Ada Henrike Braun
Gastrointestinal Cancer and Epithelial Cell Biology
Vanderbilt University Medical Center
Colorectal cancer is a major cause of worldwide cancer morbidity and mortality, and is the second-leading cause of cancer-related deaths in the developed world.(1,2) About half of all colon cancer patients develop metastatic disease. For them, palliative systemic therapy may considerably improve disease control, survival and quality of life. This article reviews the clinical rationale of current systemic therapies and future perspectives in the treatment of patients with metastatic colorectal cancer.
Available anticancer agents
For more than three decades, therapeutic approaches have almost exclusively been based on 5-fluorouracil (5-FU), which remains the mainstay of treatment in colorectal cancer. Whereas single-agent bolus administration shows moderate antitumour activity, treatment outcome is improved significantly by protracted infusion, combination regimens and biochemical modulation using folinic acid (FA, Leucovorin, LV) or methotrexate (Biotrexate). Today, treatment options for advanced colorectal cancer have broadened considerably, with over half a dozen agents approved, including thymidylate synthase (TS) inhibitors, oral fluoropyrimidines (eg, tegafur–uracil [UFT] or capecitabine [Xeloda]),(3) the topoisomerase 1 interactive compound irinotecan (CPT-11, Campto),(4) the diaminocyclohexane (DACH)-platinum derivative oxaliplatin (Eloxatin),(5) and biologically targeted agents against the epidermal growth factor receptor (EGFR: cetuximab; Erbitux) or the vascular endothelial growth factor (VEGF: bevacizumab; Avastin).(6,7) Indeed, with improving understanding of cancer cell biology, novel molecular targeted therapeutics have emerged and have entered clinical evaluation. Compounds in advanced clinical development that are predicted to enter the market in the near future include the EGFR-directed antibodies panitumumab (ABX-EGF; Amgen),(8) EMD72000 (Merck KGaA)(9) and small-molecule inhibitors such as gefitinib (Iressa; AstraZeneca)(10) and erlotinib (Tarceva; OSI Pharmaceuticals/Genentech),(11) inhibitors of the EGFR tyrosine kinase, or PTK787/ZK222584 (Novartis/Schering AG), which inhibits VEGF receptor tyrosine kinases.
Approved colorectal cancer treatments
5-FU and biomodulators
5-FU is an antimetabolite that has been available in clinics since the 1950s. Combination therapy with the biomodulator LV improves 5-FU efficacy, albeit without providing survival advantage.(12) Similarly, continuous-infusion 5-FU–LV regimens are more effective than intravenous (IV) bolus regimens in terms of response,(13,14) progression-free survival or safety,(15–17) but they do not improve overall survival. Whereas infusional regimens are frequently employed in Europe, they require prior implantation of a Port-a-Cath system and portable infusion pumps. A major advance has been the generation of orally available 5-FU prodrugs.
Oral 5-FU prodrugs such as UFT and capecitabine mimic protracted 5-FU infusion and facilitate drug administration. Moreover, there is strong evidence that high intratumoural levels of thymidine phosphorylase may selectively increase capecitabine-deduced fluoropyrimidine concentrations, resulting in enhanced efficacy and reduced systemic toxicity. Four large randomised phase III trials have implemented the therapeutic value of both oral fluoropyrimidines, which are convenient and meaningful alternatives to 5-FU–LV bolus regimens.(18–21) Currently, their activity is being compared with that of infusional 5-FU–LV in combination with either irinotecan or oxaliplatin. Although they are unlikely to improve clinical efficacy results, oral formulations may considerably improve a patient’s quality of life by circumventing possible nuisances of IV drug application, such as paravasation or infection.
Oxaliplatin is a third-generation 1,2-DACH platinum compound, which differs from other platinum derivatives in clinical activity and toxicity profiles and is effective in the systemic treatment of advanced colon cancer, both as a single agent and in combination regimens with either 5-FU or irinotecan. While single-agent oxaliplatin achieved only moderate response rates and short progression-free survival in various phase II trials, considerable improvement was obtained in combinations with 5-FU–LV,(22–38) yielding improved overall response and median times to disease progression, as well as a trend towards improved survival. The combination of oxaliplatin with irinotecan achieved similar safety and efficacy results as the IFL bolus (irinotecan+5-FU–LV) protocol, and may be considered in cases of contraindications to 5-FU.(39–41)
Irinotecan has demonstrated meaningful clinical efficacy and tolerability, both as a single agent(42–45) and in combination with either bolus(46–54) or infusional(55–64) 5-FU–LV, and in concomitant versus alternating schedules of administration.(65–68) Overall, the efficacy of the combined regimens significantly surpassed that of 5-FU–LV alone; two studies in particular yielded remarkable response rates of over 70% with six-times-weekly schedules of irinotecan and intermittent infusional 5-FU–LV.(64) Newer irinotecan combinations in phase II clinical assessments include oral fluoropyrimidines(69–72) and the direct TS inhibitor raltitrexed.(73–77) Additionally, an oral irinotecan formulation is currently being evaluated in clinics, which may provide substantial benefit for cancer patients.
Combination of the anti-EGFR antibody cetuximab with irinotecan yielded 23% overall response and six months’ median response duration for patients with EGFR-positive therapy-refractory tumours.(78) In a similar population, cetuximab alone yielded only 11% overall response rate.(79,80) The most frequent adverse effect observed with EGFR-targeted agents is acneiform skin rash, the occurrence of which has been associated with tumour response. Three-drug regimens with cetuximab, irinotecan and infusional or bolus 5-FU–LV yielded remarkable overall response rates of 70% and 44% in early clinical trials.(81,82)
Bevacizumab is the first anti-VEGF antibody out of a large panel of angiogenesis-targeted agents to improve overall survival in patients with colorectal cancer; it has recently been licensed in Europe and the USA. Angiogenesis, the formation of new blood vessels, is an essential mechanism for tumour growth, invasion and metastatic spread. Combination of bevacizumab with bolus 5-FU–LV yielded increased response rates, time to progression and median survival compared with 5-FU–LV alone.(83,84) Its safety profile, however, warrants further assessment, as hypertension, thromboembolic events and bleeding have been reported.
Towards a standard therapy for advanced colorectal cancer
Tangible advances have been achieved for metastatic colorectal cancer patients over the past few years, with more treatment options available than ever, and a median survival now approaching 21 months. So far, serial schedules of infusional 5-FU–LV-based combinations with irinotecan or oxaliplatin in either sequence have reliably demonstrated survival benefit for patients with good performance status (WHO<2) and favourable prognostic factors (eg, low serum lactic dehydrogenase, alkaline phosphatase, normal complete blood count, limited number of tumour sites).(41,85–87) These and similar regimens containing oral 5-FU prodrugs continue to be evaluated in the clinic with or without sequential or concomitant biologically targeted therapeutics.(8,88–91) To date, there is no consensus standard schedule, sequence or duration of treatment for advanced colorectal cancer patients, but every option should be considered in an individualised multimodal therapeutic approach. Two recently published meta-analyses highlighted the importance of remission induction within the first-line treatment for patient outcome.(92,93) Importantly, patients with formerly unresectable metastases may potentially be rendered amenable for surgery with curative intent after effective neoadjuvant chemotherapy.(94,95) Recent results further indicate clinical benefit with continued treatment until disease progression, when compared with treatment suspension in cases of response or stable disease and same reinduction therapy upon disease progression.(96)
The future is likely to see more and more tailored systemic therapy options arising with our increasing understanding of cancer biology, but there will be a price to pay. So far, novel therapies have been added to existing treatment regimens, rather than replacing them, and we will have to face the additional economic impact in a time where healthcare costs are steadily spiralling upwards.
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US National Cancer Institute
Clinical trials for colorectal cancer and other malignancies
Colon Cancer Alliance