Yoshihiko Koshiishi

A Japanese Lung Cancer Registry Study: Prognosis of 13,010 Resected Lung Cancers

Purpose: The validation of tumor, node, metastasis staging system in terms of prognosis is an indispensable part of establishing a better staging system in lung cancer. Methods: In 2005, 387 Japanese institutions submitted information regarding the prognosis and clinicopathologic profiles of patients who underwent pulmonary resections for primary lung neoplasms in 1999 to the Japanese Joint Committee of Lung Cancer Registry. The data of 13,010 patients with only lung carcinoma histology (97.6%) were analyzed in terms of prognosis and clinicopathologic characteristics. Results: The 5-year survival rate of the entire group was 61.4%. For the small cell histology (n = 390), the 5-year survival rates according to clinical (c) and pathologic (p) stages were as follows: 58.8% (n = 161) and 58.3% (n = 127) for IA, 58.0% (n = 77) and 60.2% (n = 79) for IB, 47.1% (n = 17) and 40.6% (n = 29) for IIA, 25.3% (n = 38) and 41.1% (n = 29) for IIB, 29.0% (n = 61) and 28.3% (n = 60) for IIIA, 36.3% (n = 19) and 34.6% (n = 40) for IIIB, and 27.8% (n = 12) and 30.8% for IV (n = 13). For the non-small cell histology (n = 12,620), the 5-year survival rates according to c-stage and p-stage were as follows: 77.3% (n = 5642) and 83.9% (n = 4772) for IA, 59.8% (n = 3081) and 66.3% (n = 2629) for IB, 54.1% (n = 205) and 61.0% (n = 361) for IIA, 43.9% (n = 1227) and 47.4% (n = 1330) for IIB, 38.3% (n = 1628) and 32.8% (n = 1862) for IIIA, 32.6% (n = 526) and 29.6% (n = 1108) for IIIB, and 26.5% (n = 198) and 23.1% (n = 375) for IV. Adenocarcinoma, female gender, and age less than 50 years were significant favorable prognostic factors. Conclusion: This large registry study provides benchmark prognostic statistics for lung cancer. The prognostic difference between stages IB and IIA was small despite different stages. Otherwise, the present tumor, node, metastasis staging system well characterizes the stage-specific prognoses.

Pulmonary Resection in Patients Aged 80 Years or Over with Clinical Stage I Non-small Cell Lung Cancer: Prognostic Factors for Overall Survival and Risk Factors for Postoperative Complications

Introduction: This retrospective study was designed to identify the predictors of long-term survival and the risk factors for complications after surgery in patients aged 80 years or older with clinical (c)-stage I non-small cell lung cancer. Methods: The Japanese Joint Committee of Lung Cancer Registry collated the clinicopathological profiles and outcomes of 13,344 patients who underwent pulmonary resection for primary lung cancer in 1999. The data of 367 patients aged 80 years or older with c-stage I non-small cell lung cancer were analyzed for prognostic factors and risk factors for postoperative complications. Results: The median age was 82 years (range, 80-90 years). Of the total patient number, 102 (27.8%) had some form of comorbidity diagnosed preoperatively. Thirty-one (8.4%) patients presented with postoperative complications, and the operative mortality was 1.4%. The 5-year survival rates were 55.7% for c-stage I patients, 62.0% for c-stage IA, and 47.2% for c-stage IB. Advanced pathologic stage and comorbidity were significant independent predictors of shortened survival (p < 0.0001 and p = 0.032, respectively). Comorbidity and mediastinal lymph node dissection were identified as factors that increased the risk of postoperative complications (p < 0.0001 and p = 0.036, respectively). Survival rates were independent of the extent of pulmonary resection (lobectomy or limited resection). Conclusions: Octogenarian patients with c-stage I lung cancer in this study had a satisfactory long-term outcome and low-mortality rate. Comorbidity is a factor associated with both prognosis and operative risks. A selection of the patients who would be curable without mediastinal lymph node dissection after an accurate preoperative staging is beneficial to decrease the postoperative complications because this procedure is a risk factor.

Japanese Lung Cancer Registry Study: First Prospective Enrollment of a Large Number of Surgical and Nonsurgical Cases in 2002

Purpose: To investigate prognoses of lung cancer patients prospectively enrolled in the Japan Lung Cancer Registry Study. Methods: Patients newly diagnosed as having lung cancer exclusively in 2002 were enrolled. Follow-up surveys were performed twice, in 2004 and 2009, and the final follow-up data with prognoses were analyzed for 14,695 patients (79%). Clinical stages were defined according to the sixth edition of the International Union Against Cancer-tumor, node, metastasis classification (2002). Results: The mean age was 67.1 years (range, 18-89 years), and there were 10,194 men (69.3%) and 4315 women (29.7%). The most frequent histology was adenocarcinoma (n = 8325, 56.7%), followed by squamous cell carcinoma (n = 3778, 26%) and small cell carcinoma (n = 1345, 9.2%). The distribution of clinical stages was as follows: IA, 4245 cases (29.3%); IB, 2248 (14.5%); IIA, 208 (1.4%); IIB, 918 (6.3%); IIIA, 1700 (11.8%); IIIB, 2110 (16.3%); and IV, 3037 (21.0%). The 5-year survival rates were 44.3% for all patients, 46.8% for those with non-small cell lung cancer, and 14.7% for those with small cell lung cancer. According to the clinical stage of non-small cell lung cancer and small cell lung cancer, the 5-year survival rates were 79.4 and 52.7% for stage IA, 56.9 and 39.3% for IB, 49.0 and 31.7% for IIA, 42.3 and 29.9% for IIB, 30.9 and 17.2% for IIIA, 16.7 and 12.4% for IIIB, and 5.8 and 3.8% for IV, respectively. Conclusion: Analysis of a large cohort in the Japanese registry study found that stage-specific prognosis was within a range similar to other reports. The data presented should provide an important reference for future clinical trials in Japan.

Abnormalities of epidermal growth factor receptor in lung squamous-cell carcinomas, adenosquamous carcinomas, and large-cell carcinomas: tyrosine kinase domain mutations are not rare in tumors with an adenocarcinoma component.

Tyrosine kinase domain (TKD) gene mutations of the epidermal growth factor receptor gene (EGFR) have proven to be clinically significant in nonsmall‐cell lung cancer (NSCLC), particularly in adenocarcinoma. However, TKD mutations together with deletion mutations in the extracellular domain of EGFR (EGFRvIII) have not been fully investigated in NSCLC except for adenocarcinoma. The present study sought to gain further insight into the significance of EGFR mutations in NSCLC by focusing on nonadenocarcinoma NSCLC.

Visceral Pleura Invasion Impact on Non-small Cell Lung Cancer Patient Survival: Its Implications for the Forthcoming TNM Staging Based on a Large-Scale Nation-Wide Database

Introduction: No analyses have been reported on the impact of visceral pleura invasion (VPI) on staging, in relation with the International Association for the Study of Lung Cancer proposals for the 7th edition of the tumor, node, metastasis (TNM) classification of the International Union Against Cancer staging system. The purpose of this study was to evaluate the impact of VPI on survival and propose a method of incorporating VPI status into the TNM classification. Methods: We reviewed the data on 9758 non-small cell lung cancer patients, who underwent anatomic surgical resection in 1999, accumulated by the Japanese Joint Committee for Lung Cancer Registration, to gain insight into their clinicopathologic characteristics and outcomes. VPI was defined as tumor extension beyond the elastic layer of the visceral pleura. Patients were divided into nine groups according to VPI status and tumor diameter, in accordance with the International Association for the Study of Lung Cancer proposals. Results: On the basis of survival, the nine groups were divided into the following five levels: tumors ≤2 cm without VPI; tumors ≤2 cm with VPI and tumors 2.1 to 3 cm without VPI; tumors 2.1 to 3 cm with VPI and tumors 3.1 to 5 cm without VPI; tumors 3.1 to 5 cm with VPI and tumors 5.1 to 7 cm without VPI; and tumors 5.1 to 7 cm with VPI and tumors >7 cm without VPI or T3 tumors. Conclusions: The T status of tumors, 7 cm or less, with VPI should be upgraded to the next T level in the future edition of the TNM classification of International Union Against Cancer staging system.

Clinico-Pathological and Biological Significance of Tyrosine Kinase Domain Gene Mutations and Overexpression of Epidermal Growth Factor Receptor for Lung Adenocarcinoma

Introduction: Mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) gene have proven to be clinically significant in non-small cell lung cancer. However, relationships between these mutations and EGFR expression or deletion mutations in the extracellular domain of EGFR (EGFRvIII) remain unclear. The purpose of this study was to gain further insight into the clinical significance of these molecular abnormalities in lung adenocarcinoma. Methods: We investigated EGFR TKD mutations using direct sequencing, EGFR protein expression using Western blotting, and EGFRvIII using reverse transcriptase–polymerase chain reaction in samples from 48 adenocarcinoma patients. Correlations with various clinico-pathological features were analyzed. Results: EGFR TKD mutations were detected in 25 of 48 adenocarcinomas (52.1%), and overexpression of EGFR protein was identified in 19 patients (39.6%). Presence of EGFR TKD mutations was significantly correlated with EGFR overexpression (p = 0.021). EGFR TKD mutations were significantly correlated with never-smoker status (p = 0.043), absence of emphysematous or fibrotic appearance on computed tomography (p = 0.001), papillary subtype (p = 0.041), and bronchioloalveolar carcinoma features (p = 0.045). EGFRvIII was not detected in any adenocarcinomas. Retrospective analysis revealed that patients with EGFR TKD mutations displayed better postoperative prognosis than patients with wild-type EGFR (p = 0.033). Conclusions: These results suggest that EGFR TKD mutation is associated with EGFR overexpression, representing an important factor for consideration when investigating the clinical significance, including susceptibility to chemotherapy, of EGFR TKD mutations in adenocarcinoma. EGFRvIII does not seem to play a major role in the development of lung adenocarcinoma.

Improvements in surgical results for lung cancer from 1989 to 1999 in Japan.

Background: In 1986, Japanese Association for Thoracic Surgery started a nationwide survey of the number of primary lung cancer undergoing resection and this survey was continued annually. Thereafter, investigations of lung cancer surgical results have been conducted three times. The postoperative overall 5-year survival rate was 47.8% in resected cases in 1989, 52.3% in 1994, and 62.0% in 1999, showing improvement over the decade (p < 0.01). Objective: To clarify the factors influencing survival improvements retrospectively. Patients and Methods: The subjects of the investigation are the patients who underwent resection for primary lung cancers in 1989, 1994, and 1999. Postoperatively, after 5 years, surveys of surgical results were sent to institutes where lung cancer resection had been performed. The subjects undergoing resection who provided 10 items (age, sex, pathologic T factor, pathologic N factor, pathologic M factor, date of resection, histology, curability, prognosis, and survival time) numbered 3004 in 1989, 6895 in 1994, and 12,235 in 1999. They were classified according to the Union International Contre le Cancer 1997 revised tumor, node, and metastasis classification. Differences in age, gender, histology, pathologic stage, curability, and operative death rates were analyzed for each survey year. Results: According to the changes in proportions, the cases over 70 years of age, women, and pathologic stage I increased significantly (p < 0.001), whereas in cases with small cell lung cancer, incomplete resection and operative death decreased significantly over time (p < 0.001). Conclusion: The postoperative 5-year survival rate in Japan improved between 1989 and 1999. The main cause of this improvement was the increase in early stage lung cancer, especially cases with tumors 2 cm or less in size.

Clinical significance of pleural lavage cytology for non-small cell lung cancer: is surgical resection valid for patients with positive pleural lavage cytology?

The purpose of the present study was to retrospectively analyze the clinicopathological characteristics and clarify the validity of surgical resection for patients with positive pleural lavage cytology (PLC). Between 1993 and 2006, 563 patients who underwent complete surgical resection for primary non-small cell lung cancer and who were examined with regard to PLC were retrospectively analyzed. Forty-two patients (7.2%) showed positive PLC. The 5-year survival rates were 65.0% and 33.5% for patients with negative and positive PLC, respectively. The 5-year survival rates for patients with positive PLC were 57.1%, 50.8%, 40.0%, and 0% for pathological stage I, II, IIIA, and IIIB, respectively. Multivariate analysis revealed that preoperative carcinoembryonic antigen (CEA) level, PLC, vascular invasion, lymphatic permeation, and pathological stage were independent prognostic factors. The 5-year survival rate for the patients with a high CEA level and positive PLC was 0%. Intrathoracic recurrence was observed more frequently in patients with positive PLC. PLC was an independent prognostic factor. While positive PLC alone may not be a contraindication for surgical resection, patients who are complicated with a high CEA level preoperatively should receive special attention since no long-term survivors were observed.

The influence of relative body weight on toxicity of combination chemotherapy with cisplatin and etoposide.

Purpose: This study was conducted to determine whether there was any relationship between the adverse toxicity of combination chemotherapy and clinical values including age, sex, creatinine clearance (Ccr), body surface area and relative body weight. Methods: Cisplatin at a dose of 80 mg/m2 on day 1 and etoposide at a dose of 100 mg/m2 on days 1, 2 and 3 were given to 42 consecutive patients with solid tumors. All patients had normal major organ function and received uniform hydration therapy. Results: Body Mass Index as a measure of relative body weight was inversely correlated with the percentage decrease in white blood cells (P = 0.0681) and platelet count (P = 0.0115). Body surface area was also inversely correlated with leukopenia (P = 0.0171) and thrombocytopenia (P = 0.0058). In contrast, age, sex and Ccr had no significant relationship with adverse toxicity. Conclusions: It is concluded that dose adjustment of combination chemotherapy with cisplatin and etoposide according to age or ideal body weight is not appropriate and that a conventional dose modification method based solely on body surface area is probably not sufficient to reduce interpatient variability of cancer chemotherapy. A pharmacokinetic and pharmacodynamic study of combination chemotherapy is warranted to establish the ideal dose modification method.

Clinical significance of preoperative carcinoembryonic antigen level for clinical stage I non-small cell lung cancer: can preoperative carcinoembryonic antigen level predict pathological stage?

The purpose of the present study was to retrospectively analyze the clinicopathological characteristics and clarify whether or not the preoperative carcinoembryonic antigen (CEA) level could be used as a decision-making factor as an adjunct to the TNM staging system in patients with clinical stage I non-small cell lung cancer (NSCLC). Between 1993 and 2006, 815 patients who had clinical stage I NSCLC were analyzed retrospectively. The CEA level was defined as being either normal (CEA<or=5 ng/ml), high (530 ng/ml) sub-groups. The rate of patients with an elevated CEA level was 33.6%. The five-year disease-free survival rates for patients with normal, high and very high CEA levels were 76.7, 60.0 and 31.3%, respectively. The survival curve for patients with a normal CEA level almost overlapped that for p-stage I, that for a high CEA level nearly overlapped that for p-stage II, and that for a very high CEA level nearly overlapped that for p-stage III. The present study demonstrated that the preoperative CEA level was a very good predictor of the pathological stage. These findings suggest that the preoperative CEA level may be useful as an adjunct to the TNM staging system.