Annals of Oncology Advance Access originally published online on February 23, 2006
Annals of Oncology 2006 17(4):652-656; doi:10.1093/annonc/mdl005
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© 2006 European Society for Medical Oncology
Docetaxel and capecitabine in patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction: a phase II study from the North Central Cancer Treatment Group
1 Mayo Clinic and Mayo Foundation, Rochester, MN; 2 Michigan Cancer Consortium, Ann Arbor, MI; 3 Sioux Valley Clinic Oncology, Sioux Falls, SD; 4 Wichita Community Clinical Oncology Program, Wichita, KS; 5 Missouri Valley Cancer Consortium, Omaha, NE; 6 Metro-Minnesota Community Oncology Program, St. Louis Park, MN; 7 Duluth CCOP, Duluth, MN, USA
* Correspondence to: Dr A. Jatoi, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1-507-538-0548; Fax: +1-507-284-1803; E-mail: Jatoi.aminah{at}mayo.edu
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Abstract |
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Background: Previous studies suggest that the combination of docetaxel and capecitabine are worthy of further testing in patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. We therefore undertook this phase II study to test this combination in a multi-institutional, first-line clinical trial.
Patients and methods: Forty-four eligible patients with histologic or cytologic confirmation of the above malignancy were recruited. The cohort had Eastern Cooperative Oncology Group performance scores of 0, 1 and 2 in 59%, 39% and 2% of patients, respectively. Median age was 57 years (range 32–77 years). Adequate organ function was a requirement for study entry. All patients were prescribed docetaxel 75 mg/m2 intravenously on day 1 and capecitabine 825 mg/m2 orally twice a day on days 1–14 of a 21-day cycle.
Results: The tumor response rate was 39% [95% confidence interval (CI) 23% to 55%]. There were two complete responses and the rest were partial. Median survival was 9.4 months (95% CI 6.3–10.7 months) and median time-to-tumor progression was 4.2 months (95% CI 3.6–5.6 months). There was one treatment-related death from a myocardial infarction and dysrhythmia. Commonly occurring grade 3 adverse events included neutropenia (11 patients), infection (five patients), constipation (three patients), thrombosis (three patients), dyspnea (three patients) and hand–foot syndrome (three patients). In addition, 24/45 patients developed grade 4 neutropenia.
Conclusions: The regimen docetaxel and capecitabine shows activity in patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. This regimen merits further study.
Key words: capecitabine, chemotherapy, docetaxel, gastric cancer, gastroesophageal junction, stomach
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Metastatic gastric or gastroesophageal junction adenocarcinoma remains lethal. Although survival rates vary from report to report, Ries and others found that only 3.1% of such patients remain alive at 5 years [1
]. At the same time, previous randomized trials that tested chemotherapy against best supportive care suggest that a very modest survival advantage can be gained from the former [2–4]. These poor survival rates coupled with a need to identify more effective chemotherapy regimens for treating patients with this cancer served as the impetus for the present study, which tested the combination of capecitabine and docetaxel in the first-line setting.
The rationale for testing this particular regimen is compelling. First, as single agents, both capecitabine and docetaxel have demonstrated antineoplastic activity in patients with this malignancy [5–7]. Secondly, these two drugs appear to be synergistic, an observation that evokes the possibility that their antineoplastic effects may be more than additive in the clinical setting. Kodera and others recently confirmed this synergy in a tumor-bearing animal model, raising the prospect that some of this synergy might be explained by docetaxel-mediated up-regulation of thymidine phosphorylase [8]. Thirdly, previous clinical trials with this drug combination provide promising results. Published tumor response rates as high as 40%, 44%, 46% and 60% have been reported in single institution studies and invite further study of this regimen in a multi-institutional cooperative group setting [9–12]. Fourthly, docetaxel is emerging as one of the few drugs to yield a survival advantage when added to a commonly used regimen. Recent phase III data point out that the addition of docetaxel to cisplatin and 5-fluorouracil provides a major determinant of improved survival when tested against this two-drug regimen alone [13]. Thus, a strong rationale, hinging on the promise of improved tumor response rates and improved patient survival rates, led to the development and conduct of the present study.
The North Central Cancer Treatment Group (NCCTG) therefore undertook a phase II study to test capecitabine and docetaxel as first-line therapy in patients with adenocarcinoma of the stomach and gastroesophageal junction. End points included tumor response rate, patient survival, time-to-tumor progression and rates and severity of adverse events.
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patients and methods |
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overview
The NCCTG conducted this phase II trial and the Institutional Review Boards at each specific study site within this national cancer cooperative group approved the study protocol before patient enrollment. All patients provided signed informed consent prior to trial participation.
eligibility
Eligibility criteria consisted of the following: (1) histologic or cytologic confirmation of adenocarcinoma stomach or gastroesophageal junction deemed unresectable; (2) Eastern Cooperative Oncology Group performance status of 2 or better; (3) age 18 years or older; (4) measurable disease, as defined by the RECIST criteria; (5) physician-estimated life expectancy of 12 weeks or longer; (6) able to swallow capecitabine; (7) able to complete a questionnaires alone or with assistance; and (8) willingness to have blood drawn for research purposes.
In addition, all patients had to have the following laboratory parameters 14 days prior to registration: (1) absolute neutrophil counts 
1.5 x 103 cells/ml; (2) platelet count 100 x 103 cells/ml; (3) serum creatinine within the normal range at that institution; (4) calculated creatinine clearance 60 ml/min; (5) total bilirubin within the normal range at that institution; (6) aspartate aminotransferase 
2.5 times the upper limit of normal if the alkaline phosphatase is within the normal range or alkaline phosphatase 4 times the upper limit of normal if the aspartate aminotransferase value is within the normal range.
Finally, patients were not eligible if they had any one of the following: (1) prior treatment for metastatic cancer, although prior adjuvant or neoadjuvant treatment was permissible; (2) prior radiation to 25% or more of the marrow cavity or any radiation within 4 weeks prior to registration; (3) abdominal exploration with resection within 4 weeks or abdominal exploration without resection within 3 weeks; (4) availability of potentially curative treatment; (5) uncontrolled infection or chronic debilitating illness; (6) peripheral neuropathy of grade 2 or worse; (7) New York Heart Association class 3 or 4 heart disease; (8) established diagnosis of diabetes mellitus; (9) anaphylactic reaction to any prior taxane; (10) taking brivudine or soruvidine; (11) pregnant, nursing or of child-bearing potential and unwilling to employ adequate contraception; (12) untreated central nervous metastases, treated but symptomatic central nervous system metastases, or uncontrolled seizure disorder; (13) prior malignancy, except for adequately treated basal cell/squamous cell carcinomas or other cancer for which the patient has been disease free for 5 years or longer; (14) prior unanticipated severe reaction to fluoropyrimidine therapy or known sensitivity to 5-fluorouracil; (15) organ allograft recipient; (16) prior poor tolerance to capecitabine; (17) known dihydropyrimidine dehydrogenase deficiency.
treatment
Patients were treated with docetaxel 75 mg/m2 intravenously on day 1 and capecitabine 825 mg/m2/dose orally twice a day on days 1–14, both of which were given as part of a 21-day cycle. Prior to starting docetaxel, the protocol dictated that patients be prescribed dexamethasone 4 mg orally twice a day for three doses with the first dose given 12 h before chemotherapy.
Dosage modifications were made based in part on interval adverse events. Both docetaxel and capecitabine doses were reduced by 20% for neutropenia (absolute neutrophil count <0.5 x 103 cells/ml), infection with grade 3 or 4 neutropenia, or a platelet count less than 50 x 103 cells/ml in the preceding chemotherapy cycle. Capecitabine alone was reduced by 20% for grade 2 or worse hand–foot syndrome or for grade 2 mucositis that occurred in the preceding cycle. If grade 3 or 4 mucositis occurred, the dose was to be reduced by 30%. For grade 2 or 3 diarrhea, capecitabine was to be reduced by 20%, and for grade 4 diarrhea, capecitabine was to be reduced by 20% and docetaxel by 25%. For febrile neutropenia, both agents were to be reduced by 20% thereafter. Most other non-hematologic adverse events called for a 15%–25% dose reduction of both agents, depending on the nature and severity of that event. A calculated creatinine clearance of less than 50 ml/min at the time of retreatment prompted a delay in capecitabine treatment until resolution. Parameters, such as depressed blood counts, persistent diarrhea or hyperbilirubinemia called for holding chemotherapy until complete or partial recovery. Holding treatment for more than 3 weeks precluded continued treatment on the protocol. The protocol also provided instructions for holding capecitabine mid-cycle in the event of severe adverse events, but decisions as to when and how to resume capecitabine before the beginning of the next cycle were left in part to the discretion of the treating oncologist.
pretreatment and follow-up evaluations
A history and physical examination were to be performed on all patients within 14 days of trial registration. Laboratory testing including a hemogram, serum alkaline phosphatase, aspartate aminotransferase, total bilirubin and creatinine were to be obtained within this same time frame. A chest radiograph was required within 14 days of registration if used for tracking the indicator lesion; otherwise, this test could be performed within 28 days of registration. All patients were to complete a quality of life questionnaire within 14 days prior to registration, with each even-numbered chemotherapy cycle, and at the end of treatment. Results are to be reported in a separate translational manuscript. Finally, a blood draw for a translational component was to be obtained within 14 days of registration, and a report on this aspect of the study is to be published elsewhere.
All patients were monitored throughout the study with weekly hemograms. Monitoring of other blood tests in between chemotherapy treatments were left to the discretion of the treating oncologist. A history and physical examination in addition to laboratory testing (hemogram, serum alkaline phosphatase, aspartate aminotransferase, total bilirubin and creatinine) were performed before each 21-day chemotherapy cycle. The National Cancer Institute's Common Toxicity Criteria (CTC), version 2.0, were used to assess adverse events.
In order to assess response to therapy, tumor evaluations were performed immediately before every scheduled odd chemotherapy cycle. The RECIST criteria were used for this purpose (http://www.nci.nih.gov/bip/RECIST.htm), and as per these criteria, a 30% decrease in the sum of the largest dimension of target lesions from baseline was indicative of a possible response to treatment. Confirmatory scans at least 4 weeks apart were required before a patient was determined to have had an actual response to treatment. Chemotherapy was continued after each tumor evaluation if there appeared to be disease stability or a complete or partial response to treatment. Chemotherapy according to this protocol was discontinued for patients with evidence of tumor progression.
statistical analyses
The primary objective of this phase II study was to report the proportion of patients with a tumor response to this two-drug combination. All patients who met the eligibility criteria, signed a consent form and began treatment were included in the primary analysis.
A two-stage phase II Fleming design [14] was used to test whether there was sufficient evidence to determine if the confirmed response rate was at least 40%, a rate the study team viewed as clinically promising, versus at most 20%, a rate the study team viewed as not clinically promising. With 40 patients, this trial carried 87% power to detect a tumor response rate of 40% with a 0.05 level of significance.
An interim analysis was to be performed after the first 15 evaluable patients were enrolled. If two or fewer responses had been observed in this initial cohort, further accrual to the trial would have been abandoned. If seven or more tumor responses had been observed, the regimen would have been viewed as promising to the extent that further trial accrual was potentially unnecessary. Because neither of these a priori rules were met, the study proceeded to complete accrual.
A confidence interval for the percentage of patients with a tumor response was calculated with the method of Duffy and Santner [15].
Secondary end points include descriptive summaries of adverse events, time to tumor progression and overall survival. Adverse events are presented in part in tabular form. Time-to-tumor progression was defined as the time from study registration to tumor growth (defined as a 20% or greater increase in size of summed largest dimensions of the target lesions). Patients who died without tumor assessment were viewed as having tumor progression at death unless there was sufficient documentation to prove otherwise. Overall survival was defined as the time from study registration to death from any cause. Time-to-event distributions were estimated with the Kaplan Meier method [16].
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demographics
Forty-four eligible patients were enrolled from December 2003 to April 2005. One patient never received any study medication and one patient was later found not to meet the original eligibility criteria. These two patients were excluded from the analyses and descriptions of the study data, but the one ineligible patient who did receive chemotherapy as per the study protocol was included in the adverse event report.
Patient characteristics are listed in Table 1. This cohort had a median age of 57 years at study entry with a range of 32–77 years. Eleven percent were women. Eastern Cooperative Oncology Group performance scores of 0, 1 and 2 were observed in 59%, 39% and 2%, respectively.
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drug administration
Patients completed a median of six cycles of chemotherapy (range 1–14 cycles). Nine patients are still receiving chemotherapy at the time of this report. Most patients stopped chemotherapy because of cancer progression (n = 27) and all others stopped because of other reasons, such as patient desire to stop, severe adverse events or a desire to try a different therapy (n = 9).
Although dose reductions were necessary at times, patients received most of the anticipated dose (median 80%–100%) of docetaxel for each of the first six cycles of chemotherapy. Similarly, patients received most of the anticipated capecitabine dose (median 73%–95%) over this period as well. This slight reduction in prescribed dose presumably reflects a need to cut back on dosing because of infusion reactions or because of mid-cycle adverse events.
response data
Of the 44 patients evaluable for tumor response, there were 17 such responses, yielding a response rate of 39% (95% CI 23% to 55%). Two of these were complete responses and have been maintained so far for 2.9 and 6.7 months. The median duration of any response was 4.5 months.
Patients were to be followed until death. At the time of this report, there have been 18 deaths with a median follow-up of 6.1 months (range 1.4–12.3 months) in the living patients. Median survival and time-to-progression are 9.4 months (95% CI 6.3–10.7 months) and 4.4 months (95% CI 3.6–5.6 months), respectively. (See Figures 1 and 2 for Kaplan–Meier overall survival and time-to-tumor progression curves.)
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adverse events
Adverse event data include all 45 patients who received chemotherapy as per the study protocol, including the one ineligible patient. Only grade 2 or worse events are reported and all adverse events are included together regardless of whether they are directly attributable to chemotherapy.
There was one grade 5 event. This patient developed a myocardial infarction and died from a dysrhythmia. Frequent grade 4 adverse events, defined as having occurred in at least three patients, included only neutropenia, which occurred in 24 patients. Frequent grade 3 adverse events, defined as having occurred greater than two times within the cohort, included neutropenia (11 patients), infection (five patients), constipation (three patients), thrombosis (three patients), abdominal pain (three patients), dyspnea (three patients), and skin reaction in the form of hand–foot syndrome (three patients). See Tables 2 and 3 for listings of all grade 2+ adverse events and their frequencies.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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This multi-institutional phase II study from the NCCTG tested the regimen docetaxel and capecitabine as first-line therapy in patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction. The overall tumor response rate was 39% (95% CI 23% to 55%). For the most part, the regimen yielded an acceptable adverse event profile, although there was one death. Overall, however, these results suggest that further study of this regimen in this setting is warranted.
What accounts for the lower response rates observed in this trial compared with some of the previous studies that evaluated this drug combination in a phase II setting and reported response rates as high as 60%? First, one major difference rests in the study design. This report describes a multi-institutional study, whereas many other previous studies were single institution endeavors. In general, the former tend to reveal slightly lower response rates that appear to be more in line with what might be observed in a general practice setting. Thus, the multi-institutional design of this trial is a major strength and adds to the precision and accuracy of the reported response rate. Secondly, the dose of capecitabine in the present study was less than that tested in previous ones. Many previous studies included a capecitabine dose of 1000 mg/m2/dose given twice a day for 2 weeks. In view of the present study's adverse event profile that included one death, it appears that utilizing the lower dose of capecitabine 825 mg/m2/dose twice a day is prudent. In general, the response data presented in this manuscript as well as the adverse event data have put in place the groundwork for moving this regimen forward into phase III testing.
In addition to the response data, the survival data from this trial also suggest that further study of this regimen is warranted. The median survival of 9.4 months (95% CI 6.3–10.7 months), as reported in the present study, is very much in keeping with the median survival rates observed in other regimens that are frequently utilized in clinical practice [17]. These survival data coupled with the response rate reported here suggest that further study of this regimen should be undertaken. Potentially, future clinical trials may consider testing a combination of docetaxel and capecitabine in conjunction with one of the newer biological agents against one of the more commonly used regimens for metastatic gastric cancer.
Finally, one other point that deserves discussion is the use of oral chemotherapy in this patient population. At first glance, one might question the use of oral chemotherapy in patients who are suffering from dysphagia. Although the ability to swallow pills was included in the eligibility criteria, it is important to point out that this study appeared to accrue patients swiftly, a finding that suggests a sizable group of patients with this cancer are able to comply with oral chemotherapy. This favorable tumor response rate of 39% is further evidence that oral chemotherapy appears to be a viable option for select patients with metastatic cancer of the stomach and gastroesophageal junction.
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Acknowledgements |
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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-63826, CA-35103, CA-35431, CA-63849, CA-35267, CA-35269, CA-35195, CA-52352, CA-60276, CA-63844, CA-35101, CA-35448, CA-35113, and CA-35103.
Participating institutions included: Carle Cancer Center CCOP, Urbana, IL 61801 (K. M. Rowland); Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA 52403 (M. Wiesenfeld); Abbott Northwestern Hospital, Minneapolis, MN 55407 (D. J. Schneider); Scottsdale CCOP, Scottsdale, AZ 85259 (T. R. Fitch); Hawaii Minority-Based CCOP, Honolulu, HI 96813 (W. J. Loui); Medcenter One Health Systems, Bismarck, ND 58506 (E. J. Wos); Iowa Oncology Research Association CCOP, Des Moines, IA 50309 (R. F. Morton); Geisinger Clinic and Medical Center CCOP, Danville, PA 17822 (A. Bernath); Illinois Oncology Research Association, Peoria, IL 61615 (J. W. Kugler); Rapid City Regional Oncology Group, Rapid City, SD (L. P. Ebbert); Siouxland Hematology-Oncology Associates, Sioux City, IA 51105 (D. B. Wender).
Received for publication September 29, 2005. Revision received December 22, 2005. Accepted for publication December 27, 2005.
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References |
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1. Ries LA, Eisner MP, Kosary CL et al. SEER Cancer Statistics Review, 1975–2001. Bethesda, Maryland: National Cancer Institute 2004.
2. Pyrhonen S, Kuitenen T, Nyandoto P et al. Randomized comparison of fluorouracil, epidoxorubicin and methotrexate plus supportive care versus supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 1995; 71: 587–591.[Web of Science][Medline]
3. Murad AM, Snatiago FF, Petroianu A et al. Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 1993; 72: 37–41.[CrossRef][Web of Science][Medline]
4. Glimelius B, Ekstrom K, Hoffman K et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 1997; 8: 163–168.
5. Koizumi W, Taguchi T. A phase II study of capecitabine in patients with advanced/metastatic gastric carcinoma. Proc Soc Clin Oncol 2001; 2320A.
6. Graziano F, Catalano V, Baldelli AM et al. A phase II study of weekly docetaxel as salvage chemotherapy for advanced gastric cancer. Ann Oncol 2000; 11: 1263–1266.
7. Sulkes A, Smyth J, Sessa C et al. Docetaxel in advanced gastric cancer: results of a phase II clinical trial. Br J Cancer 1994; 70: 380–383.[Web of Science][Medline]
8. Kodera Y, Fujiwara M, Yokoyama H et al. Combination of oral fluoropyrimidine and docetaxel: reappraisal of synergistic effect against gastric carcinoma xenografts. In Vivo 2005; 19: 861–866.
9. Chun JH, Kim HK, Lee JS et al. Weekly docetaxel in combination with capecitabine in patients with metastatic gastric cancer. Am J Clin Oncol 2005; 28: 188–194.[CrossRef][Web of Science][Medline]
10. Kim JG, Sohn SK, Kim DH et al. Phase II study of docetaxel and capecitabine in patients with metastatic or recurrent gastric cancer. Oncology 2005; 68: 190–195.[CrossRef][Web of Science][Medline]
11. Lorenzen S, Duyster J, Lersch C et al. Capecitabine plus docetaxel every 3 weeks in first- and second-line metastatic esophageal cancer: final results from a phase II trial. Br J Cancer 2005; 92: 2129–2133.[Medline]
12. Park YH, Ryoo BY, Kim HT. A phase II study of capecitabine and docetaxel combination chemotherapy in patients with advanced gastric cancer. Br J Cancer 2004; 90: 1329–1333.[CrossRef][Web of Science][Medline]
13. Cunningham D, Allum WH, Stenning SP et al. Perioperative chemotherapy in operable gastric and lower oesophageal cancer: final results of a randomized, controlled trial (the MAGIC trial). Proc of the Am Society of Clin Oncol 2005; 4001.
14. Fleming TR. One sample multiple testing procedures for phase II clinical trials. Biometrics 1982; 43: 143–151.
15. Duffy D, Santner T. Confidence intervals for a binomial parameter based on multi-stage tests. Biometrics 1987; 43: 81–93.[CrossRef]
16. Kaplan E, Meier P. Nonparametric estimation for incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[CrossRef][Web of Science]
17. Thuss-Patience PC, Kretzschmar A, Repp M et al. Docetaxel and continuous infusion fluorouracil versus epirubicin, cisplatin, and fluorouracil in advanced gastric adenocarcinoma: a randomized phase II study. J Clin Oncol 2005; 23: 494–501.
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