ABSTRACT: Progress in the chemotherapy of colorectal cancer has been made in the past 10 years. After nearly 40 years since the introduction of the first drug, 5FU, for colorectal cancer into clinical practice, new active drugs have been identified. Irinotecan, a topoisomerase I inhibitor, is now routinely used as second-line treatment for metastatic colorectal cancer and will likely be offered as first-line treatment in combination with 5FU-folinic acid. Oxaliplatin, a third-generation platinum complex, is active in the treatment of colorectal cancer; studies are in progress to define its role in combination with the other drugs. Oral 5FU prodrugs and raltitrexed, a new thymidylate synthase inhibitor, may have a role in the palliation of the frail or elderly patient who cannot tolerate the side effects of intravenous chemotherapy. For Stage III colon cancer patients, postoperative chemotherapy with 5FU-folinic acid significantly reduces mortality. The combination of irinotecan and 5FU-folinic acid is being examined in a clinical trial. For Stage II and Stage III rectal cancer patients, several studies are in progress; chemotherapy with 5FU-folinic acid along with pelvic radiation is the present standard of care.
Chemotherapy for colorectal cancer has come a long way in the last 10 years, with effective new drugs now available for treatment.
The role of chemotherapy in the overall management of colorectal cancer (CRC) has changed significantly in the past decade. This has come about through the introduction of new active drugs for the treatment of patients with advanced or metastatic colorectal cancer and the demonstration of the efficacy of postoperative adjuvant therapy for high-risk patients who have undergone surgical resection.
Metastatic colorectal cancer
About 45% of patients with colorectal cancer die from their disease due primarily to metastases, most commonly to the liver. The management of metastatic CRC is largely palliative, though in selected cases regional therapy, including surgical resection, may be appropriate. The chief goals of palliative chemotherapy are the control of symptoms, the improvement of quality of life, and, possibly, the prolongation of life.
Thymidylate synthase inhibitors
Until recently, 5-fluorouracil (5FU) was the only drug with any track record in colorectal cancer. 5FU is an antimetabolite that inhibits the action of thymidylate synthase, an enzyme that metabolizes the conversion of uracil to thymidine. Its activity as a single agent in the treatment of colorectal cancer is modest, with an overall tumor response rate of 10% to 15% and no convincing evidence that treatment prolongs patient survival. Several biochemical modulators have been used to enhance the activity of 5FU. Among these, folinic acid was found to improve the response rates to about 30% to 40%. A meta-analysis of the nine randomized trials confirmed the higher response rates, though a survival gain could not be demonstrated.
The major schedule of administration of 5FU is by a rapid bolus injection for 5 consecutive days every 4 weeks (Mayo regimen), but there has been considerable interest in continuous intravenous infusion of the drug, since it has a short half-life. Because of the logistics of delivering 5FU in this manner, its use has been limited. A useful, well-tolerated regimen is the Vancouver protocol of 5FU 1000mg/m2/24 hours by continuous infusion X2 every week. This regimen has been modified by a few European groups, and there is growing interest in its routine use. Generally, response rates are higher with infusional 5FU, but survival benefits are inconsistent from study to study.
A variation on this theme is hepatic arterial perfusion of 5FU or its analogues. The rationale for this approach is the observation that the liver is the common site of metastases, and often the only site. Randomized studies have shown that the response rates are higher with 5FU hepatic arterial perfusion compared with systemic 5FU infusion, but no survival benefit has been documented, probably because of the study design that permitted patients treated with systemic 5FU to cross over to the hepatic arterial perfusion when their disease progressed. Further randomized trials are now underway to examine the role of hepatic arterial perfusion. At present this is considered an investigational treatment.
Raltitrexed is a newly developed drug with specific thymidylate synthase inhibition. It appears to have an equivalent level of efficacy in metastatic colorectal cancer with respect to response rates and overall survival.[7,8] It is, however, given in a more convenient schedule (once every 3 weeks), and it causes fewer side effects than 5FU-folinic acid. It is important to note that raltitrexed is excreted through the kidneys and, therefore, should be used with caution in those with impaired renal function, especially in the elderly.
Another recent development is the availability of oral formulations of 5FU. Capecitabine is the only one currently approved for use in Canada. While it offers a more convenient way of giving 5FU, it causes hand-foot syndrome in about one-third of patients who receive the full dose.
In summary, 5FU remains a cornerstone of chemotherapy of colorectal cancer. Its anti-tumor action can be enhanced by the co-factor, folinic acid. However, side effects can be significant, especially in elderly patients over 70 years of age. The newer thymidylate synthase inhibitor, raltitrexed, or the oral formulations of 5FU may be more appropriate for selected older patients because they are less toxic or more convenient. These advantages must be weighed against the higher costs for these drugs.
Topoisomerase I inhibitors
An important advance in the chemotherapy of colorectal cancer is the discovery of the anti-neoplastic activity of the camptothecins, a class of drugs called topoisomerase I inhibitors. Topoisomerases are enzymes that make a nick in the DNA strand, allowing it to uncoil and release the tension that builds up when the molecule unwinds during transcription or translation. The enzyme then repairs the damage. The topoisomerase I inhibitors bind to the enzyme after it has nicked the DNA and cause disruption of the DNA molecule, which kills the cell. Several Phase II studies showed that irinotecan, or CPT-11, a semi-synthetic camptothecin, produces regression or stabilization of metastatic colorectal cancer after the disease progresses on 5FU. Two randomized studies compared irinotecan with supportive care or infusional 5FU in patients with metastatic colorectal cancer who progressed during treatment with bolus 5FU. These studies demonstrated a significant prolongation of life and an improvement or maintenance of the quality of life of patients.[9,10] As a result of these studies, irinotecan was added to the BC Cancer Agency formulary as second-line chemotherapy for suitable patients whose disease progresses on 5FU chemotherapy.
With evidence of activity in 5FU refractory disease, the next step was to test irinotecan as first-line therapy for metastatic colorectal cancer. Two randomized studies have been conducted.[11,12] In a North American study, patients were randomly allocated to one of three treatment arms: irinotecan plus 5FU-folinic acid, 5FU-folinic acid, or irinotecan alone. Recent results now show a significant patient survival advantage for the combination compared to 5FU-folinic acid.
In a European study, irinotecan plus infusional 5FU was compared to infusional 5FU alone. In both studies tumor response rates were significantly higher for the combination of irinotecan plus 5FU-folinic acid compared with 5FU-folinic acid (40% vs 20%), and time to tumor progression was significantly prolonged. In the European study there was also a significant prolongation of overall patient survival, but this has not been found in the North American study to date. One reason for the lack of a survival difference may be that there was significant crossover between the treatment arms: 40% of patients who received 5FU-folinic acid were subsequently treated with irinotecan while 60% of patients in the irinotecan arm subsequently received 5FU-folinic.
An interesting observation in both studies was the attainment of complete tumor regression in a small percentage, about 3%, of patients treated with the combination; complete tumor regression is seldom achieved with 5FU-folinic acid alone. An issue of considerable clinical relevance now is whether combination chemotherapy with irinotecan-5FU-folinic acid should be the new standard of treatment for fit patients with metastatic colorectal cancer.
Another new drug with promising activity in colorectal cancer is oxaliplatin, a third-generation platinum compound. Oxaliplatin produces intrastrand, and interstrand crosslinks of the DNA strands, thereby blocking its replication, which leads to cell death. In combination with infusional 5FU, oxaliplatin produces high response rates, ranging from 31% to 53%, including complete responses in 3% to 5% of patients.[13,14] Two studies of infusional 5FU with or without oxaliplatin are in progress in Europe, and a North American study of oxaliplatin in combination with the other active drugs (5FU-folinic acid and irinotecan) has begun. These studies will clarify the role of oxaliplatin in the management of colorectal cancer. The introduction of oxaliplatin will undoubtedly improve the results of colorectal cancer treament.
The identification of new active drugs in the treatment of metastatic colorectal cancer has set the stage for the use of combination chemotherapy. The basic tenets for the combination of drugs in cancer therapy are in place. These include evidence of anti-tumor activity and drugs with different modes of action and with different toxicity profiles. The National Cancer Institute of Canada is planning a Phase II study of the combination of 5FU-folinic acid, irinotecan, and oxaliplatin in patients with metastatic colorectal cancer.
Postoperative adjuvant chemotherapy
Adjuvant therapy is given to patients who have undergone potentially curative treatments but who are at high risk for relapse. These include Stage III (positive regional lymph nodes) colon cancer patients, and Stage II (transmural extension of the primary tumor) or Stage III rectal cancer patients. The pivotal studies that show a clear advantage for Stage III colon cancer tested 5FU with levamisole compared with no postoperative treatment.[15-17] A 33% reduction in mortality was documented. As a result, adjuvant therapy became routine practice for Stage III colon cancer patients. Other studies examined 5FU plus folinic acid with or without levamisole. The conclusion from these studies is that 5FU-folinic acid confers the same benefit with less toxicity as the combination of the three drugs. The two-drug combination of 5FU-folinic acid was, therefore, adopted as the standard of treatment for Stage III colon cancer in the early 1990s.
With the recent evidence that the addition of irinotecan to 5FU-folinic acid produces better results in the more advanced stage of colorectal cancer, a trial is now underway to compare this drug combination with the standard regimen of 5FU-folinic acid for patients with Stage III colon cancer.
For rectal cancer patients, postoperative adjuvant pelvic radiation is standard for Stage II and Stage III disease to reduce the risk of pelvic recurrence of cancer. However, these patients are also at risk for metastatic disease, and adjuvant chemotherapy was, therefore, examined in a few studies in the 1970s and early 1980s. Although a firm conclusion cannot be drawn from these early studies, there was a suggestion that postoperative 5FU-based chemotherapy and radiation offer a benefit to these patients. Randomized trials of 5FU-folinic acid and radiation are in progress, but there is a consensus that in the interim, rectal cancer patients should receive postoperative adjuvant chemo-radiation. An interesting study conducted by the North Central Cancer Treatment Group showed that giving 5FU as a protracted intravenous infusion during radiation improves overall patient survival. In BC, high-risk rectal cancer patients are prescribed a course of adjuvant therapy. This includes two cycles of 5FU-folinic acid followed by radiation, after which they receive two more cycles of chemotherapy. During the 5 to 6 weeks of pelvic radiation, intravenous 5FU infusion is given. As in colon cancer patients, the role of the new drugs such as irinotecan and oxaliplatin needs to be examined for rectal cancer patients.
In addition to chemotherapy, newer therapeutic strategies are being explored. A monoclonal antibody, 17-1A, appears to be active in advanced colorectal cancer as well as in the adjuvant setting. A confirmatory trial is in progress. Another strategy comes from the improved understanding of colorectal cancer pathogenesis. The genes that malfunction during the development of colorectal cancer are now known, and this offers the platform to launch gene-based therapy.
Progress is also likely to come from our ability to identify high-risk patients more accurately. At present, transmural extension of rectal cancer or lymph node metastasis for rectal and colon cancers are the major prognostic factors used to determine the need for postoperative therapy. Other factors require closer study, such as pathological markers (histologic differentiation, mucinous histology, venous or lymphatic invasion); techniques for detecting occult lymph node metastasis (immunoperoxidase staining for cytoker-atin and TAG-72, or mutant-allele specific amplification [MASA] for gene alterations); and genetic factors (DNA aneuploidy, deletion of p53 gene on chromosome 17p, or DCC gene on chromosome 18q). The value of testing tumors for chemo-responsiveness such as intra-tumoral assays of thymidylate synthase is another area of research.
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