[MOL] Treatment Updates Series....Colorectal Cancer.... [00190] Medicine On Line

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[MOL] Treatment Updates Series....Colorectal Cancer....

Improving Therapy of Colorectal Cancer With New Agents
[Hematology-Oncology Treatment Updates - 2000 Medscape, Inc.]

A Critical Evaluation of Infusional and Oral Fluoropyrimidine Regimens

Selecting the most appropriate first-line treatment for patients with metastatic colorectal cancer is not a straightforward process. Dr. Twelves of the Department of Medical Oncology, Glasgow Royal Infirmary NHS Trust, United Kingdom, highlighted the wide range of fluoropyrimidine regimens used in clinical practice, many of which may need hospital admissions and require central venous access, whereas the newer therapies can be given orally as outpatient therapy. The availability of such a broad range of treatment options underlies the difficult task of assessing the relative strengths and weaknesses of these regimens.

While none of the most active fluoropyrimidine regimens stands out as superior in terms of efficacy, the bolus 5-FU/LV Mayo Clinic regimen is used in a large proportion of centers owing to its confirmed activity and ease of administration compared with infusional regimens. Treatment consists of bolus LV 20 mg/m2 followed by iv bolus 5-FU 425 mg/m2 on days 1 to 5, repeated every 28 days. A number of randomized, phase III trials have been conducted to compare new fluoropyrimidine regimens with the Mayo Clinic regimen as first-line treatment for colorectal cancer. Dr. Twelves described the 4 fluoropyrimidine regimens that he was going to discuss in his presentation -- 2 oral fluoropyrimidines and 2 of the most active infusional 5-FU/LV regimens:

Dr. Twelves went on to provide a critical evaluation of the data available from randomized, phase III trials of these regimens vs the Mayo Clinic regimen. The capecitabine data discussed by Dr. Twelves were the integrated data (prospective analysis) from more than 1,200 patients treated in 2 large trials first reported at ASCO 1999. One trial was conducted in the United States, Mexico, and Brazil[11] and the second was conducted in Europe and Australasia.[12] The UFT/LV data were from study 011 presented at ASCO 1999[13] and updated in September 1999 for regulatory filing to the FDA. The de Gramont data were published in 1997,[14] and the German AIO regimen data were from the EORTC/AIO study presented in May 2000 at the ASCO annual meeting in New Orleans.[15] The study by Schmoll and coworkers was a 3-arm trial with the infusional 5-FU regimen administered either with or without LV.

Before discussing the efficacy and safety data for the 4 regimens in detail, Dr. Twelves drew attention to some of the differences between the trials. He noted that in the de Gramont trial, which was not conducted for regulatory purposes, the analysis population was substantially smaller than the intent-to-treat population (448 patients randomized, 433 patients in the survival and time to disease progression (TTP) analyses, 348 patients in the response-rate analysis). He urged delegates to bear this in mind when comparing the trials. In the EORTC/AIO trial, only patients with measurable disease were included in the analysis of response rate. A notable difference in study design between the 4 studies was the longer interassessment intervals in the UFT/LV and de Gramont trials (8-10 and 12 weeks, respectively, compared with 6 and 4 weeks in the capecitabine and EORTC/AIO trials, respectively). The longer period between assessments results in cruder estimation of endpoints such as TTP. Another particularly important difference in the study designs in the context of this comparison, which was stressed later by Professor Jim Cassidy, is the different primary endpoints used in the 4 trials. For the UFT/LV, de Gramont, and EORTC/AIO trials, the primary endpoint was survival, whereas for the capecitabine analysis, the primary objective was to demonstrate at least equivalent efficacy in terms of response rate, with survival and TTP identified as secondary endpoints.

Impact on Survival

Dr. Twelves then compared the efficacy data from the 4 trials. In terms of overall survival, none of the regimens revealed a significant advantage over the Mayo Clinic regimen. Therefore, we must evaluate other endpoints such as response rate, TTP, tolerability, convenience, and medical resource utilization to assess the value of these regimens relative to one another.

Efficacy: Significant Differences in Response Rates and TTP

The primary endpoint of the capecitabine trial was response rate. Oral capecitabine achieved significantly higher response rates than the Mayo Clinic regimen (26% vs 17%, respectively; P < .0002). In addition, TTP was equivalent, with median TTP reported as 4.6 and 4.7 months, respectively (Table 1). In the UFT/LV trial, there was no statistically significant difference in response rates (12% with UFT/LV vs 15% with Mayo Clinic regimen), but the median TTP was significantly inferior with UFT/LV therapy compared with Mayo Clinic regimen (median 3.5 vs 3.8 months, respectively; P = .01).

Table 1. Median TTP (Study Drug vs the Mayo Clinic Regimen)

Median TTP (months) Relation to Mayo Clinic Regimen P value
Capecitabine 4.6/4.7 Equivalent .95
UFT/LV 3.5/3.8 Inferior .01
de Gramont 6.3/5.0 Superior .001
(+ LV)
(- LV)




Both the de Gramont and EORTC/AIO infusional 5-FU/LV regimens offered modest but significant increases in TTP. Median TTP was 6.3 months with the de Gramont regimen compared with 5.0 months in the Mayo Clinic regimen arm (P = .001), and 6.3 vs 4.1 months with the EORTC/AIO (plus LV) regimen and Mayo Clinic regimen, respectively (P = .02). The de Gramont regimen also demonstrated a significant improvement in response rates compared with the Mayo Clinic regimen (33% vs 15%, P = .004), although Dr. Twelves reminded the audience that the response rate analysis was based on only three quarters of the randomized population. There was a large difference in response rates between the EORTC/AIO (20.5%) and the Mayo Clinic regimen (11.5%), but this difference did not reach statistical significance, possibly because of the relatively small number of patients with measurable disease.

Dr. Twelves also noted that in all 4 trials, the response rates achieved with Mayo Clinic regimen were consistently in the order of 12% to 15%, suggesting that the patient populations evaluated in the 4 trials were similar (Table 2).

Table 2. Overall Response Rate

Study Treatment Mayo Clinic Regimen P value
Capecitabine 25.7 16.7 < .0002
UFT/LV 11.7 14.5 NS
de Gramont 32.6 14.5 .004
(+ LV)
(- LV)






NS = not significant

Therefore, in terms of efficacy, concluded Dr. Twelves, none of the regimens provided a significant survival advantage over the Mayo Clinic regimen. However, capecitabine and the de Gramont regimen produced significant improvements in response rates, the infusional regimens provided significant improvements in TTP, and UFT/LV resulted in significantly inferior TTP.

Improved Tolerability

Dr. Twelves then focused on the differing safety profiles of the 4 regimens, and in particular the incidence of diarrhea, nausea/vomiting, stomatitis/mucositis, and neutropenia. All 4 regimens were associated with a significantly lower incidence of grade 3/4 neutropenia and less grade 3/4 stomatitis compared with the Mayo Clinic regimen. Both of the oral regimens resulted in significantly reduced incidences of diarrhea and nausea/vomiting. When Dr. Twelves showed data for grade 3/4 events, different trends in the safety profiles of the 4 regimens could be seen. For example, there was a trend toward a higher incidence of grade 3/4 nausea/vomiting in all regimens except for capecitabine. Grade 3/4 diarrhea was significantly less frequent with the de Gramont regimen compared with the Mayo Clinic regimen, whereas severe diarrhea may be problematic in patients treated with UFT/LV. A 26% incidence of grade 3/4 diarrhea was reported in patients receiving adjuvant UFT/LV in a phase III trial.[16] All 4 regimens showed a clear advantage over the Mayo Clinic regimen in terms of grade 3/4 neutropenia.

One of the more frequent toxic effects associated with capecitabine therapy is cutaneous hand-foot syndrome, which affects palms and soles. However, this adverse event is usually mild to moderate in intensity, emphasized Dr. Twelves, and resulted in the hospitalization of only 2 of more than 600 patients treated with capecitabine in the 2 phase III trials. If patients and oncologists learn to recognize the early signs of mild or moderate hand-foot syndrome, development of severe hand-foot syndrome can usually be avoided by interrupting therapy, he added.

Improving Patient Convenience

Clearly, efficacy and safety are important considerations when identifying the most suitable treatment option for patients. Another important factor is patient convenience and the impact of treatment on quality of life. Infusional regimens require regular inpatient treatment or the use of Hickman lines or port-a-cath systems, which are cumbersome for patients and restrict daily activities. Moreover, infusional therapy is frequently associated with venous access-related complications such as infection or blockage. In addition, most patients require regular hospital visits that disrupt their daily life. For example, during a typical 24-week treatment period, a patient would need only 5-8 hospital visits for oral fluoropyrimidine therapy compared with 24-36 visits with the infusional regimens such as de Gramont or EORTC/AIO. This is a particularly important issue when survival is limited and when patients are having palliative treatment, added Dr. Twelves.

Patient preference must also be taken into consideration when choosing the ideal therapy: a questionnaire-based survey of 103 patients revealed that most patients prefer oral chemotherapy, provided this is not at the expense of efficacy. These results were supported by data from a recently reported, randomized, crossover study, in which patients showed a strong preference for oral vs iv therapy (84% in favor of oral therapy).[17] The principal reasons stated for this preference were oral administration, home-based treatment, and ability to continue daily activities.

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