Parameters Linked to Ten-Year Survival in Japan of Resected Esophageal Carcinoma Japanese Committee for Registration ofesophageal Carcinoma Cases Chairman: Toshifumi lizuka, M.D.* Members: Kaichi lsono, M.D.;t Teruo Kakegawa, M.D., F.C.C.R;+ and Hiroshi Watanabe, M.D. From January 1969 to December 1980, 8,948 patients with esophageal carcinoma were registered in Japan. Among these patients, 5,506 underwent resection. The ten-year survival rate was 12.3 percent for all registered patients and 18.7 percent for resected cases. Female patients had significantly better survival rates than male patients. Depth of invasion correlated better with ten-year survival than the superficial extent of the tumor. The TNM classification revised in 1987 was examined in relation to the survival, and it was found to have good prognostic value. (Chest 1989; 96:1005-11) arcinoma of the esophagus is one of the most C difficult carcinomas to cure, even in supposedly curative resectable cases. Although preoperative and postoperative radiotherapy or chemotherapy also have been performed during the past 20 years in an attempt to improve therapeutic results, the prognosis is still poorer than that for other carcinomas. There are few papers reporting long-term survival after treatment. This article describes the ten-year For editorial comment see page 970 survival rate of patients with esophageal carcinoma registered in Japan between 1969 and 1980. MATERIALS AND METHODS In Japan, since the Guidelines for Clinical and Pathologic Studies on Carcinoma of the Esophagus' was published in 1969, findings of patients with esophageal carcinoma have been described according to these guidelines. This has simplified collection of data on patients from many institutions in Japan. From January 1969 to December 1980, 10,113 patients with esophageal carcinoma were registered at 234 institutions. To investigate the survival rate, long, accurate follow-up of patients is essential. Seventy-eight institutions were excluded because their five-year follow-up rate was under 80 percent. Thus, 8,948 patients were included in this study; among these, 5,481 patients underwent resection. Out of 5,481, 132 patients had cancer of the esophagogastric junction and 82 with cancer of the cardia had adenocarcinoma; the remaining 5,267 patients with cancer of the esophagus had squamous cell carcinoma. The survival rates of these patients were computed according to the life-table method of Cutler with the use of a HITAC M 160-H (Hitachi Ltd., Tokyo). The significant difference between each survival rate was computed to be in the range of 95 percent confidence limits by Greenwood's formula." *The National Ooji Hospital, Tokyo, Japan. tchiba University, Chiba, Japan. ikurume University, Kurume, Japan. National Cancer Center Hospital, Tokyo, Japan. This study was supported by a Grant-in-Aid for Cancer Research (60-3)from the Ministry of Health and Welfare of Japan. Manuscript received October 31; revision accepted February 1. Reprint requests: Dr. Iizuka, NationalOoji Hospital, Akabanedai 4-17-56, Kita Ku, Tokyo, Japan 115 RESULTS The survival rate of the registered patients is shown in Table 1. The survival rate was 15.3 percent at five years and 12.3 percent at ten years. While there were more male patients, with the male-female ratio being about 5:1, female patients had better survival rates than males for each year of survival, and the difference was statistically significant. The survival rate of 5,481 resected cases was 23.8 percent at five years and 18.7 percent at ten years (Table 2). Female patients had significantly better survival than males at five and ten years. Table 3 shows the correlation between the location of the tumor and survival. Cases with lesions in the cervical, lower thoracic and abdominal esophagus had a better survival rate than cases with lesions in the upperthoracic esophagus. Patients with middle esophageal carcinoma had intermediate survival. While these results agreed with other reports, there were no statistically significant differences among the survival rates for lesions at different sites. The relationship between the length of the tumor and survival is shown in Table 4. Tumors less than 1 em showed the best survival, followed by those less than 3 em. When the length of tumor was greater than 3 em, the survival rate decreased, but there was no statistically significant difference in tumors within the Table I-Registered Cases: Sex and Survival Survival Rate (%) Patients 1 yr 2 yr 3yr 4 yr 5yr All 8,948 40.9 24.6 19.2 16.7 15.3 Male 7,388 39.0 39.0 17.6 15.2 13.8* Female 1,560 49.9 32.5 26.4 23.4 22.4* *p<o.ool. tp<o.ol. 10 yr 12.3 10.8t 18.8t CHEST I 96 I 5 I NOVEMBER, 1989 1005
Table 2-Resected Cases: Sex and Survival* Death Excluding Survival Rate (%) within Operative Patients 30 Days Deaths 1 yr 2 yr 3 yr 4 yr 5 yr 10yr All 5,481 410 5,071 2,781 1,727 1,327 1,120 932 207 (57.7) (37.1) (29.6) (25.8) (23.8) (18.7) Male 4,474 341 4,133 2,196 1.326 1,003 837 685 146 (56.0) (35.1) (27.7) (23.9) (21.7)t (16.6)+ Female 1,007 69 938 585 401 324 283 247 61 (65.1) (45.7) (37.9) (33.9) (32.5)t (27.3)+ *Nunlbers in parentheses indicate actuarial survival rate. tp<0.005. +p<0.025. Table 3-Location a/tumor in Resected Cases* Death Excluding Survival Rate (%) within Operative Pharynx 22 1 21 58.1 39.5 30.2 24.6 25.2 Cervical 248 23 225 60.3 39.7 34.4 31.9 28.2 26.4 Upper 390 35 355 50.8 26.8 21.8 18.1 16.7 11.5 Middle 2,957 221 2,736 56.9 36.8 29.0 24.9 22.5 17.0 Lowert 1,338 97 1,241 58.6 38.9 30.7 27.3 25.7 20.2 Abdominalt 310 18 292 64.4 40.3 33.3 32.1 29.1 28.7 Esophagogastric 132 9 123 64.0 41.6 31.0 26.8 26.5 22.7 Cardia] 82 0 76 59.8 40.2 39.6 33.8 33.0 20.2 *Two patients were deleted because they had no tumor at resected specimen. tlower: lower thoracic esophagus excluding abdominal esophagus. +Abdorninal: esophagus locating infradiaphragmatic abdominal cavity. Esophagogastric: tumor located in esophagogastric junction, invaded both abdominal esophagus and cardiac part of the stomach. IICardia: cardiac part of the stomach. 3- to IO-cm range. Among cases of tumors more than titia, definite invasion to the adventitia, invasion to 15 em, there was no survivor beyond four years. neighboring structures according to the Japanese Among resected cases, operated specimens were guidelines (Table 5). There was a decrease in survival examined histopathologically to evaluate the depth of with the depth of invasion and significant differences invasion and lymph node metastasis. were observed among tumors whose depth of invasion The depth of invasion was classified as being as far reached the intraepithelium, muscularis mucosa and as the intraepithelium, muscularis mucosa, submu- submucosa and submucosa and muscularis propria. cosa, muscularis propria, invasion reaching the adven- Clearly the worst survival rate was observed in cases Table 4-Resected Cases:ungth a/filling Defect an X-Ray Film within Operative No-examination 8 2 6 51.0 34.7 17.7 18.1 18.6 Tumor length 0-1 cm 21 2 19 86.0 77.0 78.8 80.8 82.9 45.3 1-2 em 85 2 83 75.7 68.2 61.7 53.6 48.8 32.7 2-3 ern 270 20 250 74.7 53.8 42.9 42.1 37.6 32.6 3-5 ern 1,367 96 1,271 65.7 43.3 34.6 30.0 27.2 20.2 5-7 em 1,760 124 1,636 57.1 35.1 27.4 24.0 21.9 17.9 7-10 em 1,476 130 1,436 50.7 31.5 25.1 21.2 20.0 15.5 10-15 em 361 23 338 41.5 24.6 19.1 16.4 14.9 12.1 15-18 ern 23 1 22 16.7 5.7 0.0 Unknown 110 10 100 59.7 42.1 35.5 29.6 30.3 24.1 1006 Ten-year Survival of Resected Esophageal Carcinoma (lizuka et aj)
Table 5-Hesected Cases: DepthofInOOBion and Survival within Operative Patients 30 Days Deaths 1 yr 2 yr 3yr 4yr 5yr 10yr Not examined 93 15 78 48.8 34.9 28.8 25.9 24.6 22.7 Depth of invasion Epithelium 21 0 21 83.7 70.9 67.8 64.5 67.1 59.9 Muscularis mucosa 31 3 28 91.2 78.4 72.7 62.9 64.8 57.5 Submucosa 344 26 318 BO.8 66.1 57.3 52.1 47.6 36.4 Muscularis propria 1,019 65 954 67.4 47.6 38.8 35.2 31.1 25.0 Reaching adventitia 893 59 834 65.7 43.3 33.3 29.7 26.6 22.5 To the adventitia 1,901 109 1,792 56.7 33.8 26.1 21.6 20.5 15.9 To neighboring 966 101 865 33.4 14.6 11.0 8.9 8.2 5.9 structures Unknown 193 29 164 47.7 31.4 26.5 24.2 23.9 18.3 Table 6-Survival According to Surgery within Operative Patients 30 Days Deaths 1 yr 2 yr 3 yr 4 yr 5 yr 10yr All 8,948 667 8,281 44.2 26.7 20.7 18.0 16.6 13.2 Resection Surgery 5,481 410 5,071 57.7 37.1 29.6 25.8 23.7 18.6 No surgery 3,467 257 3,210 22.3 8.8 5.1 4.0 3.5 0.9 Other surgery 73 8 65 12.7 4.9 3.4 1.8 1.8 2.3 (gastrostomy, jejunostomy) of tumors that had invasion to neighboring structures. Resected cases, which accounted for 60 percent of registered cases (Table 6) had apparently better survival than nonresected cases. Operations were classified as curative or noncurative resection according to the Japanese guidelines.' Curative resection means complete removal of the primary tumor and dissection of regional lymph nodes. Other operations were classified as noncurative. Both groups were divided into two subgroups, based on whether the patients received reconstructive surgery or not. The reason why reconstruction was not possible in some cases was mainly due to low puhnonary function and pneumonia. Resection and reconstruction were performed in one stage in the majority of cases. There was a clear difference of survival between the curative and noncurative groups. In curatively resected patients, if they did not receive reconstruction, survival decreased to 15.6 percent at five years and 10.7 percent at ten years, compared with 32.7 percent at five years and 26.3 percent at ten years in those receiving reconstruction surgery (Table 7). There was no difference in operative mortality (within 30 days) between these groups. Table 8 shows the results of radiotherapy alone. Radical radiotherapy means that the planned dose (50 Table 7- Resected Cases: Curability and Survival within Operative Patients 30 Days Deaths 1 yr 2 yr 3yr 4 yr 5yr 10yr Noncurative 182 29 153 18.1 5.5 4.2 2.2 2.2 2.7 without reconstruction Noncurative 1,710 151 1,559 36.9 16.8 11.8 9.2 8.4 5.6 with reconstruction Curative without 197 24 173 49.8 27.9 22.3 18.4 15.6 10.7 reconstruction Curative with 3,392 206 3,186 70.2 49.1 39.9 35.5 32.7 26.3 reconstruction CHEST I 96 I 5 I NOVEMBER, 1989 1007
Table 8-Radiation Therapy Alone Survival Rate (%) Patients lyr 2 yr 3 yr 4yr 5 yr 10 yr Total 1,532 29.5 12.2 7.1 5.3 4.5 2.5 Radical 911 37.1 16.3 9.1 6.7 5.3 3.0 Palliative 621 18.3 6.0 4.1 3.3 3.2 1.0 Gy) was given to the patients. Because of the selection for treatment, survival in the radiotherapy-only group is low, even in the radically treated group. The survival of the radical radiotherapy group was 5.3 percent at five years and 3.0 percent at ten years. In the resected cases, the extent of disease was examined based on the 1987TNM classification. 3 Table 9 shows the relationship between tumor and survival. TheTl classification had the best survival followed by T2, T3 and T4. There were statistical differences in survival for each category Table 10 indicates the survival according to lymph node metastasis. There was a statistically significant difference in survival between NO and Nl. Table 11 shows survival and metastasis classification. The M1 classification includes not only organ metastasis but also metastasis to nodes more distant than regional nodes. There was a clear difference between MO and Ml, but there were some patients surviving more than ten years in the M1 group. Stage I had the best survival rate: 64.2 percent at five years and 48.0 percent at ten years (Table 12). There was a clear difference between each of the five groups, suggesting that this staging reflected survival well. Radiation therapy, including preoperative irradiation, has been used in combination with surgery. There was no difference in the five- and ten-year survival rates of the nonirradiated and preoperative radiation groups. The postoperative radiation group had a slightly lower survival than the othertwo groups (Table 13). The histologic effect of radiation recognized on the resected specimens and survival is shown in Table 14. Histologic effect was classified as follows according to the Japanese guidelines. 1 Markedly effective: cancer is eliminated and no viable cancer cells are observed. Moderately effective: viable cancer cells occupy less than one third of the lesion, with destructive cells in the rest of the lesion. Ineffective or slightly effective: viable cancer cells occupying more than one third of the lesion. The markedly effective group had the best survival (31.0 percent) at ten years. On the contrary, the slight effect group had the worst survival, with a ten-year survival of 12.8 percent. The causes of death after surgery are shown in Table 15. In the first two years, the main cause of death was due to the primary disease, esophageal carcinoma. However, after five years death unrelated to malignancy represented about two thirds of those who died. DISCUSSION There are only a few reports concerning long-term survival of patients with cancer of the esophagus. Earlam and Cunha-Melo" collected 83,783 patients from the literature, and reported a 12 percent five- Table 9-Tumor Classification and Survival within Operative Patients 30 Days Deaths 1 yr 2 yr 3 yr 4 yr 5yr 10 yr All 5,481 410 5,071 57.7 37.1 29.6 25.8 23.7 18.6 Tl 376 29 367 81.7 67.3 59.1 53.6 49.9 36.1 T2 1,019 65 954 67.4 47.6 38.8 35.2 31.0 24.8 T3 2,794 168 2,626 59.5 36.8 28.3 24.2 22.4 17.8 T4 966 101 865 33.4 14.6 11.0 8.9 8.2 5.9 Unknown 213 32 181 50.6 34.8 29.9 27.2 27.2 22.5 Table lo-lymph Node Metastasis and Survival Patients Death within 30 Days excluding Survival Rate (%) Operative Deaths 1 yr 2 yr 3yr 4 yr 5 yr 10 yr All 5,481 410 NO 1,983 140 Nl 1,847 III Unknown 517 87 (M Lyn)* 1,134 72 5,071 57.7 37.1 29.6 25.8 23.7 18.6 1,843 74.1 57.1 48.7 44.5 41.2 32.4 1,736 57.0 32.3 23.7 19.7 17.9 14.1 430 45.1 28.1 21.7 17.7 16.9 15.4 1,062 35.4 13.9 9.1 6.4 5.5 2.9 *Metastasis to lymph nodes beyond regional nodes. 1008 Ten-year Survival of Resected Esophageal Carcinoma (Iizuka et 81)
Table 11-Meta8ta8i8 and Survival within Operative Patients 30 Days Deaths 1 yr 2yr 3 yr 4 yr 5 yr 10 yr All 5,481 410 5,071 57.7 37.1 29.6 25.8 23.7 18.6 MO 4,204 319 3,885 64.8 44.2 35.9 31.7 29.3 23.9 Ml 1,277 91 1,186 34.4 13.4 8.9 6.5 5.5 3.0 Table 12-Stage and Survival within Operative All 5,481 410 5,071 57.7 37.1 29.6 25.8 23.7 18.6 Stage 1 249 17 232 91.6 78.9 73.8 69.5 64.2 48.0 Stage 2A 1,394 88 1,306 75.6 58.2 49.1 44.3 40.9 32.2 Stage 2B 351 15 336 62.6 40.2 31.6 28.1 24.7 18.6 Stage 3 1,584 100 1,484 56.4 31.1 22.5 18.5 17.2 13.8 Stage 4 1,184 79 1,105 35.5 13.6 9.0 6.5 5.4 2.9 Unknown 719 III 608 47.0 31.7 24.3 20.9 19.8 18.1 year survival for resected cases, and an 18 percent 652 resected cases. There is no other report on tensurvival for those leaving the hospital after resection. year survival. In Japan, multi-institute registration of Kinoshita et al 5 evaluated ten-year survival after patients with esophageal carcinoma treated after 1969 resective surgery and reported 58 ten-year survivors was commenced in 1975. In 1985, we proposed a new among 1,329 radically resected cases. K'ai and Huang' TNM classification for esophageal carcinoma based on reported a 21.2 percent ten-year survival rate among 3,681 resected cases registered from 1969 to 1978. 7 Table 13-ResectedCases: Radiation and Survival within Operative No radiation 1,449 139 1,310 59.9 40.9 33.2 28.8 27.5 23.3 Preoperative 2,823 265 2,558 56.1 37.1 29.8 26.7 24.1 18.3 Intraoperative 8 0 8 76.2 51.7 26.3 26.8 27.4 31.4 Postoperative 529 1 528 56.1 32.9 25.6 21.3 19.1 14.8 Preoperative and postoperative 590 1 589 59.2 33.3 26.0 21.2 20.1 15.8 At recurrence 43 0 43 73.3 31.3 19.6 17.5 12.8 5.8 Others 4 1 3 61.6 68.6 34.8 0 Unknown 35 3 32 57.4 29.3 16.6 17.0 13.9 Table 14-Hesected Cases: Radiation Effect and Survival* within Operative Not examined 333 33 300 49.2 29.3 22.5 19.6 17.8 14.4 En 1,596 102 1,494 51.9 30.2 22.3 19.0 17.1 12.8 Ef2 i.ios 70 1,033 60.7 39.4 31.2 27.7 25.2 20.1 Ef3 510 39 471 69.0 55.3 49.4 44.1 41.0 31.0 No preoperative radiation 1,235 92 1,143 61.2 40.5 32.5 28.2 26.4 21.8 Unknown 704 74 630 55.5 33.9 27.8 24.2 22.4 18.6 *En: slightly effective; Ef2: moderately effective; Et3: markedly effective. CHEST I 96 I 5 I NOVEMBER, 1989 1009
Table I5-Cause afdeath after Surgery Death excluding Number dead Within Operative All 4,140 56 4,084 2,131 1,017 378 195 113 206 Esophageal carcinoma 2,996 22 2,974 1,605 SOl 282 133 66 84 Other carcinoma 45 4 41 5 7 4 3 7 9 No carcinoma 553 22 531 308 66 38 18 22 57 Unknown 545 8 537 213 142 54 41 18 56 We stressed that the depth of invasion had a better correlation with five-year survival than length or circumference of the tumor. We also emphasized that perigastric lymph nodes should be included in the N category rather than the M category, based on the correlation with the five-year survival rate. The present study included 10,113 registered cases, 5,506 of which were resected. The survival rate was calculated by the life table method for up to ten years. The overall survival of resected cases was 23.8 percent at five years and 18.7 percent at ten years. These results are better than those of previous reports in Japan. Female patients had better survival than males for each year of survival, both overall among all registered cases and also among resected cases. Concerning the location of the tumor in the resected cases, those with cancer of the upper thoracic esophagus had the worse survival, but there was no marked difference between those with lesions in the middle or lower thoracic esophagus. As to the length of the tumor, cases with tumors less than 3 ern had better survival, but there was no difference among those in the 3- to IO-cm category. Thus, in the present series the length of 5 em had no significance as a benchmark for survival. DeptH of invasion clearly reflected survival; If the carcinoma invasion was limited to the muscularis mucosa, the ten-year survival rate was 50 percent. However, if invasion reached the submucosa, the tenyear survival dropped to 36.4 percent, which was not very different from musularis propria (25 percent) or invasion reaching the adventitia (22.5 percent) cases. This finding suggests that submucosa invasion is an indicator of advanced stage in esophageal carcinoma, and that treatment should be performed accordingly. Comparing patients with or without resection, the former had better survival. This indicates that patients with resectable tumor should undergo surgery. Among the resected cases, patients undergoing reconstruction had better survival than those without reconstruction in both curative and noncurative resection categories. There were long-term survivors among the patients who did not receive reconstructive surgery, and it is necessary to assess the patient's status in terms of whether reconstructive surgery is possible or not, because this is closely related to the patient's quality of life after surgery. In patients receiving resection surgery, the revised TNM classification" was examined in terms of correlation with survival. The tumor classification, based on the depth of invasion, clearly reflected the survival, as seen in Table 9. The T1 cases had 49.9 percent survival at five years and 36.1 percent at ten years. There is a clear difference of survival between each tumor group. There is also a statistically significant difference between lymph node classifications NO and NI. Because patients with metastases to more distant lymph nodes had definitely worse survival, there should be no objection to this being included in MI. In the metastasis category, there were some patients with MI classification who survived ten years. There remain some problems concerning the definition of M1 because M1 includes not only organ metastasis but also distant lymph node metastasis. Furthermore, staging based on the TNM classification correlated well with survival. The stage I group had 64.2 percent survival at five years and 48.0 percent at ten years. As the stage advanced from 1 to 4, the survival decreased with statistically significant differences. Radiation frequently is combined with surgery, including preoperative irradiation, but the survival rate was lower than for the nonirradiated group. This may be due to patient selection before treatment. Furthermore, the postoperative irradiation group had lower survival than the preoperative irradiation group. This result reflects the fact that mostly patients with lymph node metastasis received postoperative radiotherapy. To clarify this, we performed a cooperative randomized trial comparing preoperative and postoperative irradiation. In this trial, the postoperative radiation group had better survival than the preoperative radiation group. 8 In the preoperatively irradiated group of cases, those in which marked effect was observed on the resected specimen had better survival than those with only slight effect. Locally effective radiation therapy enhanced the survival after surgery. As seen in Table 8, the radiation therapy-alone group 1010 Ten-year Survivalof Resected Esophageal Carcinoma (/izuka et all
had worse survival than the surgery group, probably due to selectionbeforetreatment, since more patients in the advanced stage were included in this group. Randomized trials comparing surgery and radiation are necessary ACKNOWLEDGMENTS: Other members of the Registration Committee are as follows: Hiroshi Akiyama, M.D., Toranomon Hospital, Tokyo; Mituo Endo, Tokyo Medical and Dental College, Tokyo, Syozo Mori, Tohoku University, Sendai, japan; Kinichi Nabeya, Kyorin University, Tokyo; and Keizo Sugimati, Kyushu University, Fukuoka, japan. The authors are grateful to many japanese doctors participating in registration, and Mr. Shuzo Tanimoto, Registration Section of National Cancer Center, for preparing the data. They are also grateful to Associate Professor J. Patrick Barron of St. Marianna University School of Medicine for his review of the manuscript. REFERENCES 1 japanese Society for Esophageal Disease. Guidelines for clinical and pathologic studies on carcinoma of the esophagus. jap j Surg 1976; 6:69-86 2 Cutler S], Ederer F. Maximum utilization of the life table method in analyzing survival. J Chron Dis 1958; 8:699-712 3 International Union Against Cancer. TNM classification of malignant tumours. 4th fully revised ed. Berlin: Springer-Verlag, 1987 4 Earlam R, Cunha-Melo JR. Oesophagus squamous cell carcinoma, a critical review of surgery. Br Surg 1980; 64:457-61 5 Kinoshita Y, Nakayama K, Endo M, Sato H, et al. Evaluation of ten year survival after operation for upper and mid-thoracic esophageal cancer. Int Adv Surg Onco11978; 1:173-200 6 K'ai WY, Huang GJ. Surgical treatment. In: Huang cj, K'ai WY, eds. Carcinoma of the esophagus and gastric cardia. Berlin: Springer Verlag, 1984:275-84 7 Iizuka T, Akiyama H, Isono K, Endo M, Kakegawa T, Mori S, et al. A proposal for a new TN M classification for carcinoma of the esophagus. jap J Clin Oncol 1985; 14:625-36 8 Iizuka T, Ide H, Kakegawa T, Sasake K, Takagi I, Ando N, et al. Preoperative radioactive therapy for esophageal carcinoma, randomizedevaluation trial in eightinstitutions. Chest 1988; 93:1054 58 Heart Failure and Transplantation, 1990 A two-day symposium on heart failure and transplantation will be sponsored January 19-20 by UCLA Extension Health Sciences and the UCLA School of Medicine. The symposium will beheld at the Doubletree Hotel Marine Beach in Marina del Bey; California. For details, write UCLA Extension, PO Box 24901, Los Angeles 90024-0901 (213:825-9187). CHEST I 96 I 5 I NOVEMBER, 1989 1011