Takeshi Horai

Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSEnTo evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC).nnnPATIENTS AND METHODSnThis was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomly assigned to receive either 250-mg or 500-mg oral doses of gefitinib once daily.nnnRESULTSnEfficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively.nnnCONCLUSIONnGefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC [corrected]

LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment With Erlotinib, Gefitinib, or Both

PURPOSEnNew molecular targeted agents are needed for patients with non-small-cell lung cancer (NSCLC) who progress while receiving erlotinib, gefitinib, or both. Afatinib, an oral irreversible ErbB family blocker, has preclinical activity in epidermal growth factor receptor (EGFR [ErbB1]) mutant models with EGFR-activating mutations, including T790M.nnnPATIENTS AND METHODSnThis was a Japanese single-arm phase II trial conducted in patients with stage IIIB to IV pulmonary adenocarcinoma who progressed after ≥ 12 weeks of prior erlotinib and/or gefitinib. Patients received afatinib 50 mg per day. The primary end point was objective response rate (complete response or partial response) by independent review. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.nnnRESULTSnOf 62 treated patients, 45 (72.6%) were EGFR mutation positive in their primary tumor according to local and/or central laboratory analyses. Fifty-one patients (82.3%) fulfilled the criteria of acquired resistance to erlotinib and/or gefitinib. Of 61 evaluable patients, five (8.2%; 95% CI, 2.7% to 18.1%) had a confirmed objective response rate (partial response). Median PFS was 4.4 months (95% CI, 2.8 to 4.6 months), and median OS was 19.0 months (95% CI, 14.9 months to not achieved). Two patients had acquired T790M mutations: L858R + T790M, and deletion in exon 19 + T790M; they had stable disease for 9 months and 1 month, respectively. The most common afatinib-related adverse events (AEs) were diarrhea (100%) and rash/acne (91.9%). Treatment-related AEs leading to afatinib discontinuation were experienced by 18 patients (29%), of whom four also had progressive disease.nnnCONCLUSIONnAfatinib demonstrated modest but noteworthy efficacy in patients with NSCLC who had received third- or fourth-line treatment and who progressed while receiving erlotinib and/or gefitinib, including those with acquired resistance to erlotinib, gefitinib, or both.

Oat‐cell carcinoma of the lung. Clinical and morphological studies in relation to its histogenesis

Twenty‐four cases of oat‐cell carcinoma of the lung and four cases of bronchial carcinoid tumor were studied electron microscopically. Determinations of serotonin in serum and tissue were performed on these cases, and ACTH was assayed in the tumor tissue of seven cases. Neurosecretory‐type granules were usually observed in the tumor cells, and they were found concentrated in the pseudopod‐like cytoplasmic processes. Serotonin levels in serum and tumor tissue of these cases were frequently elevated and seemed to correlate to the number of neurosecretory‐type granules in tumor cells. In five out of seven cases of oat‐cell carcinoma, ACTH and serotonin were simultaneously detected in the tumor tissue. In 139 cases of other types of lung cancer, these granules were not observed, and either serotonin level or ACTH activity was not elevated in the tumor. These results strongly suggest that oat‐cell carcinoma is a special type of lung tumor producing neurosecretory‐type granules and also that it is a highly malignant variant of bronchial carcinoid tumor developing from Kulchitsky‐type cells found in bronchial glands.

Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer.

PURPOSEnThis multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC).nnnMETHODSnChemonaïve patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS).nnnRESULTSnAfter confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p=0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p=0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p=0.9526). No new safety signals were detected.nnnCONCLUSIONnStudy JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338).

Correlation between morphology and EGFR mutations in lung adenocarcinomas Significance of the micropapillary pattern and the hobnail cell type.

The presence of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) mutations significantly correlates with tumor sensitivity to TK inhibitors, particularly in lung adenocarcinomas, the predominant histological subtype in Japan and the United States. To clarify links between EGFR mutations and pathological findings in Japanese lung cancer, detailed pathological features of adenocarcinomas were examined using the WHO criteria as well as our cell type classification (hobnail, columnar and polygonal). Medical records were reviewed for a total of 107 surgically resected tumors. Clinicopathological factors were examined and correlations with EGFR status were evaluated. EGFR mutations were found in 63 patients (59%) distributed through all four exons examined (through exons 18-21). EGFR mutations were significantly associated with female gender (P=0.003), non-smoker status (P=0.008) and hobnail cell morphology (P<0.00001). In addition, detailed pathological examination showed significant associations with bronchioloalveolar carcinoma (BAC) component and a micropapillary pattern (MPP) (P=0.012 and 0.043, respectively). We conclude that characteristic histological features, i.e. the hobnail cell morphology and the presence of BAC component and MPP are good predictors of EGFR mutations in lung adenocarcinoma.

Bronchial brushing and bronchial biopsy: comparison of diagnostic accuracy and cell typing reliability in lung cancer.

A total of 443 patients with lung cancer underwent brush and forceps biopsy through a fibreoptic bronchoscope. The biopsy was taken from the area of suspected malignancy which had been brushed. Of 443 patients, 400 (90.3%) showed positive results on brushing and 287 (64.8%) on biopsy. A combination of both techniques yielded the highest percentage of positive diagnosis (93.7%). Histologically, there was a high incidence of positive diagnosis for squamous and small cell carcinoma. One hundred and three (83.7%) of 123 specimens obtained by brushing and 75 (81.5%) of 92 specimens obtained by biopsy agreed with the cell type found in the surgical or necropsy specimen. Cell typing accuracy was higher in squamous and in small cell carcinoma in both techniques. As the cell typing accuracy of the two methods is similar, the results obtained by both techniques should be taken into consideration in the management of individual cases of lung cancer.

A cytologic study on small cell carcinoma of the esophagus

The cytologic picture of small cell carcinoma primarily arising from the esophagus was studied with 7 cases which were confirmed by histologic examination. Cytomorphologic characteristics of small cell carcinoma of the esophagus are as follows: the arrangement of groups of tumor cells is irregular and overlapping with indistinct cell boundaries. The cytoplasm is small, or sometimes absent. The nuclei are round, oval or occasionally spindle shaped. Nuclear borders are thin. The chromatin of finely granular pattern has increased and is evenly distributed.

Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer

Background:This dose-finding study evaluated lenvatinib, an oral multitargeted receptor tyrosine kinase inhibitor, in combination with carboplatin/paclitaxel in chemotherapy-naïve non-small-cell lung cancer (NSCLC) patients.Patients and Methods:Patients received lenvatinib twice daily (BID) with carboplatin (area under the curve 6u2009mgu2009ml−1u2009min−1, day 1)/paclitaxel (200u2009mgu2009m−2, day 1) every 3 weeks. The initial dose of lenvatinib was 6u2009mg BID. The primary end point was maximum tolerated dose (MTD) of lenvatinib. At the MTD, the cohort was expanded by 16 patients. Safety, pharmacokinetics, pharmacodynamics, and antitumor effects were evaluated.Results:Twenty-eight patients were treated. At 6u2009mg BID, dose-limiting toxicities (DLTs) included febrile neutropenia/gingival infection (n=2). No DLTs occurred with 4u2009mg BID, the recommended MTD for the expansion. Common grade 3/4 toxicities included neutropenia, leukopenia, hypertension, and thrombocytopenia. The combination had no significant impact on individual drug pharmacokinetics. Response rate and median progression-free survival were 68% and 9.0 months, respectively, with 4u2009mg BID. In the plasma biomarker analysis, stromal cell-derived factor 1α, stem cell factor, and granulocyte colony-stimulating factor correlated with antitumor activity.Conclusion:The MTD for lenvatinib with carboplatin/paclitaxel is 4u2009mg BID in advanced NSCLC patients. This regimen demonstrated manageable tolerability and encouraging antitumor activity.

Glycosaminoglycan in malignant pleural mesothelioma.

The quantitative analysis on glycosaminoglycan (GAG) in the tumor tissues of five patients with malignant pleural mesothelioma and in the pleural fluid of two patients was performed with the use of biochemical methods. In the tumor tissues, it was found that the average of the total amount of GAG was more than 7.9 times as high as that in adenocarcinoma of the lung, and that hyaluronic acid and chondroitin sulfate were main constituents of mesothelioma GAG. However, there was no significant difference in the content of dermatan sulfate and heparan sulfate between this neoplasm and adenocarcinoma. In the pleural fluid, the amount of hyaluronic acid was about 40 to 230 times higher than that in adenocarcinoma of the lung with the increment of chondroitin sulfate (11–87 times). These findings suggest that a marked increase in the total amount of GAG and the elevation of either the hyaluronic acid or the chondroitin sulfate level, or both, are characteristic abnormalities in malignant pleural mesothelioma.

Factors exacerbating peripheral neuropathy induced by paclitaxel plus carboplatin in non-small cell lung cancer.

No established supportive therapy to prevent and treat chemotherapy-induced peripheral neuropathy (PN) is available. Minimizing the severity of PN is therefore critical in clinical use. We aimed to determine when and how often PN occurs in association with paclitaxel plus carboplatin (PC therapy), a regimen used to treat non-small cell lung cancer, and factors that exacerbate this condition. Patients who received PC therapy for non-small cell lung cancer at the Japanese Foundation for Cancer Research, Cancer Institute Hospital, between May 20, 2009, and November 30, 2010, were included. PN was evaluated by the study pharmacist using specific questions based on the Common Terminology Criteria for Adverse Events Version 3.0. Univariate analysis was used to compare a group with no, Grade 1, or Grade 2 PN (non-serious) and a group with Grade 3 PN (serious). Analyses were conducted using the Cox proportional hazard model with patient characteristics having p < or = 0.20 when assessed as independent variables. Of 50 patients, 38 (76.0%) developed PN by day 6 of the first course of anticancer treatment. Grade 3 PN had an incidence of 25.0% in the fourth course. In multivariate analysis with the Cox proportional hazard model, pack-year [hazard ratio = 1.029; 95% confidence interval (CI): 1.009-1.050, p = 0.005] and creatinine clearance (hazard ratio = 0.957; 95% CI: 0.920-0.996, p = 0.031) were significant factors. A high pack-year and a low creatinine clearance exacerbated PN in patients treated with PC. PN must be carefully evaluated in patients with exacerbating factors.