Phase II trial of preoperative pemetrexed plus carboplatin in patients with stage IB-III nonsquamous non-small cell lung cancer (NSCLC).

OBJECTIVES: The combination of pemetrexed and carboplatin is a standard first-line treatment for patients with advanced NSCLC. In this pilot phase II trial, we evaluated the feasibility of using pemetrexed and carboplatin as neoadjuvant therapy, prior to definitive surgical resection, for patients with localized NSCLC. PATIENTS AND METHODS: Patients with potentially resectable, previously untreated, clinical stage IB-III, nonsquamous NSCLC were eligible for this trial. All patients received 4 cycles of pemetrexed (500 mg/m2) and carboplatin (AUC 6.0) administered at 21 day intervals. Three to 6 weeks after completion of chemotherapy, definitive surgical resection was attempted. The primary endpoint of this trial was the 3-year survival rate. RESULTS: Forty-six patients began protocol treatment, and 40 completed 4 courses of pemetrexed/carboplatin. Surgical resection was performed in 27 patients (59%); all had pathologic partial responses. The estimated 3-year survival rate for the entire group was 46%. Toxicity of neoadjuvant therapy was consistent with toxicity previously reported with pemetrexed/carboplatin. CONCLUSIONS: Administration of 4 courses of pemetrexed/carboplatin was feasible. The efficacy was similar to neoadjuvant regimens previously investigated. A significant number of patients 19 of 46 (41%) in this trial did not have surgical resection after neoadjuvant therapy. Further investigation of the role of neoadjuvant pemetrexed/carboplatin requires a larger, randomized clinical trial.

Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease.

INTRODUCTION: This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m2 days 1 to 3 plus LM (arm 1) or alone (arm 2). RESULTS: In the phase 1 study (n = 33), a dose of LM at 112 mg/m2 with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m2. In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. CONCLUSION: The combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes.

The burden of blood transfusion: a utilization and economic analysis--a pilot study in patients with chemotherapy-induced anemia (CIA).

OBJECTIVE: The objective is to measure the burden of blood transfusion of Packed Red Blood Cells (PRBCs) in patients with chemotherapy-induced anemia (CIA) on the institutional outpatient transfusion center. METHODS: This is a retrospective chart review (starting July 1, 2010, working backwards until 120 evaluable patients are accrued) at a single institutional transfusion center in the US. The mean and standard deviation (SD) were calculated for patient's age, pre-transfusion Hgb level, and other transfusion-related activities. RESULTS: One hundred and twenty records were reviewed. The majority included patients who were female (71%), African American (61%), and had either Medicare (48%) or private insurance (39%). The mean patient age was 59 years and the average pre-transfusion Hgb was 7.9 g/dL. The average patient visit to facility ranged from 213 min for one PRBC unit to 411 minutes for three PRBC units. The mean staff time for patient evaluation was 66 minutes. Actual time for transfusion was ∼100 min for each PRBC unit; 90% of patients received two PRBC units. Staff was engaged in direct patient care for an average of 322 min for two PRBC units. The labor cost of transfusion (in 2011 $US) ranged from $46.13-$49.33 per PRBC unit. The estimated fully loaded bundled cost was $596.49 for transfusion of one unit of PRBC. Limitations of the study include: the site included in this study may not be applicable to all sites in practice and the evaluated patient population was varied, with the exception that all patients were treated for some type of malignancy; and the review of blood bank records for 120 patients was not 120 independent events and, as such, may not have adequately captured actual variability. CONCLUSIONS: This analysis quantifies expense in terms of time for administration of the transfusion, as well as costs associated with outpatient blood transfusions.

Phase II study of gemcitabine and bevacizumab as first-line treatment in taxane-pretreated, HER2-negative, locally recurrent or metastatic breast cancer.

BACKGROUND: In first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine. PATIENTS: Women who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane-containing regimen in the neoadjuvant and/or adjuvant setting with a ≥ 12-month disease-free interval. METHODS: This was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m(2)) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Fifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non-triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%). CONCLUSION: Although the gemcitabine-bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination.

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.

Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.

Hypersensitivity pneumonitis in advanced non-small-cell lung cancer patients receiving gemcitabine and paclitaxel: report of two cases and a review of the literature.

Gemcitabine (2'-2'-difluorodeoxycytidine) is a recently developed pyrimidine antagonist that is structurally related to cytarabine (ara-C). When phosphorylated intracellularly, gemcitabine inhibits ribonucleotide reductase and arrests cell cycling in the S phase. Paclitaxel is a potent promoter and stabilizer of microtubule spindle formation and an inhibitor of cell cycling. In this report, we discuss 2 patients with advanced-stage non-small-cell lung cancer (NSCLC) treated with a combination of gemcitabine/paclitaxel who developed pulmonary symptoms of dyspnea and cough. Chest radiographs and computed tomography revealed diffuse pulmonary infiltrates. Bronchoscopic evaluation revealed diffuse alveolar damage with associated type II pneumocyte hyperplasia without evidence of infection or metastatic carcinoma, suggesting the development of a drug-induced pulmonary toxicity. Both cases improved with the discontinuation of gemcitabine/paclitaxel and with supportive care including steroids in one of the patients. We also review the published case reports of pneumonitis believed to be secondary to the taxanes or gemcitabine when used as single agents and a solitary case report describing pneumonitis in the setting of both a taxane and gemcitabine. Because the combination of gemcitabine/paclitaxel has demonstrated activity in NSCLC, the use of this combination is likely to increase. Clinicians caring for lung cancer patients receiving this combination should be aware of this potential pulmonary toxicity.