1 Second Department of Surgery, Areteion Hospital, University of Athens, Athens; 2 Third Department of Medical Oncology, Theagenion Cancer Hospital, Salonika; 3 Department of Medicine, Laikon Hospital, University of Athens, Athens; 4 Fourth Department of Surgery, Nikaia General Hospital, University of Athens, Athens; 5 Department of Surgery, Evgenidion Hospital, Athens; 6 Department of Surgery, Agios Savas Cancer Hospital, Athens; 7 Department of Gastrointestinal Medicine, Theagenion Cancer Hospital, Salonika; 8 Department of Surgery, Red Cross Hospital, Athens; 9 Department of Surgery, Evangelismos Hospital, Athens, Greece
Received 8 July 2002; revised 1 October 2002; accepted 22 October 2002
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Abstract |
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The aim of this study was to determine whether the efficacy of the combination of 5-fluorouracil (5-FU), leucovorin (LV) and radiation therapy (RT) could be improved by the addition of interferon-2b (IFN-
) in patients who have had a curative resection, for rectal adenocarcinoma (Dukes B2/C; T3 N0, T4 N0, N13).
Patients and methods:
A total of 207 eligible patients with a performance status of 0 or 1 were randomized postoperatively between days 21 and 70 to one of the two treatment groups: group A, LV 20 mg/m2 i.v. bolus and 5-FU 425 mg/m2 i.v. days 15 and 2933, LV 20 mg/m2 and 5-FU 400 mg/m2 days 5760 and 8588, LV 20 mg/m2 and 5-FU 380 mg/m2 days 15 and 2933 with the second day 1 occurring 28 days after the completion of RT (45 Gy); group B, LV, 5-FU and RT as in group A, and IFN- 5 x 106 IU s.c. three times during each week chemotherapy is given.
Results:
104 patients were randomized into group A and 103 into group B. There was no statistically significant difference in either disease-free survival or overall survival between the two groups. Toxicity was also the same, except for the flu-like syndrome associated with the IFN- administration.
Conclusions:
There was no difference in efficacy between the two combinations. Toxicity was greater with the LV + 5-FU + IFN- regimen because of the flu-like syndrome.
Key words: adjuvant chemotherapy, adjuvant radiotherapy, randomized controlled trial, rectal neoplasm
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Introduction |
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Interferon-2b (IFN-
) has been shown to enhance the cytotoxic activity of 5-FU in human cancer cell-lines. The mechanism of this enhancement is probably multifactorial, as several mechanisms have been implicated. Studies on cultured colon adenocarcinoma cells and in murine models supported the use of an IFN-
and 5-FU combination in patients with colon cancer [57].
The aim of this study was to compare the combination of 5-FU, leucovorin (LV) and RT with the combination of 5-FU, LV, IFN- and RT in patients who have had a curative resection for rectal adenocarcinoma (Dukes B2 and C; T3 N0, T4 N0 or N13), to determine whether the efficacy of the 5-FULV combination with RT can be improved by the addition of IFN-
. A comparison of the toxicity of the two regimens was carried out at the same time.
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Patients and methods |
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All patients received an initial two cycles of chemotherapy, followed by pelvic RT accompanied by two cycles of chemotherapy, and two more cycles of chemotherapy after the completion of RT.
Chemotherapy regimens
Group A. First two cycles, LV 20 mg/m2/day i.v. bolus and 5-FU 425 mg/m2/day i.v. for 5 consecutive days on days 15 and 2933; two cycles administered with RT, LV 20 mg/m2/day and 5-FU 400 mg/m2/day on days 5760 and 8588; final two cycles, LV 20 mg/m2/day and 5-FU 380 mg/m2/day on days 15 and 2933 starting 28 days after the completion of RT.
Group B. LV and 5-FU as in group A. IFN- 5 x 106 IU s.c. three times during each week chemotherapy was given.
Radiation therapy
All patients received pelvic RT with concurrent chemotherapy with LV, 5-FU ± IFN-. Field arrangement depended on surgical and pathological frindings; however, the following generalizations were used. The width of the anterior-posterior: posterior-anterior (AP:PA) ports covered the pelvic outlet with a margin around the desired internal and external iliac nodes. Lateral margins extending 11.5 cm beyond the widest point of the bony pelvis were considered sufficient. The superior margins were at least 1.5 cm above the level of the sacral promontory. The inferior margin included the obturator foramina. Treatments were given with 6 MeV linear accelerators. The adjuvant dose levels of radiation required to achieve a high incidence of local control are close to the radiation tolerance of the small bowel. Therefore, great care was taken to localize tumor volumes and decrease the amount of small intestine within the irradiation field [8, 9]. The planning system was connected to a computed tomography (CT) scan, and the treatment planning was based on the CT findings. A 4-field technique was used to minimize the amount of small bowel exposed to treatment. The use of individualized blocks allowed a larger amount of small bowel to be shielded from the radiation fields. Patients were treated in a prone position with a full bladder in order to push the small bowel as up and out from the treatment field as possible. All fields were treated daily, resulting in a lower integral dose and more homogeneous dose distribution. The whole pelvis was treated at 1.8 Gy per fraction to a total dose of 45 Gy. After the completion of the pelvis treatment, a boost dose of 5.4 Gy was given to the tumor bed to a modal dose of 50.4 Gy.
Follow-up
Patients were followed-up at 6-month intervals after the completion of therapy for 5 years, then yearly. At follow-up evaluation, patients had a history and physical examination, complete blood count, liver chemistries, carcinoembryonic antigen test, CA 19-9 assay, chest X-ray and CT scan of the abdomen. A colonoscopy was recommended at 6, 18, 30 and 54 months after surgery or when indicated.
Statistical analysis
An accrual of 103 patients in each treatment arm was planned for this study. This number was considered sufficient to test the difference between the two groups, whilst allowing the completion of the study in a reasonable period of time considering the accrual potentials of the participating institutions. A total of 207 patients were finally randomized from nine participating centers. One hundred and four patients (50.2%) received LV, 5-FU and RT, while the remaining 103 (49.8%) received LV, 5-FU, IFN- and RT. All of them were considered evaluable and analyzed.
All individual data were listed. All parameters were presented descriptively. Tables of descriptive statistical parameters (number of non-missing values, mean, standard deviation, median, range) and/or contingency tables (number of non-missing values, percentage) were constructed in each case. The baseline comparability of the treatment groups was explored with respect to demographic data and other patients characteristics. Patients age was compared with one-way analysis of variance (ANOVA). Sex, PS and type of resection were evaluated using Pearsons 2 test. Nodal involvement and T stage were analyzed using Wilcoxon rank-sum tests. Estimations of the survivor function were derived from the KaplanMeier estimates. Differences between groups of patients were tested by both the log-rank and Wilcoxon statistic. If the estimated survivor functions did not cross, the assumption of proportional hazard was justified and the log-rank test was more appropriate. Alternatively, the Wilcoxon test was more appropriate than the log-rank test for comparing the two survivor functions. The Cox regression model (proportional hazard model) was used to determine which combinations of potential explanatory variables affected the form of hazard function. All P values were not adjusted and were derived from two-sided tests. The level of significance was fixed with
at 5%. A P value of
0.05 was taken to indicate statistical significance. The statistical analysis was carried out with the software product SAS (SAS Institute, Cary, NC, USA) version 8.1.
Patient eligibility, site of relapse, cause of death and toxicity were reviewed for all patients by the principal investigator. There were no protocol violations. The study was activated in December 1990 and the last patient was registered in June 1999.
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Results |
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Disease-free survival was measured from study entry until initial tumor relapse (local recurrence or distant). Overall survival was measured from study entry until death. There were 85 (41.1%) recurrences or metastases within the follow-up period: 44 (42.3%) from group A and 41 (39.8%) from group B. The difference between the two groups was not statistically significant (2 = 0.134, d.f. 1, P = 0.715). In addition, 55 (26.6%) subjects died defore the end of the study: 29 (27.9%) in group A and 26 (25.2%) in group B. Again, the difference was not statistically significant (
2 = 0.185, d.f. 1, P = 0.667).
Analysis of the disease-free survival shows no significant difference between the treatment groups (Figure 1). Analysis of the overall survival gave similar results to the disease-free survival (Figure 2). In fact, survival curves produced for patients allocated to treatments A and B could not be distinguished.
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Toxicity
All patients were assessable for toxicity. The ECOG toxicity criteria were used. Toxic reactions are presented in Table 2. There were no toxicity-associated deaths. There was no difference in toxicity between the two groups with the exception of the flu-like syndrome. The flu-like syndrome included fever, arthralgia, myalgia, abdominal pain, chills, rigor and fatigue, and was universal in IFN- treated patients. No case of significant liver toxicity was recorded. In no case was treatment discontinued because of toxicity. In two patients from each group, 5-FU was reduced because of leucopenia. In 18 patients, 10 from group A and eight from group B, 5-FU was reduced because of diarrhea. There was no statistically significant difference between the two groups with the exception of the flu-like syndrome (P <0.001).
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Discussion |
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Interferons-, ß and
enhance the activity of 5-FU in vitro and in vivo [57, 10]. Preclinical research concerning the interaction of 5-FU and IFN-
has been summarized by Grem et al. [11]. Although the mechanism by which IFNs modulate 5-FU activity is not completely elucidated, several clinical trials have evaluated the 5-FU + IFN-
combination or the double modulation (LV and IFN-
) of 5-FU with encouraging results [1224]. We have evaluated the 5-FU + IFN-
combination in a study of 25 patients with advanced colon carcinoma with satisfactory results and acceptable toxicity [25]. Therefore, it was considered worthwhile evaluating this combination at an early stage of the disease with a low tumor burden. At this stage the immunomodulatory properties of IFN-
could be helpful.
In 1994, Frasci et al. reported the results of a study comparing 5-FU + IFN-2b with 5-FU alone in patients with Dukes C colorectal cancer [26]. In their study, which had the limitation of using historic controls, the combination seemed to improve prognosis. Both 5-year relapse-free survival and cause-specific survival were significantly better in the patients receiving the combined treatment. There was no significant toxicity and the addition of IFN-
only slightly impaired tolerance to treatment [26]. Data from the National Surgical Adjuvant Breast and Bowel Project protocol C-05, which included 2176 patients with carcinoma of the colon, did not reveal any benefit from the addition of IFN-
to 5-FU + LV [27]. The addition of IFN-
increased the overall toxicity and adversely affected patient compliance. In this study, the combination of 5-FU + IFN-
did not increase hematological toxicity and did not affect patient compliance. It was associated with increased toxicity because of the flu-like syndrome, which was universal in IFN-
treated patients. We have previously found the same toxicity results with 5-FU + IFN-
in the adjuvant treatment of carcinoma of the colon [28].
We conclude that patients with resected stage II or III rectal cancer should be offered adjuvant therapy with a combination of RT and chemotherapy [29]. Chemotherapy should include 5-FU. Intravenous infusion of 5-FU is more effective than bolus injection [29]. Long-term i.v. infusion presents several problems for the patient, as well as the medical and nursing staff, so it is reasonable to include the novel fluoropyrimidine capecitabine in future studies. Capecitabine is an oral fluoropyrimidine derivative that delivers 5-FU to target cells with predictable kinetics. Oral administration enables sustained exposure to 5-FU and avoids the technical barriers of i.v. administration [30]. There is no evidence to support the addition of IFN- in this indication.
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Footnotes |
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References |
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