Surgical and oncological advances in the treatment of esophageal cancer

Surgical and oncological advances in the treatment of esophageal cancer

Surgical and oncological advances in the treatment of esophageal cancer Takefumi Ohga, MD, Yasue Kimura, MD, Motonori Futatsugi, MD, Mitsuhiro Miyazak...

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Surgical and oncological advances in the treatment of esophageal cancer Takefumi Ohga, MD, Yasue Kimura, MD, Motonori Futatsugi, MD, Mitsuhiro Miyazaki, MD, Hiroshi Saeki, MD, and Tadahiro Nozoe, MD, Fukuoka, Japan

Background. Chemoradiotherapy (CR) and hyperthermochemoradiotherapy (HCR) have been performed on numerous patients with esophageal cancer. These neoadjuvant therapies for esophageal cancer are done widely. The purpose of this study is to demonstrate the recent advances in surgical and oncological treatment. Methods. From 1967 to 2000, 847 patients who underwent an esophagectomy were classified into 4 groups according to the date of operation. Group 1 consisted of 110 patients who underwent an esophagectomy in the first 10-year period (1967-1976), group 2 consisted of 194 patients who had operations from 1977 to 1986, group 3 comprised 400 patients who had operations from 1987 to 1996, and group 4 comprised 143 patients who had operations from 1997 to 2000. From 1967 to 2000, 322 patients with neoadjuvant therapy and esophagectomy were classified into 6 groups according to the kinds of anitcancer drugs that were administered. Group A received regimen A, using BLM (5 mg iv) 6 times as the chemotherapeutic drug in the early period (1965-1990); group B received regimen B, using cis-diaminedichloroplatinum (CDDP) (40 mg/m2) 3 times as the chemotherapeutic drug in the second period (1990-1997); and group C received regimen C, using CDDP (40 mg/m2) and 5FU (250 mg/m2) daily in the most recent period (1997-2000). The HCR group was also divided into the following 3 groups: Group D, who received regimen A and hyperthermia 6 times in the early period; group E, who received regimen B and hyperthermia 6 times in the next period; and group F, who received regimen C and hyperthermia 6 times in the most recent period. The local response and the longterm results were investigated. Results. A complete removal of the primary tumor was achieved in 29%, 39%, 62%, and 68% of the patients in groups 1, 2, 3, and 4, respectively. The 30-day operative mortality rates were 11%, 4%, 1%, and 0% in groups 1, 2, 3, and 4, respectively. The 5-year survival rates for all patients in groups 1, 2, and 3 were 16.7%, 19.2%, and 44.4%, respectively. The cases in which CR or HCR was evaluated to be effective numbered 44 (48.4%) in group A, 22 (73.3%) in group B, 8 (66.7%) in group C, 79 (63.7%) in group D, 36 (73.5%) in group E, and 12 (75.0%) in group F. Our clinical results thus showed CDDP to have a greater effect than BLM, while HCR was shown to have a greater effect than CR. Conclusions. Preoperative therapy, especially using CDDP and hyperthermia, has improved thanks to recent advances in the treatment of esophageal cancer. (Surgery 2002;131:S28-34.) From the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

THE PROGNOSIS ASSOCIATED WITH ESOPHAGEAL carcinoma remains one of the worst out of the numerous types of digestive tract cancer. Some investigators have reported, in Western countries, that the overall 5-year survival rate of patients with esophageal carcinoma treated with current methods is disappointing, ranging from 8% to 21%.1-3

Reprint requests: Takefumi Ohga, MD, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan. Copyright © 2002 by Mosby, Inc. 0039-6060/2002/$35.00 + 0 11/0/119291 doi:10.1067/msy.2002.119291

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As a result, esophageal carcinoma still remains one of the most discouraging areas in malignancy of the digestive tract. The histological type in the esophageal cancer is mainly squamous cell carcinoma in Japan4 while it tends to be adenocarcinoma in Western countries5 with symptoms such as dysphagia in both countries. In Western countries, the basis of carcinogenesis is the Barrett’s epithelium due to reflux esophagitis. Squamous cell carcinoma tends to be sensitive to radiochemotherapy while adenocarcinoma is not. In addition, a variety of biological characteristics in esophageal cancer such as the proliferative activity, carcinogenesis, and the tendency to develop lymphadenopathy has also made its treatment difficult.6-12

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Fig 1. The complete resection rate for esophageal cancer operations. The black squares show a complete resection.

The detection of esophageal disease with esophagrams or upper gastro-intestinal endoscopy is easy when the tumor is elevated, but it is difficult to recognize mucosal abnormalities when the tumor is at an early stage or is a flat type.13 The remarkable development of esophago-fiberscopic endoscopy including the usage of Lugol’s solution has made the diagnosis of early stage esophageal carcinoma easier.14 In 1985, an introduction of a Lugol’s staining made the detection of mucosal abnormalities much easier.14-16 With this endoscopic method, we have reported the detection of 6 epithelial carcinomas, 31 mucosal carcinomas, and 75 submucosal carcinomas between 1987 and 1998.17 In addition, since 1985, 43 mucosal carcinomas and 125 submucosal carcinomas were diagnosed thanks to the use of Lugol’s staining. This indicates that endoscopy with Lugol’s solution and an endoscopic biopsy are the most efficient diagnostic tools presently available for the detection of such small and early stage carcinomas of the esophagus, many of which cannot be identified by radiography. In most instances, such lesions are detected incidentally during endoscopic procedures that are frequently performed for symptoms not directly related to the esophagus. The application of Lugol’s solution greatly aids in the diagnosis when a suspicious mucosal lesion is noted, when the margin of a lesion is unclear, or when there is suspicion that a mucosal lesion may

have been overlooked. We can now detect early stage tumors, the skip lesions, and the lesions of dysplasia and correctly determine the line of oral margin using Lugol’s solution. In addition, we can confirm the oral margin of the abnormality in the esophagus using the clipping method. We herein report our results regarding both operations and preoperative therapy for esophageal carcinoma patients treated in our department. METHODS AND RESULTS Surgical advance for esophageal cancer. The most reliable treatment for malignant disease of the esophagus is surgical removal. Less than half of patients with esophageal cancer are appropriate candidates for surgery because the majority of them have widespread disease at the time of detection. Both aggressive nutritional support and a proper nutritional assessment during the perioperative period have recently become essential for achieving a satisfactory recovery because operations for esophageal cancer have become more radical and extensive.18 From 1967 to 2000, 847 patients with carcinoma of the esophagus either with or without preoperative therapy, such as hyperthermochemoradiotherapy (HCR) or chemoradiotherapy (CR), underwent an esophageal resection at the Department of Surgery and Science (Surgery II) at Kyushu University Hospital. These patients were classified into 4 groups

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Surgery January 2002

Fig 2. The 30-day operative mortality rate after esophageal cancer operations. The black circle show the 30day operative mortality.

according to the date of operation or the kinds of anticancer drugs. Group 1 consisted of 110 patients who underwent an esophagectomy in the first 10year period (1967-1976), group 2 consisted of 194 patients who had operations from 1977 to 1986, group 3 comprised 400 patients who had operations from 1987 to 1996, and group 4 comprised 143 patients who had operations from 1997 to 2000. The standard operative procedures included a subtotal esophagectomy through a right thoracotomy, usually with reconstruction using the stomach through the antesternal or thoracic route, combined with lymph node dissection.19 The stomach, colon, jejunum, isolated jejunal segment, or other conduit was used in 87.2%, 6.0%, 3.7%, 1.4% and 1.7% of the patients, respectively, to replace the resected esophagus. In our department, a complete removal of the primary tumor, including any metastatic lymph nodes, was achieved in 29%, 39%, 62% and 68% of the patients in groups 1, 2, 3, and 4, respectively (Fig 1). The number of patients now undergoing a curative resection have recently remarkably increased. In our department, preoperative treatment has been aggressively applied to patients diagnosed with advanced esophageal cancer to enable a complete removal of the lesion. Therefore, the preoperative therapy results in a downstage of the tumor, thus enabling a complete resection to be made. Esophageal cancer is more common in older

patients, and there are often serious coexisting diseases, particularly regarding the heart and lungs. As esophagectomy is associated with a high morbidity (mainly pulmonary complications and anastomotic leaks), thus, preoperative assessment of the cardiopulmonary function and nutritional state is essential.20 Because of recent advances in operative techniques and perioperative management, esophageal resection and reconstruction for patients with esophageal cancer is now a safe procedure, and the postoperative mortality within the first month is less than 5%.21-23 We usually avoid operating on patients with seriously impaired pulmonary, cardiac, or hepatic function, and the criteria that contraindicate esophageal surgery in our department are as follows: a recent myocardial infarction (within 3 months), hepatic dysfunction (child’s grade C or active hepatitis), a performance status of 3 or 424 or severe psychological disturbances. The 30-day operative mortality rates were 11%, 4%, 1%, and 0% in groups 1, 2, 3, and 4, respectively (Fig 2). The most common causes of death within 30 days are pulmonary complications and cardiac failure. The correlation between a preoperative assessment of organ function and the postoperative development of complications indicates that a preoperative pulmonary dysfunction was significantly associated with the development of all complications and of postoperative pulmonary complications. Age is no longer consid-

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Fig 3. The 5-year survival rate for esophageal cancer. The black diamonds show the 5-year survival rate.

Table I. Histopathologic evaluation of the local effects of each period in the CR Group and the HCR Group Group A(n=91) (%) CR group(n=133) Grade 0,1 Grade 2 Grade 3

HCR group(n=189) Grade 0,1 Grade 2 Grade 3

Group B(n=30) (%)

Group C(n=12) (%)

47(51.6) 35(38.5) 9(9.9)

8(26.7) 19(63.3) 3(10.0)

4(33.3) 5(41.7) 2(25.0)

Group D(n=124) (%)

Group E(n=49) (%)

Group F(n=16) (%)

45(36.3) 57(46.0) 22(17.7)

13(26.5) 19(38.8) 17(34.7)

4(25.0) 8(50.0) 4(25.0)

ered a contraindication to surgical treatment of the malignant esophagus. In the patients described above, 26.2% were over age 70, and 1.7% were over age 80 at the time of surgery. The 30-day mortality rate for patients over 70 years of age is only 2.2% since 1987. Advanced age alone should not, therefore, be regarded as a reason for withholding operation. No patient with intraepithelial carcinoma or mucosal carcinoma had a recurrence within 5 years of surgery, whereas the 5-year survival rate of those with submucosal carcinoma was only 73%. The 5-year survival rates for all patients in groups 1, 2, and 3 were 16.7%, 19.2% and 44.4%, respectively (Fig 3). The long-term survival has clearly improved since 1987. The 5-year survival rates for patients having a curative resection in groups 1, 2, and 3 were, respectively, 31%, 30%, and 58%. These

data suggested that the early detection of esophageal cancer and moderate therapy most suitable for each person may improve the surgical advances. Oncological advance in preoperative treatment for esophageal cancer. The treatment results for esophageal cancer patients still remain unsatisfactory. In our experimental observations, hyperthermia has been shown to have an antitumor effect and to decrease the proliferation of tumor cells, while it also has a synergistic response when combined with radiotherapy and chemotherapy.24-32 HCR has been performed on numerous patients with esophageal cancer before an esophagectomy. In our department, 133 and 189 patients were given either preoperative CR (CR group) or HCR (HCR group), respectively. These 322 patients who were given preoperative CR or HCR were classified

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into the following 6 groups according to the contents of the chemotherapeutic drugs. At first, the CR group was classified into 3 groups. Group A received regimen A, using BLM (5 mg iv) 6 times as the chemotherapeutic drug in the early period (19651990), group B received regimen B, using cisdiaminedichloroplatinum (CDDP) (40 mg/m2) 3 times as the chemotherapeutic drug in the second period (1990-1997), and group C received regimen C, using CDDP (40 mg/m2) and 5 FU (250 mg/m2) in the recent period (1997-2000). The HCR group was also divided into the following 3 groups; group D, who received regimen A and hypothermia 6 times in the early period, group E, who received regimen B and hyperthermia 6 times in the next period, and group F, who received regimen C and hyperthermia 6 times in the recent period. We evaluated the histopathological effects for the resected esophageal tissue among these groups after the operation of esophagectomy. In these comparisons, no significant differences were observed regarding such background factors. The local response was indicated as follows. The cases in which CR or HCR was evaluated to be effective numbered 44 (48.4%) in group A, 22 (73.3%) in group B, 8 (66.7%) in group C, 79 (63.7%) in group D, 36 (73.5%) in group E, and 12 (75.0%) in group F (Table I). As a result, these preoperative treatments were shown to have dramatically improved after the introduction of CDDP. Chemotherapy with the use of CDDP has shown a greater effect than that with the use of BLM, and preoperative HCR has increased the anticancer effect. Since recent reports have shown that the combination of CDDP and 5-FU is one of the most effective chemotherapeutic regimens for the patients with esophageal cancer, this combination is now applied to both our preoperative CR and HCR regimens.33-36 DISCUSSION Oncological treatment has also gradually improved. However, some problems regarding HCR remain to be solved. It is thought that many factors thus influence the sensitivity of preoperative treatment. Some parameters of hyperthermoradiosensitivity are based on the findings of the succinate dehydrogenase inhibition (SDI) test37 and DNA ploidy,38 while the sensitivity to CDDP is also considered to be an important factor such as amphotericin B, HMG1, or YB-1 in the effectiveness of this treatment.39-42 If we can select the sensitive esophageal cancer for preoperative therapy while referring to these parameters of hyperthermoradiosensitivity before the treatment, then we will be able to establish the better and more suitable treatments for each individual patient.

Surgery January 2002

Endoscopic surgery for esophageal tumor. Recently, introduction of endoscopic surgery allows us to perform minimally invasive surgery. In our department, 3 patients underwent an esophagectomy under the thoracoscopy. In addition, a newly developed computer enhanced surgical system, da Vinci, with master-slave manipulators now enables surgeons to perform endoscopic surgery at a technical level similar to that of open surgery regarding both the operative field and operation techniques.43,44 Our department has already performed laparoscopic operations and one thoracoscopic operation with the aid of the da Vinci robotic surgical system, including such operations as a distal partial gastrectomy, a colectomy, a splenectomy and the extirpation of a mediastinal tumor among others.45,46 We have performed 2 laparoscopic tumor extirpations for esophageal submucosal tumors and one esophagectomy for esophageal cancer using the da Vinci system. None of the patients felt any pain. We demonstrated several advantages of this system, including its 3-dimensional view about its fine and detailed cutting line between the esophageal mucosa and the tumor and the excellent movement capacity of the da Vinci arms during both suturing and ligation. Our findings suggest that this new computer enhanced surgical system, da Vinci, offers great promise as a new modality to perform esophageal operations for esophageal tumors. This newly developed computerized system was thus found to be both safe and effective. CONCLUSION In conclusion, the improvements in digestive endoscopic technology and methodology now allow for the diagnosis of early esophageal cancer, while surgical and oncological advances also enable the long survival of esophageal cancer patients in our department. In addition, endoscopic surgery, including a computer enhanced surgical system, da Vinci, with master-slave manipulators now also permits us to perform minimally invasive surgery to improve the quality of patient treatment. REFERENCES 1. Hambraeus GM, Mercke CE, Willen R, Ranstam J, Samuelsson L, Lamm IL. Prognostic factors influencing survival in combined radiotherapy and surgery of squamous cell carcinoma of the esophagus with special reference to a histopathologic grading system. Cancer 1988;62:895-904. 2. Paricio PP, Garcia Marcilla JA, Martinez de Haro L, Ortis Escandell MA, Castellanos Escrig G. Results of surgical treatment of epidermoid carcinoma of the thoracic esophagus. Surg Gynecol Obstet 1993;177:398-404. 3. Swisher SG, Hunt KK, Holmes EC, Zinner MJ, McFadden

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