously given Oxaliplatin and Irinotecan:
    • (Cetuximab or Panitumumab) with or without Irinotecan for KRAS/NRAS/BRAF wild-type¹ and left-sided tumors
    • Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation; addition of Binimetinib to Encorafenib + Cetuximab may be considered
    • Regorafenib
    • Trifluridine + Tipiracil with or without Bevacizumab
    • (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-glxy for dMMR/MSI-H without prior immunotherapy
    • Trastuzumab + (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2-amplified and RAS/BRAF wild-type gene tumors
  • For patients with previous therapy without Irinotecan or Oxaliplatin:
    • FOLFOX or CapeOx with or without Bevacizumab
    • FOLFIRI or Irinotecan with or without Bevacizumab³ or Ziv-aflibercept or Ramucirumab
    • Irinotecan + Oxaliplatin with or without Bevacizumab
    • FOLFIRINOX with or without Bevacizumab
    • Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation 
    • (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-glxy for dMMR/MSI-H without prior immunotherapy
    • Trastuzumab + (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2-amplified and RAS/BRAF wild-type gene tumors
• For patients with previous therapy without Irinotecan or Oxaliplatin given FOLFOX or CapeOx with or without Bevacizumab
  • Irinotecan
  • (Cetuximab or Panitumumab) with or without Irinotecan for KRAS/NRAS/BRAF wild-type¹ tumors
  • Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation
  • (Nivolumab w/ or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H without prior immunotherapy
  • Trastuzumab + (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2-amplified and RAS/BRAF wild-type gene tumors
• Checkpoint inhibitor immunotherapy (eg Nivolumab with or without Ipilimumab, Pembrolizumab, Dostarlimab-gxly) is a treatment option for dMMR/MSI-H-positive patients who have not previously received checkpoint inhibitor immunotherapy
  • Nivolumab ± Ipilimumab are approved for dMMR/MSI-H-positive patients that have progressed following treatment with 5-FU, Oxaliplatin, and Irinotecan
• Regorafenib is a treatment option for those who still progressed despite using available regimens 
• Larotrectinib or Entrectinib are treatment options for NTRK gene fusion-positive patients
• Selpercatinib is a treatment option for locally advanced or metastatic RET gene fusion-positive CRC tumors that have progressed during or following a prior systemic treatment or those who have no satisfactory alternative treatment options
• Trifluridine-Tipiracil with or without Bevacizumab is an oral combination drug and an additional option for patients who still progressed on standard therapies
• Fruquintinib is an additional option in patients pretreated with fluoropyrimidines, Oxaliplatin, Irinotecan and biologics
  • Approved for use in China by the National Medical Products Administration (NMPA) in September 2018 and submitted for review to the United States Food and Drug Administration in May 2023

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 CRM as per MRI evaluation
  • Safety and toxicity profile of the regimens

Preoperative Systemic Therapy

• 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
  • 5-FU/LV or Capecitabine
  • FOLFIRI: For metastatic colon cancer
  • FOLFIRINOX
  • Nivolumab with or without Ipilimumab or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H

Postoperative Systemic Therapy

• Choice of regimen include FOLFOX³ or CapeOx³ or 5-FU/LV or Capecitabine
• FOLFIRI and FOLFIRINOX may also be considered following colectomy

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 Systemic Therapy

• 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 FOLFIRINOX with or without Bevacizumab
    • FOLFOX or FOLFIRI with or without Panitumumab or Cetuximab (for KRAS/NRAS/BRAF wild-type tumors¹ and left-sided tumors only)
    • Nivolumab with or without Ipilimumab or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H (first-line option if without history of immunotherapy use and a candidate for immunotherapy)

Postoperative Systemic Therapy

• To be considered once disease becomes resectable post-systemic therapy 
• 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
  • CapeOx or FOLFOX are preferred
    • Capecitabine or 5-FU/LV can be considered
    • Treatment duration of 2-3 months is recommended
  • Observation is preferred if Oxaliplatin-based therapy was previously given or when the tumor has grown during neoadjuvant therapy
  • Systemic therapy combined with biologic agents may be considered
• (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly may be considered in patients with dMMR/MSI-H resectable metachronous metastases without history of immunotherapy use
• The following systemic therapy regimens may be considered in patients with unresectable disease given adjuvant FOLFOX/CapeOx within the past 12 months:
  • (FOLFIRI or Irinotecan) with or without Bevacizumab³ or Ziv-aflibercept or Ramucirumab
  • (FOLFIRI or Irinotecan) with or without (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type¹ tumors
  • Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation
  • Trastuzumab + (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2-amplified and RAS/BRAF wild-type gene tumors
• 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

• 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 (irreversible electropolation), 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