Japanese Journal of Clinical Oncology 33:341-345 (2003)
© 2003 Foundation for Promotion of Cancer Research
Concurrent Chemoradiotherapy with Protracted Infusion of 5-FU and Cisplatin for Postoperative Recurrent or Residual Esophageal Cancer
1 Department of Radiology and 2 Department of Surgery, Kinki University School of Medicine, Osaka-Sayama, Osaka and 3 Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Sennan-gun, Osaka, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: We carried out the present study to investigate the feasibility and effectiveness of concurrent chemoradiotherapy (CT-RT) for postoperative recurrent esophageal cancer, which are, at present, unclear.
Methods: Between 1998 and 2002, 16 patients with postoperative loco-regional recurrence of esophageal cancer, and two patients with incompletely resected esophageal cancer were treated with concurrent CT-RT. Patients received protracted infusion of 5-FU 250–300 mg/m2 on days 1 to 14, 1 hour infusion of cisplatin 10 mg/body on days 1 to 5 and 8 to 12, and a concurrent radiotherapy (RT) dose of 30 Gy in 15 fractions over 3 weeks. This treatment schedule was repeated twice with a gap of 1 week, for a total RT dose of 60 Gy administered over 7 weeks.
Results: Of the 18 patients, 13 (72%) completed the CT-RT protocol. A total RT dose of 60 Gy was administered for all except two patients, and doses of chemotherapy were reduced for five patients. Although grade 3 hematological toxicities were frequently noted, non-hematological toxicities of grades 3 and 4 were few. Of the 18 tumors, five (28%) showed complete response (CR). For patients without prior chemotherapy, the CR rate was 40% (4/10). The 2-year survival rate of 13 patients without distant metastases was 19%, with a median survival time of 9.5 months.
Conclusion: The concurrent CT-RT protocol appears feasible and effective for patients with postoperative recurrent or residual esophageal cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Concurrent chemoradiotherapy (CT-RT) demonstrated a more significant improvement in local control and overall survival for locally advanced esophageal cancer, than did RT alone (1–3). At present, four cycles of 5-FU and cisplatin combined with an RT dose of 50 Gy is the standard CT-RT regimen for locally advanced esophageal cancer (1–4). Even for unresectable T4 esophageal tumors, which are staged according to the International Union Against Cancer TNM classification (UICC 1997), 2-year survival rates of 20–27% are achieved using concurrent CT-RT (5,6).
In Japan, surgical resection is performed preferably for patients with T1–3, N0–1, M0 esophageal cancer. However, even with extended radical esophagectomy with three-field lymph node dissection, which is considered a very aggressive surgical approach, loco-regional recurrence occurs in 21% of patients (7). RT or CT-RT, which was performed for patients with loco-regional recurrence of esophageal cancer after curative resection, showed good symptomatic relief in most, and long-term survival in some patients (8,9). However, few treatment protocols have been reported for the postoperative recurrence of esophageal cancer.
Although the safety and effectiveness of concurrent CT-RT for locally advanced esophageal cancer have been adequately demonstrated (1–6), the feasibility and effectiveness of concurrent CT-RT for postoperative recurrent esophageal cancer are still unclear. A prospective phase I/II trial of protracted infusion of 5-FU and cisplatin combined with full dose RT for T4 esophageal squamous cell carcinomas was conducted at our institution (6). During that period, the same CT-RT protocol was applied for postoperative loco-regional recurrence or gross residual tumors of esophageal cancer. This investigation is a retrospective analysis of concurrent CT-RT for postoperative recurrent or residual esophageal cancer.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Population
We intended to treat patients with the same CT-RT protocol as that applied in the case of T4 esophageal cancer (6). The criteria for eligibility included, age
75 years, an ECOG performance status of 0–3, serum creatinine <1.5 mg/dl, creatinine clearance >50 ml/min, white blood cell count (WBC) >4000/mm3, platelet count >100 000/mm3. However, two patients with a creatinine clearance of 40–50 ml/min were also included because this trial was not a prospective protocol study. Informed consent was orally obtained from all patients, for treatment using the same CT-RT protocol as applied in the case of locally advanced esophageal cancer. All patients underwent physical examination and computed tomography of the chest and abdomen with contrast enhancement. Upper gastrointestinal endoscopy and bronchoscopy were performed for most patients. Between July 1998 and July 2002, 16 patients with postoperative recurrent esophageal cancer and two patients with incompletely resected esophageal cancer were treated, according to the CT-RT protocol, at our hospital. Patients and tumor characteristics are shown in Table 1. The age of patients ranged from 43 to 75 years (median, 64), and performance status (PS) was, PS0/1 13 patients, PS2 three patients, and PS3 two patients. With the exception of one adeno-squamous cell carcinoma, 17 were squamous cell carcinomas in histology. The diameters of tumors ranged from 1.5 cm to 10 cm (median; 4.0 cm). These tumors were located in the mediastinum alone for 11 patients, the mediastinum and neck for six, and the upper abdominal region for one patient. As in prior treatments, eight patients were treated with chemotherapy, which included two patients who were treated with CT-RT. None of the tumors were located in the previous RT field. Although no distant metastasis was noted in 13 patients, simultaneous distant metastases and loco-regional recurrence was noted in the remaining five patients.
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Radiation and Chemotherapy
Either 6 MV or 10 MV X-rays were used. The daily fractional dose of RT was 2 Gy, administered 5 days a week. The total RT dose was 60 Gy, administered in 30 fractions. Since a gap of a week was inserted after a dose of 30 Gy, the overall treatment time was 7 weeks. With a dose of 40 Gy, the RT field was reduced to the gross target volume with an appropriate margin, and the total RT dose to the spinal cord was limited to 40 Gy, usually carried out by using oblique opposed fields. The initial anterior/posterior RT field included the supraclavicular fossa and the mediastinum (T-shaped field) for 13 patients, the mediastinum alone for four patients, and the upper abdominal region alone for one patient. For patients with distant metastases, the initial RT field included loco-regional recurrence with a 2–3 cm margin, although the T-shaped field was used for most patients without distant metastases.
Patients received protracted infusion of 5-FU 250–300 mg/m2 (350–500 mg/body) on days 1 to 14, one h infusion of cisplatin 10 mg/body on days 1 to 5 and 8 to 12, and a concurrent RT dose of 30 Gy in 15 fractions over 3 weeks. This treatment schedule was repeated twice, with a gap of 1 week, for a total RT dose of 60 Gy administered over 7 weeks. Radiation was administered within one h of administration of cisplatin. Chemotherapy was discontinued if grade 3 leukocytopenia, or thrombocytopenia was noted. Radiation was discontinued if grade 4 leukocytopenia or thrombocytopenia, grade 4 dysphagia, fever of >38°C, or worsening of PS was observed.
For two patients with poor renal function at presentation (serum creatinine of 1.1–1.5 mg/dl and creatinine clearance of 40–50 ml/min), the daily dose of chemotherapy was reduced (cisplatin 5 mg/body, 5-FU 150–200 mg/m2). For one patient, 10 mg/body of cis-diammine-glycolatoplatinum (nedaplatin) was administered instead of cisplatin as preferred by the attending physician.
Response and Toxicity Criteria
The local tumor response was evaluated within a few months of the CT-RT, by chest and abdominal CT with contrast enhancement. Complete response (CR) was defined as the disappearance of the tumor mass on CT. Partial response (PR) was a 50–99% regression on the two-dimensional measurement on CT, and no response (NR) was less than 50% regression. Computed tomography scans were obtained at intervals of 2–6 months, and were used to evaluate the recurrence of primary tumors and regional lymph nodes.
Acute toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0). The overall survival rate was calculated from the first date of external RT. Overall survival considered deaths due to any cause. Survival curves were plotted using the Kaplan–Meier method, and differences were assessed by the log-rank test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Of the 18 patients, 13 (72%) completed the CT-RT protocol, and the dose of CT was reduced for five patients including the two with poor renal function at presentation. For two patients with PS3 at presentation, RT was terminated at 12 Gy and 50 Gy due to worsening of PS.
Table 2 shows the incidence of acute toxicities. Although grade 3 leukopenia was frequently noted (33%), non-hematological toxicities of grades 3–5 were rare. Worsening of PS (grade 4) was noted in two patients as mentioned above, which resulted in the termination of RT. Grade 4 renal toxicity was noted in one patient. Since the patient’s renal function was poor (serum creatinine of 1.1 mg/dl and creatinine clearance of 40 ml/min) before CT-RT, the dose of chemotherapy was reduced (cisplatin 5 mg/day, 5-FU 300 mg/body/24 h). However, after one course of chemotherapy, this patient underwent artificial dialysis due to massive pleural effusion and hyper-potassemia, although the serum creatinine level before dialysis was within the normal limit. The patient died two months after the commencement of CT-RT, and the autopsy revealed congestive heart failure due to the recurrent esophageal cancer invading the pericardial space.
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Late radiation toxicity of Lhermitte’s sign (grade 1) was noted in one patient and fistula of the esophago-gastric anastomosis was noted in one patient. However, as an apparent recurrent tumor invaded the anastomotic site, the fistula was not considered as a treatment-related toxicity. Another patient died of sudden tumor bleeding 3 months after the commencement of CT-RT.
Of the 18 recurrent or residual esophageal tumors, five (28%) showed CR, eight (44%) PR, four (22%) NR, and one (6%) progressive disease (PD) (Table 3). For patients without prior CT, the CR rate was as high as 40% (4/10), although it was 13% (1/8) for patients with prior CT (Table 3). Similarly, tumor responses based on the time interval between the initial operation and CT-RT, and the tumor sizes were analyzed (Tables 4, 5). No apparent relationship was noted between these parameters, and the CR rate or the response rate (CR+PR). However, in terms of tumor size, none of the tumors with the longest diameter of >5 cm, showed CR.
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The 2-year survival rate for patients without distant metastasis was 19%, with a median survival time (MST) of 9.5 months (Fig. 1). For patients with distant metastases, the MST was 7 months. The difference between the two survival curves was not significant.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the present study, we evaluated the safety and effectiveness of concurrent CT-RT with protracted infusion of 5-FU and cisplatin for postoperative recurrent or residual esophageal cancer. In Japan, various protocols of low-dose protracted infusion chemotherapy combined with full dose RT are performed for patients with advanced esophageal squamous cell carcinoma (5,6,10), although in the USA full dose chemotherapy is combined with RT (1–4). The rationale behind the use of protracted infusion is to obtain maximum radiosensitization effects with chemotherapy. Our prospective phase I/II trial of protracted infusion of 5-FU and cisplatin combined with full dose RT reveals that this protocol was feasible and effective for T4 esophageal squamous cell carcinomas (6).
The present protocol of concurrent CT-RT was completed in 72% of patients, and no serious treatment related toxicities were noted. The tumor response rate was 72%, with a CR rate of 28%. For patients without distant metastases, the 2-year survival rate was 19%, with an MST of 9.5 months (Fig. 1). These results are very similar to those previously reported (8,9). Nemoto et al. (8) reported the results of RT or CT-RT for postoperative recurrence of esophageal cancer without distant metastases. The 2-year survival rate was 15%. Raoul et al. (9) combined full dose chemotherapy of cisplatin and 5-FU with an RT dose of 60 Gy sequentially, for 31 patients with postoperative recurrence of esophageal cancer. An objective response was observed in 65% of the patients, and the 2-year survival rate was 17% with an MST of 10.7 months.
Recently, Nemoto et al. (11) reported preliminary clinical results of CT-RT using nedaplatin and 5-FU for locally advanced and recurrent esophageal cancer. Nedaplatin is a platinum derivative with reduced renal toxicity that maintains the effectiveness of cisplatin (12). The 2-year survival rate of seven patients with postoperative recurrent esophageal cancer was 69% in the case of high dose RT (60–70 Gy) combined with nedaplatin and 5-FU (11). Although the survival rate appears to be high, the number of the patients was too small to draw any conclusions.
In the present study, the MST of the five patients with metastases was 7 months, and each of these patients died within 15 months. For patients with distant metastases, chemotherapy is the preferred choice of treatment. Although the survival benefit by CT-RT may not be much for patients, various symptoms related to local recurrence were relieved by CT-RT. RT combined with full dose chemotherapy may be more beneficial than with low dose protracted chemotherapy to obtain a survival benefit for patients with metastases.
The present study is not strictly a prospective one, therefore some patients with poor renal function or those with PS3 were also included. However, the present protocol could not be tolerated by these patients. Thus, those patients with poor renal function and/or PS3 should be excluded from the next protocol study.
Although a more similar response rate was achieved with CT-RT for patients with prior chemotherapy compared with those without prior chemotherapy, four out of five CR tumors were seen in patients without prior chemotherapy (Table 3). This suggests that CT-RT is not effective enough for recurrent tumors after chemotherapy.
With regard to the toxicity of CT-RT for postoperative esophageal cancer, one concern is the tolerance dose for the esophago-gastric anastomosis and the gastric tube. Koide et al. (13) reported that in the case of esophageal cancer the incidence of ulcers in the gastric tube did not increase by a postoperative RT dose of 50 Gy. In a randomized study of adjuvant postoperative RT after curative resection of esophageal cancer (14), postoperative RT significantly increased the incidence of fibrotic strictures of the esophago-gastric or esophago-colonic anastomoses, although no increase in ulcers or fistulae was reported. Nemoto et al. (8) reported that one patient (3%) died of necrosis of the gastric tube 6 months after an RT dose of 66 Gy. In the present study, which used a total RT dose of 60 Gy, an anastomotic fistula was noted in one patient. However, this fistula was apparently related to the regrowth of the recurrent tumor. Thus, a total RT dose of 50–60 Gy by conventional fractionation appears safe at the anastomotic site or the gastric tube, however, we do not recommend administration of a total RT dose of >60 Gy for postoperative esophageal cancer.
In conclusion, the present protocol of protracted infusion chemotherapy combined with concurrent RT appears feasible and effective for patients with postoperative recurrent or residual esophageal cancer.
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ACKNOWLEDGEMENT |
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This study was supported in part by Grant-in-Aid for Scientific Research (14570887) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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FOOTNOTES |
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+ For reprints and all correspondence: Yasumasa Nishimura, Department of Radiology, Kinki University School of Medicine, 377–2, Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan. E-mail: ynishi{at}med.kindai.ac.jp
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REFERENCES |
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Received April 23, 2003; accepted June 15, 2003
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