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© 1999 American Society for Clinical Oncology Multicenter Phase II Study of Capecitabine in Paclitaxel-Refractory Metastatic Breast CancerFrom the Physician Reliance Network (PRN) Research, Baylor-Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, and M.D. Anderson Cancer Center, Houston, TX; Harper Hospital, Detroit, MI; Massachusetts General Hospital, Boston, MA; Cancer Center, North Miami Beach, FL; and Hoffman-LaRoche, Inc, Nutley, NJ. Address reprint requests to Joanne L. Blum, MD, PhD, Physician Reliance Network Research, 3535 Worth St, Suite 230, Dallas, TX 75246.
PURPOSE: Capecitabine is a novel, oral, selectively tumor-activated fluoropyrimidine carbamate. This large multicenter phase II trial tested the efficacy and safety of twice-daily oral capecitabine at 2,510 mg/m2/d given for 2 weeks followed by a 1-week rest period and repeated in 3-week cycles, in patients with paclitaxel-refractory metastatic breast cancer. PATIENTS AND METHODS: Patients were to have received at least two but not more than three prior chemotherapeutic regimens, one of which had to have contained paclitaxel given for metastatic disease. One hundred sixty-three patients were entered onto the study at 25 centers, and 162 patients received capecitabine. One hundred thirty-five patients had bidimensionally measurable disease, and 27 patients had assessable disease. RESULTS: The overall response rate was 20% (95% confidence interval, 14% to 28%). All responding patients were resistant to or had failed paclitaxel, and all had received an anthracycline. Three complete responses were seen, with complete response durations of 106, 109, and 194+ days. Median duration of response was 8.1 months, median survival time was 12.8 months, and the median time to disease progression was 93 days. The most common treatment-related adverse events were hand-foot syndrome, diarrhea, nausea, vomiting, and fatigue. Diarrhea (14%) and hand-foot syndrome (10%) were the only treatment-related adverse events that occurred with grade 3 or 4 intensity in more than 10% of patients. CONCLUSION: Capecitabine is an active drug in the treatment of paclitaxel-refractory metastatic breast cancer. It has a favorable toxicity profile with the added advantage of being an oral drug administered at home.
CAPECITABINE (XELODA; Hoffman-LaRoche, Nutley, NJ), a fluoropyrimidine carbamate, was designed as an orally active drug that would deliver fluorouracil (5-FU) selectively to the tumor. After gastrointestinal absorption, capecitabine is hydrolyzed in the liver by carboxylesterase to produce 5'-deoxy-5-fluorocytidine, and this moiety is then deaminated on its pyrimidine ring to produce 5'-deoxy-5-fluorouridine by cytidine deaminase, an enzyme located principally in hepatic and neoplastic tissue. The last enzymatic step, selective tumor activation of 5'-deoxy-5-fluorouridine to 5-FU, is catalyzed by thymidine phosphorylase, thus minimizing systemic exposure to 5-FU.1 Thymidine phosphorylase occurs at higher levels in most solid tumors than in the corresponding normal tissue2,3 and is a tumor-associated angiogenic factor (also known as platelet-derived endothelial cell growth factor3). Capecitabine has demonstrated a high level of activity in preclinical xenograft models of breast, colorectal, gastric, and cervical cancer.2,4 Activity in 5-FU–refractory tumor models has also been documented.5 Human pharmacokinetic studies have shown that the drug is well absorbed and rapidly converted to noncytotoxic intermediates6 and that intratumoral concentrations of 5-FU are significantly higher than plasma and normal tissue levels.7 This tumor-selective generation of 5-FU with low systemic exposure is hypothesized to provide an improved therapeutic ratio for capecitabine. Effective treatment is needed for patients with metastatic breast cancer, especially those found to be paclitaxel- and anthracycline-refractory. Patients who maintain a good performance status are candidates for further cytotoxic therapy. In its phase I studies, capecitabine produced several objective tumor responses in heavily pretreated breast cancer patients while causing minimal bone marrow suppression.8,9 The objective of this phase II study was to determine the efficacy and safety profile of an intermittent regimen of capecitabine, administered orally to patients with breast cancer who had progressed despite prior paclitaxel therapy. Additional goals of the study were to determine the duration of response, time to treatment failure, and overall survival of the patient population. Finally, the effect of capecitabine on pain intensity, analgesic consumption, and performance status was combined into an integrated clinical response assessment. This study was a large, multicenter, single-arm trial conducted at 25 hospitals and cancer centers in the United States and Canada.
This open-label phase II trial was designed to evaluate the efficacy and safety of intermittent, twice-daily oral capecitabine at 2,510 mg/m2/d given for 2 treatment weeks, followed by a 1-week rest period and repeated in 3-week cycles. Patients were accrued onto the study from February 6, 1996, through December 20, 1996. After informed consent was obtained, patients with either measurable or assessable metastatic breast cancer were first entered onto a 1-week run-in period, during which time patients were assessed for adequate pain control. Patients with no pain or stable pain intensity (ie, patients with pain intensity that did not vary by more than 30 mm from baseline on the Memorial Pain Assessment visual analog scale) were then entered onto the study. Patients were prospectively stratified according to the presence of bidimensionally measurable versus assessable disease. Duration of treatment was based on tumor response. The first response assessment was to be made at study day 43. Patients with objective responses or stable disease could continue to receive treatment with capecitabine in courses of 3 weeks, up to a total of 18 weeks (referred to as the treatment period). Tumor assessments were repeated at 6-week intervals and at the time of withdrawal from study. Patients who maintained a tumor response or stable disease beyond 18 weeks were allowed an additional 30 weeks (referred to as the maintenance period), with tumor response assessments obtained at 12-week intervals. Patients who had not progressed at 48 weeks could continue capecitabine treatment until disease progression (referred to as the continuation period).
Inclusion Criteria
Exclusion Criteria Patients were to have hematologic values as follows: absolute neutrophil count of 1.5 x 109/L or higher, platelet count of 75 x 109/L or higher, and hemoglobin of 9 g/dL or higher. The use of blood transfusions or growth factors to aid hematologic recovery was not allowed within the 2 weeks before treatment start. Patients' creatinine levels had to be less than 1.5 times the upper normal limit, and their calcium levels had to be less than or equal to 11.5 mg/dL. Their total bilirubin levels had to be less than 1.5 times the upper limit of normal, and their transaminase or alkaline phosphatase levels had to be less than 2.5 times the upper normal limit or less than or equal to five times the upper limit of normal in patients with liver or bone metastases. In the presence of both liver and bone involvement, patients were allowed to have alkaline phosphatase levels of up to 10 times the upper limit of normal.
Dosage
Dose Modifications
Study Assessments On study weeks 1, 4, 7, 10, 13, 16, and 19 (treatment period), vital signs, CBCs, and chemistries were obtained and physical examinations were performed. Tumor assessments were done at weeks 7, 13, and 19. During the maintenance period, patients were evaluated by physical examination and a check of their vital signs, CBCs, and chemistries every 6 weeks. Tumor assessments were made every 12 weeks and at the time of withdrawal from study. During the continuation period, vital signs and laboratory studies were obtained and physical examinations and tumor assessments were performed at the investigator's discretion.
Evaluation of Response
Clinical Benefit Response
Statistical Analysis All eligible patients who received at least one dose of test drug were to be included in the intent-to-treat analysis of efficacy and in the safety population. All analyses of efficacy information were based primarily on the intent-to-treat population. All analyses of safety information were based on the safety population. Adverse events were graded according to the NCIC common toxicity criteria, version 1, with the exception of hand-foot syndrome, which was graded using protocol-specific definitions (Table 1).
Secondary end points were Kaplan-Meier analyses for time to disease progression, survival, and duration of response according to the World Health Organization criteria. The time to disease progression was determined at the earliest time at which progression was shown for all patients and for those with measurable disease only. For probability of survival, all patients were evaluated and a Kaplan-Meier analysis was performed. For the duration of overall response, all measurable patients were included.
Patients Demographics Between February and December 1996, 163 patients were registered on the trial, and 162 patients received treatment with capecitabine. One patient was withdrawn as ineligible because of rapidly progressive disease during the screening period, before receiving capecitabine. Of the treated patients, 135 patients had measurable disease and 27 had non–bidimensionally measurable but assessable disease. All had received prior paclitaxel, 91% had received an anthracycline, and 82% had received a 5-FU–containing regimen. The majority of patients had widely disseminated metastatic breast cancer with a median of three organ/tissue sites (range, one to 11 sites) involved with metastatic disease. Overall, there was baseline documentation of bone metastases in 54% of patients, liver metastases in 43%, lung/pleural metastases in 58%, and soft tissue disease in 23%. One hundred ten patients (68%) had visceral predominant disease, 35 patients (22%) had predominantly soft tissue disease, and 17 patients (10%) had predominantly bony disease. Table 2 summarizes the patient demographics.
Response to Treatment The mean duration of response in the 27 responding patients with measurable disease was 241 days, as shown in Fig 1. In 11 responding patients, disease had not progressed at the time of the clinical cutoff. The range of duration of response in these patients was 97 to 324 days (ongoing). Of the three patients with a complete response, disease progressed 106 and 109 days after onset of the complete response for two patients and the third patient still had a complete response at the time of clinical cutoff (minimum duration of 194 days from first documented occurrence of complete response to cutoff). For the majority of the 27 confirmed responders, the onset of response occurred by the first or second tumor assessment, after 6 or 12 weeks of treatment. However, late responses were also observed, with onsets as late as study day 245.
For the 27 patients with assessable and not measurable disease, five (19%) had a tumor response. The durations of response in the five responders were 161, 182+, 215, 221+, and 235+ days.
Time to Disease Progression and Survival
Relationship Between Tumor Response and Survival
Clinical Benefit Response
Safety
The time course of five frequently reported grade 3 or 4 treatment-related adverse events (hand-foot syndrome, diarrhea, nausea, vomiting, and stomatitis) was also examined. There was no evidence of cumulative toxicity for any of the five selected adverse events. The majority of drug-related cases of grade 3 or 4 nausea, vomiting, and stomatitis had an early onset, usually occurring during the first month of treatment. Grade 3 or 4 diarrhea and hand-foot syndrome showed a slower, steadier increase in incidence of first onset over the duration of the treatment period.
Six patients developed treatment-related grade 4 adverse events: five patients had grade 4 diarrhea (one patient also developed grade 4 dehydration). One other patient experienced an asymptomatic grade 4 coagulation disorder (elevated prothrombin time while receiving warfarin) that was assessed by the investigator as possibly related to treatment. No other treatment-related grade 4 adverse events were reported in this study. No deaths were reported as being related to the study treatment. Of the 54 patients reported to have had serious adverse events, only 18 had serious adverse events that were considered related to study treatment. The two most common adverse events leading to withdrawal from the study were abdominal pain (three patients [2%]) and diarrhea (three patients [2%]). Laboratory parameters were monitored in all 162 patients enrolled. During the study, most laboratory values remained stable or worsened at most by one or two grades (Table 5). Grade 3 or 4 neutropenia occurred in five patients (3%). One patient with bone marrow metastases developed grade 4 thrombocytopenia. The most frequently reported adverse change in laboratory parameters during the study was in total bilirubin. There were 17 grade 3 or 4 bilirubin elevations, of which nine occurred concomitantly with progressive metastatic disease involving the liver. The other eight were isolated, unsustained elevations of total bilirubin to NCIC grade 3 (> 1.5 to 3.0 times the upper limit of normal for total bilirubin). No patients were withdrawn because of laboratory abnormalities.
Breast cancer is the most common form of malignancy afflicting women in the United States and Europe, and it is the second most common cause of cancer death in this population. Despite improvements in screening, locoregional control, and adjuvant therapy, recurrent metastatic breast cancer remains distressingly common. Systemic chemotherapy is widely used in this setting, particularly in patients with hormone-refractory or visceral metastases. The most active agents seem to be the anthracyclines and the taxanes, response rates for which range from 20% to 40% when used as monotherapy to 70% to 80% for combination regimens.10 Despite these high levels of activity, patients with metastatic disease are essentially incurable, and disease progression is inevitable, either during or after such chemotherapy. At that advanced stage of disease, the ideal cytotoxic drug would be one that offered a reasonable prospect of response, was administered without the need for hospitalization or cumbersome technology, and lacked a substantial risk of life-threatening toxicity. The success of alternative chemotherapies as third or fourth therapies in patients with metastatic breast cancer who have failed paclitaxel has been modest. Three small trials that specifically target this patient population have been reported. Valero et al11 reported the use of standard-dose docetaxel (100 mg/m2 every 3 weeks) in 36 patients. A small number of partial responses were seen, but myelosuppression was prohibitive. Other toxicities included febrile neutropenia (22%), severe fluid retention (7%), and severe asthenia (26%). Fazeny et al12 reported on 14 patients treated with standard-dose vinorelbine. No objective responses were seen, but four patients developed dose-limiting peripheral neuropathy. Lastly, Livingston et al13 reported on the use of dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support. This single-institution study incorporated primary continuous granulocyte colony-stimulating factor support. In the 40 patients treated, a response rate of 25%, a median time to progression of 13 weeks, and a median survival time of 33 weeks were observed. Myelosuppression and neuropathy were common, and the authors concluded that this regimen was not to be routinely recommended in this setting because of toxicity and cost. The present study has shown that capecitabine is an active drug in heavily pretreated patients with metastatic breast cancer, with a 20% response rate in the 135 patients with measurable disease. Three patients achieved a complete response. A similar magnitude of response was observed among the patients with nonmeasurable (assessable) disease. Both paclitaxel-resistant and paclitaxel-failure patients responded to capecitabine. All responding patients had also received prior anthracycline treatment. Given the advanced disease status of the patients in this study, the median survival time (384 days) was surprisingly long. However, survival results in single-arm studies can be influenced by patient selection. The large number of metastases at baseline, the visceral dominance of metastases, and the rapid recruitment of 162 patients from 25 centers make patient selection bias unlikely. Large survival studies of paclitaxel-refractory breast cancer patients are not available. Before the introduction of the taxanes, the median survival duration after second- or third-line chemotherapy in patients who had received anthracyclines was less than 6 months.14 The median survival times obtained with paclitaxel and docetaxel in anthracycline-resistant (predominantly second-line) breast cancer treatment are 9.5 months15 and 10 months,16 respectively. Therefore, the median survival time observed in the current study is noteworthy in a much more heavily pretreated study population. Howell et al17 have emphasized the prognostic significance of the "no change" or stable disease category in patients with metastatic breast cancer treated with endocrine therapy and chemotherapy. To determine the prognostic significance of stable disease as a best response in the current study, the survival time was determined for patients whose best response was complete/partial response, stable disease, or progressive disease. Patients whose best response was stable disease had a median survival time similar to that of responders, whereas patients whose disease progressed early on had a much shorter survival time. These results must not be interpreted as evidence of a drug effect, as it is well recognized that responders may survive longer than nonresponders because response may identify patients with unknown pretreatment characteristics that favor longer survival.18,19 End points related to symptom control have only recently been incorporated into oncology clinical trials. Results obtained in nonrandomized phase II trials are difficult to interpret but may still provide useful information.20 The instrument used in the present study was modified from that used to evaluate gemcitabine in patients with advanced pancreatic cancer.21 Studies on the components of this instrument have shown that the visual analog scale of pain intensity from the Memorial Pain Assessment Card is a valid measure for cancer pain22 and that the KPS score23 accurately reflects the physical functioning of the patient. A positive clinical benefit response was seen in 20% of all treated patients in this study and in 30% of patients with an objective response to treatment. This may be a conservative estimate of clinical benefit in that positive responders were required to have major improvements in pain intensity, analgesic consumption, and KPS, whereas negative changes of any magnitude defined a negative response. Notably, 47% of patients with significant pain at baseline (> 20 mm) had a significant decrease (> 50%) in pain intensity accompanied by stable or decreased analgesic consumption. Improvements in patients with positive pain responses were maintained for longer than 18 weeks (data not shown). In the absence of a randomized trial, it is not possible to be certain that these improvements are solely related to the study treatment. Patients receiving a new agent may often experience feelings of optimism and well being. However, in the present study, the heavily pretreated population and the natural history of metastatic breast cancer make such nonspecific effects unlikely. Moreover, any placebo effects on chronic pain are typically not prolonged and diminish rapidly over time.24 The sustained improvements seen in this study are therefore more consistent with a true effect of treatment on tumor-associated symptoms. The adverse events associated with the dosing schedule of capecitabine used in this study were predictable and controllable. The clinically important toxicities were those expected with a fluoropyrimidine. Diarrhea and hand-foot syndrome were the only treatment-related adverse events that occurred with a grade 3 or 4 intensity in more than 10% of patients. Diarrhea was the most frequent serious adverse event related to capecitabine in this study and was the major cause of treatment-related hospitalizations (12% of patients). Hand-foot syndrome occurred in 56% of patients treated with capecitabine and was graded as severe (grade 3) in 10% of patients. Patients with all grades of hand-foot syndrome were treated with topical emollients and with drug interruption if the intensity reached grade 2 or 3. Brief drug interruption or dose adjustment led to reinstitution of treatment in almost all patients. Other grade 3 treatment-related toxicities included fatigue (7%), mucosal inflammation (4%), nausea (4%), vomiting (4%), dehydration (3%), and stomatitis (3%). Myelosuppression was uncommon, and significant alopecia was not reported. Transient elevations of total bilirubin, similar to those described for other fluoropyrimidines,25 were the most common laboratory abnormalities associated with capecitabine treatment. No treatment-related deaths and few treatment-related serious adverse events (12%) were observed. Only six patients (3.7%) had a grade 4 treatment-related adverse event. In conclusion, capecitabine seems to be an exciting new option for the treatment of patients with metastatic breast cancer after failure of paclitaxel and an anthracycline-containing regimen. The drug is unique among currently available agents because it is selectively tumor-activated to generate 5-FU. Treatment with this dosing schedule of capecitabine produced 20% complete and partial tumor responses with excellent durability. In addition, a positive effect of treatment on tumor-related pain was documented. Toxicity is predominantly gastrointestinal and dermatologic and rarely life-threatening. Treatment was discontinued in only 7% of patients because of treatment-related adverse events. Capecitabine is minimally myelosuppressive and does not cause significant hair loss. Finally, in view of the striking preference for oral drugs among patients who are receiving chemotherapy in a palliative setting,26 capecitabine represents a significant advance by allowing home-based therapy.
Supported by Hoffman-LaRoche (study no. SO 14697).
1. Miwa M, Ura M, Nishida M, et al: Design of a novel fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumor by enzymes concentrated in human liver and cancer tissue. Eur J Cancer (in press)
2.
Ishikawa T, Sekiguchi F, Fukase Y, et al: Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res 58:685-690, 1998 3. Jones A, Harris AL: New developments in angiogenesis: A major mechanism for tumor growth and target for therapy. Cancer J 4:209-217, 1998 4. Ishikawa T, Utoh M, Sawada N, et al: Capecitabine, a new oral fluoropyrimidine carbamate, selectively delivers fluorouracil to tumor tissues in human cancer xenografts. Biochem Pharmacol 55:1091-1097, 1998[Medline] 5. Cao S, Lu K, Ishisuka H, et al: Antitumor efficacy of capecitabine against fluorouracil-sensitive and -resistant tumors. Proc Am Soc Clin Oncol 16:226a, 1997 (abstr) 6. Twelves C, Budman DR, Creaven PJ, et al: Pharmacokinetics and pharmacodynamics of capecitabine in two phase I studies. Proc Am Soc Clin Oncol 15:479, 1996 (abstr) 7. Schuller J, Cassady J, Reigner BG, et al: Tumor selectivity of Xeloda in colorectal cancer patients. Proc Am Soc Clin Oncol 16:227a, 1997 (abstr)
8.
MacKean MJ, Planting AS, Twelves C, et al: Phase I and pharmacologic study of intermittent twice daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol 16:2977-2985, 1998 9. Budman DR, Meropol NJ, Reigner B, et al: Preliminary studies of a novel fluoropyrimidine carbamate: Capecitabine. J Clin Oncol 16:1795-1802, 1998[Abstract] 10. Dickson RB, Lippman ME: Cancer of the breast, in Devita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practices of Oncology (ed 5). Philadelphia, PA, Lippincott-Raven, 1997, pp 1541-1557 11. Valero V, Burris HA, III Jones SE, et al: Multicenter pilot study of Taxotere in Taxol-resistant metastatic breast cancer. Proc Am Soc Clin Oncol 15:107, 1996 (abstr) 12. Fazeny B, Zifko U, Meryn S, et al: Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxel: A phase II study. Cancer Chemother Pharmacol 39:150-156, 1996[Medline] 13. Livingston RB, Ellis GK, Gralow JR, et al: Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 15:1395-1400, 1997[Abstract] 14. Henderson IC: Principles in the management of metastatic disease: Chemotherapy for metastatic disease, Harris JR Hellman S Henderson ICet al (eds):Breast Diseases604-665, 1991
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Abrams JS, Vena DA, Baltz J, et al: Paclitaxel activity in heavily pretreated breast cancer: A National Cancer Institute Treatment Referral Center trial. J Clin Oncol 13:2056-2065, 1995 16. Valero V, Holmes FA, Walters RS, et al: Phase II trial of docetaxel: A new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 13:2886-2894, 1995[Abstract] 17. Howell A, Mackintosh J, Jones M, et al: The definition of the "no change" category in patients treated with endocrine therapy and chemotherapy for advanced carcinoma of the breast. Eur J Cancer Clin Oncol 24:1567-1572, 1988[Medline] 18. Anderson JR, Cain KC, Gelber RD, et al: Analysis and interpretation of the comparison of survival by treatment outcome variables in cancer clinical trials. Cancer Treatment Rep 69:1139-1144, 1985[Medline] 19. Anderson JR, Cain KS, Gelber RD: Analysis of survival by tumor response. J Clin Oncol 1:710-719, 1983[Abstract]
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Seidman AD, Portenoy R, Yao TJ, et al: Quality of life in phase II trials: A study of methodology and predictive value in patients with advanced breast cancer treated with paclitaxel plus granulocyte colony-stimulating factor. J Natl Cancer Inst 87:1316-1322, 1995
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Burris HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreatic cancer: A randomized trial. J Clin Oncol 15:2403-2413, 1997 22. Fishman B, Pasdernak S, Wallenstein SC, et al: The Memorial Pain Assessment Card: A valid instrument for the evaluation of cancer pain. Cancer 60:1151-1158, 1987[Medline] 23. Schag CC, Heinrich RL, Ganz PA: Karnofsky performance status revisited: Reliability, validity, and guidelines. J Clin Oncol 2:187-193, 1984[Abstract] 24. Turner JA, Deyo RA, Loesor JD, et al: The importance of placebo effects in pain treatment and research. JAMA 271:1609-1614, 1994[Abstract] 25. Meropol NJ, Rustum YM, Petrelli NJ, et al: A phase I and pharmacokinetic study of oral uracil, ftorafur and leucovorin in patients with advanced cancer. Cancer Chemother Pharmacol 37:581-586, 1996[Medline]
26.
Liu G, Franssen E, Fitch MI, et al: Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 15:110-115, 1997 Submitted September 1, 1998; accepted October 14, 1998. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
