Sequential Arm Research Articles

Combination of vorinostat and low dose cytarabine for patients with azacitidine-refractory/relapsed high risk myelodysplastic syndromes

Outcome of patients with myelodysplastic syndrome after azacitidine failure is poor. In this population, we combined cytarabine (10-20mg/m²/day 14 days) with vorinostat (400mg/day) for escalating durations (7 days, 10 days and 14 days), and starting on day 1 (concomitant arm) or on day 14 (sequential arm) following a 3+3 phase I design. 40 patients were treated. Dose limiting toxicities were all seen in sequential arm. The overall response rate was 15% with 4 responses in concomitant arm (ORR=25%). We conclude that this combination is tolerable and concomitant administration might be less toxic and have better therapeutic effect (clinicaltrials.gov NCT00776503).

SAMIT: A phase III randomized clinical trial of adjuvant paclitaxel followed by oral fluorinated pyrimidines for locally advanced gastric cancer.

LBA4002 Background: Adjuvant chemotherapy with tegafur/uracil (UFT) used to be a tentative Japanese standard treatment and has been replaced by S-1 according to the result of the ACTS-GC trial, although there has been no direct comparison. Paclitaxel (PTX) has been widely used as one of the key drugs for unresectable GC. A randomized phase III trial with a two-by-two factorial design was planned to assess the survival benefit of sequential use of PTX and oral fluorinated pyrimidines (FPs) in comparison with FPs alone, and to compare UFT and S-1. Methods: Patients with serosa-invading GC who underwent R0/1 resection with extended (D2) lymph node dissection were randomized to receive either UFT 267mg/m2 daily (arm A), S-1 80mg/m2 daily for 2 weeks every 3 weeks (B), weekly PTX 80 mg/m2 followed by UFT (C), or PTX followed by S-1 (D) for 24 weeks. The primary endpoint was disease-free survival (DFS). 708 patients per groups were necessary to detect a hazard ratio of 0.8 with 90% power for superiority of the sequential arms, C+D, vs. A+B (two-sided 5.0% significance level). The number of patients was set to 370 per arm (total 1480) with an 88% power for noninferiority (1.33 as the margin) of UFT vs. S-1. Results: Between August 2004 and October 2007, 1,495 patients from 232 centers were randomized with the full analysis set of 1,433. Demographics were well balanced among arm A (n=359), B (n=364), C (n=355), and D (n=355); mean age was 64, 86% were PS 0, 68% of tumors were 8 cm or greater and 85% were clinically node positive. Grade 3-4 neutropenia or anorexia occurred in 11% or 6%, 13% or 7%, 13% or 2%, and 23% or 5% for arm A, B, C, and D, respectively. Other % grade 3-4 toxicities were less than 5%. Median follow-up was 1,875 days and 728 events occurred. Difference in DFS between C+D and A+B were not statistically significant (HR=0.92, 95%CI 0.80-1.07, p= 0.273). HR of A+C vs. B+D was 1.23 (95%CI 1.07-1.43) and hence the null hypothesis was not rejected. Conclusions: There was a trend for better DFS for sequential use of PTX followed by FPs. Comparison between the FPs demonstrated that UFT was inferior to S-1. Sequential PTX/S-1 is safe and effective for locally advanced GC in an adjuvant setting. Clinical trial information: C000000082.

Impact of PTEN Protein Expression on Benefit From Adjuvant Trastuzumab in Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer in the North Central Cancer Treatment Group N9831 Trial

It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) -positive trial-North Central Cancer Treatment Group (NCCTG) N9831. The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years. Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ(2) P < .001) and nodal positivity (χ(2) P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.

Randomized phase II trial of non-platinum induction or consolidation chemotherapy plus concomitant chemoradiation in stage III NSCLC patients: Mature results of the Spanish Lung Cancer Group 0008 study

The optimal schedule and regimen of chemotherapy (CT) in association with chemoradiation has not been established in stage III non-small-cell lung cancer (NSCLC). We have compared three schedules of non-platinum-based CT plus either radiotherapy or chemoradiation. From May 2001 to June 2006, 158 patients with unresectable stage III NSCLC were enrolled in a randomized phase II trial with overall response rate (ORR) as the primary endpoint. The initial design included three arms: sequential CT followed by thoracic radiation (TRT); concurrent CT/TRT followed by consolidation CT; and induction CT followed by concurrent CT/TRT. However, based on the preliminary results of the RTOG 9410 trial, the sequential arm was closed when 19 patients had been enrolled. All patients received two cycles of docetaxel 40mg/m2 days 1 and 8 plus gemcitabine 1200mg/m2 days 1 and 8, as either induction or consolidation therapy. Concurrent CT/TRT consisted of docetaxel 20mg/m2 and carboplatin AUC 2 weekly plus 60Gy TRT. No differences were found in ORR between the two arms (56% and 57%). Hematological toxicity was mild but significantly superior with consolidation CT; the esophagitis rate was similar in both arms (16% and 15%). With a median follow-up of 57 months, no differences were found in median survival (13.07 and 13.8 months) or 5-year survival (16.4% and 22%). This regimen cannot be recommended as an alternative to platinum-based CT/TRT although it has an acceptable toxicity profile and encouraging long-term survival data (ClinicalTrials.gov NCT01652820).

Taking into account successive treatment lines in the analysis of a colorectal cancer randomised trial

The FFCD 2000–05 randomised trial included 410 patients with advanced colorectal cancer and compared a sequential arm S treated with 5-fluorouracil and leucovorin (LV5FU2) followed by FOLFOX (LV5FU2+oxaliplatin) and then FOLFIRI (LV5FU2+irinotecan) and a combination arm C that begins directly with FOLFOX followed by FOLFIRI. The first aim of this study was to analyse the prognostic effects on overall survival of disease progression, and of toxicities under first-line therapy. We also studied the benefit of introducing irinotecan in each arm. Finally, we compared the effect of treatment on repeated progression and toxicities. For this purpose, we used Cox regression models with time-dependent variables and shared gamma frailty regression models.We found that early on during follow-up, the prognostic effect on survival of progression under first-line therapy was greater in C (hazard ratio [HR]=18.0 [7.9–41.2]) than in S (HR=7.7 [3.9–17.4]). This difference was significant, but it decreased over time. The prognostic effect of severe toxicities was greater in S (HR=2.0 [1.4–2.9]) than in C (HR=1.3 [0.9–1.9]). Introducing irinotecan was significantly more beneficial in S (HR=0.2 [0.1–0.4]) than in C (HR=0.3 [0.2–1.5]). The risk of repeated progression was not significantly different between the two groups (HR=0.9 [0.8–1.1]) whereas the risk of toxicities was greater in C (HR=1.7 [1.4–2.1]).Overall, this study suggests that starting with less toxic first-line treatment is a valid option since it does not exert a deleterious effect on the risk of overall progression or death.

A randomized phase II, open-label study of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) in metastatic castrate-resistant prostate cancer (mCRPC).

114 Background: Sipuleucel-T and AA are both FDA approved for mCRPC. Given that androgen deprivation therapy is immunostimulatory, increased suppression of the androgen axis with AA could provide synergy in combination with sipuleucel-T; however, AA is given with prednisone (P), which may be immunosuppressive. In order to evaluate the impact of concurrent AA + P on product characteristics, a study of sipuleucel-T with concurrent or sequential AA + P was undertaken. Methods: Pts aged ≥18 yrs with asymptomatic or minimally symptomatic mCRPC, and ECOG PS 0/1 were randomized (1:1) to sipuleucel-T (3 infusions at approx 2-week intervals) with up to 26 weeks of AA + P (AA 1000mg QD + P 5mg BID) starting 1 day after the first sipuleucel-T infusion (concurrent arm) or at week 10 (sequential arm). The primary endpoint was cumulative CD54 upregulation (measure of antigen presenting cell activation); secondary and tertiary endpoints included CD54+cell and total nucleated cell (TNC) counts (measures of product potency), safety and efficacy. Results: 29 pts have been enrolled. 16 pts in the concurrent arm (A) and 13 pts in the sequential arm (B) have completed sipuleucel-T treatment at the time of this interim analysis (7 Sept 2012). 27/29 pts received all 3 infusions of sipuleucel-T; 2 pts (both arm A) received only 1 infusion due to insufficient TNC count (n=1) and disease progression 8 days after randomization (n=1). No significant differences in median cumulative CD54 upregulation (31.6 vs 36.6) and CD54+ count (1.9 vs 2.1 x109) were observed between arms A and B, respectively. Increased CD54 upregulation with the 2nd and 3rd treatments were indicative of a prime boost effect in both arms. Similarly, the TNC profile over time was similar for both arms. The overall incidence of adverse events (AEs) was similar in arms A (81%) and B (77%). Common all-grade AEs included muscle spasms (31% vs 23%), oral paresthesia (19% vs 31%), chills (31% vs 8%) and cough (19% vs 15%). Conclusions: These data suggest that sipuleucel-T can be manufactured during treatment with AA + P with product potency and prime boost similar to that of sipuleucel-T alone. Clinical trial information: NCT01487863.

Clinical effectiveness of first-line chemoradiation for adult patients with locally advanced non-small cell lung cancer: a systematic review.

The National Institute for Health and Clinical Excellence has issued guidelines on the treatment of non-small cell lung cancer (NSCLC) and recommends that patients with stage IIIA-IIIB disease who are not amenable to surgery be treated with potentially curative chemoradiation (CTX-RT). This review was conducted as part of a larger systematic review of all first-line chemotherapy (CTX) and CTX-RT treatments for patients with locally advanced or metastatic NSCLC. However, it was considered that patients with potentially curable disease (e.g. stage IIIA) are different from those with advanced disease, who are suitable for palliative treatment only, and therefore the results should be reported separately. To evaluate the clinical effectiveness of first-line CTX in addition to radiotherapy (RT) (CTX-RT vs CTX-RT) for adult patients with locally advanced NSCLC who are suitable for potentially curative treatment. Three electronic databases (MEDLINE, EMBASE and The Cochrane Library) were searched from January 1990 to September 2010. Inclusion criteria comprised adult patients with locally advanced NSCLC, trials that compared any first-line CTX-RT therapy (induction, sequential, concurrent and consolidation) and outcomes of overall survival (OS) and/or progression-free survival (PFS). The results of clinical data extraction and quality assessment were summarised in tables and with narrative description. Direct meta-analyses using OS data were undertaken where possible: sequential CTX-RT compared with concurrent CTX-RT; sequential CTX-RT compared with concurrent/consolidation CTX-RT; and sequential CTX-RT compared with concurrent CTX-RT with or without consolidation. There were not sufficient data to perform meta-analysis on PFS. Of the 240 potentially relevant studies that were published post 2000, 19 met the inclusion criteria and compared CTX-RT with CTX-RT. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT appear to show an OS advantage for concurrent CTX-RT arms over sequential arms; this result is not statistically significant [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.50 to 1.25)]. The results from the OS meta-analysis comparing sequential CTX-RT with concurrent/consolidation CTX-RT appear to show a statistically significant OS advantage for concurrent/consolidation CTX-RT treatment over sequential treatment (HR 0.68; 95% CI 0.55 to 0.83). The results from the OS meta-analysis comparing sequential CTX-RT with concurrent CTX-RT with or without consolidation appear to show a statistically significant OS advantage for concurrent CTX-RT with or without consolidation over sequential treatment (HR 0.72; 95% CI 0.61 to 0.84). This report provides a summary and critical appraisal of a comprehensive evidence base of CTX-RT trials; however, it is possible that additional trials have been reported since our last literature search. It is disappointing that the quality of the research in this area does not meet the accepted quality standards regarding trial design and reporting. This review identified that the research conducted in the area of CTX-RT was generally of poor quality and suffered from a lack of reporting of all important clinical findings, including OS. The 19 trials included in the systematic review were too disparate to form any conclusions as to the effectiveness of individual CTX agents or types of RT. The focus of primary research should be good methodological quality; appropriate allocation of concealment and randomisation, and comprehensive reporting of key outcomes, will enable meaningful synthesis and conclusions to be drawn. The National Institute for Health Research Health Technology Assessment programme.

A comparison of results by sequential and concurrent chemo radiotherapy in locally advanced carcinoma esophagus

Many Trials using sequential and concurrent chemo radiotherapy have been done so far and has established the role of concurrent chemo radiotherapy in treatment of inoperable carcinoma esophagus. In this study, we have compared the results of concurrent chemo radiotherapy with sequential chemo radiotherapy. We have treated inoperable carcinoma esophagus in both the settings and present here the comparison of results in the two settings. There were 26 patients of carcinoma esophagus in sequential and 31 in concurrent chemo radiotherapy arm. In sequential arm methotrexate and Cisplatin followed by radiotherapy was given whereas in concurrent arm, Cisplatin was given once weekly along with radiotherapy. The 2 year survival was 38% in sequential and35.5% in the concurrent setting and the median survival was 19.5 and 18 months respectively in the two arms.The toxicities in both the arms were comparable. P value of 0.4774 with confidence interval of 95% was obtained, which is not significant. Dysphagia was improved earlier in sequential than in the concurrent arm. As the results and toxicities in both the arms are almost similar with better symptom control, so larger randomized trials are required to assess the response and the use of methotrexate in sequential chemo radiotherapy can be further explored.

Abstract P1-14-07: Neoadjuvant chemotherapy and pathologic complete response in relation to the clinical response, results from a phase III study (INTENS) of the Dutch breast cancer trialists' group (BOOG).

Abstract Background Taxanes have an established role as (neo-)adjuvant treatment of breast cancer. In the present study, we compared 4 AC–4 T with 6 cycles of TAC in the neoadjuvant setting (A = adriamycine, C = cyclophosphamide, T = docetaxel). Previously, we reported that AC-T resulted in a trend for improved outcome (odds ratio of the pathologic complete response (pCR) of the breast 1.60; 95% CI 0.90–3.21). This present analysis focuses on the results of treatment and pCR in the breast in relation to clinical response. Methods Women with breast cancer, eligible for neoadjuvant chemotherapy, were randomized to AC (60/600 mg/m2 q3wk × 4 cycles) followed by T (100 mg/m2 q3wk × 4 cycles), or to TAC (75/50/500 mg/m2 q3wk × 6 cycles). If indicated, trastuzumab and/or endocrine therapy were given as adjuvant treatment. Physical examination, ultrasound of breast and axillary lymph nodes and breast MRI were performed before start of chemotherapy, halfway and after completion of chemotherapy. These results together determined the clinical response (c) halfway and after chemotherapy. The clinical response was classified as cCR (complete response), cPR (partial response), cSD (stable disease) or cPD (progressive disease). pCR was defined as no invasive tumor in the breast at surgery. Results In total, 201 patients (n = 100 AC-T, n=101 TAC) were enrolled between February 2006 and April 2009. Baseline characteristics (AC-T/TAC) were well balanced. The clinical overall response rate (cCR and cPR) to 4 AC was comparable to that seen with 3 cycles TAC (48% versus 54%). Also, the clinical overall response rate to 8 AC-T was comparable to that seen with 6 TAC (81% versus 72%). In the AC-T arm, a third of the patients with cSD halfway reached a cCR or cPR after 8 cycles, whereas in the TAC arm only 18% of patients with cSD halfway reached a cCR or cPR after chemotherapy. In the sequential AC-T arm, 16% of the patients with cSD halfway reached a pCR after switching to docetaxel monotherapy. In contrast, in the TAC arm cSD halfway rarely resulted in pCR after 6 cycles. Patients with a cCR after chemotherapy had a pCR in 58% and 49% of cases, respectively. For patients with cPR these rates were 29% and 18%, respectively, and for patients with cSD 6% and 0%, respectively. Conclusion: Clinical response rates are related to pCR rates. The meaning of cSD halfway should be differently interpreted for sequential versus concurrent chemotherapy. In concurrent chemotherapy schedules, a switch to a non-cross resistant drug may be worthwhile. Early clinical response may be used as a decision aid during neoadjuvant chemotherapy to recognize non-responders. Support: Unrestricted grants from sanofi-aventis NL BV and Amgen BV. Dutch breast cancer trialists' group (BOOG). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-07.

S95 SOCCAR: Internationally Resonant Results from a Randomised Trial Based on UK Clinical Practise

Concurrent chemoradiation is now recognised as a standard of care for patients with inoperable Stage III NSCLC and good Performance Status. Two year survival rates in published trials ranges from...

Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) accounts for 25% of all leukaemias and is the most common lymphoid malignancy in western countries. Standard treatments include mono- or polychemotherapies, usually combined with monoclonal antibodies such as rituximab or alemtuzumab. However, the impact of these agents remains unclear, as there are hints for increased risk of severe infections. The objectives of this review are to provide an evidence-based answer regarding the clinical benefits and harms of monoclonal anti-CD20 antibodies (such as rituximab, ofatumumab, GA101) compared to no further therapy or to other anti-leukaemic therapies in patients with CLL, irrespective of disease status. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 12, 2011), MEDLINE (from January 1990 to 4 January 2012), and EMBASE (from 1990 to 20 March 2009) as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association and European Society of Medical Oncology) for randomised controlled trials (RCTs). We included RCTs examining monoclonal anti-CD20 antibodies compared to no further therapy or to anti-leukaemic therapy such as chemotherapy or monoclonal antibodies in patients with newly diagnosed or relapsed CLL. We used hazard ratios (HR) as effect measures for overall survival (OS), progression-free survival (PFS) and time to next treatment, and risk ratios (RR) for response rates, treatment-related mortality (TRM) and adverse events (AEs). Two review authors independently extracted data and assessed quality of trials. We screened a total of 1150 records. Seven RCTs involving 1763 patients were identified, but only five could be included in the two separate meta-analyses we performed. We judged the overall the quality of these trials as moderate to high. All trials were randomised and open-label studies. However, two trials were published as abstracts only, therefore we were unable to assess the potential risk of bias for these trials in detail.Three RCTs (N = 1421) assessed the efficacy of monoclonal anti-CD20 antibodies (i.e. rituximab) plus chemotherapy compared to chemotherapy alone. The meta-analyses showed a statistically significant OS (HR 0.78, 95% confidence interval (CI) 0.62 to 0.98, P = 0.03, the number needed to treat for an additional beneficial effect (NNTB) was 12) and PFS (HR 0.64, 95% CI 0.55 to 0.74, P < 0.00001) advantage for patients receiving rituximab. In the rituximab-arm occurred more AEs, World Health Organization (WHO) grade 3 or 4 (3 trials, N = 1398, RR 1.15, 95% CI 1.08 to 1.23, P < 0.0001; the number needed to harm for an additional harmful outcome (NNTH) was 9), but that did not lead to a statistically significant difference regarding TRM (3 trials, N = 1415, RR 1.19, 95% CI 0.70 to 2.01, P = 0.52).Two trials (N = 177) evaluated rituximab versus alemtuzumab. Neither study reported OS or PFS. There was no statistically significant difference between arms regarding complete response rate (CRR) (RR 1.21, 95% CI 0.94 to 1.58, P = 0.14) or TRM (RR 0.31, 95% CI 0.06 to 1.51, P = 0.15). However, the CLL2007FMP trial was stopped early owing to an increase in mortality in the alemtuzumab arm. More serious AEs occurred in this arm (43% with alemtuzumab versus 22% with rituximab; P = 0.006).Two trials assessed different dosages or time schedules of monoclonal anti-CD20 antibodies. One trial (N = 104) evaluated two different rituximab schedules (concurrent arm: fludarabine plus rituximab (Flu-R) plus rituximab consolidation versus sequential arm: fludarabine alone plus rituximab consolidation). The comparison of the concurrent versus sequential regimen of rituximab showed a statistically significant difference of the CRR with 33% in the concurrent-arm and 15% in the sequential-arm (P = 0.04), that did not lead to statistically significant differences regarding OS (HR 1.14, 95% CI 0.20 to 6.65, P = 0.30) or PFS (HR 0.96, 95% CI 0.43 to 2.15, P = 0.11). Furthermore results showed no differences in occurring AEs, except for neutropenia, which was more often observed in patients of the concurrent arm. The other trial (N = 61) investigated two different dosages (500 mg and 1000 mg) of ofatumumab in addition to FluC. The arm investigating ofatumumab did not assess OS and a median PFS had not been reached owing to the short median follow-up of eight months. It showed no statistically significant differences between arms regarding CRR (32% in the FCO500 arm versus 50%in the FCO1000 arm; P = 0.10) or AEs (anaemia, neutropenia, thrombocytopenia). This meta-analysis showed that patients receiving chemotherapy plus rituximab benefit in terms of OS as well as PFS compared to those with chemotherapy alone. Therefore, it supports the recommendation of rituximab in combination with FluC as an option for the first-line treatment as well as for the people with relapsed or refractory CLL. The available evidence regarding the other assessed comparisons was not sufficient to deduct final conclusions.

Vinorelbine and capecitabine in anthracycline- and/or taxane-pretreated metastatic breast cancer: sequential or combinational?

The difference between combinational and pre-planned sequential therapies using regimens that include non-anthracycline and taxane in the first-line setting remains unclear. The purpose of this study is to explore the interaction between vinorelbine (N) and capecitabine (X) in breast cancer cells and to compare the simultaneous or sequential administration of the two drugs in patients with metastatic breast cancer (MBC) as first-line treatment. First, we explored the effects of vinorelbine on thymidine phosphorylase (TP) and thymidylate synthase (TS) expression in breast cancer cells. Next, we designed a prospective randomized phase II trial of MBC patients comparing the combinational and pre-planned sequential administration of vinorelbine and capecitabine in the first-line metastatic setting. The primary end point was progression-free survival (PFS). The correlation between clinical characteristics and class III β-tubulin expression and patient survival was also explored. Vinorelbine upregulates TP and downregulates TS in breast cancer cells, thereby further sensitizing tumor cells to capecitabine, which indicated the proper order for sequential therapy should be N → X. Sixty patients were eligible for the phase II trial. No significant difference was observed between the combinational arm and the sequential arm in terms of progression-free survival (PFS), overall response rate (ORR), and overall survival (OS). Only in the subgroup of patients with liver metastases were median PFS and OS significantly prolonged in the combinational arm (8.5 vs. 6.4 months, P = 0.041 and 23.8 vs. 13.9 months, P = 0.028, respectively). No association between class III β-tubulin expression and patient outcome was identified. Grade 3/4 adverse events were more common in the combinational arm. Both the NX regimen and pre-planned sequential N → X regimen are acceptable as first-line treatments with comparable efficacies for MBC patients previously treated with anthracyclines and/or taxanes. Sequential monotherapies are recommended as the preferred approach to first-line chemotherapy for most MBC patients in the absence of an imminent visceral crisis and the need for rapid symptom and/or disease control.

1329 - A Multicenter, Randomized Phase II Study of V (Vinorelbine)/C (Cisplatin)/B (Bevacizumab) Followed by D (Docetaxel)/G (Gemcitabine)/B Versus D/ C /B as a First-Line Therapy for Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

ABSTRACT Background The combination of D/G has shown equal activity compared to the platinum-based doublets, which is considered the cornerstone for the treatment of NSCLC, with a more favorable toxicity profile. Sequential therapy with four active drugs, including C, was recently investigated and attributed a favorable response rate (Pallis A, et al; Lung Cancer 2006 52(2): 165-71). Incorporation of B to the standard platinum-based regimen improved its clinical outcome. The efficacy of sequential four drug treatment in combination with B was compared to the standard non platinum-based regimen combined with B. Methods Seventy-seven treatment-naive patients with unresectable stage IIIB and IV non-squamous NSCLC were randomized to receive V 60 mg/m2 PO on day 1 and 8, C 80mg/m2 IV on day 1 and B 15 mg/kg IV on day 1, for 3 cycles followed by D 75 mg/m2 IV, G 1100 mg/m2 IV and B 15 mg/kg IV, all on day 1 (Arm A) or D 75 mg/m2 IV, C 80mg/m2 IV and B 15 mg/kg IV on day. The cycles were repeated every 3 weeks for a total of 6 cycles. The primary endpoint was response rate (RR) and the secondary end points overall survival (OS) and progression free survival (PFS). Results Thirty-nine patients were randomized to arm B (control) and 38 patients to the sequential arm. The overall RR was 36.8% and 46.2% in arm A and B, respectively (p= 0.49). There were 3 complete responses, one in arm A. Median PFS was 5.77 and 5.53 months in arm A and B, respectively (p= 0.368). Median OS was 16.9 and 10.9, respectively (p= 0.39). The estimated 1 and 2-year survival for arm A versus B were 64.1% and 35% versus 48.4% and 24%, respectively. No difference in the toxicity profile was observed between the 2 arms, although more cycle-delays were observed in the experimental arm (29.5 versus 12.2; p Conclusion Sequential treatment with four active drugs is feasible and safe. The combination attributes encouraging results compared to the standard platinum-based regimen. Disclosure All authors have declared no conflicts of interest.

Six Months of Parathyroid Hormone (1–84) Administered ConcurrentlyVersusSequentially with Monthly Ibandronate Over Two Years: The PTH and Ibandronate Combination Study (PICS) Randomized Trial

PTH therapy improves bone mineral density (BMD) and decreases fractures in postmenopausal osteoporosis, but cost and the burden of daily injections limit its use. We evaluated two novel approaches to the use of 6 months of PTH therapy over 2 yr. We conducted a randomized, double-blinded trial of two combinations of daily PTH(1-84) and monthly ibandronate in 44 postmenopausal women with low bone mass. Participants received either 6 months of concurrent PTH and ibandronate, followed by 18 months of ibandronate (concurrent) or two sequential courses of 3 months of PTH followed by 9 months of ibandronate (sequential) over 2 yr. Bone turnover markers were measured. Areal and volumetric BMD were assessed by dual-energy x-ray absorptiometry and quantitative computed tomography, respectively. Over 2 yr, areal BMD at the spine and hip increased similarly in both groups, with 7.5 and 8.2% increases in spine BMD in the concurrent and sequential arms, respectively (difference -0.6%, 95% confidence interval=-3.4-2.1%). Volumetric BMD also increased similarly between groups. With concurrent therapy, mean N-propeptide of type I collagen increased 75% between baseline and month 1 and then declined. With sequential therapy, the second 3-month PTH course increased N-propeptide of type I collagen markedly (209%), although to a lesser absolute degree than the first. Six months of PTH(1-84), used over 2 yr with a bisphosphonate in either of our dosing regimens increased BMD substantially. Short PTH courses may provide the benefits of anabolic osteoporosis therapy with reduced burden for patients.

An indirect comparison of the toxicity of sunitinib and pazopanib in metastatic clear cell renal cancer

BackgroundBoth sunitinib and pazopanib are widely used as first line therapy in metastatic renal cancer (mRCC). The efficacy of these agents appears similar but they may have distinct toxicity profiles. In this study we compare the severity of symptomatic and asymptomatic toxicity associated with sunitinib and pazopanib. MethodsTwo sequential prospective single arm phase II studies investigated either 12weeks of sunitinib (n=43) or pazopanib (n=34) prior to nephrectomy in untreated mRCC. Toxicity was defined as either symptomatic (hand and foot syndrome, mucositis, nausea, fatigue, diarrhoea, oedema, headache, pain, anorexia and change in taste) or asymptomatic (liver toxicity or haematological toxicity). Pazopanib (800mg once daily (OD)) and sunitinib (50mg 4/2) were given. Regular Common Toxicity Criteria (CTC) toxicity assessment was performed during the first 12weeks of therapy. ResultsThere was no significant difference in the overall number of toxic events (grade 1–4) for sunitinib and pazopanib (mean number of toxic events/patients: 1.97 versus 1.96: p>0.05). Increased grade 2–4 symptomatic toxicity events occurred with sunitinib (hazard ratio (HR) 1.67 [95% confidence interval (CI): 1.11–2.56] p<0.03). Sunitinib was associated with an increased grade 2–4 mucositis (16% versus 0% p=0.02) and fatigue (42% versus 15% p=0.01). Pazopanib was associated with more frequent grade 1 diarrhoea (39% versus 12%: p=0.03). Dose reductions for symptomatic toxicity occurred more frequently with sunitinib (26% versus 6% p<0.05). There was no difference in the occurrence of asymptomatic toxicity. ConclusionThis indirect analysis suggests sunitinib and pazopanib have distinct toxicity profiles which may help guide patient’s choice. Further comparative data from randomised trials are awaited.

Dorsal parietal area 5 only encodes the immediate reach in sequential arm movement

To generate an action sequence, it is essential to integrate information regarding all temporally coordinating motor elements. Spatial information about both immediate and subsequent component reaches is encoded simultaneously in the parietal reach region (PRR) [1]. However, it is still unclear how a cognitive sequence conveying multiple goals in parallel is discomposed into series of discrete movement commands to be executed by the musculoskeletal system. In the present study, we recorded single-neuron activity from dorsal area 5 (area 5d) in the posterior parietal cortex while monkeys performed a memory-guided double-reach task. Briefly, the monkey was required to touch a fixation center at the trial beginning. Then, the first and second goals were simultaneously displayed for 400ms with a square and a triangle (shifted counter-clockwise from the square by 135°), respectively. After a 600ms delay, the center dot dimmed (GO signal) and the monkey was allowed to initiate the reaching sequence to touch the locations previously cued by the square and triangle in the correct order. Single-reach trials were pseudo-randomly interleaved with the double-reach trials for a control. Among all 98 task-related cells we recorded from two monkeys, 35 (36%), 75 (77%) and 75 (77%) exhibited significant directional tuning during the delay (0~400ms before GO), pre-movement (0~200ms before the onset of the 1st movement), and peri-movement (0~200ms after the onset of the 1st movement) periods, respectively. In all above groups, the tuning curves in double-reach were similar to those in the single-reach trials (p > 0.05). To quantitatively analyze tuning dynamics, we calculated the vector sum of the neuronal activity in a 200ms sliding window across all directions as the instantaneous preferred direction. Prior to the offset of the 1st movement, there was no significant difference in the preferred directions between single- and double-reach. Thereafter, the preferred direction in double-reach trials gradually rotated counter-clockwise toward the second reaching goal. Around 100ms before the onset of the 2nd movement, the shift saturated at 135° at the population level, co-varying with the switch of immediate reaching movements. We calculated the Fano Factor (FF, as the variance versus mean of the spike counts) across trials in each movement-direction/cell combination with a 100ms sliding window. In contrast to numerous other cortical sensorimotor regions [2], area 5d activity exhibited low variability (FF = ~1.0) and the FF changed modestly during the whole preparatory period. Although FF increased sharply after GO signal (up to ~1.3), this tendency could be weaken by aligning the spike trains to the movement onset (reduce to ~1.1) or by separating fast and slow reaction trials (reduce to ~1.1-1.2 only). This is generally the case regardless of aligning to the onset of the movement in the single reach trials, or 1st or 2nd movements in the double-reach trials. The results that area 5d activity only conveys information about the immediate reach with low variance stick to motor execution suggest that area 5d may play a key role in translating cognitive action sequences into executive motor commands to activate muscle synergies.

Clinical benefits of sequential administration of docetaxel and intermittent erlotinib as a second-line therapy for advanced non-small cell lung cancer (NSCLC): A phase II randomized study.

e18049 Background: Patients (p) with advanced NSCLC have few treatment options after progressing to 1st-line platinum doublet chemotherapy. Several preclinical and phase I studies have suggested that sequential administration of erlotinib (E) and docetaxel could avoid possible negative interactions and optimize the benefit obtained against NSCLC. This randomized phase II was designed to address the clinical benefit obtained with the use of sequential administration of docetaxel and intermittent E. Methods: 70 p with advanced NSCLC progressing to previous PDC for advanced disease were randomized (1:1): Group A (n = 34): Docetaxel 75 mg/m2 day 1 and intermittent E (day 2-16), up to 4 cycles, followed by E in monotherapy; and Group B (n = 36): E in monotherapy. Treatment was administered until unacceptable toxicity or disease progression. Primary endpoint: rate of p free of progression at 6 months; secondary endpoints: progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. The study has completed enrolment. At the date of cut-off for this communication, data of 60 patients were available: 30 in Group A/30 in Group B. Results: Baseline characteristics: non-adenocarcinoma (60.3%), current/former smokers (95%), male (90%) and stage IV (87.9%). 6 months PFS: 13.5% in the sequential arm. PFS: 2.7 months (m) in Group A (95% CI 2.1 – 3.8) and 2 m in Group B (95% CI 1.7 – 2.4) p value 0.08. Median OS: 11.0 m (95% CI 4.5 – 13.4) in group A and 4.7m (95% CI 2.5 – 6.6) in Group B with a p value 0.02. DCR: 44.4% in the experimental group whereas in the E one was 30.8%. Adverse events (AEs), including skin rash and diarrhea, were all generally tolerable. Of interest, the low number of p developing neutropenia in the D + E arm. Conclusions: Although the primary objective has not been met, an encouraging benefit on survival has been shown in the exploratory analysis, with a median overall survival of 11 months for patients treated with the sequential regimen (p value 0.02). Final data will be presented during the meeting.

Clinical accuracy of inflationary oscillometry in pregnancy and pre-eclampsia: Omron-MIT Elite

ObjectiveTo evaluate the accuracy of the Omron MIT Elite in pregnancy and pre-eclampsia according to the British Hypertension Society protocol (BHS). DesignProspective observational study. SettingAntenatal clinics and wards at St. Thomas’ Hospital (London, UK). PopulationForty-five pregnant women including 15 with pre-eclampsia. MethodsNine sequential same arm blood pressure (BP) measurements were taken from each woman by trained observers, alternating between mercury sphygmomanometry and the test device. Main outcome measuresGrading criteria of the BHS protocol (A/B grade=pass; C/D=fail). ResultsThe Omron MIT Elite achieved a grade A/A in both pregnancy and pre-eclampsia. The mean difference (SD) between the mercury standard and the device in pregnancy was −1.1 (5.2)mmHg and 1.5 (4.8)mmHg for systolic and diastolic BP respectively compared to 0.2 (5.3)mmHg and 2.2 (5.5)mmHg in pre-eclampsia. ConclusionThe Omron MIT Elite can be recommended for use in pregnancy and pre-eclampsia according to the BHS protocol. To date, this is the most accurate automated BP device validated in pre-eclampsia.

A multicenter, randomized phase II study of sequential vinorelbine (V)/cisplatin (C)/bevacizumab (B) followed by docetaxel (D)/gemcitabine (G)/B versus D/C/B as a first-line therapy for advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC).

e18105 Background: The combination of D with G has been shown equally active compared to the platinum-based doublets, which is considered the cornerstone for the treatment of NSCLC, with a more favorable toxicity profile (Georgoulias V. Lancet 2001 357: 1478-84). Sequential therapy with four active drugs (two doublets) in NSCLC, including C, was recently investigated and attributed a promising response rate (Pallis A. Lung Cancer, 2006, 52(2): 165-71). Incorporation of B to the standard platinum-based regimen improved its clinical outcome. Aim of this trial was to compare the efficacy of sequential four drug treatment in combination with B to the standard non platinum-based regimen combined with B. Methods: Seventy-seven treatment naïve patients (pts) with stage IIIB and IV non-squamous NSCLC were randomized to receive V 60 mg/m2 PO on day 1 and 8, C 80mg/m2 IV on day 1 and B 15 mg/kg IVon day 1, for 3 cycles followed by D 75 mg/m2 IV, G 1100 mg/m2 IV and B 15 mg/kg IV, all on day 1 (Arm A) or D 75 mg/m2 IV, C 80mg/m2 IV and B 15 mg/kg IV on day. The cycles were repeated every 3 weeks for a total of 6 cycles. The primary endpoint of the study was response rate (RR) and the secondary outcome measures were overall survival (OS) and progression free survival (PFS). Results: Thirty-nine pts were randomized to the control arm (Arm B) and 38 pts to the sequential arm. Pt demographics were balanced in both the arms. The overall RR was 36.8% and 46.2% in arm A and B, respectively (p= 0.49). There were 3 complete responses, one in arm A. Median PFS was 6.87 and 5.53 months in arm A and B, respectively (p= 0.368). Median OS was 19.6 and 10.33, respectively (p= 0.239). The estimated 1 and 2-year survival for arm A versus B were 71.1% and 36% versus 45.3% and 28%, respectively. No statistically significant difference in the toxicity profile was observed between the 2 arms. Conclusions: Sequential treatment with four active drugs is feasible and safe. The combination attributes encouraging results compared to the standard platinum-based regimen.

A randomized phase-II trial comparing sequential and concurrent paclitaxel with oral or parenteral fluorinated pyrimidines for advanced or metastatic gastric cancer

The purpose of this study was twofold: (1) to compare S-1 with infusional 5-fluorouracil (FU) to determine which would be a better partner of paclitaxel (PTX), and (2) to compare a concurrent strategy with a sequential one, the latter strategy being the one that is widely used in Japanese general practice. The 161 eligible patients were randomized into four arms to receive the following regimens: A (sequential), intravenous 5-FU at 800mg/m(2) for 5days every 4weeks followed by weekly PTX at 80mg/m(2); B (sequential), S-1 at 80mg/m(2) for 4weeks and 2-week rest followed by PTX; C (concurrent), intravenous 5-FU at 600mg/m(2) for 5days and weekly PTX at 80mg/m(2) every 4weeks; and D (concurrent), S-1 for 14days and PTX at 50mg/m(2) on days 1 and 8 every 3weeks. The primary endpoint was the overall survival (OS) rate at 10months. The ten-month OS rates in arms A, B, C, and D were 63, 65, 61, and 73%, respectively. The OS was best in the concurrent S-1/PTX arm, with a mean survival time of 15.4months, but no significant difference was observed between the four arms. Response rates were higher in the concurrent arms than in the sequential arms. Our study did not show sufficient prolongation of survival with the concurrent strategy to proceed to a phase-III trial; however, the sequential arms showed survival comparable to that in the concurrent arms, with less toxicity. In patients who are ineligible for cisplatin (CDDP), sequential treatment starting with S-1 and proceeding to PTX would be a good alternative strategy, considering quality of life (QOL) and the cost-benefits of an oral agent as first-line treatment.