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© 2003 American Society for Clinical Oncology Phase I and II Study of Exisulind in Combination With Capecitabine in Patients With Metastatic Breast Cancer
From the Departments of Breast Medical Oncology, Department of Biostatistics, and the Division of Medicine and Pathology of the University of Texas M.D. Anderson Cancer Center, Houston TX; and Cell Pathways Inc, Horsham, PA. Address reprint requests to Lajos Pusztai, MD, PhD, Box 424, Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: lpusztai{at}mdanderson.org.
Purpose: We studied the safety and clinical activity of exisulind in combination with capecitabine in 35 patients with metastatic breast cancer (MBC). Patients and Methods: All patients had received previous anthracycline and taxane chemotherapies. Two dose levels of exisulind were explored, 125 and 250 mg orally bid as continuous daily therapy, concomitant with capecitabine 2,000 mg/m2 for 14 days in 21-day cycles. In the phase I study, the dose-limiting toxicities were hand-foot syndrome and diarrhea. The 125-mg bid dose was selected for phase II testing. Results: The most common nonhematologic grade 2 to 3 adverse events were hand-foot syndrome (57%) and fatigue (48%). The most frequent grade 2 to 3 laboratory abnormality was granulocytopenia. No death, unexpected adverse events, or cumulative toxicity were encountered. One complete and four partial responses were achieved (objective response rate, 16%) in the 31 patients assessable for response. The median duration of response was 31 weeks; three patients experienced stable disease longer than 26 weeks. Overall clinical benefit (complete response, partial response, or stable disease > 26 weeks) was 23%. Fourteen specimens were available for immunohistochemical assessment of phosphodiesterase-5 isoenzyme (PDE-5) and PDE-2 expression, which are the targets of exisulind. Eighty percent of tumors showed some expression of PDE-5 in the invasive cancer cells including 35% that showed moderate or strong staining. PDE-2 showed moderate or strong staining in 78% of tumors. There was no apparent association between tumor response and staining intensity. Conclusion: Exisulind (125 mg orally bid) in combination with capecitabine is well tolerated and the combination has anticancer activity similar to that of capecitabine alone in heavily pretreated patients with MBC.
SINGLE-AGENT CAPECITABINE treatment results in approximately 20% objective tumor response rate with a median duration of 32 weeks in patients with metastatic breast cancer who experienced disease progression after anthracycline and paclitaxel chemotherapies.1 On the basis of these results, capecitabine was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic breast cancer that is resistant to paclitaxel and anthracycline therapy. However, these results also indicate that improvements in the treatment of anthracycline- and taxane-resistant breast cancer are needed. One strategy to improve the antitumor activity of cytoxic drugs is to combine these agents with novel, biologically targeted molecules that are designed to enhance the sensitivity of neoplastic cells to chemotherapy-induced apoptosis. Exisulind (sulindac sulfone, FGN-1, Aptosyn, Cell Pathways Inc, Horsham, PA) is a sulfone metabolite of the nonsteroidal anti-inflammatory drug (NSAID) sulindac, and belongs to a novel class of proapoptotic molecules. Exisulind selectively stimulates programmed cell death in a variety of neoplastic cells including colon, prostate, and breast cancer cells, without affecting normal epithelial cells in vitro.2–5 It also inhibits chemically induced mammary carcinogenesis in rats.6,7 Exisulind is synergistic with a diverse group of cytotoxic compounds in vitro.8,9 Exisulind induces apoptosis through inhibition of cyclic guanosine monophosphate (cGMP)-phosphodiesterases that results in sustained elevation of intracellular cGMP levels. Exisulind is most active on a novel phosphodiesterase-5 isoenzyme (PDE-5), but also inhibits to a lesser extent other isoenzymes including PDE-2.10 Increased cGMP concentration results in activation of protein kinase G, proteosomal degradation of beta-catenin, and activation of JUN-kinase, which in turn leads to activation of caspases and apoptosis (Fig 1  ).11,12 At higher concentrations exisulind also inhibits transcription factor nuclear factor-kappa B (NF- ß) in vitro.13 The NF-ß pathway is activated by cellular stress including exposure to cytotoxic agents.14 Activation of NF-ß protects cells from apoptosis and therefore, inhibition of this transcription factor may also contribute to the proapoptotic effect of exisulind. Importantly, exisulind lacks inhibitory activity on the two isoforms of cyclooxygenase, cyclooxygenase-1 (COX-1) and COX-2, and is devoid of gastrointestinal and renal toxicity that is associated with NSAIDs.15
The pharmacokinetics and toxicity of exisulind was studied in healthy volunteers. The half-life of the drug was 9.5 hours and only few grade 1 transient adverse events were reported (data on file at Cell Pathways Inc). A phase I study was conducted in 18 patients with familial adenomatous polyposis who had subtotal colectomies and received the drug for 6 months.16 Exisulind was well tolerated at doses of 200 to 300 mg orally (PO) bid. At the 400-mg PO bid dose level, three of the six patients developed transient, asymptomatic, grade 2 and 3 elevations of liver enzymes that resolved after discontinuation of the drug. Pharmacokinetics indicated a half-life of 6 to 9 hours and no drug accumulation was noted. Another clinical trial with patients who had a history of sporadic colon polyps showed exisulind 250 mg PO bid to be well tolerated and effective in inducing regression of sporadic adenomatous polyps.17 Long-term safety of exisulind was also assessed in a study in which patients received exisulind for 12 months for recurrent prostate cancer.18 The treatment was well tolerated without any cumulative side effects and suppressed the increase of prostate-specific antigen, suggesting that the drug has antitumor activity. On the basis of the favorable toxicity profile and promising preclinical results, we conducted a phase I and II study to determine a safe dose for the combination of exisulind with capecitabine and to assess the antitumor activity of this regimen in patients with metastatic breast cancer. The primary end point of the phase II study was to assess the objective tumor response rate. We also studied the expression of PDE-2 and PDE-5 in breast cancer tumor specimens.
Patient Eligibility Patients with metastatic breast cancer were eligible if they had previously received both anthracycline-containing and taxane chemotherapies either as adjuvant treatment or for metastatic breast cancer. Patients must have demonstrated good performance status (Zubrod performance status  2); adequate organ function defined as platelets  100,000/µL, absolute neutrophil count 1,500 cells/µL, hemoglobin 8 g/dL, creatinine 2.0 mg/dL, bilirubin 1.5 mg/dL; and ALT, AST, or alkaline phosphatase levels 1.5 x the upper limit of normal in the absence of bone or liver metastasis, or 2.5 x the upper limit of normal in the presence of liver or bone metastasis, respectively. All patients had bidimensionally measurable disease. Exclusion criteria included known hypersensitivity to sulindac, prior therapy with capecitabine (but not infusional fluorouracil), or brain metastasis diagnosed within 6 months. This clinical trial was approved by the Institutional Review Board of the University of Texas M.D. Anderson Cancer Center and all patients signed an informed consent for voluntary participation before receiving therapy. All patients had a full physical examination and a computed tomographic scan of chest, abdomen, and bone before receiving treatment on study. Plain radiographs of bone or magnetic resonance imaging were obtained if abnormality was detected on bone scan. CBC and serum chemistries including blood urea nitrogen, creatinine, total bilirubin, alkaline phosphatase, lactate dehydrogenase, AST, ALT, total protein, albumin, glucose, and electrolytes were also measured at baseline. A serum pregnancy test was performed in women of childbearing potential. Patients who participated in the phase I part of the study had weekly CBCs, total bilirubin, alkaline phosphatase, lactate dehydrogenase, AST, and ALT measurements during the first 6 weeks of therapy.
Response Evaluation
Complete response (CR) was defined as disappearance of all evidence of tumor by physical examination and imaging evaluation. Bone lesions must have improved by bone scan and shown complete recalcification by x-ray. The patient also must have been free of all symptoms of cancer and tumor markers must have been normal. Response confirmation was performed at 6 weeks. Partial response (PR) was defined as 50% or greater decrease in the sum of the products of diameters of all index lesions persisting for at least one cycle of therapy. Bone lesions must have improved by scan and shown some reossification by x-ray. All objective responses were confirmed by review of films by two medical oncologists. Progressive disease (PD) was defined as either an increase of
Treatment Plan The following dose modifications were recommended for toxicity: for toxicity other than liver function impairment, only the dose of capecitabine was interrupted or reduced first. Dose interruption or dose modification of capecitabine was made according to the package insert of this drug. Briefly, with first appearance of grade 2 diarrhea, nausea, vomiting, hand-and-foot syndrome, or stomatitis, capecitabine was interrupted until toxicity subsided to less than grade 1, then the drug was restarted at 100% dose. Second and third recurrences of grade 2 toxicity required dose reduction of capecitabine to 75% and 50%, respectively. The first appearance of grade 3 toxicity warranted dose interruption of capecitabine until recovery and subsequent reduction of capecitabine dose to 75% and to 50% after the second appearance. Initially, exisulind was not withheld for capecitabine-related toxicity; however, if toxicity progressed or did not improve within 72 hours after interruption of capecitabine, then exisulind was also discontinued. Exisulind was also interrupted if grade 2 or greater liver toxicity developed, and it could be restarted at 50% dose after liver function returned to baseline. If recovery from grade 3 toxicity required greater than 2 weeks or grade 4 toxicity of any organ system was observed, then the patient was removed from the study. Concomitant use of sulindac (Clinoril, Merck Co Inc, West Point, PA) was not permitted during the study. Other NSAIDS could be used at the discretion of the treating physician. Bisphosphonate treatment was allowed for patients with bone metastases. No patient received trastuzumab or concomitant hormonal therapy during this study.
Statistical Considerations The primary objective of the phase II study was to estimate antitumor efficacy of this combination regimen measured by objective tumor response (CR + PR) rate. Time to progression and overall survival were also estimated using the Kaplan-Meier method. The trial was conducted according to Simon’s optimal design with one interim analysis after assessment of response in the first 12 patients treated with the phase II dose of exisulind. If no more than one objective response was seen the trial was to be terminated, otherwise the protocol was to continue to enroll a maximum of 35 patients. If the true response rate was 10%, the probability of termination at the interim analysis would be .66 when the type I and II errors are both set at 0.10. Patients who received phase II dose during the phase I part of the study were included in the final assessment of response rate.
For the purpose of analysis, response and immunohistochemistry (IHC) staining intensity were considered nominal variables, and
Correlative Studies Briefly, sections were deparaffinized and then hydrated through an ethanol series. Primary antibodies, antihuman PDE-2, and anti-antihuman PDE-5 were diluted 1/1,500 and 1/2,000, respectively, in blocking buffer (5% goat serum, 5% glycerol, 1% gelatin, and 0.04% NaN3 in phosphate-buffered saline) and incubated with the samples for 2 hours at room temperature in a humidified chamber. Sections were washed twice for 5 minutes in phosphate-buffered saline and then incubated with a biotin-conjugated secondary antibody diluted 1/2,500 in blocking buffer (Jackson ImmunoResearch, West Grove, PA) for 1 hour at room temperature and developed using a 3.3'-diaminobenzidine (DAB) substrate kit (Vector Laboratories, Burlingame, CA) according to manufacturer’s protocol. The signal was quantified with the Automated Cellular Imaging System (ACIS; Chromavision, San Juan Capistrano, CA) instrument. Five separate 40x fields of view were obtained from representative tumor areas. From these regions the average brown (DAB label) intensity and the percentage of labeled cells along with standard deviations were obtained. The data obtained were then used to classify the tumors into four groups of PDE expression: 0, negative; 1, low; 2, moderate; and 3, high staining. Tumors with none or negligible labeling were scored as 0. Tumors with variable labeling intensities and low percentages were scored 1, and those with moderate percentages were scored as 2. Tumors with strong signal intensity and high and consistent labeling percentages were scored as 3. All slides were also reviewed by a breast pathologist (W.F.S.) to assess cellular distribution of staining.
Patient Characteristics Thirty five patients with metastatic breast cancer were entered into this clinical trial that was conducted at the Nellie B. Connally Breast Center of the University of Texas M.D. Anderson Cancer Center from January through December 2001. Thirteen patients participated in the phase I part of the study and 22 patients were enrolled onto the phase II part. All patients had prior exposure to both anthracyclines and taxanes. Eighteen patients received docetaxel, 17 patients received paclitaxel, and 48% received two or more prior chemotherapy regimens for metastatic breast cancer. All estrogen or progesterone receptor–positive patients received prior hormonal therapy and were considered refractory to additional hormonal treatment. Sixty-nine percent had two or more organ sites involved with cancer. Patient demographics and baseline disease characteristics are presented in Table 1 .
Toxicity In the phase I part of the study, three of the five patients in the first cohort (dose level 1, 125 mg bid) were advanced to dose level 2 (250 mg exisulind bid). The remaining two patients had dose-limiting diarrhea and hand-foot syndrome. Subsequently, eight additional patients started therapy at dose level 2. Of the first 13 patients who participated in the phase I part of the study, six patients (46%) required dose reduction for toxicity. Three patients experienced grade 2 asymptomatic elevation of liver enzymes and required dose reduction for exisulind to dose level 1 with reversal of the laboratory abnormality. The dose of capecitabine was reduced in four patients (31%) for either grade 3 diarrhea (n = 2) or grade 3 hand-foot syndrome (n = 2). One patient experienced both the elevation of liver enzymes and hand-foot syndrome. All symptomatic adverse events were consistent with toxicity from capecitabine. The recommended dose for the phase II part of the study was 125 mg exisulind PO bid daily for 21 days together with capecitabine 1,000 mg/m2 PO bid for 14 days. This dose was selected because only seven of 13 patients tolerated advance to the higher dose level of 250 mg bid; the remaining patients required dose reduction or could not be advanced to the higher dose.
During the entire clinical trial, 127 courses were given at dose level 1 and 37 courses were given at dose level 2. Table 2
No deaths or serious unexpected adverse events were encountered and there was no evidence of cumulative toxicity. Two patients withdrew from study because of toxicity. All adverse events were consistent with known toxicity from capecitabine. We previously reported our adverse event experience with single-agent capecitabine in a similar patient population.19 For comparison, in 39 patients who received 2,000 mg/m2 capecitabine in two divided doses, we observed fatigue (grades 1 to 3) in 31%, nausea in 36% (5% grade 3), hand-foot syndrome in 69% (20% grade 3), and diarrhea in 46% (3% grade 3) of patients. The current results with the combination regimen are similar to those was seen with single-agent capecitabine.
Response
PDE-2 and PDE-5 Expression in Breast Cancer Fifteen of 35 patients (43%) who participated in the study had paraffin-embedded tissue sections of their cancer available for IHC. All but one of these specimens were obtained from the primary breast lesion at the time of diagnosis. One patient had tumor tissue from a metastatic site (chest wall recurrence). Fourteen of the 15 specimens contained sufficient tumor cells for analysis. Eighty percent of tumors showed some staining for PDE-5 in the invasive cancer cells, including six tumors (43%) with weak, three tumors (21%) with moderate, and two tumors (14%) with strong staining for this enzyme. Three tumors (21%) had no detectable staining for PDE-5. Ninety-three percent of tumors showed staining for PDE-2, including two samples (14%) with weak, four samples with moderate (28%), and seven tumors (50%) with strong staining for this enzyme. Only one tumor showed no staining with PDE-2 antibody. Staining was invariably cytoplasmic with both antibodies. Cytoplasmic PDE-5 and PDE-2 expression was absent or was less in adjacent normal breast epithelial cells compared with neoplastic cells (Fig 2 ). There was no apparent association between tumor response and staining intensity for either PDE-5 or PDE-2. A summary of these results is presented in Table 5.
This phase I and II study was conducted to determine the safe dose of exisulind in combination with capecitabine and to assess the antitumor activity in metastatic breast cancer. All patients who participated in the trial had previously received both taxane- and anthracycline-based chemotherapies as adjuvant treatment and/or treatment for metastatic disease. Forty-eight percent of patients received two or more prior chemotherapies for metastatic breast cancer. In the phase I study, the dose-limiting toxicities were hand-foot syndrome and diarrhea. Exisulind dose of 125 mg PO bid was selected for phase II testing. This dose was selected because only seven of 13 patients tolerated an advance to the higher dose level of 250 mg bid; the remaining patients required dose reduction or could not be advanced to the higher dose. In the phase II part of the study, the most commonly observed nonhematologic grade 2 to 3 adverse events were hand-foot syndrome (57%) and fatigue (48%). The most frequent grade 2 to 3 laboratory abnormalities were granulocytopenia and thrombocytopenia. All of these toxicities are consistent with the known toxicities of capecitabine. No death, unexpected serious adverse events, or cumulative toxicity were encountered. Postmarketing clinical experience with single-agent capecitabine suggests that grade 2 and greater diarrhea and hand-foot syndrome may be more common with the FDA-recommended dose of 2,500 mg/m2/d than early studies suggested.20 A retrospective review of clinical experience within the Department of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center indicated that only 34% of patients tolerated the FDA-recommended dose of capecitabine and 33% of patients required dose reduction because of toxicity after their first cycle of therapy.19 These observations led us to select a fixed dose of 2,000 mg/m2 of capecitabine for this study. The frequency and intensity of toxicities seen with the combination of exisulind (125 mg PO bid) and capecitabine in this study were comparable to those reported with capecitabine alone.19 Among the 31 patients who were assessable for response, one CR and four PRs were observed (ORR, 16%; 95% CI, 5% to 34%). The median duration of response was 31 weeks (range, 13 to 51 weeks). Three additional patients experienced SD of more than 26 weeks duration; therefore, overall clinical benefit was seen in 23% (eight of 35) of patients. These results are similar to those reported by the pivotal phase II trial with single-agent capecitabine in metastatic breast cancer.1 In that study, 162 patients who had received an anthracycline before and were resistant to paclitaxel therapy were enrolled. Capecitabine was administered at a daily dose of 2,510 mg/m2 for 2 weeks followed by a 1-week rest period, given as 3-week cycles. The ORR was 20%, the median duration of response was about 32 weeks, and the median survival was 12.8 months. Combined retrospective analysis of four phase II studies including 321 patients with metastatic breast cancer also reported an overall response rate of 22%, which was independent of dose modifications.20 More recently, the results of a randomized trial that compared capecitabine alone with capecitabine and anti–vascular endothelial growth factor antibody (bevacizumab, Avastin, Genentech, San Francisco, CA) in anthracycline- and taxane-exposed metastatic breast cancer were reported in abstract form.21 The ORR was 19% with capecitabine alone and 30% in combination with bevacizumab. The antitumor activity of the exisulind (125 mg bid) and capecitabine combination in our study is similar to that reported with capecitabine alone in heavily pretreated patients with metastatic breast cancer. We also assessed the expression of PDE-5 and PDE-2, the enzyme targets of exisulind, with IHC. There are no previous reports published on PDE-5 or PDE-2 expression in breast cancer. We found that approximately one third of the primary tumors showed moderate or strong staining with PDE-5 antibody and about one fifth of tumors showed no staining at all. PDE-2 was more frequently expressed; 93% of samples had some staining and 78% of samples showed strong to moderate staining. We could not detect an association between tumor response and staining intensity for either PDE-5 or PDE-2. However, this observation has limited power because of the small number of patients assessed, and it remains important to include these correlative studies in future clinical trials with inhibitors of PDEs. Our findings indicate that enzymes of cGMP metabolism (PDE-2 and PDE-5) are commonly expressed by a subset of human breast cancers. The role of these enzymes in apoptosis is supported by numerous in vitro observations. Therefore, additional clinical testing of this pathway by second-generation, more active PDE inhibitors, in combination with other cytotoxic drugs, is warranted. A more active analog of exisulind, CP-461, was recently developed and tested in a phase I clinical trial.22 Phase II studies are planned to investigate further the potential of this compound in combination with chemotherapy drugs. In summary, PDE-5 is commonly expressed in invasive breast cancer, and therefore provides a potential target for drug development in a subset of patients with breast cancer. Exisulind, a selective inhibitor of PDE-5, can be safely combined with capecitabine. The antitumor activity of the combination of exisulind 125 mg PO bid and capecitabine 1,000 mg/m2 bid is within the range reported with capecitabine alone. Therefore, synergism between these two drugs at these doses, if any, is likely to be modest.
The following authors or their immediate family members have indicated a financial interest as follows. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Lajos Pusztai acted as a consultant for Cell Pathways Inc within the past 2 years. Clark Whitehead, W. Joseph Thompson, and Amy Gibbs served as officers or members of the board of Cell Pathways Inc.
Supported by Cell Pathways Inc, Horsham, PA.
1. Blum JL, Jones SE, Buzdar AU, et al: A multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485–493, 1999
2. Piazza GA, Kulchak-Rahm AL, Krutzsch M, et al: Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 55:3110–3116, 1995 3. Piazza GA, Lloyd M, David M, et al: Selective apoptosis of human prostate tumor cells by exisulind and an analog via a cyclooxygenase (COX)-independent pathway. Proc Am Assoc Cancer Res 40:4a, 1999 (abstr 27) 4. Izbicka E, Lawrence R, Davidson K, et al: FGN-1 and analog, CP248, show anticancer activity against human tumor specimens taken directly from patients. Proc Am Assoc Cancer Res 39:225a, 1998 (abstr 1533) 5. Han EK, Arber N, Yamamoto H, et al: Effects of sulindac and its metabolites on growth and apoptosis in human mammary epithelial and breast carcinoma cell lines. Breast Cancer Res Treat 48:195–203, 1998[CrossRef][Medline] 6. Thompson HJ, Briggs S, Paranka NS, et al: Inhibition of mammary carcinogenesis in rats by sulfone metabolite of sulindac. J Natl Cancer Inst 87:1259–1260, 1995[Medline]
7. Thompson HJ, Jiang C, Lu J, et al: Sulfone metabolite of sulindac inhibits mammary carcinogenesis. Cancer Res 57:267–271, 1997 8. Chan D, Soriano A, Helfrich B, et al: Synergistic effects of exisulind with conventional chemopreventive and therapeutic agents against human lung cancer cells in vitro and in vivo. Proc Am Soc Clin Oncol 18:488a, 1999 (abstr 1884)
9. Chan DC, Earle KA, Zhao TL, et al: Exisulind in combination with docetaxel inhibits growth and metastasis of human lung cancer and prolongs survival in athymic nude rats with orthotopic lung tumors. Clin Cancer Res 8:904–912, 2002 10. Thompson WJ, Piazza GA, Li H, et al: Exisulind induction of apoptosis involves guanosine 3', 5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation and attenuated beta-catenin. Cancer Res 6:3338–3342, 2000 11. Soh JW, Mao Y, Kim MG, et al: Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. Clin Cancer Res 60:4136–4141, 2000
12. Soh JW, Mao Y, Liu L, et al: Protein kinase G activates the JNK1 pathway via phosphorylation of MEKK1. J Biol Chem 276:16406–16410, 2001
13. Yamamoto Y, Yin M-J, Lin K-M, et al: Sulindac inhibits activation of NF-kB pathway. J Biol Chem 274:27307–27314, 1999
14. Mercurio F, Manning AM: Multiple signals converging on NF-
15. Piazza GA, Rahm AK, Finn TS, et al: Apoptosis primarily accounts for the growth-inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction. Cancer Res 57:2452–2459, 1997
16. van Stolk R, Stoner G, Hayton WL, et al: Phase I trial of exisulind (sulindac sulfone, FGN-1) as a cancer chemopreventive agent in patients with familial adenomatous polyposis. Clin Cancer Res 6:78–89, 2000 17. Arber N, Rex D, Sjodhal R, et al: Exisulind induced regression of sporadic adenomatous polyps in a randomized, double blind, placebo controlled trial. Proc Dig Disease Week: 2002 (abstr 611) 18. Goluboff ET, Prager D, Rukstalis D, et al: Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy. J Urol 166:882–886, 2001[CrossRef][Medline] 19. Michaud LB, Gauthier MA, Wojdylo JR, et al: Improved therapeutic index with lower dose capecitabine in metastatic breast cancer. Proc Am Soc Clin Oncol 19:104a, 2000 (abstr 401) 20. O’Shaughnessy J, Blum J: A retrospective evaluation of the impact of dose reduction in patients treated with Xeloda (capecitabine). Proc Am Soc Clin Oncol 19:104a, 2000 (abstr 400) 21. Miller KD, Rugo HS, Cobleigh MA, et al: Phase III trial of capecitabine plus bevacizumab versus capecitabine alone in women with metastatic breast cancer previously treated with anthracycline and a taxane. Breast Cancer Res Treat 76:S37, 2002 (suppl 1, abstr 36)[CrossRef]
22. Sun W, Stevenson JP, Gallo JM, et al: Phase I and pharmacokinetic trial of the pro-apoptotic sulindac analog CP-461 in patients with advanced solid tumors. Clin Cancer Res 8:3100–3104, 2002 Submitted February 21, 2003; accepted June 30, 2003. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 was used to test for significant association between these two categories of variables. 
