Chemotherapy for Advanced Colorectal Carcinoma - Recent advances
Dinesh Chandra Doval
Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, Sector- 5, New Delhi-110085,India.
Colorectal cancer is the second most common cause of death from cancer in the industrialised countries. The incidence of colorectal cancer varies according to geographic locations worldwide. The highest rates are reported from Australia, New Zealand, North America and certain Countries in Northern and Western Europe1.
Though the incidence of colorectal cancer is less in India, still they form the 7 or 8th commonest cancer in most of the population based cancer registries in India2. The incidence rates are 10 and 9.5/lakh populations for males and female respectively. About 20% of the patients will present with metastatic disease at the time of initial diagnoses and another 50% will eventually fail the program of adjuvant treatment and develop distant metastasis.
The prognosis of patients with advanced colorectal cancer is dismal, with estimated 5-year survival rates of 5%. These patients have a median survival of 6-9 months from the diagnosis of metastatic disease. The aim of chemotherapy in these group of patients is to prolong survival with a good quality of life. The role chemotherapy as palliative itself was controversial in these group of patients. However, the meta-analysis by the Colorectal cancer collaborative group confirmed that chemotherapy improves both survival and quality of life of patients with advanced colorectal cancer. There was a 35% reduction in the risk of death and a median survival of 11.7 months in patients treated with chemotherapy compared with a median survival of 8.0 months in patients who received the best supportive care3. Until recently only 5-FU and its derivatives were available for the treatment of these patients. Here we review the newer agents available or in various stages of development for the treatment of advanced colorectal cancer.
Among medical management, 5-fluorouracil (5-FU) has been the main stay of treatment of colorectal cancers since its introduction into clinical practice some 40 yeas ago both for adjuvant treatment and for treatment of advanced metastatic disease. Administration of 5-FU as a single agent produces response rate of normally less than 15% in patients of metastatic colorectal cancers, which is far from ideal and produces median survival of 6 to 9 months.
Attempts to improve the efficacy of 5-FU4 in chemotherapy naive patient have included i) modification of schedule and route of administration of 5-FU, ii) combination of 5FU with other cytotoxic agents like semustine (Methyl CCNU), mitomycin C or cisplatin etc iii) biochemical modulation of 5-FU cytotoxicity by combination with folinic acid (FA), methotrexate, alpha interferon, PALA or other modulators iv) local or regional administration such as direct hepatic artery infusion for patients with liver metastasis. Some of the approaches especially the biochemical modulation with leucovorin have improved the response rate up to 30%. Unfortunately there has been little survival advantage with median survival reported from multicenter trials seldom exceeding 12 months.
The need for alternative or second-line chemotherapy is much more a need in view of refractoriness or relapses after 5-FU based regimens. Several newer agents have been developed for use in the treatment of advanced colorectal cancers.
A. Oral fluorinated pyrimidines:
Currently, there are several oral fluoropyrimidines in clinical practice or in advanced stages of development. They have been in common use in Japan.
UFT Plus Oral Leucovorin:
UFT is a combination of tegafur, a prodrug of 5-FU, and uracil in a molar ratio of 1:4. Tegafur is converted to 5-FU by hepatic cytochrome P450 pathway5; whereas uracil enhances the half-life of converted 5-FU by competing for its degradation by dihydropyrimidine dehydrogenase (DPD), which is the rate-limiting enzyme in the catabolism of 5-FU. This leads to higher intracellular concentrations of 5-FU with increased antitumor activity in preclinical models 6 and in tumor tissues when given to humans. UFT demonstrated clinical activity in colorectal, gastric, breast and head and neck cancers. Oral leucovorin biochemically modulates the 5FU generated from UFT.
The recommended doses for Phase II trials were UFT 300mg/day and leucovorin 75-90mg/day in divided doses and administered 8 hourly for 28 consecutive days, next cycle was given on day 35. The most common toxicities were myelosuppression on the five-day schedule and diarrhea on the 28-day schedule. Results of one phase III trial in metastatic colorectal cancer have now been reported for the UFT/oral leucovorin combination. In this study7, 816 patients were randomized between Orzel (UFT at 300 mg/m2/day with 75-90 mg/day of leucovorin) and intravenous 5-FU and leucovorin arms (5-FU 425 mg/m2/day and leucovorin 20 mg/m2/day for five days every 28 days). The overall response rates in both arms were comparable (12% for UFT/leucovorin and 15% for intravenous 5-FU and leucovorin). The UFT/leucovorin arm had reduced incidence of febrile neutropenia and hand-foot syndrome.
S-1 is a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and oxonic acid. CDHP inhibits activity of DPD and oxonic acid prevents intestinal phosphorylation of 5-FU by pyrimidine-phosphoribosyl-transferase. In one study8, 36 patients were treated with S-1 at a dose of 35 mg/m2 twice daily after meals (the first four patients at a dose of 40 mg/m2 twice daily had gastrointestinal toxicity). The most common side effects at this dose were diarrhea, nausea, fatigue, and anorexia. Four patients had a partial response and further development work is underway.
Eniluracil is an extremely potent noncompetitive inhibitor of DPD. Eniluracil potentiates the effects of 5-FU by causing virtually complete inhibition of DPD. As the intestinal and hepatic DPD activity is responsible for the erratic bioavailability of oral 5-FU, a combination of oral 5-FU and eniluracil has been developed. In the phase I trial by Schilsky et al9, eniluracil therapy caused a sustained decrease in DPD activity by at least 90% in mononuclear cells for 24 h or longer. In a phase II trial, eniluracil in combination with oral 5-FU was administered on a twice-daily schedule for 28 days of a five-week course10. In untreated patients with metastatic colorectal cancer this regimen had a 24% response rate. Diarrhea (13%), stomatitis (3%), and myelosuppression (3%) were the major dose-limiting toxicities.
Is a new oral fluropyrimidine carbamate11. It was developed as an orally active tumour selective fluropyrimidine to achieve highest intra-tumoural 5FU level and less toxicity than 5' DFUR or 5FU. It achieves highest intra tumoral levels than 5-FU and is less toxic than 5 'DFUR or 5FU. Capecitabine passes through the intestinal mucosa as an intact molecule and as 5-FU is not directly released in the small bowel, diarrhea should be reduced. Capecitabine is initially metabolized in liver. Subsequently it is metabolized to 5'-deoxy-5-fluorouridine (5-d5-FUR) and doxifluoridine and finally to 5-FU via thymidine phosphorylase, which is present in higher levels in tumour tissue. Capecitabine has been used as single agent or in combination with leucovorin and paclitaxel. Two phase III studies in colorectal cancer showed that response rates were higher in the capecitabine arm (23.2% versus 15.5%) but this did not translate into higher CR rates, duration of response, or progression-free survival12,13.
(B) Thymidylate synthase inhibitors:
Presently, four folate-based agents that have been designed to interact with the folate-binding site of TS by using binding side-structure analysis, are either available as licensed products or in clinical trials at various stages, viz. reltitrexed, nolatrexed, LY231514 a multitargeted antifolate (MTA) and ZD9331.
Raltitrexed, a water-soluble antifolate agent, is a specific inhibitor for TS. This agent prevents the production of nucleic acid precursor thymidylate, while having no effect on RNA or protein synthesis. Inhibition of thymidylate synthase prevents cell division, causing cell death. Results of three randomized phase III trials have been reported. The European trial 14 compared TOM with 5-FU/LV administered using the "Mayo" schedule. This study showed no significant differences between the two treatments in terms of response rate (19% versus 17%), median survival (10.3 months), or time to progression (4.7 versus 3.6 months). The North American trial15 showed a same response rate for the two treatments (14% and 15% respectively), although the median survival time was significantly shorter for the TOM treatment group (9.7 versus 12.7 months). The international trial that compared TOM with 5-FU/LV ("Machover schedule") reported comparable response rates (19% versus 18% respectively) and median survival times (10.7 versus 11.8 months) for the two treatments 16. Raltitrexed appears to have an advantage in terms of less myelotoxicity and mucositis, but a disadvantage in terms of transaminitis (reversible), nausea and sometimes prolonged asthenia, as compared with 5-FU.
Nolatrexed (Thymitaq, AG337)
Nolatrexed is a water-soluble lipophilic inhibitor of TS and can enter the cell by passive diffusion. This makes it different from other antifolates such as TOM or MTA. It has a short plasma half-life, and since it cannot form polyglutamates and thus be retained in cells, this necessitates a prolonged (5-day) infusion. Its spectrum of toxicities is more similar to 5-FU than TOM, with myelosuppression and mucosal toxicity being dose-limiting17.
MTA has multiple targets in the folate pathway. It causes inhibition of a range of enzymes involved in folate metabolism, the most important being TS, dihydrofolate reductase (DHFR), human monofunctional glycinamide ribonucleotide formyltransferase (hGARFT), and aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT). MTA is transported across the cell membrane using the reduced folate carrier system (like TOM) and has low affinity to folate receptors, as well as being an excellent substrate for the enzyme FPGS. Early results indicate encouraging activity in colorectal cancer, with responses in the range of 15%-17%.
This molecule is of particular interest because of its unique preclinical profile. It is a potent TS inhibitor, while neither being lipophilic nor polyglutamated. It is currently undergoing phase I studies.
(C) Topoisomerase-1 inhibitors:
Several new camptothecin derivatives have been discovered that acts as a topoisomerase I inhibitors. Topoisomerase are nuclear enzymes responsible for topological control of DNA during its transcription and replication. These enzymes are responsible for functions akin to unknotting of DNA. Both topoisomerase I and II mediate ligation of DNA-enzyme complex. Thus their inhibition results in DNA strand break and subsequent cell death. Topoisomerase I inhibitors presently available in clinical practice are topotecan and irinotecan (CPT-11).
Irinotecan (CPT 11) is a semisynthetic derivative of camptothecin that acts as a topoisomerase inhibitor. Overall response rates of 10-30% have been achieved with irinotecan both in chemotherapy naive patients and refractory pretreated patients with advanced colorectal carcinoma. Tumour growth control for median of four months was demonstrated in 58% of patients resistant to 5FU. The major toxicity of irinotecan is neutropenia and diarrhoea (WHO grade 3 or 4) in 20-30% of patients respectively. The results of two phase III trials comparing irinotecan to 5-FU plus leucovorin to the combination of all three drugs have been reported recently. In the US trial overall response rate and overall median survival were superior in the irinotecan, 5-FU, and leucovorin group (39% and 14.8 months) compared with the 5-FU and leucovorin group (21% and 12.6 months)18. Results for irinotecan alone were similar to those for fluorouracil and leucovorin. The European trial showed a significant advantage in the irinotecan plus 5-FU plus leucovorin arm in terms of tumor regression (41 percent vs. 23 percent), the median time to tumor progression (7 months vs. 4 months), and the median overall survival (17 months vs. 14 months)19.
(D). Platinum derivatives
Of the many thousands of platinum compounds synthesized over the last 30 years, only a few dozen have reached pre clinical or early clinical development. Of these until recently only cisplatin and carboplatin were available. Both have similar clinical profile, and carboplatin was solely approved because of its superior safety profile. Oxaliplatin is a third generation platinum compound.
Oxaliplatin when used as single agent in 5FU refractory advanced colorectal cancer showed response rate of 10% with 20-40% of patients demonstrating stabilization of disease. In chemonaive patient's response rate of 27% was reported20. In two randomized trials, the addition of oxaliplatin to a regimen of fluorouracil and leucovorin as the initial treatment for metastatic colorectal cancer increased the probability of tumor regression and slightly prolonged the time to tumor progression but had no significant effect on survival21, 22. The objective response rate in those patients receiving oxaliplatin arm was 53% v 16% (P < .001) and 50.7% v 22.3% (P = .0001) when compared with the control arm respectively.
(E). Farnesyltransferase Inhibitors
Ras proteins are normally associated with the inner surface of plasma membrane and act as intermediates in transmitting a wide variety of extracellular signals to the cytoplasm and the nucleus. Ras oncogenes are mutated in more than 40% of colonic adenocarcinomas and mutation leads to constitutive activation of ras 23. Association of ras with the inner surface of plasma membrane is facilitated by farnesyl protein transferase (FPT), which modifies the cysteine residues on the protein. A variety of farnesyl transferase inhibitors is in clinical development.
SCH66336 - is a nonpeptidic small molecule which is a potent and selective inhibitor of FPT. In preclinical studies, this compound inhibits growth of cell lines expressing mutated K-ras. Phase II trials are ongoing with SCH66336 as a single agent in chemotherapy-resistant colorectal cancers, and phase I trials in combination with 5-FU are in progress.
R115777 - is an oral quinolone analog that inhibits farnesylation with consequent inhibition of growth of a variety of human tumor cell lines at nanomolar concentrations24. Two phase I trials have been reported with this compound. The principal toxicities were myelosuppression (neutropenia and thrombocytopenia), fatigue, and confusion.
Until very recently second line treatment of patients with colorectal cancers was limited therapeutic option confined mainly to locoregional (intra-arterial) or infusional 5FU treatment in 5FU failures. The availability of both irinotecan oxaliplatin and the incoming wave of new thymidylate synthase inhibitors (oral administration appears to be feasible and reliably active) multiplies the association possibilities of these three different agents. The demonstration of activity of irinotecan and oxaliplatin in advanced and metastatic colorectal cancers have led investigators to examine the combination of these two agents. Encouraging clinical results of activity in patients with 5FU refractory disease have been observed with this combination.
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Address for Correspondence:
Dr.K.Pavithran, MD, DM
Department of Medical Oncology
Rajiv Gandhi Cancer Institute and Research Centre