Masayuki Shinoda

Mutations of the Epidermal Growth Factor Receptor Gene Predict Prolonged Survival After Gefitinib Treatment in Patients With Non–Small-Cell Lung Cancer With Postoperative Recurrence

PURPOSE To evaluate the relationship between mutations of the epidermal growth factor receptor (EGFR) gene and the effectiveness of gefitinib treatment in patients with recurrent lung cancer after pulmonary resection. PATIENTS AND METHODS We sequenced exons 18-21 of the EGFR gene using total RNA extracted from 59 patients with lung cancer who were treated with gefitinib for recurrent lung cancer. Gefitinib effectiveness was evaluated by both imaging studies and change in serum carcinoembryonic antigen (CEA) levels. RESULTS EGFR mutations were found in 33 patients (56%). Of these mutations, 17 were deletions around codons 746-750 and 15 were point mutations (12 at codon 858, three at other codons), and one was an insertion. EGFR mutations were significantly more prevalent in females, adenocarcinoma, and never-smokers. Gefitinib treatment resulted in tumor shrinkage and/or CEA decrease to less than half of the baseline level in 26 patients, tumor growth and/or CEA elevation in 24 patients, and gefitinib effect was not assessable in nine patients. Female, never-smoking patients with adenocarcinoma tended to respond better to gefitinib treatment. Gefitinib was effective in 24 of 29 patients with EGFR mutations, compared with two of 21 patients without mutations (P < .0001). Of note, del746-750 might be superior to L858R mutations for prediction of gefitinib response. Patients with EGFR mutations survived for a longer period than those without the mutations after initiation of gefitinib treatment (P = .0053). CONCLUSION EGFR mutations were a good predictor of clinical benefit of gefitinib in this setting.

Surgery Plus Chemotherapy Compared With Surgery Alone for Localized Squamous Cell Carcinoma of the Thoracic Esophagus: A Japan Clinical Oncology Group Study—JCOG9204

PURPOSE We performed a multicenter randomized controlled trial to determine whether postoperative adjuvant chemotherapy improves outcome in patients with esophageal squamous cell carcinoma undergoing radical surgery. PATIENTS AND METHODS Patients undergoing transthoracic esophagectomy with lymphadenectomy between July 1992 and January 1997 at 17 institutions were randomly assigned to receive surgery alone or surgery plus chemotherapy including two courses of cisplatin (80 mg/m2 of body-surface area x 1 day) and fluorouracil (800 mg/m2 x 5 days) within 2 months after surgery. Adaptive stratification factors were institution and lymph node status (pN0 versus pN1). The primary end point was disease-free survival. RESULTS Of the 242 patients, 122 were assigned to surgery alone, and 120 to surgery plus chemotherapy. In the surgery plus chemotherapy group, 91 patients (75%) received both full courses of chemotherapy; grade 3 or 4 hematologic or nonhematologic toxicities were limited. The 5-year disease-free survival rate was 45% with surgery alone, and 55% with surgery plus chemotherapy (one-sided log-rank, P =.037). The 5-year overall survival rate was 52% and 61%, respectively (P =.13). Risk reduction by postoperative chemotherapy was remarkable in the subgroup with lymph node metastasis. CONCLUSION Postoperative adjuvant chemotherapy with cisplatin and fluorouracil is better able to prevent relapse in patients with esophageal cancer than surgery alone.

A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: The Japan clinical oncology group study

OBJECTIVE To determine whether postoperative adjuvant chemotherapy confers a survival benefit on patients with esophageal squamous cell carcinoma undergoing radical surgery, we undertook a cooperative, prospective randomized controlled trial. METHODS A total of 205 patients underwent transthoracic esophagectomy with lymphadenectomy at eleven institutions between December 1988 and July 1991. These patients were prospectively randomized into two groups (100 patients underwent surgery alone and 105 patients had additional two courses of combination chemotherapy with cisplatin (70 mg/m2) and vindesine (3 mg/m2). The two groups did not differ with respect to sex, age, location of tumor, and distributions of pT, pN, pM, or p stage. RESULTS The 5-year survival was 44.9% in the surgery alone group and 48.1% in the surgery plus chemotherapy group. The relative risk was estimated to be 0.89 (95% confidence interval, 0.61 to 1.31) in the surgery plus chemotherapy group compared with the surgery alone group. No significant differences in survival were detected between the two groups, even with lymph node stratification. CONCLUSION Postoperative adjuvant chemotherapy with cisplatin and vindesine has no additive effect on survival in patients with esophageal cancer compared with surgery alone.

Comprehensive Registry of Esophageal Cancer in Japan, 2009

These data were first made available on January 2016, as the Comprehensive Registry of Esophageal Cancer in Japan, 2009. Not all the tables and figures are reprinted here. The authors were members of the Registration Committee for Esophageal Cancer, the Japan Esophageal Society, and made great contributions to the preparation of this material.

A Phase II Trial of Chemoradiotherapy for Stage I Esophageal Squamous Cell Carcinoma: Japan Clinical Oncology Group Study (JCOG9708)

OBJECTIVE The study objective was to evaluate the efficacy and toxicity of chemoradiotherapy with 5-fluorouracil (5-FU) plus cisplatin in patients with Stage I esophageal squamous cell carcinoma (ESCC). The primary endpoint was proportion of complete response (%CR). METHODS Patients with Stage I (T1N0M0) ESCC, aged 20-75 years, without indication of endoscopic mucosal resection were eligible. Treatment consisted of cisplatin 70 mg/m(2) (day 1) and 5-FU 700 mg/m(2)/day (days 1-4) combined with 30 Gy radiotherapy (2 Gy/day, 5 days/week, days 1-21). The cycle was repeated twice with 1-week split. Salvage surgery was recommended for residual tumor or local recurrence. RESULTS From December 1997 to June 2000, 72 patients were enrolled. No ineligible patient or major protocol violation was observed. There were 63 CRs for %CR of 87.5% [95% confidence interval (CI): 77.6-94.1]. Six patients with residual tumor successfully underwent esophagectomy. There was no Grade 4 toxicity. Four-year survival proportion was 80.5% (95% CI: 71.3-89.7), and 4-year major relapse-free survival proportion was 68% (95% CI: 57.3-78.8) (mucosal recurrence removed by endoscopy was not counted as an event). CONCLUSIONS High CR proportion and survival proportion with mild toxicity suggest that this regimen could be considered as a candidate of new standard treatment to be compared with surgery in patients with Stage I ESCC.

NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T polymorphism and the risk of eight cancers for Japanese.

AbstractMethods. The cases were 102 patients with esophageal cancer, 143 with stomach cancer, 74 with colon cancer, 72 with rectal cancer, 192 with lung cancer, 237 with breast cancer, 56 with prostate cancer, and 108 with malignant lymphoma. Controls consisted of outpatients from two sources: 241 noncancer outpatients who underwent gastroscopy and 399 first-visit outpatients, expected to include about 20% with cancer. Genotyping was conducted by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). Results. The TT genotype with null enzyme activity was found in 19.9% of the 241 noncancer gastroscopy examinees, 16.5% of the 399 first-visit outpatients, 12.7% of the esophageal cancer patients, 16.8% of the stomach cancer patients, 13.5% of the colon cancer patients, 9.7% of the rectal cancer patients, 17.7% of the lung cancer patients, 14.3% of the breast cancer patients, 16.1% of the prostate cancer patients, and 15.7% of the malignant lymphoma patients. The odds ratios (ORs) of the genotypes were not significant for any cancers combined or for any site of cancer, except for lung cancer (OR, 0.66; 95% confidence interval [CI], 0.46–0.96 for CT relative to CC). The OR of current smoking for cancers of the esophagus and lung combined was different between the CC genotype (OR, 2.06; 95% CI, 1.06–3.98) and TT genotype (OR, 5.11; 95% CI, 1.37–19.05), although the difference was not significant. Conclusion. This study suggests that the CC genotype of the NQO1 C609T polymorphism is associated with the risk of lung cancer, and that the TT genotype increases the risk of smoking for cancers of the esophagus and lung.

No associations of p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro polymorphisms with the risk of digestive tract cancers in Japanese

A case-control study was conducted to examine the possible association between digestive tract cancers and p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro polymorphisms in Japanese. Cases were 102 esophageal cancer patients, 144 stomach cancer patients, and 147 colorectal cancer patients, and controls were 241 non-cancer outpatients. The genotype frequencies among controls were 55.3% for p73 GG at position 4, 40.4% for GA, and 4.3% for AA, and 37.7% for p53 ArgArg, 44.4% for ArgPro, and 18.0% for ProPro. No significant differences in the genotype frequencies were observed between the controls and each case group or cases as a whole.

Evaluation of the accuracy of preoperative staging in thoracic esophageal cancer.

BACKGROUND Exact clinical staging before treatment of esophageal cancer has become increasingly important in the evaluation and comparison of the results of different treatment modalities, including surgery, chemotherapy, and radiotherapy. METHODS The accuracy of preoperative tumor staging by using an esophagography, esophagoscopy, percutaneous and endoscopic ultrasonography, and computed tomography was assessed in 224 patients with resectable esophageal cancer. The results of tumor staging by these tests were compared prospectively with the pathologic stage of the esophagectomy specimens with respect to the T and N categories defined by the International Union Against Cancer TNM classification. RESULTS For the T category, the overall accuracy was 80%. For the N category, overall accuracy was 72%, with a sensitivity of 78%, a specificity of 60%, and a positive predictive value of 78%. Overall, the accuracy of stage grouping was 56%. CONCLUSIONS Either the T or N categories can be predicted reliably by clinical staging techniques. However, the preoperative stage grouping might not be valid in resectable, localized esophageal cancer.

Association of a polymorphism of the phospholipase D2 gene with the prevalence of colorectal cancer

Phospholipase D plays an important role in transmembrane signaling in a variety of cell types and its activity is increased in certain cancers, suggesting that it also contributes to tumorigenesis. A C→T transition at nucleotide 1814 of the human phospholipase D2 gene, which results in a Thr→Ile substitution at amino acid 577, was noted in the GenBank database. The relationship of this polymorphism to the prevalence of cancer of the esophagus, stomach, colon-rectum, lung, and breast in Japanese was investigated in a case-control study. The genotype of the phospholipase D2 gene was determined by the polymerase chain reaction with confronting two-pair primers. Multivariate logistic regression analysis with adjustment for age, gender, and smoking status revealed that the frequency of the T allele of the 1814C→T polymorphism was significantly higher in individuals with colorectal cancer than in controls. A significant association of the polymorphism with the prevalence of colorectal cancer was found in analyses assuming either dominant (TT+CT vs. CC) or additive (CT vs. CC) effects of the T allele, but the T allele was not associated with the prevalence of esophageal, gastric, lung, or breast cancer. The activities of phospholipase D in cell lysates or membrane fractions did not differ between cells transfected with cDNAs encoding the Thr-577 or Ile-577 variants of phospholipase D2. These results suggest that the phospholipase D2 gene is a susceptibility locus for colorectal cancer in Japanese individuals, although a functional effect of the 1814C→T (Thr577Ile) polymorphism was not detected.

Subsite-specific risk factors for hypopharyngeal and esophageal cancer (Japan).

AbstractObjectives: To clarify subsite-specific risk factors for hypopharyngeal and esophageal cancers (HC and EC), we concluded a hospital-based case–referent study in Nagoya, Japan. Methods: Subjects comprised 346 male cases with cancer of the hypopharynx (n = 62) or esophagus (upper [U-EC] 53, middle [M-EC] 159, lower [L-EC] 72), and 11,936 male referents free from cancer among first-visit outpatients aged 40–79 years in 1988–1997. Of histological confirmed cases, 93% comprised squamous cell carcinoma. Odds ratios (ORs) were estimated by a logistic regression model with adjustment for potential confounding factors. Results: Cigarette smoking increased the OR for M-EC, and alcohol drinking elevated the ORs for all subsites. The trend of ORs for combined cases of M- and L-EC tended to increase with number of cigarettes (p = 0.056), and a decreasing trend of the ORs was found with years after quitting smoking (p = 0.006). The ORs for smoking with drinking were multiplicatively greater than those for smoking or drinking in combined cases of HC and EC. In contrast, daily raw vegetable consumption lowered the ORs for all subsites. Conclusions: This study suggests that the magnitude of risk with smoking is stronger for M-EC within the esophagus, and drinking increases the risk at any subsite.