Chemotherapy for advanced colorectal cancer

Advanced colorectal cancer is that which is metastatic or locally advanced such that surgical resection is not likely to be curative. This may be at initial presentation (25% of new cases) or develop during follow-up of previously treated patients (50% of'curatively' resected). It has a poor prognosis with five-year survival <5%.

Indications for chemotherapy

Any patient with good performance status. Patients who are eligible for surgery for isolated metastasis (e.g. liver, lung) should be excluded. Resection of such metastasis may be curative in a small subset of patients.

Timing of chemotherapy

A single randomized study has demonstrated that chemotherapy given early imparts a small but significant survival advantage when compared to delaying treatment until symptoms arise.

First-line chemotherapy

5-Fluorouracil (5-FU)

First introduced in 1957, 5-FU is still the most widely used single agent. It acts, following conversion to active metabolites, as a false substrate for thymidylate synthase, preventing DNA synthesis. Several trials suggest a response rate of 10-20%. No increase in overall survival is seen when analyzing all patients treated. A number of small randomized trials, comparing chemotherapy to best supportive care, suggest that there may be an average survival benefit of around six months in favour of chemotherapy.

Modulation

Understanding the complex pathways by which 5-FU acts has allowed the development of biochemical modulation techniques. Leucovorin enhances 5-FU toxicity by stabilizing the interaction of thymidylate synthase and active 5-FU metabolites. Several studies, when meta-analysed, have shown a doubling of response rate with the addition of leucovorin to 5-FU compared to 5-FU alone (23% vs. 11%). No difference in response rate has been seen when comparing high-dose to low-dose leucovorin.

Table 18.1 Commonly used regimens in first-line treatment of advanced colorectal cancer

Regimen

Mode

5-FU

Leucovorin

Duration

Interval

Mayo

Bolus

425 mg/m2

20 mg/m2

Daily for 5 days

4-5 weeks

DeGramont

Bolus/infusion

400 mg/m2

Bolus, 8 g/m2, 46 hrs

200 mg/m2

2 days

2 weeks

Lokich

Continuous infusion

300 mg/m2

per day

-

8-12 weeks

-

Tomudex

Bolus

3 mg/m2

-

15 mins

Table 18.2 Toxicities of commonly used regimens in first-line treatment of advanced colorectal cancer

Mayo

DeGramont

Lokich

Tomudex

Nausea/vomiting

+

+

+

+

Diarrhoea

+++

+

+

Mucositis

+++

+

+

+

Myelosuppression

++

+

+

+

Alopecia

±

-

-

-

Hand/food syndrome

-

-

++

-

Modes of administration

The optimum schedule of 5-FU ± leucovorin administration has yet to be elucidated.

Intravenous bolus 5-FU, usually given with leucovorin, is currently most commonly used (e.g. Mayo). Such regimes have the advantage of being outpatient-based. Bolus/infusion regimes (e.g. DeGramont) have been shown to increase response rates and improve treatment tolerability. Continuous infusion 5-FU regimes, delivered by portable pumps, have the theoretical 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 to bolus 5-FU. They suffer from the disadvantage of venous thrombosis and intravenous line occlusion.

Raltitrexed ('Tomudex')

Raltitrexed is a potent inhibitor of thymidylate synthase. It can be used as an alternative to 5-FU-based regimes for first-line treatment. It does not require co-administration of a biochemical modulator. Response rates appear to be similar to those seen with 5-FU/ leucovorin. It has the advantage of being administered as an intravenous bolus every three weeks and causes less neutropenia and mucositis.

Regional chemotherapy

Intra-hepatic 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.

Second-line chemotherapy

Irinotecan, CPT-1

Further chemotherapy depends on patient wishes and performance status. For patients previously treated with 5-FU-based chemotherapy, there is currently no standard treatment regime. Irinotecan is a novel topoisomerase I inhibitor.

Several non-randomized studies have demonstrated activity in colo-rectal cancer. A recent randomized controlled trial, comparing irino-tecan with best supportive care in patients with 5-FU-refactory disease, has shown a significant increase in one-year survival (36% vs. 14%) and a significantly improved quality of life favouring irinotecan. A further study, comparing irinotecan with infusional 5-FU, has demonstrated a 40% improvement in one-year survival in the irinotecan-treated group.

Novel cytotoxic agents

Oxaliplatin This platinum derivative is not effective as a single agent against colorectal cancer. However, oxaliplatin combined with 5-FU/leucovorin can increase response rate and progression-free survival (but not overall survival) when compared with 5-FU/leucovorin alone.

Oral 5-FU analogues Because of marked variability in bioavailability, 5-FU cannot be given orally. Capecitabine is an oral agent, which is activated by a series of enzymes, resulting in 5-FU release preferentially at the site of tumour. Preliminary data suggest activity against colorectal cancer, with fewer side-effects than intravenous 5-FU.

Future directions Results of clinical trials using several new agents, including novel thymidylate synthase inhibitors (e.g. uracil/tegafur, UFT) and novel biochemical modulators (e.g. trimetrexate, 5-ethyny-luracil) are awaited.

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