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Factors Predicting for Efficacy and Safety of Docetaxel in a Compassionate-Use Cohort of 825 Heavily Pretreated Advanced Breast Cancer Patients

From the Paul Brousse Hospital and Institut Gustave Roussy, Villejuif; Cvitkovic & Associés Consultants, Kremlin-Bicêtre; Centre Oscar Lambret, Lille; Saint Louis Hospital, Paris; Centre Léon Bérard, Lyon; Centre Paoli Calmettes, Marseille; and Roger Bellon and Rhône-Poulenc Rorer, Montrouge, France.

Address reprint requests to Esteban Cvitkovic, MD, Hôpital Paul Brousse,12 Avenue Paul Vaillant Couturier, 94804 Villejuif Cedex, France; email e.cvitkovic{at}cvitkovic-ac.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To identify predictive factors for efficacy and safety in advanced breast cancer (ABC) patients treated in the French compassionate-use docetaxel program.

PATIENTS AND METHODS: A total of 825 ABC patients treated with docetaxel (100 mg/m² every 3 weeks) were source-reviewed and analyzed for prognostic factors associated with overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), febrile neutropenia, mucositis, and severe fluid retention syndrome by univariate and multivariate analysis.

RESULTS: The ORR was 22.9% (95% confidence interval, 20.2% to 26.2%). The median TTF and OS were 4.0 and 9.8 months, respectively. By multivariate analysis, secondary anthracycline-resistant disease was significantly associated (P < .05) with lower ORR and shorter TTF and OS, whereas anthracycline-refractory disease was associated with shorter OS. Poor performance status was associated with lower ORR, shorter TTF, and shorter OS. Liver dysfunction (transaminase levels > 1.5 times the upper limit of normal [ULN] and alkaline phosphatase [AP] level > three times ULN) and time since first relapse less than 24 months were associated with shorter TTF and OS. Other significant correlations included the following: elevated CA 15-3 serum level with lower ORR; more than two involved sites, and minor transaminase and AP level abnormalities with shorter OS; and no previous chemotherapy for ABC with shorter TTF. According to multivariate analysis, ORR, TTF, and OS were not decreased in patients with liver metastases but without liver dysfunction.

CONCLUSION: Docetaxel activity was maintained in heavily pretreated ABC patients and in those with liver metastasis; docetaxel must be used cautiously, however, in patients with liver dysfunction in whom high morbidity risk necessitates strict adherence to dose-adaptation guidelines.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ADVANCED BREAST cancer (ABC) is an incurable lethal disease. The use of systemic chemotherapy and hormonal manipulations in ABC improves survival rate and quality of life, but their aim remains mostly palliative.¹ Prognostic factors relevant to systemic treatment efficacy and survival in ABC have been extensively studied. The most relevant clinical factors seem to be specific sites of relapse,^2-4 number of metastatic sites,^3,5 performance status,^2,3,6 disease-free interval,^2,4,6 and prior adjuvant chemotherapy.⁷ Liver metastases have been associated with poor overall survival^2,4 as well as with decreased response rates for treatment with anthracycline^8,9 and vinorelbine.^10,11

Anthracycline-based combinations remain the standard first-line treatment for ABC, but despite an objective tumor response in 50% to 60% of patients,¹ virtually all of them will develop progressive disease within a few months. The efficacy of further chemotherapy is generally lower than first-line therapy and decreases as more lines of chemotherapy are given. Moreover, tumors that fail to respond to anthracyclines or that relapse quickly are often cross-resistant to unrelated drugs, probably because the tumor cells acquire a multidrug resistance phenotype. Unfortunately, there is no consensus on the clinical definition of anthracycline resistance either in routine clinical practice or in new drug evaluation.¹²

Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is an anticancer agent of the taxane class that has recently become available. It has been highly effective in treating ABC in second- as well as first-line treatment in several phase II studies.^13-18 Of particular interest is the fact that early trials showed similar response rates in patients considered to be anthracycline-resistant^15,17,18 and in patients with liver metastasis.^13-17 The principal severe clinical adverse events were fluid retention syndrome (FRS) and febrile neutropenia. The FRS, characterized by peripheral edema, weight gain, and sometimes nonmalignant serious effusions, was related to the cumulative dose of docetaxel administered. Its incidence and severity were reduced by a 3-day corticosteroid regimen, starting the day before the administration of docetaxel.¹⁹ However, the pathophysiology of FRS remains poorly understood, and reliable predictive factors for its occurrence are needed. Febrile neutropenia occurred in 10% to 20% of patients in early trials.

Hepatobiliary extraction is the major elimination route for docetaxel.²⁰ Concomitant elevations of transaminase levels greater than 1.5 times the upper limit of normal (ULN) and of alkaline phosphatase (AP) levels greater than 2.5 times ULN are correlated with a 27% decrease in docetaxel clearance.²¹ A high risk of febrile neutropenia has been reported in patients exhibiting such abnormalities in liver biochemical tests.²²

Positive results in the initial clinical studies led Rhône-Poulenc Rorer to submit a marketing authorization dossier for docetaxel to the European Medical Agency in July 1994. From this date until the marketing of docetaxel in France in December 1995, Rhône-Poulenc Rorer and the French Agence du Médicament made docetaxel available to practicing oncologists through a compassionate-use program, with the aim of providing the drug to patients with relapsing ABC, for whom no standard salvage treatment was available and who could not be entered onto ongoing clinical trials with docetaxel.

The objective of this study is to identify predictive factors for docetaxel efficacy and for the occurrence of the main adverse events (febrile neutropenia, mucositis, and severe FRS) in this patient cohort by means of relevant univariate and multivariate statistical analyses. In particular, we have assessed whether docetaxel efficacy, as determined by overall response rate (ORR), median time to treatment failure (TTF), and overall survival (OS), is influenced by liver metastases, severe liver impairment, and strictly defined anthracycline resistance.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between August 8, 1993, and December 31, 1995, 889 patients with ABC were treated with docetaxel in 67 French centers through a compassionate-use program sponsored by Roger Bellon and Rhône-Poulenc Rorer Laboratories (Montrouge, France), which became a formal program sponsored by the French Agence du Médicament in July 1994 (25 of these patients were treated between August 1993 and July 1994). All patients registered on the program were reported to and comonitored by the Agence du Médicament. All patients included in this program were to have received at least one standard chemotherapy regimen for advanced disease and could not be candidates for anthracycline treatment because of the identification of anthracycline-resistant disease, medical contraindication, or the patient’s attainment of the maximum permitted cumulative dose. Moreover, patients had to be ineligible for inclusion in ongoing docetaxel studies. Patients with serum bilirubin levels greater than 1.5 times ULN, transaminase levels greater than five times ULN, platelet counts less than 100 x 10⁹/l, or neutrophil counts less than 2 x 10⁹/L were not to be included in the compassionate-use program.

The recommended dose of docetaxel was 100 mg/m² every 3 weeks. However, a 25% dose reduction (ie, 75 mg/m² every 3 weeks) was recommended in the case of abnormal liver function tests: grade 3 bilirubin, transaminase levels greater than three times ULN, or transaminase levels greater than 1.5 times ULN associated with AP levels greater than 2.5 times ULN. Premedication with dexamethasone (4 mg orally bid) starting the day before treatment and lasting for 5 days was recommended before each administration.

A retrospective analysis of safety and efficacy data has already been performed.²³ The data were obtained from two sources. First, a prospective review of data concerning safety was performed by the treating physicians. In addition, once the accrual was closed, a retrospective and complementary review of data was undertaken through the examination of hospital records concerning pretreatment characteristics, treatment, safety, and efficacy for all patients treated in centers that had recruited more than five patients. Nineteen patients were excluded from all of the analyses because of insufficient data. Therefore, from the initial data collection, 870 patients were assessable for adverse events. Forty-five patients were excluded from the clinical source-record review because they were from centers that enrolled fewer than five patients. The analyses of factors predicting for efficacy and safety were therefore carried out in 825 patients and source-reviewed by a team of oncologists. Response was assessed from clinical record data according to World Health Organization (WHO) criteria.²⁴ Being a compassionate-use program, this study included no strict guidelines regarding frequency or thoroughness of antitumor activity assessment (at least two were expected to be carried out, one at the start and another at the end of the treatment). Such assessment was performed by each investigator according to his or her customary practice. Investigator assessments of disease progression or treatment failure (clinical, biologic, and/or iconographic) made during the assessment of docetaxel were also source-verified. TTF was calculated based on the time between the first day of treatment and the date of the first event considered as treatment failure (progression, discontinuation of treatment before the fourth cycle [whatever its cause], or death). OS was calculated based on the time between the first day of treatment and the time of death. Adverse events were graded, according to a three-level clinical system, as mild (National Cancer Institute common toxicity criteria [NCI-CTC] grade 1), moderate (NCI-CTC grade 2), or severe (NCI-CTC grades 3 and 4).

Data Collection and Classification of Patients
For each of the 825 patients included in this analysis, the following information was obtained: sex; date of birth; dates of initial diagnosis of breast cancer, of first and subsequent relapses, and of inclusion in the compassionate-use program; hormonal (estrogen and/or progesterone) receptor status of the primary tumor; WHO performance status (PS), number of involved sites, site of metastasis (visceral and hepatic), biochemical liver test results (bilirubin, AST/ALT transaminase, and AP levels), and CA 15-3 serum level at start of treatment; number of previous chemotherapy lines for advanced disease; indication of last treatment with anthracycline (adjuvant or advanced disease); best response to this treatment, if applicable; and subsequent date of relapse or progression. The response to docetaxel, according to the prescribing physician (verified in the medical records, but without third-party review of imaging evidence) and the dates of treatment failure and death were also recorded as well as safety data concerning febrile neutropenia, mucositis, and FRS. At least one, but more often two or three, complete blood count per cycle (plus one from an intercycle visit) was available for review.

Biochemical liver tests and CA 15-3 serum level were evaluated as the ratio of the measured value to the ULN. Liver dysfunction was defined as AP levels greater than three times ULN associated with transaminase levels greater than 1.5 times ULN. Patients with transaminase and/or AP levels 1.5 times ULN without other signs of liver dysfunction were classified as having minor abnormalities, and patients with serum bilirubin levels 1.5 times ULN were classified as having hyperbilirubinemia.

Patients were considered to have anthracycline-resistant disease if they relapsed within 6 months or showed disease progression within 3 months after the completion of adjuvant or palliative anthracycline-based treatment. Such patients were further considered to have anthracycline-refractory disease if the best response to anthracycline-based chemotherapy for advanced disease was tumor progression or if they had relapsed during anthracycline-based adjuvant treatment. Patients whose disease was anthracycline-resistant but not anthracycline-refractory were considered to have secondary anthracycline-resistant disease. Patients who had never been treated with anthracyclines or whose disease progressed more than 6 months after anthracycline-containing adjuvant chemotherapy or more than 3 months after anthracycline-based palliative chemotherapy were all classified as having nonresistant disease.

The time since first relapse was computed as the interval between the date of the diagnosis of the first advanced disease assessment and the date of the first cycle of docetaxel. This period of time was arbitrarily divided into two ranges (< 24 months and 24 months). The rates of febrile neutropenia, mucositis (severe and moderate), and severe FRS in each group of patients were assessed on a worst-grade-per-patient basis.

Data Analysis
TTF and OS curves for the various groups were computed using the Kaplan-Meier method. Both univariate and multivariate analyses were used to assess potential prognostic factors. For univariate analyses, dichotomous (objective responses and adverse events) and censored (TTF and OS) data were compared by means of Pearson’s ² test and the log-rank test, respectively. Age at diagnosis and at time of docetaxel treatment was taken as a dichotomous variable (< 50 years or 50 years) related to menopausal status. The variables included in the univariate analysis were as follows: age at initial diagnosis, age at inclusion, hormonal receptor status of primary tumor, PS, number of involved sites, visceral and liver metastasis, biochemical liver test results (transaminase, AP, and bilirubin levels) and CA 15-3 level at inclusion, number of previous lines of chemotherapy for ABC, anthracycline resistance status, and time since first relapse. Each variable that was associated with the probability of response, treatment failure, death, or adverse events with P .10 in the univariate analysis was included in the multivariate analysis. Hormonal receptor status and bilirubinemia were never included in the multivariate analysis, the former because of the heterogeneous assessment methodology and numerous missing data points concerning this variable and the latter because of the small number of patients with hyperbilirubinemia (n = 28), most of whom had liver dysfunction. For multivariate analysis, dichotomous and censored outcomes were analyzed by means of a multivariate logistic model²⁵ and a Cox proportional hazards model,²⁶ respectively. A forward stepwise procedure was used, based on the Wald statistic. The P value used as a criterion for retaining variables in the final model was P .10. The sizes of the patient cohorts that were available for the different outcomes that were submitted to multivariate analysis varied because of missing data for the covariates selected in the univariate analysis (P .10).

	RESULTS

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Patient Characteristics
The main characteristics of the 825 patients are listed in Table 1. Nine men treated with docetaxel for ABC were included in the analysis. Tumoral hormonal receptor status was available for 478 patients (57.9%) only, 59.6% of whom had positive estrogen receptor and/or progesterone receptor status. One hundred sixty-nine patients (20.6%) had a PS of 2 or 3 at the start of docetaxel treatment. Six hundred five patients (73.5%) had visceral involvement, with liver metastases present in 404 (49.1%). At the start of treatment, minor abnormalities of transaminase and/or AP levels ( 1.5 times ULN) were recorded in 217 patients (28%), whereas 74 patients (9.6%) had liver dysfunction as defined above. Twenty-eight patients (3.7%) had increased bilirubin levels ( 1.5 times ULN). Of these 28, 20 had liver dysfunction, five had minor abnormalities in their transaminase or AP levels, and three had transaminase and AP levels that were normal or unknown. All 825 patients had previously been treated by chemotherapy: 410 patients (50.4%) had received adjuvant chemotherapy, 205 (24.9%) had received one line of chemotherapy for ABC, and 531 (64.4%) had received at least two lines. Out of 413 patients (50.8%) classified as anthracycline-resistant and/or refractory, 87 were considered to have anthracycline-refractory disease, according to the aforementioned definition. The 88 patients who had not received previous chemotherapy for advanced disease were not eligible for anthracycline treatment, mainly because they had failed anthracycline-containing adjuvant therapy during treatment or within 6 months of its discontinuation.

Five hundred eighty-three patients were analyzed using the multivariate proportional hazards model for TTF (Table 4). Independent variables associated with a higher probability of the treatment failure of docetaxel (hazard ratio, > 1) included poor PS (hazard ratio, 2.15), liver dysfunction (hazard ratio, 1.69), and secondary anthracycline-resistant disease (hazard ratio, 1.18; P = .07). Of note, minor abnormalities in transaminase and AP levels were not associated with the probability of treatment failure, nor was anthracycline-refractory disease. Two variables were associated with a lower probability of treatment failure (hazard ratio < 1): having received one or more previous chemotherapy lines for ABC (compared with none) and time since first relapse 24 months. Bilirubinemia was not included in the multivariate analysis. A separate multivariate analysis was performed after elimination of the 28 patients with hyperbilirubinemia, in whom liver dysfunction remained an independent prognostic factor, without a change in the hazard ratio (data not shown).

OS. At the cutoff date of June 30, 1997, with a median follow-up of 17.9 months (range, 0 to 32.7 months), 192 patients (23.3%) were still alive. Among the 825 patients, the median OS was 9.8 months (95% CI, 8.8 to 10.7 months). By univariate analysis (Table 3), a statistically significant shorter survival time was associated with liver metastasis (median OS of 8.2 v 11.2 months for those without), with abnormal transaminase or AP levels (median OS of 6.7 and 4.1 months, for patients with minor abnormalities and liver dysfunction, respectively, v 12.1 months for those with normal liver function), and with hyperbilirubinemia (median OS of 2.8 v 10.2 months for those without). Anthracycline resistance was also significantly associated with a decreased median OS (8.6 and 7.7 months for refractory and secondary resistant patients, respectively, v 12 months for those who were considered not to be anthracycline-resistant). Other factors significantly associated with a shorter OS were as follows: age at initial diagnosis 50 years, negative hormonal receptor status, poor PS, more than two involved sites, visceral metastasis, elevated CA 15-3 serum levels, and time since first relapse less than 24 months.

Multivariate analysis for OS was performed in 582 patients (Table 4). Independent variables associated with higher probability of death were as follows: liver dysfunction (hazard ratio, 2.57), minor abnormalities in transaminase or AP levels (hazard ratio, 1.50), altered PS (hazard ratio, 2.51), more than two involved sites (hazard ratio, 1.38), and secondary anthracycline-resistant disease (hazard ratio, 1.37). Anthracycline-refractory disease was weakly associated with probability of death (P = .09). Time since first relapse 24 months was associated with a lower probability of death. As with TTF, a multivariate analysis was performed that excluded patients with hyperbilirubinemia, which confirmed that the negative influence of liver dysfunction and minor abnormalities in transaminase or AP levels on OS was independent of hyperbilirubinemia (data not shown).

Docetaxel Safety
Febrile neutropenia. In the initial analysis previously reported, safety was evaluated in 870 patients²³ (Table 2). In the present analysis, adverse events were computed for all 825 source-reviewed patients. Within the whole group, 204 patients (24.7%) experienced febrile neutropenia. By univariate analysis, the following factors were associated with a higher risk of febrile neutropenia (Table 5): liver metastasis, previous chemotherapy for ABC, lack of anthracycline resistance, and time since first relapse 24 months. Elevated transaminase or AP levels were weakly associated with a risk of febrile neutropenia (P = .08) and were also included in the multivariate analysis.

Severe FRS. Among the 825 patients, 61 (7.4%) experienced severe FRS. Only the number of lines of prior chemotherapy administered for ABC exhibited a statistically significant correlation with an increased risk of severe FRS (Table 5). Thus, no multivariate analysis was performed.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The aim of this compassionate-use program was to provide docetaxel to heavily pretreated patients for whom no adequate salvage treatment was yet available. Given that patients included in this program had to be ineligible for ongoing phase II to III trials and that selection criteria were only moderately restrictive, the main characteristics of the patient cohort reported here are different from those usually described in clinical trials. Clinical trials impose strict eligibility criteria, often related to the likelihood of both toxicity/morbidity and the achievement of objective response. Thus, 20.6% of patients had poor PS (WHO grades 2 to 3) and 64.4% had received two or more lines of chemotherapy for ABC. Moreover, 9.6% displayed evidence of liver dysfunction and 3.7% had hyperbilirubinemia. Again, about 1% of the patients who received treatment in this study were men, a subset of ABC patients rarely included in clinical trials, even though this percentage represents the proportion of men as part of the total breast cancer population. Thus, this cohort study, which more closely reflects the patient population actually treated in everyday practice and which was conducted during the early period of availability of a new active agent, offered a rare opportunity to reliably and relevantly identify factors predicting the efficacy and safety of docetaxel.

Several acknowledged prognostic factors for the efficacy and survival of systemic chemotherapy^2-7 did not seem to be modified by the administration of docetaxel. Indeed, lower PS remained an independent predictive factor for low ORR, as well as short TTF and OS. Moreover, the efficacy and survival rate associated with docetaxel were lower in patients with large tumor burdens. According to multivariate analysis, an elevated CA 15-3 serum level (for which a significant relationship with the overall tumor load has been previously shown²⁷ ) was significantly associated with a low ORR and having more than two metastatic sites with a short OS. In patients with liver metastasis, TTF and ORR were not significantly decreased. This result agrees with previous clinical trials reporting docetaxel efficacy in patients with liver involvement. According to our univariate analysis, patients with liver metastasis have a significantly shorter survival time (median OS of 11.2 v 8.2 months for those without). However, when multivariate analysis was performed that included elevated levels of AP and transaminase, liver metastases were no longer associated with a higher probability of death.

Liver dysfunction was an independent predictive factor of a high probability of docetaxel failure (hazard ratio, 1.69) and death (hazard ratio, 2.57), whereas minor liver function abnormalities were correlated only with a higher probability of death (hazard ratio, 1.49). According to our multivariate analysis, liver dysfunction was also an important predictive factor for the probability of febrile neutropenia (odds ratio, 1.86) and mucositis (odds ratio, 2.25). Bonneterre et al²³ have previously reported, concerning the same patient cohort, that nearly one half of the 74 patients presenting with liver dysfunction each received a dose of more than 75 mg/m² every 3 weeks. In addition, among the 10 patients who died from sepsis during a neutropenic period, six had presented with severe liver function impairment and three had received a dose of more than 75 mg/m² every 3 weeks.²³ Similar results have been reported among 53 patients with liver dysfunction who were treated with docetaxel at 100 mg/m² every 3 weeks in several phase I to II trials.²² These results, taken together with the population pharmacokinetics/pharmacodynamics study data,²⁸ confirm that the decrease in docetaxel clearance observed in patients with liver dysfunction is responsible for an increased risk of severe myelotoxicity, mucositis, and infection when the drug is used at a dose of 100 mg/m² every 3 weeks. A 25% dose reduction (ie, 75 mg/m² every 3 weeks) should normalize the exposure of docetaxel in patients with liver dysfunction and is currently recommended. In agreement with Klink-Alakl et al,²² we did not find an increased risk of febrile neutropenia in patients with liver metastasis but without liver dysfunction, which confirms the report by Bruno et al²⁸ that docetaxel clearance is unchanged in this subset of patients. Therefore, docetaxel can probably be safely given at the full recommended dose of 100 mg/m² every 3 weeks in patients with liver metastases but without liver dysfunction.

By univariate analysis, hyperbilirubinemia was found to be significantly associated with a short median TTF (0.9 v 4.1 months for those without hyperbilirubinemia) and median OS (2.8 v 10.2 months), whereas its relationship with ORR, febrile neutropenia, and mucositis did not achieve statistical significance, probably because of the small number of patients under consideration. Hyperbilirubinemia reflects severe intrahepatic cholestasis and/or severe impairment of liver function, which seriously alter docetaxel clearance.²⁹ However, there is little known about the pharmacokinetics of docetaxel in patients with hyperbilirubinemia because it has been an exclusion criterion in all previous clinical trials.

According to multivariate analysis, secondary anthracycline-resistance was an independent predictive factor for low ORR to docetaxel as well as for short TTF and OS. However, docetaxel activity remained clinically relevant in this subset of patients, with an ORR of 18.1% and a median TTF of 3.4 months. The absence of any prognostic significance of the anthracycline-refractory disease may be a result of the small size of this subgroup. Nonetheless, in multivariate analysis, anthracycline-refractory disease was not associated with a worse prognosis than was secondary-resistant disease.

Several phase II clinical trials with taxanes performed in ABC patients whose disease is considered to be anthracycline-resistant have been reported, in which were used several different definitions of such resistance. Three studies with docetaxel have been performed specifically with anthracycline-resistant patients^15,17,18 and are summarized in Table 7. The higher response rates and survival reported in these three studies compared with our patient cohort are not surprising, given the fact that all patients included in these clinical studies had fulfilled formal eligibility criteria, including a PS 2 and normal results for biochemical liver tests. With the same definition of anthracycline resistance, a 6% ORR to paclitaxel given at 250 mg/m² for 3 hours has been reported.³⁰ Two studies using longer infusion times (250 mg/m² for 24 hours and 140 mg/m² for 96 hours) reported response rates in anthracycline-resistant patients of 33% and 48%, respectively, with toxicity and morbidity levels that exceed even our current compassionate-use results.^31,32 Furthermore, the definition of anthracycline-resistant disease used was extensive because it included all patients who did not experience any objective response to anthracyclines (even if the disease had been stabilized for several months). Lastly, also using a broad and less restrictive definition of anthracycline resistance, the United States compassionate-use program for paclitaxel reported a 23% response rate.³³ Among 82 anthracycline-refractory patients (progressive disease as best response) treated with docetaxel through the United Kingdom compassionate-use program, the ORR was 35%.³⁴ However, the recorded response assessment was at the clinician’s discretion, without any attempt at validation by either source review or criteria verification. Given the heterogeneity of the definitions of anthracycline resistance used in the different studies, a comparison of docetaxel and paclitaxel activities in anthracycline-resistant patients is difficult. However, it is notable that a recent phase II study showed significant docetaxel activity (ORR, 18.1%; median OS, 10.5 months) among 44 patients with paclitaxel-resistant ABC.³⁵ A recent study in nude mice reported that human tumor xenografts that overexpressed the multidrug resistance protein were highly resistant to doxorubicin and paclitaxel but more sensitive to docetaxel.³⁶

Patients who received at least two prior lines of chemotherapy for ABC were at increased risk for febrile neutropenia, probably because of the effect of extensive prior treatment on bone marrow reserve. Surprisingly, prior treatment for ABC was also the sole parameter correlated with the risk of severe FRS according to univariate analysis. There is no clear explanation for this result. However, the cumulative dose of docetaxel received, which is the most important known predictive factor, was not integrated into the statistical analysis.

Among the 825 ABC patients treated in this compassionate-use program, docetaxel activity was maintained in patients with liver metastases and in those heavily pretreated by chemotherapy. Thus, our study supports the results of phase II and III trials, confirming in a treatment context that reflects the realities of clinical practice that docetaxel is an active treatment choice for patients with liver metastasis who relapse after anthracycline therapy. However, in patients with severe liver impairment, docetaxel must be used with care, given the associated high severe toxicity and morbidity rates. Results are needed from prospective and ongoing trials on the efficacy and safety of lower docetaxel doses to draw up dose-adjustment guidelines appropriate for this subset of patients.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted March 30, 1999; accepted September 7, 1999.

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