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Address for correspondence: Noriyoshi Sawabata, MD, PhD, Office of Japanese Joint Committee for Lung Cancer Registration, Osaka University Graduate School of Medicine, (L-5) 2-2 Yamadaoka, Suita, Osaka 565-0879, Japan
The Japan Lung Cancer Society, the Japanese Association for Chest Surgery, and the Japanese Respiratory Society jointly established the Japanese Joint Committee for Lung Cancer Registration, which has regularly conducted lung cancer registries for surgical cases in 5-year periods. We analyzed data obtained in these registries to reveal the most recent surgical outcomes and trends related to lung cancer surgery in Japan.
Using data from the registry in 2010 for cases of surgery performed in 2004, demographics, surgical results, and stage-specific prognoses were analyzed. In addition, trends for those parameters over 10 years were assessed.
The 5-year survival rate for all cases (n = 11,663, 7369 males, mean age 66.7 years) was 69.6%. The 5-year survival rates by c-stage and p-stage were as follow: IA, 82.0% (n = 6295) and 86.8% (n = 4978); IB, 66.8% (n = 2339) and 73.9% (n = 2552); IIA, 54.5% (n = 819) and 61.6% (n = 941); IIB, 46.4% (n = 648) and 49.8% (n = 848); IIIA, 42.8% (n = 1216) and 40.9% (n = 1804); IIIB, 40.3% (n = 90) and 27.8% (n = 106); and IV, 31.4% (n = 256) and 27.9% (n = 434), respectively. The percentages of female patients, cases with adenocarcinoma, stage I or II disease, and tumors sized less than 2 cm were increased, while those of operative and hospital deaths were decreased. Furthermore, the prognoses of all cases and cases in each stage improved over the decade.
In Japanese cases of lung cancer surgery, demographics, surgical results, and stage-specific prognoses changed over the 10-year study period, while the 5-year survival rate for surgical cases improved to 69.6% in 2004.
As such, it is crucial to understand the demographics, tumor-specific backgrounds, and prognoses by related factors and stage. In addition, elucidation of trends for those parameters is helpful to compose strategies for lung cancer treatment.
The Japan Lung Cancer Society, the Japanese Association for Chest Surgery, and the Japanese Respiratory Society jointly established the Japanese Joint Committee of Lung Cancer Registry (JJCLCR), which has regularly conducted nationwide registrations every 5 years for cases treated surgically, with the results of cases treated in 1994 and 1999 published in English in 1999 and 2004, respectively.
have been published. In addition to the regular registries, prospective enrollment and retrospective analyses of surgical and nonsurgical cases treated in 2002 were performed and the results published.
However, the investigated points regarding preoperative parameters are limited in that registry and fewer than those noted in the regular registry for surgical cases conducted every 5 years.
A new regular nationwide registry for lung cancer cases surgically treated in 2004 in Japan was conducted in 2010 by the JJCLCR. This registry investigated detailed tumor node metastasis (TNM) factors, thus it was possible to analyze the data using UICC-TNM ver. 7 (2009).
In this study, we analyzed data obtained by these registries to reveal the most recent surgical outcomes and trends related to lung cancer surgery in Japan.
PATIENTS AND METHODS
The JJCLCR conducted a retrospective observational study of patients who underwent surgery for lung cancer between January 1, 2004, and December 31, 2004. The committee asked the 605 teaching hospitals certified by the Japanese Board of General Thoracic Surgery to join the study, of which 253 (41.3%) participated. This registry was opened on January 1, 2010, and closed on June 31, 2010. In addition, 303 institutes (the number of invited institutes is unknown) participated in the registry for cases in 1994 that was performed in 2000, and 386 (75.2%) of 513 invited institutes participated in the registry for cases in 1999 that was performed in 2005.
The participating institutions took part in this registry by accessing a web site established by the JJCLCR, after receiving information that had been mailed to the 605 teaching hospitals. Each participating institute was sent a universal serial bus (USB) flash memory stick that contained software to be used for the registry. Each institute was authorized to use the registration form in the server located at the JJCLCR office after entering their ID and password, which was also mailed to the institution.
For these procedures, the JJCLCR used the secure sockets layer protocol for communication and digest (most reliable) certification, which was considered to be more secure than postal mail. The data sheet containing the patient's ID and registration no., used for anonymity in a linkable fashion, was kept in the USB flash memory stick and placed in a location that could be locked by each participating institution. In addition, each USB flash memory stick was coded with an individual serial key sent from the JJCLCR office and known only by the institution. The JJCLCR completed confirmation of participation in the registry by the end of 2009 and distributed the USB flash memory sticks to the institutions in 2009.
This registry followed the ethical guidelines for epidemiologic studies published jointly by the Japan Ministry of Science, Culture, and Education and the Japan Ministry of Health, Labor, and Welfare on June 17, 2002, which was revised on August 16, 2007. In addition, it was approved by the institutional review board of Osaka University Medical Hospital, where the registry office is located, after discussions published on August 13, 2009 (approval no. 09124).
Inclusion criteria were as follows: (1) pathological (including cytology findings) diagnosis of any type of lung cancer at a participating institution; (2) diagnosis obtained in 2004; and (3) treated by surgery. Patients with lung cancer recurrence or metastasis were excluded. The following points were investigated: (1) demographic background, (a) date of registry, (b) gender, (c) birth month and year, (d) date of diagnosis; (2) preoperative status, (a) Eastern Cooperative Oncology Group performance status (PS), (b) preoperative comorbidity, (c) smoking status, (d) status of serum tumor markers (CEA, SCC or CYFRA, SLX and NSE or Pro-GRP); (3) clinical T factors, (a) tumor size, (b) status of invasion at the main bronchus, (c) pleural invasion, (d) intrapulmonary metastasis, (e) status of pleural effusion, (f) status of atelectasis, (g) status of invaded organ; (4) clinical N factor (status of lymph nodes); (5) clinical M factor (metastasized organ); (6) surgery, (a) induction therapy, (b) operation, (c) place of tumor origin, (d) extent of lymph node removal, (e) gross curative status, (f) status of residual rumor, (g) lavage cytology findings, (h) combined resection; (7) postoperative morbidity; (8) tumor histology; (9) adjuvant therapy; (10) pathological T factors, (a) tumor size, (b) extent of bronchial involvement, (c) pleural invasion, (d) intrapulmonary metastasis, (e) status of pleural effusion, (f) pleural dissemination, (g) status of pleural effusion, (h) status of atelectasis, (i) status of invaded organ; (11) pathological N factor (status of removal of and metastasis to each lymph node); and (12) pathological M factor (metastasized organ). The extent of resection (exploration, R0, R1, or R2) was also registered.
Tumor size, detailed T factors, and lymph node status were classified using both UICC-TNM ver. 6 (1999)
For this classification, the #10 lymph node of the Naruke map was converted to #7 of UICC-TNM ver. 7 (2009). To comprehend demographic and prognostic alterations over a decade, data from the Japanese nationwide registries in 1994 and 1999 are also presented. The data quoted were taken from official reports of the JJCLCR published in 2002
Data from the submitted cases were stored and converted to excel files, which were transferred to a JJCLCR member biological statistician (E.M.), who independently reviewed the files for cases from 1994, 1999, and 2004. The follow-up period was defined as the time from the date of surgery to the latest follow-up examination. Survival period was defined as the number of months from the day of surgery to the day of death or the latest day of confirmed survival. Cases of death immediately after the operation were included. Survival curves were estimated according to the Kaplan-Meier method for the subsets clinical stage, pathological stage, sex, and histological subtype of tumor. Differences in survival were tested using the log-rank method. A p value less than 0.05 was considered to be statistically significant.
The number of registered cases was 11,663, which were provided by 253 institutions. Demographic backgrounds are shown in Table 1. In 2004, there were 7369 males and 4294 females registered, with a mean age of 66.7 years (range, 14–91), a follow-up period that ranged from 2 to 78 months (median, 58 months), and a percentage of PS 0 or 1 of 96.7%. The rates of female patients, mean age, and percentage of PS 0 or 1 showed increasing trends. As shown in Table 2, the most frequent tumor histology in 2004 was adenocarcinoma, followed by squamous cell carcinoma, although the ratio of adenocarcinoma was increasing and that of squamous cell carcinoma was decreasing. Induction chemotherapy was performed in 518 (4.4%) and adjuvant therapy in 2903 (24.9%) cases. The rate of anti-epidermal growth factor receptor is unknown, as it was not noted. The rate of R0 was 93.6% in 2004, 88.5% in 1999, and 80.4% in 1994. In addition, the 5-year survival rate (5-YSR) for each histology type improved. Moreover, the rate of small-sized tumor cases was also increasing, as the rates of tumors sized less than 1 and 2 cm were 9.1% and 36.9%, respectively (Table 3).
Clinical and pathological TNM factors based on UICC-TNM ver. 6 (1999) are shown in Table 4. In 2004, clinical T1 diseases comprised more than half of the cases, and the rate of clinical N0 disease was greater than 80%. Both showed increasing trends as compared with the 1999 results. Furthermore, a similar trend was shown in the pathological classification based on UICC-TNM ver. 6 (1999). Clinical and pathological stages based on UICC-TNM ver. 7 (2009) are shown in Table 5, while the distributions of clinical and pathological stages based on UICC-TNM ver. 6 (1999) and UICC-TNM ver. 7 (2009) are presented in Table 6. In 2004, the rate of clinical stage IA disease was greater than 50%, while that of pathological IA disease was less than 50%.
The trends for survival for all cases and each stage are also shown in Table 6. In 2004, the 5-YSR for all cases was 69.6%, which showed an improving trend for both total cases and each stage. The c-stage and p-stage (UICC-TNM ver. 7, 2009) specific 5-YSRs were as follows: IA, 82.0% (n = 6295) and 86.8% (n = 4978); IB, 66.8% (n = 2339) and 73.9% (n = 2552); IIA, 54.5% (n = 819) and 61.6% (n = 941); IIB, 46.4% (n = 648) and 49.8% (n = 848); IIIA, 42.8% (n = 1216) and 40.9% (n = 1804); IIIB, 40.3% (n = 90) and 27.8% (n = 106); and IV, 31.4% (n = 256) and 27.9% (n = 434), respectively (Table 7). The survival curves based on clinical and pathological stages determined with the modified UICC-TNM ver. 7 (2009) are shown in FIGURE 1, FIGURE 2, respectively. For clinical stage, there were no statistically significant differences between IIB and IIIA (p = 0.5), IIIA and IIIB (p = 0.7), IIB and IIIB (p = 0.5), and IIIB and IV (p = 0.08), whereas for pathological stage, there was no statistically significant difference between IIIB and IV (p = 0.9).
TABLE 7Stage Distribution and Specific Survival by Modified UICC-TNM ver. 7 (2009)
Ver. 7 2004
256 (2.2) 0 (0)
434 (3.7) 0 (0)
For the N classification, all 10 lymph nodes in the Naruke map were converted to 7 in UICC-TNM ver. 7 (2009).
Postoperative morbidity and mortality are shown in Table 8. In 2004, the rate of severe postoperative complications (greater than National Cancer Institute Common Toxicity Criteria grade 3) had decreased from the former registry in 1999. Furthermore, the rate of operation-related deaths showed a decreasing trend, as the percentage of operative deaths (death within 30 days after the operation) was 0.4% and that of hospital deaths was 0.4% in the 2004 registry.
In cases of lung cancer that underwent surgery in Japan, demographics and stage-specific prognoses changed in the decade studied. In that time period, the percentages for female patients, adenocarcinoma, small-sized tumors (<2 cm), and aged patients increased, whereas the rate of surgery-related deaths decreased to only 0.8%. With those changes, the 5-YSR in 2004 of all lung cancer patients who underwent surgery was 69.6%.
A retrospective study of a large number of surgical cases carried out by JJCLRC in 2004 showed that gender is a prognostic indicator.
A more detailed analysis using the same registry data showed that women with non-small cell lung cancer, especially with adenocarcinoma histology, had better survival than men and were more likely to have stage IA disease, which might account for their better prognosis.
Thus, the increase in number of females with adenocarcinoma may have contributed to the improvement of survival rate in the current JJCLCR registry.
Alteration of tumor size may also have contributed to survival in the JJCLCR registry. Tumor size itself is a prognostic factor, as that less than 2.0 cm was reported to be an indicator of good survival in N0M0 patients in the International Association for the Study of Lung Cancer staging project presented in 2007, in which the 5-YSR was 77%.
In the current Japanese registry of surgical cases treated in 2004, pathological findings showed that the ratio of tumors sized less than 2.0 cm was 36.9% and that of those less than 1.0 cm in size was 9.1%, which indicated a gradual increase from 1994 and might be attributable to recent widespread use of computed tomography in Japan.
The contribution of those changes to the prognosis of patients with lung cancer who undergo surgery must be carefully watched.
Regardless of the increasing number of patients older than 70 years, the postoperative mortality and morbidity rates improved in the recent registry of surgical cases in Japan. This improvement may be related to the increase in cases of small-sized early-stage lung cancer, which can be treated by less invasive surgery. Furthermore, the decrease in percentage of postoperative deaths may also contribute to the recent trend of good survival.
The results of the current registry of surgical cases treated in 2004 in Japan include data from selected educational hospitals that participated in the registry. However, clinical diagnosis methods have recently changed, including widespread use of PET-CT, thus selection bias and “Will Rogers phenomenon” should be considered. Nevertheless, the data presented here provide an important reference source, as a large number of patients were registered and analyzed.
The authors thank all of the contributors at the participating institutions and members of the working group of this registry; Dr. Haruhiko Kondo at Shizuoka Cancer Center, Shizuoka, Japan, Dr. Tatsuo Tanida at Iwate Medical University, Iwate, Japan, Dr. Morihito Okada at Research Institute for Radiation Biology and Medicine Hiroshima University, Hiroshima, Japan, Dr. Tsutomu Suzuki at Department of Respiratory Medicine, Juntendo University, Tokyo, Japan, and Dr. Tsuneo Shimokawa at Department of Respiratory Medicine, Nippon Medical School.
American College of Chest Physicians
Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition).