Randomized phase II trial of adjuvant chemotherapy with docetaxel plus cisplatin versus paclitaxel plus carboplatin in patients with completely resected non-small cell lung cancer: TORG 0503.

OBJECTIVE: Adjuvant chemotherapy is standard of care for patients with completely resected stage IB, II and IIIA NSCLC. However, optimum chemotherapy regimen has not been determined. TORG0503 was undertaken to select a preferred platinum-based 3rd generation regimen in this clinical setting. MATERIALS AND METHODS: Patients with completely resected stage IB, IIA, IIB or stage IIIA NSCLC were stratified by stage (IB/IIA vs. IIB/IIIA) and institutions, and randomized to receive 3 cycles of docetaxel (60 mg/m2) plus cisplatin (80 mg/m2) (arm A) or paclitaxel (200 mg/m2) plus carboplatin (AUC 6) (arm B) on day 1, every 3 weeks. The primary endpoint of the study was 2-year relapse free survival, and the key secondary endpoints included overall survival, feasibility and toxicity. RESULTS: 111 patients were randomized, 58 patients to arm A and 53 to arm B. Patient demographics were balanced between the two arms. 93 % (54/58) of patients on the arm A and 92 % (49/53) patients on the arm B completed the planned 3 cycles of chemotherapy. There was no treatment-related death in both arms. The 2 and 5 year relapse free survival was 74.5 % (95 %CI: 68.6-80.4) and 61.6 % in the arm A, and 72.0 % (95 %CI: 65.7-78.3) and 46.0 % in the arm B. The overall 2, 5-year survival was 89.7 %, 73.9 % in the arm A and 86.9 %, 67.5 % in the arm B. CONCLUSION: Both docetaxel plus cisplatin and paclitaxel plus carboplatin are safe and feasible regimens as adjuvant chemotherapy. We choose docetaxel plus cisplatin as the control regimen for the next clinical trial.

Overall Survival Results of the Feasibility Study of Adjuvant Chemotherapy With Docetaxel Plus Cisplatin Followed by Long-term Single-agent Administration of S-1 in Patients With Completely Resected Non-Small Cell Lung Cancer: Thoracic Oncology Research Group (TORG) 0809.

OBJECTIVES: The TORG0809 study was a multicenter feasibility study of long-term single-agent therapy with S-1 after docetaxel plus cisplatin therapy in patients with completely resected stage II or stage IIIA non-small cell lung cancer. We report the results of the final overall survival (OS) analysis. PATIENTS AND METHODS: A total of 129 eligible patients received 3 cycles of docetaxel (60 mg/m, day 1) plus cisplatin (80 mg/m, day 1), followed by S-1 at 40 mg/m twice daily for 14 consecutive days, for >6 months (maximum, 1 y). RESULTS: At the cutoff date of April 13, 2016, the median follow-up time was 6.0 years. Of the 129 patients, 43 had died, and 74 patients developed disease recurrence or died. The median OS had not been reached. The 5-year OS rate was 71% [95% confidence interval (CI), 62-78]. The 5-year OS rates in the patients with stage II and stage IIIA were 76% and 68%, respectively. The median recurrence-free survival (RFS) duration was 3.4 years (95% CI, 2.3-5.7). The 5-year RFS rate was 44% (95% CI, 36-53). The 5-year RFS rates in patients with stage II and stage IIIA disease were 57% and 38%, respectively. Disease recurrence occurred in 68 patients, and 62 of these patients received second-line chemotherapy. The most common sites of recurrence were the brain (n=22) and mediastinal lymph nodes (n=22). CONCLUSION: The survival data obtained from this study are promising and comparable to those reported from a previous study conducted in Japan.

Phase I/II study of induction chemotherapy using carboplatin plus irinotecan and sequential thoracic radiotherapy (TRT) for elderly patients with limited-disease small-cell lung cancer (LD-SCLC): TORG 0604.

BACKGROUND: The role of irinotecan for elderly patients with LD-SCLC has been unclear, and the timing of TRT combined with chemotherapy has not been fully evaluated. METHODS: Patients aged > 70 years with untreated, measurable, LD-SCLC, performance status (PS) 0-2, and adequate organ function were eligible. Treatment consisted of induction with carboplatin on day 1 and irinotecan on days 1 and 8, every 21 days for 4 cycles, and sequential TRT (54Gy in 27 fractions). Carboplatin doses were based on AUC of 4 and 5 (levels 1 and 2, respectively), with a fixed irinotecan dose (50 mg/m2). Primary objective of the phase II study was overall responce rate. RESULTS: Forty-three patients were enrolled and forty-one were finally analyzed (median age: 75 years [range 70-86 years); males 31; PS 0/1/2, n = 22/18/1]. Two patients were excluded because of protocol violation (ascertained to be extensive disease). Twelve patients were accrued at phase I and the number of patients with carboplatin dose-limiting toxicities at levels-1 (n = 6) and -2 (n = 6) were 1(grade 3 hypertension) and 2 (grade 4 thrombocytopenia), respectively. The phase II trial was expanded to 29 additional patients receiving the level 1 carboplatin dose, total of 35 patients. The median number of chemotherapy cycles was 4 (range 1-4), and the median radiation dose was 54Gy (range 36-60). Toxicities were generally mild. There were 4 complete and 27 partial responses (response rate 88.6%). With a median follow-up of 52 months, the median progression-free and overall survival times of phase II were 11.2 and 27.1 months, respectively. CONCLUSIONS: Induction chemotherapy of carboplatin plus irinotecan and sequential TRT was well tolerated and effective for elderly patients with LD-SCLC. Additional confirmatory studies are warranted. TRIAL REGISTRATION: Trial registration number: UMIN000007352 Name of registry: UMIN. Date of registration: 1/Dec/2006. Date of enrolment of the first participant to the trial: 6/Feb/2007. Clinical trial registration date: 1/Feb/2006 (prospective).

Feasibility study of first-line chemotherapy using Pemetrexed and Bevacizumab for advanced or recurrent nonsquamous non-small cell lung cancer in elderly patients: TORG1015.

BACKGROUND: The addition of bevacizumab to cytotoxic agents prolongs survival in patients with nonsquamous non-small cell lung cancer (NSCLC). To date, there is no evidence to suggest that treatment with a cytotoxic agent plus bevacizumab is more effective than a cytotoxic agent alone for nonsquamous NSCLC in elderly patients. We conducted a feasibility study of pemetrexed plus bevacizumab as a first-line treatment for advanced or recurrent nonsquamous NSCLC in elderly patients. METHODS: Major eligibility and exclusion criteria included: chemotherapy-naive status; non-fitness for bolus combination chemotherapy; stage III/IV or relapsed nonsquamous NSCLC; age ≥70; performance status 0-1; absence of brain metastasis; and no history of hemoptysis and thoracic irradiation. Pemetrexed (500 mg/m(2)) and bevacizumab (15 mg/kg) were administered intravenously on day 1, and repeated every 3 weeks thereafter. The primary endpoint was safety, and the secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the percentage of patients who completed ≥3 cycles. RESULTS: From October 2010 to April 2012, a total of 12 patients were enrolled. No dose-limiting toxicity or treatment-related deaths were observed. Three patients achieved PR, and the ORR was 25 %. The median PFS and OS were 5.4 months (95 % CI 1.1-8.8 months) and 13.6 months (95 % CI 5.3-15.6 months), respectively. Seven of 12 patients (58 %) received ≥3 cycles. CONCLUSIONS: Pemetrexed plus bevacizumab in the treatment of elderly patients with nonsquamous NSCLC was well tolerated and shows promise as first-line treatment. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004263 . Registered on 25 September, 2010.

Quality of life and survival survey of cancer cachexia in advanced non-small cell lung cancer patients-Japan nutrition and QOL survey in patients with advanced non-small cell lung cancer study.

PURPOSE: Although cancer cachexia is mainly characterized by persistent loss of body weight (BW), usually in response to a malignancy, the pathophysiology of cachexia remains unresolved. To elucidate the relationship between the loss of BW and other related clinical factors, we conducted a nationwide, multi-institutional, prospective, observational study in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Treatment-naïve stage IV NSCLC patients with an Eastern Cooperative Oncology Group performance status (PS) of 0-2 were eligible. BW, handgrip strength (HGS), quality of life (QOL), Karnofsky Performance Scale (KPS), biochemical parameters, and survival were evaluated at baseline and every 4 weeks for 1 year. The relationship between BW loss and other factors was examined by linear regression analysis. Estimated survival curves were drawn by the Kaplan-Meier method and applied by the log-rank test. Clinical factors associated with cancer cachexia were identified through principal component analysis. The generalized estimating equation approach was used to analyze the deterioration of QOL resulting from the progression of cachexia. RESULTS: A total of 406 patients were analyzed. BW loss was significantly associated with worsening of QOL, HGS, KPS, and biochemical parameters. The incidence of BW loss was observed throughout the study period. Overall survival was significantly shorter in patients as BW loss progressed. BW loss, decrease in HGS, anorexia, and fatigue were identified as core factors of cachexia that contributed to the deterioration of QOL. CONCLUSION: BW loss most likely deteriorated QOL and shortened survival in patients with advanced NSCLC and should be closely monitored.

Multicenter Phase II Study of Nedaplatin and Irinotecan for Patients with Squamous Cell Carcinoma of the Lung: Thoracic Oncology Research Group 0910.

Squamous cell carcinoma (SCC) of the lung is moderately responsive to anticancer drugs, but no specific chemotherapy regimens have yet been established. We conducted a multicenter phase II study of nedaplatin (NP) and irinotecan (CPT) for SCC of the lung. Fifty patients underwent 4 to 6 cycles of chemotherapy comprising of NP at 100 mg/m(2) on day 1 and CPT at 60 mg/m(2) on days 1 and 8 every 4 weeks. Twenty-seven patients received 4 to 6 cycles of chemotherapy (median=4 cycles). Major toxicities included neutropenia (46.0%), grade 3 or 4 anorexia (22.0%), febrile neutropenia (16.0%), diarrhea (12.0%), hyponatremia (12.0%), grade 4 anemia (10.0%), thrombocytopenia (10.0%) and infection (10.0%). There were no treatment-related deaths. One patient achieved a complete response and 16 a partial response, with an overall response rate of 34.0%. The median survival time was 11.8 months (95% CI=8.3-15.8 months) and the 2-year survival rate was 22.0%. In conclusion, the NP and CPT regimen is not recommend for further evaluation for patients with advanced SCC of the lung.

Feasibility study of docetaxel plus bevacizumab as first line therapy for elderly patients with advanced non-small-cell lung cancer: Thoracic Oncology Research Group (TORG) 1014.

BACKGROUND: Docetaxel monotherapy is one of the standard treatments for non-small-cell lung cancer in elderly patients. The addition of bevacizumab to docetaxel seems promising; however, the feasibility of this combination has not been investigated in such patients. METHODS: Patients with advanced non-squamous non-small-cell lung cancer aged 70 years or older who had not previously received cytotoxic chemotherapy were enrolled. Patients in the Level 0 cohort received docetaxel 60 mg/m(2) and bevacizumab 15 mg/kg, whereas those in the Level-1 cohort received docetaxel 50 mg/m(2) and bevacizumab 15 mg/kg. Chemotherapy was repeated 3 weekly for six cycles. The primary endpoint was toxicity and the secondary endpoints were response rate, progression-free survival, overall survival, and proportion of patients who underwent three or more cycles of chemotherapy. RESULTS: Twenty-one patients were enrolled from December 2010 to September 2012 at six institutes. Of the nine patients enrolled in Level 0, two experienced dose-limiting toxicity (febrile neutropenia and prolonged Grade 4 neutropenia in one patient, and Grade 3 infection in another patient) during the first cycle. Enrollment to the Level 0 cohort was terminated because two patients developed Grade 4 sepsis during later cycles. The remaining 12 patients were enrolled in the Level-1 cohort, in which two dose-limiting toxicities (prolonged Grade 4 neutropenia and Grade 3 increased aminotransferase level) were observed. No patient in the Level-1 cohort experienced Grade 4 nonhematologic toxicity. Grade 4 neutropenia occurred in 89 % of Level 0 patients and 50 % of Level-1 patients. The proportion of patients who experienced Grade 3/4 infection, febrile neutropenia or sepsis was 44 % in the Level 0 cohort, and 8 % in the Level-1 cohort. The overall response rate to chemotherapy and progression-free survival were 29 % (95 % CI, 11-52 %) and 5.9 months (95 % CI, 3.6-9.1 months), respectively. Efficacy outcomes did not differ significantly between the cohorts. CONCLUSIONS: Toxicities were tolerable in level-1 cohort. The recommended dose of combination chemotherapy with docetaxel and bevacizumab for elderly patients was determined as 50 mg/m(2) of docetaxel and 15 mg/kg of bevacizumab and toxicities were tolerable. Further studies are warranted. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004240 .

A prospective, multicentre phase II trial of low-dose erlotinib in non-small cell lung cancer patients with EGFR mutations pretreated with chemotherapy: Thoracic Oncology Research Group 0911.

BACKGROUND: Low-dose erlotinib may be as effective as gefitinib or erlotinib at full dose in non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR) gene. METHODS: Patients with chemotherapy pretreated NSCLC harbouring EGFR mutations received erlotinib at 50 mg/d until disease progression or unacceptable toxicities. The dose was escalated to 150 mg/d in patients showing no response (i.e. without major tumour shrinkage according to Response Evaluation Criteria in Solid Tumours (RECIST)) to the initial dose during the first 4 weeks. The primary end-point was the objective response rate at the dose of 50 mg/d. RESULTS: Thirty-four patients from seven institutes were enrolled. The study was closed early when no response was confirmed in 15 patients, excluding the possibility that the primary end-point would be met. The objective response and disease control rates at the dose of 50 mg/d as determined by an independent review committee were 54.5% and 84.8%, respectively. Four additional patients achieved partial response with increased 150 mg/d dose. Progression-free survival and median survival times during the entire period of the study were 9.5 and 28.5 months, respectively. Treatment-related toxicities were generally mild, the most common being skin disorders and diarrhoea. Only one case experienced grade 3 toxicity, which was transient increase of hepatic enzymes. CONCLUSION: The primary end-point was not met; low-dose erlotinib is not recommended for fit patients with NSCLC harbouring EGFR mutations. However, it may merit further evaluation for elderly or frail patients.

A phase I trial of concurrent chemoradiotherapy with non-split administration of docetaxel and cisplatin for dry stage III non-small-cell lung cancer (JCOG9901DI).

PURPOSE: This study aimed to establish the maximum tolerated dose of concurrent chemoradiotherapy (cCRT) with conventional administration of the docetaxel (D) plus cisplatin (P) (conv-DP) regimen. METHODS: Patients (aged ≤70 years) with unresectable dry stage III non-small-cell lung cancer (NSCLC) and having performance status 0 or 1 and adequate organ function were eligible. They received radiotherapy (60 Gy in 30 fractions) once daily starting on day 2. Concurrent P (day 1; 60 mg/m(2) at Levels 1-3, 80 mg/m(2) at Level 4) and D (day 1; 30 mg/m(2) at Level 1, 40 mg/m(2) at Level 2, 50 mg/m(2) at Levels 3-4) were administered every 4 weeks for 2-4 courses. RESULTS: Eighteen patients were enrolled (stage IIIA/IIIB, 5/13 patients). Three cases of dose-limiting toxicity were observed in this study, although another 3 cases were added at Levels 2 and 3. Radiotherapy was completed in 15 patients. Seventeen patients received more than 2 courses of chemotherapy. Neither Grade 3/4 esophagitis nor severe hematological events were observed at Levels 1-4. However, dose escalation to Level 5 (P [80 mg/m(2)], D [60 mg/m(2)]) was stopped because the Level 5 dose was the recommended dose (RD) of chemotherapy alone for stage IIIB/IV NSCLC in Japan. Therefore, the RD was determined as D50/P80 mg/m(2) in this cCRT. The objective response rate was 89%, and the median survival time was 23.6 months. CONCLUSIONS: cCRT with non-split DP was a tolerable and effective regimen, and RD was 50/80 mg/m(2) every 4 weeks.

Phase II study of topotecan with cisplatin in Japanese patients with small cell lung cancer.

BACKGROUND: We conducted a phase II study of topotecan (Tp) with cisplatin (CDDP) in previously untreated Japanese patients with extensive-disease small cell lung cancer (ED-SCLC). PATIENTS AND METHODS: In stage 1, a total of 30 patients were allocated to Tp 0.65 mg/m(2) with CDDP 60 mg/m(2) day 1 or Tp 1.00 mg/m(2) with CDDP day 5 following prophylactic granulocyte colony stimulating factor (G-CSF) from day 6. In stage 2, the selective combination in 29 patients was evaluated for response rate, toxicity and overall survival. RESULTS: In stage 1, Tp 1.00 mg/m(2) with CDDP day 5 was selected this schedule had a better hematological profile. In stage 2, the response rate was 83%, and grade 3/4 adverse events were hematological-toxicities. The median survival time was 17.5 months and the 1 year survival rate was 79%. CONCLUSION: Combination of Tp and CDDP on day 5 with G-CSF support is safe and effective for previously untreated ED-SCLC Japanese patients.

The PCR-invader method (structure-specific 5' nuclease-based method), a sensitive method for detecting EGFR gene mutations in lung cancer specimens; comparison with direct sequencing.

BACKGROUND: Several sensitive assays, including the PCR-invader method (structure-specific 5' nuclease-based method), have been used to detect EGFR mutations in non-small-cell lung cancer (NSCLC). However, validation has not been reported. We assessed the detection rate of EGFR mutation by the PCR-invader method and direct sequencing using same clinical specimens. PATIENTS AND METHODS: EGFR mutations were analyzed with the PCR-invader method and compared with direct sequencing using paraffin tissues and pleural and pericardial effusions from NSCLC patients. The relationships between the treatment responses and mutations were evaluated retrospectively. RESULTS: Fifty-four samples from 42 NSCLC patients were studied. EGFR mutations were identified in 52% of the patients and 52% of the samples with the PCR-invader method, but only in 43% of the patients and in 35% of the samples by direct sequencing. In the samples obtained from the same patients at different sites and different times, EGFR mutations were coincident in nine out of ten patients by the PCR-invader method but in six out of ten patients by direct sequencing. Seventeen patients with EGFR mutations were treated with gefitinib; the response rate (RR) and disease control rate (DCR) were 41 and 94%, and median treatment duration was more than 6 months. Seven EGFR mutation-negative patients were treated with gefitinib; the RR and DCR were 0 and 14%, and median treatment duration was 1 month. CONCLUSION: The PCR-invader method was useful for detecting EGFR mutations in clinical lung cancer specimens and is more sensitive than direct sequencing.

Phase I study of topotecan and cisplatin in patients with small cell lung cancer.

OBJECTIVE: A single-agent topotecan has an indication for the treatment of small cell lung cancer in Japan. Previous studies demonstrated that topotecan combined with a platinum agent could provide additional antitumor efficacy. This study was to find the recommended dose of topotecan in combination with cisplatin and preferred administration sequence in untreated patients with extensive disease small cell lung cancer for Phase II study. METHODS: Patients received topotecan as a 30 min infusion for 5 days in escalating doses (starting at 0.5 mg/m(2)/day), and cisplatin at a fixed dose of 60 mg/m(2), 3 weeks cycle. This study employed the following stages: cisplatin was given before topotecan on day 1 to previously treated patients (Stage 1). After the maximum-tolerated dose level was achieved, the same schedule was applied for untreated patients (Stage 2). Subsequently, cisplatin was given after topotecan on day 5 to untreated patients (Stage 3). The recommended doses of cisplatin on day 1 and 5 schedules were estimated by considering results obtained from Stages 2 and 3, respectively. RESULTS: A total of 34 patients were enrolled. The maximum-tolerated doses in Stages 1-3 were estimated at 0.65, 0.65, and 1.4 mg/m(2), respectively. The recommended doses of cisplatin on day 1 and 5 schedules in untreated patients were determined at 0.65 and 1.0 mg/m(2), respectively. The major toxicity in this combination was hematological events. CONCLUSIONS: For treatment-naive patients, the combined use of 0.65/60 mg/m(2) topotecan/cisplatin with cisplatin on day 1 schedule or 1.0/60 mg/m(2) topotecan/cisplatin with cisplatin on day 5 schedule is recommended for Phase II study.

Single-agent gefitinib with concurrent radiotherapy for locally advanced non-small cell lung cancer harboring mutations of the epidermal growth factor receptor.

INTRODUCTION: A feasibility study was performed to examine the safety and toxicity profile of daily gefitinib (250 mg) administration with concurrent definitive thoracic radiation therapy (TRT) in patients with unresectable non-small cell lung cancer (NSCLC) of stage III. METHODS: Patients received a 14-day induction therapy with gefitinib at 250 mg daily. TRT was initiated on day 15 in 2-Gy fractions administered five times weekly to a total dose of 60 Gy. The primary end point of the study was the rate of treatment completion. Mutation status of the epidermal growth factor receptor gene (EGFR) was evaluated for patients with available tumor specimens. RESULTS: Nine eligible patients enrolled in the study received induction gefitinib monotherapy. Two patients were unable to begin TRT because of the development of progressive disease during the first 2 weeks of the protocol. Three of the remaining seven patients treated with gefitinib and concurrent TRT were unable to complete the planned treatment (two because of pulmonary toxicity and one because of progressive disease), and the study was therefore closed according to the protocol definition. Tumor samples were available for eight patients. EGFR mutations (deletion in exon 19) were detected in two patients, both of whom achieved a partial response and exhibited an overall survival of >5 years. CONCLUSIONS: Our results do not support further trials of gefitinib and TRT for unselected NSCLC patients. This therapeutic strategy may hold promise, however, for locally advanced NSCLC in patients with sensitizing EGFR mutations.

Long-term administration of second-line chemotherapy with S-1 and gemcitabine for platinum-resistant non-small cell lung cancer: a phase II study.

BACKGROUND: Standard second-line chemotherapies for non-small cell lung cancer (NSCLC) have been established but have limited clinical relevance. S-1 is a recently developed agent with potential activity against NSCLC. METHODS: Patients with confirmed NSCLC recurrence after previous single- or two-regimen chemotherapy with platinum, performance status of 0 to 1, adequate organ functions, and measurable lesions were treated with S-1 (60 mg/m/d, twice a day) on days 1 to 14 and gemcitabine (1000 mg/m) on days 8 and 15, which were repeated every 3 weeks until tumor progression. RESULTS: Treatment was administered for a median of 4 courses (range, 1-13) over a median of 125-day period in 34 patients. The overall response rate was 23.5% (no complete response and eight partial response; 95% confidence interval: 9.1-38.0%). The median progression-free and overall survival times were 6.6 and 19.9 months, respectively. The 1- and 2-year survival rates were 58.8 and 30.9%, respectively. Toxicity was mild during the entire treatment period, except for three grade 3 interstitial pneumonia. CONCLUSION: The primary end point was met with the relatively high overall response rate. Randomized phase III studies for elucidating survival outcome of the regimen are warranted.

Phase I/II trial of gemcitabine plus oral TS-1 in elderly patients with advanced non-small cell lung cancer: Thoracic oncology research group study 0502.

A phase I/II trial of TS-1 combined with gemcitabine was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients older than 70 years of age received TS-1 orally b.i.d. on days 1-14 and gemcitabine intravenously on days 8 and 15 every 4 weeks. In phase I (n=22), each cohort received escalating doses of TS-1 (30-40 mg/m(2) b.i.d.) and gemcitabine (800-1000 mg/m(2)); MTD was 40 mg/m(2) b.i.d. TS-1 and 1000 mg/m(2) gemcitabine; RD was 30 mg/m(2) b.i.d. TS-1 and 1000 mg/m(2) gemcitabine. Dose-limiting toxicities included a grade 3 infection, skin toxicity, and stomatitis. In phase II (n=37), the overall response rate was 27% (90% confidence interval (CI): 15-42%) and the median time to progression and overall survival were 4.2 months (90% CI: 3.2-5.7) and 12.9 months (90% CI: 10.4-14.7), respectively. The most common grade 3 or higher toxicity was neutropenia (45.9%), and thrombocytopenia was observed in 13.5% of patients. Two cases each of grade 3 pneumonitis and skin toxicity were observed, but nonhematological toxicities occurred at generally low frequencies. TS-1 with gemcitabine is a promising doublet regimen in elderly patients with advanced NSCLC with acceptable toxicities.

A phase II study of cisplatin and irinotecan as induction chemotherapy followed by accelerated hyperfractionated thoracic radiotherapy with daily low-dose carboplatin in unresectable stage III non-small cell lung cancer: JCOG 9510.

OBJECTIVE: It is important to find optimal regimens of cisplatin (CDDP)-based third-generation chemotherapy and radiotherapy for patients with unresectable Stage III non-small cell lung cancer (NSCLC). METHODS: This Phase II study was designed to determine the toxicity and efficacy of two courses of chemotherapy (CDDP 80 mg/m(2) on day 1 and irinotecan 60 mg/m(2) on days 1 and 8) followed by accelerated hyperfractionated thoracic radiotherapy (60 Gy/40 fractions in 4 weeks) combined with daily carboplatin (CBDCA) administration. CBDCA was administered at a target area under the plasma level-time curve of 0.4 x (24 h creatinine clearance + 25), according to Calvert's formula. RESULTS: Twenty-six patients were enrolled in the study. The patients' median age was 63 years (range 40-74 years) and included 22 males and 4 females. Seven patients were Stage IIIA and 19 were Stage IIIB. Twenty had a performance status (PS) of 1 versus six with a PS of 0. There was one treatment-related death due to sepsis and pneumonia associated with Grade 4 neutropenia and diarrhea during chemotherapy. Grade 3 or 4 neutropenia and diarrhea were observed in 14 and 5 patients, respectively. Toxicity of the radiotherapy was mild. There were 0 complete response and 13 partial responses, giving a response rate of 50.0%. Median survival time and 2-year survival were 16.4 months and 21.5%, respectively. This study was designed with Simon's two-stage design, and the response rate did not meet the criteria to proceed to the second stage and the study was terminated early. CONCLUSIONS: This regimen might be inactive for patients with unresectable Stage III NSCLC.

Dose-escalating and pharmacokinetic study of a weekly combination of paclitaxel and carboplatin for inoperable non-small cell lung cancer: JCOG 9910-DI.

OBJECTIVE: Combined paclitaxel and carboplatin is a standard regimen for inoperable non-small cell lung cancer (NSCLC). Although an every-3-week schedule is common, weekly paclitaxel is clinically effective for various cancers. A Phase I clinical trial was conducted to determine maximum-tolerated doses (MTDs) for weekly combined paclitaxel and carboplatin, and to evaluate anti-tumor response, toxicity and pharmacokinetics of paclitaxel in patients with inoperable NSCLC. METHODS: Twenty patients with inoperable NSCLC received weekly carboplatin at area under the curve (AUC) = 2 mg/ml min and paclitaxel. Paclitaxel was escalated if MTD was not reached. Three patients each were entered at levels 1 and 2 (level 1, paclitaxel 50 mg/m(2) and carboplatin AUC = 2 mg/ml min; level 2, 60/2), six at level 3 (70/2), five at level 4 (80/2) and three at level 5 (90/2). RESULTS: One patient had grade 4 (G4) neutropenia at level 2, one had G3 hepatic toxicity at level 3 and one had G3 cardiac toxicity at level 4. MTD was not reached for all dose levels. Response rate (RR) was 35% (7/20) and median survival was 11.1 months. Severe neutropenia (G3 and G4) was seen in seven patients associated with greater AUC, peak concentration (C(max)) and the duration of plasma concentration >50 ng/ml of paclitaxel. CONCLUSIONS: Weekly combined paclitaxel (up to 90 mg/m(2)) and carboplatin (AUC = 2 mg/ml min) was well tolerated. A higher dose intensity of paclitaxel can be given, and RR and survival are not less than the every-3-week protocol. The weekly regimen is an alternative for untreated inoperable NSCLC patients.

Efficacy and safety of erlotinib monotherapy for Japanese patients with advanced non-small cell lung cancer: a phase II study.

INTRODUCTION: The aim of this study was to evaluate the efficacy and safety of Erlotinib in Japanese patients with previously treated non-small cell lung cancer (NSCLC). Available tumor biopsy samples were analyzed to examine relationships between biomarkers and clinical outcome. METHODS: This open-label phase II trial enrolled stage III/IV NSCLC patients who had progressive disease after at least one prior platinum-based chemotherapy regimen. Erlotinib was administered at a dose of 150 mg/d orally until disease progression or intolerable toxicity. Analysis of epidermal growth factor receptor gene mutations in exon 18-21 by direct sequencing was performed in tumor tissue specimens obtained at the first diagnosis. RESULTS: Sixty-two patients were enrolled and 60 patients were evaluable for efficacy. Objective response rate and disease control rate were 28.3% and 50.0%; median time to progression and overall survival were 77 days and 14.7 months, respectively. In logistic regression analysis, only smoking history was proved to be a statistically significant predictive factor for response (odds ratio: 0.06, p < 0.001). Only 7 patients had samples available for mutation analysis. Three patients who had deletion mutations on exon 19 (del E746-A750 or del S752-I759) exhibited objective response. Common toxicities were rash (98%), dry skin (81%), and diarrhea (74%). Discontinuation due to adverse events occurred in 11 patients (18%). Four patients (6%) experienced interstitial lung disease-like events, one of whom died. CONCLUSIONS: Erlotinib is efficacious in Japanese patients with previously treated NSCLC. The toxicity profile was similar to that in Western patients, except for a somewhat higher incidence of skin disorders and interstitial lung disease. Further studies are needed to determine the relationship between epidermal growth factor receptor mutations and outcomes with Erlotinib in Japanese patients.

[Case of bilateral chylothorax with systemic lupus erythematosus complicated by steroid-/immunosuppressant-resistant pleural effusion].

A 20-year-old woman, with systemic lupus erythmatosus complicated by steroid-and immunosuppressant-resistant bilateral pleural effusion, was admitted to the emergency room because of dyspnea and fever. Chest Xray film revealed bilateral massive pleural effusion. Bilateral thoracocentesis yielded fluid with chyle. Conservative treatment including intravenous hyper-alimentation and continuous drainage were performed but with no remarkable improvement. She underwent thoracoscopy-aided ligation of the thoracic duct. After the operation, bilateral pleurodesis was performed by intrathoracic injection of OK-432, because of uncontrolled pleural effusion. There have been no signs of recurrence at 10 months in this case of SLE with steroid-and immunosuppressant-resistant pleural effusion.