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Background While immune checkpoint inhibitors (ICIs) have been shown to be effective for non-small cell lung cancer (NSCLC), their monotherapeutic response rate (RR) is roughly 20%. It has been noted that local radiation therapy (RT) might potentially activate off-target antitumor effect, which is so called “abscopal effect” induced by immune-mediated mechanism. We evaluated whether palliative-RT induced abscopal effect, resulting in improvement of Nivolumab (Nivo) effectiveness. Methods Pretreated advanced NSCLC patients (pts) who were indicated for Nivo and scheduled for palliative-RT were started on RT within 10 days of administration of Nivo 3 mg/kg q2 weeks until attached document was revised to 240 mg/body q2 weeks. The primary endpoint was RR of non-irradiated tumor lesions. Results Twenty-eight pts were enrolled from May 2016 to January 2019. The study was terminated before completion of targeted initial sample size (n = 35), because of poor accrual. The median age was 67 years (range: 53-89). 15 pts were male. 21 pts had adenocarcinoma histology, 2 pts squamous histology, and 6 pts driver oncogene alterations. 25 pts were PS0/1, and 3 pts PS2. 14 pts were treated as 2nd-line, 2 pts as 3rd-line, and 12 pts as 4th-line or later. The median number of treatment cycles was 4 (range: 1-6). Median radiation dose was 30 Gy (range: 25-40), and 16 pts were irradiated on the bone, 5 pts on the adrenal grand, and 2 pts on the primary lesion. The objective RR of non-irradiated tumor lesions was 14.3% (95% CI: 1.3–27.2). Partial response (PR) was observed in 3 pts treated as 2nd-line (3/14, 21.4%), and 1 pt as 3rd-line (1/2, 50%). No PR was observed in pts treated as 4th-line or later (0/12, 0%). The median PFS was 2.7 months (95% CI: 1.0–3.5). No severe and specific adverse events (AEs) of Nivo in combination with RT were observed compared to historical data of Nivo monotherapy. Conclusions Although the sample size was small, cleared abscopal effect by palliative-RT was not observed in Nivo treatment. However, some pts well responded to Nivo with palliative-RT during early-lines of treatment (2nd/3rd-line). Further investigations in the early-lines are warranted to evaluate a substantial synergistic effect of RT with ICIs. Clinical trial identification UMIN000023646. Legal entity responsible for the study HANSHIN Oncology Group. Funding ONO Pharmaceutical Company. Disclosure A. Hata: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Chugai; Research grant / Funding (institution): MSD. M. Satouchi: Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (institution): ONO; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Takeda; Speaker Bureau / Expert testimony: Taiho. D. Harada: Honoraria (self): ONO; Honoraria (self): BMS. All other authors have declared no conflicts of interest.

Background This report describes quality of life (QoL) findings of a randomized study comparing gefitinib with docetaxel in patients with advanced/metastatic pretreated non-small-cell lung cancer. Patients and methods This open-label, phase III study randomized 490 Japanese patients to gefitinib (250 mg/day) or docetaxel (60 mg/m2/3 weeks), with survival as the primary outcome. Preplanned QoL analyses included Functional Assessment of Cancer Therapy-Lung (FACT-L), Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS) improvement rates, and mean change from baseline. Results Gefitinib showed statistically significant benefits over docetaxel in QoL improvement rates (FACT-L 23% versus 14%, P = 0.023; TOI 21% versus 9%, P = 0.002) and mean change from baseline score [mean treatment difference: FACT-L 3.72 points, 95% confidence interval (CI) 0.55–6.89, P = 0.022; TOI 4.31 points, 95% CI 2.13–6.49, P Conclusions Gefitinib improved aspects of QoL over docetaxel, with superior objective response rate and a more favorable tolerability profile and no statistically significant difference in overall survival (although noninferiority was not statistically proven).

The purpose of this study was to evaluate the efficacy of gefitinib and the feasibility of screening for epidermal growth factor receptor (EGFR) mutations among select patients with advanced non-small cell lung cancer (NSCLC). Stage IIIB/IV NSCLC, chemotherapy-naive patients or patients with recurrences after up to two prior chemotherapy regimens were eligible. Direct sequencing using DNA from tumour specimens was performed by a central laboratory to detect EGFR mutations. Patients harbouring EGFR mutations received gefitinib. The primary study objective was response; the secondary objectives were toxicity, overall survival (OS), progression-free survival (PFS), 1-year survival (1Y-S) and the disease control rate (DCR). Between March 2005 and January 2006, 118 patients were recruited from 15 institutions and were screened for EGFR mutations, which were detected in 32 patients – 28 of whom were enrolled in the present study. The overall response rate was 75%, the DCR was 96% and the median PFS was 11.5 months. The median OS has not yet been reached, and the 1Y-S was 79%. Thus, gefitinib chemotherapy in patients with advanced NSCLC harbouring EGFR mutations was highly effective. This trial documents the feasibility of performing a multicentre phase II study using a central typing laboratory, demonstrating the benefit to patients of selecting gefitinib treatment based on their EGFR mutation status.

Background To compare the efficacy and toxicity of three platinum-based combination regimens against cisplatin plus irinotecan (IP) in patients with untreated advanced non-small-cell lung cancer (NSCLC) by a non-inferiority design. Patients and methods A total of 602 patients were randomly assigned to one of four regimens: cisplatin 80 mg/m(2) on day 1 plus irinotecan 60 mg/m(2) on days 1, 8, 15 every 4 weeks (IP) carboplatin AUC 6.0 min x mg/mL (area under the concentration-time curve) on day 1 plus paclitaxel 200 mg/m(2) on day 1 every 3 weeks (TC); cisplatin 80 mg/m(2) on day 1 plus gemcitabine 1000 mg/m(2) on days 1, 8 every 3 weeks (GP); and cisplatin 80 mg/m(2) on day 1 plus vinorelbine 25 mg/m(2) on days 1, 8 every 3 weeks (NP). Results The response rate, median survival time, and 1-year survival rate were 31.0%, 13.9 months, 59.2%, respectively, in IP; 32.4%, 12.3 months, 51.0% in TC; 30.1%, 14.0 months, 59.6% in GP; and 33.1%, 11.4 months, 48.3% in NP. No statistically significant differences were found in response rate or overall survival, but the non-inferiority of none of the experimental regimens could be confirmed. All the four regimens were well tolerated. Conclusion The four regimens have similar efficacy and different toxicity profiles, and they can be used to treat advanced NSCLC patients.

The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of pemetrexed with folate and vitamin B12 supplementation (FA/VB(12)) in Japanese patients with solid tumours and to investigate the safety, efficacy, and pharmacokinetics of pemetrexed. Eligible patients had incurable solid tumours by standard treatments, a performance status 0-2, and adequate organ function. Pemetrexed from 300 to 1,200 mg m(-2) was administered as a 10-min infusion on day 1 of a 21-day cycle with FA/VB(12). Totally, 31 patients were treated. Dose-limiting toxicities were alanine aminotransferase (ALT) elevation at 700 mg m(-2), and infection and skin rash at 1,200 mg m(-2). The MTD/RD were determined to be 1,200/1,000 mg m(-2), respectively. The most common grade 3/4 toxicities were neutropenia (grade (G) 3:29, G4:3%), leucopenia (G3:13, G4:3%), lympopenia (G3:13%) and ALT elevation (G3:13%). Pemetrexed pharmacokinetics in Japanese were not overtly different from those in western patients. Partial response was achieved for 5/23 evaluable patients (four with non-small cell lung cancer (NSCLC) and one with thymoma). The MTD/RD of pemetrexed were determined to be 1,200/1,000 mg m(-2), respectively, that is, a higher RD than without FA/VB(12) (500 mg m(-2)). Pemetrexed with FA/VB(12) showed a tolerable toxicity profile and potent antitumour activity against NSCLC in this study.

Combination chemotherapy with irinotecan (CPT-11) and platinum compounds is effective for treating cervical cancer. Nedaplatin (254-S) is a new cisplatin analogue that achieves a high response rate (53%) in patients with primary cervical cancer. We performed a phase I-II study of combination chemotherapy with CPT-11 plus 254-S for advanced or recurrent cervical cancer. The inclusion criteria were stage IV disease or recurrence. CPT-11 and 254-S were administered intravenously on day 1, while rhG-CSF (50 microg) was given on days 3-12. This regimen was repeated after 4 weeks. Dose escalation was carried out in tandem (CPT-11/254-S: 50/70, 50/80, and 60/80 mg m(-2)). A total of 27 patients (stage IV=seven, recurrence=20) were enrolled. The phase I study enrolled eight patients. At dose levels 1 and 2, no dose-limiting toxicities were observed. At dose level 3, the first two patients developed DLTs. The maximum tolerated dose of CPT-11 and 254-S was 60 and 80 mg m(-2), respectively, and the recommended doses were 50 and 80 mg m(-2). Grade 3/4 haematologic toxicity occurred in 67% in phase II study, but there were no grade 3 non-haematologic toxicities except for nausea or lethargy. In all 27 patients, there were two complete responses (7%) and 14 Partial responses (52%), for an overall response rate of 59% (95% confidence interval: 39-78%). Among the 12 responders with recurrent disease, the median time to progression and median survival were 161 days (range: 61-711 days) and 415 days (range: 74-801 days). This new regimen is promising for cervical cancer.

Background The purpose of this study was to evaluate the toxicity and antitumor effect of cisplatin, irinotecan and etoposide combinations on two schedules, arms A and B, for previously untreated extensive small-cell lung cancer (E-SCLC), and to select the right arm for phase III trials. Patients and methods Sixty patients were randomized to receive either arm A (cisplatin 25 mg/m2 day 1, weekly for 9 weeks, irinotecan 90 mg/m2 day 1, on weeks 1, 3, 5, 7 and 9, and etoposide 60 mg/m2 days 1–3, on weeks 2, 4, 6, 8), or arm B (cisplatin 60 mg/m2 day 1, irinotecan 60 mg/m2 days 1, 8, 15, and etoposide50 mg/m2 days 1–3, every 4 weeks for four cycles). Prophylactic granulocyte colony-stimulating factor support was provided in both arms. Results Full cycles were delivered to 73% and 70% of patients in arms A and B, respectively. Incidences of grade 3–4 neutropenia, anemia, thrombocytopenia, infection and diarrhea were 57, 43, 27, 7 and 7%, respectively, in arm A, and 87, 47, 10, 13 and 10%, respectively, in arm B. A treatment-related death developed in one patient in arm A. Complete and partial response rates were 7% and 77%, respectively, in arm A, and 17% and 60%, respectively, in arm B. Median survival time was 8.9 months in arm A, and 12.9 months in arm B. Conclusions Arm B showed a promising complete response rate and median survival with acceptable toxicity in patients with E-SCLC, and should be selected for the investigational arm in phase III trials.

To determine a standard combination chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC), we conducted a phase III trial of irinotecan (CPT-11) to test the hypotheses that CPT-11+cisplatin is superior to cisplatin+vindesine and that CPT-11 monotherapy is not inferior to cisplatin+vindesine. A total of 398 patients with previously untreated NSCLC were randomised to receive cisplatin+CPT-11 (CPT-P), cisplatin+vindesine (VDS-P) or CPT-11 alone (CPT). In the CPT-P arm, CPT-11 60 mg m(-2) was administered on days 1, 8 and 15, and cisplatin 80 mg m(-2) was administered on day 1. In the VDS-P arm, cisplatin 80 mg m(-2) was administered on day 1, and vindesine 3 mg m(-2) was administered on days 1, 8 and 15. In the CPT arm, CPT-11 100 mg m(-2) was administered on days 1, 8 and 15. The median survival time was 50.0 weeks for patients on CPT-P, 45.6 weeks for those on VDS-P and 46.0 weeks for those on CPT (P=0.115, CPT-P vs VDS-P; P=0.089, CPT vs VDS-P), and the hazard ratio was 0.85 (95% confidence interval (CI): 0.65-1.11) for CPT-P vs VDS-P and 0.83 (0.64-1.09) for CPT vs VDS-P. The response rate was 43.7% for patients on CPT-P, 31.7% for those on VDS-P and 20.5% for those on CPT. Major adverse reactions were grade 4 neutropenia observed in 37, 54 and 8% of the patients on CPT-P, VDS-P and CPT, respectively; and grades 3 and 4 diarrhoea observed in 12, 3 and 15% of the patients, respectively. CPT-P therapy produces comparable survival to VDS-P in patients with advanced NSCLC. CPT-11 monotherapy is not inferior to VDS-P in terms of survival. The CPT-11-containing regimen is one of the most efficacious and well tolerated in the treatment of advanced NSCLC.

Background: Patients with cervical cancer who develop pelvic recurrence after primary surgery are usually treated with radiation-based therapy. However, their prognoses are dismal. We conducted a phase I study of combined radiation, hyperthermia and intra-arterial (IA) carboplatin for local recurrence of cervical cancer. Patients and methods: Patients with local recurrence of cervical cancer without extrapelvic recurrence were included in this study. Carboplatin was given as a 5-min IA infusion without hydration just before pelvic radiation every day. External pelvic irradiation (1.8 Gy/day for 28 days) was performed according to local standard schedules. After 20 Gy had been administered, hyperthermia was performed once a week with a radio frequency heating system for four cycles. Results: Fifteen patients were entered through the four dose levels of carboplatin. The maximum tolerated dose was determined to be 25 mg/m2 and the dose-limiting toxicities were leukocytopenia, neutrocytopenia and diarrhea. Grade 3/4 leukocytopenia and diarrhea were observed in nine (60%) and three (20%) of 15 patients. Tumor responses included five complete responses and nine partial responses, and the overall response rate was 93.3% (14 of 15) (95% confidence interval 59.4% to 100%). Tumor reductions were observed only at 20 Gy in 10 cases of 14 responders (71.4%). Conclusion: The combination therapy of radiation, hyperthermia and IA carboplatin is safe and well-tolerated for locally recurrent cervical cancer.

Dose-escalation study was performed to evaluate the maximum tolerated dose, recommended dose and toxicity profile of weekly irinotecan with daily carboplatin and concurrent thoracic radiotherapy in patients with locally advanced non-small-cell lung cancer. Thirty-one previously untreated patients with unresectable stage III non-small-cell lung cancer were enrolled in this study. Patients received weekly irinotecan plus carboplatin (20 mg m−2 daily for 5 days a week) for 4 weeks and thoracic radiotherapy (60 Gy in 30 fractions). The irinotecan dose was escalated from 30 mg m−2 in increments of 10 mg m−2. Four irinotecan dose levels were given and 30 patients were assessable. Their median age was 62 years (range: 52–72 years), 28 had a performance status of 0–1 and two had a performance status of 2, 12 had stage IIIA disease and 18 had IIIB disease. There were 19 squamous cell carcinomas, 10 adenocarcinomas, and one large cell carcinoma. The dose-limiting toxicities were pneumonitis, esophagitis, thrombocytopenia and neutropenia. The maximum tolerated dose of irinotecan was 60 mg m−2, with two patients developing grade 4 pulmonary toxicity and one patient died of pneumonitis (grade 5). The recommended dose of irinotecan was 50 mg m−2. Other grade 3 or 4 toxicities were nausea and vomiting. Three patients achieved complete remission and 15 had partial remission, for an objective response rate of 60.0%. The median survival time was 14.9 months, and the 1- and 2-year survival rates were 51.6% and 34.2%, respectively. The study concluded that the major toxicity of this regimen was pneumonitis. This therapy may be active against unresectable non-small-cell lung cancer and a phase II study is warranted. British Journal of Cancer (2002) 87, 258–263. doi:10.1038/sj.bjc.6600464 www.bjcancer.com © 2002 Cancer Research UK

9034 Background: Irreversible EGFR-TKI monotherapies showed only moderate efficacy after AR to reversible EGFR-TKIs. Preclinical studies suggested that addition of Bev to EGFR-TKIs could overcome AR, and Bev demonstrated synergistic effects with Afa in TKI-resistant xenograft models. Methods: ECOG PS 0-2 patients (pts) with EGFR-mutant NSCLC after AR to EGFR-TKIs were enrolled at any lines. Rebiopsy was essential to confirm T790M status after AR. Afa was prescribed at 30 mg, and Bev administered at 15 mg/kg tri-weekly until progression. Results: Between October 2014 and September 2016, 33 eligible pts were enrolled. Median age was 66 (range, 48-86). Twenty-one (64%) pts were female, and 22 (67%) were never smoker. Mutation subtypes were 20 (61%) Del-19, 12 (36%) L858R, and 1 (3%) L861Q. T790M was detected in 14 (42%) pts. Median number of prior regimens was 4 (range, 1-10). First prior TKIs were 20 (61%) gefitinib, 10 (30%) erlotinib or 3 (9%) Afa. Six pts obtained partial response and 23 stable disease, resulting in response rate (RR) of 18.2% (95% confidence interval [CI], 7.0-35.5%) and disease control rated of 87.9% (95% CI, 71.8-96.6%). Median progression-free survival (PFS) and overall survival were 5.9 (95% CI, 3.5-8.8) months and not reached, respectively. Median RR and PFS of T790M+ vs. T790M- were 14.3% vs. 21.2% (p = 0.6189) and 6.2 vs. 5.2 months (p = 0.8619), respectively. Median RR and PFS of Del-19 vs. L858R were 20.0% vs. 8.3% (p = 0.3789) and 5.9 vs. 5.1 months (p = 0.8996), respectively. Afa dosage was reduced to 20 mg in 15 (45%) pts and increased to 40 mg in 2 (6%) pts. Median number of Bev administrations was 6 (range, 1-14). Bev was interrupted in 5 (15%) pts. Adverse events ≥grade 3: rash (3%); paronychia (24%); mucositis (6%); diarrhea (3%); liver dysfunction (3%); hypertension (39%); and proteinuria (15%) were observed. There were no treatment-related deaths, interstitial lung disease, nor Bev-associated severe bleedings. Conclusions: Afa + Bev demonstrated the efficacy and safety after AR to EGFR-TKIs. It could be a therapeutic salvage option for T790M- populations. Clinical trial information: UMIN000014710.

Several trials have confirmed that the pathological complete response (pCR) rates after neoadjuvant chemotherapy (NAC) are significantly lower in HER2-positive/ER-positive patients than in HER2-positive/ER-negative patients. To understand this phenomenon, we investigated the association between NAC resistance and CCND1, which is frequently overexpressed in ER-positive tumors. Pretreatment formalin-fixed tumor tissues were collected from 75 HER2-positive patients receiving NAC comprised anthracyclines, taxanes, and trastuzumab. Seventeen gene transcripts along with PIK3CA mutations were detected using MassARRAY (Sequenom, San Diego, CA). The gene expression levels were dichotomized according to the median values. The immunohistochemical expression of ER, PTEN, BCL-2, and cyclin D1 was scored. The relationship between the variables was assessed using the Spearman correlation. A logistic regression analysis was performed to detect predictors of pCR, which was defined as no invasive tumor in the breast or axilla. Forty-seven percent of the cases were ER-positive and 52 % (40/63 % in ER-positive/ER-negative) achieved a pCR. Among the ER-positive patients, the CCND1 gene expression level was 2.1 times higher than that in ER-negative patients and was significantly correlated with the expression of cyclin D1 protein. In a univariate analysis, a pCR was associated with high mRNA levels of ESR1, PGR, LMTK3, HER2, IGF1R, INPP4B, PDL-1, BCL-2, and CCND1 (P ≤ 0.05). In contrast, none of these genes were significantly correlated with a pCR among the ER-negative tumors and only EGFR was significantly correlated with a pCR. PIK3CA mutations or PTEN loss were not associated with a pCR in either group. After excluding ESR1 (r = 0.58), PGR (r = 0.64), and IGF1R (r = 0.59), the expressions of which were correlated with CCND1, a multivariate analysis revealed that CCND1 [P = 0.043; OR, 0.16] and HER2 [P = 0.012; OR, 11.2] retained its predictive value for pCR among ER-positive patients, but not among ER-negative patients. A High Level of CCND1 gene expression is a poor predictor of a pCR and provides a rationale for evaluating CDK4/6 inhibitors in HER2-positive/ER-positive breast cancer patients.

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities, and the response rate of irinotecan administered weekly with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, surgically unresectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) were enrolled. Irinotecan was administered as a 90 min intravenous infusion once weekly for 6 weeks. The starting dose was 30 mg m−2 and dose escalation was done in 15 mg m−2 increments. Dose-limiting toxicity was defined as grade 3 nonhaematologic toxicity (excluding nausea, vomiting and alopecia) or grade 4 haematologic toxicity according to the WHO criteria. Radiation was delivered to the primary tumour and regional lymph nodes (40 Gy), followed by a boost to the primary tumour (20 Gy). Twenty-seven patients were entered into this study at three irinotecan dose levels (30, 45 and 60 mg m−2). Twenty-six eligible patients were evaluated for toxic effects and clinical outcome. Severe oesophagitis, pneumonitis, and diarrhoea occurred at 45 and 60 mg m−2. Three of the five patients given 60 mg m−2 developed grade 3 or 4 oesophagitis and pneumonitis. In addition, one patient died of pneumonitis after completing therapy at 45 mg m−2 in the phase II study. The objective response rate was 76.9% (95% CI, 53.0–88.9%). Oesophagitis, pneumonitis, and diarrhoea are the dose-limiting toxicities of weekly irinotecan combined with thoracic irradiation. The maximum tolerated dose and the dose for the phase II study were 60 and 45 mg m−2 wk−1, respectively. This combined therapy for locally advanced non-small cell lung cancer is promising and shows acceptable toxicity. © 1999 Cancer Research Campaign

A phase I trial of the combination of irinotecan (CPT-11) with cisplatin in advanced non-small cell lung cancer (NSCLC) showed a very promising response rate of 54% in previously untreated NSCLC patients. This study was conducted to confirm the activity and toxicities of CPT-11 and cisplatin combination for previously untreated NSCLC in a multi-institutional phase II study. Seventy patients with stage IIIB or IV NSCLC received CPT-11 60 mg m(-2) intravenously (i.v.) on days 1, 8 and 15, and cisplatin 80 mg m(-2) (i.v.) on day 1 every 4 weeks. Assessments were made of response, survival and toxicities. Sixty-nine were eligible, and evaluable for toxicities and survival, and 64 patients evaluable for response. Thirty-three patients (52%; 95% confidence interval 39-64%) achieved an objective response, with one complete response (2%) and 32 partial responses (50%). The median duration of response was 19 weeks and the overall median survival time was 44 weeks. The 1-year survival rate was 33%. The major toxic effects were leucopenia and diarrhoea. Grade 3 or 4 leucopenia, neutropenia, and diarrhoea occurred in 32 patients (46%), 53 patients (80%), and 13 patients (19%) respectively. A combination of CPT-11 and cisplatin is very effective against non-small-cell lung cancer with acceptable toxicities.

A phase II trial was conducted to evaluate the efficacy and toxicity of the Egorin's carboplatin dosing formula with 14-day oral etoposide in 38 elderly patients with small-cell lung cancer (SCLC). The overall response rate was 81%. Median survival times were 15.1 months for 16 limited-disease (LD) and 8.6 months for 22 extensive-disease (ED) patients. Myelosuppression was the principal side-effect. This regimen is an active regimen in the treatment of elderly SCLC patients.

The importance of the dose intensity of chemotherapy in achieving maximal therapeutic effect has recently been reported for several chemosensitive malignant diseases, with Murray et al. reporting that intensive weekly chemotherapy using the cisplatin, vincristine, doxorubicin, and etoposide (CODE) regimen in small-cell lung cancer (SCLC) is very effective. However, leukopenia is the major obstacle to delivering the planned dose in intensive regimens. Therefore, we investigated whether recombinant human granulocyte colony-stimulating factor (rhG-CSF) could allow full drug doses to be given as scheduled, thereby improving the final outcome. Extensive-stage (ES) SCLC patients were randomized to receive either CODE alone or CODE with rhG-CSF, with the CODE regimen consisting of cisplatin given i.v. at 25 mg/m2 weekly for 9 weeks; vincristine given i.v. at 1 mg/m2 during weeks 1, 2, 4, 6, and 8; and doxorubicin given i.v. at 40 mg/m2 and etoposide given i.v. at 80 mg/m2 for 3 days during weeks 1, 3, 5, 7, and 9, rhG-CSF at 50 micrograms/m2 was given s.c. on the days on which cytotoxic drugs were not given. From May 1989 to September 1991; 64 patients were enrolled in the study, of whom 63 were analyzable (31 for CODE alone and 32 for CODE with rhG-CSF). No difference in any of the patients' characteristics except gender was found between the two groups. The complete response (CR) rate was 34% in the CODE with rhG-CSF group and 23% in the CODE alone group; the median survival was 59 and 32 weeks, respectively, in these groups (P = 0.004). Therefore CODE with rhG-CSF improved the survival of ES SCLC patients. On the basis of these results a phase III study to determine whether CODE with rhG-CSF would increase survival as compared to the standard regimen in ES SCLC was designed by the Japan Clinical Oncology Group.

Sixty-three patients with extensive-stage small-cell lung cancer were randomized to receive either cyclophosphamide, vincristine, doxorubicin and etoposide (CODE) alone or CODE plus recombinant human granulocyte colony-stimulating factor (rhG-CSF). rhG-CSF administration in support of CODE chemotherapy resulted in increased mean total received dose intensity for all drugs (P = 0.03) with a significant improvement in survival (P = 0.004).

Summary Purpose We compared the activity and toxicity of vinorelbine (VRB) and vindesine (VDS) in a randomized crossover study in patients with previously untreated stages IIIB or IV non-small-cell lung cancer (NSCLC). Patients and methods Two hundred four patients were assessable for response and toxicity. VRB was administered at a dose of 25 mg/m2 weekly and VDS at a dose of 3 mg/m2 weekly. Patients who failed to respond after 4 cycles of initial monotherapy were switched to a combination chemotherapy (VRB → VDS + cisplatin (P) or VDS ← VRB + P). Results Objective response was observed in 31.1% of patients in the VRB arm versus 8.9% of those in the VDS arm (P = 0.0002). The median duration of response to VRB was 18.5+ weeks (range, 7.9 to 107.5+ weeks) compared with 11.7+ weeks (range, 6.0 to 35.0+ weeks) for VDS. Of the 69 patients who failed to respond to initial monotherapy, 33 in the VRB group who subsequently received VDS + P did not respond and 13 (26.5%) of 49 initially on VDS who received subsequent VRB + P responded. The rates of grades 3 and 4 leukopenia were similar in the two monotherapy arms (VRB, 55.3% vs. VDS, 48.5%). However, grade 3 anemia was more frequent in the patients on VRB than in those on VDS. The incidence of peripheral neurotoxicity was significantly higher with VDS than with VRB (P = 0.002), but VRB induced a slightly higher rate of local cutaneous reaction than VDS (P = 0.012). With the combination of cisplatin and these vinca alkaloids, peripheral neurotoxicity was less frequent in the VRB group than in the VDS group. Conclusion Our results demonstrate that VRB yields a higher response rate than VDS in stage IIIB or IV NSCLC, with the same extent of toxicity in terms of leukocytopenia. The peripheral neurotoxic effects were also milder with VRB than with VDS. In second-line chemotherapy, there was a notable difference in response between the VRB + P and VDS + P regimens.

In this study, we compare the time to normalization of CA125 after cytoreductive surgery between a paclitaxel-containing regimen and a non-paclitaxel regimen. This study demonstrates that CA125 regression in a paclitaxel-containing regimen was slower than that in a non-paclitaxel regimen. When we determine the CA125 regression rate to predict overall survival in ovarian cancer, we should take into account the kind of chemotherapy regimen, especially the use of paclitaxel.

We have conducted a Phase I trial to determine the maximum tolerated dose of CPT-11 together with a fixed dose of cisplatin in patients with advanced lung cancer, and the dose-limiting toxicities of this combination. Fourteen previously untreated patients with stage IIIB or IV disease were treated with CPT-11 (90-min intravenous infusion on days 1, 8, and 15) plus cisplatin (60 mg m-2, intravenously on day 1). The starting dose of CPT-11 was 60 mg m-2, and diarrhea was the dose-limiting toxicity at the 90 mg m-2 dose level. All three patients (all four cycles) given 90 mg m-2 of CPT-11 experienced grade 3 diarrhea. Hematologic toxicity was relatively mild. Elimination of CPT-11 was biphasic with a mean (+/- s.d.) beta half-life of 11.36 +/- 7.26 h. The mean terminal half-life of the major metabolite (7-ethyl-10-hydroxycamptothecin; SN-38) was 22.13 +/- 13.28 (s.d.) h, and modest escalation of the CPT-11 dose from 80 mg m-2 to 90 mg m-2 resulted in a statistically significant apparent increase in the plasma concentrations of SN-38. There were one complete response (7%) and five partial responses (36%) among the 14 patients for an overall response rate of 43%. The recommended dose for Phase II studies is 80 mg m-2 of CPT-11 and 60 mg m-2 of cisplatin.

PURPOSE The purpose of this study was to determine the maximum-tolerated dose and the dose-limiting toxicities of CPT-11, a new derivative of camptothecin, in combination with a fixed dose of cisplatin in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Twenty-seven previously untreated patients with stage IIIB or IV NSCLC were assessable for toxicity, and 26 were assessable for response. The initial dose of CPT-11 was 30 mg/m2 given as a 90-minute intravenous (IV) infusion on days 1, 8, and 15 in combination with cisplatin (80 mg/m2 IV on day 1) given every 4 weeks. The dose of CPT-11 was escalated in increments of 10 mg/m2 until severe or life-threatening toxic effects were observed. RESULTS Significant toxicity was infrequent up to 60 mg/m2 of CPT-11. The maximum-tolerated toxicity was reached at a dose of 70 mg/m2. Three of six patients either had leukocyte count nadirs of less than 2,000/microL or experienced grade 4 diarrhea during the first cycle of therapy at 70 mg/m2. The major toxic effects were leukopenia and diarrhea. There were 14 partial responses (54%) among the 26 patients. CONCLUSIONS A combination of CPT-11 and cisplatin seems to be effective against NSCLC with acceptable toxicities. The recommended dose for phase II studies is 60 mg/m2 of CPT-11 on days 1, 8, and 15, and 80 mg/m2 of cisplatin on day 1 every 4 weeks.

Background This trial evaluated whether a combination of docetaxel and gemcitabine provides better survival than docetaxel alone in patients with previously treated non-small-cell lung cancer (NSCLC). Patients and methods Eligibility included pathologically or cytologically proven NSCLC, failure of one platinum-based regimen, performance status of zero or one, 20–75 years old, and adequate organ function. Patients received docetaxel 60 mg/m2 (day 1) or docetaxel 60 mg/m2 (day 8) and gemcitabine 800 mg/m2 (days 1 and 8), both administered every 21 days until disease progression. Results Sixty-five patients participated in each arm. This trial was terminated early due to an unexpected high incidence of interstitial lung disease (ILD) and three treatment-related deaths due to ILD in the combination arm. Docetaxel plus gemcitabine compared with docetaxel-alone patients experienced similar grade and incidence of toxicity, except for ILD. No baseline factor was identified for predicting ILD. Median survival times were 10.3 and 10.1 months (one-sided P = 0.36) for docetaxel plus gemcitabine and docetaxel arms, respectively. Conclusion Docetaxel alone is still the standard second-line treatment for NSCLC. The incidence of ILD is higher for docetaxel combined with gemcitabine than for docetaxel alone in patients with previously treated NSCLC.

Patients with inoperable non-small-cell lung cancer (NSCLC) were randomly assigned to receive one of three dosage regimens: (1) vindesine and cisplatin (VP); (2) mitomycin, vindesine, and cisplatin (MVP); or (3) etoposide and cisplatin alternating with vindesine and mitomycin (EP/VM). In 199 assessable patients, the response rates were VP, 33%; MVP, 43%; and EP/VM, 19%. The addition of mitomycin to the VP regimen did not significantly improve the response rate. The response rate was significantly lower with the EP/VM regimen than with the MVP regimen (P less than .01). The median survival times were VP, 50 weeks; MVP, 42 weeks; and EP/VM, 40 weeks. These differences were not significant. Grade III or IV thrombocytopenia was significantly greater (P less than .01) in MVP patients (22%) than in the VP (5%). Other toxicities were similar in the three groups. Analyses of prognostic factors showed that treatment with MVP, sex, and histologic classification (squamous cell carcinoma) were predictive of improved response. Important factors for improved survival, according to the Cox regression analysis, were the stage of disease, performance status, sex, weight loss before diagnosis, and hemoglobin concentration.

切除不能の肺非小細胞癌17例に対して, シスプラチン (100mg/m2, day 1), ビンデシン (3mg/m2, daylandday8) と胸部放射線照射 (2Gy/day, day 2～15) の同時併用療法を行った.適格例は16例で, 腫瘍効果はPR12例, NC3例, PD1例, 奏効率は75%であった.骨髄抑制は強く, 食道炎も高頻度に発生したが一過性で, その他に重篤な合併症はみられなかった.本療法は許容範囲内の副作用で, 高い奏効率が示されたことから, III A, III B期の切除不能肺非小細胞癌に有効な治療法と考えられた.

Gemcitabine and docetaxel are non-platinum agents with activity in non-small cell lung cancer (NSCLC). This study was conducted to determine and evaluate the recommended regimen of gemcitabine-docetaxel and evaluated its efficacy and safety in chemonaive Japanese NSCLC patients.In phase I, patients with stage IIIB/IV NSCLC were randomized and received either gemcitabine on days 1 and 8 plus docetaxel on day 1 or gemcitabine on days 1 and 8 plus docetaxel on day 8. The recommended regimen was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. Efficacy and toxicity were evaluated in all patients.Twenty-five patients were enrolled in phase I and six patients were given the recommended regimen; gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 50 mg/m(2) on day 8. An additional 34 patients were enrolled into phase II and administered with the recommended regimen. The response rate was 32.2% [95% confidence interval (CI) 20.6-45.6%] overall and 30.0% (95% CI 16.6-46.5%) in patients with the recommended regimen (40 patients). Although grade 3 interstitial pneumonia was observed in two patients (5.0%) who received the recommended regimen, both recovered shortly after steroid treatment. No unexpected events were observed throughout this study.Gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 50 mg/m(2) on day 8 has comparable efficacy and more tolerable toxicities than previously reported platinum-based regimens. These results should be verified by a phase III study.

Background Amrubicin, a totally synthetic 9-amino-anthracycline, demonstrated excellent single-agent activity for extensive-stage small-cell lung cancer (ED-SCLC). The aims of this trial were to determine the maximum-tolerated doses (MTD) of combination therapy with amrubicin and cisplatin, and to assess the efficacy and safety at their recommended doses (RD). Patients and methods Eligibility criteria were patients having histologically or cytologically proven measurable ED-SCLC, no previous systemic therapy, an Eastern Cooperative Oncology Group performance status of 0–2 and adequate organ function. Amrubicin was administered on days 1–3 and cisplatin on day 1, every 3 weeks. Results Four patients were enrolled at dose level 1 (amrubicin 40 mg/m2/day and cisplatin 60 mg/m2) and three patients at level 2 (amrubicin 45 mg/m2/day and cisplatin 60 mg/m2). Consequently, the MTD and RD were determined to be at level 2 and level 1, respectively. The response rate at the RD was 87.8% (36/41). The median survival time (MST) was 13.6 months and the 1-year survival rate was 56.1%. Grade 3/4 neutropenia and leukopenia occurred in 95.1% and 65.9% of patients, respectively. Conclusions The combination of amrubicin and cisplatin has demonstrated an impressive response rate and MST in patients with previously untreated ED-SCLC.

Unfortunately, non-small-cell lung cancer (NSCLC) is a member of the group of neoplastic diseases that is relatively chemoresistant. Recent meta-analyses show that cisplatin-based chemotherapy improves survival (Non-Small Cell Lung Cancer Collaborative Group, 1995), and it is considered a standard treatment for NSCLC, Most cisplatin-based regimens have substantial toxicities that require close monitoring and supportive care. Thus, there is a need to develop active and less toxic chemotherapy regimens that include new active compounds with novel mechanisms of action. In the 1990s, several new, active therapies with single-agent response rates of 15–30% became available for NSCLC, including irinotecan, docetaxel, paclitaxel, vinorelbine, and gemcitabine. Because irinotecan and docetaxel were approved for NSCLC earlier than the other drugs in Japan, development of regimens containing irinotecan or docetaxel is more advanced. Docetaxel 60 mg m−2 showed good antitumour activity against advanced NSCLC (Kunitoh et al, 1996), and the combination of docetaxel plus cisplatin (DC) is one of the most effective regimens for advanced NSCLC (Rodriguez et al, 2001; Schiller et al, 2002). Studies in Japan included a phase II study in which DC yielded a response rate of 42% (Okamoto et al, 2002), and a phase III study in which DC was associated with better survival than the vindesine and cisplatin (VC) combination (Kubota et al, 2002). Irinotecan demonstrated activity similar to that of VC in stage IIIb/IV NSCLC (Negoro et al, 2003), and significant longer overall survival time than VC in stage IV NSCLC (Fukuoka et al, 2000). We reported a phase I study of docetaxel plus irinotecan (DI) in patients with advanced NSCLC, in which a promising response rate of 48% and the median survival time of 48 weeks were achieved with acceptable toxicities (Masuda et al, 2000). Thus, DI appeared to be a promising non-cisplatin-containing regimen. Based on the above findings, we conducted a randomised trial of DC vs DI in patients with advanced NSCLC to compare the respective response rates, survival data, and toxicity profiles of the two regimens. This was a multicentred phase II study.

Background This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included. Patients and methods Patients initially received a single oral dose of gefitinib followed by 10–14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT). Results Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. Cmax was reached within 3–7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8–79.7 h). A partial response (duration 35–361 days) was observed in five of the23 patients with non-small-cell lung cancer over a range of doses (225–700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40–127 days). Conclusions In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.

Aim: Use of plasma DNA to detect mutations has spread widely as a form of liquid biopsy. The gatekeeper T790M mutation of EGFR has been observed in half of lung cancer patients who acquired resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI). We recently developed a novel sensitive, fully-automated monitoring system, MBP-QP(mutaton-based PCR and quenching probe), to detect T790M using plasma DNA. This study was performed to determine the usefulness of the MBP-QP method for monitoring T790M during treatment with EGFR-TKI. Methods: This was a prospective, multicenter, observational study involving lung adenocarcinoma patients carrying EGFR activating mutations, such as L858R and exon 19 deletions, who were treated with EGFR-TKI. The primary objective was to determine whether T790M could be detected using plasma DNA at the time of progressive disease (PD). The secondary objective was to assess correspondence between T790M measured using plasma and that using cancer specimens. The association between detection of T790M and effect of EGFR-TKI was also investigated as an exploratory objective. Results: Ninety non-small cell lung cancer patients treated with EGFR-TKI were enrolled from seven hospitals in Japan: 92.1% had adenocarcinoma, 62% at stage IV, and 29% had postoperative recurrent disease. According to the investigators' evaluations, T790M was detected in 26% (15/58) of the patients who acquired resistance to EGFR-TKI. A central review showed that the frequency of T790M positives among the patients with PD was 22% (12/55). When EGFR-TKI was discontinued because of PD, T790M was detected in 33% (17/52), whereas any patients who were discontinued for other reasons such as adverse effects did not show T790M positivity. Eight re-biopsy specimens were obtained at the time of occurrence of PD, and the concordane rate was 63%. The frequncy of T790M positive was higher when metastatic lesions were spread compared to enlargement of primary lesions. The cases with T790M positive have been analyzing in detail. Conclusions: T790M was detected in plasma DNA at the time of PD occurrence. Compared to the frequency using re-biopsy reported by other papers, liquid biopsy covered approximately half of the total patiets with PD. The relationship between T790M positivity and detailed characteristics of progression was analyzed. Disclosure: Y. Urata: other substantive relationships(myself):AstraZeneca, Chugai pharmaceutical; M. Satouchi: other substantive relationships(myself):AstraZeneca, Chugai pharmaceutical; K. Aoe: corporate-sponsored research:Elli Lilly(myself). All other authors have declared no conflicts of interest.

Background Febrile neutropenia is one of the oncology emergencies, which usually should be timely assessed and treated at the hospital. In some areas of Japan, however, medical resources are limited in especially nights and holidays. In Hyogo Cancer Center department of medical oncology, majority of patients have breast and gynecologic (GYN) malignant disease, those who are relatively young and without COPD. These patients may be managed by a self-assessment system of FN, although the feasibility is still unknown. Methods Self-assessment system consists of three steps, such as prescription of Ciprofloxacin 1200 mg b.i.d., educating patients by the team (doctors, pharmacists, and nurses) with written material, and evaluation at the hospital if febrile episode (FE) continues for longer than 48 h. FE is defined as body temperature higher than 38°C. Frequency of FE, admission to the hospital, ICU stay, and 30 days mortality rate were assessed retrospectively. Results From August 2006 to October 2011, 476 patients were treated in ambulatory chemotherapy center under self-assessment system. The median age was 58 years (range 17–82), 87% of them were under 60 years old. The literacy rate was 100%. All had solid tumors, 75% of them had breast (n = 157) or GYN (ovary and primary peritoneal cancer; n = 155, cervix; n = 40, corpus; n = 4) malignancy. Platinum-based regimens (n = 184) and anthracycline based regimens (n = 131) were dominant. FE occurred in 159 patients (33.4%). Forty-three patients (9%) were admitted to the hospital. Two patients were admitted to ICU. The thirty-day mortality rate was 0 %. The median MASCC score of admitted patients was 21 (range 14–21). About half (47%) had high risk score (≤20). Conclusions In areas with limited resources, self-assessment of FN can be an alternative option, although that should be applied to young and literate patients educated by skilled medical team.

Background The prognosis of gastric cancer with peritoneal metastasis is extremely poor. Neither systemic chemotherapy nor surgery alone prolongs survival of patients significantly. Methods Patients diagnosed with advanced gastric cancer underwent staging laparoscopy and received chemotherapy when peritoneal dissemination and/or cancer cells on peritoneal cytology were confirmed. The chemotherapy regimen consisted of S-1, weekly intravenous and intraperitoneal paclitaxel, which was verified in our phase II trial (Ann Oncol 2009). S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8. Clinical response of chemotherapy was assessed by computed tomography, gastroendoscopy, peritoneal cytology and second-look laparoscopy. Radical gastrectomy was carried out when macroscopic curative resection was made achievable by chemotherapy. Chemotherapy was restarted after operation as soon as possible. Overall survival, relapse free survival, morbidity and mortality of gastrectomy were evaluated. Results Out of 100 patients with peritoneal metastasis who received chemotherapy, 60 patients underwent gastrectomy after response to chemotherapy, including 54 with macroscopic metastasis and 6 with positive peritoneal cytology only. A median of three courses were administered preoperatively (range 1–16). Total or distal gastrectomy with lymphnode dissection was carried out in 54 or 6 patients, respectively. The median survival time was 34.5 months. The median relapse-free survival was 16.7 months. The first site of relapse was the peritoneum in 24 patients and the other organ site in 17 patients. Postoperative complications included anastomotic leakage and pancreatic fistula in two patients each, which were healed conservatively. There were no treatment-related deaths. Conclusions Gastrectomy combined with S-1, intravenous and intraperitoneal paclitaxel is safe and active for gastric cancer patients with peritoneal metastasis.

Background Single-agent chemotherapy (i.e. doxetaxel, gemcitabine or vinorelbine) is one of the standard treatments for elderly patients with advanced NSCLC. Pemetrexed has clinically equivalent efficacy, but with less toxicity compared with doxetaxel in the second-line setting of patients with advanced NSCLC. We conducted a phase II trial to evaluate the efficacy and safety of frontline pemetrexed in elderly patients with advanced non-squamous (non-Sq) NSCLC. Methods In this multicenter phase II trial, we recruited elderly patients with non-Sq NSCLC. Eligibility criteria were as follows: chemonaive; locally advanced or metastatic non-Sq NSCLC; age 75 or older; ECOG performance status 0-1; adequate organ function. Patients received pemetrexed (500 mg/m2) intravenously on day 1 every 3 weeks until disease progression had been confirmed. The primary end point was response rate (RR). The secondary end points included progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. The planned sample size was 45 patients. Results Between August 2009 and July 2011, 47 patients were enrolled. Median age was 79 years (range: 75–91), 57% (20 of 47) were male, 36% (17 of 47) had never smoked, 85% (40 of 47) had adenocarcinoma, 72% (34 of 47) had stage IV and 41% (16 of 39) had EGFR tyrosine kinase activating mutation. Median number of cycles was 4 (1 to 15). RR was 13.3% (95% CI: 5.1, 26.8), DCR was 66.7% (95% CI: 51.0, 80.0), PFS was 4.9 months (95% CI: 3.0, 6.2 months), median OS was not reached. The most frequent treatment-related AEs were anemia, fatigue, hypocalcemia, mostly grade 1/2. Treatment-related grade 3/4 AEs were reported in 17.8% of patients (mostly neutropenia and fatigue). No treatment-related death occurred. Conclusions The efficacy and limited side-effects of pemetrexed are promising in elderly patients with non-Sq NSCLC.

Background Four cycles of EP plus AHTRT is the standard treatment for LD-SCLC. IP demonstrated statistically significant overall survival (OS) improvement compared with EP for extensive-stage SCLC (JCOG9511; Noda et al., N Eng J Med, 2002). EP plus AHTRT followed by three cycles of IP is feasible with acceptable toxic effects for LD-SCLC (Kubota et al., CCR, 2005). Method Eligibility criteria included patients with previously untreated LD-SCLC with measurable lesion, ECOG PS of 0-1, age: ≤20, ≤70 years old. Eligible patients received one cycle of EP (etoposide 100 mg/m2 on days 1–3 and cisplatin 80 mg/m2 on day 1) plus AHTRT (1.5 Gy b.i.d. total 45 Gy/3 weeks). Patients who achieved CR, good PR, PR or SD with induction EP/AHTRT were randomized to receive either three cycles of consolidation EP or IP (irinotecan 60 mg/m2 and cisplatin 60 mg/m2 on days 1, 8, 15). Patients with CR or good PR after consolidation chemotherapy received prophylactic cranial irradiation. The primary end point is OS after the randomization. The planned sample size for randomization is 250 with a one-sided alpha of 2.5% and at least 70% power to detect a difference between groups, 30% in EP versus 42.5% in IP group in 3-year survival. Results From September 2002 to September 2006, 281 patients from 36 institutions were registered. After the induction EP/AHTRT, 258 patients were randomized to consolidation EP (n = 129) or IP (n = 129). Patient demographics were well balanced between the two groups. At the final analysis, the superiority of IP in OS was not demonstrated (hazard ratio of IP to EP, 1.085 [95% CI 0.80–1.46]; one-sided P = 0.70, stratified log-rank test). Median OS, 3-year survival and 5-year survival on EP were 3.2 years, 53% and 36%, versus 2.8 years, 47% and 34%, respectively (one-sided P = 0.7030). Median PFS on EP was 1.14 years and 1.03 years on IP (P = 0.7259). Grade 3/4 neutropenia (95%/78%), anemia (35%/39%), thrombocytopenia (21%/5%), neutropenic fever (17%/14%), diarrhea (2%/10%) were observed in EP and IP groups, respectively. Conclusion EP plus AHTRT followed by three cycles of IP failed to demonstrate survival advantage over four cycles of EP plus AHTRT which still is the standard treatment of LD-SCLC.

Background For patients with HER2+ breast cancer, the achievement of pCR after neoadjuvant chemotherapy is regarded as a surrogate end point of prognosis, however, which is not clear among HER2 + HR+ patients. Methods We retrospectively investigated 163 HER2+ patients who received neoadjuvant chemotherapy in Hyogo Cancer Center between 2003 and 2010. HR+ was defined as estrogen or progesterone receptor positive, and pCR was no evidence of invasive carcinoma in the breast and axillary lymph nodes at surgery. Logistic regression analysis and logrank test were carried out to identify predictive factors of pCR and its prognostic significance on recurrence-free survival. Results The median age was 55 years (range, 25–84) and the median follow-up was 59 months (range 12–104). Stages I, IIA, IIB, and III were 4, 57, 56, 46 patients, HER2 + HR+ and HER2 + HR- were 89 and 74 patients, respectively. The rates of patients receiving anthracycline, taxane and trastuzumab (T) were 66, 82 and 51%, respectively. After surgery, 98% of HER2 + HR+ patients received hormonal therapy. Multivariate analysis revealed that HER2 + HR+ (OR, 0.46; P = .047) and inclusion of T (OR, 2.87; P = .01) were significant predictors of pCR. Although 5 years recurrence-free survival rate was significantly higher in HER2 + HR- patients with pCR compared with non-pCR (88% versus 64%; P = .03), which was not in HER2 + HR+ patients (94% versus 84%; P = .49). Conclusions HER2 + HR+ breast cancer patients had significantly lower achievement rate of pCR, which was less prognostic compared with that in HER2 + HR- patients. On the other hand, HER2 + HR+ patients had better prognosis; therefore, the reduction in side-effects by replacing cytotoxic drugs with anti-HER2 agents and hormonal therapy might be be more beneficial than the improvement of pCR in neoadjuvant settings. The predictive factors of response to achieve the replacement would be needed.

Background Our previous phase III trial has demonstrated that S-1 in combination with carboplatin has promising activity as well as superior toxicity profile compared with carboplatin/paclitaxel for the first-line treatment of advanced non-small-cell lung cancer (NSCLC) (JCO vol 28, 2010). This study evaluated the efficacy and safety of new combination of S-1 and carboplatin plus bevasizumab (Cb/S1/Bev) followed by continuation maintenance of S-1 and bevacizumab (S1/Bev) in chemo-naive patients (patients) with advanced non-squamous NSCLC. Methods Patients receive carboplatin AUC 5 and bevacizumab 15 mg/kg on day 1 plus oral S-1 (40 mg/m2 b.i.d.) on days 1 to 14. Treatment is repeated every 21 days up to 6 cycles. For the patients with SD or PR, S-1 combined with bevacizumab are continued every 21 days until disease progression or toxicity. Primary end point of this study was response rate (RR). Results Between April 2010 to October 2011, 48 patients were enrolled. Median age was 65 years (range: 35–77), male/female = 33/15, PS 0/1 = 15/33, Adeno/Non-adeno = 42/6. Median cycles of Cb/S1/Bev treatment were 4 (range = 1–6), and 59% (n = 28) of patients shifted to maintenance therapy. Among patients who shifted to maintenance phase, median cycles treated with S1/Bev were 3.5 (range = 1–10). During treatment with Cb/S1/Bev, grade 3/4 toxic effects included: neutropenia (23.4%/4.3%), anemia (4.3%/6.4%), thrombocytopenia (6.4%/6.4%) and hypertension (8.3%/0%). No treatment-related death was occurred. Forty-six patients were evaluable for response. Overall RR was 50% and disease control rate was 78%, with a median time to progression of 7.4 months (95% CI: 3.9–10.8). Conclusions Treatment with S-1 and carboplatin plus bevacizumab with maintenance S-1 and bevacizumab in patients with advanced non-squamous NSCLC is feasible with an acceptable toxicity profile. The encouraging activity justifies further development of this new regimen.

PURPOSE For patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC), radiotherapy (RT) has been used conventionally for many years. Few prospective trials have determined the role of RT. Recently, chemotherapy (CT) has been shown to produce excellent responses in regionally advanced disease. We therefore conducted a randomized trial using cisplatin (P)-based CT regimens with or without thoracic irradiation. PATIENTS AND METHODS We randomly assigned 92 patients with locally advanced NSCLC to receive one of three arms of P-based combination chemotherapy: vindesine (V) plus P, mitomycin (M) plus V plus P, or etoposide (E) plus P alternating with V plus M. After two cycles of CT, patients were reevaluated and those with stage III were again randomized to receive RT or not. RT consisted of 50 to 60 Gy in 5 to 6 weeks; 2 Gy was delivered once daily in conventional fractions. RESULTS Sixty-three patients were included in the second randomization. The patients in the CT/RT group (n = 32) and CT-alone group (n = 31) were comparable in terms of age, sex, performance status, histologic features, stage of disease, and induction CT regimen. The median durations of survival were similar for the two groups (461 days in CT/RT group and 447 days in CT-alone group). The survival rate in the CT/RT group was 58% at 1 year, 36% at 2 years, and 29% at 3 years, as compared with 66%, 9%, and 3% at 1, 2, and 3 years, respectively, in the CT-alone group. One patient in the CT/RT group died of pneumonitis, but there were no CT-related deaths. CONCLUSION In locally advanced NSCLC, P-based combination CT followed by chest irradiation significantly increases the number of long-term survivors as compared with CT alone. RT to bulky disease in the thorax is thus an important part of combined modality therapy, and a necessary part of further studies in locally advanced disease.

7586 Background: Amrubicin (AMR), a totally synthetic 9-aminoanthracycline and potent topoisomerase II inhibitor, is approved in Japan for the treatment of lung cancer. We investigate the recommend...

PURPOSE Camptothecin-11 (CPT-11) is a new semisynthetic derivative of CPT, and has been shown to inhibit DNA topoisomerase I and to have a strong antitumor activity with low toxicity in murine tumors. To evaluate the effectiveness of CPT-11 in patients with non-small-cell lung cancer (NSCLC), a phase II study was conducted between April 1989 and February 1990. PATIENTS AND METHODS Seventy-three patients were entered onto the study. All patients had had no previous therapy and had measurable disease. Their median age was 67 years (range, 34 to 75 years). Fifty-four patients had a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale, and 19 had a PS of 2. CPT-11 was given at a dose of 100 mg/m2 by intravenous 90-minute infusion once a week. The dose of CPT-11 was modified based on the WBC count obtained on the day of drug administration. RESULTS Of 72 assessable patients, 23 (31.9%) showed a partial response (95% confidence interval, 20.2% to 43.6%). Of 40 patients with a stage IV disease, 13 (32.5%) responded. Response rates for patients with PS 0 or 1 and those with PS 2 did not differ (34.0% and 26.3%, respectively). The median duration of response in patients showing a PR was 15 weeks. The median survival time for all patients was 42 weeks. The major toxicities were leukopenia and diarrhea. Grade 3 or 4 leukopenia and diarrhea occurred in 18 patients (25%) and 15 patients (21%), respectively. These toxicities were unpredictable. Other toxicities of greater than or equal to grade 3 included nausea/vomiting (22%), anemia (15%), alopecia (4%) and pneumonitis (3%). One patient died of pulmonary toxicity (interstitial pneumonitis). CONCLUSIONS CPT-11 is a very active agent for NSCLC with acceptable toxicities. Further trials in combination with other agents for this disease are warranted.

8059 Background: AMR is a totally synthetic 9-aminoanthracycline and a novel topoisomerase II inhibitor. AMR has shown promising clinical activity for advanced NSCLC as well as SCLC. This trial was conducted to evaluate the efficacy and safety of AMR for pts with NSCLC previously treated with platinum-based chemotherapy. Methods: Eligible pts had a performance status 0 to 1, previous treatment with one platinum-based chemotherapy for advanced NSCLC, and adequate organ function. Pts received AMR 40 mg/m2 intravenously on days 1–3 every 3 weeks. The primary endpoint was the objective response rate, which determined the sample size based on an optimal two-stage design. With the target activity level of 18% and the lowest response rate of interest set at 5%, 60 eligible patients were required with a 90% power to accept the hypothesis and a 5% significance level to reject the hypothesis. Results: Sixty-one pts (median age, 63 years; range 51–74 years) were enrolled. The median treatment cycles were 2 (range, 1–15). No complete responses and 7 partial responses were observed, giving an overall response rate of 11.5% (95% CI, 4.7–22.2%). Twenty patients (32.8%) had stable disease and 34 patients (55.7%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 44.3% (95% CI, 31.5–57.6%). The median overall survival and 1-year survival rate were 8.5 months and 32.0%, respectively. Grade 3/4 hematological toxicities were neutropenia (82%), anemia (27.9%) and thrombocytopenia (24.6%). Grade 3/4 non-hematological toxicities were anorexia (9.8%), febrile neutropenia (29.5%) and pneumonitis (1.6%). No treatment-related death and cardiac toxicity were observed. Conclusions: AMR exhibits significant activity with manageable toxicities as second-line therapy for advanced NSCLC. [Table: see text]

7556 Background: Standard treatment of resectable N2 disease is not yet established. To gain insights on significance of preoperative chemoradiotherapy, we tried to evaluate feasibility and efficacy of induction chemotherapy with or without radiotherapy followed by surgery in patients with stage IIIA NSCLC with mediastinal lymph node metastases. Methods: Patients with histologically proven N2 disease were randomized either to receive induction chemotherapy (taxotere 60 mg/m2 and carboplatin AUC 5x2 cycles) with concurrent radiation therapy of 40Gy/20fr (CRS group) or without it (CS group). Patients subsequently underwent pulmonary resection if the tumor was judged resectable. Original sample size was 180 to detect a 20% of survival difference (2 sided P=0.05) with a power of 0.8. The primary endpoint was overall survival. Results: Between Jan. 2001 and Dec 2005, 60 patients were randomized Because of poor accrual of the patients, the study was prematurely terminated. Two patients assigned to CRS group were ineligible due to staging misconducts. Median age was 57 years (range 34–70 years), and 66% were male. Two groups were well balanced with regard to age, gender, histology, and operative procedures. Induction therapy was well tolerated, and there was no treatment related death. Grade 3 and 4 neutropenia occurred in 74 and 89%, respectively. Objective response rate was 25% for the both groups. Surgical resection was performed in 86% and 89%of the patients in CS and CRS groups, respectively. There have been 37 deaths to date. Event free survival at 3 year was 18% and 32% for patients in CS and CRS group, respectively (HR=0.64; 95% CI: 0.36–1.17, P=0.15). Overall survival at 3 year was 44.4 %. and 52.7% (HR=0.84; 95% CI: 0.44–1.62, P=0.62), respectively. Conclusions: Because of small sample size, there was no statistically significant difference. However, our study suggested that addition of radiotherapy to induction chemotherapy could potentially prolong survival of NSCLC patients with N2 disease. [Table: see text]

8103 Background: TS-1, a novel oral fluorouracil derivative, has been shown to have anti-tumor activity with relatively mild adverse effects, and it is used in the treatment of NSCLC in Japan. The ...