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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)
This study was undertaken to explore the response rate of a first-line, three-drug regimen that consisted of bortezomib, paclitaxel, and carboplatin in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction, or gastric cardia.
Patients and Methods
Patients with the above diagnosis and acceptable organ function were treated intravenously on a 21-day cycle with the following: bortezomib 1.2 mg/m2 on days 1, 4, and 8; paclitaxel 175 mg/m2 on day 2; and carboplatin with an area under the curve of 6 on day 2. Patients received indefinite treatment unless they manifested tumor progression or severe adverse events. All were monitored for tumor response as well as other clinical outcomes.
Results
The cohort included 35 eligible patients with a median age of 59 years (range, 36–78) and an Eastern Cooperative Oncology Group performance score of 0, 1, and 2 in 60%, 34%, and 6% of patients, respectively. Although this regimen was well tolerated, the tumor response rate was lower than that anticipated at 23% (95% confidence interval: 10%, 40%), thereby prompting premature study closure. There were no complete responses. The median survival for 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.
Bortezomib is a modified dipeptidyl boronic acid that inhibits the 26S proteasome and, in turn, leads to chaos within the ubiquitin proteasome pathway.
The latter is critical to cell protein regulation, and plays a key role in the degradation of damaged or senescent proteins. In the setting of cancer, bortzomib's effects on the 26S proteasome result in altered protein homeostasis and disruption of cell signaling pathways, thereby detracting from the cancer cell's ability to remain viable.
Indeed, proof of concept has already been established: bortezomib provides a survival advantage to chemotherapy-refractory multiple myeloma patients, and this drug is the first such class of agents approved by the Food and Drug Administration for a cancer indication.
This study therefore sought to determine the response rate of a three-drug regimen that included bortezomib in patients with metastatic cancer of the esophageal cancer, gastroesophageal junction, and gastric cardia, herein referred to as “esophageal cancer.” This issue is relevant for several reasons. First, esophageal cancer cells do also rely on an intricate cell signaling system, and it is plausible that proteasome inhibition might disrupt one or more of these pathways and thereby result in the death of esophageal cancer cells.
Pathways involving such mediators as NF kappa B, BAX, and P27 have been implicated in therapy resistance in esophageal cancer, and they are targets of bortezomib.
A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib, in combination with paclitaxel and carboplatin in patients with advanced malignancies.
Second, preclinical data suggest that bortezomib carries antineoplastic activity in this setting. Fujita and others examined the gastric cancer cells lines AZ521, MKN45, and NUGC3 and observed that exposure to bortezomib resulted in cell growth inhibition.
Synergy occurred when bortezomib was combined with a conventional chemotherapy agent, such as paclitaxel, presumably from greater down-regulation of NF kappa B and increasing certain cell cycle regulatory proteins.
A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib, in combination with paclitaxel and carboplatin in patients with advanced malignancies.
Although this study focused on gastric cancer cell lines, not esophageal, the adjacency of these two organs coupled with established similar treatment approaches suggest that these data are in fact relevant even to the latter. Third, favorable, mounting clinical evidence in patients with other solid tumor malignancies suggests that this agent merits further study in patients with esophageal cancer.
Ocean AJ, Schnoll-Sussman F, Chen XE, et al. Recent results of phase II study of PS-341 with or without irinotecan in patients with advanced gastric adenocarcinoma. Proceedings of the American Society of Clinical Oncology, abstract #45, Gastrointestinal Cancers Symposium, 2007.
Bortezomib + gemcitabine/carboplatin results in encouraging survival in advanced non-small cell lung cancer: results of a phase II Southwest Oncology Group trial (S0339). ASCO Annual Proceedings Part I.
Ocean AJ, Schnoll-Sussman F, Chen XE, et al. Recent results of phase II study of PS-341 with or without irinotecan in patients with advanced gastric adenocarcinoma. Proceedings of the American Society of Clinical Oncology, abstract #45, Gastrointestinal Cancers Symposium, 2007.
The latter regimen yielded a 44% response rate, and the former a 9% response rate. These findings led these investigators to conclude that bortezomib is “active” in patients with metastatic gastric cancer. Hence, the foregoing suggests a rationale for further testing bortezomib in patients with metastatic esophageal cancer.
Thus, the present study was undertaken. The study team used a phase II study design to test a three-drug regimen of bortezomib, paclitaxel, and carboplatin. This three-drug regimen was chosen based on the following three factors that summarize rationale and feasibility: (1) the preclinical and clinical synergistic antitumor effects, as described earlier; (2) the fact that the regimen paclitaxel and carboplatin has demonstrated antineoplastic activity in this setting
A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib, in combination with paclitaxel and carboplatin in patients with advanced malignancies.
had generated the prerequisite phase I data for the appropriate dosing of this combination. These phase I data defined the optimal dosing of all three of these agents based on sequencing of bortezomib with respect to chemotherapy and dose-escalation of both bortezomib and paclitaxel.
PATIENTS AND METHODS
Overview.
This phase II study was designed and conducted within the North Central Cancer Treatment Group, and the Institutional Review Boards at each study site had approved the study protocol. All patients were required to provide written consent before enrollment.
Eligibility.
Eligibility criteria consisted of the following: (1) patient age of ≥18 years; (2) histologic or cytologic evidence of adenocarcinoma of the esophagus, esophagogastric junction, or gastric cardia; (3) no curative therapeutic options; (4) measurable disease, as defined by the RECIST criteria
; (5) Eastern Cooperative Oncology Group performance status of 2 or better; (6) a negative pregnancy test 7 days before registration or earlier; and (7) patient's estimated life expectancy of 12 weeks or longer.
In addition, all patients had to have had the following laboratory parameters within 14 days before registration: (1) absolute neutrophil counts ≥1.5 × 103 cells/mL; (2) platelet count ≥100 × 103 cells/mL; (3) total bilirubin equal to or below the upper limit of normal; (4) aspartate aminotransferase ≤3 times the upper limit of normal; (5) the alkaline phosphatase ≤2 times the upper limit of normal; and (6) serum creatinine ≤1.5 times the upper limit of normal.
Patients were not allowed to enter the trial in the event of any one of the following: (1) pregnant, nursing, or of child-bearing potential and unwilling to use effective contraception; (2) previous radiation to greater than 25% of the marrow cavity; (3) open abdominal surgery in the previous 4 weeks or a laparoscopic procedure within the previous 2 weeks; (4) an uncontrolled infection or a chronic debilitating illness; (5) known central nervous system metastases; (6) peripheral neuropathy of grade 2 or worse; (7) a previous allergic reaction to either carboplatin or paclitaxel; (8) a prior malignancy, except for adequately treated basal cell or squamous cell carcinoma of the skin or any other cancer for which the patient has been cancer-free for 5 years or longer; or (9) prior chemotherapy, radiation, immunotherapy, or biologic therapy for recurrent or metastatic disease. For clarification, prior radiotherapy and/or chemotherapy was permissible if administered in the neoadjuvant or adjuvant setting after complete resection of the original tumor. Moreover, previous combination chemotherapy and radiation for locally advanced disease given with curative intent were also permissible if a complete clinical or pathologic response had been achieved with this therapy and if the last chemotherapy or radiation was ≥6 months before enrollment.
Pretreatment Evaluation.
All patients underwent a history and physical examination, which included a brief neurologic examination, within 14 days of study registration. In addition, a hemogram, a total bilirubin, a serum creatinine, an alkaline phosphatase, an aspartate aminotransferase, and a chest radiograph were also obtained. A computerized tomography scan or a magnetic resonance imaging study that included a site of measurable tumor was required within 30 days of study registration.
Treatment.
Patients were treated with bortezomib 1.2 mg/m2 intravenously on days 1, 4, and 8 of a 21-day chemotherapy cycle. Additionally, paclitaxel 175 mg/m2 was administered intravenously over 3 hours on day 2. Finally, carboplatin with an area under the curve (AUC) of 6 was also administered intravenously on day 2. The protocol specified appropriate premedication with dexamethasone, diphenhydramine, and ranitidine or an equivalent medication in an effort to prevent drug reactions.
Patients were to continue on the regimen indefinitely, until cancer progression, or until unacceptable toxicity occurred. The patient's decision to stop therapy with no apparent explanation was also considered acceptable and was specified in the protocol.
Dose modifications were specified for each agent. For bortezomib, an interval absolute neutrophil count of less than 1.0 × 103 cells/mL and/or a platelet count of less than 50 × 103 cells/mL required that this agent be omitted on day #8 and then reduced by 20% for subsequent cycles. A similar approach was specified in the event of febrile neutropenia, defined as the above neutrophil count with a concurrent fever. Similarly, the above parameters at any point during a treatment cycle prompted a 20% dose reduction of both paclitaxel and carboplatin. Grade 3 or worse gastrointestinal toxicity or other nonhematologic toxicity also required dose reductions for both these drugs. Finally, at the beginning of each treatment cycle, all cancer treatment was to be held until the absolute neutrophil count and platelet count exceeded 1.5 × 103 cells/mL and 100 × 103 cells/mL, respectively. Treatment was also to be held in the event of grade 3 or worse nonhematologic toxicity with resumption of chemotherapy when toxicities either returned to baseline or dropped to less than grade 1. Patients with grade 2 neuropathy could proceed with chemotherapy with a 20% dose reduction of all three drugs, but patients with neuropathy of grade 3 or worse were to discontinue treatment on protocol. In the event that chemotherapy needed to be held for more than 3 weeks, patients were again to discontinue treatment on protocol.
The protocol stated that full supportive care measures were to be used while patients received chemotherapy on study. The use of blood products, antibiotics, nutrition support, and antiemetics were allowed as clinically appropriate. The use of neutrophil growth factor support was allowed in the event of severe neutropenic complications.
Follow-up Evaluations.
Visits with an oncologist were required every 3 weeks, but patients were otherwise monitored with a weekly hemogram and other weekly blood testing as deemed clinically appropriate by their healthcare providers. Tumor measurements were to be obtained immediately before the anticipated third cycle, and every other cycle thereafter unless more frequent assessments were required to confirm a tumor response. RECIST criteria were used to define a confirmed tumor response.
Adverse events were recorded with the National Cancer Institute's Common Toxicity Criteria, version 3.0 and tracked throughout the study period.
Statistical Analyses.
The primary objective of this trial was to assess the proportion of patients with a confirmed tumor response treated as per the regimen outlined in this protocol. The largest success proportion whereby the proposed treatment regimen would be considered unworthy of further study was 30%, based on earlier data that tested carboplatin and paclitaxel alone, and the smallest success proportion that would warrant further study was 50%. These parameters were conservative based on previously reported response rates with carboplatin and paclitaxel in similar settings.
Bortezomib + gemcitabine/carboplatin results in encouraging survival in advanced non-small cell lung cancer: results of a phase II Southwest Oncology Group trial (S0339). ASCO Annual Proceedings Part I.
If 8 or fewer confirmed responses were observed in the first 25 patients, it was thought appropriate to terminate the study. Accrual was not terminated during the interim analysis. A confidence interval for the percentage of patients with a confirmed response was calculated using the exact binomial method.
Secondary endpoints included descriptive summaries of time-to-cancer progression, adverse events, and overall survival. Time-to-cancer progression is the time from enrollment on study to the time of evidence of cancer progression. Adverse events are presented in part in tabular form. Overall survival is defined as the time from study registration to death from any cause. Time-to-event distributions are estimated with the Kaplan Meier method.
Thirty-five eligible patients were enrolled and treated between November 2005 and June 2006. One patient cancelled and did not receive any of the drugs, and another was subsequently found to be ineligible; thus, these two patients are not included in the tumor response and survival analyses shown below. The median age of this 35-patient cohort at study entry was 59 years with a range from 36 to 78 years. Eleven percent were women. Eastern Cooperative Oncology Group performance scores of 0, 1, and 2 were observed in 60%, 34%, and 6% of the cohort, respectively (Table 1).
Patients completed a median of four cycles of chemotherapy (range, 1–13). Reasons for discontinuation are as follows: cancer progression (n = 23), adverse events or patient declined further,
Although intermittent dose reductions were required for medical reasons, most patients nonetheless received the majority of the originally intended chemotherapy dosing. For bortezomib, the range of the median percentage of targeted dose prescribed was 67 to 100% over the first 6 cycles of chemotherapy; and, for paclitaxel, it was 72 to 100%. For carboplatin, the percentage of patients who maintained an AUC of 6 over the first 6 cycles ranged from 7% for cycle 6 to 100% for cycle 1 (median 45%). For the first 3 cycles, the majority of patients did receive carboplatin at an AUC of 6. During the first 2 cycles of therapy, 17 patients (47%) received approximately the full dose of all 3 drugs.
Response, Progression, and Survival Data.
At the time of this report, within this 35-patient cohort, eight patients had manifested a confirmed partial tumor response, thus providing a response rate of 23% (95% confidence interval: 10%, 40%). There were no complete responses. The median duration of response was 4.7 months (95% confidence interval: 2.8, 9.0).
The median survival for the cohort was 8.9 months (95% confidence interval: 5.9, 12.8) (Figure 1). The median time-to-cancer progression was 4.2 months (95% confidence interval: 2.5, 5.1) (Figure 2). At the time of this report, 97% of patients have shown evidence of cancer progression, and 86% have died. For the five patients who remain alive, the median follow-up has been 16.8 months (range, 14.7, 21.6).
FIGURE 1The median survival for the cohort was 8.9 months (95% confidence interval: 5.9, 12.8 months).
Adverse event data pertain to all 36 patients who received any study drug; the one ineligible patient is included. Only grade 2 or worse events are reported. Of the 36 patients treated on this trial, all suffered at least one grade 3 or worse event, and 25 (69%) suffered at least one grade 4 event. Grade 3 events included the following: neutropenia (22%), thrombocytopenia (25%), vomiting (14%), diarrhea (17%), neurologic symptoms (22%), and fatigue (17%) with parenthetical percentages referring to the percentage of patients who sustained at least one such event. Grade 4 events included primarily neutropenia (58%). There were no grade 5 events (Table 2).
This study was undertaken to explore the role of a three-drug regimen that included bortezomib in patients with metastatic esophageal cancer. The agents bortezomib, paclitaxel, and carboplatin were tested for this purpose. The tumor response rate of 23% (95% confidence interval: 10%, 40%) was well below the anticipated threshold to suggest promise, and the study was therefore terminated prematurely. In effect, previously reported tumor response rates in the range of 43% with paclitaxel and carboplatin alone were not observed in the present study.
One might argue that an end point, other than tumor response rate, should have been used in this trial, particularly because bortezomib may exert only static effects. In reply, it is important to point out that other outcome data from this study also did not suggest that bortezomib was providing clinical benefit. The median survival in previous studies that evaluated the doublet of paclitaxel and carboplatin was 9 months
; and, in the present study, it was 8.9 months—roughly comparable. Thus, based on these overall survival data, this three-drug combination does not appear to be providing a favorable clinical impact over and above what would be expected from paclitaxel and carboplatin alone. This finding underscores the need to evaluate other regimens for the treatment of patients with metastatic cancer of the esophagus, stomach, and gastroesophageal junction.
A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib, in combination with paclitaxel and carboplatin in patients with advanced malignancies.
Ocean AJ, Schnoll-Sussman F, Chen XE, et al. Recent results of phase II study of PS-341 with or without irinotecan in patients with advanced gastric adenocarcinoma. Proceedings of the American Society of Clinical Oncology, abstract #45, Gastrointestinal Cancers Symposium, 2007.
Bortezomib + gemcitabine/carboplatin results in encouraging survival in advanced non-small cell lung cancer: results of a phase II Southwest Oncology Group trial (S0339). ASCO Annual Proceedings Part I.
Disclosure: The authors declare no conflicts of interest.
This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants: CA-25224, CA-37404, CA-15083, CA-63848, 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.
Additional participating institutions include: Siouxland Hematology-Oncology Associates, Sioux City, IA 51105 (Donald B. Wender, MD); Missouri Valley Cancer Consortium, Omaha, NE 68131 (Gamini S. Soori, MD); Mayo Clinic Jacksonville, Jacksonville, FL 32224 (Edith Perez, MD); Duluth CCOP, Duluth, MN 55805 (Daniel A. Nikcevich, MD); Medcenter One Health Systems, Bismarck, ND 58506 (Edward J. Wos, D.O.); Meritcare Hospital CCOP, Fargo, ND 58122 (Preston D. Steen, MD); Upstate Carolina CCOP, Spartanburg, SC 29303 (James D. Bearden, III, MD); Abbott Northwestern Hospital, Minneapolis, MN 55407 (Daniel J. Schneider, MD); Mayo Clinic Scottsdale, Scottsdale, AZ 85259-5404 (Tom R. Fitch, MD); Mobile Infirmary Medical Center, Mobile, AL 36607 (Paul Schwarzenberger, MD).
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