CHEMOTHERAPY FOR COLORECTAL CANCER

Dr. Lim Kean Ghee FRCS

After decades of relative stagnation, chemotherapy for colorectal cancer is at last beginning to show some exciting developments. In reviewing this topic it should be noted that, although it is the adenocarcinoma of the colorectal mucosa that is in question, just one type of cancer, its treatment is considered in different settings.

Usually the first setting a new regime of chemotherapy is tried for metastatic colorectal cancer, where the need is most desperate. With the best supportive care, such patients have a median survival of approximately 9 months. Secondly, what works there is tried in the adjuvant setting. In this case, patients are first treated with surgery and hopefully cured of the disease. However because we know that up to 50% of patients with operable disease will relapse, because of residual microscopic disease not detectable at surgery, chemotherapy is administered. How chemotherapy is used in the first setting cannot be equally applied in the same way. Studies need to determine exactly how many are actually saved from having a relapse of the disease by chemotherapy and whether those at a lower risk of relapse, namely; those with operable colon cancer who do not have mesenteric nodes involved (stage II or B), should be treated at all in view of the toxic effects of chemotherapy. In the adjuvant setting it is important to note that some studies are confined to colon cancer and do not include rectal cancer.

There is a third setting, and that is for rectal cancer. In cases of T3/4 rectal tumours, chemotherapy has a role in combination with radiotherapy in the pre-operative setting to reduce tumour bulk to facilitate better local control of disease and sphincter preservation at surgery. Alternatively, chemotherapy and radiotherapy may be given post-operatively. Although the best timing and dose has to be determined specifically for rectal cancer, the regime used usually follows what is best in the metastatic disease and adjuvant therapy setting. However as radiotherapy is involved making the subject longer, it will not be discussed here.

5-Fluorouracil
5-fluorouracil (5-FU), is a prodrug that irreversibly inhibits thymidylate synthase when it is metabolised to 5-dUMP. This leads to depletion of dTMP that is required for DNA synthesis. 5-FU also disrupts RNA function by being incorporated in RNA synthesis. For four decades up to the 1990s, despite experiments with numerous agents in various combinations, 5-FU on its own, without any other cytotoxic, emerged as the most effective form of chemotherapy available for colorectal cancer, with response rates of about 20% and minimal survival benefit. With no other promising drug combinations, studies had years to modulate and refine the most effective way of using 5-FU.

5-FU in Metastatic Colorectal Cancer
By the early 1990s it was established that for metastatic disease, 5-FU using a bolus dose modulated with leucovorin(LV), (a drug that is metabolized into a co-factor the inhibition of thymidylate synthase by 5-dUMP depends on) was more effective than 5-FU alone (response rates of 23% vs 11%)¹ giving patients a median survival of 12.6 months versus 7.6months.² Infusional 5-FU appeared slightly better than bolus therapy, with or without LV, on account of a better toxicity profile, response rate (22% vs 14%) and even a small survival advantage (12.4 months vs 11.4 months) in a meta-analysis of 1,219 patients.³

5-FU in Adjuvant Colon Cancer
For adjuvant therapy, studies showed first that 5-FU with levamisole (5-FU/lev)⁴ and then 5-FU with leucovorin (5-FU/LV)⁵ improved disease free survival and overall survival for patients with mesenteric lymph node positive (Dukes' C or stage III) colon cancer. The bolus 5-FU/LV regime resulted in a 3 year disease-free survival of 62% versus 44% among untreated controls, and was superior with regards to overall mortality at 5 years.^5,6 Then it was learned that levamisole was not necessary⁷ and leucovorin at low dose was equivalent to high dose, and that 6 months therapy was comparable to 12 months therapy. Weekly and monthly bolus regimes give comparable results.^6,8 Infusional 5-FU regimes appear to have no survival advantage over bolus regimes in the adjuvant setting but have less toxic effects.⁹ Even elderly patients over 80 years old were found to benefit from adjuvant chemotherapy.¹⁰ For Dukes' B (stage II) disease, however, the results had been inconsistent, ^*(11,12) as one would expect a smaller benefit, which, if present, would be harder to detect. However, a larger trial of over 3,000 colorectal (68% colon 32% rectal) cancer patients has now shown a small, 3% (but significant P=0.02), absolute survival benefit also in this group of patients.¹³

There were hardly any other promising options beside 5-FU up till the last 10 years. However, several phase III trials have now begun to show convincing evidence for a number of new agents that have never been observed before. Coming almost at the same time, irenotecan, oxaliplatin and capecitabine have each shown benefit in their respective combination trials. It will however, take years to come to sort out the best of the permutations of using them in various doses, regimens, combinations and sequences.

Oxaliplatin
Addition of Oxaliplatin in Metastatic Colorectal Cancer
Oxaliplatin (trans-1-diaminocyclohexane oxalatoplatinum), is a platinum complex that does not show cross resistance with cisplatin and carboplatin. The oxalate group when displaced from the diaminocyclohexane ligand complex, leads to dichloride species that react with DNA. It differs presumably from the other platins by forming adducts that are more difficult to repair.¹⁴ The use of oxaliplatin with 5-FU/LV in metastatic colorectal cancer has shown a better response rate of 50% compared to using 5-FU/LV alone (22%) and increased progression free survival. Overall survival though, was not significantly improved compared to 5-FU/LV alone.¹⁵ Neutropenia, diarrhoea and neurosensory toxicity were more common in the oxaliplatin treated group. This better response to chemotherapy has enable treatment to be taken one step further. The liver is often the only site of metastases in colorectal cancer. Reduction in liver tumour size on oxaliplatin/5-FU/LV chemotherapy has, in a minority of patients, enable potentially curative liver tumour resections to be performed on patients with disease previously considered inoperable.^16,17 The survival rates at 5 and 10 years achieved were comparable to patients undergoing primary liver surgery without prior chemotherapy.

Addition of Oxaliplatin in Adjuvant Colon Cancer
In the adjuvant setting, the three-year results of patients with Dukes's B and C colon cancer of a large study designed to have enough power to show a significant difference in the small benefit expected, have recently been published. Adding oxaliplatin to 5-FU/LV resulted in a 72% (vs 65% on 5-FU/LV alone) 3-year disease free survival for Dukes'C patients and a 87% (vs 84% on 5-FU/LV alone) 3-year disease free survival for Dukes' B patients.¹⁸ Three-year disease free survival has been found to be a reliable predictor of overall survival but the final outcome is awaited.

Irinotecan
Addition of Irinotecan in Metastactic Colorectal Cancer
Irinotecan is a drug that inhibits topoisomerase I and thereby inhibits cell division. This is a novel molecular mechanism and irinotecan has no cross-resistance with fluorouracil. In combination with 5-FU/LV, irinotecan has also improved response rates (35-39% vs 21-22%), progression-free survival (7 vs 4 months) and even overall survival (15-17 vs 13-14 months) of patients with metastatic colorectal cancer in phase III trials in both North America and Europe.^19,20 Although it is possible such therapy may lead to hepatic metastases which are unresectable becoming resectable there are no results of prospectively randomized trials for this yet. Irinotecan regimes tend to give more toxic effects, particularly diarrhoea and neutropenia, compared to those with 5-FU/LV only. The combination of irinotecan and oxaliplatin without 5-FU/LV did not compare as well as either of them with 5-FU/LV.²¹

In the adjuvant setting there have been two large trials. One of them, the CALGB 89803 trial following the IFL regime of Saltz was stopped when the 60-day all-cause mortality was greater with the IFL regime and the futility boundary was crossed. The other, the Pan-European Trials in Adjuvant Colon Cancer (PETACC-3) which compared the infusional regime of 5FU-LV with and without irinotecan closed in March 2003 and its results are awaited.

Novel Anti-folates
Capecitabine
Capecitabine is an oral fluoropyrimidine carbamate. It is a non-toxic prodrug that is rapidly absorbed and converted to 5'-deoxy-5-fluorocytidine (5'-DFCR) primarily in the liver and to 5'deoxy-5-fluorouridine (5'-DFUR) and then into 5-FU by enzymes cytidine deaminase and thymidine phosphorylase which are more active in tumour cells then normal tissue. 5-FU concentrations appear 21 times higher in colorectal tumour cells compared to plasma, and 3.2 times higher compared to adjacent tissues after capecitabine administration. Capecitabine therefore, provides not an addition to but a replacement of 5-FU/LV therapy. It provides a continuous presence of the drug like the infusional state without the logistics of parenteral administration. It causes less myelosuppression, diarrhoea and stomatitis but more hand-and-foot syndrome in comparison to 5-FU/LV in bolus therapy. As a single agent it achieved a higher objective tumour response rate (19-25% vs 11-15%) for metastatic colorectal cancer than when compared to a bolus regime of 5-FU/LV. However, it did not increase time to disease progression nor overall survival.^22,23 Capecitabine may be more effective in patients whose predominant site of metastases is the lung.

These results suggests that capecitabine would match the best infusional regimes in terms of both efficacy and side effect profile. However, the ability to get 5-FU into tumour cells at higher concentrations than in adjacent tissues and the blood, does not push up response rates and overall survival very much higher. A phase III trial of 1987 patients using capecitabine as adjuvant treatment for stage III colon cancer has now reported a 3 year relapse free survival of 65.5% for capecitabine versus 62% for 5FU/LV.²⁴ The result for its use in combinations with oxaliplatin and irinotecan are eagerly awaited. Such results are beginning to appear and capecitabine with oxaliplatin looks likely to match the 50% response rate seen for 5-FU/LV with oxaliplatin.²⁵ (phase II study - 55% objective response rate, 7.7 months median time to progression and 19.5 months overall survival).

Other oral fluoropyrimidines
UFT is a combination of tegafur and uracil. Tegafur is a prodrug that is transformed to 5-FU in the body. Uracil is used in combination to retard the phosphorylation that degrades on 5-FU and so maintain a higher tissue presence of 5-FU. A response rate of 18-25% have been reported for metastatic colorectal cancer.²⁶ There have not been many large scale trials of its use but it has been studied like capecitabine in the adjuvant setting, in combination with oxaliplatin and irinotecan. It has also been studied in chemoradiation therapy for rectal cancers.

Eniluracil is an inactivator of dihydropyrimidine dehydrogenase and allows for oral dosing of 5FU. A phase III trial of 981 patients has shown a mean survival rate of 13.3 months for eniluracil plus oral 5FU compared to 14.5 months for 5FU/LV for metastatic colorectal cancer patients.²⁷

S-1, is a combination of tegafur, CDHF (a dihydropyrimidine dehydrogenase inhibitor) and oxonic acid (an orotate phosphoribosyltransferase inhibitor) that has been produced with a similar role in mind. No large studies have yet been reported. Early studies (phase I & II) have reported a partial response rate from 24-40% and a mean survival of 11.8 months for patients with metastatic colorectal cancer.

Pemetrexed
Pemetrexed is another antifolate antineoplastic agent that blocks DNA and RNA synthesis through inhibition of thymidylate synthase, and also dihydrofolate reductase and glycinamide ribonucleotide formyltransferase (multiple targets). It is however not an oral drug. In small trials it has shown response rate of 15-17% with a median survival of 15-16 months as a single agent in first line therapy of patients with metastatic colorectal cancer.^28,29 It is used in combination with folic acid and cyanocobalamin (B12) to decrease haematological toxicity. Like the other antifolates it has been studied in combination with the other new chemotherapy drugs.

Targetted Therapy
The field of chemotherapy for colorectal cancer is clearly on the move. Hot on the heels of these new pharmaceutical chemicals are a new range of drugs which are monoclonal antibodies raised to specific cell receptors. A number of them have already shown impressive results in colorectal cancer.

Cetuximab
Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR), also known as HER1. One of the epigenetic changes of colorectal cancer is overexpression of receptor tyrosine kinases such as EGFR. Therefore it might be expected that such an antibody might suppress tumour progression. Initial studies in patients with EGFR expressing metastatic colorectal cancer have shown an objective response rate of 23% using irinotecan plus cetuximab in irinotecan resistant patients compared with 11% for those on cetuximab alone. Median overall survival was 8.6 months versus 6.9 months for cetuximab alone. Time to progression was 4.1 months versus 1.5 months.³⁰

Bevacizumab
Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF). In patients with metastatic colorectal cancer, addition of bevacizumab to 5FU/LV when compared to 5FU/LV alone produced a mean survival duration of 18 months versus 14 months. Progression free survival (8.8 vs 5.6months) and tumour response rates (34% vs 24.5%) were also superior in the bevacizumab group.³¹ In a phase III trial of 813 patients with previous untreated metastatic colorectal cancer, a combination of bevacizumab with IFL produced an overall survival rate of 20.3 months versus 15.6 months for IFL alone. A longer progression free survival (10.6 vs 6.2 months) and tumour response rate (45% vs 35%) was also noted.³² Bevacizumab with 5FU/LV appears also to be slightly superior to IFL alone.³³

Each coming year will make it clearer which regime would be most appropriate for first-line therapy and for failures and relapses. Being the third most commonly diagnosed malignancy about 800,000 cases of colorectal cancer are diagnosed worldwide annually, 75% of them in the operable category. An improvement of 5-10% in the overall survival rate in the adjuvant setting would mean the potential to save 30-60,000 lives a year. The ability to make 20% of patients with metastatic disease operable and giving them a 35% chance of survival after surgery means the potential to save another 14,000 lives. For the 200,000 or so with metastatic disease, currently chemotherapy adds one or two years to their lives. The impact of improving chemotherapy for colorectal cancer is good news.

* IMPACT B2 investigators found no statistical significant difference at a median of 5.75 years follow-up ¹¹(3 year disease-free survival was 79% vs 76%). In contrast meta-analysis of 5-year data from four NSABP studies demonstrated a reduction in mortality.¹²

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