Tumori, 94: 70-74, 2008
The management of gastric adenocarcinoma with postoperative chemoirradiation. A non-randomized comparison of oral UFT and 5-FU Serdar Surenkok1, Murat Beyzadeoglu1, Kaan Oysul1, Gokhan Ozyigit1, Selmin Ataergin2, Fikret Arpaci2, and Ahmet Ozet2 1 Department of Radiation Oncology, 2Department of Medical Oncology, Gulhane Military Medical School, Ankara, Turkey
ABSTRACT
Aims and background. We assessed the therapeutic results and tolerability of postoperative chemoradiotherapy with either oral UFT or 5-fluorouracil for carcinoma of the stomach. Methods and study design. Forty-six patients treated with chemoradiotherapy following total or subtotal gastrectomy for gastric carcinoma formed the cohort evaluated. The group included 39 males and 7 females whose ages ranged from 21 to 74 years (median, 53 years). In all patients, surgical therapy was the initial approach with a curative intent. The types of operations performed were total gastrectomy in 11 or subtotal gastrectomy in 35 patients. Radiotherapy began from 14 to 161 days after surgery (median, 55 days). Twenty patients received concomitant oral UFT (200 mg/m2), and 26 patients were given 5-fluorouracil (425 mg/m2, iv bolus) concurrently with irradiation consisting of one or two cycles, usually as a 3-day bolus at the start and last 3 days of irradiation therapy for radiosensitizing purposes. The patients were treated using either cobalt-60 or 6 MV photons, and irradiation doses delivered to the tumor bed and regional lymphatics ranged from 40 to 50 Gy (median, 46 Gy). Results. Median follow-up for the entire group was 24 months (range, 2-67). The 2-year overall survival of the entire group of patients was 64%. The 2-year overall survival rates for 5-fluorouracil and oral UFT groups were 72% and 66%, respectively (P = 0.3). Treatment-related factors were reviewed to identify any impact on survival. Analyses included type of surgery and dissection, fraction size, the total dose of irradiation and the type of chemotherapy. A significant detrimental effect in survival in the patients treated with D2 dissection compared to the patients treated with D1 dissection was noted (P = 0.01). Overall grade II-III toxicity of oral UFT was significantly lower than 5-FU (4 patients vs 14 patients, P = 0.03). Conclusions. Concomitant use of oral UFT with radiation seems to be more tolerable and an equally effective regimen in the treatment of locally advanced gastric cancer compared with 5-fluorouracil. D2 dissection was found to have detrimental effects on survival in this cohort.
Introduction The potential for chemoradiotherapy to improve survival in gastric cancer compared to irradiation alone was first reported by Moertel et al.1 in 1969 in a series of patients with unresectable tumors. Combined chemotherapy with 5-fluorouracil (5-FU) and irradiation has clearly shown a survival benefit as adjuvant therapy following gastrectomy for patients at high risk of recurrence in a large intergroup trial2. Thus, we
Key words: 5-fluorouracil, chemotherapy, combined modality therapy, gastric carcinoma, oral UFT (tegafur-uracil), radiotherapy. Correspondence to: Serdar Surenkok, MD, Department of Radiation Oncology, Gulhane Military Medical School, Ankara, Turkey. Tel +90-312-304-4689; e-mail
[email protected] Received April 17, 2007; accepted October 5, 2007.
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have adapted our institutional policy consistent with many other centers worldwide based on this intergroup trial. However, bolus 5-FU was not tolerated well in a significant proportion of our patients. In this aspect, we have started to test the tolerability and efficacy of oral UFT as a concurrent regimen in postoperative radiotherapy for locally advanced gastric cancer. Oral chemotherapeutic agents for postoperative adjuvant chemotherapy in locally advanced gastric cancer have been used as a unique approach for decades in Japan. Among them, UFT (tegafur and uracil) has been most widely used in both clinical trials and general clinical practice3-9. Phase II trials suggest that UFT has activity against gastric carcinoma similar to 5-FU, and the tolerability of UFT is reported to be excellent compared with bolus schedules of intravenous 5-FU3-9. In the present study, we evaluated our gastric cancer patients treated with chemoradiotherapy following total or subtotal gastrectomy and compared the therapeutic results and toxicity of concurrent UFT with 5-FU.
(200 mg/m2) throughout the radiotherapy course excluding weekends, and 26 patients were given 5-FU (425 mg/m2, iv bolus) concurrently with irradiation consisting of one or two cycles usually as a 3-day bolus at the start and last three days of irradiation therapy for radiosensitizing purposes. The characteristics of these two groups of patients are summarized in Table 1. After chemo-irradiation, all patients received some form of maintenance adjuvant chemotherapy consisting of 5FU-based regimens (5-FU and folinic acid; 5-FU, adriamycin, mitomycin-C). The patients were treated using either cobalt-60 or 6 MV photons, and irradiation doses delivered to the tumor bed and regional lymphatics ranged from 40 to 50 Gy (median, 46 Gy). All patients were treated with one fraction a day in a continuous course (usually 1.8-2 Gy daily) with a parallel opposed two-field approach. No patient received preoperative or intraoperative irradiation. All patients were conventionally planned, and perigastric, celiac, splenic, suprapancreatic, pancreotoduodenal, porta hepatic and proximal paraaortic lym-
Patients and methods Sixty-three patients who received postoperative chemoradiotherapy for stomach cancer in the Department of Radiation Oncology at the Gulhane Military Medical School were evaluated. Patients treated for unresectable disease, recurrent disease, distant metastatic disease identified prior to or during irradiation were excluded from the analysis. One patient treated with external beam irradiation without concurrent chemotherapy followed by surgery was also excluded. The remaining 46 patients who were treated with chemoradiotherapy following total or subtotal gastrectomy for gastric carcinoma form the cohort evaluated. This group included 39 male and 7 female patients with ages ranging from 21 to 74 years (median, 53 years). All patients were subjected to a careful staging and evaluation before treatment, and informed consent was obtained. This included a medical history, physical examination, a complete blood count, and a biochemical analysis including renal and hepatic function tests, chest X-ray, abdominal and pelvic computed tomography, and bone scan only in symptomatic patients. All pathology specimens were centrally reviewed, and patients were staged according to the American Joint Committee for Cancer Staging System (AJCC) 1997. In all patients, surgical therapy was the initial approach with a curative intent. The types of operations performed were total gastrectomy in 11 or subtotal gastrectomy in 35 patients. Tumor localization was the antrum in 7, corpus in 30, and pylor in 9 patients. Radiotherapy began from 14 to 161 days after surgery (median, 55 days). All patients received one cycle of systemic chemotherapy (5-FU, 425 mg/m2 iv bolus daily for 5 days, with folinic acid, 20 mg/m2 iv bolus) prior to chemo-irradiation. Twenty patients received concomitant oral UFT
Table 1 - Characteristics of patient groups
Gender Male Female Type of surgery Total gastrectomy Subtotal gastrectomy Type of dissection D1 D2 Median ECOG performance status Median surgery-RT interval (days) Pathology Adenocarcinoma Signet-ring cell Surgical margin Positive Negative T stage T2 T3 T4 N stage N0 N1 N2 N3 AJCC stage II IIIa IIIb IV Median RT fraction dose (Gy) RT total dose (Gy)
Oral UFT group (n = 20)
5-FU group (n = 26)
P
17 3
22 4
0.9
18 2
17 9
0.06
14 6 1 55
16 10 1 60
0.5
18 2
21 5
0.4
3 17
5 21
0.7
3 17 0
2 21 3
0.1
2 10 4 4
7 12 5 2
5 7 4 4 2 46
8 11 3 4 1.8 45
0.9 0.4
0.1
0.4
0.003 0.07
ECOG, The Eastern Cooperative Oncology Group; AJCC, American Joint Committee on Cancer; RT, radiotherapy; 5-FU, 5-fluorouracil.
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Median follow-up for the entire group was 24 months (range, 2-67 months). There was generally no significant difference between oral UFT and 5-FU groups with regard to the characteristics of patients and prognostic factors (Table 1). The only difference between the two groups was that daily fraction dose (2 Gy vs 1.8 Gy) and total dose (46 Gy vs 45 Gy) was significantly higher in patients receiving concurrent oral UFT (Table 1). The 2-year overall survival of the entire group of patients was 64%. The 2-year overall survival rates for 5-FU and oral UFT groups were 72% and 66%, respectively (P = 0.3). Fifteen patients receiving oral UFT and 17 patients receiving oral UFT were alive without evidence of disease at the last follow-up. Nine in the 5-FU and 2 in the oral UFT group of patients died. There were 9 local recurrences (5 in the 5-FU arm versus 4 in the UFT arm, P = 0.6) and 12 distant metastases (8 in the 5-FU arm versus 4 in the UFT arm, P = 0.5). Local relapse-free survival and disease-free survival rates were 75.7% (67.7% for the 5-FU arm versus 71% for the UFT arm, P = 0.5) and 65.9% (55% for the 5-FU arm versus 66% for the UFT arm, P = 0.3), respectively. All recurrences (local or distant) were unresectable and were treated with secondline systemic therapy. Three patients with bone metastases received palliative radiotherapy in addition to biphosphonates and chemotherapy. Tumor-related factors analyzed for possible prognostic significance included the number of positive lymph nodes, T stage, N stage, American Joint Committee on Cancer (AJCC) stage and surgical margin. None proved of statistical prognostic significance for overall survival. Treatment-related factors were reviewed to identify any impact on survival. Analyses included type of surgery and dissection, fraction size, the total dose of irradia-
1.0
.8 D1 dissection Overall survival
Results
tion, and the type of chemotherapy. No statistically significant differences except one factor in overall survival were noted for these variables. A significant detrimental effect on survival in the patients treated with D2 dissection was noted compared to the patients treated with D1 dissection (P = 0.01) (Figure 1). Patients with positive margins had a lower but non-significant 2-year overall survival compared with those with negative margins (38% vs 62%, P = 0.2) (Figure 2).
.6 D2 dissection .4
.2
0.0 0
12
24
36
48
60
72
Months Figure 1 - Kaplan-Meier overall survival in relation to type of dissection. 1.0
.8
R0 Overall survival
phatics were covered. The tumor bed ± remaining stomach was also in the target volume with 3-5 cm margins according to nearby critical structures. The tumor bed was determined according to preoperative abdominal computed tomography. Oral barium contrast and iv contrast materials were given to all patients in order to determine anastomotic sites, small intestines and kidneys during a simulation procedure. Patients were recorded as having acute toxicity if they required hospitalization, intravenous hydration, or outpatient parenteral support during treatment. Treatment breaks due to acute toxicity were also recorded as acute toxicity. Acute and late toxicity was recorded using the Radiation Therapy Oncology Group (RTOG) late morbidity scoring system. Survival estimations were calculated with the Kaplan-Meier product limit method. Statistical differences were calculated with the logrank test. Multivariate analysis was performed with the Cox proportional hazards analysis.
S SURENKOK, M BEYZADEOGLU, K OYSUL ET AL
.6
R1
.4
.2
0.0 0
12
24
36
48
60
72
Months Figure 2 - Kaplan-Meier overall survival in relation to surgical margin. R0, no residual disease; R1, microscopic residual disease.
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RTOG grade II-III acute toxicity is summarized in Table 2. Twenty-five patients required nutritional and/or intravenous fluids. In comparing the subgroups treated with oral UFT versus 5-FU, patients in the oral UFT arm actually had a lower incidence of grade II-III acute complications. Two patients required breaks due to acute effects of radiotherapy. However, there was no significant difference in the rate of individual complications between two arms (Table 2). However, the overall incidence of grade II-III toxicity with oral UFT was significantly less than that of 5-FU (4 patients in the oral UFT arm versus 14 patients in the 5-FU arm, P = 0.03).
FU, with 10-42% response rates7-9. UFT is not regarded as standard practice as an adjuvant postoperative treatment of gastric cancer in most Western countries. Our current study adds to the limited data on the promising results of the concurrent use of oral UFT in patients at high risk following total or subtotal resection of gastric cancer. In Japanese series, the tolerability of UFT was reported to be excellent compared with bolus schedules of intravenous 5-FU4-7. Similarly, the incidence of grade II-III toxicity in the present series was significantly less in patients receiving oral UFT than in the bolus 5-FU arm. Furthermore, no patient required a treatment break due to acute toxicity of the concurrent UFT chemoradiotherapy schedule without serious hematological toxicity. As regards survival, preliminary results of our study revealed no difference for the two concomitant regimens except for a higher tolerability with the UFT arm. In the analysis of the treatment variables in the current series, one finding was noteworthy with regard to the type of dissection. It did appear that patients treated with D2 dissection had lower overall survival than those treated with D1 dissection. From basic principles, it would be expected that patients with D2 dissection may have increased morbidity and mortality, as well as more chance of upstaging due to the number of dissected nodes. There are clearly limitations in our conclusion due to the retrospective nature and limited number of patients in this analysis. However, two recent large randomized multi-center studies comparing D1 and D2 dissections support our findings10,11. In the British Medical Research Council Gastric Cancer Surgical Trial (MRC), 400 patients with gastric adenocarcinoma were randomly assigned to D1 and D2 dissections10. Postoperative mortality was significantly higher in the D2 arm, with postoperative complications being significantly higher in the D2 group in the MRC trial. In the Dutch Gastric Cancer Trial, a total of 996 patients was randomly assigned to D1 or D2 lymph node dissection11. After curative resection, D2 patients had a higher postoperative mortality. They also demonstrated significantly more complications for patients after D2 dissection.
Table 2 - RTOG grade II-III acute toxicity of chemoradiotherapy for oral UFT and 5-FU arms Toxicity
Hematological Diarrhea Emesis and vomiting Radiotherapy break Overall grade II-III toxicity*
Oral UFT group (n = 20)
5-FU group (n = 26)
P
1 1 4 0 4 (20%)
4 3 10 2 14 (54%)
0.4 0.6 0.2 0.5 0.03
*Since more than one toxicity may simultaneously be seen in one patient, the overall toxicity is not equal to the numbers in that column.
Discussion
The optimal adjuvant chemoradiotherapy for stomach cancer has not yet been established. For resectable tumors, surgery remains the sole standard treatment. In the United States, MacDonald et al.2 reported a large intergroup trial (INT116) comparing only surgery versus surgery and postoperative chemoradiation with a median survival of 27 months and 36 months, respectively (P
