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Martin H Cohen*
Division of Oncology Drug Products
Center for Drug Evaluation and Research
US Food and Drug Administration
From 1957 to the early 21st century, metastatic colorectal cancer (MCR) was treated with 5-flurouracil (5-FU) or 5-FU/leukovorin. New cytotoxic and biological agents are now available. Current treatment issues include who should be treated, with what, when, and for how long.
Treatment selection depends on the number of disease sites as well as the number of metastases at each site (modalities available to treat MCR are listed in Table 1). Patients who have metastatic disease solely or predominantly confined to a single organ may have prolonged survival with surgery alone. Similarly, patients with limited metastatic disease who are technically not resectable at presentation may become resectable after an objective treatment response.
A large majority of MCR patients receive palliative therapy designed to relieve symptoms, maintain quality of life and prolong survival. USA-approved drugs and biologics are listed in Table 2.
Which, if any, chemotherapy regimen should be offered to a patient is influenced by patient and disease-related characteristics. Suitable patients should have at least one lesion that is measurable or evaluable so that treatment can be stopped if the lesion is growing. Adequate haematological, renal and hepatic function is required as is an ambulatory ECOG (Eastern Co-operative Oncology Group) or Karnofsky performance status. Patients should have recovered from any prior treatment-related toxicities. Patients are not generally offered a specific drug if they are susceptible to toxicities associated with it. Patient age (> 65 years) is not a treatment disqualification.
When should patients be treated? For those who are symptomatic at presentation, the goal of MCR chemotherapy is to reduce symptoms, improve quality of life and prolong survival for as long as possible. Treatment should be offered to all patients who are suitable candidates for chemotherapy and who accept offered treatment. With current regimens, median survival is approaching two years. But increased survival is accompanied by increased treatment toxicity. Adverse events generally occur more frequently and more severely with newer, more aggressive regimens. However, most patients seem willing to accept the trade-off of increased toxicity for increased survival.
Whether newer treatment regimens improve quality of life and more effectively palliate symptoms is open to question. It is extremely difficult to design and carry out patient reported outcome studies. At a minimum, trials have to be randomised and double-blind, questionnaires must be validated and meaningful improvements rigorously defined. If several countries participate, questionnaire translation must be adequate and all the items must have comparable meaning in all countries. Moreover, there are statistical challenges associated with multiple comparisons and missing data. Of USA-approved MCR drugs, only irinotecan has labeled quality-of-life information. Results were inconclusive.
For MCR patients who are asymptomatic at presentation and who will never be surgical candidates, it is not established whether immediate treatment is superior to treatment initiated when symptoms occur. In one randomised trial, survival was statistically better in the immediate treatment group by the Breslow-Gehan test that focuses on the early portion of the survival curve.
But this was not the case with the more standard log-rank test that compares the entire survival curve. A meta-analysis of two additional randomised trials, stopped early for poor accrual, concluded that immediate chemotherapy did not produce survival benefit.
With these results in mind, informed patient preference becomes important. It should be emphasised that if a patient does not want immediate therapy he or she should be available for follow-up at regular intervals so that therapy can start at the first evidence of symptomatic disease progression.
The usual MCR treatment plan is to administer a drug regimen until disease progression and then initiate a new regimen. The rationale is that stopping and restarting therapy may promote multi-drug resistance. Curative drug therapy for MCR does not exist, however, and all patients develop treatment resistance. Consequently, planned drug holidays or temporary interruption of drugs thought to be responsible for significant toxicities have been evaluated. This does not appear to compromise overall survival,[1,4] but can maintain or improve quality of life.
In conclusion, there are now more alternatives for the treatment of MCR than in the recent past, and even more are being developed. Clinical trials remain the best way to define optimal treatment strategies. One promising new approach is individualised therapy based on genomic microarray analysis. Already markers have been discovered that predict irinotecan and 5-FU toxicity and oxaliplatin resistance. Additional efficacy and safety markers are currently being defined.
*The views expressed are the result of independent work and do not necessarily represent the views and findings of the US Food and Drug Administration
1. Goldberg RM, Rothenberg ML, Van Cutsem E, et al. The continuum of carer. Oncologist 2007;12:38-50.
2. Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Expectant or primary chemotherapy in patients with advanced asymptomatic colorectal cancer. J Clin Oncol 1992; 10: 904-911.
3. Ackland SP, Jones M, Tu D, et al. A meta-analysis of two randomized trials of early chemotherapy in asymptomatic metastatic colorectal cancer. Br J Cancer 2005;93:1236-1243.
4. Maughan TS, James RD, Kerr DJ, et al. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer. Lancet 2003;361:457-464.
5. Boyer J, Wendy L. Allen WL, Estelle G. McLean EG, et al. Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res 2006;66:2765-77.