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© 2001 American Society for Clinical Oncology Efficacy of Docetaxel 60 mg/m2 in Patients With Metastatic Breast Cancer According to the Status of Anthracycline ResistanceFrom the Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. Address reprint requests to Toru Watanabe, MD, Department of Medical Oncology, National Cancer Center Hospital, 1-1 Tsukiji 5 chome, Chuo-ku, Tokyo 104-0045, Japan; email twatanab{at}ncc.go.jp
PURPOSE: To evaluate the efficacy of docetaxel 60 mg/m2 in metastatic breast cancer (MBC) according to the status of anthracycline resistance. PATIENTS AND METHODS: Ninety-nine patients with anthracycline-resistant MBC were treated with docetaxel 60 mg/m2 intravenously for a 90-minute period every 3 to 4 weeks. Anthracycline resistance was defined as primary and secondary resistance. Primary resistance was defined as progression during or within 6 months after completion of adjuvant anthracycline, and no MBC response to a first-line regimen that contained anthracycline. Secondary resistance was defined as progression after a documented clinical response to a first-line anthracycline treatment for MBC. Secondary resistance was further divided into three categories: (1) absolute resistance, or progression during treatment with anthracycline after a period of response; (2) relative resistance, or progression within 6 months after anthracycline administration ended; and (3) sensitive regrowth, or progression more than 6 months after the conclusion of anthracycline administration. RESULTS: The response rate in the 99 patients was 35.4% (95% confidence interval, 30.1% to 44.8%). The response rates according to the status of anthracycline resistance were as follows: primary resistance (n = 46), 19.6%; secondary resistance (n = 53), 49.1% (absolute resistance [n = 16], 56.3%); relative resistance (n = 17), 47.1%; and sensitive regrowth (n = 20), 45.0%. The median time to treatment failure in patients with primary resistance was 2.9 months, compared with 5.2 months in patients with secondary resistance (P = .0022). CONCLUSION: Docetaxel at a dose of 60 mg/m2 seemed to be effective in MBC with secondary resistance to anthracycline. The status of anthracycline resistance is important for the prediction of response to second-line treatment with docetaxel.
DRUG REGIMENS THAT contain anthracycline, such as doxorubicin (DOX) plus cyclophosphamide or cyclophosphamide plus DOX and fluorouracil, are widely used as first-line chemotherapy for metastatic breast cancer (MBC).1,2 Although various regimens are used as second- or third-line chemotherapy, few have been proven beneficial in palliation of symptoms or prolongation of life.2,3 Because the vast majority of MBC patients die from their disease, chemotherapeutic regimens that provide durable tumor response and improvement in the quality of life are needed.4 Docetaxel (Taxotere [Rhone-Poulenc Rorer, Collegeville, PA]; N-debenzoyl-N-tert- butoxycarbonyl-10-deacetyl taxol; RP 56,976), at a dose of 100 mg/m2 administered every 3 weeks, demonstrated reproducible efficacy in MBC patients as second-line chemotherapy; response rates ranged from 29% to 53% in phase II trials conducted in Europe, Canada, and the United States.5-8 In a randomized phase III study that compared docetaxel with mitomycin and vinblastine, docetaxel demonstrated a higher response rate and longer survival.9 Docetaxel is approved for the treatment of patients with MBC in Japan, and the dose has been set at 60 mg/m2 on the basis of phase I and II trials in Japanese patients.10,11 In the phase II trial, 72 patients with MBC were enrolled and the response rate was 44.4%. Among the 72 patients, only 28 had received treatment with anthracycline for MBC before docetaxel, and the response rate to docetaxel among these 28 patients was 32.1%.11 The report of the phase II trial does not provide detailed information regarding response to the previous regimens that contained anthracycline. In this study, we evaluated the response rate, time to treatment failure, and the toxicity of docetaxel 60 mg/m2 administered every 3 or 4 weeks according to the strictly defined status of anthracycline resistance in MBC patients.
Patient Selection Eligibility criteria were as follows: (1) histologically or cytologically documented breast cancer and histologically, cytologically, or clinically proven metastatic or recurrent breast cancer; (2) measurable or assessable disease; (3) anthracycline-resistant disease as defined herein; (4) recovery from all side effects of previous therapies at least 4 weeks after completion of the prior chemotherapy or irradiation for an extra-assessable site of disease; (5) an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2 (patients with PS 3 or 4 as a result of bone metastases were eligible); (6) life expectancy greater than 3 months; (7) adequate organ function (WBC count  3,000/µL and  10,000/µL; platelet count 100,000/µL; hemoglobin level 8.0 g/dL; transaminase level without liver metastasis two times the normal upper limit, or transaminase level with liver metastases three times the normal upper limit; total bilirubin level 1.5 mg/dL; serum creatinine and blood urea nitrogen concentrations the normal upper limit; (8) age greater than 20 years and less than 75 years; and (9) no prior treatment with taxanes.
Exclusion criteria included (1) unfavorable medical conditions, such as uncontrolled infection, diabetes mellitus, or cardiac disease; (2) prior bone marrow transplantation; (3) symptomatic brain metastases; and (4) hypercalcemia (serum calcium level
Definition of Anthracycline Resistance
Administration of Docetaxel and Dose Reduction
Evaluation of Response and Toxicity Tumor response was evaluated according to Japanese Breast Cancer Society criteria.12 Complete response (CR) was defined as the disappearance of all clinical evidence of active tumor with complete reossification of bone lesions and absence of disease-related symptoms for more than 4 weeks. Partial response (PR) was defined as greater than 50% reduction in the sum of the products of the bidimensional diameters of all measurable lesions and marked reossification of osteolytic lesions with no new lesions or less than 25% increase in any lesion for more than 4 weeks. No change was defined as less than 50% reduction or no more than 25% increase in the sum of the products of the bidimensional diameters of all measurable lesions, no marked improvement with no new lesions for at least 4 weeks, and no deterioration of bone lesions with no new bone lesions for at least 8 weeks. Progressive disease was defined as greater than 25% increase in the product of the biperpendicular diameters of any measured lesion or the sum of the products of the biperpendicular diameters of all measured indicator lesions. Toxicities were graded according to the National Cancer Institute common toxicity criteria or as mild, moderate, or severe if the common toxicity criteria were not applicable. Statistical analyses of response according to the status of anthracycline resistance were analyzed using Fisher’s exact probability test, and P values less than .05 were considered indicative of statistical significance. Time to progression and survival time were estimated with the Kaplan-Meier method. Statistical analyses were calculated using Stat View 4.5J software (Abacus Concepts, Inc, Berkeley, CA). Time to treatment failure was defined as the time between the start of docetaxel and the discontinuation of treatment because of progression of disease, patient refusal to continue, or unacceptable toxicity.
Patient Characteristics Ninety-nine patients were treated between June 1997 and October 1998. Patients’ characteristics are listed in Table 1. All patients were assessable for toxicity and 94 were assessable for response. The median age was 52 years. The median number of involved organs was three (range, one to 10). Four patients received a regimen that contained anthracycline as an adjuvant treatment only, 77 were given the regimen for metastatic disease only, and 18 received the regimen as both adjuvant and metastatic treatments. The median cumulative dose of DOX was 340 mg/m2 (range, 40 to 860 mg/m2). Fifty-six patients received hormonal therapy before docetaxel was administered. Fifty-eight patients received irradiation for metastases of the spine or chest wall before they were given docetaxel.
Treatment With Docetaxel The median number of docetaxel cycles was four (range, one to 15). In patients who received more than two cycles of docetaxel, the median duration between treatment cycles was 28 days (range, 21 to 35 days). The median cumulative dose of docetaxel was 240 mg/m2 (range, 45 to 900 mg/m2). The dose was reduced in 38 patients. The reasons for dose reduction were poor PS in 17 patients, elevated transaminase level with liver metastases in eight patients, and febrile neutropenia in 13 patients. The reasons for discontinuation of docetaxel were disease progression in 52 patients, toxicity in 28 patients, and refusal to continue in 14 patients. Forty-seven patients were premedicated with dexamethasone from the first cycle, and 13 patients received dexamethasone premedication from the middle of treatment because of fluid retention or hypersensitivity reaction in the previous cycle.
Anthracycline Resistance and Response to Docetaxel
Toxicity Hematologic toxicity during the first cycle and nonhematologic toxicity are summarized in Table 3. Fifty-six (56.7%) of the 99 patients experienced grade 3 or 4 neutropenia during the first cycle. The median duration of grade 4 neutropenia was 3 days (range, 2 to 7 days). Fifteen patients demonstrated grade 2 fever with neutropenia. Six patients demonstrated neutropenic fever during two or more cycles. Four patients received granulocyte colony-stimulating factor for neutropenic fever. Two patients who received docetaxel 45 mg/m2 died of infection with severe myelosuppression and diarrhea during the first cycle. These two patients had elevated transaminase levels (approximately two times the normal upper limit) and diffuse metastases in bone and liver. Forty-eight patients experienced fluid retention, and 15 of them were treated subsequently with dexamethasone premedication. The median cumulative dose of docetaxel received until the onset of fluid retention was 300 mg/m2, with no difference between patients who were and were not premedicated with dexamethasone. Three patients with moderate fluid retention received more than five cycles. Skin toxicity was observed in 25 patients, and common manifestations were erythema and nail change. The administration of dexamethasone caused a moderate decrease in the incidence of skin reactions (33% v 17% of total cycles). Among 33 patients who had received irradiation before docetaxel and no dexamethasone premedication, four patients experienced recall dermatitis during the first cycle of docetaxel. Erythema was observed in the skin of the previously irradiated fields a few days after administration of docetaxel and was resolved within 2 weeks by topical application of corticosteroid ointment. The interval between completion of irradiation treatment and initiation of docetaxel administration was 2 weeks to 1.5 months, and the total irradiation dose was 30 to 50 Gy. Three of the four patients received a second cycle of docetaxel with dexamethasone premedication, and no dermal toxicity was observed. Among 25 patients who received irradiation before docetaxel with dexamethasone premedication, four patients experienced recall dermatitis during the first docetaxel cycle.
In the present study, we determined the variation in the response rate and time to treatment failure with docetaxel 60 mg/m2 as a second-line chemotherapy for MBC patients according to their anthracycline resistance status. Various definitions of anthracycline resistance have been used in previous reports. Ravdin et al5 defined anthracycline resistance as progression while receiving an anthracycline-containing regimen for MBC. The rate of objective response was reported as 50% (21 of 42 patients). In another report by Valero et al,6 patients whose disease failed to respond to first- or second-line chemotherapy, including anthracycline for MBC, or who demonstrated progression during the administration of an adjuvant regimen that contained anthracycline, were defined as primarily resistant. Secondary resistance was defined as disease progression after an initial objective response to a first- or second-line treatment that contained anthracycline. Fourteen (54%) of 26 patients with primary resistance demonstrated PR, as did and four (50%) of eight patients with secondary resistance.6 In a European study, patients were categorized as anthracycline-resistant if they had progressive metastatic disease without response to regimens that contained anthracycline or if their disease progressed during adjuvant anthracycline treatment. Fifteen (29%) of 51 patients demonstrated PR, and the response rate in the European study was lower than those in the United States because the definition of anthracycline resistance was more strict.7 In these studies, the median time to disease progression was approximately 7 months.5-7 In a phase III study of docetaxel 100 mg/m2 , the response rate was 30.4% in 46 patients with the same definition of resistance as that used in the European phase II study.9 In a report on docetaxel in practical use in the United Kingdom, the response rate was 35.4% (29 of 82 patients) for MBC patients with progressive disease after a documented clinical response to previous treatment that contained anthracycline.13 In the present study, the definition of primary resistance to anthracycline is identical to that used in the European studies. The response rate observed in our primarily resistant patients was 19.6%, which seems slightly lower than the rates in the European studies.7,9 This lower response rate for the patients in our study whose disease demonstrated primary resistance may be attributable in part to the difference in docetaxel dose (60 mg/m2 in our study v 100 mg/m2 in the European studies). In the studies of MBC patients with any response to previous chemotherapy that contained anthracycline, the response rates with docetaxel 60 mg/m2 and 100 mg/m2 were similar.6,10 In the phase I study of docetaxel in Japan, the recommended dose for phase II trials was lower than the recommended doses in the United States and Europe.10 This is because of the different definitions of dose-limiting toxicity in the various countries. The maximum-tolerated dose of docetaxel in the Japanese phase I study was 70 to 90 mg/m2, and neutropenia was the dose-limiting toxicity.10 Salminen et al14 reported that because of toxicity, docetaxel 100 mg/m2 is not recommended for MBC patients who have been heavily pretreated with chemotherapy; their recommendation for initial therapy in patients who have undergone heavy pretreatment was docetaxel 75 mg/m2. In MBC patients, the response rate with docetaxel 75 mg/m2 was 52% as first-line chemotherapy and 33% as second-line chemotherapy.13,15 Because the safety of docetaxel in the dose range of 70 mg/m2 to 90 mg/m2 has already been confirmed in the Japanese phase I study, it seems necessary to reconsider the recommended dose of docetaxel in breast cancer patients without documented response to previous anthracycline. A randomized trial will be necessary to evaluate whether 60 mg/m2, 75 mg/m2, or 100 mg/m2 is the optimal dose of docetaxel. Although early studies suggest that docetaxel is not clinically cross-resistant to previous regimens that contained anthracycline,5,6 it seems likely that docetaxel has some cross-resistance to anthracycline whether anthracycline resistance is strictly defined. In the present study, we divided secondary resistance into three categories on the basis of similar categories used in a study of platinum resistance in ovarian cancer patients.16 The differences in response rates or time to treatment failure were not significant among the three categories of secondary resistance. This might be attributable to the small number of patients in each category. In the present study, most adverse events were manageable, but two patients died of infection with severe myelosuppression despite dose reduction of docetaxel. From the pharmacokinetic study of docetaxel, a 25% dosage reduction is recommended in patients with impaired liver function.17,18 In MBC patients treated with second- or further-line chemotherapy, liver metastases and elevated transaminase levels are frequently observed. Therefore, it will be important to conduct a pharmacodynamic study for defining the optimal dose level of docetaxel in patients with impaired liver function. In the Japanese phase II study of docetaxel 60 mg/m2 without corticosteroid premedication, 15 (21.1%) of 71 patients demonstrated fluid retention (mild in 13 and moderate in two), which was first documented after the median cumulative dose of 240 mg/m2.11 In our study, 15 of 60 patients premedicated with dexamethasone demonstrated fluid retention. It has been reported that 5-day premedication with corticosteroids before treatment with docetaxel reduced the severity of fluid retention and delayed its onset.19,20 In our study of a 5-day schedule of oral dexamethasone 8 mg/d premedication, the fluid retention observed was similar to that seen in a previous study of docetaxel 60 mg/m2 without corticosteroid premedication.11 The term recall dermatitis is defined as an inflammatory reaction of the skin in a previously irradiated site associated with the administration of various agents.21-25 These reactions range from mild erythema to vesiculation, and they occur in a sharply defined area corresponding to the previously irradiated field after administration of the precipitating agents. The precise mechanism of recall dermatitis is unknown. Radiation recall dermatitis with docetaxel has been reported.26,27 In those reports, the intervals between completion of irradiation and initiation of chemotherapy were a few days to several months.21-27 In our study, none of the four patients with recall dermatitis received premedication with corticosteroids. None of the 25 patients who received irradiation before docetaxel and premedication with corticosteroid demonstrated recall dermatitis. Therefore, it can be speculated that the prophylactic use of corticosteroid may decrease the frequency of recall dermatitis and other docetaxel-induced skin toxicity unrelated to radiation. It is still unclear whether corticosteroid premedication is beneficial in patients treated with docetaxel 60 mg/m2. Therefore, further studies are necessary to determine the efficacy and optimal schedule of corticosteroid premedication. In conclusion, our study results suggest the usefulness of categorizing patients according to our definition of anthracycline resistance, and they demonstrate that the response rate to docetaxel 60 mg/m2 in MBC patients with primary anthracycline resistance was lower than that in patients with secondary resistance. Compared with the results documented with docetaxel at a dose of 100 mg/m2 in the United States and Europe, the treatment efficacy we observed with docetaxel 60 mg/m2 seems unsatisfactory in MBC patients with primary anthracycline resistance. A definitive comparative study to address the docetaxel dose-response relationship is warranted.
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Salminen E, Bergman M, Huhtala S, et al: Docetaxel: Standard recommended dose of 100 mg/m2 is effective but not feasible for some metastatic breast cancer patients heavily pretreated with chemotherapy—A phase II single-center study. J Clin Oncol 17: 1127-1131, 1999 15. Dieras V, Chevallier B, Kerbrat P, et al: A multicentre phase II study of docetaxel 75 mg m-2 as first-line chemotherapy for patients with advanced breast cancer: Report of the Clinical Screening Group of the EORTC—European Organization for Research and Treatment of Cancer. Br J Cancer 74: 650-656, 1996[Medline] 16. Blackledge G, Lawton F, Redman C, et al: Response of patients in phase II studies of chemotherapy in ovarian cancer: Implications for patient treatment and the design of phase II trials. Br J Cancer 59: 650-653, 1989[Medline] 17. Francis P, Bruno R, Seidman AD, et al: Pharmacodynamics of Taxotere (docetaxel) in patients with liver metastases. Proc Am Soc Clin Oncol 13: 138, 1994 (abstr 346)
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Bruno R, Hille D, Riva A, et al: Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16: 187-196, 1998 19. Ravdin PM, Valero V, Nabholtz JM, et al: Efficacy of a 5-day corticosteroid premedication in ameliorating Taxotere-induced fluid retention. Proc Am Soc Clin Oncol 15: 115, 1996 (abstr 124) 20. Piccart MJ, Klijn J, Paridaens R, et al: Corticosteroids significantly delay the onset of docetaxel-induced fluid retention: Final results of a randomized study of the European Organization for Research and Treatment of Cancer Investigational Drug Branch for Breast Cancer. J Clin Oncol 15: 3149-3155, 1997[Abstract] 21. Donaldson SS, Glick JM, Wilbur JR: Adriamycin activating a recall phenomenon after radiation therapy. Ann Intern Med 81: 407-408, 1974 (letter) 22. Greco FA, Brereton HD, Kent H, et al: Adriamycin and enhanced radiation reaction in normal esophagus and skin. Ann Intern Med 85: 294-298, 1976 23. Raghavan VT, Bloomer WD, Merkel DE: Taxol and radiation recall dermatitis. Lancet 341: 1354, 1993 (letter) 24. Schweiter VG, Juillard GJF, Bajada C, et al: Radiation recall dermatitis and pneumonitis in a patient treated with paclitaxel. Cancer 76: 1069-1072, 1995[Medline]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
