Colon and Rectal Cancer Pharmacology Review

Overview^[1-9]

• Fourth most common type of cancer, estimated new cases in 2022: 151,030
• Median age at diagnosis: 66 years
• Highest incidence in males
• Estimated deaths in 2022: 52,580
• Five-Year Relative Survival: 65.1%

1. Modifiable:
   • Smoking
   • Alcohol consumption
   • Red and processed meats
   • Obesity
   • Low physical activity
2. Non modifiable:
   • Older age
   • Personal or family history of patients with colorectal cancer (CRC) and the presence of adenomatous polyps
   • Genetic susceptibility
     • Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC): Up to 4% of total CRC cases, germline mutation in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2)
     • Familial adenomatosis polyposis (FAP): up to 1% of total CRC cases, autosomal dominant disorder
   • Personal history of Crohn’s disease or ulcerative colitis

1. RAS (KRAS, NRAS): Activating RAS mutations predict lack of response to anti-epidermal growth factor receptor (EGFR) therapy. NCCN and ASCO guidelines recommend testing all patients with metastatic disease prior to starting an anti-EGFR for treatment.
2. BRAF: BRAF V600E mutation occurs in 5-15% of colorectal cancers and results in poorer prognosis. NCCN guidelines recommends all patients at diagnosis of metastatic disease undergo genetic testing for BRAF.
3. dMMR/MSI-H: Status predicts increased benefit from checkpoint inhibitors in patients with metastatic disease. NCCN recommends all patients newly diagnosed with CRC, undergo testing for deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H).
4. HER2 Testing: Only about 2-3% of metastatic colorectal cancers harbor HER2-amplification. HER2-amplified tumors that are also RAS and BRAF wild type are eligible to receive anti-HER2 therapy.

• Anemia
• Weight loss
• Nausea and vomiting
• Malaise
• Abdominal pain
• Bowel habit changes
• Obstruction
• Perforation
• Common sites of metastasis: liver, lung, and bones.

Colon Cancer Treatment ^[7,9]

• Early stage disease: treatment of choice with curative intent
• Metastatic disease: utilized with palliative intent only
• 12 nodes need to be examined for adequate sampling to determine node status of disease

• Neoadjuvant: not often utilized
• Adjuvant:

Adjuvant Treatment for Early Stage Colon Cancer by Pathological Stage
Tis;T1, N0, M0; T2, N0, M0;T3-4, N0, M0 (dMMR/MSI-H)	Observation
T3, N0, M0 (pMMR/MSS and no high risk features)	Observation Capecitabine or 5-FU/LV (6 months)
T3, N0, M0 at high risk of systemic recurrence; T4, N0, M0 (pMMR/MSS)	Observation Capecitabine or 5-FU/LV (6 months) FOLFOX (6 months) or CAPEOX (3 months)
T1-3, N1 (low-risk stage III)	Preferred: FOLFOX (3-6 months) or CAPEOX (3 months) Other: Capecitabine or 5-FU/LV (6 months)
T4, N1-2; T any, N2 (high-risk stage III)	Preferred: FOLFOX (6 months) or CAPEOX (3-6 months) Other: Capecitabine or 5-FU/LV (6 months)
High-risk features for recurrence for colon cancer: Poorly differentiated/undifferentiated histology, lymphatic/vascular invasion, bowel obstruction, <12 lymph node examined, perineural invasion, localized perforation, positive margins, tumor budding pMMR: proficient mismatch repair; MSS: microsatellite stable Dose and schedule: Capecitabine every 3 weeks 1000-1250 mg/m2 orally (PO) twice daily for 14 days 5-FU every 8 weeks, Day 1: 5-FU intravenously (IV) 500 mg/m2, leucovorin IV 500 mg/m2 weekly for 6 weeks OR 5-FU every 2 weeks, Day 1: 5-FU IV 400 mg/m2, leucovorin IV 400 mg/ m2, 5-FU continuous IV infusion (CIVI) 1200 mg/ m2/day x 2 days (over 46 hours) FOLFOX every 2 weeks, Day 1: 5-FU IV 400 mg/m2, leucovorin IV 400 mg/ m2, oxaliplatin IV 85 mg/m2, 5-FU CIVI 1200 mg/ m2/day x 2 days (over 46 hours) CAPEOX every 3 weeks, Day 1: Oxaliplatin IV 130 mg/m2, Days 1-14, capecitabine PO 1000 mg/ m2/dose BID

• The MOSAIC trial compared 5-FU/LV to FOLFOX in patients with resected stage II and stage III colon cancer
  • FOLFOX was superior in overall survival (OS) to 5-FU/LV at 6 years (72.9% vs. 68.7%; p=0.023) for stage III colon cancer
  • At a 6 year and a 10 year follow up, there was no difference in disease-free survival (DFS, hazard ratio (HR) 0.84 (95% CI, 0.62-1.14)) or overall survival (OS, HR 1.00 (95% CI, 0.7-1.41).
• Based on the MOSAIC Trial, NCCN does not consider FOLFOX to be an appropriate adjuvant therapy for stage II patients with no risk features.

• For stage II low-risk patients:
  • 3 months of CAPEOX is non-inferior to 6 months of CAPEOX
  • Non-inferiority of 3 vs 6 months of CAPEOX has not been shown
• For stage III high-risk patients:
  • Non-inferiority of 3 vs 6 months of FOLFOX has not been shown
  • 3 months is inferior to 6 months of FOLFOX

• Advanced or metastatic disease: NCCN recommends continuing therapy until progression or intolerable toxicity.

Initial Therapy	Dosing and schedule
FOLFOX  +/- Bevacizumab or CAPEOX +/- Bevacizumab	FOLFOX every 14 days, Day 1: 5-FU IV 400 mg/m2, leucovorin IV 400 mg/m2, oxaliplatin IV 85 mg/m2, 5-FU CIVI 1200 mg/m2/day x 2 days (over 46 hours) CAPEOX every 21 days, Day 1: Oxaliplatin IV 130 mg/m2, Days 1-14, Capecitabine PO 1000 mg/m2/dose BID every 21 days   Bevacizumab 5 mg/kg IV every 14 days or 7.5 mg/kg IV every 21 days
FOLFIRI  +/- Bevacizumab Cetuximab (KRAS/BRAF/NRAS wild type (WT) only and left sided tumors) Panitumumab (KRAS/BRAF/NRAS WT only and left sided tumors)	FOLFIRI every 14 days, Day 1: 5-FU IV 400 mg/m2, leucovorin IV 400 mg/m2, irinotecan IV 180 mg/m2, 5-FU CIVI 1200 mg/m2/day x 2 days (over 46 hours) Bevacizumab as above Cetuximab IV 400 mg/m2 for first infusion, then 250 mg/m2 weekly OR 500 mg/m2 every 14 days Panitumumab IV 6 mg/kg every 14 days
FOLFIRINOX +/- Bevacizumab	FOLFIRINOX every 14 days , Day 1: 5-FU IV 400 mg/m2, leucovorin IV 400 mg/m2, irinotecan IV 180 mg/m2, oxaliplatin IV 85 mg/m2, 5-FU CIVI 1200 mg/m2/day x 2 days (over 46 hours) Bevacizumab as above
If dMMR/MSI-H only Nivolumab +/- Ipilimumab or Pembrolizumab (preferred)	Nivolumab 240 mg IV every 2 weeks OR 480 mg every 4 weeks Nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV every 3 weeks for 4 doses followed by nivolumab 240 mg IV every 2 weeks OR 480 mg every 4 weeks Pembrolizumab 200 mg IV every 3 weeks or 400 m IV every 6 weeks
Subsequent Therapy if previous oxaliplatin based therapy without irinotecan
FOLFIRI +/- Bevacizumab (preferred) Ziv-aflibercept Ramucirumab Cetuximab (KRAS/BRAF/NRAS WT only) Panitumumab (KRAS/BRAF/NRAS WT only)	FOLFIRI as above Bevacizumab as above Ziv-aflibercept 4 mg/kg IV every 14 days Ramucirumab 8 mg/kg IV every 14 days Cetuximab as above Panitumumab as above
Irinotecan +/- Bevacizumab (preferred) Ziv-aflibercept Ramucirumab Cetuximab (KRAS/BRAF/NRAS WT only) Panitumumab (KRAS/BRAF/NRAS WT only)	Irinotecan 180 mg/m2 IV every 2 weeks Bevacizumab as above Ziv-aflibercept as above Ramucirumab as above Cetuximab as above Panitumumab as above
Subsequent Therapy if previous irinotecan based therapy without oxaliplatin
FOLFOX  +/- Bevacizumab Cetuximab (KRAS/BRAF/NRAS WT only) Panitumumab (KRAS/BRAF/NRAS WT only)	FOLFOX as above Bevacizumab as above Cetuximab as above Panitumumab as above
CAPEOX +/- Bevacizumab	CAPEOX as above Bevacizumab as above
Irinotecan +/- Cetuximab (KRAS/BRAF/NRAS WT only) Panitumumab (KRAS/BRAF/NRAS WT only)	Irinotecan as above Cetuximab as above Panitumumab as above
Subsequent Therapy if treatment with oxaliplatin and irinotecan
Irinotecan +/- Cetuximab (KRAS/BRAF/NRAS WT only) Panitumumab (KRAS/BRAF/NRAS WT only)	Irinotecan as above Cetuximab as above Panitumumab as above
Encorafenib + [Cetuximab or Panitumumab] (BRAF V600E mutation positive)	Enocrafenib 300 mg PO daily Cetuximab as above Panitumumab as above
If dMMR/MSI-H only Nivolumab +/- ipilimumab (preferred) or Pembrolizumab (preferred) or Dostarlimab-gxly	Nivolumab +/- ipilimumab as above Pembrolizumab as above Dostarlimab-gxly 500 mg IV every 3 weeks for 4 doses followed by 1000 mg IV every 6 weeks
If HER2-amplified and RAS and BRAF WT Trastuzumab + pertuzumab or Trastuzumab + lapatinib or Fam-trastuzumab deruxtecan-nxki	Trastuzumab 8 mg/kg IV loading dose on day 1 of cycle 1 followed by 6 mg/kg IV every 3 weeks, pertuzumab 840 mg IV loading dose on day 1 of cycle 1 followed by 420 mg IV every 3 weeks Trastuzumab 4 mg/kg IV loading dose on day 1 of cycle 1 followed by 2 mg/kg IV weekly, lapatinib 1000 mg PO daily Fam-trastuzumab deruxtecan-nxki 6.4 mg/kg Iv on day 1 every 3 weeks
Trifluridine + tipiracil +/- bevacizumab	Trifluridine + tipiracil 35 mg/m2 PO BID days 1-5 and 8-12 every 28 days, maximum 80 mg per dose, doing based on trifluridine component Bevacizumab as above
Regorafenib	Regorafenib 80 mg PO daily n days 1-7, followed by 120 mg daily days 8-14, followed by 160 mg daily on days 15-21 every 28 days, subsequent cycles regorafenib 160 mg daily on days 1-21 every 28 days

Rectal Cancer Treatment: ^[8,13]

• Early stage disease: treatment of choice with curative intent
• Metastatic disease: utilized with palliative intent only
• 12 nodes need to be examined for adequate sampling to determine node status of disease

• For early stage disease: administered prior to or following surgery with curative intent
• Metastatic disease: utilized for palliative intent only
• Short course RT: 25 Gy in 5 total fractions
• Long course RT: 45-50 Gy in 25-28 fractions concomitantly with fluoropyrimidine chemotherapy

• Neoadjuvant: used in combination with radiation to increase radiation sensitization and improve systemic control disease
• Adjuvant: Ideally within 4-8 weeks after surgery.

Clinical Stage	Treatment	Pathologic Stage (post surgery)	Adjuvant treatment (6 months perioperative treatment)
I	Transanal excision (if appropriate)	I without high-risk features	Observation
		I with high-risk features	Transabdominal resection (preferred, follow ^)
			ChemoRT	NED → consider observation or chemotherapy
				Evidence of disease → transabdominal resection → chemotherapy
	^Transabdominal resection	I	Observation
		II (T3)	Sequential chemotherapy (chemotherapy → chemoRT or chemoRT → chemotherapy)
			Chemotherapy
			Observation
		II (T3) or III	Sequential chemotherapy (chemotherapy → chemoRT or chemoRT → chemotherapy)
Clinical Stage	Neoadjuvant treatment		Surgery	Adjuvant treatment
II/III (not T4) with clear CRM	Neoadjuvant Therapy: Long-course chemoRT OR Short-course RT		Transabdominal resection	Chemotherapy: FOLFOX or CAPEOX (3-4 months)
			Resection contraindicated	Systemic therapy for advanced or metastatic disease
	Total Neoadjuvant Therapy (preferred) Chemotherapy: FOLFOX or CAPEOX (3-4 months) → Long-course chemoRT OR Short-course RT OR Long-course chemoRT OR Short-course RT → FOLFOX or CAPEOX (3-4 months)		Transabdominal resection	Surveillance
			Resection contraindicated	Systemic therapy for advanced or metastatic disease
Clinical Stage II/III with involved or threatened CRM OR Clinical Stage II/III with T4 OR Locally unresectable or medically inoperable	Total Neoadjuvant Therapy (preferred) Chemotherapy: 3- 4 months of FOLFOX or CAPEOX or FOLFIRINOX for T4, N+ → Long-course chemoRT OR short-course RT OR Long-course chemoRT OR short-course RT → 3- 4 months of FOLFOX or CAPEOX or FOLFIRINOX for T4, N+		Transabdominal resection	Surveillance
			Resection contraindicated	Systemic therapy for advanced or metastatic disease
FOLFOX every 2 weeks, Day 1: 5-FU IV 400 mg/m2, leucovorin IV 400 mg/m2, oxaliplatin IV 85 mg/m2, 5-FU CIVI 1200 mg/m2/day x 2 days (over 46 hours) CAPEOX every 3 weeks, Day 1: Oxaliplatin IV 130 mg/m2 ,Days 1-14, capecitabine PO 1000 mg/m2/dose BID FOLFIRINOX every 2 weeks, Day 1: 5-FU IV 400 mg/m2, leucovorin IV 400 mg/m2, irinotecan IV 180 mg/m2, oxaliplatin IV 85 mg/m2, 5-FU CIVI 1200 mg/m2/day x 2 days (over 46) ChemoRT – 5-FU CIVI 225 mg/m2/day x 5 or 7 days/week during RT – Capecitabine PO 825 mg/m2/dose BID 5 days/week during RT – 5-FU IV 400 mg/m2, leucovorin IV 20 mg/m2, then 5-FU CIVI 1200 mg/m2/day x 4 days during week 1 and 5 of XRT High-risk features: positive margins, lymphovascular invasion, poorly differentiated tumors, submucosal invasion to the lower third of the submucosal level.

• Advanced or metastatic disease:
  • Summary of NCCN guidelines advanced or metastatic colorectal cancer if intensive therapy is summarized table 2.
  • NCCN recommends continuing therapy until progression or intolerable toxicity.

Pharmacology

• Mechanism of action: Fluorouracil is a pyrimidine analog antimetabolite that interferes with DNA and RNA synthesis. After activation, F-UMP (an active metabolite) is incorporated into RNA to replace uracil and inhibit cell growth. The active metabolite F-dUMP inhibits thymidylate synthetase, depleting thymidine triphosphate (a necessary component of DNA synthesis).
• Metabolism:
  • Fluorouracil is metabolized hepatically via dihydropyrimidine dehydrogenase (DPD). DPD catalyzes the first catabolic step of the 5-FU degradation pathway, converting 80% of 5-FU to its inactive metabolite.
  • DPD deficiency: Patients with select homozygous or compound heterozygous DPD gene mutations that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity.
• Hepatic dose adjustments: none
• Renal dose adjustments: none
• Side effects: hand-foot syndrome (HFS), neutropenia, thrombocytopenia, nausea, mucositis, diarrhea, alopecia, and rarely coronary vasospasm
• Antidote: uridine triacetate is available commercially for patients who experience fluoropyrimidine overdose or overexposure, and has shown efficacy in patients with DPD deficiencies experiencing severe toxicity. For 5-FU overdose, administer 10 g every 6 hours for 20 doses beginning as soon as possible after overdose or early-onset toxicity. Administer the full course of 20 doses, even if the patient appears or feels well. Initiate within 96 hours after the end of fluorouracil or capecitabine administration.

• Mechanism of action: Capecitabine is an oral prodrug that is converted to its only active metabolite, 5-FU, by thymidine phosphorylase
• Administration: Administer with or without food.
• Hepatic dose adjustments for hepatotoxicity during treatment:
  • Hyperbilirubinemia, grade 3 or 4: Interrupt treatment until total bilirubin ≤3 times upper limit of normal (ULN)
• Renal dose adjustments:
  • CrCl >50 mL/minute: No dosage adjustment necessary
  • CrCl 30 to 50 mL/minute: Administer 75% of the usual indication-specific daily dose
  • CrCl <30 mL/minute: Use is contraindicated
• Side effects: similar toxicity profile to 5-FU. Compared with bolus 5-FU/LV, capecitabine is associated with more hand-foot syndrome and diarrhea, but less stomatitis, alopecia, neutropenia requiring medical management.
  • Prevention of HFS:
    • Pre-existing skin conditions should be treated prior to starting chemotherapy
    • Reduce stress on skin area by wearing loose-fitting shoes and clothes
    • Avoid contact with high temperature
    • Moisturize 3-4 times a day using alcohol-free and fragrance-free creams and emollients or a urea-based cream
  • Management of HFS:
    • Grade 2 or 3: Interrupt capecitabine until resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, decrease subsequent capecitabine doses.
    • Temporary relief of pain symptoms can be achieved by analgesics and topical anesthetics
    • Topical wound care by a dermatologist for any blisters or ulcerations that maybe present
    • Topical-high potency corticosteroids can be applied to affected area

• Mechanism of action: Regorafenib is a multikinase inhibitor. It targets kinases involved with tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment which results in inhibition of tumor growth.
• Administration: Administer within 1 hour after completion of meals.
• Hepatic dose adjustments:
  • Preexisting severe impairment (total bilirubin >3 times ULN): Use is not recommended (has not been studied).
  • Hepatotoxicity during treatment:
  • Grade 3 Aspartate transaminase (AST) and/or alanine aminotransferase (ALT) elevation: Hold dose until recovery.
  • AST or ALT >20 times ULN: Discontinue permanently.
  • AST or ALT >3 times ULN and bilirubin >2 times ULN: Discontinue permanently.
  • Recurrence of AST or ALT >5 times ULN despite dose reduction to 120 mg: Discontinue permanently
• Renal dose adjustments: none
• Side effects:
  • Prevention of Hand foot skin reaction (HFSR): Use alcohol-free and fragrance-free moisturizers, reduce exposure to hot water, wear loose filling clothing and shoes, reduce excessive skin friction, and avoid vigorous exercise/activities that may stress hands or feet.
  • Management of HFSR: For grade 1, use moisturizing creams, cotton gloves and socks with urea-based creams. For grade 2, apply topical steroids twice daily on affected area in addition to continuing grade 1 management. For grade 3, interrupt treatment until resolution to grade 1 in addition to grade 1 and 2 management.
  • GI Perforation: Permanently discontinue.
  • Wound healing impairment: Withhold regorafenib treatment for ≥2 weeks prior to surgery.

• Mechanism of action:
  • Trifluridine, the active cytotoxic component of trifluridine/tipiracil, is a thymidine-based nucleic acid analogue; the triphosphate form of trifluridine is incorporated into DNA which interferes with DNA synthesis and inhibits cell proliferation.
  • Tipiracil is a potent thymidine phosphorylase inhibitor which prevents the rapid degradation of trifluridine, allowing for increased trifluridine exposure.
• Administration: Administer with food.
• Hepatic dose adjustments: None
• Renal dose adjustments:
  • CrCl ≥30 mL/minute: No initial dosage adjustment is necessary.
  • CrCl 15 to 29 mL/minute: 20 mg/m² (based on the trifluridine component) twice daily on days 1 to 5 and days 8 to 12 of a 28-day cycle.
  • If unable to tolerate the 20 mg/m² dose: Further reduce the dose to 15 mg/m² (based on the trifluridine component) twice daily on days 1 to 5 and days 8 to 12 of a 28-day cycle.
  • If unable to tolerate the 15 mg/m² dose: Permanently discontinue trifluridine/tipiracil.
  • CrCl <15 mL/minute and end-stage renal disease: limited to no data
• Side effects include: Minimal to low risk of nausea, fatigue, diarrhea, neutropenia and thrombocytopenia
• Hematological toxicities:
  • Monitor complete blood count with differential (CBC-D) prior to each cycle and on day 15 of each cycle
  • A maximum of 3 dose reductions are allowed (to a minimum dose of 20 mg/m²); permanently discontinue in patients unable to tolerate 20 mg/m². Do not re-escalate dose after it has been reduced.
  • ANC <500/mm³ (uncomplicated or resulting in >1 week delay in the start of the next cycle) or febrile neutropenia: Interrupt therapy; following recovery to ANC ≥1,500/mm³ or resolution of febrile neutropenia, may resume therapy with the dose reduced by 5 mg/m²/dose from the previous dose.
  • Platelets <50,000/mm³ (or resulting in >1 week delay in the start of the next cycle): Interrupt therapy; following recovery to platelets ≥75,000/mm³, may resume therapy with the dose reduced by 5 mg/m²/dose from the previous dose.

References

1. Alzahrani SM, Al Doghaither HA, Al‑Ghafari AB. General insight into cancer: An overview of colorectal cancer. Molecular and Clinical Oncology. 2021 Dec 1;15(6):1-8.
2. SEER Cancer Stat Facts: Colorectal Cancer. National Cancer Institute. Bethesda, MD. Accessed January 1, 2023. https://seer.cancer.gov/statfacts/html/colorect.html
3. Smith D, Ballal M, Hodder R, Soin G, Selvachandran SN, Cade D. Symptomatic presentation of early colorectal cancer. The Annals of The Royal College of Surgeons of England. 2006 Mar;88(2):185-90.
4. Rosen SA, Buell JF, Yoshida A, Kazsuba S, Hurst R, Michelassi F, Millis JM, Posner MC. Initial presentation with stage IV colorectal cancer: how aggressive should we be?. Archives of surgery. 2000 May 1;135(5):530-4.
5. Imyanitov E, Kuligina E. Molecular testing for colorectal cancer: Clinical applications. World Journal of Gastrointestinal Oncology. 2021 Oct 10;13(10):1288.
6. Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, Monzon FA. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. American journal of clinical pathology. 2017 Mar 1;147(3):221-60.
7. National Comprehensive Cancer Network. Colon Cancer. (Version 2.2022).
8. National Comprehensive Cancer Network. Rectal Cancer. (Version 3.2022).
9. Skibber, J., et al. “Cancer: Principles and practice of oncology.” (2001): 1216-71.
10. André, Thierry, et al. “Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.” New England Journal of Medicine 350.23 (2004): 2343-2351.
11. André, Thierry, et al. “Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.” Journal of Clinical Oncology 27.19 (2009): 3109-3116.
12. André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. New England Journal of Medicine. 2004 Jun 3;350(23):2343-51.
13. Skibber J, Minsky B, Hoff P, DeVita V, Hellman S, Rosenberg S. Cancer: Principles and practice of oncology.
14. Adrucil (fluorouracil injection) bulk [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA Inc; February 2017
15. Van Kuilenburg AB. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. European journal of cancer. 2004 May 1;40(7):939-50.
16. Walko CM, Lindley C. Capecitabine: a review. Clinical therapeutics. 2005 Jan 1;27(1):23-44.
17. Gressett SM, Stanford BL, Hardwicke F. Management of hand-foot syndrome induced by capecitabine. Journal of Oncology Pharmacy Practice. 2006 Sep;12(3):131-41.
18. Kwakman JJ, Elshot YS, Punt CJ, Koopman M. Management of cytotoxic chemotherapy-induced hand-foot syndrome. Oncology Reviews. 2020 Feb 18;14(1).
19. Xeloda (capecitabine) [prescribing information]. South San Francisco, CA: Genentech USA Inc; May 2021.
20. Stivarga (regorafenib) [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; December 2020.
21. 21.   Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. The Lancet. 2013 Jan 26;381(9863):303-12.
22. Lonsurf (trifluridine and tipiracil) [prescribing information]. Princeton, NJ: Taiho Oncology; December 2019.
23. Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. New England Journal of Medicine. 2015 May 14;372(20):1909-19.