Gemcitabine Alone Versus Gemcitabine Plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial

Indiana University Melvin and Bren Simon Cancer Center, 980 West Walnut St, Suite C528, Indianapolis, IN 46202, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 11/2011; 29(31):4105-12. DOI: 10.1200/JCO.2011.34.8904
Source: PubMed


The purpose of this trial was to evaluate the role of radiation therapy with concurrent gemcitabine (GEM) compared with GEM alone in patients with localized unresectable pancreatic cancer.
Patients with localized unresectable adenocarcinoma of the pancreas were randomly assigned to receive GEM alone (at 1,000 mg/m(2)/wk for weeks 1 to 6, followed by 1 week rest, then for 3 of 4 weeks) or GEM (600 mg/m(2)/wk for weeks 1 to 5, then 4 weeks later 1,000 mg/m(2) for 3 of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/Fx for total of 50.4 Gy). Measurement of quality of life using the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire was also performed.
Of 74 patients entered on trial and randomly assigned to receive GEM alone (arm A; n = 37) or GEM plus radiation (arm B; n = 34), patients in arm B had greater incidence of grades 4 and 5 toxicities (41% v 9%), but grades 3 and 4 toxicities combined were similar (77% in A v 79% in B). No statistical differences were seen in quality of life measurements at 6, 15 to 16, and 36 weeks. The primary end point was survival, which was 9.2 months (95% CI, 7.9 to 11.4 months) and 11.1 months (95% CI, 7.6 to 15.5 months) for arms A and B, respectively (one-sided P = .017 by stratified log-rank test).
This trial demonstrates improved overall survival with the addition of radiation therapy to GEM in patients with localized unresectable pancreatic cancer, with acceptable toxicity.

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Available from: David Cella, Jul 22, 2014
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    • "Standard treatment for locally advanced pancreatic cancer is concurrent antimetabolite-based chemoradiation. In particular, the combination of gemcitabine with radiation is superior to gemcitabine alone [3] [4]. Thus, in the development of targeted agents for the treatment of pancreatic cancer, interactions with gemcitabine are an important consideration. "
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    ABSTRACT: In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Translational oncology 02/2015; 8(1):47-54. DOI:10.1016/j.tranon.2014.12.004 · 2.88 Impact Factor
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    • "It can be treated by chemotherapy alone, chemoradiotherapy (CRT), or induction chemotherapy followed by CRT. Median overall survival (OS) is in the order of 11 months when CRT is used [3]. Recently, a large Phase III trial comparing induction chemotherapy prior to CRT and chemotherapy alone was closed at its first interim analysis as the addition of CRT did not offer a survival advantage (LAP07) [4]. "
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    ABSTRACT: Background The best method of identifying regions within pancreatic tumours that might benefit from an increased radiotherapy dose is not known. We investigated the utility of pre-treatment FDG-PET in predicting the spatial distribution of residual metabolic activity following chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC). Methods 17 patients had FDG-PET/CT scans at baseline and six weeks post-CRT. Tumour segmentation was performed at 40% and 50% of SUVmax at baseline and 60%, 70%, 80% and 90% post-CRT. FDG-PET scans were non-rigidly registered to the radiotherapy planning CT using the CT component of the FDG-PET/CT. Percentage overlap of the post-CRT volumes with the pre-CRT volumes with one another and the gross tumour volume (GTV) was calculated. Results SUVmax decreased during CRT (median pre- 8.0 and post- 3.6, p < 0.0001). For spatial correlation analysis, 9 pairs of scans were included (Four were excluded following complete metabolic response, one patient had a non-FDG avid tumour, one had no post-CRT imaging, one had diffuse FDG uptake that could not be separated from normal tissues and one had an elevated blood glucose). The Pre40% and 50% of SUVmax volumes covered a mean of 50.8% and 30.3% of the GTV respectively. The mean% overlap of the 90%, 80%, 70%, 60% of SUVmax post-CRT with the Pre40% and Pre50% volumes were 83.3%, 84.0%, 83.7%, 77.9% and 77.8%, 69.9%, 74.5%, 64.8% respectively. Conclusions Regions of residual metabolic activity following CRT can be predicted from the baseline FDG-PET and could aid definition of a biological target volume for non-uniform dose prescriptions.
    Radiation Oncology 06/2014; 9(1):146. DOI:10.1186/1748-717X-9-146 · 2.55 Impact Factor
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    • "The poor prognosis of pancreatic cancer is due to the failure of early diagnosis for curative surgical resection combined with adjuvant chemotherapy, the aggressive biological behavior of the tumor and insensitivity to most conventional therapies including chemotherapy and radiotherapy (3). Although a recent study shows that FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan and oxaliplatin) is superior option for patients with advanced pancreatic cancer and good ECOG (Eastern Cooperative Oncology Group) performance status, gemcitabine (difluorodeoxycitidine, dFdC) still remains the first-line standard drug as a treatment available for metastatic and non-metastatic with locally advanced pancreatic cancer (4,5); however, the disease rapidly develops resistance to the drug and no apparent improvement in overall survival rate over the last decade (2,6). "
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