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Journal of Clinical Oncology, Vol 17, Issue 9 (September), 1999: 2915
© 1999 American Society for Clinical Oncology

Definitive Chemoradiotherapy for T4 and/or M1 Lymph Node Squamous Cell Carcinoma of the Esophagus

Atsushi Ohtsu, Narikazu Boku, Kei Muro, Keisho Chin, Manabu Muto, Shigeaki Yoshida, Mitsuo Satake, Satoshi Ishikura, Takashi Ogino, Yoshinori Miyata, Shigeki Seki, Kazuhiro Kaneko, Akira Nakamura

From the Departments of Gastrointestinal Oncology/Gastroenterology and Radiation Oncology, National Cancer Center Hospital East, Kashiwa; Department of Internal Medicine, Saku Central Hospital, Nagano; Second Department of Internal Medicine, Showa University Hospital, Tokyo; and Department of Internal Medicine, Asahi Central Hospital, Asahi, Japan.

Address reprint requests to Atsushi Ohtsu, MD, Department of Gastrointestinal Oncology/Gastroenterology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577 Japan; email aohtsu{at}east.ncc.go.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To investigate the efficacy and feasibility of concurrent chemoradiotherapy for locally advanced carcinoma of the esophagus.

PATIENTS AND METHODS: Fifty-four patients with clinically T4 and/or M1 lymph node (LYM) squamous cell carcinoma of the esophagus were enrolled. Patients received protracted infusion of fluorouracil 400 mg/m2/24 hours on days 1 to 5 and 8 to 12, 2-hour infusion of cisplatin 40 mg/m2 on days 1 and 8, and concurrent radiation therapy at a dose of 30 Gy in 15 fractions over 3 weeks. Filgrastim was prophylactically administered to 35 patients. This schedule was repeated twice every 5 weeks, for a total radiation dose of 60 Gy, followed by two courses of fluorouracil (800 mg/m2/24 hours for 5 days) and cisplatin (80 mg/m2 on day 1).

RESULTS: There were 21 patients with T4M0 disease, one with T2M1 LYM, 17 with T3M1 LYM, and 15 withT4M1 LYM. Forty-nine patients (91%) completed at least the chemoradiotherapy segment. The 18 patients (33%) who achieved a complete response included nine (25%) of the 36 with T4 disease and nine (50%) of the 18 with non-T4 disease. Major toxicities were leukocytopenia and esophagitis; there were four (7%) treatment-related deaths. Prophylactic filgrastim reduced the incidence of grade 3 or worse leukopenia without improving dose-intensity or response. With a median follow-up duration of 43 months, median survival time was 9 months. The 3-year survival rate was 23%.

CONCLUSION: Despite its significant toxicity, this combined modality seemed to have curative potential even in cases of locally advanced carcinoma of the esophagus.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CARCINOMA OF THE esophagus is a highly virulent disease. Although surgery is the standard therapy for local regionally confined esophageal cancer, results of surgery alone remain poor, with 5-year survival rates of 6% to 24% in Western countries.1 Recent improvement of surgical results after radical node dissection has been reported at some Japanese institutions, with 5-year survival rates of 31% to 55%.2-4 In a Japanese prospective randomized study that compared surgery alone with surgery followed by adjuvant chemotherapy, the group that received surgery with radical dissection alone showed a 5-year survival rate of 45%, although the study did not show a survival advantage over treatment with adjuvant chemotherapy.5 The success of radical surgery led Japanese surgeons at some institutions to extend the indications of surgery to include locally advanced carcinoma. However, most institutions do not indicate surgery for such disease because of its complexity and generally unsatisfying results.

A combination of fluorouracil (5-FU) and cisplatin (CDDP) has become a standard regimen, not only because of its clinical outcome, but also because of the synergism between the two agents and their radiosensitizing effects.6-8 Recent reported results of chemoradiotherapy as definitive and preoperative treatments have indicated various advantages for treatment against carcinoma of the esophagus.9,10 Significant impact was made by results of a prospective randomized trial by the Radiation Therapy Oncology Group that compared chemoradiotherapy with radiation alone, in which the combined-modality arm demonstrated a significant survival improvement.11 The final result of the study showed a 5-year survival rate of 27% in the chemoradiotherapy group compared with 0% in the group that received radiation alone.12 However, the clinical staging in that study was performed according to the 1983 American Joint Committee staging criteria, which is now outdated. Hence, no precise information for locally advanced diseases was described in that study. There remain controversies with regard to indications for chemoradiotherapy as a curative approach in cases of such locally advanced diseases.

To resolve the controversy surrounding these treatments, we conducted a phase II study for locally advanced carcinoma of the esophagus. We divided the regimen used in this study into two courses, ie, 2 weeks of simultaneous chemoradiotherapy followed by an additional week of radiotherapy in each course, as described in Patients and Methods, to conserve the antitumor effects of chemotherapy and to conserve the radiosensitizer effects. At first, the schedule of the chemoradiotherapy segment included a 1-week break between sessions. However, in our earlier study, most of the patients required a 2-week break because of prolonged leukocytopenia or esophagitis that had shown no difference in response. These observations led us to include a 2-week break for the present study. The primary end point of the study was an antitumor effect, complete response (CR) rate, and the feasibility of the chemoradiotherapy for patients with T4 and/or M1 lymph node (LYM) disease. According to the 1987 criteria of the tumor-node-metastasis classification of the International Union Against Cancer, T4 was defined as a tumor that invades contiguous structures and M1 LYM was defined as nodal metastasis out of the regional lymph nodes. The secondary end point was to evaluate overall survival and differences in toxicity and dose-intensity between the treatments with and without filgrastim.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
We initiated a single-institution study at the National Cancer Center Hospital East in August 1992. Preliminary results showed an excellent response, with a CR rate of 30% in 20 patients.13 However, the treatment chosen for the study was associated with significant toxicity, particularly leukocytopenia and esophagitis, including two treatment-related deaths. These results led us to modify the study, using the prophylactic administration of filgrastim to prevent the major causes of toxicity. The modified study was extended to include a total of four institutions. The study was then reactivated in May 1994.

During the period between August 1992 and May 1997, 69 patients aged <= 75 years were diagnosed with T4/M1 LYM carcinoma of the thoracic esophagus. Of the 69 patients, 14 were not entered onto the present study for the following reasons: malignant fistula (n = 7), medical conditions (n = 3; ineligible laboratory data defined in Eligibility Criteria, below), simultaneous gastric cancer (n = 2), and incurable distant nodes (n = 2). Thus, a total of 55 patients were enrolled onto the study. However, one patient in the earlier study who had small-cell carcinoma was reclassified as ineligible and was therefore excluded from analysis in the modified study. Therefore, the study consisted of 54 patients: 19 in the earlier study, and 35 in the latter study.

Eligibility Criteria and Pretreatment Evaluation
Patients eligible for this study had to have histologically proven carcinoma of the thoracic esophagus and clinically judged T4 and/or M1 LYM disease as defined by the criteria of the International Union Against Cancer. No prior treatment was allowed. Small-cell carcinoma in histology was not allowed in the modified study with filgrastim. Patients with esophagobronchial fistulas were also excluded from the study. All areas of nodal disease had to be able to be encompassed in the radiation port. Furthermore, patients who had nodes more distant than the celiac region in the abdomen, for example, were also excluded. Eligibility also required that subjects be <= 75 years of age with an Eastern Cooperative Oncology Group performance status 0 to 2, WBC count >= 3,000/µL, platelet count >= 100,000/µL, AST and ALT levels within three times the normal upper limit, serum bilirubin level <= 2.0 mg/dL, creatinine level <= 1.5 mg/dL, creatinine clearance >= 50 mL/min, PaO2 >= 70 mmHg, normal electrocardiogram, and life expectancy >= 8 weeks. Patients with serious complications, a history of ischemic heart disease, or active carcinoma at another site were also excluded from the study.

Prestudy evaluation included barium esophagography, esophagoscopy, and cervical, chest, and abdominal computed tomography (CT) scans. Endoscopic ultrasound and cervical ultrasound were optional. However, endoscopic ultrasound was actually performed in fewer than 10 patients because, in most of the patients, stenosis did not allow the scope to pass through the primary lesion. Bronchoscopy was required when tracheobronchial involvement was suspected. Adjacent organs were considered to be involved if the tumors extended into the lumen or caused a deformity of the airway to the tracheobronchial tree and if the tumors were attached to the organs at a contact angle >= 90° in the thoracic aorta as observed on the CT scan. T3 or lesser extent of disease was determined by endoscopic ultrasound. In cases for which such procedures were impossible, esophagoscopy was used to evaluate gross appearance and degree of stenosis. Accuracy rate for T1-3 stage diagnosis by esophagoscopy was approximately 80% in the participating institution (data not shown). Positive lymph nodes were defined if they were >= 1 cm on any of the images. Such evaluations for staging were reviewed and judged as potentially incurable with surgery by diagnostic radiologists as well as surgeons and medical oncologists at each institution. This study was approved by the review boards at the participating institutions. Written informed consent was obtained from all patients.

Treatment Schedule
Chemotherapy consisted of protracted infusion of 5-FU 400 mg/m2/d on days 1 to 5 and 8 to 12 combined with CDDP 40 mg/m2 with adequate hydration and antiemetic coverage on days 1 and 8. This schedule was repeated twice every 5 weeks. Radiation therapy using megavoltage x-rays was started on day 1 concomitantly with chemotherapy. The planning target volume for carcinoma of the upper or middle third esophagus included the primary tumor with a 3-cm margin craniocaudally, metastatic nodes with a 1- to 1.5-cm margin, supraclavicular fossa, and mediastinum. For carcinoma of the lower third esophagus, the field was extended to include the perigastric nodes, and the supraclavicular fossa was excluded if the cervical nodes tested negative. When the planned volume included both the supraclavicular fossa and upper abdominal nodes, the daily dose of 1.8 Gy was allowed. A 2-week break took place after a dose of 30 Gy. Radiation therapy was restarted on day 36 along with the same schedule of chemotherapy as before. The irradiation techniques used were anterior- and posterior-opposed equally weighted beams up to a dose of 40 Gy. Then the radiation portals were changed to shield the spinal cord and to encompass craniocaudally the primary tumor with a 2- to 3-cm margin. Metastatic nodes were encompassed with a 1- to 1.5-cm margin. The radiation dose to the spinal cord was kept at a maximum of 50 Gy. The homogeneity of the dose within the planning target volume was within ±10% of the prescribed dose. For patients treated with prophylactic filgrastim, a daily dose of 75 µg/total body was administered subcutaneously during the period between days 18 and 31. If a leukocyte count of 10,000/µL or neutrocyte count >= 5,000/µL was observed, the dose of filgrastim was reduced by half. The administration was discontinued when leukocyte or neutrophil counts remained at higher levels. Patients had to wait until they had recovered from all treatment-related toxicity except alopecia before starting the second course. The doses of 5-FU and CDDP were reduced to 75% if grade 4 leukocytopenia, thrombocytopenia, diarrhea, grade 3 mucositis, or esophagitis was observed during the previous course. When necessary, nutritional support was provided by intravenous hyperalimentation. The treatment was discontinued when disease progression, patient refusal, or delay of recovery from the toxicity in excess of 6 weeks from the initiation of the treatment occurred.

For patients who showed an objective response to treatment, additional chemotherapy was administered and consisted of protracted infusional 5-FU 800 mg/m2/d on days 1 to 5 and 2-hour infusion of CDDP 80 mg/m2 on day 1. This treatment was repeated every 4 weeks for two courses. Further additional courses of chemotherapy were optional, although they were limited to a total of four courses. No further treatment was conducted if no disease progression was observed.

Evaluation for Response and Toxicity
We used World Health Organization response criteria for measurable diseases. Briefly, a CR was defined as the complete disappearance of all measurable and assessable disease for a minimum of 4 weeks. A partial response (PR) was defined as a >= 50% reduction in the sum of the products of the longest diameter of measurable disease for a minimum of 4 weeks. Stable disease was defined as the failure to observe a PR, CR, or progressive disease for at least 4 weeks. Progressive disease was defined as a >= 25% increase in the sum of the products of the longest diameter of measurable disease or the appearance of new lesions. Response of the primary tumor was evaluated by modified criteria of the Japanese Society for Esophageal Diseases.14 Uncertain CR, used for evaluation of lymph nodes, was defined when small nodes (< 1 cm) persisted with no evidence of progression >= 3 months after completion of treatment. The uncertain CR was accounted for the reported CR rate. CR for primary tumors was determined when all visible tumors, including ulcerations, disappeared for >= 4 weeks; this was evaluated by esophagoscopy with negative biopsy results. PR was assigned if the primary tumor was observed on esophagography as being reduced in area by >= 50%. Progressive disease was considered to be an increase of >= 25% in the area of the tumor. Response was evaluated by esophagography, esophagoscopy, and chest and abdominal CT scans in each course. Objective responses were confirmed by extramural review.

Toxicity was evaluated using criteria defined by the Japan Clinical Oncology Group.15 These criteria were based on the National Cancer Institute Common Toxicity Criteria. Toxicity was assessed on a weekly basis during chemoradiotherapy and then biweekly during the subsequent chemotherapy.

Statistics
In the revised study with prophylactic filgrastim, the sample size was calculated using Flemming's two-stage design with an expected CR rate of 20% and alpha and beta error of 0.1. Including the expectation of ineligible cases in 10% of the sample size, a total of 35 patients was required. Thus, the total number of patients registered onto both studies was 54.

Follow-up evaluations were performed every 3 months for the first 2 years and every 6 months thereafter by endoscopy and CT scan. Statistical differences between the two groups were calculated by the {chi}2 test. Survival was calculated from the date of initiation of treatment by the actuarial Kaplan-Meier method.16 Survival differences between the two groups were assessed by log-rank test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Characteristics of the 54 patients are listed in Table 1. The median age was 62 years (range, 38 to 75 years). Most of the patients had good performance status. There were 36 patients with T4 disease, 33 with M1 LYM disease, and 15 with both. Clinically involved sites in the 36 cases of T4 disease were as follows: thoracic aorta (n = 14), tracheobronchial tree (n = 14), both sites (n = 7), and atrium (n = 1). There were 17 patients with cervical node metastases, 14 with abdominal nodes, and two with metastases in both nodes. Most of the primary tumors (85%) were more than 5 cm in length (median, 8 cm). All 54 patients had histologically proven squamous cell carcinoma. There were no significant differences in patients' backgrounds between the patients treated with and without filgrastim. Forty-nine patients (91%) completed at least the chemoradiotherapy segment with a total radiation dose of 60 Gy. Thirty patients (56%) received the additional two courses of chemotherapy; five patients received an additional four courses. The five patients who did not complete the chemoradiotherapy included three patients who suffered treatment-related deaths and two who experienced disease progression.


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  		Table 1. Patient Characteristics
 

Response
Response results are summarized in Table 2. Of the 54 eligible patients, 18 (33%) achieved a CR, including five uncertain CRs (95% confidence interval, 21% to 46%). Twenty-nine patients demonstrated a PR according to the Japanese evaluation criteria, which resulted in a response rate of 87% (95% confidence interval, 78% to 96%). There was a trend toward a lower CR rate in patients with T4 disease than in those with non-T4 disease (P = .0529). However, no significant differences in CR rate were observed between patients treated with and without filgrastim (P = .5825).


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  		Table 2. Response Results
 

Toxicity
The worst toxicity throughout the treatment period is listed in Table 3. Major treatment toxicities included myelosuppression and esophagitis. Grade 3 or higher toxicities of leukopenia, anemia, thrombocytopenia, and esophagitis occurred in 24%, 28%, 17%, and 15% of patients, respectively. Prophylactic filgrastim reduced the grade 3 or higher leukocytopenia significantly (P = .006). However, no significant differences were observed in the incidence of infections and in the toxicity profile between patients who received filgrastim and those who did not. Five patients (10%) developed treatment-related perforation of the esophageal wall: two esophagobronchial fistulas, two mediastinal fistulas, and one aortic fistula. All five patients had T4 disease before treatment, and these events occurred during the chemoradiation segment. Three patients recovered from the fistula by continuing with the treatment after the disappearance of inflammatory findings and achieved a CR from the primary tumor. One patient with an esophagobronchial fistula died of unknown causes 1 month after completion of chemoradiotherapy; there was no evidence of inflammation surrounding the fistula upon autopsy. The remaining patient had an esophagoaortic fistula and died of massive bleeding despite marked reduction of the tumor upon autopsy. These two patients were judged as treatment-related deaths.


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  		Table 3. Summary of Toxicity
 

Treatment was interrupted during the chemoradiotherapy segment in 22 patients for the following reasons: persistent leukopenia (n = 14), developing fistula (n = 5), and other causes (n = 3). There were four (7%) deaths related to treatment. All of these four events occurred during the second course of chemoradiotherapy. Two patients died of a developing fistula, as previously mentioned. Another patient with T4 disease who was treated without filgrastim died of neutropenic sepsis despite a rescue administration of filgrastim at the nadir. The remaining patient with positive cervical nodes developed pneumonitis and died of respiratory failure despite high-dose corticosteroid therapy. In all patients, change of body weight before and after treatment was low at a rate of –0.9% ± 9.2%. There was a slight improvement of relative dose-intensity in the 35 patients who were administered the filgrastim compared with the 19 who did not; the averages were 0.932 and 0.851, respectively. However, this difference was not statistically significant (P = .3018).

Survival
With a median follow-up period of 43 months (range, 16 to 73 months), the median survival time of the 54 patients was 9 months (Fig 1). One- and 3-year survival rates were 41% and 23%, respectively. The 36 patients with T4 disease showed an inferior survival rate compared with the 18 patients with non-T4 disease (M1 LYM only; 3-year survival rate, 14% v 38%, respectively; Fig 2). This difference was also not statistically significant (P = .1312). When the 54 patients were divided into subgroups of 32 with M1 LYM and 22 without M1 LYM (T4 only), the 3-year survival rates were 27% and 21%, respectively. Median time to disease progression in the 54 patients was 6 months. There were significant differences in progression-free survival between the 18 CR cases and the 29 PR cases (P < .0001). Median progression-free survival duration of the 29 PR cases was 5 months, whereas the 18 CR cases showed a 3-year progression-free survival rate of 59%; the latter patients have not yet reached the median time. To date, 40 patients, including eight of the 18 CR cases, have shown some evidence of disease progression. Patterns of first failure after treatment for these 40 patients were 19 locoregional, nine distant, and 12 both, whereas in the eight CR cases, six patients showed distant and two showed both patterns. There were no significant differences in survival parameters and failure patterns between the 13 patients who achieved definitive CR and the five who were determined as having uncertain CR. Fourteen patients (27%) are still alive, including 11 with no evidence of disease. One of the 11 patients achieved a second CR with a combination of Nedaplatin (Shionogi Co Ltd, Osaka, Japan) plus vindesine for recurrence in the parietal pleura 18 months after the initial treatment. This patient is still alive 2 years after the second treatment. One of the three patients who survived with disease developed pulmonary metastasis 5 years after obtaining a CR with the initial treatment. Forty patients (74%) have already died, of whom 34 had primary disease and four died of treatment-related causes. Of the remaining two patients, one died a sudden death with disease progression 8 months after completion of treatment, and one died of fulminant hepatitis caused by hepatitis B virus from an unknown transmitted route after achieving a CR. The causes of death in the 34 patients who died of primary disease consisted of 24 cases of locoregional disease and 10 cases of distant disease.



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  		Fig 1. Overall survival of the 54 patients enrolled onto the study.

 


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  		Fig 2. Survival of 36 patients with T4 disease and 18 patients with non-T4 disease.

 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study, which produced a CR rate of 33% and a 3-year survival rate of 23%, suggests that chemoradiotherapy might have curative potential even in patients with locally advanced carcinoma of the esophagus. However, these results were associated with significant toxicity, predominantly leukocytopenia and perforation of the esophageal wall. High incidence of leukocytopenia might be caused by the extended field of irradiation, which had been used to cover the dissected area by extended surgery in Japan. This toxicity was significantly reduced by a prophylactic administration of filgrastim. However, because of the small number of patients treated with and without filgrastim and because of a nonrandomized retrospective comparison, any conclusions from this study are limited. Despite these limitations, the prophylactic use of filgrastim cannot be considered as necessary in a practical viewpoint because the incidence of infection that required antibiotic therapy was not reduced, and no significant improvement of dose-intensity was observed. Perforation of the esophageal wall was an unavoidable significant toxic effect of treatment indicated for T4 diseases. However, no perforations occurred in patients with non-T4 disease. Roussel et al17 reported that the development of fistula occurred in 29% of 94 patients with esophagobronchial involvement who were treated with radiation therapy alone. All of the complicated cases ended in early death at a median of 1.7 months. The present study showed a perforation rate of 14% (five of 36 patients) in patients with T4 disease, which was lower than that reported by Roussel et al. Furthermore, three of the five perforations in our study were successfully closed with additional chemoradiotherapy after improvements of the inflammatory findings, and the patients achieved a CR for the primary tumors. These results do not support the criticism that chemoradiotherapy would be a contraindication for T4 disease, especially in cases that involve fistula. However, because all of the five perforations occurred in tumors located in the upper or middle portion of the esophagus, significant care should be taken in such cases. Despite the significant perforation rate, local control of T4 disease was significantly lower than that of non-T4 disease. In the case of T4 disease, the major dilemma for oncologists remains whether to reduce toxicity or improve local control.

With the development of imaging techniques such as CT scan, magnetic resonance imaging, and endoscopic ultrasonography, clinical staging has become more accurate in recent years. These advances have made it possible for us to determine an optimal treatment modality by clinical staging. Although there are some "gray zones" with respect to determining T4 disease by imaging, several studies have reported successful use of CT scans and/or magnetic resonance imaging with an accuracy rate of >= 80%.18,19 We adopted their reported criterion to define T4 disease. Diagnostic radiologists, together with a review of surgeons and medical oncologists, were responsible for final staging. With regard to the determination of positive nodes, there are no reliable diagnostic staging criteria to date. Therefore, we used a 1-cm size to indicate a positive node. This criteria had only 50% of the positive predictive value in a study by Curtin et al.20 This lower predictive value might explain our good results in cases of M1 LYM disease, although 32 of the 33 patients with M1 LYM disease in our study had advanced T3 or T4 disease. Moreover, the patients classified with T4M0 LYM disease would have had occult nodal involvement that was not detected by CT scan. Because the 3-year survival rate of 27% for the 32 patients with M1 LYM disease was not different from the 21% survival rate of the 22 with T4M0 LYM disease, it is likely that attempting to separate these groups is rather artificial.

Whether they have curative intent or not, surgical treatments for locally advanced carcinoma of the esophagus in Japan remain controversial. Many Japanese institutions seem to exclude T4 disease from an indication for surgery. However, they include M1 LYM disease with a successful 3-year survival rate of approximately 30%.2,3,21 These data are based on assessment of pathologic stages, and some discrepancy existed between clinical and pathologic stages, as previously mentioned. Thus, it remains problematic to compare nonsurgical with surgical results. Kato et al21 reported that only 18 of 41 patients (44%) with pathologic M1 LYM disease who were rediagnosed during extended surgery had been diagnosed with M1 LYM before surgery. In that study, the diagnostic criteria were not described; 10 of the 28 patients (36%) clinically diagnosed with M1 LYM disease did not have pathologic M1 LYM disease. Although no precise data with regard to the survival of patients with clinical M1 LYM disease were provided in their report, survival of these patients seemed to be similar to or worse than that of patients with pathologic M1 LYM disease (3-year survival rate, 35%). Our results indicated a 3-year survival rate of 38% in 18 patients with M1 LYM disease only and of 27% in the 32 patients with M1 LYM with or without T4 disease. These results seem to be comparable to those from reports on extended surgery. Therefore, this nonsurgical approach would be a potential candidate for standard care in such cases.

There have been few reports that indicate chemoradiotherapy for locally advanced disease. Coia et al22 reported long-term results of 5-FU/mitomycin chemotherapy and radiation therapy. In their study, 33 patients with stage III or IV disease according to the 1978 American Joint Committee criteria were treated with chemotherapy and 50 Gy of radiation therapy with palliative intent; this treatment resulted in a median survival duration of 9 months and a 2-year survival rate of only 3%.9 Zeone et al23 reported the results of curative nonsurgical treatment that consisted of 5-FU, CDDP, and 64 Gy of radiotherapy combined with neodymium:yttrium-aluminum garnet (Nd:YAG) laser therapy in appropriate patients. They treated 65 patients who had predominantly T1-3 disease, but their study included five patients with T4 disease. Although the 3-year survival rate of the 65 eligible patients was 37%, all five patients with T4 disease died within 18 months. Another large study was reported from Australia in which 79 patients with advanced-stage carcinoma, including those with 25 systemic metastases, were treated with 5-FU, CDDP, and 30 to 35 Gy of radiation therapy.24 A 3-year survival rate of 9% was achieved in patients with advanced disease. However, clinical stages according to the tumor-node-metastasis classification were not described in the report; therefore, it is unknown at which stage patients survived longer. A literature search produced no other reports that specifically indicated chemoradiotherapy for locally advanced disease, such as T4 and/or M1 LYM, with a sufficient number of patients. Our results, especially with regard to long-term survival, encouraged us to suggest that definitive chemoradiotherapy has curative potential for such locally advanced disease defined by clinical imaging. Further investigation of this combined modality as a curative approach is warranted in cases of locally advanced carcinoma of the esophagus.


   ACKNOWLEDGMENTS
 
Supported in part by a grant from the Pharmaceutical Division of Kirin Brewery Co, Tokyo, Japan.

We thank Professor Ritsuko Komaki, M.D. Anderson Cancer Center, Houston, TX, for reviewing the manuscript.


   NOTES
 
Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 18, 1998.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Roth JA, Putnam JB Jr: Surgery of cancer of the esophagus. Semin Oncol 21:453-461, 1994[Medline]

2. Akiyama H, Tsurumaru M, Udagawa H, et al: Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg 220:364-373, 1994[Medline]

3. Baba M, Aikou T, Yoshinaka H, et al: Long-term results of subtotal esophagectomy with three-field lymphadenectomy for carcinoma of the thoracic esophagus. Ann Surg 219:310-316, 1994[Medline]

4. Fujita H, Kakegawa T, Yamana H, et al: Mortality and morbidity rates, postoperative course, quality of life and prognosis after extended radical lymphadenectomy for esophageal cancer: Comparison of three-field lymphadenectomy with two-field lymphadenectomy. Ann Surg 222:654-662, 1995[Medline]

5. Ando N, Iizuka T, Kakegawa T, et al: A randomized trial of surgery with and without chemotherapy for localized squamous cell carcinoma of the thoracic esophagus: The Japan Clinical Oncology Group Study. J Thorac Cardiovasc Surg 114:205-209, 1997[Abstract/Free Full Text]

6. Scanlon KJ, Newman YL, Priest DG: Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci U S A 83:8923-8925, 1986[Abstract/Free Full Text]

7. Byfield JE: Combined modality infusional chemotherapy with radiation, Lokich JJ (ed):Cancer Chemotherapy by Infusion (ed 2)521-551Chicago, IL, Percepta Press, 1990

8. Douple EB, Richmond RC: A review of interactions between platinum coordination complexes and ionizing radiation: Implication for cancer therapy, in Prestayko AW, Crooke ST, Karter SK (eds): Cisplatin: Current Status and New Developments. Orlando, FL, Academic, 1980, pp 125-147

9. Coia LR: Chemoradiation as primary management of esophageal cancer. Semin Oncol 21:483-492, 1994[Medline]

10. Forastier AA, Orringer MB, Perez-Tamayo C, et al: Preoperative chemoradiation followed by transhiatal esophagectomy for carcinoma of the esophagus: Final report. J Clin Oncol 11:1118-1123, 1993[Abstract/Free Full Text]

11. Herskovic A, Martz K, Al-Sarraf M, et al: Combined chemotherapy and radiotherapy in patients with cancer of the esophagus. N Engl J Med 326:1593-1598, 1992[Abstract]

12. Al-Sarraf M, Martz K, Herskovic A, et al: Progress report of combined chemoradiotherapy versus radiotherapy alone in patientswith esophageal cancer: An intergroup study. J Clin Oncol 15:277-284, 1997[Abstract/Free Full Text]

13. Ohtsu A, Yoshida S, Boku N, et al: Concurrent chemotherapy and radiation therapy for locally advanced carcinoma of the esophagus. Jpn J Clin Oncol 25:261-266, 1995[Abstract/Free Full Text]

14. Japanese Society for Esophageal Diseases: Guidelines for the Clinical and Pathologic Studies on Carcinoma of the Esophagus (ed 8). Tokyo, Japan, Kanehara Syuppan, 1992

15. Tobinai K, Kohno A, Shimada Y, et al: Toxicity grading criteria of the Japan Clinical Oncology Group. Jpn J Clin Oncol 23:250-257, 1993[Free Full Text]

16. Kaplan EL, Meiyer P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

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Submitted October 27, 1998; accepted May 7, 1999.


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