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Nicolas B Tsavaris
School of Medicine
University of Athens
Colorectal cancer is defined as advanced if the tumour is metastatic, or locally advanced if surgical resection is not likely to be curative. Colorectal cancers account for 10–15% of all cancers and are the second leading cause of cancer deaths in Western countries. Approximately half of all patients develop metastatic disease and are likely to die as a result of the disease process.(1)
Colorectal cancers can already be at an advanced stage at the time of initial presentation (25% of new cases) or they can develop during follow-up of previously treated patients (50% of curatively resected tumours). Colorectal cancers have a poor prognosis, with 5-year survival rates of <5%. Indications for chemotherapy in the advanced disease are a good performance status and no other comorbid condition. Patients who are eligible for surgery for isolated metastasis (eg, to the liver or lungs) should be excluded. Resection of such metastases may be curative in a small subset of patients. Palliative chemotherapy is more effective at prolonging survival and improving quality of life than the best supportive care.(2)
Different drugs used
Drug therapy for colorectal cancer mainly consists of cytostatic drugs. The oldest cytostatic drug, 5-fluorouracil (5-FU), is still the most widely used single agent.(3,4) Addition of folinic acid enhances the DNA-directed effects of 5-FU and prolongs its duration of action.(5) More effective methods of administering 5-FU involve higher doses delivered by continuous or intermittent intravenous (IV) infusions.(6–10) 5-FU is not reliably absorbed if given orally, but a number of new oral preparations containing prodrugs of 5-FU and/or inhibitors of 5-FU catabolism are being evaluated.(11–13)
The common side-effects associated with fluopyrimidines such as 5-FU are mild hair loss and vomiting, oral mucositis, diarrhoea and fatigue; rare side-effects include red painful palms and soles, photosensitivity of the face, irritation of the eyes and nose, myelosuppression, cardiotoxicity (angina, infarction and arrhythmias), cerebellar syndrome (ataxia, slurred speech and nystagmus). Some patients may also experience unwanted psychological or social effects of adjuvant chemotherapy, such as prolongation of the patient’s status, feelings of anxiety or depression and strains on family relationships.(14–17)
New cytotoxic agents include irinotecan (CPT-11), which binds and inactivates the nuclear enzyme topoisomerase-I via its active metabolite SN38,(18,19) and oxaliplatin, a cytotoxic agent from the diaminocyclohexane (DACH) family of platinum-based coordination compounds, which forms adducts with DNA (mostly intrastrand cross-links) through covalent bonds. The mechanism of action of oxaliplatin is similar to that of other platinum derivatives, but its spectrum of antitumour activity against tumour models differs from that of cisplatin and carboplatin.(20) The activity of oxaliplatin against cisplatin-resistant carcinoma and colon carcinoma cell lines was demonstrated in vitro. In addition, experimental data showed synergistic activity for the oxaliplatin–5-FU combination.(21) Finally, raltitrexed is a new, potent inhibitor of thymidylate synthetase. New cytotoxic agents are continually under investigation, the most promising of which are bevacizumab (Avastin), a monoclonal antibody targeted against the vascular- endothelial growth factor receptor (VEGFR), and cetuximab (Erbitux), a monoclonal antibody targeted against EGFR.(22,23)
Until recently, the antimetabolite 5-FU, which has been available for over 40 years, and leucovorin (LV) modulation was the standard of care, despite having no major impact on survival.(24) Colon cancer chemotherapy has rapidly evolved in the past 10 years, with a switch from 5-FU chemotherapy modulated by LV to polychemotherapy regimens (5-FU–LV in combination with oxaliplatin or irinotecan).
A response rate of 10–20% with no increase in overall survival is observed with 5-FU. Several small, randomised trials comparing chemotherapy with the best supportive care suggest there may be an average survival benefit of about 6 months in favour of chemotherapy. LV enhances 5-FU cytotoxicity by stabilising the interaction of thymidylate synthetase (the main target of 5-FU) with the active metabolites of 5-FU. A meta-analysis showed an increase of response rates of about twofold, compared with 5-FU alone, if LV is added to 5-FU (23% vs 11%). No difference in response rate is observed between high- and low-dose LV.(24,25)
The optimum schedule of 5-FU–LV administration has yet to be elucidated. An IV bolus of 5-FU, usually in combination with LV, is currently the most commonly used regimen (Mayo regimen). Such regimens have the advantage of being administered in the outpatient setting. Bolus followed by 24–48h infusion with a fortnightly regimen LV–FU(*), which combines LV–FU bolus and infusion, is safer and more active than LV–FU as a bolus.(26) This regimen was further developed into a simplified fortnightly LVFU(*) regimen, which combines LV–FU bolus on day 1 only with high-dose 5-FU infusion.(10,27,28) This regimen achieved promising activity without increasing toxicity.(29)
Continuous 5-FU infusion regimens delivered by portable pumps have theoretically the advantage of increasing the likelihood of cancer cells being exposed to 5-FU during cell cycle, and show improved response rates and good tolerability compared with bolus 5-FU. However, these regimens may lead to venous thrombosis, IV line occlusion and catheter-related sepsis.
Intrahepatic 5-FU (following surgical placement of a hepatic artery catheter) may be considered for patients with unresectable liver metastases. Response rates of 40–60% have been reported, although survival benefits are marginal.(30,31)
New drugs irinotecan and oxaliplatin have demonstrated survival improvement when given alone or in combination with LV–5-FU in first- or second-line therapy.(18,19,32–35) In phase III studies of patients whose disease had progressed after first-line, irinotecan as a single agent increased survival compared with best supportive care or LV–5-FU infusion.(18,19,36,37) In two first-line phase III studies, a significant survival advantage was demonstrated for irinotecan combined with LV–5-FU, compared with LV–5-FU alone.(32,33) Phase II studies of the combination of 5-FU–LV and oxaliplatin demonstrated activity in patients previously treated with 5-FU.(33–36) A randomised study showed that the combination of the de Gramont LV–5-FU(*) regimen with oxaliplatin (FOLFOX regimen) prolonged progression-free survival (PFS).(37) Another phase III study showed improved survival for FOLFOX over irinotecan in combination with LV–5-FU as a bolus (IFL).(38) The simplified LV–5-FU(*) regimen has been combined with irinotecan (FOLFIRI) and with oxaliplatin (FOLFIRIOX) and evaluated in second-line therapy.(37,39–44)
Raltitrexed, which does not require coadministration of a biochemical modulator, can be used as an alternative to 5-FU-based regimens for first-line treatment. Response rates appear to be similar to those seen with 5-FU–LV. Raltitrexed can be administered as an IV bolus every 3 weeks and causes less neutropenia and mucositis, but it failed in second-line chemotherapy.(45–47)
In conclusion, two main strategies can be used for the treatment of advanced colorectal cancer. First, drugs can be administered sequentially, starting from LV–5-FU. Secondly, drugs can be administered as a combination. Which of these strategies improves survival rate and quality of life has not yet been demonstrated.