© The Author (2008). Published by Oxford University Press. All rights reserved
A Phase I Trial of 5-Fluorouracil with Cisplatin and Concurrent Standard-dose Radiotherapy in Japanese Patients with Stage II/III Esophageal Cancer
1 Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo
2 Medical Oncology Division, Aichi Cancer Center Hospital, Nagoya
3 Radiology Oncology Division, National Cancer Center Hospital, Tokyo
4 Gastrointestinal Oncology Division, National Cancer Center Hospital East, Chiba
5 Radiology Division, National Cancer Center Hospital East, Chiba
6 Gastrointestinal Oncology Division, Shizuoka Cancer Center, Shizuoka, Japan
For reprints and all correspondence: Takako Eguchi Nakajima, Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: taeguchi{at}ncc.go.jp
Received September 8, 2008; accepted October 6, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: In Japan, 5-fluorouracil (5-FU) 400 mg/m2 on Days 1–5, 8–12, 36–40 and 43–46 with cisplatin (CDDP) 40 mg/m2 on Days 1, 8, 36 and 43 plus concurrent radiotherapy with 2 weeks planned interruption (60 Gy) was standard for the patients with esophageal cancer. This Phase I trial was designed to determine the maximal tolerated dose (MTD) and dose-limiting toxicity (DLT) of 5-FU on Days 1–4 and 29–32 with CDDP on Days 1 and 29 plus concurrent radiotherapy (50.4 Gy) among the Japanese.
Methods: Escalating doses of 5-FU and CDDP were administered with concurrent radiotherapy (50.4 Gy). Treatment was continued until DLT appeared.
Results: Twelve patients with previously untreated clinical Stage II/III squamous cell esophageal carcinoma were studied. One of six patients given Level 1 (5-FU 800 mg/m2 on Days 1–4 and 29–32 with CDDP 75 mg/m2 on Days 1 and 29) developed a DLT of incomplete protocol treatment due to Grade 3 esophagitis. The MTD was not reached at Level 2 (5-FU 1000 mg/m2 with CDDP 75 mg/m2). The complete response rate was 67% at Level 1 and 100% at Level 2.
Conclusions: Dose Level 2 with 50.4 Gy radiotherapy was recommended for Japanese patients.
Key Words: esophageal cancer • chemoradiotherapy • 5-fluorouracil • cisplatin • Japanese
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INTRODUCTION |
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Chemotherapy with concurrent radiation therapy is one of the treatment options for patients with localized esophageal carcinoma [International Union Against Cancer (UICC) classification clinical stage I/II/III] selected for nonsurgical treatment. On the basis of the results of the Radiation Therapy Oncology Group (RTOG) Phase III intergroup trial (INT 0123, RTOG 94-05), the standard regimen for such patients is 5-fluorouracil (5-FU) 1000 mg/m2 on Days 1–4 and 29–32 with cisplatin (CDDP) 75 mg/m2 on Days 1 and 29 plus concurrent radiotherapy (50.4 Gy) (1). In that trial, patients were randomly assigned to receive combined treatment with 5-FU and CDDP plus a higher dose (64.8 Gy) of radiation therapy or the same chemotherapy regimen plus a standard dose (50.4 Gy) of radiation therapy. There was no significant difference in 2-year survival (31 versus 40%) or in local/regional failure or persistence of disease (56 versus 52%) between the high- and standard-dose arms. As for toxicity, the rate of treatment-related mortality was higher in the high-dose arm, but was apparently unrelated to the higher dose of radiation.
In Japan, different chemoradiotherapy regimens have been used to treat localized esophageal carcinoma. In the Japan Clinical Oncology Group Phase II trial (JCOG9516), patients with advanced esophageal carcinoma, who had either T4 tumors or distant lymph node metastasis (M1 Lym), received 5-FU 700 mg/m2 on Days 1–4 and 29–32 with CDDP 70 mg/m2 on Days 1 and 29 plus concurrent radiotherapy (60 Gy) (2). This regimen was well tolerated and considered a treatment option for unresectable esophageal cancer. In the JCOG9906 Phase II trial, patients with UICC clinical stage II/III esophageal carcinoma (excluding those with T4 tumors) received 5-FU 400 mg/m2 on Days 1–5, 8–12, 36–40 and 43–46 with CDDP 40 mg/m2 on Days 1, 8, 36 and 43 plus concurrent radiotherapy with 2 weeks planned interruption (60 Gy) (3). The 3-year survival rate was 47.1% (90% CI, 37.5–56.7), and the complete response (CR) rate was 62.2%. Acute toxic effects were manageable. Late toxicity, however, was considerable and needed to be reduced (i.e. 
Grade 3 pericardial effusion, 16%; Grade 3 dysphagea/stenosis or fistula of the esophagus, 13%; Grade 3 pleural effusion, 9%).
As compared with the JCOG9906 regimen, the RTOG regimen was characterized by: (i) a strong recommendation for base treatment planning on computed tomographic (CT) findings, (ii) 2 radiation fields, (iii) no planned interruption of radiotherapy, (iv) a lower radiation dose, (v) smaller radiation fields and (vi) higher doses of 5-FU and CDDP. We speculate that the RTOG regimen will overcome the weak points of the JCOG9906 regimen, such as a high incidence of late toxicity (especially pericardial effusion), without compromising efficacy. We therefore conducted a Phase I trial to determine whether the dose of the RTOG chemotherapy regimen could be the recommended dose (RD) for Japanese patients with UICC clinical stage II/III squamous cell esophageal carcinoma (excluding those with T4 tumors).
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PATIENTS AND METHODS |
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Subjects and Eligibility
National Cancer Center Hospital (Tokyo and East), Aichi Cancer Center Hospital and Shizuoka Cancer Center Hospital participated in this trial. The National Cancer Center Hospital, Tokyo coordinated the study and was responsible for data collection and analysis. Patient enrollment was started in April 2004 and completed in January 2005.
Eligibility criteria included the following: histologically proved squamous cell, adenosquamous cell or adenocarcinoma of the thoracic esophagus, excluding the esophagogastric junction; UICC clinical stage II/III disease, excluding T4 tumors; no prior treatment for esophageal cancer; an age of 20–70 years; an Eastern Cooperative Group performance status (PS) of 0 or 1 and written informed consent. Eligible patients also had to have a white blood cell count of 4000/mm3, a platelet count of 100 000/mm3, a hemoglobin concentration of 10 g/dl, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of 
2.5 times the upper limit of normal; a total serum bilirubin concentration of 1.5 mg/dl; a serum creatinine concentration of 1.2 mg/dl, a 24-h creatinine clearance of 50 ml/min, a PaO2 of 70 torr while breathing room air and no electocardiographic abnormalities.
Patients were excluded if they had any of the following: esophageal fistula; massive pleural effusion, pericardial effusion or ascites; evidence of interstitial pneumonia or pulmonary fibrosis on chest X-ray film; active gastrointestinal bleeding; a history of other malignancies, except for mucosal carcinoma or a cancer from which the patient had not remained disease free for 5 years; prior thoracic radiation; a history of severe cardiovascular disease or severe diabetic mellitus; active infection; pregnancy; nursing infants or psychiatric illness. All patients provided written informed consent. The institutional review boards of the National Cancer Center Hospital, Tokyo, the National Cancer Center Hospital, East and Shizuoka Cancer Center Hospital reviewed and approved the protocol.
Pretreatment Evaluation
The pretreatment evaluation included a complete history, physical examination, assessment of PS, serum chemistry profile, complete blood cell count, arterial blood gas analysis, chest radiography, electrocardiography, endoscopy with biopsy and CT scans of the neck, chest and abdomen. The clinical TNM system stage was defined according to the 2002 (version 6.0) UICC Classification of Malignant Tumors (4).
Treatment Details
This Phase I trial was an open-label, nonrandomized and dose-escalation study. Groups of 6–12 patients received sequentially increasing doses of 5-FU and CDDP (Table 1), concurrently with a fixed dose of 50.4 Gy radiotherapy.
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Chemotherapy
Two cycles of chemotherapy were given at an interval of 28 days. CDDP was given over the course of 2 h with
3000 ml/day hydration on Day 1 and 2000 ml/day hydration on Days 2–4. Diuretics were given to produce a urine volume of 2000 ml/day on Day 1 and 1500 ml/day on Days 2–4. In addition, antiemetics were given before administration of CDDP. 5-FU was given as a 24-h continuous infusion on Days 1–4. After treatment according to the protocol, follow-up treatment with 5-FU and CDDP was strongly recommended.
Radiotherapy
Radiotherapy was delivered with megavoltage equipment (6 MV) using a multiple-field technique. Three-dimensional treatment planning was required. Patients received 1.8 Gy/day of radiation for 5 days per week, and the total radiation dose was 50.4 Gy. For carcinoma of the middle or lower thoracic esophagus, the use of three or four fields was strongly recommended. The clinical target volume (CTV) included the primary tumor with a 2-cm margin craniocaudally, metastatic lymph nodes and regional lymph nodes. The regional lymph nodes bilaterally included the supraclavicular fossa and superior mediastinal lymph nodes for carcinoma of the upper thoracic esophagus, and the mediastinal and perigastric lymph nodes for carcinoma of the middle or lower thoracic esophagus. In addition, the celiac axis lymph nodes were included for carcinoma of the lower thoracic esophagus. Planning target volume (PTV) was defined as the CTV plus a 1- to 2-cm margin in the cranio-caudal direction and a 0.5- to 1-cm margin in the lateral direction in consideration of respiratory organ motion and daily set-up error. After the PTV had been treated up to a dose of 41.4 Gy, an additional dose of 9.0 Gy was given to a reduced irradiated volume, including only the primary tumor and metastatic lymph nodes with margins, for a total dose of 50.4 Gy. The dose was prescribed to the center of the PTV. Lung inhomogeneity corrections were not used. Spinal-cord exposure was maintained <44 Gy. The percentage of pulmonary volume receiving (20?Gy was limited to (25%, and the mean heart dose was limited to (40?Gy.
Dose Escalation
The trial design was based on a conventional dose-escalation schema, with the primary objective of defining the maximal tolerated doses (MTDs) of 5-FU and CDDP in combination with a fixed dose of radiotherapy. The doses of 5-FU and CDDP were escalated in a stepwise fashion and given to the cohorts of 6–12 patients. Initially, six patients received each dose level. If dose-limiting toxicity (DLT) occurred in 2 of the six patients, the next dose level was administered. If 3 of the six patients in the cohort had DLT, the MTD was defined as one level below the dose causing such DLT. Six additional patients then received the MTD level; if toxicity was tolerable, the MTD was defined as the RD. If no DLT occurred at Level 2, this dose level was defined as the RD.
DLT was defined as any of the following: Grade 3/4 nonhematologic toxicity, except for the common toxicity of chemoradiotherapy for esophageal cancer such as anorexia, nausea, vomiting, temporary electrolyte abnormalities, oral mucositis, pharyngitis and esophagitis; Grade 4 thrombocytopenia or febrile neutropenia persisting for 4 days; inability to complete the protocol treatment within 60 days from the start of chemoradiotherapy because of toxicity; radiation pneumonitis requiring steroid treatment. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Late radiation toxicity, occurring 90 days from the start of radiotherapy, was scored according to the RTOG/EORTC late radiation morbidity scoring scheme.
Dose Modification
If WBC < 2500/mm3, platelets < 75 000/mm3, creatinine > 1.5 mg/dl, total bilirubin > 1.5 mg/dl, AST/ALT > 2.5 times the upper limit of normal, body temperature 38.0°C due to infection or Grade 3/4 esophagitis or dysphagia occurred, both chemotherapy and radiotherapy were withheld until such toxicity resolved. If WBC < 1000/mm3, neutrophils < 500/mm3, platelets < 25 000/mm3, body temperature 38.0°C due to infection, Grade 3/4 esophagitis or dysphagia, or radiation pneumonitis requiring steroid treatment occurred during radiotherapy alone, radiotherapy was withheld until such toxicity resolved.
Efficacy Assessment and Definitions
Patients were scheduled to undergo endoscopy with biopsy and CT scanning 3–4 weeks after the completion of radiotherapy. For the primary esophageal tumor, a CR was defined as no evidence of residual or recurrent tumor on endoscopy, as verified histologically; all other responses were defined as non-CR. For lymph nodes, CR was defined as a reduction in lymph-node size from 1 to <1 cm; all other responses were defined as non-CR.
Follow-up Evaluation
A history and physical examination, toxicity assessment, serum chemistry profile, complete blood cell count, gastrointestinal endoscopy, chest X-ray and CT scanning of the neck, chest and abdomen were performed every 3 months during the first year after the start of chemoradiotherapy.
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RESULTS |
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Patient Characteristics
Twelve patients were enrolled between April 2004 and January 2005. Toxicity and response were assessable, and complete follow-up data were available for all patients. Median follow-up time was 26 months (range, 21–28 months). The patients’ characteristics are listed in Table 2. Median age was 59.5 years (range, 47–68 years). Median PS was 1, and 11 patients were men. All patients had squamous cell carcinoma. The clinical disease stage was IIA in four patients, IIB in one and III in seven.
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Treatment Status
All but one patient who received Level 1 completed the protocol treatment within 60 days from the start of chemoradiotherapy. The median treatment period was 44 days (range, 40–67 days). Radiotherapy was transiently withheld because of toxicity in five patients given Level 1, but could be resumed after recovery in all of these patients. The second course of chemotherapy was withheld because of Grade 2 leukopenia in two patients given Level 1.
Toxicity
Table 3 describes the hematologic toxicities according to the dose level. At Level 1, two of six patients (33%) had Grade 3 hematologic toxicity. At Level 2, three of six patients (50%) had Grade 3 hematologic toxicity. No patient had Grade 4 hematologic toxicity, and no patient received granulocyte colony stimulating factor or blood transfusion.
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Nonhematologic toxicities are listed in Table 4. Grade 3 esophagitis occurred in three patients at Level 1 and one patient at Level 2. One of the patients given Level 1 could not complete the planned treatment within 60 days because of Grade 3 esophagitis, defined as DLT.
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All toxicities including esophagitis were manageable, and the MTD was not reached, even at Level 2. We considered 5-FU 1000 mg/m2 with CDDP 75 mg/m2 plus 50.4 Gy radiotherapy to be the RD.
Late toxicity due to radiotherapy was evaluated 90 days after the start of radiotherapy (Table 5). Only one patient had Grade 2 toxicity (pleural effusion). All other toxicities were mild and manageable (median follow-up period, 26 months; range 21–28 months).
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Response
Four (67%) of six patients who received Level 1 had a CR. Three of them had recurrence in lymph nodes, and two patients died of disease progression. The two patients who had a non-CR at Level 1 had lung/bone and liver metastases, respectively, and died of disease progression. At Level 2, all patients had a CR (100%). Two of them had recurrence in lymph nodes and lung, respectively. At a median follow-up of 26 months (range, 21–28 months), two patients given Level 1 and six given Level 2 were still alive.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Our primary endpoint was to determine the RD of 5-FU and CDDP with concurrent radiotherapy of 50.4 Gy. The results of this Phase I trial indicated that 5-FU 1000 mg/m2 on Days 1–4 and 29–32 with CDDP 75 mg/m2 on Days 1 and 29 plus concurrent 50.4 Gy radiotherapy was well tolerated as the RD and may be clinically beneficial for Japanese patients with squamous cell esophageal cancer. Toxic effects were generally mild to moderate and could be managed by conventional strategies.
The standard non-surgical treatment for localized carcinoma of the esophagus is chemoradiation, based on the results of the RTOG 85-01 study (local/regional control rate, 54%; median survival, 14 months; and treatment-related mortality rate, 2%) (5). Subsequently, however, the INT 0122 (RTOG 90-12) Phase II trial did not demonstrate an improved local/regional control rate (61%) or a survival advantage (median survival, 20 months) of neoadjuvant 5-FU and CDDP followed by concurrent 5-FU, CDDP and high-dose radiotherapy (64.8 Gy), as compared with the results of RTOG 85-01 (6,7). Moreover, the treatment-related mortality rate was 9%. Another high-dose radiotherapy regimen showed no advantage of a brachytherapy boost after treatment with 5-FU, CDDP and 50.4 Gy external-beam radiation therapy in the RTOG 92-07 study. The local/regional control rate was 37%, and median survival was 11 months (8). The treatment-related mortality rate was 10%. Thereafter, the INT 0123 (RTOG 94-05) study, a randomized Phase III trial, confirmed the efficacy of 5-FU 1000 mg/m2 on Days 1–4 and 29–32 with CDDP 75 mg/m2 on Days 1 and 29 plus concurrent 50.4 Gy radiotherapy as compared with 64.8 Gy high-dose radiotherapy (local/regional control rate, 45%; median survival, 18 months; and treatment related mortality rate, 2%) (1).
In the JCOG 9906 Phase II trial, however, a different regimen of chemoradiotherapy (5-FU 400 mg/m2 on Days 1–5, 8–12, 36–40 and 43–46 with CDDP 40 mg/m2 on Days 1, 8, 36 and 43 plus concurrent 60 Gy radiotherapy with 2 weeks planned interruption) was used to study the role of chemotherapy as a radiosensitizer (3). The local/regional control rate and median survival were promising (62% and 29 months), but treatment-related mortality was 5.3% (pericarditis in one patient, pleural effusion in one and pneumonitis in two). Late toxicity, especially a 16% incidence of Grade 3 pericardial effusion, needed to be reduced.
Studies assessing long-term survival and late toxicity in patients with esophageal cancer who received chemoradiotherapy are scant (9–11). In contrast, radiation-induced heart disease after thoracic radiotherapy has been studied extensively in patients with Hodgkin's lymphoma. A causal relationship between thoracic radiotherapy and coronary artery disease has been suggested (12–17). Pleural effusion after thoracic radiotherapy has also been reported, mainly in patients with Hodgkin's lymphoma (18,19). Ishikura studied late toxicity in 139 patients with esophageal cancer treated by the JCOG 9906 regimen. The median follow-up was 53 months (11). Eight patients had Grade 3 pericarditis, two had Grade 4 heart failure, eight had Grade 3 pleural effusion, three had Grade 3 radiation pneumonitis and two died of acute myocardial infarction. With the JCOG 9906 regimen, 40 Gy delivered by anteroposterior–posteroanterior opposed portals was radiated to a wide nodal area, and >60% of the entire heart volume received at least 40 Gy in most patients. About 60% of patients with clinical stage II/III esophageal cancer have recurrence of residual disease (3). Salvage surgery improves the survival of such patients who have recurrence after chemoradiation, but is associated with high morbidity and mortality (20,21). A relation between thoracic radiotherapy and postoperative pulmonary complications is suspected (22).
The RTOG regimen of radiotherapy strongly recommends treatment planning by CT, 2 radiation fields, and smaller radiation fields, which we speculate reduces irradiation to ‘high-risk’ organs, with consequent late toxicity and the risk of salvage surgery. We think that higher doses of 5-FU/CDDP and radiotherapy without planned interruption may produce efficacy similar to that of the JCOG 9906 regimen, despite the smaller radiation dose and fields.
In conclusion, the RDs of 5-FU and CDDP with concurrent radiotherapy (50.4 Gy) in Japanese patients with UICC clinical stage II/III esophageal carcinoma (excluding T4 tumors) were 1000 mg/m2 on Days 1–4 and 29–32, and 75 mg/m2 on Days 1 and 29, respectively, which were the doses used in the RTOG regimen. On the basis of the results of this Phase I trial, we have already started a Phase II trial of the RTOG regimen in patients meeting similar eligibility criteria.
Conflict of interest statement
None declared.
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References |
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