Chemotherapy is a kind of cancer treatment that involves drugs that are able to act on cancer cells and prevent them from growing and multiplying (Blows, 2005). In this essay, I will describe a specific chemotherapy regimen used to treat patients with metastatic colorectal cancer, this regimen is the administration of FOLFIRI (Folinic acid or Leucovorin, Fluorouracil also called 5-FU and Irinotecan). I will identify and describe the FOLFIRI chemotherapy agents and also analyse the principles and mode of action by which these drugs act on the cells, being especially common in patients with digestive tract cancer.
Authors: David Casalduero Cidón, Asunción Cuenca Sánchez, María Dolores Cuenca Sánchez.
Colorectal cancer (CRC) is the second most common cancer in Europe and the third largest worldwide, with a rate of age-adjusted incidence in the EU of 46.3 / 100,000 inhabitants in 2012 (Ferlay J. et al., 2013).
Most of CRC patients are older than 60 years at diagnosis, being less common in people under 40 years (Figure 1).
Certain foods, obesity, a sedentary lifestyle, smoking, age, history of colorectal polyps, inflammatory bowel disease and a CRC family history have been identified as major risk factors for CRC.
Histologically, adenocarcinoma is the most common type, accounting about 95% of CRC. It is estimated that 20-25% of patients are initially diagnosed with metastatic CRC stadium, and 20-25% of patients with CRC develop metastases during treatment (Schmoll HJ et al., 2012).
When determining the treatment of choice for a patient with CRC there are several factors to consider, such as general health, comorbidities, stage and type of tumor, treatment tolerance and prognostic factors of the patient. Considering the stage of the disease, it can be established the following guidelines (Sobien LH et al., 2009):
- Stage 0: Local excision.
- Stage 1: Wide surgical resection. Resection with anastomosis / colectomy.
- Stage 3: Wide surgical resection and anastomosis / colectomy. It will be evaluated the use of adjuvant chemotherapy based on 5-fluorouracil + radiotherapy (in the case of rectal cancer).
- Stage 4: the treatment comprises different approaches depending on the resectability of the primary tumor and metastases identified. The surgical option, pharmacological and radiotherapy can also be considered from the palliative point of view.
Some chemotherapy treatment options for metastatic CRC (mCRC) is based on the combination of a fluorouracil (5-FU) with folinic acid (Leucovorin) and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). Capecitabine option with oxaliplatin (XELOX) is used in certain situations.
FOLFIRI is a systemic anti-cancer therapy composed by:
Irinotecan is an antineoplastic agent that inhibits DNA topoisomerase I (Figure 2), an enzyme that stabilizes the topographic structure of DNA during replication and transcription (Creemers GJ et al., 1994). The inhibition of topoisomerase I, yields fragments of DNA single-strand leading to the arrest of cell division and death of cells undergoing division. The mechanism of action of irinotecan confers pharmacological activity on various types of solid as gliomas (Ahn BJ et al., 2010) lung, ovary, stomach, pancreas or tumors and is indicated as first-line treatment for colorectal carcinoma metastatic (Castro Nuñez I et al., 2006) in combination with 5- fluorouracil (5-FU) and folinic acid. Table 1 presents the side effects of Irinotecan.
Fluorouracil (5-FU) is a fluorinated pyrimidine that belongs to the class of antineoplastic antimetabolites. It is a cell cycle phase-specific, acting in the S-phase of cell division (Figure 3 explains its mode of action). It is often used in combination with other drugs in the treatment of many solid tumors such as colorectal and breast cancer, with good results (Lehne, 2013). The toxicity and efficacy of Fluorouracil depends on the form of administration, there are a high variability between patients and the route and direction. For example, in treating colorectal cancer, continuous infusion administration provides better antitumour results than the same dose administered bolus less toxic hematological effects (Daniel B et al., 2003).
The fluorouracil is an antimetabolite that inhibits thymidylate synthase, an enzyme necessary for DNA synthesis (Wilkes and Barton-Bure, 2014). To do this, Fluorouracil is converted into a fluorodeoxyuridine monophosphate (FDUMP).
5FU can cause side effects, although everyone is affected in different ways. It’s unusual to get all the possible side effects (Pancreatic Cancer UK, 2015). Table 2 presents the side effects of Fluorouracil.
Leucovorin is a folic acid derivative, also known as folinic acid. It is used as an antidote to drugs that act as antagonists of folic acid. It is used as a relief for antagonize toxic effects of methotrexate and as an adjuvant in cancer treatments.
Leucovorin administration counteracts the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.
On the other hand, leucovorin increases the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as fluorouracil (5-FU). Concomitant administration of leucovorin does not seem to alter the plasma pharmacokinetics of 5-FU. This is metabolized to fluorodeoxyuridylic acid which binds and inhibits the enzyme thymidylate synthase (an enzyme important in the repair and DNA replication). (Tabernero J. el at., 2014). Regarding the side effects of folinic acid, according to BNF (September 2015- March 2016) it is rare occurrence, but it can appears, after high doses, agitation, depression and insomnia. And pyrexia may also occur after parenteral administration.
In conclusion, in this essay, I have discussed colorectal cancer incidence, risk factors and one of the main ways to treat it, FOLFIRI chemotherapy regimen as well as the principles of this regimen and its mode of action.
Figure 1. Percent of New Cases by Age Group: Colon Cancer. 2008-2012. (National Cancer Institute USA)
Figure 2. Main sites of action of anti-metabolites (Cassidy et al., 2010).
Figure 3. Effects of the topoisomerase I inhibitor irinotecan on the structure of DNA with subsequent cellular changes. (Pommier, Y 2006)
Figures – Colorectal cancer and FOLFIRI
Figures – Colorectal cancer and FOLFIRI.pdf
Table 1. Side effects of Irinotecan (Cancer Research UK, 2015).
Side effects of Irinotecan
- Diarrhoea (can occasionally become severe).
- Nausea and vomiting.
- Loss of appetite.
- Increased sweating.
- Increased saliva production.
- Watery eyes.
- Abdominal cramps.
- Drop on white cells, red cells and platelets.
- Hair loss.
- Mouth shores.
- Liver changes.
- Skin rashes.
- Loss of fertility.
- Temporary eyesight changes
Table 2. Side effects of Fluorouracil (Pancreatic Cancer UK, 2015).
Side effects of 5-FU
- Sore mouth or mouth ulcers.
- Taste changes.
- Watery eyes.
- Bruising or bleeding.
- Tiredness and breathlessness from anaemia.
- Nausea and vomiting.
- Hair loss.
- Skin Changes.
- Soreness, redness and peeling on the palms of the hands and soles of the feet.
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