Shoichi Kuyama

A Phase II Trial of Erlotinib Monotherapy in Pretreated Patients with Advanced Non-small Cell Lung Cancer Who Do Not Possess Active EGFR Mutations: Okayama Lung Cancer Study Group Trial 0705

Backgrounds: Efficacy of gefitinib therapy strongly depends on epidermal growth factor receptor (EGFR)-mutation status in Asian patients with non-small cell lung cancer. Recently, the survival advantage of erlotinib, another tyrosine kinase inhibitor, was not affected by EGFR mutation status in a phase III trial, indicating that patients with EGFR-wild-type (EGFR-wt) tumors might also benefit from this tyrosine kinase inhibitor. The aim of this trial was to evaluate the efficacy and toxicity of erlotinib in Japanese patients with EGFR-wt tumors. Methods: The primary end point was an objective response. Patients with EGFR-wt tumors previously receiving one to three chemotherapy regimens were enrolled in this trial. The mutation status was assessed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Erlotinib was administered (150 mg/d) until disease progression or unacceptable toxicities occurred. Results: Thirty patients were enrolled between January and December 2008. Objective response was observed in one patient (3.3%), and the disease became stable in 18 patients (60.0%). Skin rash was the most common side effect. Grades 3–4 adverse events included pulmonary embolism, keratitis, and anemia. Two other patients developed interstitial lung disease (grades 1 and 2). Nevertheless, all these events were reversible, resulting in no treatment-related deaths. With a median follow-up time of 10.7 months, the median survival time and median progression-free survival times were 9.2 and 2.1 months, respectively. Conclusion: This is the first prospective biomarker study showing that erlotinib therapy for pretreated patients with EGFR-wt tumors seems to have a modest activity with no irreversible toxicity.

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.

Phase II Trial of Gefitinib in Combination with Bevacizumab as First-Line Therapy for Advanced Non–Small Cell Lung Cancer with Activating EGFR Gene Mutations: The Okayama Lung Cancer Study Group Trial 1001

Purpose: Whether bevacizumab enhances the effect of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on EGFR mutant non–small cell lung cancers (NSCLCs) remains unknown. We conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with bevacizumab as first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations. Methods: In this trial, 42 patients with a performance status of 0 to 2 received gefitinib (250 mg/d) and bevacizumab (15 mg/kg, every 3 weeks). The primary end point of this study was the 1-year progression-free survival (PFS) rate. We assumed that a 1-year PFS rate of 55% would indicate potential usefulness and that a 1-year PFS rate of 40% would constitute the lower limit of interest. Results: Forty-two patients were enrolled in the study with a median age of 73 (range 42–86) years. Activating EGFR gene mutations included exon 19 deletion (57%) and L858R point mutations in exon 21 (38%). The objective response rate was 73.8% and included two complete responses. The 1-year PFS rate and median PFS time were 56.7% (95% confidence interval [CI] 39.9–70.5) and 14.4 months (95% CI 10.1–19.2), respectively. The median PFS differed significantly between EGFR exon 19 deletion and the L858R point mutation (18.0 versus 9.4 months, respectively; p = 0.006). The median overall survival had not yet been reached. Severe adverse events included grade 3 skin rash (15%), hypertension (17%), aspartate transaminase/alanine aminotransferase elevation (17%), proteinuria (7%), intracranial hemorrhage (2%), and grade 4 perforation of the digestive tract (2%). There were no treatment-related deaths. Conclusion: Gefitinib in combination with bevacizumab as first-line therapy seems to be a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was not met because the lower limit of the CI was less than 40%.

Impact of HER2 Gene and Protein Status on the Treatment Outcome of Cisplatin-Based Chemoradiotherapy for Locally Advanced Non-small Cell Lung Cancer

Background: It has not been fully evaluated whether both HER2 gene copy number and HER2 protein expression are related to the outcome of chemoradiotherapy in patients with locally advanced non-small cell lung cancer (LA-NSCLC). The aim of this study was to evaluate their relationships. Methods: HER2 gene copy number determined by fluorescence in situ hybridization (FISH) and HER2 protein expression determined by immunohistochemistry (IHC) were assessed in 68 patients with LA-NSCLC enrolled in our previous phase II trials of concurrent cisplatin-based chemoradiotherapy, and a multivariate analysis was conducted for response and survival. Results: HER2-IHC-positive tumors were detected in 23 patients (34%), and the median ratio of HER2 to chromosome 17 copy number was 0.93 (range, 0.55–2.00). The HER2-FISH results were marginally correlated with the IHC results (p = 0.0715). When the median ratio in the FISH analysis was used as a cut-off level for its positivity, there was no association between either HER2-FISH or IHC status and objective response to chemoradiotherapy. Contrary, a multivariate analysis revealed HER2-FISH result but not IHC result was an independent poor prognostic factor for both overall survival and progression-free survival (hazard ratio = 2.568, 95% confidence interval [CI] = 1.117–5.903, p = 0.0264 and hazard ratio = 2.283, 95% CI = 1.005–5.189, p = 0.0487, respectively). Conclusions: Patients with HER2 FISH-positive LA-NSCLC had a poorer outcome even when treated with cisplatin-based chemoradiotherapy, despite the strong need for validation assessment of these observations. Development of more effective treatment for these high-risk patients is needed to improve their poor prognosis.

Long-term survival following concurrent chemoradiotherapy in patients with non-small-cell lung cancer with concomitant brain metastases only.

We report two patients with non-small-cell lung cancer (NSCLC) with concomitant metastases to the brain only who received chemotherapy with concurrent radiotherapy for the thoracic disease and brain disease, resulting in long-term survival. One patient was a 56-year-old woman who was diagnosed as having adenocarcinoma and showed T2N1 thoracic disease; the other patient was a 57-year-old man diagnosed with squamous cell carcinoma who had T1N3 thoracic disease. Both patients demonstrated multiple metastases to the brain only. Chemotherapy, consisting of cisplatin (40 mg/m2) and docetaxel (40 mg/m2), was administered on days 1 and 8, with the drugs being given separately, and the chemotherapy was repeated every 4 weeks for up to three cycles. Whole-brain irradiation (2 Gy/day; total, 36 Gy) and thoracic irradiation (2 Gy/day; total, 60 Gy) were started on days 1 and 29, respectively. Toxicities encountered were manageable by conventional therapy. The concurrent chemoradiation therapy resulted in complete regression of the brain disease in both patients. Brain disease relapsed in the female patient, but it is being controlled by the administration of gefitinib. She has survived for 53 months since the start of treatment, without new metastatic lesions or relapse of the thoracic lesions. The male patient has survived for 37 months without new metastatic lesions or relapses. Concurrent chemoradiotherapy in which radiotherapy is applied to both the brain and thoracic lesions may be effective for patients with NSCLC with metastases to the brain only.

A phase I study of combination S-1 plus cisplatin chemotherapy with concurrent thoracic radiation for locally advanced non-small cell lung cancer

A combination of S-1, a newly developed oral 5-fluorouracil derivative, and cisplatin is reported to show anti-tumour activity against advanced non-small cell lung cancer (NSCLC). Because S-1 shows synergistic effects with radiation, we conducted a phase I study to evaluate the maximum tolerated doses (MTDs), recommended doses (RDs), and dose-limiting toxicities (DLTs) of cisplatin and S-1 when combined with concurrent thoracic radiation (total dose of 60 Gy with 2 Gy per daily fraction) in patients with locally advanced NSCLC. Chemotherapy consisted of two 4-week cycles of cisplatin administered on days 1 and 8, and S-1 administered on days 1-14. S-1/cisplatin dosages (mg/m(2)/day) were escalated as follows: 60/30, 60/40, 70/40, 80/40 and 80/50. Twenty-two previously untreated patients were enrolled. The MTDs and RDs for S-1/cisplatin were 80/50 and 80/40, respectively. DLTs included febrile neutropaenia, thrombocytopaenia, bacterial pneumonia and delayed second cycle of chemotherapy. No patient experienced radiation pneumonitis>grade 2 and only one patient experienced grade 3 radiation oesophagitis. The overall response rate was 86.4% with a median survival time of 24.4 months. These results indicate that combination cisplatin-S-1 chemotherapy with concurrent thoracic radiation would be a feasible treatment option and a phase II study is currently under way.

A phase II study of amrubicin and topotecan combination therapy in patients with relapsed or extensive-disease small-cell lung cancer: Okayama Lung Cancer Study Group Trial 0401

BACKGROUNDS Chemotherapy is a mainstay in the treatment of extensive-disease small-cell lung cancer (ED-SCLC), although the survival benefit remains modest. We conducted a phase II trial of amrubicin (a topoisomerase II inhibitor) and topotecan (a topoisomerase I inhibitor) in chemotherapy-naïve and relapsed SCLC patients. METHODS Amrubicin (35 mg/m(2)) and topotecan (0.75 mg/m(2)) were administered on days 3-5 and 1-5, respectively. The objective response rate (ORR) was set as the primary endpoint, which was assessed separately in chemotherapy-naïve and relapsed cases. RESULTS Fifty-nine patients were enrolled (chemotherapy-naïve 31, relapsed 28). The ORRs were 74% and 43% in the chemotherapy-naïve and relapsed cases, respectively. Survival data were also promising, with a median progression-free survival time and median survival time of 5.3 and 14.9 months and 4.7 and 10.2 months in the chemotherapy-naïve and relapsed cases, respectively. Even refractory-relapsed cases responded to the treatment favorably (27% ORR). The primary toxicity was myelosuppression with grades 3 or 4 neutropenia in 97% of the patients, which led to grades 3 or 4 febrile neutropenia in 41% of the patients and two toxic deaths. CONCLUSION This phase II study showed the favorable efficacy and moderate safety profiles of a topotecan and amrubicin two-drug combination especially in relapsed patients with ED-SCLC.

Desire for Information and Involvement in Treatment Decisions: Lung Cancer Patients' Preferences and Their Physicians' Perceptions: Results from Okayama Lung Cancer Study Group Trial 0705

Introduction: This study explores patient preferences for involvement in lung cancer treatment decisions and the extent of concordance between the views of patients and physicians on decisional roles. The impact of demographic and psychosocial characteristics on the decisional role of patients is also examined. Methods: Patients with relapsed non-small cell lung cancer who were candidates for a phase II trial of erlotinib monotherapy were recruited. Patients were interviewed after they had learned of their relapse and the treatment decision had been made but before pharmacologic intervention. Results: Most of the 28 participants were married, had a smoking history, and were well educated. They reported moderate levels of depression and anxiety. Initially, 14% of the patients reported a preference for active decision making; later, 29% believed that the primary responsibility for the treatment decision had been theirs. Only 54% of the patients agreed with the physicians assessment of how the treatment decision was made (&kgr; = 0.31; test of symmetry, p = 0.23). The depression score was significantly associated with a patients preferred level of control (p < 0.01). Conclusions: The limited concordance between patient preference and perception and between patient and physician perceptions regarding how the treatment decision was made suggests that physicians should more accurately identify patient preferences by directly asking patients at the beginning of each clinical encounter.

A phase II study of cisplatin plus S-1 with concurrent thoracic radiotherapy for locally advanced non-small-cell lung cancer: The Okayama Lung Cancer Study Group Trial 0501

BACKGROUND Although cisplatin-based chemotherapy combined with thoracic irradiation (TRT) is a standard treatment for unresectable, locally advanced non-small cell lung cancer (NSCLC), this treatment outcome has remained unsatisfactory. We had previously conducted a phase I trial of cisplatin plus S-1, an oral 5-fluorouracil derivative, and TRT, which were safe and effective. METHODS In this phase II trial, 48 patients with stage III NSCLC received cisplatin (40mg/m(2) on days 1, 8, 29 and 36) and S-1 (80mg/m(2) on days 1-14 and 29-42) and TRT (60Gy). The primary endpoint was the response rate. RESULTS A partial response was observed in 37 patients (77%; 95% confidence interval: 63-88%). At a median follow up of 54 months, the median progression-free survival and median survival time were 9.3 and 31.3 months, respectively. No difference in efficacy was observed when the patients were stratified by histology. Toxicities were generally mild except for grade 3 or worse febrile neutropenia and pneumonitis of 8% and 4%, respectively. No patient developed severe esophagitis. At the time of this analysis, 35 (73%) of the 48 patients recurred; 15 (31%) showed distant metastasis, 17 (35%) had loco-regional disease, and 2 (4%) showed both loco-regional disease and distant metastasis. CONCLUSIONS This chemoradiotherapy regimen yielded a relatively favorable efficacy with mild toxicities in patients with locally advanced NSCLC.

Phase II Study of Amrubicin Combined with Carboplatin for Thymic Carcinoma and Invasive Thymoma: North Japan Lung Cancer Group Study 0803

Background: There has been no standard chemotherapy for advanced or recurrent thymic malignancies including thymic carcinoma (TC) and invasive thymoma (IT), though platinum and anthracycline have been reported as effective agents for the treatment of these diseases. The objective of this study was to evaluate the efficacy and safety of the combination of amrubicin (AMR), a new anthracycline agent, and carboplatin (CBDCA) in patients with advanced thymic malignancies. Methods: Patients with histologically confirmed thymic malignancies received AMR (35 mg/m2, days 1–3) and CBDCA (area under the curve 4.0, day 1) every 3 weeks. Patients who had received previous chemotherapy were treated with a reduced dose of AMR (30 mg/m2). The primary end point was objective response rate (ORR), and secondary endpoints were progression-free survival, overall survival, and toxicity profile. Results: From December 2008 to October 2012, 51 patients (33 TC and 18 IT) were enrolled. The median number of treatment cycles was four in each group. The ORR and progression-free survival were 30% (95% confidence interval, 14–46) and 7.6 months in the TC group, and 17% (95% confidence interval, 0–34) and 7.6 months in the IT group, respectively. The ORR of TC patients without previous chemotherapy (n = 19) was 42%. Although grade 3 or 4 hematological toxicities were common including neutropenia (82%) and febrile neutropenia (22%), these were transient and manageable. Nonhematological toxicities were moderate and no treatment-related death was observed. Conclusions: The combination of AMR with CBDCA was active for TC with acceptable toxicity, although it was not effective for IT. Further investigation of this regimen for advanced TC is warranted.