A phase II study of pemetrexed in patients with previously heavily treated non-squamous non-small cell lung cancer (HANSHIN Oncology Group 001)

Purpose

Pemetrexed has shown substantial activity in non-squamous non-small cell lung cancer (NSCLC) and is one of the current standard agents in second-line settings due to its efficacy and favorable tolerability profile. We conducted phase II study to evaluate the safety and efficacy of pemetrexed in Japanese patients with previously heavily treated, advanced non-squamous NSCLC.

Methods

Patients with stage IIIB or IV non-squamous NSCLC, performance status (PS) 0–2, previous two to five regimens of chemotherapy were enrolled and received pemetrexed (500 mg/m²) on day 1 every 21 days until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.

Results

From August 2009 to May 2010, 46 patients were enrolled: median age 65 years; 52 % women; PS 0/1/2 26/67/7 %; previous treatment regimen 2/3/4/5 48/28/20/4 %; epidermal growth factor receptor activating mutation positive/wild/unknown 30/48/22 %. The median follow-up period was 13.5 months. The median number of treatment cycles was 4 (range 1–18 cycles). The median PFS was 5.2 months (95 % CI 3.0–5.8 months). The median OS was 14.4 months (95 % CI 9.4–21.3 months). The ORR was 8.7 % and DCR was 63.0 %. The grade 3/4 hematological adverse events include 8 patients with leukopenia, 11 with neutropenia, 5 with anemia, and 2 with thrombocytopenia. There were no reports of febrile neutropenia and no treatment-related death was observed.

Conclusion

Treatment with pemetrexed in previously heavily treated Japanese non-squamous NSCLC patients is feasible and shows encouraging activity.     

Maintenance therapy with pemetrexed versus docetaxel after induction therapy with carboplatin and pemetrexed in chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer: a randomized, phase II study

Purpose

The optimal strategy for maintenance chemotherapy is controversial. We evaluated the efficacy and safety of continuation maintenance with pemetrexed and switch maintenance with docetaxel in advanced non-squamous non-small-cell lung cancer (NSCLC).

Methods

Chemotherapy-naïve patients with non-squamous NSCLC were enrolled in this randomized phase II study. Patients who achieved disease control after four cycles of induction therapy with carboplatin (AUC 6) and pemetrexed (500 mg/m²) were randomized to maintenance therapy with pemetrexed (500 mg/m²) or docetaxel (60 mg/m²). The primary endpoint was survival without toxicity, defined as the time from the initiation of maintenance therapy to the first date of any grade 3/4 toxicity or death due to any cause.

Results

A total of eighty-five patients were enrolled in the induction phase, and 26 patients were assigned to the pemetrexed maintenance therapy and 25 patients were assigned to the docetaxel maintenance therapy. Survival without toxicity was significantly longer in the pemetrexed group (median 20.8 months, 95 % confidence interval (CI) 0.7–not estimable) than in the docetaxel group (median 0.5 months, 95 % CI 0.2–2.0, hazard ratio 0.36, 95 % CI 0.17–0.74).

Conclusions

Continuation maintenance with pemetrexed may be a feasible treatment option for patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin and pemetrexed. Switch maintenance with docetaxel may also be efficacious but frequently causes severe hematologic toxicity.     

Phase II study of carboplatin and pemetrexed in advanced non-squamous, non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0902

Background

Subgroup analyses of randomized studies have consistently shown that pemetrexed is exclusively effective in non-small-cell lung cancer (NSCLC) other than squamous cell carcinoma and the combination of pemetrexed and platinum agents is recommended for first-line chemotherapy in advanced non-squamous NSCLC; however, there have been few prospective studies of a selected population.

Patients and methods

This was a single-arm phase II study of carboplatin and pemetrexed in Japanese patients with chemo-naive advanced non-squamous NSCLC. Patients received six cycles of pemetrexed (500?mg/m²) combined with carboplatin (area under the curve: AUC 6) every 3?weeks. Maintenance chemotherapy with pemetrexed was permitted in patients whose disease did not progress after combination chemotherapy. The primary endpoint was the response rate, and secondary endpoints were safety and survival.

Results

Fifty-one patients were enrolled between November 2009 and March 2011, and 49 patients were evaluable for both safety and efficacy. All but one patient had adenocarcinoma histology. Forty-four (90?%) patients completed four cycles, and 33 (67?%) completed six cycles of chemotherapy. Partial response was achieved in 25 patients (response rate: 51?%) and stable disease in 18 patients (37?%). Median progression-free survival (PFS) and overall survival (OS) were 6.3?months and 24.3?months, respectively. The median PFS and OS were 7.9?months and 24.3?months in patients with epidermal growth factor receptor (EGFR) mutation, and 6.3?months and 21.0?months in patients with EGFR wild type or unknown. There were no statistical differences between EGFR mutants and non-mutants for both PFS (p?=?0.09) and OS (p?=?0.23). Grade 3/4 neutropenia and thrombocytopenia were observed in 16 (33?%) and 9 (18?%) patients, respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths.

Conclusions

The combination of carboplatin and pemetrexed was safe and effective in advanced non-squamous NSCLC. Although the sample size was small, our results indicate that pemetrexed is a key drug for advanced non-squamous NSCLC, irrespective of the EGFR mutation status (UMIN-CTR number 000002451).     

A phase II study of carboplatin,pemetrexed, and bevacizumab followed by erlotinib and bevacizumab maintenance for non-squamous non-small cell lung cancer with wild-type <Emphasis Type="Italic">EGFR</Emphasis> (HOT1101)

Background

This study evaluated the efficacy and safety of switch maintenance erlotinib and bevacizumab after induction therapy with carboplatin/pemetrexed/bevacizumab for non-squamous non-small cell lung cancer (NSCLC) with wild-type EGFR.

Methods

Enrolled patients had treatment-naïve, advanced non-squamous NSCLC with wild-type EGFR. Carboplatin [area under the curve (AUC) 5.0], pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) were administered on day 1 every 3 weeks for 4–6 cycles. Maintenance therapy with erlotinib (150 mg/body) on day 1 through 21 plus bevacizumab on day 1 every 3 weeks was continued until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), toxicity, and quality of life (QOL).

Results

Fifty-one patients were enrolled between September 2011 and June 2014. The median number of cycles for induction and maintenance therapy was 4 (range 1–6) and 4 (range 1–20). Twenty-nine patients (58%) received maintenance therapy. The 6-month PFS rate was 59.5% [95% confidence interval (CI) 45.0–72.6%]. The ORR was 48.0% (95% CI 34.8–61.5%), and disease control rate was 86.0% (95% CI 73.8–93.0%). The median PFS and OS were 6.5 months (95% CI 5.8–7.2 months) and 21.4 months (95% CI 15.9–26.9 months), respectively. Although grades ≥?3 adverse events were observed in 33 patients (66.0%), most were hematologic; there was no febrile neutropenia. QOL was maintained throughout treatment.

Conclusions

Carboplatin/pemetrexed/bevacizumab followed by erlotinib and bevacizumab maintenance showed modest efficacy and was well tolerated in non-squamous NSCLC patients with wild-type EGFR.

Trial registration

UMIN000005872.

     

Phase II study of pemetrexed as first-line treatment in elderly (≥75) non-squamous non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0901

Background

Single-agent chemotherapy with third-generation non-platinum agents, such as docetaxel, vinorelbine, is a standard therapeutic option for elderly patients with non-small-cell lung cancer (NSCLC). Subset analysis of a previous phase III study comparing pemetrexed with docetaxel in the second-line setting showed the superiority of pemetrexed in an elderly (≥70) population in both efficacy and toxicity.

Patients and methods

This was a single-arm phase II study of pemetrexed in elderly (≥75) Japanese patients with advanced non-squamous NSCLC. Patients received four cycles of pemetrexed (500 mg/m²) every 3 weeks. The primary endpoint was the response rate, and secondary endpoints were safety and survival.

Results

Twenty-eight patients were enrolled between January 2010 and April 2012. The median age of the patients was 77 years (range 75–88). All but one patient had adenocarcinoma histology. The median number of chemotherapy cycles administered was 4 (range, 1–12). Seventeen (60 %) patients completed four cycles of chemotherapy. Partial response was achieved in 7 patients (response rate: 25 %) and stable disease in 11 patients (disease control rate: 64 %). Median progression-free survival and overall survival were 3.3 and 17.5 months, respectively. Grade 3/4 neutropenia and thrombocytopenia were observed in 8 patients (29 %) and 2 (7 %), respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths.

Conclusions

Although this study did not meet our primary endpoint, pemetrexed showed favorable antitumor activity with mild toxicity in elderly patients with non-squamous NSCLC. Further investigations of pemetrexed in this population are warranted (UMIN-CTR number, 000002452).     

Clinical effect of erlotinib as first-line treatment for Asian elderly patients with advanced non-small-cell lung cancer

Purpose

To evaluate the efficacy and toxicities of erlotinib as first-line treatment for Asian elderly patients with advanced non-small-cell lung cancer (NSCLC).

Patients and methods

Untreated patients with advanced NSCLC were included in this study; erlotinib was orally administered at a dose of 150 mg daily until disease progression or intolerable toxicity or for other reasons.

Results

A total of 35 patients were enrolled. Patient characteristics were as follows: mean age 75.6 years (ranged 70–81 years), 24 (68.6%) male, 16 (45.7%) former or current smokers, 13 (37.1%) adenocarcinoma, 18 (51.4%) squamous cell carcinoma and 4 (11.4%) bronchioloalveolar carcinoma. Out of 35 patients, 1 CR, 16 PR and 10 SD, resulting in an overall response rate (CR + PR) of 48.6% and disease control rate (DCR = CR + PR + SD) of 77.1%. The median TTP was 6.4 months, and the median OS was 12.7 months. The CBR was 80%, and the 1-year survival rate was 48.6%. The most common adverse event (AE) was mild skin rash and diarrhea (CTC AE 1/2). Among them, the female never smokers with a non-squamous cell carcinoma histology was superior to the male smokers with a squamous cell carcinoma in disease control rate, with significant differences (P < 0.05).

Conclusion

The results suggest that erlotinib monotherapy is an effective and well-tolerated treatment option for Asian elderly patients with advanced NSCLC.     

A multicenter phase II study of docetaxel, oxaliplatin, and bevacizumab in first-line therapy for unresectable locally advanced or metastatic non-squamous cell histology non-small-cell lung cancer (NSCLC)

Introduction

Platinum-based doublets are standard of care for advanced non-small-cell lung cancer (NSCLC). The combination of docetaxel and oxaliplatin has shown acceptable toxicity and encouraging activity. This phase II study aimed to determine the safety and efficacy of this doublet with bevacizumab as first-line treatment for stage IIIB/IV NSCLC.

Methods

Newly diagnosed patients ≥18 years with histologically proven non-squamous NSCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 received six 21-day cycles of docetaxel, oxaliplatin, and bevacizumab followed by single-agent bevacizumab for a total of 1 year. Primary efficacy end point was radiographically documented progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), time to treatment failure, and safety.

Results

Fifty-three patients were enrolled. Median age was 62.0 years, 71.7 % male, 79.2 % Caucasian. A total of 88.7 % had stage IV or recurrent disease; 94.3 % adenocarcinoma; and 94.3 % ECOG PS 0 or 1. Efficacy results are as follows: median PFS 5.6 months, ORR 30.2 % (complete response 1.9 %, partial response 28.3 %); 37.7 % stable disease; and OS 14.0 months. At least one adverse event (AE) was reported in all patients (n = 52); 98.1 % of AEs were treatment related. The most common treatment-emergent grade ≥3 AEs were neutropenia (15.4 %), diarrhea (13.5 %), and fatigue (11.5 %). A serious AE was present in 32.7 %; the most common were pneumonia (7.7 %) and abdominal pain (5.8 %). Dehydration, diarrhea, febrile neutropenia, sepsis, and supraventricular tachycardia each occurred in 3.8 %.

Conclusions

The addition of bevacizumab to docetaxel/oxaliplatin is effective with an acceptable safety profile in patients with chemotherapy-naïve advanced NSCLC.     

Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pre-treated with a non-platinum-based regimen in the first-line setting: a randomized phase II study of the Hellenic Oncology Research Group (HORG)

Background

Platinum-based chemotherapy is the standard front-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, non-platinum combinations of third-generation chemotherapeutic agents are considered an alternative therapeutic option for patients who cannot tolerate the toxic effects of platinum compounds. In this study, the efficacy and toxicity of the combination of irinotecan plus cisplatin (IC) was compared to pemetrexed plus cisplatin (PC) regimen, in platinum-naïve patients with advanced NSCLC, who had been previously treated with the combination of a taxane plus gemcitabine.

Patients and methods

A total of 124 patients with locally advanced or metastatic NSCLC were randomly assigned to either irinotecan 110 mg/m² on day 1 and 100 mg/m² on day 8 plus cisplatin 80 mg/m² on day 8 every 3 weeks (IC arm) or pemetrexed 500 mg/m² plus cisplatin 80 mg/m² on day 1 every 3 weeks (PC arm). The primary endpoint of the study was the overall response rate (ORR).

Results

The ORR and median progression-free survival (PFS) in the IC arm were 18 % and 3.3 months, respectively, while in the PC arm were 19 % and 4.2 months (p = ns). Median overall survival (OS) was significantly higher in patients with PC (6.9 vs. 10.9; p = 0.013). PC regimen had a better toxicity profile compared to IC, with a statistically significant lower incidence of grade 3/4 neutropenia (3 vs. 31 %; p = 0.0001) and diarrhea (1.6 vs. 14.7 %, p = 0.018).

Conclusions

In patients with advanced NSCLC pretreated with docetaxel/gemcitabine, the combination of pemetrexed/cisplatin is associated with increased OS and is better tolerated than the combination of irinotecan/cisplatin and should be considered as a valid therapeutic option for platinum-naive, previously treated patients.

ClinicalTrials.gov Identifier

NCT00614965.

     

Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma

Purpose

To determine the maximum tolerated dose (MTD), safety and tolerability of sunitinib plus pemetrexed and cisplatin for advanced solid malignancies.

Methods

Using a 3 + 3 dose-escalation design, patients received oral sunitinib (37.5 or 50 mg) qd on a continuous daily dosing (CDD) schedule or Schedule 2/1 (2 weeks on, 1 week off treatment) plus pemetrexed (400 or 500 mg/m² IV) and cisplatin (75 mg/m² IV) q3w up to 6 cycles.

Results

Sunitinib 37.5 mg/pemetrexed 400 mg/m²/cisplatin 75 mg/m² CDD (n = 5) was not tolerated. Lower doses on this schedule were not explored. The Schedule 2/1 MTD (n = 15) was sunitinib 37.5 mg/pemetrexed 500 mg/m²/cisplatin 75 mg/m², based on one dose-limiting toxicity (myocardial infarction) out of six patients. The MTD was further studied in an expansion cohort of 10 non-small cell lung cancer (NSCLC) patients and one mesothelioma patient. There were no clinically significant drug–drug interactions. Cumulative myelosuppression was problematic: the median relative dose intensity (% actual/intended) across all cycles was 61 % for sunitinib, 78 % for pemetrexed, and 74 % for cisplatin. Four of eight NSCLC patients in the dose-escalation and expansion cohorts at the Schedule 2/1 MTD who were evaluable for efficacy had stable disease ≥8 weeks, and the one patient with mesothelioma had a partial response.

Conclusions

In patients with advanced solid malignancies, sunitinib was not tolerated at 37.5 mg CDD with standard pemetrexed and cisplatin doses. Dose reductions were often needed due to cumulative myelosuppression following cycle 1. The MTD showed modest antitumor activity.     

Study of Gefitinib and Pemetrexed as First-Line Treatment in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutation

To evaluate the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Patients and methods Patients with advanced non-squamous NSCLC harboring asensitive EGFR mutation were included in this study and randomly divided into gefitinib + placebo group and gefitinib + pemetrexed group. Pemetrexed or placebo was administered on day 1 at a dose of 500 mg/m², and gefitinib was sequentially administered on days 2 ~ 16. This treatment regimen was repeated every 3 weeks until disease progression. All investigators and participants were masked to treatment allocation. The overall response rate (ORR) and disease control rate (DCR) of gefitinib + pemetrexed group were higher than that of gefitinib + placebo group but only the difference of DCR between two groups was statistically significant (P < 0.05). The median progression-free survival (PFS) of gefitinib + placebo group and gefitinib + pemetrexed group were 14.0 months vs. 18 months respectively and the difference was statistically significant (P < 0.05). The 2-year PFS rates of gefitinib + pemetrexed group (20.00 %) was higher than that of gefitinib + placebo group (8.89 %) and the difference was statistically significant (P < 0.05). The median overall survival (OS) of gefitinib + placebo group and gefitinib + pemetrexed group were 32.0 months vs. 34 months respectively and the difference was not statistically significant (P > 0.05). The 3-year OS rates of gefitinib + pemetrexed group (44.44 %) was higher than that of gefitinib + placebo group (35.56 %) but the difference was not statistically significant (P > 0.05). Major grade 3 or 4 hematological toxicities included neutropenia, leukopenia and anemia. The main grade 3 or 4 non-hematological toxicities were infection, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, fatigue, diarrhea and pneumonitis. The difference of toxicities between two groups was not statistically significant (P > 0.05). The combination regimen of gefitinib + pemetrexed used in this study showed a higher ORR and DCR, longer median PFS and acceptable toxicity.     

Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non–Small-Cell Lung Cancer

Background

Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non–small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC.

Bevacizumab plus chemotherapy for advanced non-squamous non-small-cell lung cancer with malignant pleural effusion

Purpose

The presence of malignant pleural effusion (MPE) indicates a poorer prognosis for patients with non-small-cell lung cancer (NSCLC) and impairs their quality of life. Because vascular endothelial growth factor (VEGF) is the key mediator MPE production, we evaluated the efficacy and safety of chemotherapy plus bevacizumab, an anti-VEGF antibody, in non-squamous NSCLC patients with MPE, especially regarding the control of pleural effusions.

Methods

From November 1, 2009 to September 30, 2011, medical charts of 13 consecutive patients with MPE who received bevacizumab plus chemotherapy as the initial or secondary treatment were retrospectively analyzed.

Results

Of the 13 patients, 6 did not undergo pleurodesis, 3 were unsuccessfully treated by pleurodesis, 2 had encapsulated pleural effusion, and 2 had no re-expansion of the lung. Twelve patients (92.3 %) achieved MPE control lasting >8 weeks following bevacizumab plus chemotherapy. Five of 10 patients with measurable lesions had confirmed partial responses. Of 3 patients without measurable lesions, one had confirmed CR. Median progression-free survival time without re-accumulation of MPE was 312 days. Grade 3 or 4 neutropenia, thrombocytopenia, hypertension, or proteinuria was observed in 2, 2, 1, or 1 patient, respectively.

Conclusions

This is the first study to report that bevacizumab plus chemotherapy is highly effective for the management of MPE in non-squamous NSCLC patients. Prospective clinical trials are warranted to investigate the efficacy of bevacizumab for MPE.     

Effect of front-line chemotherapy on circulating CK-19 mRNA-positive cells in patients with metastatic breast cancer

Purpose

The incidence of lung cancer in patients with interstitial lung disease (ILD) is higher than in the general population; however, the clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with ILD remain unclear. This study was conducted to elucidate the safety and efficacy of palliative chemotherapy with gemcitabine or pemetrexed, both in combination with a platinum agent in NSCLC patients with ILD.

Patients and methods

Patients with advanced or recurrent NSCLC and ILD who received gemcitabine or pemetrexed in combination with a platinum agent as first-line chemotherapy were retrospectively analyzed. Clinical outcomes, including response rate, overall survival (OS), and progression-free survival (PFS), in addition to the acute exacerbation of ILD after chemotherapy were investigated.

Results

Between January 2007 and December 2011, 52 patients were analyzed. The median age at chemotherapy was 67. Thirty-two patients (61.5 %) had adenocarcinoma histology. With respect to the types of ILD, idiopathic interstitial pneumonia (IIP) and non-IIP were observed in 42 (80.8 %) and 10 (19.2 %) patients, respectively. The FEV1 level was less than 80 % of the predicted value in 15 of the 41 patients in whom it was measured. The overall response rate was 42.3 % (95 % CI 28.8–55.9), and the median PFS was 5.4 months (95 % CI 4.6–6.2). The median OS was 7.9 months (95 % CI 5.5–10.3), and the 1-year survival rate was 31.7 % (95 % CI 19.0–44.4). Eight patients (15.4 %) died within 3 months of first-line chemotherapy. Multivariate analysis demonstrated that a heavy smoking history (40 or more pack-year smoking history) was an independent adverse prognostic factor for OS. An acute exacerbation of ILD (AE-ILD) caused by first-line chemotherapy was noted in 5.8 % of patients.

Conclusion

Our results suggest that gemcitabine or pemetrexed in combination with platinum agents could be a feasible option for advanced NSCLC with ILD with some risk of AE-ILD or early death. To establish the efficacy of palliative chemotherapy for patients with NSCLC and ILD, further well-controlled prospective studies are needed.     

Safety Analyses of Pemetrexed-cisplatin and Pemetrexed Maintenance Therapies in Patients With Advanced Non-squamous NSCLC: Retrospective Analyses From 2 Phase III Studies

Background

In a phase III study, maintenance pemetrexed showed superior survival over placebo (PARAMOUNT) for patients with advanced non-squamous non-small cell lung cancer (NSCLC) who completed 4 cycles of pemetrexed plus cisplatin (PC) induction therapy, with low incidence of treatment-emergent adverse events (TEAEs) generally associated with pemetrexed. Prior analyses did not account for toxicities carried over from induction; thus, the current analysis was developed to understand toxicities that may be attributed to pemetrexed maintenance versus PC induction, and how treatment duration affects toxicity.

Gemcitabine and vinorelbine as second-line or beyond treatment in patients with malignant pleural mesothelioma pretreated with platinum plus pemetrexed chemotherapy

Background

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined.

Methods

Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated.

Results

Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 %, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 % of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 %) and phlebitis (6 %).

Conclusion

Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment.     

Chemotherapy management of malignant pleural mesothelioma: a phase II study comparing two popular chemotherapy regimens

Purpose

The aim of this prospective, phase II clinical study is to evaluate the activity of gemcitabine and cisplatin in comparison to pemetrexed and carboplatin in patients with malignant pleural mesothelioma.

Patients and methods

The patients were recruited from May 2008 to May 2011. One group included 21 cases who received cisplatin and gemcitabine. The other group included 19 cases who received pemetrexed and carboplatin.

Results

Response is superior in the pemetrexed group (p = 0.041). The median follow-up was 18 months (range 6–30 months). Cumulative survival at 1.5 years was 57.8 % for the pemetrexed carboplatin group. For the gemcitabine cisplatin group, the cumulative survival proportion at 1.5 years was 41 % (p = 0.0599).

Conclusions

Pemetrexed plus carboplatin are a step forward in the treatment of mesothelioma, the prognosis for these patients remains poor. Cheaper combinations as gemcitabine and cisplatin may be considered sufficient to treat cases with advanced mesothelioma.     

Clinical significance of human leukocyte antigen loss and melanoma-associated antigen 4 expression in smokers of non-small cell lung cancer patients

Background

Melanoma-associated antigen-A4 (MAGE-A4) is one of the candidates for a target of immunotherapy and is expressed in non-small cell lung cancer (NSCLC). However, tumors sometimes lose human leukocyte antigen (HLA) class I expression, and tumor-specific T cells cannot eliminate the tumor with loss of HLA. However, the relationship between MAGE-A4 expression and HLA loss has remained unclear.

Methods

Among 363 NSCLC patients who consecutively underwent curative surgery, 187 cases whose material could be analyzed were reviewed. The expression of HLA class I molecules was assessed by immunohistochemical staining. The expression of MAGE-A4 was analyzed by RT-PCR.

Results

Seventy-seven tumors expressed HLA normally; however, 110 tumors lost HLA. The proportion of patients with a smoking habit and expressing the MAGE-A4 gene in patients with HLA loss was higher than those with HLA expression (p = 0.04 and 0.028, respectively). Five-year overall survival (OS) rate in the patients expressing MAGE-A4 but with loss of HLA was 52.4 %, and OS was significantly poorer than their counterparts (74.0 %, p = 0.036). Multivariate analysis indicated that advanced stage or history of smoking and HLA loss was an independently poor prognostic predictor of OS in NSCLC (p < 0.01 and p = 0.04, respectively).

Conclusion

HLA class I loss in NSCLC was related to smoking history and MAGE-A4 expression of tumors. HLA class I loss in smokers or patients with the MAGE-A4 gene was a prognostic factors in NSCLC.     

Predictive and prognostic value of early response assessment using 18FDG-PET in advanced non-small cell lung cancer patients treated with erlotinib

Background

[18F]fluorodeoxyglucose (FDG)-PET is being evaluated as a tool for the early detection of response to various targeted agents in solid tumors. The aim of this study was to evaluate the predictive value of PET response after 2 days of erlotinib in unselected pretrated patients with stage IV NSCLC.

Patients and methods

FDG-PET/CT scans were conducted at baseline and after 2 days of erlotinib, with a CT evaluation performed at baseline and after 45–60 days of therapy. PET responses were evaluated by quantitative changes on SUVmax tumor/non-tumor ratio and classified according to EORTC criteria. PET responses were compared with RECIST responses and related to progression-free (PFS) and overall (OS) survival. Erlotinib effects on glucose uptake were also studied in a panel of NSCLC cell lines.

Results

Fifty-three patients were enrolled. At 2 days of erlotinib, 20 (38 %) patients showed partial metabolic response (PMR), 25 (47 %) had stable metabolic disease (SMD) and 8 (15 %) had progressive metabolic disease (PMD). All patients with PMD had confirmed RECIST progression at 45–60 days. Patients with early PMR and SMD had significantly longer PFS (p < 0.001 and p = 0.001, respectively) and OS (p = 0.001 for both) than PMD patients.

Conclusions

FDG-PET assessment after 2 days of erlotinib could be useful to identify early resistent patients and to predict survival in unselected NSCLC pretreated population.     

Docetaxel plus cisplatin and bevacizumab for untreated patients with advanced/metastatic non-squamous non-small-cell lung cancer: a multicenter phase II study of the Hellenic Oncology Research Group

Background

The docetaxel/cisplatin (DC) combination is an active regimen against advanced/metastatic non-small-cell lung cancer (NSCLC), and bevacizumab (B) improves the efficacy of frontline chemotherapy. This phase II study was designed in order to explore the efficacy and safety of DCB regiment in this setting.

Methods

Chemotherapy-naïve patients (n = 48) with measurable, histologically confirmed non-squamous, IIIB (wet)/IV NSCLC, and PS 0–2 were eligible. Patients received D (75 mg/m² IV), C (80 mg/m² IV), and B (15 mg/kg IV) every 3 weeks. Maintenance of bevacizumab was not mandatory.

Results

Complete and partial responses were achieved in two (4.2 %) and 14 (29.2 %) patients, respectively [overall response rate: 33.3 %; 95 % CI = 20.0–46.7 %], whereas stable disease was documented in 14 [disease control rate = 62.5 %; 95 % CI = 48.8–76.2 %]. The median progression-free survival was 4.4 months and the median overall survival 13.3 months. Treatment-related grade 3 or 4 hematologic adverse events were leukopenia, neutropenia, and anemia in 8.4, 18.7, and 2.1 % of the patients, respectively. Febrile neutropenia occurred in three (6.3 %) patients. Bleeding was documented in 4 % of the patients, thrombotic episodes in 8 %, and proteinuria in 3 %. There was one treatment-related death.

Conclusions

Frontline DCB in patients with advanced non-squamous NSCLC is an active regimen with manageable toxicity and merits to be further investigated.