Treatment Results of Radical Surgery and Definitive Chemoradiotherapy for Patients with Submucosal Esophageal Squamous Cell Cancinomas

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1 Treatment Results of Radical Surgery and Definitive Chemoradiotherapy for Patients with Submucosal Esophageal Squamous Cell Cancinomas YASUSHI TOH 1, TAKEFUMI OHGA 1, SHUHEI ITOH 1, AKIRA KABASHIMA 1, KAZUHARU YAMAMOTO 1, EISUKE ADACHI 1, YOSHIHISA SAKAGUCHI 1, TAKESHI OKAMURA 1 and HIDEKI HIRATA 2 1 Department of Gastroenterological Surgery and 2 Department of Radiology, National Kyushu Cancer Center, Fukuoka, , Japan Abstract. Background: A radical esophagectomy with extensive lymph node dissection is the mainstay treatment for submucosal esophageal cancer, though definitive chemoradiotherapy (CRT) has also been applied. However, the treatment outcomes have not yet been extensively investigated. Patients and Methods: Forty-nine patients with submucocal esophageal squamous cell carcinoma, 24 and 25 of whom had been treated by a radical esophagectomy with extensive lymph node dissection (Surgery group) and definitive CRT using 5-Fluorouracil and CDDP with concurrent radiation of 60 Gy (CRT group), respectively, formed the study cohort. Results: In the Surgery group, the overall and cause-specific 5-year survival rates were 75.4% and 90.0%, respectively. No operative or hospital deaths had occurred. In the CRT group, a complete response (CR) had been achieved in 22 (88%) patients. The 3- and 5-year overall survival rates were 79.3% and 36.9%, respectively, while the cause-specific 3- and 5-year survival rates were 75.2% and 55.7%, respectively. No treatment-related deaths had occurred. Conclusion: These data suggest that: (i) a radical esophagectomy with extensive lymph node dissection can be a standard treatment offering excellent survival and (ii) a definitive CRT is a reasonable alternative to surgery, especially for patients with complications. Owing to numerous advances in diagnostic modalities, such as endoscopy with Lugol dye staining and endoscopic ultrasonography, the detected incidence of superficial esophageal cancer, including Tis and T1 (International Union Against Cancer/UICC, 1997), is currently increasing (1, 2). According to the Reports of Esophageal Cancer Registration in Japan, the percentage of superficial Correspondence to: Yasushi Toh, MD, Ph.D., Department of Gastroenterological Surgery, National Kyushu Cancer Center, Notame, Minami-ku, Fukuoka, , Japan. Tel: , Fax: , ytoh@nk-cc.go.jp Key Words: Submucosal esophageal cancer, surgery, chemoradiation. esophageal carcinoma among all cases of registered esophageal carcinomas was 19% in 1998 (3). Of superficial carcinoma of the esophagus, submucosal cancers showed a high incidence of lymph node metastasis (4). As a result, radical esophagectomy with extensive lymph node dissection was considered to be the mainstay treatment (5). However, the mortality and morbidity rates after an esophagectomy still remain high. Metzger et al. reported the mortality rate to be as high as 4.9%, even in high-volume hospitals where more than 20 esophagectomies were performed annually (6). Moreover, the decrease in a patient s post-operative quality of life caused by the loss of the esophagus remains problematic. On the other hand, the outcome of chemoradiation (CRT) for more advanced cases of esophageal cancer is improving. For example, Ohtsu et al. reported that a concurrent CRT for T4 and/or M1 lymph squamous cell carcinoma of the esophagus resulted in a complete response rate of 33% and a 3-year survival rate of 23% (7). Hironaka et al. also reported the results of a concurrent CRT for T2-3NanyM0 squamous cell carcinoma of the esophagus, showing a 5-year survival rate of 46% (8). Due to this improvement in results of definitive CRT for advanced esophageal cancer, the number of patients choosing this mode of treatment instead of surgery is on the increase in Japan. However, the outcomes of submucosal esophageal cancer treated by CRT alone or surgery alone have not yet been extensively investigated. The purpose of this study was to analyze the clinical results of radical esophagectomy with extensive lymph node dissection and definitive CRT in the treatment of submucosal esophageal cancer. Patients and Methods Patient population. Between 1995 and 2003, 49 patients with submucosal esophageal squamous cell carcinoma were treated in the National Kyushu Cancer Center, Japan. Twenty-four patients underwent an esophagectomy (Surgery group) and 25 underwent definitive CRT (CRT group). The patient and tumor characteristics /2006 $

2 are shown in Table I. The mean age at diagnosis was 64 years old in the Surgery group and 73 in the CRT group. All the lesions had been histologically confirmed to be squamous cell carcinoma. The assessment of tumor invasion was performed by endoscopy, endoscopic ultrasonography and radiographic appearance. Five patients in the Surgery group had lymph node metastases, three of which were M1-lymph-positive. Two patients in the CRT group were also diagnosed as having regional lymph node metastasis. As a result, in the Surgery group, 19 patients were clinically classified as T1N0M0, two as T1N1M0 and three as T1N1M1-lym. In the CRT group, 23 patients were classified as T1N0M0 and the remaining two as T1N1M0. In these cases, there were no patients with mucosal cancer, thus indicating that all cases had submucosal cancer. Therefore, endoscopic mucosal resection was not chosen for these patients, since the risk of lymph node metastasis was quite high (4). The median follow-up period was 32 months ( months) in the Surgery group and 38 months ( months) in the CRT group. When a tumor was judged to be resectable and the patient s condition such as to allow an esophagectomy, surgical treatment was normally recommended. The indications for definitive CRT were: (i) refusal to undergo surgery by eight patients, all of whom were medically operable; (ii) medically inoperability or the poor general condition of 14 patients; and (iii) simultaneous double carcinomas in three patients. Surgery. Among the 24 patients in the Surgery group, 19 underwent a right transthoracic subtotal esophagectomy with cervicothoracoabdominal lymph node dissection (so-called three-field dissection), four underwent a right transthoracic subtotal esophagectomy with a thoracoabdominal lymph node dissection (two-field dissection) and one underwent a transhiatal esophagectomy (blunt dissection). Treatment schedule of a definitive CRT. Chemotherapy consisted of a 24-hour continuous infusion of 250 mg/m 2 /day of 5-fluorouracil (5-FU) combined with a 1-hour infusion of 6 mg/m 2 /day of CDDP, 5 days a week, for 4 weeks. Radiation was concurrently administered at 1.6 Gy/day, 5 days a week, for 4 weeks. After a break of 2 or 3 weeks, this CRT was repeated to a total dose of 60 Gy. The irradiation techniques used were: anterior- and posterior-opposed equally-weighted beams up to 40 Gy; the radiation portals were changed to shield the spinal cord; the irradiation field craniocaudally encompassed the primary tumor with a 3-cm margin; and possible metastatic lymph nodes were included in the irradiation field. Evaluation of response and toxicity. The response criteria of the World Health Organization were used in evaluating the response of measurable lesions to definitive CRT. The responses were evaluated by esophagography, endoscopy and chest and abdominal CT scans. The definitions of response were as follows: a complete response (CR)=complete disappearance of all measurable and assessable diseases for a minimum of 4 weeks; a partial response (PR)=more than a 50% reduction in the sum of the products of the longest diameter of measurable disease for a minimum of 4 weeks; no change (NC)=the failure to observe a PR, CR or progressive disease for at least 4 weeks; progressive disease (PD)=more than a 25% increase in the sum of the products of the longest diameter of measurable disease or the appearance of new lesions. The response of the primary tumor was evaluated by the criteria of the Japanese Society for Esophageal Disease (9). Table I. Patient characteristics. Characteristics Surgery Chemoradiation (n=24) (n=25) Gender Male Female 4 1 Age Median Range PS Primary site of tumor Upper 3 2 Middle Lower 5 3 Reason for a definitive CRT Morbid conditions 14 Multiple cancers 3 Refusal of surgery 8 Histology Squamous cell carcinoma Clinical stage T1(sm)N0M T1(sm)N1M0 2 2 T1(sm)N0M1-lym 0 0 T1(sm)N1M1-lym 3 0 PS: The performance status evaluated by the criteria of ECOG (European Cooperative Oncology Group), CRT: chemoradiation, sm: submucosal cancer. Toxicity was evaluated using the criteria defined by the Japanese Clinical Oncology Group (JCOG) (10). Statistics. The survival curves were calculated from the start of treatment by the Kaplan-Meier method. Results Outcome of surgery for submucosal esophageal carcinoma. Five of the 24 cases in the Surgery group had been preoperatively diagnosed as having lymph node metastases. Pathological examination of the resected specimen revealed that nine cases had lymph node metastasis (lymph node metastasis rate=37.5%). Twenty-three patients underwent a subtotal esophagectomy through the right thoracotomy, 19 of whom also underwent cervicothoracoabdominal lymph node dissection (so-called three-field lymph node dissection). The remaining patient underwent a transhiatal esophagectomy, because his systemic condition did not allow for a subtotal esophagectomy through the right thoracotomy. Post-operative complications occurred in nine (37.5%) cases, including pulmonary complication in three 2488

3 Toh et al: Surgery and Chemoradiation for Submucosal Esophageal Cancer Figure 1. The overall and cause-specific survival curves of the 24 patients who had undergone a radical esophagectomy. Figure 2. The overall and cause-specific survival curves of the 25 patients who had undergone definitive chemoradiation. cases, anastomotic leakage in five and acute cholecystitis in one case. No operative or hospital deaths occurred. The number of cases with pn0, pn1, pm1-lymph metastasis were 15, three and six, respectively. Six out of nine cases with lymph node metastasis had more than two metastasized lymph nodes. The pathological depth of cancer invasion was mucosal in three cases, submucosal in 19 cases, muscular layer in one case and adventitia in one case. The accuracy of the pre-operative diagnosis concerning depth of invasion was 79.2%. Pathological stage I, IIB and IVA was the classification for 15, three and six cases, respectively. The overall 3-year and 5-year survival rates were 84.8% and 75.4%, respectively (Figure 1). Two of the 24 cases had a recurrence, one with bone and mediastinal lymph node metastases and the other with pretracheal lymph node metastasis. Two patients died of other diseases and, thus, the cause-specific 5-year survival rate was 90.0% (Figure 1). Outcome of definitive CRT for submucosal esophageal carcinoma. Twenty-two out of 25 cases (88.0%) treated by definitive CRT achieved a complete response (CR); two obtained a partial response (PR) and the remaining one no change (NC); giving a response rate (CR + PR) of 96.0%. The severe toxicities throughout the treatment period are listed in Table II. The major treatment toxicity was myelosuppression, though mostly grade 2 or lower. Grade 3 toxicities of leukopenia, neutropenia and thrombocytopenia occurred in three, seven and two patients, respectively. No grade 4 toxicities occurred. Furthermore, neither pulmonary toxicity, diarrhea nor nausea/vomiting of grade 2 or higher occurred. The second course was not performed in two of the 25 patients, at their own choice because they had experienced grade 2 esophagitis and grade 3 neutropenia in their first course. No treatment-related deaths occurred. With a median follow-up period of 38 months (range; 10 to 100 months), the 3- and 5-year overall survival rates were Table II. Summary of toxicity of definitive CRT. grade 1 grade 2 grade 3 grade 4 Leukopenia Neutropenia Anemia Thrombocytopenia Esophagitis Renal Appetite loss % and 36.9%, respectively (Figure 2). Four patients who had achieved a CR died of other causes such as cerebrovascular disease, cardiac failure and pulmonary abscess and, thus, the cause-specific 3- and 5-year survival rates were 75.2% and 55.7%, respectively (Figure 2). The 3- and 5-year survival rates of the 18 CR cases, excluding four patients who died of other diseases, were 88.2% and 65.4%, respectively. Three cases, who did not achieve a CR, died of esophageal cancer within 10 ~ 23 months. The clinical data of 22 patients who achieved a CR, seven (32%) of whom had recurrences, are shown in Table III. Five of the seven cases showed a local recurrence and the remaining two showed lymph node metastasis. The average time of local recurrence was 8.6 months (range; 4-22) after the completion of definitive CRT. Three patients underwent salvage esophagectomy with a three-field lymph node dissection, two of whom survived for a long time without any further recurrence (Case 1 died of cardiac failure at 49 months after the operation). Cases 4 and 5, with local recurrence, underwent further CRT combined with brachytherapy, both again achieving CR. Case 4 had a further local recurrence, thus resulting in a cause-specific death at 50 months after the completion of the first definitive CRT. Lymph node recurrence in the mediastinum 2489

4 Table III. Recurrence pattern of the complete response patients after definitive CRT. Case Site of rec Time of rec *1 Tx for rec Prognosis *2 1 local 5 months salvage ope 49 months died *3 2 local 4 months salvage ope 92 months alive 3 local 6 months salvage ope 8 months died 4 local 6 months CRT 44 months died 5 local 22 months CRT 16 months alive 6 lymph node 11 months CRT 17 months died 7 lymph node 22 months CRT 36 months died *1 Time of the recurrence after the completion of definitive CRT (chemoradiation). *2 Prognosis after the time of recurrence. *3 Case 1 died of cardiac failure. Tx: treatment, rec: recurrence. (paraesophageal and peri-recurrent nerve lymph nodes) occurred in Cases 6 and 7. They both received CRT but death occurred at 28 and 58 months after the completion of the first definitive CRT. No distant organ metastases were observed in our series. Discussion The outcomes of surgery and definitive CRT for submucosal esophageal squamous cell carcinoma were studied here. According to the Physician Data Queries from the National Cancer Institute of the USA, the standard treatment of stage I (T1N0M0) esophageal cancer is surgery. Surgery is also the standard treatment in Japan. The reason for this choice of the treatment is that lymph node metastasis is found in about 40 % of submucosal esophageal cancers, thus suggesting the importance of extensive lymph node dissection (4, 5). However, the mortality and morbidity rates after an extended radical esophagectomy still remain high even in high-volume institutions (6) and a reduction in the post-operative quality of life caused by loss of the esophagus is still problematic. Therefore, a reasonable alternative for the treatment of submucosal esophageal cancer is necessary, especially for patients in compromised conditions such as those with cardiopulmonary complications. Some groups reported that combined CRT using 5-FU and CDDP is more beneficial than radiotherapy alone in patients with locally advanced cancer of the thoracic esophagus (11, 12). However, the efficacy and toxicity of CRT for stage I esophageal cancer are still not clear. Ura et al. reported a retrospective series of definitive CRT in stage I disease, showing a 93% CR rate (13). They treated the remaining non-cr patients by salvage endoscopic resection or surgery. The 3- and 5-year survival rates were 80% and 77%, respectively, which were comparable to those for ordinary surgery by a Japanese group (14) and our group. Similarly, Kato et al. reported the results of a multiinstitutional prospective phase II study of definitive CRT in patients with stage I esophageal squamous cell carcinoma by the Japan Clinical Oncology Group (JCOG 9708) (15). In this study, 96% CR was achieved and the 2-year overall and recurrence-free survival rates were 96% and 75%, respectively. Furthermore, recurrent diseases were successfully treated with surgery and endoscopic resection. As a result, the combined CRT may be a standard treatment option for stage I esophageal cancer. In our study, the 3- and 5-year overall survival rates after definitive CRT were 79.3% and 36.9%, respectively. Although the 3-year survival rate appeared to be comparable to the studies mentioned above, the 5-year survival rate was apparently lower than that in Ura et al s. report. This difference might be due to the fact that most of the patients in our study were medically inoperable and showed a complicated systemic condition. In fact, four patients died of other diseases within 5 years of completing definitive CRT and the cause-specific 5-year survival rate was 55.7 %. Another reason may be that more than 60 % of the patients in our study had carcinomas which invaded the lower (deeper) third stratum of the submucosal layers (data not shown). The risk of lymph node metastasis becomes higher as a cancer invades the deeper layers of the esophageal wall. The risk of lymph node metastasis was reported to be 11% in cancers invading the upper third stratum of the submucosal layer, whereas it was 30% and 61% in those invading the middle third and lower third strata of the submucosal layers, respectively (4). Salvage surgery could be performed for only three of the seven recurrent cases because of their systemic condition and no patients could be cured by endoscopic resection after local recurrence had occurred. Differences in regimens may also account for differing results among groups. We used the socalled a low-dose 5-FU and CDDP regimen for chemotherapy, while the two studies mentioned above used the standard dose of chemotherapy. When treating patients with submucosal esophageal cancer, the irradiation field should be carefully taken into consideration. In our institution, the irradiation field was basically restricted to within about 3 cm above and below the main primary tumor. Both of the two lymph node recurrences occurred outside this irradiation field. It is well known that lymph node metastases from esophageal carcinomas are observed in cervical, mediastinal and abdominal areas (16). In fact, lymph node metastases were found in 38% of the patients who received a radical operation, occurring in the above-mentioned areas (data not shown). To avoid lymph node recurrence, the irradiation field thus has to be widened to these three fields. However, a wider irradiation field may cause an 2490

5 Toh et al: Surgery and Chemoradiation for Submucosal Esophageal Cancer increase in adverse effects and lower compliance in definitive CRT. Furthermore, it may cause more postoperative complications, such as anastomotic leakage, when salvage surgery is considered and the planned anastomotic site has been included in the irradiation field. In conclusion, this study showed that: (i) radical esophagectomy with extensive lymph node dissection can be a low-risk standard treatment offerring excellent survival, and (ii) definitive CRT is a promising treatment alternative to surgery for submucosal esophageal cancer, especially for patients with some complications. If it were possible to predict the sensitivity of esophageal cancer to chemoand/or radiotherapy by several biological markers (17), definitive CRT would be a more powerful tool for treatment of this disease. To clarify that definitive CRT can be a standard treatment for superficial esophageal cancer, a randomized clinical trial should, thus, be performed comparing definitive CRT and a radical esophagectomy for medically operable patients, such as is now being planned by the JCOG. Acknowledgements The authors thank Dr. Brian T. Quinn for his critical comments. References 1 Endo M and Kawano T: Detection and classification of early squamous cell esophageal cancer. Dis Esophagus 10: , Murata Y, Suzuki S, Ohta M, Mitsunaga A, Hayashi K, Yoshida K and Ide H: Small ultrasonic probes for determination of the depth of superficial esophageal cancer. Gastrointest Endosc 44: 23-28, The Registration Committee for Esophageal Cancer: Comprehensive Registry of Esophageal Cancer in Japan (1998, 1999). Third edition. Chiba, The Japanese Society for Esophageal Diseases, Endo M, Yoshino K, Kawano T, Nagai K and Inoue H: Clinicopathologic analysis of lymph node metastasis in surgically resected superficial cancer of the thoracic esophagus. Dis Esophagus 13: , Fujita H, Sueyoshi S, Yamana H, Shinozaki K, Toh U, Tanaka Y, Mine T, Kubota M, Shirouzu K, Toyonaga A, Harada H, Ban S, Watanabe M, Toda Y, Tabuchi E, Hayabuchi N and Inutsuka H: Optimum treatment strategy for superficial esophageal cancer: endoscopic mucosal resection versus radical esophagectomy. World J Surg 25: , Metzger R, Bollschweiler E, Vallbohmer D, Maish M, DeMeester TR and Holscher A: High volume centers for esophagectomy: what is the number needed to achieve low postoperative mortality? Dis Esophagus 17: , Ohtsu A, Boku N, Muro K, Chin K, Muto M, Yoshida S, Satake M, Ishikura S, Ogino T, Miyata Y, Seki S, Kaneko K and Nakamura A: Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus. 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Jpn J Clin Oncol 23: , Herskovic A, Martz K, al-sarraf M, Leichman L, Brindle J, Vaitkevicius V, Cooper J, Byhardt R, Davis L and Emami B: Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326: , al-sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, Cooper J, Byhardt R, Davis L and Emami B: Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 15: , Ura T, Muro K, Shimada Y, Shirao K, Igaki H, Tachimori Y, Kato H, Ito Y, Imai A and Kagami Y: Definitive chemoradiotherapy may be standard treatment options in clinical stage I esophageal cancer. 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Anticancer Res 25: , Received December 19, 2005 Revised April 4, 2006 Accepted April 27,