Intensified chemotherapy and simultaneous treatment with heparin in outpatients with pancreatic cancer - the CONKO 004 pilot trial

Uwe Pelzer, Andreas Hilbig, Jens M Stieler, Marcus Bahra, Marianne Sinn, Bernhard Gebauer, Bernd Dörken, Hanno Riess, Uwe Pelzer, Andreas Hilbig, Jens M Stieler, Marcus Bahra, Marianne Sinn, Bernhard Gebauer, Bernd Dörken, Hanno Riess

Abstract

Background: Advanced pancreatic cancer (APC), beside its high mortality, causes the highest rates of venous thromboembolic events (VTE). Enoxaparin, a low molecular weight heparin (LMWH), is effective in prevention and treatment of VTE. Some small studies indicated that this benefit might extend to patients with cancer and probably prolong survival due to independent mechanisms. We initiated this safety investigation to get feasibility information on intensified chemotherapy combined with LMWH in outpatients with APC treated in 1st line.

Methods: The trial was a prospective, open-label, single center investigation in outpatients with inoperable pancreatic cancer who were treated with intensified first-line chemotherapy along with concomitant application of subcutaneous LMWH. The combined chemotherapy consisted of gemcitabine 1 g/m2 (30 min), 5-FU 750 mg/m2 (24 h), folinic acid 200 mg/m2 (30 min), and Cisplatin 30 mg/m2 (90 min) on day 1 and 8; q3w for the first 12 weeks (GFFC) followed by gemcitabine alone in patients without cancer progression. The simultaneous application of prophylactic enoxaparin started on day 1 of chemotherapy with a fixed dose of 40 mg daily. Statistical analyses were performed using R 3.01 with software package CMPRSK and SPSS software v19.0.

Results: The investigation was stopped after recruitment of 19 patients. At this time 15 patients had completed the required 12 weeks of treatment. Based on 71 cycles of GFFC + enoxaparin (median 4/pt [range: 2-4]) and 108 cycles of single-agent gemcitabine + enoxaparin (median 4/pt [range: 0-18]) the cumulative frequency of NCI-CTC toxicities grade 3/4 was below 10%. One case (5%) of a symptomatic non-lethal thromboembolic event was observed while receiving LMWH treatment. No severe bleeding event as defined in the protocol has been observed. The median overall survival was 10.05 [95% CI: 8.67-18.14] months.

Conclusions: The addition of enoxaparin to GFFC chemotherapy is feasible, safe and does not appear to affect the efficacy or the toxicity profile of the chemotherapy regimen in patients with advanced pancreatic adenocarcinoma. Based on these findings we have initiated the randomized CONKO-004 trial to examine whether enoxaparin reduces the incidence of thromboembolic events or increases overall outcome.

Trial registration: Clinical Trials NCT01945879.

Figures

Figure 1
Figure 1
Hematological and non-hematological toxicities (no. out of 179 cycles). Numbers represent the count of treatment cycles with corresponding toxicity.
Figure 2
Figure 2
Kaplan-Meier plot for overall survival.
Figure 3
Figure 3
Forest plot of prognostic factors.

References

    1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi: 10.3322/caac.20107.
    1. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR. u. a. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403–2413.
    1. Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A. u. a. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12–9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the national cancer institute of Canada clinical trials group. J Clin Oncol. 2003;21(17):3296–3302. doi: 10.1200/JCO.2003.02.098.
    1. Arshad A, Al-Leswas D, Al-Taan O, Stephenson J, Metcalfe M, Steward WP. u. a. Pooled survival and response data from phase III randomized controlled trials for gemcitabine-based regimes in the treatment of advanced pancreatic cancer. Am J Clin Oncol. 2013;36(4):411–414. doi: 10.1097/COC.0b013e3182124216.
    1. Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol. März. 2010;7(3):163–172. doi: 10.1038/nrclinonc.2009.236.
    1. Pelzer U. First-line chemotherapy in advanced pancreatic cancer. Recent Results Cancer Res. 2008;177:57–60. doi: 10.1007/978-3-540-71279-4_7.
    1. Heinemann V, Philip PA, Pelzer U. Accomplishments in 2008 in the treatment of metastatic pancreatic cancer. Gastrointest Cancer Res. 2009;3(5 Supplement 2):S43–S47.
    1. Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W. u. a. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009;27(33):5513–5518. doi: 10.1200/JCO.2009.24.2446.
    1. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y. u. a. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825. doi: 10.1056/NEJMoa1011923.
    1. Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer. 2008;8:82. doi: 10.1186/1471-2407-8-82.
    1. Menapace LA, Peterson DR, Berry A, Sousou T, Khorana AA. Symptomatic and incidental thromboembolism are both associated with mortality in pancreatic cancer. Thromb Haemost. 2011;106(2):371–378. doi: 10.1160/TH10-12-0789.
    1. Sørensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000;343(25):1846–1850. doi: 10.1056/NEJM200012213432504.
    1. Khorana AA. Cancer and thrombosis: implications of published guidelines for clinical practice. Ann Oncol. 2009;20(10):1619–1630. doi: 10.1093/annonc/mdp068.
    1. Lee AYY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C. u. a. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23((10):2123–2129.
    1. Chew HK, Davies AM, Wun T, Harvey D, Zhou H, White RH. The incidence of venous thromboembolism among patients with primary lung cancer. J Thromb Haemost. 2008;6(4):601–608. doi: 10.1111/j.1538-7836.2008.02908.x.
    1. Icli F, Akbulut H, Utkan G, Yalcin B, Dincol D, Isikdogan A. u. a. Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer. J Surg Oncol. 2007;95((6):507–512.
    1. Riess H, Pelzer U, Hilbig A, Stieler J, Opitz B, Scholten T. u. a. Rationale and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy) BMC Cancer. 2008;8:361. doi: 10.1186/1471-2407-8-361.
    1. Oettle H, Arnold D, Kern M, Hoepffner N, Settmacher U, Neuhaus P. u. a. Phase I study of gemcitabine in combination with cisplatin, 5-fluorouracil and folinic acid in patients with advanced esophageal cancer. Anticancer Drugs. 2002;13(8):833–838. doi: 10.1097/00001813-200209000-00008.
    1. Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res. Juni. 2010;125(6):490–493. doi: 10.1016/j.thromres.2009.12.023.
    1. Kleber F-X, Witt C, Vogel G, Koppenhagen K, Schomaker U, Flosbach CW. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J. 2003;145(4):614–621. doi: 10.1067/mhj.2003.189.
    1. Turpie AG. Thrombosis prophylaxis in the acutely ill medical patient: insights from the prophylaxis in MEDical patients with ENOXaparin (MEDENOX) trial. Am J Cardiol. 2000;86(12B):48M–52M.
    1. Turpie AGG, Norris TM. Thromboprophylaxis in medical patients: the role of low-molecular-weight heparin. Thromb Haemost. Juli. 2004;92(1):3–12.
    1. Zacharski LR, Henderson WG, Forman WB, Edwards RL, Cornell CJ Jr, Forcier RJ. u.a. Bleeding complications from warfarin anticoagulation in patients with malignancy. J Med. 1985;16(5–6):535–561.
    1. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S. u. a. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960–1966. doi: 10.1200/JCO.2006.07.9525.

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