First-line Induction Chemotherapy Research Articles

Capecitabine plus bevacizumab (Cape-Bev) as a maintenance treatment after induction treatment with FOLFIRI plus bevacizumab (FOLFIRI-Bev) in metastatic colorectal cancer (mCRC).

e14683 Background: Bevacizumab is human monoclonal antibody that inhibits vascular endothelial growth factor and has been shown improvement progression-free survival and overall survival when combined with chemotherapy for treatment of mCRC in the first and second-line settings. The purpose of this study is to show the effectiveness of maintenance therapy with Cape-Bev in patients with mCRC who benefit of first-line (induction) chemotherapy with FOLFIRI-Bev. Methods: The study included patients with mCRC who received FOLFIRI-Bev as first-line chemotherapy. Maintenance therapy with Cape-Bev (Cape 1000 mg/m2 bid d1-14, Bev 7,5 mg/kg d1 q3w) was given until disease progression to patients who had achieved an objective response after 6-months FOLFIRI-Bev regimen. The time to disease progression, survival and toxic effects were analyzed from the beginning of bevacizumab-based chemotherapy. Results: We enrolled 30 patients, 16 men and 14 women. The mean age of the patients was 62 years. The patients who administered maintenance treatment received a median number of 11 cycles. The median progression-free and overall survivals were 22±4 months and 39±4 months, respectively. Significantly higher PFS and OS were seen among patients who complete or near-complete response to induction therapy with FOLFIRI-Bev (Table). Acceptable hand-foot syndrome was observed 14 patients (%51) treated with the Cape-Bev. No patient experienced severe toxicity. Conclusions: Cape-Bev regimen may be an effective maintenance treatment after response to first-line (induction) FOLFIRI plus bevacizumab treatment in selected mCRC with favorable safety profile. Further studies will be needed to demonstrate conclusively that. [Table: see text]

985P - The Efficacy of Taxans in Combined Treatment of Ovarian Cancer

ABSTRACT Objective The efficacy of paclitaxel plus carboplatin (TC) or gemcitabine plus carboplatin (GC) induction regimens with or without paclitaxel consolidation therapy were assessed in ovarian cancer (OC). Methods Patients with stage T2NoMo- T3N1Mo were randomized to either GC (1 group) (gemcitabine 1,000 mg/m2), days 1 and 8, plus carboplatin area under the curve [AUC] 5, day 1 and TC (2 group) (paclitaxel 175 mg/m2) plus carboplatin AUC 6, day 1 every 21 days for up to six-eight cycles. Patients with complete response were allowed optional consolidation with paclitaxel 135 mg/m2 every 28 days for ≤ 12 months. Patients without complete response received single-agent crossover therapy at induction doses/schedules until complete response, disease progression, or unacceptable toxicity. Disease progression or death in 124 patients was required to compare induction arms with 80% statistical power for progression-free survival, the primary endpoint. Results Randomized induction therapy was received by 230 of 256 patients enrolled; 152 patients with complete response received paclitaxel consolidation whereas 56 patients without complete response received single-agent crossover therapy. Progression-free survival was similar for GC and TC (median, 19.0 and 21.3 months, respectively; P = 0.199). Despite high censoring rates (>50%), overall survival was longer for TC (median, 48.3 versus 43.8 months for GC; P = 0.011). Controlling for patient characteristics including performance status, residual tumor size, and tumor stage, there was no statistical difference in a multivariate analysis. Conclusions The regiment gemcitabine plus carboplatin does not improve progression-free survival over paclitaxel plus carboplatin as first-line induction chemotherapy in ovarian cancer. Although favouring paclitaxel plus carboplatin, overall survival analyses were limited by the study design and high censoring rates. Disclosure All authors have declared no conflicts of interest.

Management of Non-Small Cell Lung in Cancer Patients with Stable Disease

Disease stabilization after first-line chemotherapy, also known as induction chemotherapy, is defined, according to the Response Evaluation Criteria in Solid Tumours (RECIST), as having neither sufficient shrinkage to qualify as a partial response (PR) nor sufficient increase to qualify as progressive disease (PD). In oncology, stable disease (SD) has often been viewed as an equivocal result and is therefore of unclear clinical value. In SD patients with advanced non-small cell lung cancer (NSCLC) who have already received four cycles of first-line chemotherapy with platinum agents plus a third-generation agent (gemcitabine, vinorelbine, docetaxel or paclitaxel) or pemetrexed, the continuation of the original treatment is not recommended according to the American Society of Clinical Oncology (ASCO) guidelines. The ASCO guidelines recommend maintenance with bevacizumab or cetuximab, as tolerated until progression, only for platinum-based chemotherapy combined with bevacizumab or cetuximab. Several trials and a meta-analysis have, however, suggested a role for maintenance treatment in patients without progression after induction chemotherapy. The National Comprehensive Cancer Network guidelines recently suggested that maintenance therapy may be considered after four to six cycles of induction platinum doublets for patients with tumour responses or SD, and recommended first-line treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutated patients to continue until PD. More recently, two randomized clinical trials that compared pemetrexed or erlotinib with a placebo demonstrated a better overall survival in favour of maintenance therapy. In subgroup analyses for both trials, patients with SD after first-line induction chemotherapy had pronounced survival benefits when erlotinib or pemetrexed maintenance therapy was given, although this result was not achieved in patients with a complete response or PR after induction chemotherapy. The management of patients with SD after first-line chemotherapy is an important issue because only a minority of patients with advanced NSCLC experience tumour shrinkage after standard platinum-based chemotherapy. Many more patients experience either SD or PD. The notion that the prognosis of SD patients varies greatly due to the complexity of SD should, however, be taken into careful consideration for the treatment decision. Therefore, suggestions for the further classification of SD are urgently needed to enable the use of an alternative therapy at an early time.

In vivo efficacy of a novel liposomal formulation of safingol in the treatment of acute myeloid leukemia

Prognosis of patients with acute myeloid leukemia (AML) remains poor despite the use of first-line induction chemotherapy. Therefore, it is imperative to find effective treatment for AML patients. Safingol is a bioactive sphingolipid which has demonstrated promising in vitro anti-leukemic properties; however, translation into clinical use is hampered by its low water solubility and dose-limiting hemolysis. The present study is the first to describe a rationally designed liposome formulation of safingol and demonstrate the anti-leukemic potential using a panel of human AML cell lines and patient samples as well as a human xenograft model in SCID mice. Encapsulation efficiency of safingol into liposomes was approximately 100%, and the release of drug followed square-root-of-time release model. The presence of a transmembrane pH gradient completely abolished the biological activity of liposomal safingol. A positive zeta potential, which influenced cellular accumulation of liposomal safingol, was crucial to the anti-leukemic activity. Liposomal safingol was effective against a wide range of AML subtypes with minimal hemolytic toxicity, and was able to extend the median survival time of the U937-inoculated mice to 31days as compared to 23days by free drug. The increase in therapeutic efficacy could be related to the increase in systemic drug exposure as a result of liposome encapsulation.

Phase III trial of induction gemcitabine or paclitaxel plus carboplatin followed by paclitaxel consolidation in ovarian cancer

Objective The safety and efficacy of gemcitabine plus carboplatin (GC) or paclitaxel plus carboplatin (TC) induction regimens with or without paclitaxel consolidation therapy were assessed in ovarian cancer (OC). Methods Patients with stage IC–IV OC were randomized to either GC (gemcitabine 1000 mg/m 2, days 1 and 8, plus carboplatin area under the curve [AUC] 5, day 1) or TC (paclitaxel 175 mg/m 2 plus carboplatin AUC 6, day 1) every 21 days for up to six cycles. Patients with complete response (CR) were allowed optional consolidation with paclitaxel 135 mg/m 2 every 28 days for ≤ 12 months. Patients without CR received single-agent crossover therapy at induction doses/schedules until CR, disease progression (PD), or unacceptable toxicity. PD or death in 636 patients was required to compare induction arms with 80% statistical power for progression-free survival (PFS), the primary endpoint. Results Randomized induction therapy was received by 820 of 919 patients enrolled; 352 patients with CR received paclitaxel consolidation whereas 155 patients without CR received single-agent crossover therapy. PFS was similar for GC and TC (median, 20.0 and 22.2 months, respectively; P = .199). Despite high censoring rates (> 52%), overall survival was longer for TC (median, 57.3 versus 43.8 months for GC; P = .013). Controlling for patient characteristics including performance status, residual tumor size, and tumor stage, there was no statistical difference in a multivariate analysis (HR = 1.22; 95% CI = 0.99–1.52; P = .067). Conclusions GC does not improve PFS over TC as first-line induction chemotherapy in OC. Although favoring TC, overall survival analyses were limited by the study design and high censoring rates.

In Vitro Efficacy of a Novel Liposomal Formulation of a Protein Kinase C Inhibitor In the Treatment of Acute Myeloid Leukemia

AbstractAbstract 3282The prognosis of patients with acute myeloid leukemia (AML) remains poor, despite the use of the first-line, anthracycline- and cytarabine-based induction chemotherapy aiming to induce complete remission in patients. Given the recent findings that intensive chemotherapy may not benefit older leukemia patients who are not candidates for stem cell transplantation (Kantarjian, H. et al, Blood, 2010; DOI: 10.1182/blood-2010-03-276485) and that the monoclonal antibody-based cytotoxic agent, gemtuzumab ozogamicin, has been voluntarily withdrawn from the market, there is a pressing need to find effective treatment for recurrent AML patients who are >60 years. Safingol [(2S, 3S)-2-amino-1,3-octadecanediol] is a potential anti-cancer bioactive lipid that induces apoptosis through PKC inhibition in leukemia cells and other cancer types. Owing to its poor solubility, safingol is administered as an oil-based emulsion; however, this formulation suffers from severe hemolysis as the dose-limiting toxicity in pre-clinical models, and its toxicity profile is yet to be determined from an ongoing Phase I clinical trial for advanced solid tumors. Liposome is a commonly used drug delivery system to solubilize hydrophobic drugs. It is anticipated that liposome encapsulation of safingol would yield a viable injectable drug product without the need of toxic vehicle such as ethanol or Cremophor-EL, and would substantially reduce the hemolytic toxicity of safingol. In this study, our intention is to develop a suitable liposome formulation of safingol and to test its therapeutic efficacy using human AML cell lines and primary patient samples. Safingol could be formulated into stable liposomes using distearyolphosphatidylcholine and cholesterol with encapsulation efficiency of ∼100%. Safingol was released from the liposomes with a sustained release profile, mainly by a diffusion-controlled mechanism. The extent of hemolysis of 0.5 mM safingol could be significantly reduced from 76% to 14% through liposome encapsulation, as determined by an in vitro hemolysis assay. The cytotoxicity of liposomal safingol was tested with MTT assay on various AML cell lines representing different subtypes, including KG-1 (M1), HL-60 (M2), NB4 (M3), U937 (M5), MV4-11 (M5) and HEL (M6), as well as K562, a cell line of blast crisis of chronic myelogenous leukemia (BC-CML). All cell lines tested responded well to the treatment of liposomal safingol, with IC50 values ranging from 1.5–14 μM. Among the various AML subtypes, NB4 was found to be the most sensitive cell line with the lowest IC50 value of 1.5±0.2 μM. Importantly, liposome encapsulation of safingol did not compromise the ability of the drug to induce apoptosis as compared to the free drug, which was mediated possibly through a mechanism dependent on the generation of reactive oxygen species and caspase activation. Liposomal safingol was further tested in 10 leukemic patient samples, and the formulation was able to induce complete loss of viability of the primary cell samples at 20 μM after 72 h of treatment. Taken together, our results demonstrated the therapeutic potential of liposomal safingol for the treatment of various AML subtypes. Further evaluation of the pharmacokinetics and the efficacy of the formulation in animal models is warranted. Disclosures:No relevant conflicts of interest to declare.

Maintenance treatment with Pegylated liposomal doxorubicin versus observation following induction chemotherapy for metastatic breast cancer: GEICAM 2001-01 study

This randomized multicenter phase III trial evaluated the role of maintenance therapy with pegylated liposomal doxorubicin (PLD) after induction chemotherapy in patients with metastatic breast cancer (MBC). Patients without disease progression following first-line induction chemotherapy consisting of three cycles of doxorubicin (75 mg/m(2)) followed by three cycles of docetaxel (100 mg/m(2)) both every 21 days, were randomized to PLD (40 mg/m(2)) every 28 days for six cycles or to observation. Time to progression (TTP) was the primary endpoint. 288 patients were enrolled and received induction first-line chemotherapy. One hundred and fifty-five achieved response or stable disease and were randomized to maintenance PLD (n = 78) or observation (n = 77). With a median follow-up of 20 months from randomization (range 1-56), disease progression occurred in 94% of patients. PLD significantly improved TTP by 3.3 months (8.4 vs. 5.1 months; hazard ratio [HR] = 0.54, 95% CI: 0.39 to 0.76, P = 0.0002) compared with observation. Overall survival was not significantly prolonged with PLD (24.8 vs. 22.0 months, respectively; HR = 0.86, 95% CI: 0.58-1.27, P = 0.44). PLD-induced toxicity was mild and manageable with up to 5% of patients experiencing grade 3/4 non-hematologic events (fatigue, mucositis, palmar-plantar erythrodysesthesia). Grade 3/4 neutropenia occurred in 12% of patients; two patients developed febrile neutropenia. This phase III trial demonstrated that maintenance chemotherapy with PLD is well tolerated and offers improved TTP in patients with MBC following first-line chemotherapy.

First‐line autologous stem cell transplantation in primary CNS lymphoma

The treatment of primary central nervous system lymphoma (PCNSL) has been considerably improved over recent years. In this article, we report six cases of PCNSL treated by first-line induction chemotherapy followed by intensive chemotherapy and autologous stem cell transplantation (ASCT). Six immunocompetent patients presenting with a PCNSL, confirmed by thoraco-abdomino-pelvic computer tomography scan and bone marrow biopsy, were treated with induction chemotherapy followed by BEAM intensive chemotherapy and ASCT and radiotherapy. At the end of the treatment, all the patients were in complete remission. After a median follow-up of 41.5 months (17-70 months), four patients were alive without signs of relapse (median survival: 35.5 months). Two patients died from relapse at 19 and 23 months. The neurotoxicity was low with epilepsy in one patient and persistent left side dysesthesia in another one. These results are fairly encouraging. Other studies with greater numbers of patients and longer follow-up are needed to confirm this study.

Good and poor CD34+ cells mobilization in acute leukemia: analysis of factors affecting the yield of progenitor cells.

The factors possibly affecting the collection of peripheral blood stem cells (PBSC) were evaluated in 104 de novo acute leukemia patients (66 myeloid and 38 lymphoblastic leukemias) in first cytological complete remission (CR); all patients achieved CR after first-line induction chemotherapy. The acute myeloid leukemia patients (AML) were given consolidation-mobilization chemotherapy with cytarabine, and daunoblastin or mitoxantrone or idarubicin; the acute lymphoblastic leukemia patients (ALL) were given consolidation-mobilization chemotherapy with cytarabine and etoposide. In all patients, the collection of PBSC was performed during recovery after giving consolidation chemotherapy and granulocyte colony-stimulating factor (G-CSF). Two main groups were considered according to the CD34+ cells x 10(6)/kg b.w. collected, that is, poor mobilizers (PM), with a collection of <2 x 10(6)/kg and good mobilizers, with a collection of >2 x 10(6)/kg. Of 104 patients, 27 (25.9%) were PM; 20/27 had AML and 7/27 had ALL. At multivariate analysis, a lower CD34+ cells count premobilization chemotherapy (CD34 steady state), the presence of FUO (fever of unknown origin) or infection, and a lower number of CD34+ cells on the first day of collection correlated with poor mobilization. These results may enable early recognition of patients who may have poor mobilization, and aid selection of patients for different mobilization regimens.