44 results on '"Pancreatic Neoplasms radiotherapy"'
Search Results
2. Randomized Phase II Study of Nivolumab With or Without Ipilimumab Combined With Stereotactic Body Radiotherapy for Refractory Metastatic Pancreatic Cancer (CheckPAC).
- Author
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Chen IM, Johansen JS, Theile S, Hjaltelin JX, Novitski SI, Brunak S, Hasselby JP, Willemoe GL, Lorentzen T, Madsen K, Jensen BV, Wilken EE, Geertsen P, Behrens C, Nolsoe C, Hermann KL, Svane IM, and Nielsen D
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, C-Reactive Protein, Humans, Interleukin-6, Interleukin-8, Ipilimumab adverse effects, Ligands, Nivolumab adverse effects, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Radiosurgery adverse effects
- Abstract
Purpose: To evaluate the clinical benefit of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy (SBRT) in patients with refractory metastatic pancreatic cancer (mPC)., Methods: Between November 2016 and December 2019, patients with refractory mPC were randomly assigned 1:1 to SBRT of 15 Gy with nivolumab or nivolumab/ipilimumab stratified by performance status (ClinicalTrials.gov identifier: NCT02866383). The primary end point was the clinical benefit rate (CBR), defined as the percentage of patients with complete or partial response (PR) or stable disease, according to RECIST 1.1. Simon's 2-stage phase II optimal design was used independently for both arms, with CBR determining expansion to the second stage. Secondary end points included safety, response rate, duration of response, progression-free survival, and overall survival. Exploratory analyses included biomarkers related to the benefits., Results: Eighty-four patients (41 SBRT/nivolumab and 43 SBRT/nivolumab/ipilimumab) received at least one dose of study treatment. CBR was 17.1% (8.0 to 30.6) for patients receiving SBRT/nivolumab and 37.2% (24.0 to 52.1) for SBRT/nivolumab/ipilimumab. PR was observed in one patient receiving SBRT/nivolumab and lasted for 4.6 months. Six patients receiving SBRT/nivolumab/ipilimumab achieved a PR with a median duration of response of 5.4 months (4.2 to not reached). Grade 3 or higher treatment-related adverse events occurred in 10 (24.4%) and 13 (30.2%) patients in the SBRT/nivolumab and SBRT/nivolumab/ipilimumab groups, respectively. Programmed cell death ligand-1 expression by tumor proportion score or combined positivity score of ≥ 1% was not associated with clinical benefits. On-treatment decreased serum interleukin-6, interleukin-8, and C-reactive protein levels were associated with better overall survival., Conclusion: Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with SBRT/nivolumab/ipilimumab in patients with refractory mPC. However, the contribution from SBRT is unknown. Further studies are warranted.
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- 2022
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3. Value of Neoadjuvant Radiation Therapy in the Management of Pancreatic Adenocarcinoma.
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Hall WA, Dawson LA, Hong TS, Palta M, Herman JM, Evans DB, Tsai S, Ferrone CR, B Fleming J, Chang DT, Crane C, Koong AC, Oar A, Parikh P, Erickson B, Hoffe S, and Goodman KA
- Subjects
- Female, Humans, Male, Adenocarcinoma radiotherapy, Pancreatic Neoplasms radiotherapy, Radiosurgery methods
- Abstract
Competing Interests: William A. HallResearch Funding: ElektaTravel, Accommodations, Expenses: Elekta Laura A. DawsonResearch Funding: Merck Theodore S. HongStock and Other Ownership Interests: PanTher TherapeuticsConsulting or Advisory Role: Merck, Synthetic Biologics, Novocure, SyndaxResearch Funding: Taiho Pharmaceutical, AstraZeneca, IntraOp, Tesaro, Bristol Myers Squibb, Ipsen Manisha PaltaHonoraria: OakstoneConsulting or Advisory Role: Syntactx, VoxelMetrixResearch Funding: Merck, Varian Medical SystemsPatents, Royalties, Other Intellectual Property: UpToDate—Annual royalties for being a section author Joseph M. HermanHonoraria: Sirtex MedicalTravel, Accommodations, Expenses: Varian Medical SystemsOther Relationship: 1440 Foundation Jason B. FlemingLeadership: Bio-Path Holdings, IncConsulting or Advisory Role: Johnson and Johnson, GlycosBio, Moleculin Biotech, Perthera, Covidien LP/Medtronic, PanTher TherapeuticsPatents, Royalties, Other Intellectual Property: US Application No. 15/780,799, based on International Application No. PCT/US2016/065763, titled Polymeric Drug Delivery Systems for Treatment of Disease, by Chun Li et al; In the Name of Board of Regents, The University of Texas System Daniel T. ChangStock and Other Ownership Interests: ViewRayResearch Funding: Varian Medical Systems, Reflexion MedicalOther Relationship: ViewRay Christopher CraneStock and Other Ownership Interests: Oncternal TherapeuticsHonoraria: ElektaConsulting or Advisory Role: TriSalus Life SciencesResearch Funding: Elekta Albert C. KoongStock and Other Ownership Interests: Aravive Parag ParikhStock and Other Ownership Interests: NuvairaHonoraria: ViewRaySpeakers' Bureau: ViewrayResearch Funding: ViewRayTravel, Accommodations, Expenses: IBA Beth EricksonResearch Funding: ElektaTravel, Accommodations, Expenses: Elekta Sarah HoffeStock and Other Ownership Interests: VitalAireHonoraria: UpToDateConsulting or Advisory Role: MerckResearch Funding: Varian Medical Systems, Galera TherapeuticsPatents, Royalties, Other Intellectual Property: I cowrote the bone metastases chapter for UpToDate. They pay royalties/honoraria for that yearlyTravel, Accommodations, Expenses: Varian Medical SystemsOther Relationship: Beyond the White Coat, VitalAireUncompensated Relationships: Galera Therapeutics, ViewRay Karyn A. GoodmanConsulting or Advisory Role: RenovoRx, Roche/Genentech, NovartisNo other potential conflicts of interest were reported.
- Published
- 2021
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4. Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer.
- Author
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Cuneo KC, Morgan MA, Sahai V, Schipper MJ, Parsels LA, Parsels JD, Devasia T, Al-Hawaray M, Cho CS, Nathan H, Maybaum J, Zalupski MM, and Lawrence TS
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cell Cycle Proteins antagonists & inhibitors, Chemoradiotherapy, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Deoxycytidine analogs & derivatives, Dose-Response Relationship, Drug, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors adverse effects, Female, Humans, Male, Middle Aged, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrazoles administration & dosage, Pyrazoles adverse effects, Pyrimidinones administration & dosage, Pyrimidinones adverse effects, Survival Rate, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: AZD1775 (adavosertib) is an inhibitor of the Wee1 kinase. In this study, we built on our preclinical studies to evaluate the safety and efficacy of AZD1775 in combination with gemcitabine and radiation in patients with newly diagnosed locally advanced pancreatic cancer., Patients and Methods: Thirty-four patients with locally advanced pancreatic cancer were enrolled with the intention to receive four 21-day cycles of gemcitabine (1,000 mg/m
2 days 1 and 8) with AZD1775 (once daily on days 1, 2, 8, and 9). Cycles 2 and 3 were administered concurrently with radiation, and cycles 5 to 8 were optional. AZD1775 was dose escalated using a time-to-event continual reassessment method on the basis of the rate of dose-limiting toxicities within the first 15 weeks of therapy. The primary objective was to determine the maximum tolerated dose of AZD1775 given in conjunction with gemcitabine and radiation. Secondary objectives were to estimate overall and progression-free survival and determine pharmacodynamic activity of AZD1775 in surrogate tissues., Results: The recommended phase II dose of AZD1775 was 150 mg/d. Eight patients (24%) experienced a dose-limiting toxicity, most commonly anorexia, nausea, or fatigue. The median overall survival for all patients was 21.7 months (90% CI, 16.7 to 24.8 months), and the median progression-free survival was 9.4 months (90% CI, 8.0 to 9.9 months). Hair follicle biopsy samples demonstrated evidence of Wee1 inhibition with decreased phosphorylation of cyclin-dependent kinase 1 staining by immunohistochemistry after AZD1775 administration at the recommended phase II dose., Conclusion: AZD1775 in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue. The overall survival is substantially higher than prior results combining gemcitabine with radiation therapy and warrants additional investigation.- Published
- 2019
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5. Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results.
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Herman JM, Wild AT, Wang H, Tran PT, Chang KJ, Taylor GE, Donehower RC, Pawlik TM, Ziegler MA, Cai H, Savage DT, Canto MI, Klapman J, Reid T, Shah RJ, Hoffe SE, Rosemurgy A, Wolfgang CL, and Laheru DA
- Subjects
- Adult, Aged, Chemotherapy, Adjuvant, DNA administration & dosage, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Disease-Free Survival, Drug Administration Schedule, Erlotinib Hydrochloride, Female, Fluorouracil administration & dosage, Humans, Injections, Intralesional, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Staging, Odds Ratio, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Quinazolines administration & dosage, Radiotherapy, Adjuvant, Treatment Failure, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chemoradiotherapy, Pancreatic Neoplasms pathology, Pancreatic Neoplasms therapy
- Abstract
Purpose: TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer. We herein report final results of the largest randomized phase III trial performed to date among patients with locally advanced pancreatic cancer (LAPC) and the first to test gene transfer against this malignancy., Patients and Methods: In all, 304 patients were randomly assigned 2:1 to standard of care plus TNFerade (SOC + TNFerade) versus standard of care alone (SOC). SOC consisted of 50.4 Gy in 28 fractions with concurrent fluorouracil (200 mg/m(2) per day continuous infusion). TNFerade was injected intratumorally before the first fraction of radiotherapy each week at a dose of 4 × 10(11) particle units by using either a percutaneous transabdominal or an endoscopic ultrasound approach. Four weeks after chemoradiotherapy, patients began gemcitabine (1,000 mg/m(2) intravenously) with or without erlotinib (100 to 150 mg per day orally) until progression or toxicity., Results: The analysis included 187 patients randomly assigned to SOC + TNFerade and 90 to SOC by using a modified intention-to-treat approach. Median follow-up was 9.1 months (range, 0.1 to 50.5 months). Median survival was 10.0 months for patients in both the SOC + TNFerade and SOC arms (hazard ratio [HR], 0.90; 95% CI, 0.66 to 1.22; P = .26). Median progression-free survival (PFS) was 6.8 months for SOC + TNFerade versus 7.0 months for SOC (HR, 0.96; 95% CI, 0.69 to 1.32; P = .51). Among patients treated on the SOC + TNFerade arm, multivariate analysis showed that TNFerade injection by an endoscopic ultrasound-guided transgastric/transduodenal approach rather than a percutaneous transabdominal approach was a risk factor for inferior PFS (HR, 2.08; 95% CI, 1.06 to 4.06; P = .032). The patients in the SOC + TNFerade arm experienced more grade 1 to 2 fever and chills than those in the SOC arm (P < .001) but both arms had similar rates of grade 3 to 4 toxicities (all P > .05)., Conclusion: SOC + TNFerade is safe but not effective for prolonging survival in patients with LAPC.
- Published
- 2013
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6. Keys to personalized care in pancreatic oncology.
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Crane CH and Iacobuzio-Donahue CA
- Subjects
- Female, Humans, Male, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Published
- 2012
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7. Open-label, multicenter, randomized phase III trial of adjuvant chemoradiation plus interferon Alfa-2b versus fluorouracil and folinic acid for patients with resected pancreatic adenocarcinoma.
- Author
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Schmidt J, Abel U, Debus J, Harig S, Hoffmann K, Herrmann T, Bartsch D, Klein J, Mansmann U, Jäger D, Capussotti L, Kunz R, and Büchler MW
- Subjects
- Adenocarcinoma pathology, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Chemoradiotherapy, Chemotherapy, Adjuvant, Cisplatin administration & dosage, Cisplatin adverse effects, Female, Fluorouracil administration & dosage, Fluorouracil adverse effects, Humans, Interferon alpha-2, Interferon-alpha administration & dosage, Interferon-alpha adverse effects, Leucovorin administration & dosage, Leucovorin adverse effects, Male, Middle Aged, Pancreatic Neoplasms pathology, Prognosis, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Survival Analysis, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: Adjuvant chemotherapy prolongs survival in patients with pancreatic cancer, but its benefit is limited. Long-term survival times of up to 44 months after adjuvant chemoradioimmunotherapy in phase II trials motivated the present study., Patients and Methods: Between 2004 and 2007, 132 R0/R1 resected patients received either fluorouracil (FU), cisplatin, and interferon alfa-2b (IFN α-2b) plus radiotherapy followed by two cycles of FU (arm A, n=64) or six cycles of FU monotherapy (arm B, n=68). One hundred ten patients (arm A, n=53; arm B, n=57) received at least one dose of the study medication, and these patients composed the per-protocol (PP) population. Biomarkers were analyzed longitudinally for their predictive value., Results: Median survival for all randomly assigned patients was 26.5 months (95% CI, 21.6 to 39.5 months) in arm A and 28.5 months (95% CI, 20.4 to 38.6 months) in arm B. The hazard ratio was 1.04 (arm A v arm B: 95% CI, 0.66 to 1.53; P=.99). Median survival for the PP population was 32.1 months (95% CI, 22.8 to 42.2 months) in arm A and 28.5 months (95% CI, 19.5 to 38.6 months) in arm B (P=.49). Eighty-five percent of patients in arm A and 16% of patients in arm B experienced grade 3 or 4 toxicity. The quality of life was temporarily negatively affected in arm A., Conclusion: The FU, cisplatin, and IFN α-2b plus radiotherapy regimen did not improve the survival compared with FU monotherapy. Given the substantial adverse effects, this treatment can currently not be recommended. Nevertheless, the outcome in both arms represents the best survival, to our knowledge, ever reported for patients with resected pancreatic cancer in randomized controlled trials. Future studies will demonstrate whether immune response to IFN α-2b challenge has a predictive value.
- Published
- 2012
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8. Role of radiation therapy in the management of locally advanced pancreatic cancer.
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Aref A and Berri R
- Subjects
- Female, Humans, Male, Adenocarcinoma drug therapy, Adenocarcinoma genetics, Adenocarcinoma radiotherapy, Antimetabolites, Antineoplastic therapeutic use, Carcinoma, Adenosquamous genetics, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms radiotherapy, Smad4 Protein genetics
- Published
- 2012
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9. Radiotherapy improves survival in unresectable pancreatic cancer: small trial but big (and credible) results.
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Ben-Josef E, Taylor JM, and Lawrence TS
- Subjects
- Female, Humans, Male, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Antimetabolites, Antineoplastic therapeutic use, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Published
- 2012
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10. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial.
- Author
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Loehrer PJ Sr, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, Flynn P, Ramanathan RK, Crane CH, Alberts SR, and Benson AB 3rd
- Subjects
- Adenocarcinoma pathology, Adult, Aged, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Deoxycytidine therapeutic use, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms pathology, Radiotherapy, Adjuvant, Survival Analysis, Treatment Outcome, Gemcitabine, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Antimetabolites, Antineoplastic therapeutic use, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: 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 and Methods: 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., Results: 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)., Conclusion: This trial demonstrates improved overall survival with the addition of radiation therapy to GEM in patients with localized unresectable pancreatic cancer, with acceptable toxicity.
- Published
- 2011
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11. Locally advanced pancreatic cancer: where should we go from here?
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Philip PA
- Subjects
- Deoxycytidine therapeutic use, Female, Humans, Male, Gemcitabine, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Antimetabolites, Antineoplastic therapeutic use, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Published
- 2011
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12. Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression.
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Crane CH, Varadhachary GR, Yordy JS, Staerkel GA, Javle MM, Safran H, Haque W, Hobbs BD, Krishnan S, Fleming JB, Das P, Lee JE, Abbruzzese JL, and Wolff RA
- Subjects
- Actuarial Analysis, Adenocarcinoma metabolism, Adenocarcinoma pathology, Adult, Aged, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cetuximab, Chemotherapy, Adjuvant, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Disease Progression, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Neoplasm Staging, Organoplatinum Compounds administration & dosage, Oxaliplatin, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Patient Selection, Radiotherapy, Adjuvant, Remission Induction, Research Design, Treatment Outcome, Gemcitabine, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor metabolism, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Smad4 Protein metabolism
- Abstract
Purpose: This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC)., Patients and Methods: Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m(2)) and oxaliplatin (100 mg/m(2)) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m(2) twice daily on radiation treatment days). Cetuximab (500 mg/m(2)) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression., Results: Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016)., Conclusion: This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized pancreatic cancer.
- Published
- 2011
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13. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study.
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Van Laethem JL, Hammel P, Mornex F, Azria D, Van Tienhoven G, Vergauwe P, Peeters M, Polus M, Praet M, Mauer M, Collette L, Budach V, Lutz M, Van Cutsem E, and Haustermans K
- Subjects
- Adult, Aged, Antimetabolites, Antineoplastic adverse effects, Antimetabolites, Antineoplastic therapeutic use, Chemotherapy, Adjuvant, Combined Modality Therapy, Deoxycytidine adverse effects, Deoxycytidine therapeutic use, Diarrhea chemically induced, Drug Administration Schedule, Fatigue chemically induced, Feasibility Studies, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Nausea chemically induced, Pancreatic Neoplasms surgery, Radiotherapy, Adjuvant, Treatment Outcome, Gemcitabine, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: The role of adjuvant chemoradiotherapy (CRT) in resectable pancreatic cancer is still debated. This randomized phase II intergroup study explores the feasibility and tolerability of a gemcitabine-based CRT regimen after R0 resection of pancreatic head cancer., Patients and Methods: Within 8 weeks after surgery, patients were randomly assigned to receive either four cycles of gemcitabine (control arm) or gemcitabine for two cycles followed by weekly gemcitabine with concurrent radiation (50.4 Gy; CRT arm). The primary objective was to exclude a < 60% treatment completion and a > 40% rate of grade 4 hematologic or GI toxicity in the CRT arm with type I and II errors of 10%. Secondary end points were late toxicity, disease-free survival (DFS), and overall survival (OS)., Results: Between September 2004 and January 2007, 90 patients were randomly assigned (45:45). Patient characteristics were similar in both arms. Treatment was completed per protocol by 86.7% and 73.3% (80% CI, 63.1% to 81.9%; 95% CI, 58.1% to 85.4%) in the control and CRT arms, respectively, and grade 4 toxicity was 0% and 4.7% (two of 43; 80% CI, 1.2% to 11.9%), respectively. In the CRT arm, three patients experienced grade 3-related late toxicity. Median DFS was 12 months in the CRT arm and 11 months in the control arm. Median OS was 24 months in both arms. First local recurrence was less frequent in the CRT arm (11% v 24%)., Conclusion: Adjuvant gemcitabine-based CRT is feasible, well-tolerated, and not deleterious; adding this treatment to full-dose adjuvant gemcitabine after resection of pancreatic cancer should be evaluated in a phase III trial.
- Published
- 2010
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14. Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation Therapy Oncology Group RTOG 0411.
- Author
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Crane CH, Winter K, Regine WF, Safran H, Rich TA, Curran W, Wolff RA, and Willett CG
- Subjects
- Adult, Aged, Aged, 80 and over, Angiogenesis Inhibitors administration & dosage, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized, Antimetabolites, Antineoplastic administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bevacizumab, Capecitabine, Chemotherapy, Adjuvant, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Disease-Free Survival, Female, Fluorouracil administration & dosage, Fluorouracil analogs & derivatives, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Pancreatectomy, Pancreatic Neoplasms mortality, Pancreatic Neoplasms pathology, Pancreatic Neoplasms surgery, Pancreaticoduodenectomy, Radiotherapy, Adjuvant, Time Factors, Treatment Outcome, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: The primary objective of this study was to assess the 1-year survival of patients with locally advanced, unresectable pancreatic cancer treated with the combination of bevacizumab, capecitabine, and radiation. Secondary end points were toxicity, progression-free survival (PFS), and response rate (RR)., Patients and Methods: Patients with locally advanced pancreatic cancer without duodenal invasion were treated with 50.4 Gy per 28 fractions to the gross tumor with concurrent capecitabine 825 mg/m(2) orally twice daily on days of radiation and bevacizumab 5 mg/kg on days 1, 15, and 29 followed by maintenance gemcitabine 1 g/m(2) weekly for 3 weeks and bevacizumab 5 mg/kg every 2 weeks, both in 4-week cycles until progression. Treatment plans were reviewed for quality assurance (QA)., Results: Between January 2005 and February 2006, 82 eligible patients were treated. The median and 1-year survival rates were 11.9 months (95% CI, 9.9 to 14.0 months) and 47% (95% CI, 36% to 57%). Median PFS was 8.6 months (95% CI, 6.9 to 10.5), and RR was 26%. Overall, 35.4% of patients had grade 3 or greater treatment-related gastrointestinal toxicity (22.0% during chemoradiotherapy, 13.4% during maintenance chemotherapy). Unacceptable radiotherapy protocol deviations (ie, inappropriately generous volume contoured) correlated with grade 3 or greater gastrointestinal toxicity during chemoradiotherapy (45% v 18%; adjusted odds ratio, 3.7; 95% CI, 0.98 to 14.1; P = .05)., Conclusion: The addition of bevacizumab to chemoradiotherapy followed by bevacizumab and gemcitabine resulted in a similar median survival to previous Radiation Therapy Oncology Group studies in patients with locally advanced pancreatic cancer. Prospective QA may help limit toxicity in future trials.
- Published
- 2009
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15. Nonmetastatic pancreatic cancer: many trials, little progress.
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Kleeff J and Friess H
- Subjects
- Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Deoxycytidine therapeutic use, Humans, Neoadjuvant Therapy, Gemcitabine, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Published
- 2008
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16. Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer.
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Brunner TB, Geiger M, Grabenbauer GG, Lang-Welzenbach M, Mantoni TS, Cavallaro A, Sauer R, Hohenberger W, and McKenna WG
- Subjects
- Aged, Cisplatin administration & dosage, Combined Modality Therapy, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Female, HIV Protease Inhibitors adverse effects, Humans, Male, Middle Aged, Nelfinavir adverse effects, Pancreatic Neoplasms pathology, Pancreatic Neoplasms radiotherapy, Treatment Outcome, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, HIV Protease Inhibitors therapeutic use, Nelfinavir therapeutic use, Pancreatic Neoplasms drug therapy
- Abstract
Purpose: Preclinically, HIV protease inhibitors radiosensitize tumors with activated PI3-kinase/Akt pathway. We determined the toxicity of nelfinavir chemoradiotherapy in borderline resectable and unresectable pancreatic cancer., Patients and Methods: Oral nelfinavir (2 x 1,250 mg) was started 3 days before and continued throughout chemoradiotherapy to 50.4 Gy (boost, 59.4 Gy) in 12 patients. Two gemcitabine dose levels (DL) were tested (200 mg/m(2) and 300 mg/m(2) on days 1, 8, 22, and 29). Cisplatin was administered on the same days at 30 mg/m(2). Phospho-Akt downregulation by nelfinavir was monitored by immunoblotting in patient leukocytes. Restaging positron emission tomography (PET)/computed tomography (CT) and CA19-9 levels served to assess response, and responding tumors were resected., Results: At each DL, five of six patients completed chemoradiotherapy, and two of 12 patients had incomplete chemoradiotherapy because of clinical depression (DL1) and peritoneal metastasis (DL2). Grade 4 toxicities were a transaminase elevation (DL2) as a result of biliary stent occlusion and acute cholecystitis as a result of peritoneal metastasis (DL2). Stent occlusions led to dose-limiting toxicities of grade 3 liver enzyme and bilirubin elevations (two patients at DL1, one patient at DL2). Grade 3 nausea and vomiting occurred in a DL2 patient, and weight loss occurred in a DL1 patient who refused supportive feeding. Secondary complete resection was possible in six of 10 patients with complete chemoradiotherapy, including one tumor with pathologic sterilization. Partial CT responses were observed in five of 10 patients who completed chemoradiotherapy. Of nine patients assessable by PET,responses were complete in five patients and partial patients, and stable disease was observed in two patients., Conclusion: The combination of nelfinavir and chemoradiotherapy showed acceptable toxicity and promising activity in patients with pancreatic cancer.
- Published
- 2008
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17. Concomitant administration of weekly oxaliplatin, fluorouracil continuous infusion, and radiotherapy after 2 months of gemcitabine and oxaliplatin induction in patients with locally advanced pancreatic cancer: a Groupe Coordinateur Multidisciplinaire en Oncologie phase II study.
- Author
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Moureau-Zabotto L, Phélip JM, Afchain P, Mineur L, André T, Vendrely V, Lledo G, Dupuis O, Huguet F, Touboul E, Balosso J, and Louvet C
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Adult, Aged, Aged, 80 and over, Combined Modality Therapy, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Feasibility Studies, Female, Fluorouracil administration & dosage, Humans, Infusions, Intravenous, Male, Middle Aged, Organoplatinum Compounds administration & dosage, Oxaliplatin, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Survival Rate, Treatment Outcome, Gemcitabine, Adenocarcinoma therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms therapy
- Abstract
Background: According to previously reported Groupe Coordinateur Multidisciplinaire en Oncologie (GERCOR) studies in locally advanced pancreatic cancer (LAPC), concomitant chemoradiotherapy (CCRT) may be recommended for patients who do not experience disease progression after systemic induction chemotherapy (CT). To further improve patient outcome with classical fluorouracil (FU)-based CCRT, this study was designed to prospectively investigate a CCRT with FU infusion and weekly oxaliplatin after 2 months of gemcitabine and oxaliplatin (GEMOX) induction chemotherapy., Patients and Methods: Nonpretreated patients with LAPC having WHO performance status (PS) of 0 to 2 received four induction cycles of GEMOX (gemcitabine 1 g/m(2) on day 1 and oxaliplatin 100 mg/m(2) on day 2; day 1 of a 15-day cycle). One month after cycle 4, patients who did not experience disease progression with PS 0 to 2 received 45 Gy over 5 weeks + 10 Gy (as a concomitant boost during the last 2 weeks) of radiotherapy (RT), with daily 250 mg/m(2) FU as a continuous infusion and 60 mg/m(2)of oxaliplatin weekly., Results: Of 59 patients, 50 patients (84.7%) received CCRT, whereas nine patients did not because of disease progression (seven patients), CT toxicity (one patient), or personal decision (one patient). Forty-four patients (74.5%) completed the fully planned CCRT. Median progression-free survival and overall survival durations were 7.6 and 12.2 months, respectively, for the whole population and 9.4 and 12.6 months, respectively, for patients who completed CCRT. CCRT grade 3 to 4 toxicities (National Cancer Institute Common Toxicity Criteria) were neutropenia (10.4%), thrombocytopenia (8.4%), nausea and vomiting (16.7%), and diarrhea (12.5%)., Conclusion: Concomitant administration of weekly oxaliplatin, continuous-infusion FU, and RT in patients with LAPC is feasible, with an acceptable acute and late safety profile. The encouraging results observed despite a nonoptimal patient selection (owing to the short induction time) indicates that further randomized evaluation to better define the specific role of oxaliplatin in CCRT is deserved.
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- 2008
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18. Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial.
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Small W Jr, Berlin J, Freedman GM, Lawrence T, Talamonti MS, Mulcahy MF, Chakravarthy AB, Konski AA, Zalupski MM, Philip PA, Kinsella TJ, Merchant NB, Hoffman JP, Benson AB, Nicol S, Xu RM, Gill JF, and McGinn CJ
- Subjects
- Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Biomarkers, Tumor blood, CA-19-9 Antigen blood, Chemotherapy, Adjuvant, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Deoxycytidine therapeutic use, Female, Humans, Male, Middle Aged, Nausea chemically induced, Neoplasm Staging, Neutropenia chemically induced, Pancreatic Neoplasms immunology, Pancreatic Neoplasms pathology, Pancreatic Neoplasms surgery, Radiotherapy, Adjuvant, Radiotherapy, Conformal, Survival Analysis, Treatment Outcome, Vomiting chemically induced, Gemcitabine, Antimetabolites, Antineoplastic therapeutic use, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: Gemcitabine is effective in the treatment of pancreatic cancer and is a potent radiosensitizer. This study assessed safety and efficacy of full-dose gemcitabine administered before and during concurrent three-dimensional conformal radiation (3D-CRT) in patients with nonmetastatic pancreatic cancer., Patients and Methods: During cycles 1 and 3, patients received gemcitabine at 1,000 mg/m(2) on days 1 and 8 of each 21-day cycle. Cycle 2 included the same dose of gemcitabine on days 1, 8, and 15 of a 28-day cycle with concurrent 3D-CRT at 36 Gy, administered in 15 fractions of 2.4 Gy, over 3 weeks. Resectable patients underwent surgery 4 to 6 weeks after treatment. The primary objective was evaluation of toxicity. Tumor response, CA 19-9, and 1-year survival were also assessed., Results: Forty-one patients enrolled at six institutions between April 2002 and October 2003. Among the 39 treated patients, the most common toxicities were grade 3 neutropenia (12.8%), grade 3 nausea (10.3%), and grade 3 vomiting (10.3%). The response rate was 5.1% and disease control rate was 84.6%. Mean post-treatment CA 19-9 levels (228 +/- 347 U/mL) were significantly (P = .006) reduced compared with pretreatment levels (1,241 +/- 2,124 U/mL). Thirteen (81%) of 16 patients initially judged resectable, three (33%) of nine borderline-resectable patients, and one (7%) of 14 unresectable patients underwent resection after therapy. One-year survival rates were 73% for all patients, 94% for resectable patients, 76% for borderline-resectable patients, and 47% for unresectable patients., Conclusion: Full-dose gemcitabine with concurrent radiotherapy was well tolerated and active. Evaluation of this regimen in a larger, randomized trial for patients with resectable or borderline-resectable disease may be warranted.
- Published
- 2008
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19. Radiotherapy for locally advanced pancreatic cancer.
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Ben-Josef E, Lawrence TS, and Zalupski MM
- Subjects
- Adenocarcinoma secondary, Humans, Pancreatic Neoplasms pathology, Adenocarcinoma radiotherapy, Pancreatic Neoplasms radiotherapy
- Published
- 2007
- Full Text
- View/download PDF
20. Phase I study of oxaliplatin, full-dose gemcitabine, and concurrent radiation therapy in pancreatic cancer.
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Desai SP, Ben-Josef E, Normolle DP, Francis IR, Greenson JK, Simeone DM, Chang AE, Colletti LM, Lawrence TS, and Zalupski MM
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Deoxycytidine administration & dosage, Disease-Free Survival, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Oxaliplatin, Time Factors, Treatment Outcome, Gemcitabine, Combined Modality Therapy methods, Deoxycytidine analogs & derivatives, Organoplatinum Compounds administration & dosage, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: To determine a biweekly dose of oxaliplatin for combination with full-dose gemcitabine and concurrent radiation therapy (RT) in pancreatic cancer., Patients and Methods: Patients with previously untreated pancreatic cancer received gemcitabine days 1, 8, and 15, and oxaliplatin days 1 and 15, repeated at 28-day intervals. RT (27 Gy in 1.8-Gy fractions) was administered during cycle 1. Dose escalation was guided using the time-to-event continuous reassessment method. Dose levels 1 to 4 included gemcitabine 1 g/m2 intravenously (IV) during 30 minutes and oxaliplatin 40, 55, 70, or 85 mg/m2 IV during 90 minutes, respectively; for dose levels 5 and 6, oxaliplatin dose remained 85 mg/m2 but infusion time for gemcitabine 1 g/m2 was increased to 65 or 100 minutes, respectively. The trial objective was to determine the dose level associated with dose-limiting toxicity (DLT) through cycle 2 in < or = 20% of patients., Results: Forty-four patients were enrolled (median age, 64 years; 27 men, 17 women) with resectable (n = 12), unresectable (n = 29), and metastatic (n = 3) pancreatic cancer. Ten DLTs occurred in nine patients, including grade 4 platelets (n = 4), decline in performance status (n = 2), GI bleeding (n = 2), and GI toxicity (n = 2). The estimated probability of DLT for dose level 3 was .21 (90% posterior probability interval [PI], .12 to .33); for dose level 4, the estimated probability was .24 (90% PI, .14 to .36)., Conclusion: The addition of oxaliplatin 85 mg/m2 days 1 and 15 to full-dose gemcitabine and radiation therapy was well tolerated. On the basis of these results, a multi-institutional neoadjuvant phase II study in resectable pancreatic cancer is planned.
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- 2007
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21. Gemcitabine, cisplatin, and radiotherapy for patients with locally advanced pancreatic adenocarcinoma: results of the North Central Cancer Treatment Group Phase II Study N9942.
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Haddock MG, Swaminathan R, Foster NR, Hauge MD, Martenson JA, Camoriano JK, Stella PJ, Tenglin RC, Schaefer PL, Moore DF Jr, and Alberts SR
- Subjects
- Adult, Aged, Combined Modality Therapy, Deoxycytidine administration & dosage, Disease Progression, Female, Humans, Male, Middle Aged, Radiotherapy Dosage, Survival Rate, Treatment Outcome, Gemcitabine, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cisplatin administration & dosage, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: A phase II study was conducted to determine the efficacy and toxicity of radiotherapy with concomitant gemcitabine and cisplatin for patients with locally advanced pancreatic adenocarcinoma., Patients and Methods: Forty-eight patients with locally advanced pancreatic adenocarcinoma received gemcitabine (30 mg/m2) and cisplatin (10 mg/m2) twice weekly during the first 3 weeks of radiotherapy. The radiation dose to the primary tumor and regional nodes was 45 Gy in 25 fractions, and the gross tumor volume received an additional 5.4 Gy in three fractions. Four weeks after radiotherapy, patients received gemcitabine (1,000 mg/m2) once weekly every 3 of 4 weeks for a 12-week period. The primary end point was survival at 12 months. Secondary end points were time to progression, toxicity, and quality of life., Results: Survival at 1 year was 40% for 47 eligible patients. The median survival was 10.2 months. Confirmed responses were observed for 8.5% (two partial, two complete), and median time to progression was 7.3 months. Grade 4 or higher toxicity was observed for 31% and consisted primarily of hematologic and GI toxicity. There was a trend toward improved overall quality of life, measured by the Symptom Distress Scale (P = .06), with significant improvements in domains of insomnia, pain, and outlook., Conclusion: The combination of radiotherapy, gemcitabine, and cisplatin was well tolerated. Survival results were similar to those achieved with other treatment regimens for patients with locally advanced pancreatic cancer but did not meet our predefined criteria for additional evaluation of this regimen.
- Published
- 2007
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22. Lessons learned in the management of advanced pancreatic cancer.
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Van Cutsem E, Verslype C, and Grusenmeyer PA
- Subjects
- Humans, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Pancreatic Neoplasms surgery, Signal Transduction, Pancreatic Neoplasms therapy
- Published
- 2007
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23. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies.
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Huguet F, André T, Hammel P, Artru P, Balosso J, Selle F, Deniaud-Alexandre E, Ruszniewski P, Touboul E, Labianca R, de Gramont A, and Louvet C
- Subjects
- Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Combined Modality Therapy, Disease Progression, Female, Humans, Male, Middle Aged, Multicenter Studies as Topic, Pancreatic Neoplasms pathology, Retrospective Studies, Survival Analysis, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: The management of locally advanced (LA) pancreatic cancer patients remains controversial. To select patients who could benefit from chemoradiotherapy (CRT), the therapeutic strategy used by the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) consisted of initial chemotherapy (CT) for at least 3 months. The decision to administer CRT or continue CT in nonprogressive patients was the investigator's choice., Patients and Methods: Retrospective analysis of outcome in 181 patients with LA pancreatic cancer (76 women and 105 men; mean age, 61 years; range, 37 to 85 years) enrolled onto prospective phase II and III GERCOR studies was performed to compare the survival of patients who received CRT with that of patients who continued CT alone., Results: Median progression-free survival (PFS) and overall survival (OS) times for the 181 patients were 6.3 and 11.4 months, respectively. Fifty-three patients (29.3%) had metastatic disease after 3 months of CT and were not eligible for CRT. Among the 128 remaining patients (70.3%) who had no disease progression and who were, therefore, eligible for CRT, 72 (56%) received CRT (group A), whereas 56 (44%) continued with CT (group B). The two groups were balanced for initial characteristics (performance status, sex, age, and type of CT), as well as for induction CT results. In groups A and B, the median PFS times were 10.8 and 7.4 months, respectively (P = .005), and the median OS times were 15.0 and 11.7 months, respectively (P = .0009)., Conclusion: These results suggest that, after control of disease by initial CT, CRT could significantly improve survival in patients with LA pancreatic cancer compared with CT alone. A prospective phase III study is ongoing to evaluate this strategy.
- Published
- 2007
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24. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer.
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Crane CH, Ellis LM, Abbruzzese JL, Amos C, Xiong HQ, Ho L, Evans DB, Tamm EP, Ng C, Pisters PW, Charnsangavej C, Delclos ME, O'Reilly M, Lee JE, and Wolff RA
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Bevacizumab, Capecitabine, Chemotherapy, Adjuvant, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Deoxycytidine analogs & derivatives, Digestive System drug effects, Drug Administration Schedule, Female, Fluorouracil analogs & derivatives, Humans, Male, Middle Aged, Neoplasm Staging, Pancreatic Neoplasms pathology, Pancreaticoduodenectomy, Peptic Ulcer Hemorrhage chemically induced, Radiotherapy, Adjuvant, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols adverse effects, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: To study the safety of bevacizumab with capecitabine-based chemoradiotherapy., Patients and Methods: Patients with inoperable pancreatic adenocarcinoma received bevacizumab 2 weeks before radiotherapy (50.4 Gy treating the primary tumor and gross adenopathy), every 2 weeks during radiotherapy (12 patients each at 2.5, 5.0, 7.5, and 10 mg/kg), and after radiotherapy until disease progression. Capecitabine was administered on days 14 through 52 (650 mg/m2 orally twice daily for the first six patients; 825 mg/m2 for the remaining patients)., Results: Significant acute gastrointestinal (43% grade 2; 4% grade 3), hand and foot syndrome (21% grade 2), and transient hematologic (8% grade 3 or greater) events were uncommon with protocol mandated dose reductions of capecitabine grade 2 toxicity (43% of patients). Among the first 30 patients treated, three patients had tumor-associated bleeding duodenal ulcers, and one had a contained duodenal perforation. No additional bleeding events occurred among the final 18 patients after patients with duodenal involvement by tumor were excluded. Nine (20%) of 46 assessable patients had confirmed partial responses until distant progression for a median of 6.2 months. Four patients have undergone pancreaticoduodenectomy without perioperative complication. The median survival was 11.6 months (95% CI, 9.6 to 13.6), from the start of protocol therapy., Conclusion: Concurrent bevacizumab did not significantly increase the acute toxicity of a relatively well-tolerated chemoradiotherapy regimen. However, ulceration and bleeding in the radiation field possibly related to bevacizumab occurred when tumor involved the duodenal mucosa. The encouraging efficacy end points suggest that the further study of bevacizumab with chemoradiotherapy is warranted.
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- 2006
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25. Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results.
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Czito BG, Willett CG, Bendell JC, Morse MA, Tyler DS, Fernando NH, Mantyh CR, Blobe GC, Honeycutt W, Yu D, Clary BM, Pappas TN, Ludwig KA, and Hurwitz HI
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Capecitabine, Chemotherapy, Adjuvant adverse effects, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Female, Fluorouracil analogs & derivatives, Gefitinib, Humans, Male, Middle Aged, Neoplasm Staging, Pancreatic Neoplasms pathology, Quinazolines administration & dosage, Radiotherapy, Adjuvant adverse effects, Rectal Neoplasms pathology, Deoxycytidine analogs & derivatives, ErbB Receptors antagonists & inhibitors, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Quinazolines adverse effects, Rectal Neoplasms drug therapy, Rectal Neoplasms radiotherapy
- Abstract
Purpose: Overexpression of epidermal growth factor receptor (EGFR) has been associated with aggressive tumor phenotypes, chemotherapy, and radiation resistance, as well as poor survival in preclinical and clinical models. The EGFR inhibitor gefitinib potentiates chemotherapy and radiation tumor cytotoxicity in preclinical models, including pancreatic and colorectal cancer. We initiated two phase I trials assessing the combination of gefitinib, capecitabine, and radiation in patients with localized pancreatic and rectal cancer., Patients and Methods: Patients with pathologically confirmed adenocarcinoma of the pancreas and rectum were eligible. Pretreatment staging included computed tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external-beam radiation therapy to the tumor in 28 fractions. Capecitabine and gefitinib were administered throughout the radiation course. Following completion, patients were restaged and considered for resection. Primary end points included determination of dose-limiting toxicity (DLT) and a phase II dose; secondary end points included determination of non-DLTs and preliminary radiographic and pathologic response rates., Results: Ten patients were entered in the pancreatic study and six in the rectal study. DLT was seen in six of 10 patients in the pancreatic study and two of six patients in the rectal study. The primary DLT in both studies was diarrhea. Two patients developed arterial thrombi., Conclusion: The combination of gefitinib, capecitabine, and radiation in pancreatic and rectal cancer patients resulted in significant toxicity. A recommended phase II dose was not determined in either of our studies. Further investigation with this combination should be approached with caution.
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- 2006
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26. Locally advanced pancreatic cancer.
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Willett CG, Czito BG, Bendell JC, and Ryan DP
- Subjects
- Chemotherapy, Adjuvant, Combined Modality Therapy, Humans, Pancreatic Neoplasms mortality, Pancreatic Neoplasms pathology, Randomized Controlled Trials as Topic, Treatment Failure, Pancreatic Neoplasms radiotherapy
- Abstract
Of the 32,180 patients diagnosed with pancreatic carcinoma in the United States this year, approximately 40% will present with locally advanced disease. Radiotherapeutic approaches are often employed because these patients have unresectable tumors by virtue of local invasion into the retroperitoneal vessels in the absence of clinically detectable metastases. These treatments include external-beam irradiation with and without fluorouracil-based chemotherapy, intraoperative irradiation, and, more recently, external-beam irradiation with new systemic targeted agents.
- Published
- 2005
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27. Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer.
- Author
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Muler JH, McGinn CJ, Normolle D, Lawrence T, Brown D, Hejna G, and Zalupski MM
- Subjects
- Aged, Cisplatin administration & dosage, Cisplatin adverse effects, Combined Modality Therapy, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Endpoint Determination, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Pancreatic Neoplasms pathology, Radiotherapy, Conformal, Survival Analysis, Time Factors, Treatment Outcome, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: The primary objective of this study was to determine the maximum-tolerated dose of cisplatin that could be added to full-dose gemcitabine and radiation therapy (RT) in patients with pancreatic cancer., Patients and Methods: Nineteen patients were treated. Gemcitabine 1,000 mg/m(2) was administered over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Cisplatin followed gemcitabine on days 1 and 15. The initial dose level of cisplatin was 30 mg/m(2), escalated to a targeted dose of 50 mg/m(2) using Time-to-Event Continual Reassessment Method. RT was initiated on cycle 1, day 1, in 2.4 Gy fractions to a total dose of 36 Gy. A second cycle of chemotherapy was planned following a 1-week rest., Results: Four of eight patients experienced acute dose limiting toxicity at the 50 mg/m(2) cisplatin dose level. Patients treated at 30 and 40 mg/m(2) cisplatin dose level tolerated therapy without dose-limiting toxicity. Median survival was 10.7 months (95% CI, 5.4 to 18.2) for all patients, and 12.9 months (95% CI, 7.4 to 21.2) for those without metastasis., Conclusion: Cisplatin at doses up to 40 mg/m(2) may be safely added to full-dose gemcitabine and conformal RT. The Time-to-Event Continual Reassessment Method trial design allowed rapid completion of the study and confidence in the conclusion about the maximum tolerated dose, but accrued more patients to a dose level above the maximum tolerated dose than the typical phase I design. Local and systemic disease control and survival in this study cohort supports further investigation of gemcitabine-based RT and combination chemotherapy in this disease.
- Published
- 2004
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28. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome.
- Author
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Pisters PW, Wolff RA, Janjan NA, Cleary KR, Charnsangavej C, Crane CN, Lenzi R, Vauthey JN, Lee JE, Abbruzzese JL, and Evans DB
- Subjects
- Adenocarcinoma mortality, Combined Modality Therapy, Disease-Free Survival, Dose Fractionation, Radiation, Follow-Up Studies, Humans, Neoplasm Staging, Pancreatectomy, Pancreatic Neoplasms mortality, Pilot Projects, Survival Rate, Treatment Outcome, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Antineoplastic Agents, Phytogenic therapeutic use, Paclitaxel therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: To evaluate the toxicity of a preoperative regimen of paclitaxel and concurrent external-beam radiation therapy, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma., Patients and Methods: Patients with localized, potentially resectable pancreatic adenocarcinoma were treated with 30 Gy external-beam radiation therapy and concomitant weekly 3-hour infusions of paclitaxel (60 mg/m(2)). Radiographic restaging was performed 4 to 6 weeks after chemoradiation, and patients with localized disease underwent pancreatectomy with EB-IORT., Results: Thirty-five patients completed chemoradiation; 16 (46%) experienced grade 3 toxicity. Four patients (11%) required hospitalization for dehydration due to grade 3 nausea and vomiting. Twenty (80%) of 25 patients who underwent surgery underwent pancreatectomy; EB-IORT was used in 13 patients. There were no histologic complete responses to preoperative therapy; 21% of specimens demonstrated more than 50% nonviable cells (grade 2b treatment effect). With a median follow-up period of 46 months, the 3-year overall survival rate with chemoradiation and pancreatectomy was 28%., Conclusion: Preoperative paclitaxel-based concurrent chemoradiation is feasible. The toxicity of this regimen seems greater than that with fluorouracil. The histologic responses and survival are similar, suggesting no advantages to paclitaxel-based preoperative treatment.
- Published
- 2002
- Full Text
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29. Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer.
- Author
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McGinn CJ, Zalupski MM, Shureiqi I, Robertson JM, Eckhauser FE, Smith DC, Brown D, Hejna G, Strawderman M, Normolle D, and Lawrence TS
- Subjects
- Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Combined Modality Therapy, Follow-Up Studies, Humans, Infusions, Intravenous, Maximum Tolerated Dose, Middle Aged, Pancreatic Neoplasms pathology, Radiation Dosage, Tomography, X-Ray Computed, Treatment Outcome, Gemcitabine, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Deoxycytidine analogs & derivatives, Deoxycytidine therapeutic use, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Radiation-Sensitizing Agents therapeutic use
- Abstract
Purpose: The primary objective of this phase I trial was to determine the maximum-tolerated dose of radiation that could be delivered to the primary tumor concurrent with full-dose gemcitabine in patients with advanced pancreatic cancer., Patients and Methods: Thirty seven patients with unresectable (n = 34) or incompletely resected pancreatic cancer (n = 3) were treated. Gemcitabine was administered as a 30-minute intravenous infusion at a dose of 1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Radiation therapy was initiated on day 1 and directed at the primary tumor alone, without prophylactic nodal coverage. The starting radiation dose was 24 Gy in 1.6-Gy fractions. Escalation was achieved by increasing the fraction size in increments of 0.2 Gy, keeping the duration of radiation constant at 3 weeks. A second cycle of gemcitabine alone was intended after a 1-week rest., Results: Two of six assessable patients experienced dose-limiting toxicity at the final planned dose level of the trial (42 Gy in 2.8-Gy fractions), one with grade 4 vomiting and one with gastric/duodenal ulceration. Two additional patients at this dose level experienced late gastrointestinal toxicity that required surgical management., Conclusion: The final dose investigated (42 Gy) is not recommended for further study considering the occurrence of both acute and late toxicity. However, a phase II trial of this novel gemcitabine-based chemoradiotherapy approach, at a radiation dose of 36 Gy in 2.4-Gy fractions, is recommended on the basis of tolerance, patterns of failure, and survival data.
- Published
- 2001
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30. Eastern Cooperative Oncology Group Phase I trial of protracted venous infusion fluorouracil plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer: a regimen with unexpected early toxicity.
- Author
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Talamonti MS, Catalano PJ, Vaughn DJ, Whittington R, Beauchamp RD, Berlin J, and Benson AB 3rd
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Combined Modality Therapy, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Drug Administration Schedule, Female, Fluorouracil administration & dosage, Fluorouracil adverse effects, Humans, Infusions, Intravenous, Male, Middle Aged, Radiotherapy adverse effects, Survival Analysis, Gemcitabine, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Antineoplastic Combined Chemotherapy Protocols adverse effects, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: We performed a phase I trial of protracted venous infusion (PVI) fluorouracil (5-FU) plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer to determine the maximum-tolerated dose of gemcitabine that could be safely administered. We also sought to identify the toxicities associated with this treatment protocol., Patients and Methods: Seven patients with locally advanced pancreas cancer were treated with planned doses of radiation (59.4 Gy) and PVI of 5-FU (200 mg/m(2)/d) with gemcitabine doses of 50 to 100 mg/m(2)/wk., Results: Two of three patients at the 100-mg/m(2)/wk dose level experienced dose-limiting toxicity (DLT), as did three of four at the 50-mg/m(2)/wk dose level. One patient experienced a mucocutaneous reaction described as a Stevens-Johnson syndrome that was attributed to chemotherapy. Three patients developed gastric or duodenal ulcers with severe bleeding requiring transfusion. One patient developed severe thrombocytopenia lasting longer than 4 weeks. Three of the five episodes of DLT developed at radiation doses < or = 36 Gy., Conclusion: Based on this experience, we cannot recommend further investigation of regimens incorporating gemcitabine into regimens of radiation with PVI 5-FU. The mechanism of this synergistic toxicity remains to be determined.
- Published
- 2000
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31. Preoperative chemoradiation for patients with pancreatic cancer: toxicity of endobiliary stents.
- Author
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Pisters PW, Hudec WA, Lee JE, Raijman I, Lahoti S, Janjan NA, Rich TA, Crane CH, Lenzi R, Wolff RA, Abbruzzese JL, and Evans DB
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Adult, Aged, Aged, 80 and over, Ampulla of Vater, Antimetabolites, Antineoplastic administration & dosage, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Common Bile Duct Neoplasms drug therapy, Common Bile Duct Neoplasms radiotherapy, Common Bile Duct Neoplasms surgery, Deoxycytidine administration & dosage, Deoxycytidine analogs & derivatives, Female, Fluorouracil administration & dosage, Follow-Up Studies, Hospitalization, Humans, Incidence, Liver drug effects, Liver radiation effects, Male, Middle Aged, Paclitaxel administration & dosage, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Radiotherapy Dosage, Retrospective Studies, Gemcitabine, Adenocarcinoma surgery, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bile Ducts pathology, Neoadjuvant Therapy, Pancreatic Neoplasms surgery, Pancreaticoduodenectomy, Stents adverse effects
- Abstract
Purpose: A recent multicenter study of preoperative chemoradiation and pancreaticoduodenectomy for localized pancreatic adenocarcinoma suggested that biliary stent-related complications are frequent and severe and may prevent the delivery of all components of multimodality therapy in many patients. The present study was designed to evaluate the rates of hepatic toxicity and biliary stent-related complications and to evaluate the impact of this morbidity on the delivery of preoperative chemoradiation for pancreatic cancer at a tertiary care cancer center., Patients and Methods: Preoperative chemoradiation was used in 154 patients with resectable pancreatic adenocarcinoma (142 patients, 92%) or other periampullary tumors (12 patients, 8%). Patients were treated with preoperative fluorouracil (115 patients), paclitaxel (37 patients), or gemcitabine (two patients) plus concurrent rapid-fractionation (30 Gy; 123 patients) or standard-fractionation (50.4 Gy; 31 patients) radiation therapy. The incidences of hepatic toxicity and biliary stent-related complications were evaluated during chemoradiation and the immediate 3- to 4-week postchemoradiation preoperative period., Results: Nonoperative biliary decompression was performed in 101 (66%) of 154 patients (endobiliary stent placement in 77 patients and percutaneous transhepatic catheter placement in 24 patients). Stent-related complications (occlusion or migration) occurred in 15 patients. Inpatient hospitalization for antibiotics and stent exchange was necessary in seven of 15 patients (median hospital stay, 3 days). No patient experienced uncontrolled biliary sepsis, hepatic abscess, or stent-related death., Conclusion: Preoperative chemoradiation for pancreatic cancer is associated with low rates of hepatic toxicity and biliary stent-related complications. The need for biliary decompression is not a clinically significant concern in the delivery of preoperative therapy to patients with localized pancreatic cancer.
- Published
- 2000
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32. Phase I trial dosing of gemcitabine and concurrent involved field irradiation in patients with localized pancreatic carcinomas.
- Author
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Nanfro JJ
- Subjects
- Deoxycytidine administration & dosage, Deoxycytidine therapeutic use, Dose-Response Relationship, Radiation, Drug Administration Schedule, Humans, Gemcitabine, Antimetabolites, Antineoplastic therapeutic use, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Published
- 1999
33. Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer.
- Author
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Blackstock AW, Bernard SA, Richards F, Eagle KS, Case LD, Poole ME, Savage PD, and Tepper JE
- Subjects
- Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic pharmacology, Combined Modality Therapy, Deoxycytidine pharmacology, Deoxycytidine therapeutic use, Dose-Response Relationship, Drug, Humans, Middle Aged, Gemcitabine, Antimetabolites, Antineoplastic therapeutic use, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: To determine the maximum-tolerated dose, dose-limiting toxicities, and potential antitumor activity of twice-weekly gemcitabine and concurrent radiation in patients with locally advanced pancreatic cancer., Patients and Methods: Nineteen patients with histologically confirmed adenocarcinoma of the pancreas were studied at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. The initial dose of gemcitabine was 20 mg/m(2) by 30-minute intravenous infusion each Monday and Thursday for 5 weeks concurrent with 50.4 Gy of radiation to the pancreas. Gemcitabine doses were escalated in 20-mg/m(2) increments in successive cohorts of three to six additional patients until dose-limiting toxicity was observed., Results: The dose-limiting toxicities at 60 mg/m(2) given twice-weekly were nausea/vomiting, neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a 40-mg/m(2) dose was well tolerated. Of the eight patients eligible for a minimum follow-up of 12 months, three remain alive, one of whom has no evidence of disease progression., Conclusion: A dose of twice-weekly gemcitabine at 40 mg/m(2) produced mild thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent radiation to the upper abdomen in patients with advanced pancreatic cancer. These data suggest this regimen is well tolerated and may possess significant activity. These data and other observations have resulted in a phase II Cancer and Leukemia Group B study to ascertain the efficacy of this treatment regimen in patients with locally advanced pancreatic cancer.
- Published
- 1999
- Full Text
- View/download PDF
34. Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma.
- Author
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Pisters PW, Abbruzzese JL, Janjan NA, Cleary KR, Charnsangavej C, Goswitz MS, Rich TA, Raijman I, Wolff RA, Lenzi R, Lee JE, and Evans DB
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Adenocarcinoma surgery, Adult, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic adverse effects, Combined Modality Therapy, Dose Fractionation, Radiation, Electrons therapeutic use, Female, Fluorouracil administration & dosage, Fluorouracil adverse effects, Humans, Male, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Pancreatic Neoplasms surgery, Radiotherapy, Adjuvant adverse effects, Radiotherapy, Adjuvant methods, Survival Analysis, Treatment Outcome, Adenocarcinoma therapy, Antimetabolites, Antineoplastic therapeutic use, Fluorouracil therapeutic use, Pancreatic Neoplasms therapy, Pancreaticoduodenectomy
- Abstract
Purpose: To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma., Patients and Methods: Patients with radiographically resectable localized adenocarcinoma of the pancreatic head were entered onto a preoperative protocol that consisted of a 2-week course of fluorouracil (5-FU) 300 mg/m2 daily 5 days per week and concomitant rapid-fractionation radiation 30 Gy, 3 Gy daily 5 days per week. Radiographic restaging was performed 4 weeks after chemoradiation, and patients with localized disease underwent pancreaticoduodenectomy with EB-IORT 10 to 15 Gy., Results: Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%., Conclusion: Combined modality treatment with preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and EB-IORT is associated with minimal toxicity and excellent locoregional control. This represents one approach to maximize the proportion of patients who receive all components of combined modality therapy and avoids the toxicity of pancreaticoduodenectomy in patients found to have metastatic disease at the time of restaging.
- Published
- 1998
- Full Text
- View/download PDF
35. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study.
- Author
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Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, and Benson AB 3rd
- Subjects
- Adenocarcinoma mortality, Adenocarcinoma pathology, Adenocarcinoma surgery, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chemotherapy, Adjuvant, Disease-Free Survival, Feasibility Studies, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Staging, Pancreatic Neoplasms mortality, Pancreatic Neoplasms pathology, Pancreatic Neoplasms surgery, Prospective Studies, Radiotherapy, Adjuvant, Treatment Outcome, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: A prospective, multiinstitutional trial was initiated in 1991 to examine the tolerance to and efficacy of a program of preoperative chemoradiotherapy (CTRT) and surgical resection for patients with localized adenocarcinoma of the pancreas., Patients and Methods: Fifty-three patients were assessable for analysis, with a median follow-up of 52 months for survivors. Radiation therapy (RT) totaling 5,040 cGy in 180 cGy fractions with mitomycin 10 mg/m2 day 2 and fluorouracil (5-FU) 1,000 mg/m2/d continuous infusion days 2 through 5 and 29 through 32 were given as preoperative adjuvant therapy. Twelve patients did not proceed to surgery (one death, one toxicity, three local progression, six distant metastases, one intercurrent illness), whereas 41 patients underwent surgery. Of these, 17 patients did not have resection (11, hepatic and/or peritoneal metastases and six local extension that precluded resection). Twenty-four patients had tumor resection (19 Whipple, four total pancreatectomy, one distal pancreatectomy)., Results: Treatment toxicity was primarily hematologic, although a comparable number suffered biliary tract complications, either from obstruction or cholangitis as a result of an occluded stent or the primary tumor. There was one postoperative death. Median survival for the entire group and for the 24 patients with resection was 9.7 and 15.7 months. This survival rate reflected the advanced state of most resected cancers (positive peritoneal cytology, three patients; margins within 2 mm, 13 patients; involved lymph nodes, four patients; and need for superior mesenteric vein (SMV) resection, four patients). Tumor progression was most frequent at metastatic sites., Conclusion: This preoperative CTRT protocol was feasible and safe in a cooperative group setting. Entry of patients with advanced tumors probably accounted for the suboptimal resectability and survival results.
- Published
- 1998
- Full Text
- View/download PDF
36. Hypofractionation, not rapid-fractionation.
- Author
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Thomas CR Jr, Milito S, and Turrisi AT 3rd
- Subjects
- Humans, Dose Fractionation, Radiation, Pancreatic Neoplasms radiotherapy
- Published
- 1997
- Full Text
- View/download PDF
37. Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study.
- Author
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Safran H, King TP, Choy H, Hesketh PJ, Wolf B, Altenhein E, Sikov W, Rosmarin A, Akerley W, Radie-Keane K, Cicchetti G, Lopez F, Bland K, and Wanebo HJ
- Subjects
- Adult, Aged, Aged, 80 and over, Combined Modality Therapy, Humans, Middle Aged, Neutropenia chemically induced, Pancreatic Neoplasms diagnostic imaging, Pancreatic Neoplasms pathology, Pancreatic Neoplasms surgery, Remission Induction, Stomach Neoplasms diagnostic imaging, Stomach Neoplasms pathology, Stomach Neoplasms surgery, Tomography, X-Ray Computed, Antineoplastic Agents, Phytogenic therapeutic use, Paclitaxel therapeutic use, Pancreatic Neoplasms radiotherapy, Radiation-Sensitizing Agents therapeutic use, Stomach Neoplasms radiotherapy
- Abstract
Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and potential antitumor activity of weekly paclitaxel with concurrent radiation (RT) for locally advanced pancreatic and gastric cancer., Patients and Methods: Thirty-four patients with locally advanced adenocarcinoma of the pancreas or stomach were studied. The initial dose of paclitaxel was 30 mg/m2 by 3-hour intravenous (I.V.) infusion repeated every week for 6 weeks with 50 Gy RT. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients until dose-limiting toxicity was observed., Results: The dose-limiting toxicities at 60 mg/m2/wk were abdominal pain within the RT field, nausea, and anorexia. Of 23 patients with assessable disease, 11 (seven with gastric, four with pancreatic cancer) had objective responses for an overall response rate of 48%., Conclusion: Concurrent paclitaxel with upper abdominal RT is well tolerated at dosages that have substantial activity. A phase II trial of neoadjuvant paclitaxel and RT at the MTD of 50 mg/m2/wk is underway.
- Published
- 1997
- Full Text
- View/download PDF
38. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas.
- Author
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Spitz FR, Abbruzzese JL, Lee JE, Pisters PW, Lowy AM, Fenoglio CJ, Cleary KR, Janjan NA, Goswitz MS, Rich TA, and Evans DB
- Subjects
- Adenocarcinoma pathology, Adenocarcinoma surgery, Clinical Protocols, Combined Modality Therapy, Follow-Up Studies, Humans, Pancreatic Neoplasms pathology, Pancreatic Neoplasms surgery, Prospective Studies, Survival Analysis, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy, Pancreaticoduodenectomy
- Abstract
Purpose: The effects of preoperative versus postoperative fluorouracil (5-FU)-based chemotherapy and irradiation on treatment toxicity, duration of treatment, tumor recurrence, and survival were compared in patients who underwent potentially curative therapy for adenocarcinoma of the pancreatic head during a 5-year period., Methods: From July 1990 to July 1995, 142 patients with localized adenocarcinoma of the pancreatic head deemed resectable on the basis of radiographic images were treated with curative intent using a multimodality approach involving either preoperative or postoperative chemoradiation. Patients with biopsy confirmation of adenocarcinoma and a low-density mass in the pancreatic head identified by computed tomography (CT) received preoperative chemoradiation. Patients without a mass on CT or in whom the preoperative biopsy was negative underwent pancreaticoduodenectomy with planned postoperative chemoradiation. Protocol-based preoperative chemoradiation consisted of external-beam irradiation at a dose of 50.4 Gy (standard fractionation; 1.8 Gy/d, 5 d/wk) or 30 Gy (rapid fractionation; 3 Gy/d, 5 d/wk) combined with continuous infusion 5-FU (300 mg/m2/d, 5 d/wk). Postoperative chemoradiation combined 50.4 Gy of external-beam irradiation (standard fractionation) with continuous-infusion 5-FU., Results: No patient who received preoperative chemoradiation experienced a delay in surgery because of chemoradiation toxicity, but six of 25 eligible patients (24%) did not receive postoperative chemoradiation because of delayed recovery after pancreaticoduodenectomy. No significant differences in toxicities from chemoradiation were observed between groups. Patients treated with rapid-fractionation preoperative chemoradiation had a significantly (P < .01) shorter duration of treatment (median, 62.5 days) compared with patients who received postoperative chemoradiation (median, 98.5 days) or standard-fractionation preoperative chemoradiation (median, 91.0 days). At a median followup of 19 months, no significant differences in survival were observed between treatment groups. No patient who received preoperative chemoradiation and pancreaticoduodenectomy experienced a local recurrence; peritoneal (regional) recurrence occurred in 10% of these patients. Local or regional recurrence occurred in 21% of patients who received pancreaticoduodenectomy and postoperative chemoradiation., Conclusion: Delivery of preoperative and postoperative chemoradiation in patients who underwent potentially curative pancreaticoduodenectomy for adenocarcinoma of the pancreatic head resulted in similar treatment toxicity, patterns of tumor recurrence, and survival. Rapid-fractionation preoperative chemoradiation ensured the delivery of all components of therapy to all eligible patients with a significantly shorter duration of treatment than with standard-fractionation chemoradiation given either before or after pancreaticoduodenectomy. Prolonged recovery after pancreaticoduodenectomy prevents the delivery of postoperative adjuvant chemoradiation in up to one fourth of eligible patients.
- Published
- 1997
- Full Text
- View/download PDF
39. Phase I trial of iodine 131-labeled COL-1 in patients with gastrointestinal malignancies: influence of serum carcinoembryonic antigen and tumor bulk on pharmacokinetics.
- Author
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Yu B, Carrasquillo J, Milenic D, Chung Y, Perentesis P, Feuerestein I, Eggensperger D, Qi CF, Paik C, Reynolds J, Grem J, Curt G, Siler K, Schlom J, and Allegra C
- Subjects
- Antibodies, Monoclonal, Carcinoembryonic Antigen immunology, Colorectal Neoplasms radiotherapy, Dose-Response Relationship, Radiation, Gastrointestinal Neoplasms diagnostic imaging, Gastrointestinal Neoplasms immunology, Gastrointestinal Neoplasms pathology, Humans, Iodine Radioisotopes adverse effects, Iodine Radioisotopes pharmacokinetics, Pancreatic Neoplasms radiotherapy, Radionuclide Imaging, Radiotherapy Dosage, Stomach Neoplasms radiotherapy, Carcinoembryonic Antigen blood, Gastrointestinal Neoplasms radiotherapy, Iodine Radioisotopes therapeutic use, Radioimmunotherapy adverse effects
- Abstract
Purpose: COL-1 is a high-affinity murine monoclonal antibody (MAb) specific for carcinoembryonic antigen (CEA). A phase I trial was conducted in which a uniform quantity of antibody labeled with escalating doses of iodine 131 (131I) was administered to patients with advanced gastrointestinal (GI) malignancies to evaluate tolerance and pharmacokinetics., Patients and Methods: Eighteen patients with advanced, assessable GI malignancies (16 colon, one pancreas, and one gastric) previously treated with conventional chemotherapy (but no pelvic radiation) received 20 mg of COL-1 labeled with 131I, with doses from 10 mCi/m2 to 75 mCi/m2. In this cohort, the baseline serum CEA level ranged from 6 to 2,739 ng/mL (mean +/- SD, 500 +/- 639)., Results: Nuclear imaging detected at least one tumor site in all 18 patients; 82% of all tumor involved organs were positive and 58% of all lesions > or = 1.0 cm were detected. Immune complexes were detected in 89% of patients 5 minutes after completion of infusion, and levels correlated with CEA levels (r = .71). Elevated CEA (> 500 ng/mL) and tumor bulk (total tumor area > 150 cm2) correlated directly with clearance of serum radioactivity and inversely with serum half-life and cumulative serum radioactivity parameters. Nonhematologic toxicity was mild and non-dose-limiting. Hematologic toxicity, particularly thrombocytopenia, was both dose-related and dose-limiting. The maximal-tolerated dose is 65 mCi/m2. The correlation between dose (millicuries per square meter) and thrombocytopenia was made stronger, by accounting for either variation in pharmacokinetics, or variation in serum CEA and tumor bulk., Conclusion: 131I-COL-1 is well tolerated, except for hematologic toxicity. These data suggest that patients with highly elevated circulating CEA levels and/or increased tumor bulk may clear 131I-labeled COL-1 more rapidly from the circulation and experience less myelosuppression.
- Published
- 1996
- Full Text
- View/download PDF
40. Combined intraoperative radiation and perioperative chemotherapy for unresectable cancers of the pancreas.
- Author
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Mohiuddin M, Regine WF, Stevens J, Rosato F, Barbot D, Biermann W, and Cantor R
- Subjects
- Actuarial Analysis, Adenocarcinoma drug therapy, Adenocarcinoma mortality, Adenocarcinoma radiotherapy, Adult, Aged, Combined Modality Therapy, Female, Fluorouracil therapeutic use, Humans, Intraoperative Period, Male, Middle Aged, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms mortality, Pancreatic Neoplasms radiotherapy, Postoperative Period, Survival Rate, Adenocarcinoma therapy, Pancreatic Neoplasms therapy
- Abstract
Purpose: To evaluate the effectiveness of combined intraoperative radiation therapy (IORT) and perioperative chemotherapy in the management of unresectable pancreatic cancer., Materials and Methods: Forty-nine patients with localized unresectable adenocarcinoma of the pancreas were treated in a multimodality program of initial IORT and perioperative chemotherapy (fluorouracil [5-FU]/leucovorin) followed by combined external-beam radiation (40 to 55 Gy) and continued chemotherapy. Patients were evaluated for toxicity, pattern of failure, and survival. The follow-up times of these patients range from a minimum of 12 months to a maximum of 62 months, with a median of 28 months., Results: The incidence of perioperative mortality was 0%. Early postsurgical morbidity (grade 3/4) was observed in seven of 49 patients (14%) and late treatment-related morbidity (grade 3/4) in eight of 43 patients (19%) alive beyond 6 months. Morbidity was primarily gastrointestinal (GI), with no hematologic toxicities observed. The median survival time in the total group of patients is 16 months, with a 2-year survival rate of 22% and a 4-year survival rate of 7%. Freedom from local progression of disease was achieved in 71% of patients., Conclusion: The patients who undergo IORT with electrons and treated with perioperative chemotherapy (5-FU leucovorin) followed by additional external-beam radiation and chemotherapy appear to have improved survival, with few early or late complications. Dose escalation of external-beam radiation and chemotherapy may further improve local control of disease and survival of patients.
- Published
- 1995
- Full Text
- View/download PDF
41. Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial.
- Author
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Whittington R, Neuberg D, Tester WJ, Benson AB 3rd, and Haller DG
- Subjects
- Adult, Aged, Bile Duct Neoplasms mortality, Cholangiocarcinoma mortality, Combined Modality Therapy, Drug Administration Schedule, Female, Fluorouracil adverse effects, Humans, Infusions, Intravenous, Male, Middle Aged, Neoplasm Recurrence, Local, Neoplasms, Second Primary, Pancreatic Neoplasms mortality, Survival Rate, Bile Duct Neoplasms drug therapy, Bile Duct Neoplasms radiotherapy, Bile Ducts, Intrahepatic, Cholangiocarcinoma drug therapy, Cholangiocarcinoma radiotherapy, Fluorouracil administration & dosage, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Purpose: The purpose of this study was to determine the maximum-tolerated dose (MTD) of fluorouracil (5-FU) administered as a protracted intravenous (IV) infusion with concurrent radiation in patients with pancreaticobiliary carcinoma., Methods: Twenty-five patients with recurrent, residual, or unresectable carcinoma of the pancreas or biliary tract were treated on a phase I trial of protracted IV infusions of 5-FU, beginning at 200 mg/m2/d, concurrent with radiation therapy (59.4 Gy in 33 fractions over 6 to 7 weeks). Chemotherapy began on the first day of radiation and continued through the entire course of treatment. After each cohort of five patients had been treated and observed, the daily dose was escalated in 25-mg/m2 increments until dose-limiting toxicity was encountered. An additional cohort of five patients was treated at the MTD. Clinical examination and computed tomography (CT) were used to evaluate response and patterns of progression., Results: The MTD of 5-FU was 250 mg/m2/d. The dose-limiting toxicity was oral mucositis. The median survival duration of all patients treated was 11.9 months and the 2-year survival rate was 19%. Eleven of 25 patients remain free of local progression and four patients are without evidence of progression at 18+, 18+, 34+, and 44+ months following treatment., Conclusion: Concurrent radiation with protracted 5-FU infusion at 250 mg/m2/d is well tolerated and shows evidence of activity against tumors of the pancreas and biliary system.
- Published
- 1995
- Full Text
- View/download PDF
42. Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study.
- Author
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Klaassen DJ, MacIntyre JM, Catton GE, Engstrom PF, and Moertel CG
- Subjects
- Adenocarcinoma radiotherapy, Adult, Aged, Combined Modality Therapy adverse effects, Female, Fluorouracil adverse effects, Humans, Male, Middle Aged, Pancreatic Neoplasms radiotherapy, Random Allocation, Stomach Neoplasms radiotherapy, Adenocarcinoma drug therapy, Fluorouracil therapeutic use, Pancreatic Neoplasms drug therapy, Stomach Neoplasms drug therapy
- Abstract
One hundred ninety-one patients with pathologically confirmed, locally unresectable adenocarcinoma of the stomach (57 patients) and pancreas (91 patients), were randomly allocated to therapy with 5-fluorouracil (5-FU) alone, 600 mg/m2 intravenously (IV) once weekly, or radiation therapy, 4,000 rad, plus adjuvant 5-FU, 600 mg/m2 IV, the first three days of radiotherapy, then follow-up maintenance 5-FU, 600 mg/m2, weekly. Forty-three patients (22%) could not be analyzed because of ineligibility or cancellation, thus 148 patients were evaluable. The median survival time was similar for both treatment programs and for both types of primary carcinoma, and was as follows: gastric primary carcinoma, 5-FU, 9.3 months; 5-FU plus radiotherapy, 8.2 months; pancreatic primary carcinoma, 5-FU, 8.2 months; 5-FU plus radiotherapy, 8.3 months. Substantially more toxicity was experienced by patients treated with the combined modality arm than by those patients receiving 5-FU alone. Severe or worse toxicity experienced by patients with gastric primary carcinoma treated by 5-FU was 19%, and the combined modality arm was 31%. The toxicity experienced by patients with pancreatic primary carcinoma treated with 5-FU was 27%, and the combined modality arm was 51%. Significant prognostic variables included: weight loss in stomach-cancer patients; and performance status, degree of anaplasia, and reduced appetite in pancreas-cancer patients.
- Published
- 1985
- Full Text
- View/download PDF
43. Combination chemotherapy for locally advanced pancreatic cancer: equivalence to external beam irradiation and implication for future management.
- Author
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Smith FP, Stablein D, Korsmeyer S, Neefe J, Chun BK, Woolley PV, and Schein PS
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Doxorubicin administration & dosage, Doxorubicin adverse effects, Female, Fluorouracil administration & dosage, Fluorouracil adverse effects, Humans, Male, Middle Aged, Mitomycin, Mitomycins administration & dosage, Mitomycins adverse effects, Pancreatic Neoplasms mortality, Pancreatic Neoplasms radiotherapy, Radiotherapy Dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pancreatic Neoplasms drug therapy
- Abstract
Chemotherapy with 5-fluorouracil, doxorubicin, and mitomycin-C was administered to 17 patients with locally advanced pancreatic cancer. The median survival for these patients was 8 months. With a multiaxial retrospective analysis, the overall survival of this study group appears to be least equivalent to that reported with 6,000 photon rad alone or of neutrons, and compares favorably to that achieved with combined 6,000 photo rad plus 5-fluorouracil. Of 15 relapses, only 4 had presented with evidence of disseminated disease. Based upon this analysis we recommend additional studies of combination chemotherapy with radiation therapy in future prospective randomized trials.
- Published
- 1983
- Full Text
- View/download PDF
44. The role of misonidazole combined with intraoperative radiation therapy in the treatment of pancreatic carcinoma.
- Author
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Tepper JE, Shipley WU, Warshaw AL, Nardi GL, Wood WC, and Orlow EL
- Subjects
- Actuarial Analysis, Adenocarcinoma diagnostic imaging, Adenocarcinoma pathology, Combined Modality Therapy, Follow-Up Studies, Humans, Intraoperative Period, Pancreatic Neoplasms mortality, Pancreatic Neoplasms radiotherapy, Tomography, X-Ray Computed, Adenocarcinoma surgery, Misonidazole therapeutic use, Pancreatic Neoplasms surgery
- Abstract
We tested the efficacy of the hypoxic cell sensitizer misonidazole in conjunction with intraoperative electron beam radiation therapy (IORT) and external beam irradiation in patients with locally advanced, nonmetastatic adenocarcinoma of the pancreas. Misonidazole was delivered intravenously (IV) at a dose of 3.5 g/m2 in conjunction with IORT of 1,500 to 2,000 cGy to the pancreas. Additional external beam radiation as administered to 4,960 cGy. The study was based on the premise that the effect of misonidazole would be maximized when a high dose of the drug was administered and, thus, high hypoxic cell sensitization could be obtained when using a high single dose of radiation where the hypoxic fraction would be expected to dominate in the survivors. In a nonrandomized study of 41 patients treated with misonidazole and 22 without, the 1-year local control was 67% and 55%, and 1-year survival was 50% and 77%, respectively. Although there was a bias towards larger tumors in the patients treated with the sensitizer, we were unable to demonstrate an advantage to misonidazole in this clinical situation.
- Published
- 1987
- Full Text
- View/download PDF
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