Article

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

ABSTRACT

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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    • "Radiation in combination with concurrent gemcitabine or 5-fluorouracil is the standard of care for locally advanced pancreatic cancer. In combination with gemcitabine, radiation significantly improves survival compared with gemcitabine treatment alone [1]. Furthermore, recent studies from our group and others suggest that intensification of highly conformal radiation may extend survival in locally advanced patients beyond the approximate 1-year survival associated with standard chemoradiation therapies [2] [3]. "
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    ABSTRACT: To improve the efficacy of chemoradiation therapy for locally advanced pancreatic cancer and begin to establish patient selection criteria, we investigated the combination of the WEE1 inhibitor AZD1775 with gemcitabine-radiation in homologous recombination (HR) repair proficient and deficient pancreatic cancers. Sensitization to gemcitabine-radiation by AZD1775 was assessed in pancreatic cancer cells by clonogenic survival and in patient-derived xenografts by tumor growth. The contributions of HR repair inhibition and G2 checkpoint abrogation to sensitization were assessed by γH2AX, BRCA2 manipulation, and RAD51 focus formation and pHistone H3 flow cytometry, respectively. We found that AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type but not BRCA2 mutant pancreatic cancer cells. In all cells, AZD1775 caused inhibition of CDK1 phosphorylation and G2 checkpoint abrogation. However, sensitization by AZD1775 was associated with persistent γH2AX and inhibition of RAD51 focus formation. In HR-proficient (BRCA2 wild-type) or -deficient (BRAC2 null) isogenic cells, AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type, but not in BRCA2 null cells, despite significant G2 checkpoint abrogation. In patient-derived pancreatic tumor xenografts, AZD1775 significantly inhibited tumor growth and impaired RAD51 focus formation in response to gemcitabine-radiation. In conclusion, WEE1 inhibition by AZD1775 is an effective strategy for sensitizing pancreatic cancers to gemcitabine chemoradiation. Although this sensitization is accompanied by inhibition of CDK1 phosphorylation and G2 checkpoint abrogation, this mechanism is not sufficient for sensitization. Our findings demonstrate that sensitization to chemoradiation by WEE1 inhibition results from inhibition of HR repair and suggest that patient tumors without underlying HR defects would benefit most from this therapy.
    Full-text · Article · Oct 2015 · Neoplasia (New York, N.Y.)
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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.
    Full-text · Article · Feb 2015 · Translational oncology
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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.
    Full-text · Article · Jun 2014 · Radiation Oncology
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