Chemotherapy in Advanced Colorectal Cancer
Birgit Kallinowski
B. Kallinowski ( u)
Praxis for Gastroenterology and Oncology, Scheffelstr. 63, 68723 Schwetzingen, Germany
e-mail: [email protected]
Abstract
Since the introduction of combined systemic chemotherapy with 5-folinic-acid (FA) and/or oxaliplatin or irinotecan, the median survival in patients with ad- vanced colorectal cancer has increased to more than 20 months. Novel agents in so-called targeted therapies such as monoclonal antibodies will further increase these excellent survival data in the near future.
Introduction
The role of systemic chemotherapy in patients with metastatic colorectal cancer (CRC) has been clearly established. However, only 10% of patients with metastatic CRC will survive more than 5 years. New combination therapies coming up in the last 5 years improved the median overall survival to nearly 20 months for the majority of patients. The main reason for this major breakthrough has been the integration of oxaliplatin and irinotecan in 5-FU-based chemotherapies. Further- more, the substitution of intravenous 5-FU by oral 5-FU prodrugs such as tegafur and capecitabine in the mono- or combination therapy optimised the chemother- apeutic regimes as well. The following article is intended to give a short review of the present standard chemotherapeutic strategies in metastatic CRC and will give an outlook for future biologicals and targeted therapies.
Standard Principles in Palliative Chemotherapy for Colorectal Cancer
Data by Scheithauer et al. from the early 1990s demonstrated that chemotherapy prolongs survival time in patients with advanced CRC from 5 to 11 months com- pared to patients receiving best supportive care alone [1]. In addition the use of palliative chemotherapy often ameliorates tumour-associated symptoms and im- proves quality of life in these patients [2, 3]. This is also valid for older patients.
Recent Results in Cancer Research, Vol. 165
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Another dogma for palliative chemotherapy which needs to be respected is that chemotherapy should be started as long as the asymptomatic patient is in good clinical condition, because a later start of chemotherapy in symptomatic patients worsens the prognosis [3]. The addition of folinic acid (FA) to 5-fluorouracil (5- FU) as a modulator has been superior to monotherapy with 5-FU. Response rates and time to progression, i.e. the progression-free survival (PFS) time, have been improved by the modulation of 5-FU by FA. However, the overall survival time for patients remained unchanged despite the modulation by FA [4]. The response rate is also dependent on the rate of 5-FU infusion. Maximal response rates and progression-free survival time with the same toxicity can only be achieved by ul- trashort 5-FU infusion times of 2–4 min, the so-called bolus 5-FU. Longer infusion times of 10–20 min decrease the response rates from 27% to 13% and the PFS from 5.5 to 4.2 months [5]. Another progress in palliative chemotherapy was made when it was discovered that the infusional regime of 5-FU was more effective than the use of the bolus 5-FU. Due to the short half-life of bolus 5-FU, 5-FU is integrated mainly in RNA, while infusional 5-FU with its constantly low FU level mainly in- terferes with DNA synthesis. Weekly protocols with intermittent 24- or 48-h 5-FU infusions combined with FA significantly increased RR and PFS compared to the 5-FU bolus protocol, with a tendency for better overall survival (11.2 months ver- sus 9.9 months with the bolus protocol). In addition, the infusional 5-FU protocols induce less gastrointestinal and hematological toxicity.
Oral 5-FU Prodrugs
Oral 5-FU prodrugs such as capecitabine and UFT imitate the continuous 5-FU infusion without the need for an intravenous port system. UFT consists of a com- bination of uracil and tegafur in a 4:1 ratio. UFT needs to be taken three times per day fasting with the addition of folinic acid, whereas capecitabine needs to be taken only twice a day without FA. Both prodrugs are less toxic compared to intravenous 5-FU referring to neutropoenia, diarrhoea and mucositis. However, capecitabine more often induces a hand-foot syndrome than its oral counterpart UFT. In randomised prospective trials comparing capecitabine and UFT and the Mayo protocol, the PFS and the overall survival with a median of 12 months were not different (Table 1) [6–8]. However, capecitabine has been demonstrated to be at least as effective as 5-FU bolus protocols with a response rate of 25.8% versus 11.6%. These response rates have usually been only achieved by infusional 5-FU regimes.
Combination Therapy with 5-FU/FA and Irinotecan and/or Oxaliplatin
The dramatic breakthrough with response rates in excess of 50% and median sur-
vival times of more than 20 months in patients with metastatic CRC were achieved
in the last 3 years by the combination of infusional 5-FU/FA with the camptothecin
Table 1. Oral fluoropyrimidines versus bolus 5-FU/FA: phase III trials
Authors Treatment Patients Response rate Survival PFS
(n) (%) (months) (months)
Hoff et al. 2001 Capecitabine 302 25.8
∗12.5 4.3
Bolus 5-FU/FA 303 11.6 13.3 4.7
Cutsem et al. 2001 Capecitabine 301 18.9 13.2 5.2
Bolus 5-FU/FA 301 15.0 12.1 4.7
Douillard et al. 2002 UFT/FA 409 12.0 12.4 3.5
Bolus-5-FU/FA 407 15.0 13.4 3.8
Carmichael et al. 2002 UFT/FA 190 11.0 12.2 3.4
Bolus 5-FU/FA 190 9.0 10.3 3.5
∗
p <0.05.
PFS, progression-free survival.
Table 2. 5-FU combination therapies: phase III trials
Author and publication source Patients (n) Response rate (%) 5-FU/LV Combination
De Gramont et al. JCO 2000 420 22 57 (Oxaliplatin)
∗Giacchetti et al. JCO 2000 200 16 53 (Oxaliplatin)
∗Grothey et al. ASCO 2002 252 23 49 (Oxaliplatin)
∗Douillard et al. Lancet 2000 387 31 49 (Irinotecan)
∗Saltz et al. NEJM 2000 666 27 49 (Irinotecan)
∗Köhne et al. ASCO 2003 440 30 50 (Irinotecan)
∗∗
