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© 2000 American Society for Clinical Oncology Docetaxel for Patients With Paclitaxel-Resistant Müllerian CarcinomaFrom the Departments of Internal Medicine Specialties and Biomathematics, University of Texas M.D. Anderson Cancer Center, Houston; M.D. Anderson Outreach, Clear Lake, TX; Department of Obstetrics and Gynecology, Chulalongkorn University, Bangkok, Thailand; and Department of Gynecologic Oncology, Irmandade Santa Casa Misericordia de Porto Alegre Hospital, Porto Alegre, Brazil. Address reprint requests to Claire F. Verschraegen, MD, Department of Internal Medicine Specialties, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 39, Houston, TX 77030; email cverschr{at}mdanderson.org
PURPOSE: To determine the efficacy and toxicity of docetaxel in patients with müllerian carcinoma resistant to paclitaxel. PATIENTS AND METHODS: Thirty-two patients with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who failed paclitaxel-based chemotherapy received either 100 or 75 mg/m2 of docetaxel every 3 weeks. Resistance to paclitaxel was defined as either progression of disease during treatment, failure to achieve regression of disease after at least four courses, or rapid recurrence (within 6 months) after completion of therapy. RESULTS: Eighteen patients were treated on a formal protocol and fourteen with the commercially available docetaxel. Thirty were assessable for response. Toxicities were thoroughly evaluated in the 18 patients on protocol. Twenty-seven patients (85%) had epithelial ovarian cancer. The overall response rate was 23% (one complete and six partial responses), with a median survival time of 44 weeks (9.5 months). Nine patients had stable disease and 14 progressive disease. Among 19 patients who progressed during prior paclitaxel treatment, two (11%) responded to docetaxel, compared with five (45%) of 11 patients in other paclitaxel-resistance categories. The responders had a median taxane-free interval (ie, the time between the last paclitaxel and first docetaxel treatment) of 73 weeks, compared with 19 weeks for the nonresponder group. Toxic effects were as expected. CONCLUSION: Docetaxel is an active chemotherapeutic agent in patients with müllerian carcinoma previously treated with paclitaxel-based chemotherapy, especially in the patients who had a long taxane-free interval after a previous short response to paclitaxel.
OVARIAN CANCER IS the fifth most frequent cause of cancer death in women and the leading cause of gynecologic cancer death in the United States.1 In 2000, it is expected that approximately 23,100 new cases of ovarian cancer will be diagnosed in the United States and that more than 14,000 women will die of this disease. With the introduction of paclitaxel as frontline therapy in combination with platinum,2 the overall response rate has reached 70%, with a median survival time of 38 months. However, disease still recurs in the majority of treated patients after a median disease-free interval of 18 months. Recurrent disease is classified as being either sensitive or resistant to platinum. For disease that is platinum-sensitive, reinduction with platinum-based treatment is the therapy of choice and leads to response rates of 20% to 50%.3,4 For platinum-resistant disease, chemotherapy relies on other agents, such as topotecan, etoposide, liposomal doxorubicin, gemcitabine, and vinorelbine, which yield response rates between 10% and 30%.5 Second-line therapy has not been shown to influence long-term survival,6 and fewer than 20% of women with advanced ovarian cancer survive 5 years.7 To date, taxane sensitivity or resistance has not been considered in planning for second-line therapies. Docetaxel is a semisynthetic drug derived from a precursor extracted from the needles of Taxus baccata.8 Docetaxel uses the same tubulin-binding site as paclitaxel9 and, like paclitaxel, promotes microtubule assembly and inhibits microtubule disassembly, but docetaxel has different effects on Tau binding sites and on microtubule-associated proteins.10 These two agents also differ somewhat in their in vitro and in vivo activities, and in some tumor cell lines8 and fresh human cancer specimens,11 docetaxel has been shown to inhibit tumor cell growth better than paclitaxel. Furthermore, research has shown that some human tumor cell lines resistant to paclitaxel are not resistant to docetaxel; thus, resistance to paclitaxel does not automatically indicate resistance to docetaxel.12 This finding was substantiated by the results of a recent phase II study in which docetaxel showed significant antitumor activity against paclitaxel-resistant breast cancer.13 Thus, docetaxel may be active against some tumors that are resistant to paclitaxel. Because previous studies of docetaxel in epithelial ovarian cancer focused only on platinum resistance,14-17 this study sought to determine the clinical efficacy and toxicity of docetaxel given to patients with paclitaxel-resistant müllerian carcinoma.
Eligibility and Evaluation Criteria Women 18 years or older were enrolled onto the prospective study, which was approved by the institutional review board, if they had histologically proven epithelial ovarian cancer resistant to paclitaxel-based therapy. Resistance to paclitaxel was defined as disease progression while receiving paclitaxel-based chemotherapy, evidence of persistent disease after four courses of paclitaxel-based chemotherapy, or clinical remission followed by relapse within 6 months after completion of paclitaxel-based chemotherapy. However, it is important to note that patients did not necessarily receive docetaxel immediately on demonstration of paclitaxel resistance and may have been treated with other, potentially non–cross-resistant regimens first. Thus, the taxane-free interval (ie, the time between the last paclitaxel and first docetaxel treatment) ranged from 4 to 134 weeks. Other patient eligibility requirements included a performance status of 2 or less as determined using criteria of the Eastern Cooperative Oncology Group, a life expectancy of more than 3 months, and bidimensionally measurable tumor with documented disease progression within 2 months before entry onto the study. Pleural effusions, ascites, and osseous metastases were not considered measurable disease, and lesions located in previously irradiated areas were excluded from the final evaluation. Blood laboratory requirements included a granulocyte count of at least 1,500 cells/µL, a platelet count of at least 100,000 cells/µL (no minimum hemoglobin level was required), a serum creatinine level of  2 mg/dL, a normal serum bilirubin level, a serum level of alkaline phosphatase less than five times the upper limit of normal, and a serum level of transaminases 1.5 times the upper limit of normal. Patients could have no dysrhythmia or unstable heart function, and all patients were required to give written informed consent. In addition, patients had to have recovered from any toxic effects from previous treatments and could not have had more than two chemotherapy regimens (including first-line therapy) before entry onto the study; all treatments that contained carboplatin or cisplatin and/or paclitaxel were considered one regimen for the purpose of eligibility. Pretreatment with docetaxel was not allowed. Radiotherapy or chemotherapy within 4 weeks or chemotherapy with nitrosoureas and/or mitomycin 6 weeks before the protocol treatment were not permitted. Other exclusion criteria included the following: symptomatic pleural effusion or brain metastases, history of malignancies other than cervical intraepithelial neoplasia treated by cone biopsy or adequately treated basal or squamous cell carcinoma of the skin, symptomatic neuropathy grade 2 or greater, and identification as a poor medical risk because of nonmalignant systemic disease. Before entry, a complete medical history was recorded, a physical examination was performed, performance status was noted, lesions were measured, and a complete blood survey of cell counts and relevant chemistry levels, including CA-125, in serum were analyzed. A 12-lead ECG was required. Chest x-rays and other indicated studies were performed as needed every 6 weeks to evaluate disease response. Before each course, patients underwent clinical and neurologic examinations and a blood chemistry survey and provided information concerning toxic effects. Patients with paclitaxel-resistant müllerian carcinoma, who were considered ineligible for this protocol and never received docetaxel, were treated off protocol with the same regimen. Reasons for ineligibility included müllerian carcinoma of extraovarian origin, refusal of treatment in a tertiary referral center, or history of more than two chemotherapy regimens. These patients were analyzed retrospectively and were included in the nonprotocol group.
Treatment Plan Toxicity was graded according to the National Cancer Institute common toxicity criteria. Chemotherapy was delayed for a maximum of 3 weeks if the granulocyte count was less than 1,500 cells/µL or the platelet count less than 100,000 cells/µL. Patients with febrile neutropenia (absolute granulocyte count < 500 cells/µL) or granulocytopenia lasting longer than 7 days during the first course could receive G-CSF beginning with the second course. Afterwards, if patients had febrile neutropenia (absolute granulocyte count < 500 cells/µL) or granulocytopenia lasting longer than 7 days despite the use of G-CSF or a platelet count of less than 25,000 cells/µL, the docetaxel dose was reduced by 25%. A 25% dose reduction was also made for grade 4 vomiting, grade 2 neuropathy, or any grade 3 or greater nonhematologic toxic effect. No dose reduction was allowed for hypersensitivity reaction or fluid retention. Patients were removed from the study for grade 3 neuropathy, anaphylaxis to docetaxel, toxicity that required more than two dose-level reductions or delay of treatment for more than 3 weeks. The record of side effects in the nonprotocol group included only the major events.
Assessments of Clinical Response
Patient Characteristics Thirty-two patients who were 37 to 86 years of age (median, 59.5 years) were treated between December 1995 and April 1998 (Table 1). Eighteen patients were registered onto the study, and fourteen were treated in the nonprotocol group. The median Eastern Cooperative Oncology Group performance status was 1, and the most common tumor site was the ovary (27 patients). Most patients had poorly differentiated malignant serous tumor, and all had disease resistant to paclitaxel as defined above. Disease had progressed during prior paclitaxel treatment in 20 patients and had persisted in six patients; disease recurred within 6 months in six patients whose disease had initially responded (Table 2). The median taxane-free interval for all patients was 25 weeks.
Response Evaluation In this study, a total of 123 courses of docetaxel were administered (median number of courses, four; range, one to eight). After the first course, two patients treated on protocol left the study. One patient dropped from the study because of multiple prolonged toxic effects, and the other decided to receive further treatment nearer to her home. Response to docetaxel treatment was assessable in the remaining 30 patients (Table 3). Overall, a clinical CR was observed in one patient, a PR in six, stable disease in nine, and progressive disease in 14. Time to CR was 6 weeks, and median time to PR was 9 weeks. Patients with CR, PR, and stable disease had median progression-free intervals of 28, 21, and 17 weeks, respectively. The response rate on the intent-to-treat basis was 22%, and the overall response rate was 23% (95% CI, 10% to 42%). Median survival time for all patients was 44 weeks (95% CI, 12 to 76 weeks; range, 4 to 164 weeks). Figures 1 and 2 show the Kaplan-Meier probability curves for the survival of patients treated on protocol versus those nonprotocol (insignificant difference of P = .42) and overall survival, respectively. With docetaxel treatment, disease continued to progress in 17 of 19 patients in whom it had progressed with prior paclitaxel treatment. Among 11 patients who had persistent disease after paclitaxel or whose disease recurred within 6 months of paclitaxel completion, five responded to docetaxel (Table 4). The median taxane-free interval was 73 weeks for patients whose disease responded to docetaxel and 19 weeks for patients whose disease did not respond to docetaxel.
Toxicity Evaluation Docetaxel toxicity was assessed in all 32 patients. The most common hematologic toxic effects in all patients were grade 4 granulocytopenia (50%) and grade 2 anemia (53%) (Table 5). Thirteen patients (72%) treated on protocol required prophylactic G-CSF for grade 4 granulocytopenia after the first course. Febrile neutropenia occurred in six patients (33%). There was no septic death. Thrombocytopenia occurred in two patients (one grade 2 and one grade 3). Grade 2 nonhematologic toxic effects were similar to those reported previously for docetaxel.21 Most patients (83%) experienced fatigue during the treatment. Gastrointestinal effects, including nausea (67%), vomiting (33%), and diarrhea (44%), were common. Grade 1 paresthesia was observed in 33% of patients, skin rash in 22%, nail change in 37%, and fluid retention (no severe cases) in 33%.
The majority of patients with epithelial ovarian cancer are currently treated with a paclitaxel-platinum combination as frontline therapy after cytoreductive surgery.22,23 Hence, physicians are frequently confronted with patients whose recurrent disease is platinum- and potentially paclitaxel-resistant. The platinum-sensitivity status of disease and the platinum-free interval are routine considerations when determining further treatment options.4,24 However, the history of taxane-sensitivity status and the taxane-free interval is not commonly used to make therapeutic decision, because there is no standard definition of paclitaxel resistance. In a study of docetaxel in paclitaxel-refractory metastatic breast cancer,13 every patient had disease that was considered refractory to paclitaxel because it progressed during paclitaxel treatment. In our study, we recruited müllerian carcinoma patients whose disease was absolutely resistant to paclitaxel and patients whose disease was relatively resistant to paclitaxel, with "absolutely" and "relatively" being defined as they are for platinum-resistant disease.6 That is, disease that progressed during paclitaxel treatment was considered absolutely resistant to paclitaxel, and disease that partially regressed during paclitaxel treatment or that recurred within 6 months of paclitaxel treatment completion was considered relatively resistant. In our study, the overall response rate of 23%, with a median progression-free survival time of 21 weeks and a median overall survival time of 44 weeks, is comparable to those observed in other studies of second-line chemotherapy for recurrent ovarian cancer.24,25 However, only 11% of patients whose disease was considered absolutely resistant to paclitaxel responded to docetaxel. For patients whose disease was relatively resistant to paclitaxel, a 45% response rate was observed (five of 11 patients). Both patients who achieved a CR with prior paclitaxel treatment subsequently responded to docetaxel, and patients whose disease was responsive to docetaxel had received lower monthly and cumulative doses of paclitaxel than patients whose disease was nonresponsive (median dose of paclitaxel, 135 v 175 mg/m2 [P = .025]; median cumulative dose, 810 v 1,050 mg/m2 [P = .23]). Docetaxel responders also had had a longer taxane-free interval than docetaxel nonresponders (73 v 19 weeks; P = .09). These observations suggest that the pattern of prior response to paclitaxel, as well as the interval between taxane exposure, may determine the likelihood of disease response to docetaxel. Furthermore, compared with reinduction with paclitaxel, docetaxel is potentially more convenient because it has a shorter infusion time (1 v 3 to 24 hours).26 Nevertheless, re-treatment with standard dose of paclitaxel has not been precisely studied in paclitaxel-resistant patients as defined in our trial. A direct comparison between docetaxel, standard-dose paclitaxel, and unconventional doses and schedules of paclitaxel as second-line reinduction treatments for paclitaxel-resistant disease would be of interest to determine tolerability and efficacy.27
Hematologic toxicity is the major problem of docetaxel treatment. This was demonstrated by the occurrence of grades The mechanisms of docetaxel sensitivity in paclitaxel-resistant tumors are not yet clear, but we believe that this difference cannot be explained by P-glycoprotein–mediated multidrug resistance, because both agents are exported from the tumor cells by the multidrug resistance pump.32,33 Docetaxel has been shown to be more potent than paclitaxel in inducing bcl-2 phosphorylation, which leads to apoptosis,34 to bind to tubulin with twice the affinity of paclitaxel,9 and to induce microtubule assembly at one half the critical protein (tubulin) concentration required for paclitaxel. Whether these actions are mediated through microtubule-associated proteins remains under investigation.35 Our finding that docetaxel has definite antitumor activity in paclitaxel-resistant müllerian carcinoma supports previous preclinical observations12 and findings concerning docetaxel sensitivity in paclitaxel-refractory breast cancer.13 Patients with paclitaxel-treated müllerian carcinoma who have not progressed during the paclitaxel treatment and/or have a long taxane-free interval may benefit from docetaxel. In these situations, docetaxel is probably as effective as other approved second-line treatments for recurrent ovarian cancer. Because of the activity of docetaxel against ovarian cancer, its ease of administration, and the known safety profile, the use of this agent in first-line treatment should be seriously considered. The results of an ongoing phase III study comparing carboplatin-paclitaxel and carboplatin-docetaxel regimens as frontline therapy in patients with ovarian cancer are expected in the near future.36 Future clinical research should also explore the efficacy of docetaxel in various combination regimens.37-39
Supported by Rhône-Poulenc Rorer, Collegeville, PA. We acknowledge Patricia Mayers and Kimberly Herrick for editorial help.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3 granulocytopenia, often with neutropenic fever, in 78% of the patients treated on protocol during the first course, when the use of prophylactic G-CSF was forbidden. Far fewer cases of grades 
