Japanese Journal of Clinical Oncology 31:375-381 (2001)
© 2001 Foundation for Promotion of Cancer Research
Concurrent Chemoradiotherapy for Squamous Cell Carcinoma of Thoracic Esophagus: Feasibility and Outcome of Large Regional Field and High-dose External Beam Boost Irradiation
Department of Radiology, University of the Ryukyus School of Medicine, Okinawa, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: To assess the feasibility and outcome of concurrent chemoradiotherapy (CT-RT) with large regional field and high-dose external beam boost irradiation in thoracic esophageal cancer.
Methods: Patients with clinical stage T1 (submucosal)–4N0–1M0 (UICC 1997) squamous cell carcinoma of the thoracic esophagus were eligible. Radiotherapy consisted of regional irradiation (extending from supraclavicular fossa to the paracardial area) with 39.6 Gy followed by high-dose external beam boost up to 66.6 Gy (1.8 Gy/day, five times per week). Two-hour infusion of cisplatin (80 mg/m2 on day 1) and continuous infusion of 5-fluorouracil (800 mg/m2/day on days 2–6) were administered concurrently with radiotherapy, every 3–4 weeks, for two cycles.
Results: Thirty patients (stage I, 3; stage II, 11; stage III, 16) were entered into the study. Twenty-one patients (70%) completed the planned treatment. In elderly (
70 years) patients, four of six withdrew. Grade 3 and 4 toxicities (NCI-CTC) were observed in 20 (67%) and three (10%) patients, respectively. Major toxicities were blood, gastrointestinal (i.e. nausea and esophagitis) and pulmonary. There was no grade 5 (fatal) toxicity. The median follow-up period for surviving patients was 27 months (range: 9–49 months). The median survival time was 21 months. The 1- and 2-year survival rates were 65 and 49% for all 30 patients. The incidence of esophageal stricture (grade 1–2: RTOG) was 21%. No patient suffered fistula formation.
Conclusions: Despite poor compliance for elderly patients and frequent severe toxicities, our concurrent CT-RT resulted in a favorable outcome in thoracic esophageal cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The treatment results of definitive radiotherapy (RT) alone have been poor mainly owing to a high incidence of local failure for patients with thoracic esophageal cancer (1,2). Therefore, improving local control is desirable in RT. Some approaches have been attempted to improve the local control, including intraluminal brachytherapy (3), accelerated hyperfractionation (4) and concurrent chemoradiotherapy (CT-RT) (5–12).
A clinical problem with esophageal cancer is that it is not only locoregional but also systemic. Concurrent CT-RT could address these problems simultaneously (1). Encouraging results of phase 2 studies have been reported for concurrent CT-RT (5,6,10,11). An intergroup phase 3 study (RTOG 8501) demonstrated a significant decrease both in locoregional failure and distant metastases for patients treated with concurrent CT-RT using CDDP/5-FU compared with those treated with RT alone (7,8). Nevertheless, frequent persistence/locoregional recurrence was observed even for patients treated with CT-RT (7,8). We consider that this resulted from a low total dose of RT (50 Gy) to the primary tumor.
For more than a decade, three-field lymphadenectomy (consisting of bilateral cervical, mediastinal and upper abdominal nodes) has been widely performed by Japanese surgeons (13–15). A large amount of the data have shown that esophageal cancer had lymph node metastases frequently and broadly, even for submucosal T1 disease (13–15). Nishimaki et al. have shown that about one quarter of patients had jumping metastases to the neck and/or abdominal nodes without associated intrathoracic metastases (14). Sugahara et al. demonstrated that clinically N0 patients treated with a localized RT field suffered frequent nodal failure outside the field (16). Therefore, inclusion of all regional lymph nodes in the clinical target volume might be appropriate in radical RT of esophageal cancer. However, large regional field RT including supraclavicular, mediastinal and upper abdominal region has not usually been applied owing to fear of toxicity. In most studies of CT-RT, a localized RT field was employed (5,9–11). In the RTOG 8501 study, the total dose for the regional field was limited to 30 Gy in the CT-RT arm. Although patterns of recurrence within the RT field (i.e. primary/lymph nodes) were not presented in detail (7,8), we consider that a total dose of 30 Gy might be insufficient for eradicating subclinical disease (17). Therefore, we consider that both the feasibility and therapeutic value of large regional field RT with a higher total dose followed by high-dose boost over 50 Gy should be studied in concurrent CT-RT.
Four courses of cisplatin and 5-FU were given during/after RT in the RTOG 8501 study (7,8). However, high incidences of life-threatening/fatal toxicities were reported despite the lower total dose of RT in that series (7,8). We consider that four courses of chemotherapy might be intolerable if a higher dose of RT were given.
Based on this background, we conducted a pilot study of concurrent CT-RT mainly to improve the locoregional control of thoracic esophageal squamous cell cancer. Radiotherapy consisted of large-field regional RT (39.6 Gy) followed by high-dose external beam boost (up to 66.6 Gy). Two cycles of chemotherapy consisting of cisplatin and 5-FU were concurrently delivered with RT and no additional chemotherapy was planned. In this paper, we analyze the feasibility and outcome of the study.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility Criteria
Eligible patients were required to have previously untreated, histologically confirmed squamous cell carcinoma of the thoracic esophagus. The tumors had to be clinical stage T1 (submucosal)–4N0–1M0 according to the UICC system (1997). The extent of disease in each patient was evaluated by physical examination, barium esophagogram, esophagoscopy, laryngo-pharyngoscopy, computed tomography (CT) of the chest and abdomen and radionuclide bone scanning. Bronchoscopy was performed when tracheobronchial involvement was suspected. Endoesophageal ultrasonography (EUS) was applied when its transducer could pass through the tumor. EUS was used to determine clinical T stage from T1 through T3. We assessed T3 or T4 based on the CT findings. Tumor was staged as T4 when it abutted the thoracic aorta at a contact angle
90° and/or caused deformity of the airway to the tracheobronchial tree. N stage was assessed by CT. Lymph node short-axis diameter 10 mm was counted as positive.
To compare the treatment results with those of other Western studies, T classification using the 1983 UICC staging system was also applied. Only findings of esophagoscopy and/or esophagograms were used to determine the length of the primary tumor (
5 versus >5 cm) and the extent of luminal involvement (entire versus non-entire circumference). Extraesophageal spread was assessed only by clinical findings of recurrent or phrenic nerve pulsy and bronchoscopic evidence of tracheoesophageal/bronchoesophageal fistula. No patient was up-staged to T3 based solely on the CT findings.
Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, adequate bone marrow function (WBC 4000/mm and platelets 100 000/mm) and normal hepatic (serum bilirubin <2.0 mg/dl) and renal (serum creatinine <1.5 mg/dl) function. All patients gave written informed consent. This study was not approved by the institutional review board, since this was not strictly planned as a prospective phase 2 study.
Radiotherapy
The planning target volume (PTV) for regional RT extended from the supraclavicular fossa to the paracardial area, including the entire mediastinum. In cases with lesser curvature node metastases, the PTV was extended to involve this area. The PTV for boost RT to primary tumor extended at least 3 cm above and below the gross tumor as defined by esophagograms and esophagoscopy. The planned total dose for the regional RT was 39.6 and 66.6 Gy for the boost to the primary tumor. For positive nodes, a total dose of 50.4–66.6 Gy was planned according to the site and size of the nodes. These were delivered with a daily dose of 1.8 Gy, five times per week. The regional RT was delivered through anteroposterior portals using 4 or 6 MV photon beams and the boost through parallel opposed oblique portals using 10–18 MV photon beams.
When grade 4 leukocytopenia/thrombocytopenia, grade 1 fever and grade 2 symptomatic (i.e. cough and dyspnea) pulmonary toxicity occurred, RT was interrupted until these recovered. Radiotherapy was discontinued permanently when esophageal fistula and/or grade 3 symptomatic pulmonary toxicity occurred.
Chemotherapy
Cisplatin at a dose of 80 mg/m2 was infused over 2 h with hyperhydration on day 1 and 5-FU at a dose of 800 mg/m2 as a continuous infusion on days 2–6 (120 h). All patients received antiemetics with granisetron and metoclopramide before and after the cisplatin infusion. This schedule was started concomitantly with RT and repeated every third or fourth week for two cycles.
When grade 3 leukocytopenia/thrombocytopenia occurred, the second course of chemotherapy was withheld until these recovered to grade 2. The dose of 5-FU was reduced by 25% if grade 4 leukocytopenia/thrombocytopenia for more than 5 days and/or grade 3 mucositis/esophagitis occurred during the previous course.
Evaluation of Response and Toxicity
The response was determined within 1 month following the completion of treatment. World Health Organization response criteria were used for response analysis (18). Since several investigators have indicated the inaccuracy of CT scans in the assessment of response to CT-RT for esophageal cancer (19), the response of the primary tumor was evaluated by the criteria of the Japanese Society for Esophageal Diseases, which were based on findings from esophagograms and esophagoscopy (20). Histopathological evaluation was optional. Patients were followed up every 1–2 months for the first 2 years and then every 3 months.
Esophagograms were taken every 3–4 months for 2 years and then twice a year. If suspicious mucosal irregularity was observed on the esophagogram, endoscopic examination was performed. Repeat biopsy was encouraged but optional. Assessment of local recurrence was based on clinical findings from esophagograms/endoscopy. Chest and abdominal CT and pulmonary function tests were performed every 6 months for 3 years and then yearly. Acute toxicity was scored by the National Cancer Institute Common Toxicity Criteria (NCI-CTC Version 2.0). Late toxicity was assessed using the RTOG/EORTC Late Radiation Morbidity Scoring Scheme. Survival estimates were calculated using the Kaplan–Meier method. Survival was calculated from the date of treatment start until death or last follow-up evaluation.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Between January 1997 and June 2000, 30 patients with squamous cell carcinoma of the thoracic esophagus were entered into the study. Table 1 shows the patients’ characteristics. All patients entered into the study were evaluated according to intent-to-treat analysis.
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Compliance
Twenty-one patients (70%) completed the planned treatment. Four of six elderly patients (
70 years) withdrew. Three of these had T4N1 and the other had T3N0 disease. These patients received only one cycle of chemotherapy and incomplete regional RT (30.6, 30.6, 34.2 and 36 Gy) at the discretion of the treating physicians, three because of febrile status and one because of severe dizziness. Planned full-dose (66.6 Gy) RT was delivered to the primary site for these patients. Five of 24 patients less than 70 years old could not complete the planned treatment. One patient (T3N1) received only the segment of the first cycle of chemotherapy (cisplatin only) because he suffered cerebrovascular ischemia (grade 4) on day 1. He did not complete RT (53.4 Gy). One (T3N0) gave up the second course of chemotherapy because of diminished performance status (PS 3). He was able to receive full course RT, but with an incorrect total dose (70.2 Gy). One (T3N0) received an incomplete course of CT-RT (39.6 Gy and one course of chemotherapy) and subsequently underwent surgery at his suggestion. The dose of 5-FU was reduced by 25% in the second course for one patient (T3N1) because of severe oral mucositis and anal erosion. One patient (T1N0) received an incorrect total dose (61.2 Gy) by decision of the treating physician. Consequently, compliance rates for RT and chemotherapy were both 73% for all 30 eligible patients. Twenty-six (87%) patients received the planned full dose RT (66.6 Gy) to the primary tumor. The second course of chemotherapy was delayed in five patients for 2–3 weeks, three because of leukocytopenia, one owing to patient refusal and one for dermatitis (considered treatment-unrelated). The overall treatment time of RT was 49–72 days (mean 60 days). Pauses of RT treatment for over 7 days occurred with 11 patients, five because of holidays, three for febrile status, one for esophagitis, one for dizziness and one for iatrogenic pneumothorax due to percutaneous infraclavicular subclavian catheter insertion.
Toxicity
The worst acute side effects during the treatment are shown in Table 2.
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There was no fatal (grade 5) toxicity. Life-threatening toxicities (grade 4) were documented for three patients (10%), viz. two esophagitis and one cerebrovascular ischemia. Severe toxicities (grade 3) were observed for 20 patients (67%). Major toxicities were blood, gastrointestinal (nausea, esophagitis) and pulmonary. Most these toxicities were manageable and the patients recovered. None developed bleeding or severe infection. Whereas one third suffered grade 3 nausea, only one patient experienced grade 3 vomiting. Symptomatic esophagitis occurred in all 30 patients. However, only five experienced grade
3. None developed esophageal fistula. Five of 25 evaluable patients (20%) suffered grade 3 decreased pulmonary function with decreased DLco value. However, none experienced severe subjective symptoms and all recovered without the use of corticosteroids.
Response, Survival and Pattern of Failure
Tumor response results for the 30 patients are shown in Table 3. The overall CR rate was 30%. There was no CR in the lymph nodes.
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The median follow-up for all eligible 30 patients was 14 months (range: 3–49 months). At the time of analysis, 16 patients had died, all from esophageal cancer. The median follow-up for 14 patients alive at the time of analysis was 27 months (range: 9–49 months). Two of these have had less than 12 months of follow-up. One was lost to follow-up at 10 months. The median survival time was 21 months. The 1- and 2-year overall survival rates for 30 eligible patients were 65 and 49%, respectively (Fig. 1). The 1-year survival rates by UICC 1997 stage were 100% for stage I, 91% for stage II and 44% for stage III. Eighteen patients (60%) developed recurrence. Sites of the first failure are shown in Table 4. Patients who demonstrated PR/NC and suffered no progression for >1 year were also counted as locoregionally controlled. The predominant failure site was primary. Eleven of 30 patients (37%) were assessed as having local failure. Table 5 shows the details of the 11 patients. Six were assessed histopathologically and the other five clinically. One patient developed intramural metastasis remote from the primary tumor. The site of the intramural metastasis had received only 39.6 Gy. He did not suffer primary tumor recurrence until death (after 13 months). One patient (Table 5; case No.8) with local recurrence was treated with salvage surgery but subsequently developed multiple bone and liver metastases. Two developed regional nodal recurrence. One was the patient who underwent surgery after incomplete CT-RT and another had not received boost RT (only 39.6 Gy) to the enlarged (N1) node. The 1-year locoregional control rate was 66%. The sites of distant metastasis (as a first failure) were lung in three patients, bone and liver in one and abdominal nodes (out-field) in one. The 1-year distant metastasis-free rate was 72%.
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Late Complications
Three patients suffered grade 2 radiation pneumonitis which occurred >90 days after RT. All these three recovered after conservative treatment (without medication with steroids) and survived for 12, 32 and 49 months. One suffered grade 3 pericarditis which required pericardiocentesis. He also recovered after the treatment and survived for 38 months. In 19 patients without local recurrence and followed up over 6 months, four (21%) suffered grade 1–2 esophageal stricture. One was T4 and the other three were T3. None needed dilatation. No fistula formation was observed.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Severe (grade 3) acute toxicities were frequently observed in our concurrent CT-RT series. Major toxicities were blood, gastrointestinal (nausea, esophagitis) and pulmonary. We consider that the main reason for the frequent severe acute toxicity is the large regional field with a higher total dose of 39.6 Gy. However, life-threatening (grade 4) toxicities were less frequent. Most toxicities were manageable and patients recovered, and none suffered treatment-related death. The incidence of grade 4–5 toxicity was low compared with those of the RTOG 8501 study (7,8) and the INT 0123 trial, which was a randomized trial of concurrent CT-RT, standard (50.4 Gy) versus high-dose (64.8 Gy) (21). We consider that the main reason for this difference is the number of courses of chemotherapy (two versus four). Four of six patients over 70 years old could not complete both the planned regional RT and chemotherapy in our series. In surgical series with three-field lymphadenectomy, low compliance for elderly patients has been reported (15). This suggested that our concurrent CT-RT was too extensive for the elderly patients. One might question the feasibility also for less elderly patients, because five of 24 (21%) could not complete the planned treatment. However, only three withdrew with toxicities (including one with dose reduction of 5-FU) and the other two had protocol violations. Therefore, we consider our regimen is almost feasible for less elderly (<70 years) patients. However, special attention should be paid to the potential toxicities.
The primary purpose of the present study was to improve local control by escalating the total RT dose to the primary tumor. Table 6 shows the results of the RTOG 8501 study and our present series. The main differences in treatment between the studies were the total dose of RT (50 versus 66.6 Gy) and the number of courses of chemotherapy (four versus two). Locoregional control in the present study was slightly better than that of RTOG 8501. The incidence of distant failure was almost the same. However, these data of the RTOG 8501 study should be interpreted carefully because of its inadequate follow-up (data not available, 8%; died of disease but other details unknown, 7%). The median survival time and the 2-year survival rate of our study seemed to be favorable compared with those of RTOG 8501. Although significant acute/late esophageal toxicity was observed in RTOG 8501, the incidence was low in our series despite the higher RT dose delivered. This was consistent with the results of other Western series (5,9) and a Japanese phase 2 study (6) which employed a total RT dose of >60 Gy. One possible explanation could be given for this discrepancy. We consider that an uncertainty of diagnosis between tumor recurrence/persistence and benign stricture/ulceration exists. In the RTOG 8501 study, Herskovic et al. noted that only a limited number of patients (42 out of 61 patients in the CT-RT arm) underwent planned follow-up examination (i.e. esophagogram, esophagoscopy and repeat biopsy) (7). In another RTOG study (RTOG 9207), fistulae were considered treatment-related if biopsy or autopsy showed no local tumor persistence or recurrence (12). However, we observed one case with local failure that could not be diagnosed by repeat biopsy (three times) but post-mortem examination (Table 5, case No.5). Submucosal persistent/recurrent disease could hardly be confirmed with a standard biopsy procedure. This problem could only be resolved with adequate follow-up procedures/periods and/or post-mortem examination. We suspect some degree of patients with ‘esophageal complication’ in RTOG 8501 have persistent/recurrent disease. From these findings, we consider that RT dose escalation to primary tumor up to 66.6 Gy might positively affected the outcome in our CT-RT.
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Recently, Minsky et al. reported that CT-RT with 64.8 Gy did not offer a survival benefit compared with 50.4 Gy in their preliminary report of the intergroup INT 0123 randomized trial (21). However, we cannot accept their conclusion for the following reasons. First, they only showed the incidence of cancer death without details of patterns of failure. Second, they reported that most of the treatment-related deaths occurred during the low-dose part (<50.4 Gy) of the protocol and noted that the excess deaths did not appear to be related to the higher radiation dose but rather to an unexplained imbalance in the arms (21). We consider that the value of dose escalation over 50 Gy could not clearly be evaluated from the available data from the INT0123 study.
The incidence of regional node recurrence was low even in N1 patients in our series. This suggests that large-field regional RT with 39.6 Gy and boost to positive nodes (up to 50.4–66.6 Gy) have a certain value in preventing regional recurrence in concurrent CT-RT. However, as described above, we consider that the frequent severe toxicities observed in this study resulted mainly from this large-field regional RT with a high total dose of 39.6 Gy. We consider that evaluation of both the feasibility and regional control rate by decreasing the total dose of regional RT deserve further study.
Although the 1–2-year locoregional control rate was favorable, as mentioned above, the overall complete response rate assessed immediately after the end of the CT-RT was poor compared with those in other studies (10–12). We consider this discrepancy to be due to the difficulty in assessing the objective response using standard imaging studies. As indicated in the response evaluation criteria in solid tumors (RESIST) guide lines (22), it may be difficult to distinguish residual disease from normal (scar) tissue. Ohtsu et al. proposed the new response criterion ‘uncertain CR’ for evaluation of the lymph nodes (6). A new method for the assessment between malignant and benign lesions such as PET is also encouraged (23).
The incidence of distant failure was not low in this series. This suggested that our chemotherapy of two courses was insufficient to eradicate microscopic systemic disease. To decrease the incidence of distant failure, the addition of adjuvant chemotherapy could be considered. The RTOG 8501 study claimed a positive effect of adjuvant chemotherapy in preventing distant metastases (7,8). A Japanese randomized trial of adjuvant chemotherapy for surgically treated patients demonstrated the positive value of adjuvant chemotherapy (24). However, no phase 3 evaluation is available comparing the outcome by the number of courses of chemotherapy. Both the grade and incidence of toxicity might increase if additional chemotherapy were to be applied. Furthermore, several authors have shown poor compliance in adjuvant chemotherapy (7,11). We consider that additional adjuvant chemotherapy should be limited to selected patients as indicated in a Japanese phase 2 study (6).
In conclusion, our concurrent CT-RT approach consisting of large-field regional RT (39.6 Gy) and high-dose external beam boost (up to 66.6 Gy) resulted in a favorable outcome for patients with thoracic esophageal squamous cell cancer. However, we observed poor compliance for elderly patients and frequent severe toxicities. We consider that this regimen is unsuitable for elderly patients and a dose reduction of regional RT is indicated in further studies.
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FOOTNOTES |
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+ For reprints and all correspondence: Takafumi Toita, Department of Radiology, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa, 903-0215, Japan. E-mail:b983255@med.u-ryukyu.ac.jp
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REFERENCES |
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Received December 18, 2000; accepted May 7, 2001.
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