Toshiro Yonei

Phase III Trial Comparing Docetaxel and Cisplatin Combination Chemotherapy With Mitomycin, Vindesine, and Cisplatin Combination Chemotherapy With Concurrent Thoracic Radiotherapy in Locally Advanced Non–Small-Cell Lung Cancer: OLCSG 0007

PURPOSE To demonstrate the efficacy of docetaxel and cisplatin (DP) chemotherapy with concurrent thoracic radiotherapy (TRT) for patients with locally advanced non-small-cell lung cancer (LA-NSCLC). PATIENTS AND METHODS Patients age 75 years or younger with LA-NSCLC, stratified by performance status, stage, and institution, were randomly assigned to two arms consisting of DP (docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2) on days 1, 8, 29, and 36) or mitomycin, vindesine, and cisplatin (MVP) chemotherapy with concurrent TRT. RESULTS Between July 2000 and July 2005, 200 patients were allocated into either the DP or MVP arm. The survival time at 2 years, a primary end point, was favorable to the DP arm (P = .059 by a stratified log-rank test as a planned analysis and P = .044 by an early-period, weighted log-rank as an unplanned analysis). There was a trend toward improved response rate, 2-year survival rate, median progression-free time, and median survival in the DP arm (78.8%, 60.3%,13.4 months, and 26.8 months, respectively) compared with the MVP arm (70.3%, 48.1%, 10.5 months, and 23.7 months, respectively), which was not statistically significant (P > .05). Grade 3 febrile neutropenia occurred more often in the MVP arm than in the DP arm (39% v 22%, respectively; P = .012), and grade 3 to 4 radiation esophagitis was likely to be more common in the DP arm than in the MVP arm (14% v 6%, P = .056). CONCLUSION DP chemotherapy combined with concurrent TRT is an alternative to MVP chemotherapy for patients with LA-NSCLC.

Interstitial lung disease in Japanese patients with non-small cell lung cancer receiving gefitinib : An analysis of risk factors and treatment outcomes in okayama lung cancer study group

ABSTRACTRisk factors for the development of interstitial lung disease in patients with non-small cell lung cancer receiving gefitinib and the prognostic factors after interstitial lung disease development have not been established. The aim of this study was to retrospectively identify and evaluate these possible factors. PATIENTS AND METHODSWe reviewed the clinical records and radiographs of 365 consecutive patients with non-small cell lung cancer who received gefitinib in West Japan between 2000 and 2003. RESULTSIn total, 330 patients were eligible for interstitial lung disease evaluation, and 15 patients (4.5%) were finally confirmed to have developed interstitial lung disease by blinded expert review. Multivariate analysis revealed that preexisting pulmonary fibrosis, poor performance status, and prior thoracic irradiation were independent risk factors for interstitial lung disease, with odds ratios of 21.0 (95% confidence interval, 5.12–86.3, P < 0.0001), 9.70 (2.27–41.4, P= 0.001), and 4.33 (1.27–14.8, P= 0.019), respectively. Among the 15 patients who developed interstitial lung disease, eight have died of the condition. Short interval from the initiation of gefitinib treatment to the onset of interstitial lung disease, acute interstitial pneumonia pattern, and the presence of pre-existing pulmonary fibrosis were associated with poor prognosis. DISCUSSIONOur results suggest the importance of patient selection for gefitinib treatment based on interstitial lung disease risk factors in the Japanese population identified.

Comparison of the Incidence and Pattern of Interstitial Lung Disease During Erlotinib and Gefitinib Treatment in Japanese Patients with Non-small Cell Lung Cancer: The Okayama Lung Cancer Study Group Experience

Background: Data comparing the incidence and pattern of interstitial lung disease (ILD) in non-small cell lung cancer patients receiving treatment with gefitinib versus erlotinib, both of which are epidermal growth factor receptor tyrosine kinase inhibitors, are scarce. We investigated the incidence of ILD in Japanese patients treated with gefitinib or erlotinib. Methods: We reviewed the clinical records of 209 patients treated with erlotinib in 2008 (cohort A) and 330 treated with gefitinib between 2000 and 2003 (cohort B). Toxicity within the first month of treatment was investigated. Results: The patients in cohort A had fewer known risk factors for ILD (e.g., poor performance status and prior pulmonary fibrosis). ILD was detected in two patients (1.0%) from cohort A and eight patients (2.4%) from cohort B during the first month of treatment. The events were graded as follows: one patient each in grades 1 and 2 (cohort A), and one, one, and six patients in grades 3, 4, and 5, respectively (cohort B). Multivariate analysis revealed that poor performance status and prior pulmonary fibrosis were significantly correlated with the occurrence of ILD, but the type of epidermal growth factor receptor tyrosine kinase inhibitor administered was not. Conclusion: There was a somewhat lower incidence of ILD with erlotinib therapy than with gefitinib therapy, despite no statistically significant difference. Patient selection based on awareness by Japanese physicians of the risk factors for ILD, rather than the type of agent, may explain the difference in ILD incidence between the two treatments.

Fractionated administration of irinotecan and cisplatin for treatment of lung cancer : a phase I study

SummaryA combination chemotherapy of irinotecan (CPT-11) and cisplatin (CDDP) has been reported to be active for lung cancer. In the previous trial, however, diarrhoea and leucopenia became the major obstacle for sufficient dose escalation of CPT-11 to improve the treatment outcome. We conducted a phase I study to investigate whether the fractionated administration of CDDP and CPT-11 at escalated dose was feasible and could improve the treatment outcome. Twenty-four previously untreated patients with unresectable non-small-cell lung cancer (NSCLC) or extensive disease of small-cell lung cancer (SCLC) were eligible. Both CDDP and CPT-11 were given on days 1 and 8, and repeated every 4 weeks. The dose of CDDP was fixed at 60 mg m–2 and given by 1-h infusion before CPT-11 administration. The starting dose of CPT-11 was 40 mg m–2, and the dose was escalated by an increase of 10 mg m–2. The maximally tolerated dose of CPT-11 was determined as 60 mg m–2 because grade 4 haematological or grade 3 or 4 non-haematological toxicities developed in six patients out of 11 patients evaluated. Diarrhoea became a dose-limiting toxicity. The objective response rates were 76% for NSCLC and 100% for SCLC. The recommended dose of CPT-11 and CDDP in a phase II study will be 50 mg m–2 and 60 mg m–2 respectively.

Second primary cancer in survivors following concurrent chemoradiation for locally advanced non-small-cell lung cancer

Long-term cancer survivors risk development of second primary cancers (SPC). Vigilant follow-up may be required. We report outcomes of 92 patients who underwent chemoradiation for unresectable stage III non-small-cell lung cancer, with a median follow-up of 8.9 years. The incidence of SPC was 2.4 per 100 patient-years (95% confidence interval: 1.0–4.9).

Safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group Experience

We evaluated the safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer (NSCLC). We retrospectively compared toxicity, response and survival outcomes for gefitinib in patients aged 75 years or older (elderly group) with the same outcomes in patients aged younger than 75 years. In total, 350 patients were eligible for this analysis, of whom 92 were in the elderly group and 258 in the non-elderly group. In the elderly group, adverse events were generally mild to moderate and grade 3–4 adverse events were observed in 8 (9%) patients. The objective response rate (17 vs. 21% for elderly vs. non-elderly, respectively) and median survival time (7.6 vs. 9.3 months) were also similar in the two groups. Multivariate analysis revealed elderly patients with lower Brinkman index tended to be more sensitive to gefitinib (odds ratio: 4.57, 95% confidence interval: 0.91–22.72, p = 0.0642). In this study, treatment with gefitinib appeared to be as safe and effective in elderly patients (aged 75 or older) with NSCLC as in non-elderly patients.

Phase I/II study of altered schedule of cisplatin and etoposide administration and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-stage small-cell lung cancer

To improve the efficacy of a combination of cisplatin and etoposide and concurrent accelerated twice-daily thoracic radiotherapy against limited-stage small-cell lung cancer, we conducted a phase I/II study using an altered schedule of chemotherapy administration. Chemotherapy consisted of four cycles of cisplatin (days 1 and 8) and etoposide (days 1, 2, 8, and 9) every 4 weeks. Accelerated hyperfractionated thoracic radiation (1.5 Gy twice daily x 30 fractions, total dose of 45 Gy) was concurrently given with the first cycle of chemotherapy. The recommended doses of cisplatin and etoposide determined in the phase I study were 40 and 80 mg/m(2), respectively. In the phase II study, the overall response rate was 100% (complete response: 32%, partial response: 68%). By a median follow-up time of 29 months, median radiation-outfield progression-free survival was 13.4 months, while radiation-infield progression-free survival did not reach median value. The median overall survival time was 22.9 months, with survival rate of 48.4% at 2 years. Major toxicities were leukopenia and neutropenia (>/=grade 3, 92% each). The local control and overall survival demonstrated in this study were excellent. However, the insufficient distant control suggests a need for development of more active chemotherapy regimens.

Interstitial lung disease (ILD) during gefitinib treatment in Japanese patients with non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group

7063 Background: Risk factors of ILD during gefitinib treatment in patients with NSCLC are undetermined. The objective of this study was to elucidate the risk factors of ILD by analyzing the characteristics of patients with ILD. METHODS We retrospectively reviewed the clinical records of 325 patients with NSCLC who had received gefitinib in 12 hospitals between November 2000 and October 2003. Correlations between the various factors and the frequency of ILD following gefitinib treatment were investigated. RESULTS Patients characteristics were as follows; male/female: 68%/32%, Ad/others: 74%/26%, median age: 67 (range; 29-88), and ECOG PS 0-1/2-4: 66%/34%. An objective response rate by gefitinib treatment was 20% (62/307 patients). The median survival time after the initiation of gefitinib treatment was 6.7 months, with a median follow-up time of 10.8 months. Toxicities (grade 3 or more by the National Cancer Institute-Common Toxicity Criteria) included hepatic toxicity (5.0%), skin rash (2.2%), diarrhea (0.6%), and nausea/vomiting (0.3%). Twenty-two patients (6.8%) developed ILD after gefitinib treatment. The median toxicity grade of ILD was 3 (range; 2-4), and 10 (3.1%) patients have died. The median time to ILD after initiation of gefitinib treatment was 18 days (range; 3-123). Half of the patients developing ILD manifested the acute onset of dyspnea. Radiographic findings of the ILD were characterized mainly by diffuse ground-glass opacity. Statistically significant factors affecting the occurrence of ILD by multivariate analysis were presence of pulmonary fibrosis before gefitinib treatment and poor PS. CONCLUSIONS The results of this study indicate that ILD during gefitinib treatment is considerably frequent. Physicians should carefully decide the indication of gefitinib treatment, especially for patients with lung comorbidities or poor PS. No significant financial relationships to disclose.

nab-Paclitaxel in Combination with Carboplatin for a Previously Treated Thymic Carcinoma.

We present the case of a 40-year-old man with previously treated thymic carcinoma, complaining of gradually worsening back pain. Computed tomography scans of the chest showed multiple pleural disseminated nodules with a pleural effusion in the right thorax. The patient was treated with carboplatin on day 1 plus nab-paclitaxel on day 1 and 8 in cycles repeated every 4 weeks. Objective tumor shrinkage was observed after 4 cycles of this regimen. In addition, the elevated serum cytokeratin 19 fragment level decreased, and the patients back pain was relieved without any analgesics. Although he experienced grade 4 neutropenia and granulocyte colony-stimulating factor (G-CSF) injection, the severity of thrombocytopenia and nonhematological toxicities such as reversible neuropathy did not exceed grade 1 during the treatment. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and nab-paclitaxel against thymic carcinoma. This case report suggests that nab-paclitaxel in combination with carboplatin can be a favorable chemotherapy regimen for advanced thymic carcinoma.

Toxicity manifesting as cosmetic hair alterations during erlotinib treatment.

Erlotinib, an orally administered epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has shown promising antitumor activity for non-small-cell lung cancer (NSCLC) as compared with the best supportive care [1]. It inhibits the intracellular phosphorylation of the tyrosine kinase domain associated with EGFR in cancer cells. This activity also occurs in tissues that normally express EGFR, such as the basal and suprabasal layers of the epidermis, sebaceous glands, and the outer root sheath of hair follicles [2], which results in papulopustules, pruitus, paronychia, xerosis, and telangiectasias. Recently, several researchers have independently reported cases with hair alterations as rarely occurring adverse events that were potentially induced by erlotinib treatment. However, it has never been investigated how rare these events are. In this report, we present our case series in a single institution that developed toxicity of cosmetic hair alterations during erlotinib treatment, and then focus on the frequency of these events. An 81-year-old woman, diagnosed with advanced pulmonary adenocarcinoma in December 2005 and treated with platinum-based chemotherapy, was admitted to our hospital in July 2008 due to progression of her disease. We treated her with erlotinib at a dose of 150 mg once daily, which achieved a partial response. The deletion of exon 19 in the EGFR gene was detected retrospectively using a specimen previously obtained by transbronchial biopsy. At fi rst, toxicity was mild and manageable with only a grade 2 cutaneous rash. However, around fi ve