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Bortezomib, Paclitaxel, and Carboplatin As a First-Line View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector ORIGINAL ARTICLE Bortezomib, Paclitaxel, and Carboplatin as a First-Line Regimen for Patients with Metastatic Esophageal, Gastric, and Gastroesophageal Cancer Phase II Results from the North Central Cancer Treatment Group (N044B) Aminah Jatoi, MD,* Shaker R. Dakhil, MD,† Nathan R. Foster, MD,* Cynthia Ma, MD,‡ Kendrith M. Rowland, Jr., MD,§ Dennis F. Moore, Jr., MD,† Anthony J. Jaslowski, MD,ʈ Sachdev P. Thomas, MD,¶ Mark D. Hauge, MD,# Patrick J. Flynn, MD,** Philip J. Stella, MD,†† and Steven R. Alberts, MD* they manifested tumor progression or severe adverse events. All were Purpose: This study was undertaken to explore the response rate of monitored for tumor response as well as other clinical outcomes. a first-line, three-drug regimen that consisted of bortezomib, pacli- Results: The cohort included 35 eligible patients with a median age taxel, and carboplatin in patients with metastatic adenocarcinoma of of 59 years (range, 36–78) and an Eastern Cooperative Oncology the esophagus, gastroesophageal junction, or gastric cardia. Group performance score of 0, 1, and 2 in 60%, 34%, and 6% of Patients and Methods: Patients with the above diagnosis and patients, respectively. Although this regimen was well tolerated, the acceptable organ function were treated intravenously on a 21-day tumor response rate was lower than that anticipated at 23% (95% 2 cycle with the following: bortezomib 1.2 mg/m on days 1, 4, and 8; confidence interval: 10%, 40%), thereby prompting premature study 2 paclitaxel 175 mg/m on day 2; and carboplatin with an area under closure. There were no complete responses. The median survival for the curve of 6 on day 2. Patients received indefinite treatment unless the cohort was 8.9 months (95% confidence interval: 5.9, 12.8). Conclusion: As prescribed in this trial and for this indication, this regimen does not merit further testing. *Mayo Clinic and Mayo Foundation, Rochester, MN; †Wichita Community (J Thorac Oncol. 2008;3: 516–520) Clinical Oncology Program, Wichita, KS; ‡Washington University, St. Louis, Missouri; §Carle Cancer Center CCOP, Urban, IL; ʈSt. Vincent Regional Cancer Center CCOP, Green Bay, WI; ¶Illinois Oncology Research Assn. CCOP, Peoria, IL; #CentraCare Clinic, St. Cloud, MN; ortezomib is a modified dipeptidyl boronic acid that **Metro-Minnesota Community Clinical Oncology Program, St. Louis inhibits the 26S proteasome and, in turn, leads to chaos Park, MN; and ††Michigan Cancer Research Consortium, Ann Arbor, MI. B 1 Disclosure: The authors declare no conflicts of interest. within the ubiquitin proteasome pathway. The latter is crit- This study was conducted as a collaborative trial of the North Central Cancer ical to cell protein regulation, and plays a key role in the Treatment Group and Mayo Clinic and was supported in part by Public degradation of damaged or senescent proteins. In the setting Health Service grants: CA-25224, CA-37404, CA-15083, CA-63848, of cancer, bortzomib’s effects on the 26S proteasome result in CA-35195, CA-35090, CA-35269, CA-37417, CA-52654, CA-35267, CA-63849, CA-35113, CA-60276, CA-35119, CA-35103, and CA-35431. altered protein homeostasis and disruption of cell signaling Additional participating institutions include: Siouxland Hematology-Oncol- pathways, thereby detracting from the cancer cell’s ability to ogy Associates, Sioux City, IA 51105 (Donald B. Wender, MD); Mis- remain viable.1 Indeed, proof of concept has already been souri Valley Cancer Consortium, Omaha, NE 68131 (Gamini S. Soori, established: bortezomib provides a survival advantage to MD); Mayo Clinic Jacksonville, Jacksonville, FL 32224 (Edith Perez, MD); Duluth CCOP, Duluth, MN 55805 (Daniel A. Nikcevich, MD); chemotherapy-refractory multiple myeloma patients, and this Medcenter One Health Systems, Bismarck, ND 58506 (Edward J. Wos, drug is the first such class of agents approved by the Food and D.O.); Meritcare Hospital CCOP, Fargo, ND 58122 (Preston D. Steen, Drug Administration for a cancer indication.2,3 MD); Upstate Carolina CCOP, Spartanburg, SC 29303 (James D. Bear- This study therefore sought to determine the response den, III, MD); Abbott Northwestern Hospital, Minneapolis, MN 55407 (Daniel J. Schneider, MD); Mayo Clinic Scottsdale, Scottsdale, AZ rate of a three-drug regimen that included bortezomib in 85259-5404 (Tom R. Fitch, MD); Mobile Infirmary Medical Center, patients with metastatic cancer of the esophageal cancer, Mobile, AL 36607 (Paul Schwarzenberger, MD). gastroesophageal junction, and gastric cardia, herein referred Address for correspondence: Aminah Jatoi, MD, Mayo Clinic, 200 First to as “esophageal cancer.” This issue is relevant for several Street, SW, Rochester, MN 55905. E-mail: [email protected] Copyright © 2008 by the International Association for the Study of Lung reasons. First, esophageal cancer cells do also rely on an Cancer intricate cell signaling system, and it is plausible that protea- ISSN: 1556-0864/08/0305-0516 some inhibition might disrupt one or more of these pathways 516 Journal of Thoracic Oncology • Volume 3, Number 5, May 2008 Journal of Thoracic Oncology • Volume 3, Number 5, May 2008 Metastatic Esophageal, Gastric, and Gastroesophageal Cancer and thereby result in the death of esophageal cancer cells.4 In addition, all patients had to have had the following Pathways involving such mediators as NF kappa B, BAX, laboratory parameters within 14 days before registration: (1) and P27 have been implicated in therapy resistance in esoph- absolute neutrophil counts Ն1.5 ϫ 103 cells/mL; (2) platelet ageal cancer, and they are targets of bortezomib.5 Second, count Ն100 ϫ 103 cells/mL; (3) total bilirubin equal to or preclinical data suggest that bortezomib carries antineoplastic below the upper limit of normal; (4) aspartate aminotransfer- activity in this setting. Fujita and others examined the gastric ase Յ3 times the upper limit of normal; (5) the alkaline cancer cells lines AZ521, MKN45, and NUGC3 and observed phosphatase Յ2 times the upper limit of normal; and (6) that exposure to bortezomib resulted in cell growth inhibi- serum creatinine Յ1.5 times the upper limit of normal. tion.6 Synergy occurred when bortezomib was combined with Patients were not allowed to enter the trial in the event a conventional chemotherapy agent, such as paclitaxel, pre- of any one of the following: (1) pregnant, nursing, or of sumably from greater down-regulation of NF kappa B and child-bearing potential and unwilling to use effective contra- increasing certain cell cycle regulatory proteins.5 Although ception; (2) previous radiation to greater than 25% of the this study focused on gastric cancer cell lines, not esophageal, marrow cavity; (3) open abdominal surgery in the previous 4 the adjacency of these two organs coupled with established weeks or a laparoscopic procedure within the previous 2 similar treatment approaches suggest that these data are in weeks; (4) an uncontrolled infection or a chronic debilitating fact relevant even to the latter. Third, favorable, mounting illness; (5) known central nervous system metastases; (6) clinical evidence in patients with other solid tumor malignan- peripheral neuropathy of grade 2 or worse; (7) a previous cies suggests that this agent merits further study in patients allergic reaction to either carboplatin or paclitaxel; (8) a prior with esophageal cancer.7–9 Ocean and others treated 36 gas- malignancy, except for adequately treated basal cell or squa- tric cancer patients with bortezomib alone versus bortezomib mous cell carcinoma of the skin or any other cancer for which plus irinotecan.7 The latter regimen yielded a 44% response the patient has been cancer-free for 5 years or longer; or (9) rate, and the former a 9% response rate. These findings led prior chemotherapy, radiation, immunotherapy, or biologic these investigators to conclude that bortezomib is “active” in therapy for recurrent or metastatic disease. For clarification, patients with metastatic gastric cancer. Hence, the foregoing prior radiotherapy and/or chemotherapy was permissible if suggests a rationale for further testing bortezomib in patients administered in the neoadjuvant or adjuvant setting after with metastatic esophageal cancer. complete resection of the original tumor. Moreover, previous Thus, the present study was undertaken. The study team combination chemotherapy and radiation for locally ad- used a phase II study design to test a three-drug regimen of vanced disease given with curative intent were also permis- bortezomib, paclitaxel, and carboplatin. This three-drug reg- sible if a complete clinical or pathologic response had been imen was chosen based on the following three factors that achieved with this therapy and if the last chemotherapy or summarize rationale and feasibility: (1) the preclinical and radiation was Ն6 months before enrollment. clinical synergistic antitumor effects, as described earlier; (2) Pretreatment Evaluation. All patients underwent a history the fact that the regimen paclitaxel and carboplatin has and physical examination, which included a brief neurologic demonstrated antineoplastic activity in this setting10–12; and examination, within 14 days of study registration. In addition, (3) the fact that Ma et al.5 had generated the prerequisite a hemogram, a total bilirubin, a serum creatinine, an alkaline phase I data for the appropriate dosing of this combination. phosphatase, an aspartate aminotransferase, and a chest ra- These phase I data defined the optimal dosing of all three of diograph were also obtained. A computerized tomography these agents based on sequencing of bortezomib with respect scan or a magnetic resonance imaging study that included a to chemotherapy and dose-escalation of both bortezomib and site of measurable tumor was required within 30 days of paclitaxel. study registration. Treatment. Patients were treated with bortezomib 1.2 mg/m2 intravenously on days 1, 4, and 8 of a 21-day chemo- PATIENTS AND METHODS 2 Overview. This phase II study was designed and con- therapy cycle.
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