Fluorouracil-based chemotherapy for colorectal cancer usually is not limited by cumulative toxic effects and can be continued for long periods. The optimal duration of therapy is unknown. Short courses of chemotherapy might lead to more rapid disease progression. One survey reported that about one half of British cancer specialists stopped chemotherapy after six months if patients with metastatic disease responded well, whereas 30 percent would stop therapy after three months, and 20 percent would continue therapy indefinitely. Maughan and colleagues compared intermittent chemotherapy with continuous treatment in patients whose advanced colorectal cancer responded or stabilized after an initial 12-week course of chemotherapy.
They recruited 354 patients with inoperable or metastatic colorectal cancer from 42 British cancer centers. Patients were required to have adequate bone marrow and renal function and could not have had previous chemotherapy for metastatic disease. Patients were randomly assigned to intermittent (178 patients) or continuous therapy (176 patients). In the intermittent therapy group, treatment was stopped, and the patient was reassessed every six weeks. If the disease progressed, therapy was reinstituted at the clinician's discretion; resumption of the previous regimen was encouraged. Patients in the continuous therapy group also were reassessed every six weeks, but treatment was stopped only if clinically indicated by disease progression, unacceptable side effects, or patient choice. Patients were assessed at baseline and every 12 weeks with a full history, physical examination, laboratory investigations, computed tomography, or other methods of assessing disease burden. Every six weeks, patients completed quality-of-life and anxiety/depression inventories, and questionnaires about symptoms and the relative value of treatment.
The groups were comparable at the beginning of the trial. The median age was 64 years, and 36 percent of participants were women. In 59 percent, the disease stabilized after the first 12-week course of chemotherapy. The remaining patients had complete or partial response after initial treatment. In the intermittent therapy group, 66 patients (37 percent) restarted therapy. The median time to restart was 130 days (range, zero to 756 days). In 80 percent of cases, therapy was reinstituted because of disease progression. Other reasons for reinstitution of therapy included patient choice (11 percent) and clinical decision (3 percent). The median duration of treatment in the continuous therapy group was 92 days (range, zero to 748 days). Most patients who stopped continuous therapy (44 percent) did so because of disease progression, but other reasons included toxicity (16 percent), clinical decision (16 percent), and patient choice (14 percent).
Overall, patients averaged 28 weeks of treatment, and 30 percent of them progressed to second-line chemotherapy. Of the 66 patients in the intermittent therapy group who restarted treatment, 14 (21 percent) responded, and 17 (26 percent) stabilized. The length of time without therapy did not influence the response to renewed therapy. Serious adverse events were reported by 17 patients in the continuous treatment group and six in the intermittent therapy group. Although patients who were treated continuously reported more side effects, the groups were similar in reported overall functioning and general health, including psychologic aspects.
Most patients in each group considered their treatment worthwhile. Median survival after randomization was 10.8 months in the intermittent therapy group and 11.3 months in the continuous therapy group; one-year survival was 46 percent in the intermittent therapy group compared with 45 percent in the continuous therapy group; and two-year survival was 19 percent in the intermittent therapy group compared with 13 percent in the continuous therapy group. No subgroup of patients appeared to have derived increased risk or benefit from either treatment regimen.
The authors conclude that intermittent therapy was associated with reduced toxicity without compromising survival. They found no advantage to continuing therapy until disease progression, and they recommend that serious consideration be given to pausing chemotherapy after the initial treatment course. A policy of stopping and rechallenging with the same chemotherapy extends the patient's treatment options and delays the introduction of second-line treatments.
editor's note: Patients with advanced colorectal cancer require significant support from family physicians. Many patients and their families are overwhelmed by conflicting recommendations from oncologists, surgeons, radiation oncologists, and others. A well-informed family physician can help them navigate the maze of information. Most patients with advanced colorectal cancer have a life expectancy of about one year. Chemotherapy can greatly affect their quality of life during that time. Some patients may welcome the “treatment holidays” validated by this study. Others may prefer to fight the disease continuously or may decline intermittent therapy because restarting therapy seems too psychologically damaging. By working through the treatment options we can help patients maintain a sense of control and ensure that they receive optimal therapy.—a.d.w.