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© 2001 American Society for Clinical Oncology Weekly Docetaxel in the Treatment of Elderly Patients With Advanced Breast Cancer: A Minnie Pearl Cancer Research Network Phase II TrialByFrom the Sarah Cannon Cancer Center and Tennessee Oncology, PLLC, Nashville, TN; Upstate Carolina Community Clinical Oncology Program, Spartanburg, SC; Consultants in Blood Disorders and Cancer, Louisville, KY; and Oncology/Hematology Group of South Florida, Miami, FL. Address reprint requests to John D. Hainsworth, MD, Sarah Cannon Cancer Center, 250 25th Ave, North Ste 412, Nashville, TN 37203; email: jhainsworth{at}tnonc.com
PURPOSE: To evaluate the efficacy and toxicity of docetaxel administered weekly to elderly or poor-performance status patients with advanced breast cancer. PATIENTS AND METHODS: Forty-one patients with advanced breast cancer who were either over the age of 65 or considered to be poor candidates for combination chemotherapy received docetaxel 36 mg/m2 weekly for 6 consecutive weeks, followed by 2 weeks without treatment. The median age of patients in this trial was 74 years, and 73% of patients had one or more visceral sites of metastases. Seventy-five percent of patients received weekly docetaxel as first-line treatment for metastatic breast cancer, and the other 25% received it as second-line treatment. Thirty-six patients were assessable for efficacy, and all patients were assessed for toxicity. RESULTS: A total of 448 doses of weekly docetaxel were administered to 41 patients. Thirteen patients (36%) had objective responses to treatment, and an additional 13 patients (36%) had stable disease or minor response. Median time to progression for responding and stable patients was 7 months (range, 3 to 27 months). Median survival for the entire group was 13 months, with 1- and 2-year actuarial survival rates of 61% and 29%, respectively. Severe neutropenia occurred in only 0.4% of courses, and no other hematologic toxicity was observed. Grade 3/4 fatigue was the most common toxicity, occurring in 20% of patients. CONCLUSION: Weekly docetaxel therapy is active and well tolerated by elderly and/or poor-performance status patients with advanced breast cancer. This treatment can be administered with minimal myelosuppression. Weekly docetaxel provides an additional option for treatment in this difficult subgroup of patients with metastatic breast cancer. Well-tolerated combination regimens containing weekly docetaxel merit evaluation for this patient population.
DURING THE PAST several years, the introduction of the taxanes has changed the treatment of patients with breast cancer. Docetaxel and paclitaxel are the first drugs to show a high level of efficacy in anthracycline-refractory patients.1-3 In the first-line treatment of patients with metastatic breast cancer, the combination of a taxane (either docetaxel or paclitaxel) and doxorubicin has produced consistently high response rates ranging from 46% to 94%.4-6 Recently, the combination of docetaxel and doxorubicin has proved superior to doxorubicin and cyclophosphamide in a randomized trial.7 Therefore, treatment with a taxane, either alone or in combination with other agents, has become a standard part of the therapy of metastatic breast cancer. In its initial clinical development, docetaxel was almost always administered as a bolus dose once every 3 weeks. Using this dosing schedule, myelosuppression was the dose-limiting toxicity; at the commonly used dose of 100 mg/m2, greater than 90% of patients experienced severe (grade 3 or 4) neutropenia.1,2 In addition, a variety of nonhematologic toxicities occurred frequently, including fatigue, skin and nail toxicity, and peripheral edema. In a recent phase I trial, we demonstrated that the toxicity of docetaxel is markedly decreased when the drug is administered weekly.8 With weekly administration, grades 3 and 4 myelosuppression were uncommon when doses as high as 43 mg/m2/wk were administered, and other nonhematologic toxicities were also infrequent. Antitumor activity was observed in three of seven patients with heavily pretreated metastatic breast cancer in our phase I trial. In many ways, the experience with weekly docetaxel parallels previous observations with paclitaxel.9 When evaluated as a single agent in patients with metastatic breast cancer, weekly paclitaxel produced a 53% response rate with mild myelosuppression.10 In the phase II trial reported here, we assessed the efficacy of weekly docetaxel in the treatment of elderly or poor-performance status patients with metastatic breast cancer. In this trial, we used a docetaxel dose of 36 mg/m2/wk because this dose was extremely well tolerated in our phase I trial. We targeted elderly patients in this trial because these patients often have difficulty tolerating combination chemotherapy regimens or full doses of taxanes administered every 3 weeks.
Between September 1997 and September 1999, 41 patients were entered onto this phase II trial by 12 participating sites in the Minnie Pearl Cancer Treatment Network (Appendix). All patients entering this trial had biopsy-proven metastatic breast cancer and had received a maximum of one previous chemotherapy regimen for metastatic disease. Patients were 65 years of age or older or were considered poor candidates for combination chemotherapy regimens because of coexistent medical illnesses or poor tolerance of previous chemotherapy. Previous treatment with taxanes for metastatic disease was not allowed; however, patients who had received a taxane as part of adjuvant therapy and relapsed more than 6 months after completion of this treatment were eligible. All patients had measurable or assessable disease; patients with only bone pain and bone scan abnormalities were ineligible. Additional eligibility criteria included Eastern Cooperative Oncology Group performance status of 0, 1, or 2; WBC  4,000/µL and platelets 100,000/µL; normal liver function (bilirubin < 1.5 mg/dL, AST  1.5 times the upper limit of normal); and serum creatinine 1.5 mg/dL. Patients were required to be at least 4 weeks from the most recent treatment with radiation therapy and to have recovered from all treatment-related toxicity. Patients with a history of brain metastases were eligible but only if they had been previously treated, were experiencing stable disease, and were without neurologic symptoms. Patients were required to give written informed consent before entering this study. This clinical trial was approved by the institutional review board at Centennial Medical Center and by the institutional review boards at participating network sites. Routine evaluation before study entry included complete history, physical examination, and determination of complete blood counts and chemistry profile. Radiologic evaluation included chest radiograph, radionuclide bone scan, and computed tomography of the head, chest, and abdomen. Tumor measurements were recorded in each patient. All patients received docetaxel 36 mg/m2/wk administered by 1-hour intravenous infusion in the outpatient setting. Docetaxel was administered for 6 consecutive weeks, and then the patient had 2 weeks without treatment. An abbreviated course of prophylactic corticosteroids was administered with each dose of docetaxel to minimize peripheral edema. All patients received dexamethasone 8 mg orally 12 hours before docetaxel administration, at the time of docetaxel administration, and 12 hours after treatment. Cytokines were not routinely administered. Instead, the dose of docetaxel was reduced if unacceptable myelosuppression occurred. After 8 weeks of therapy, patients were re-evaluated for response. All patients with either objective tumor response or stable disease continued weekly docetaxel according to the same schedule. Patients with progressive disease were removed from the trial. Docetaxel was continued for a maximum of four 8-week courses (32 weeks) in responding and stable patients. All patients’ blood counts were measured before each dose of docetaxel. Dose modifications were made on the basis of the blood counts on the days of scheduled treatment. Full doses of docetaxel were administered if the leukocyte count was more than 1,500/µL and platelet count was more than 75,000/µL. If either count was less than this minimum level, the dose of docetaxel was omitted, and the patient was re-evaluated the following week. Docetaxel was restarted as soon as the leukocyte count had risen to more than 1,500/µL and the platelet count was more than 75,000/µL. There were no dose escalations of docetaxel in this trial. Any patient who experienced grade 3 or 4 nonhematologic toxicity had treatment withheld until the toxicity had resolved to grade 2 or less, and then the docetaxel was reinstituted at 75% of the original dose. Patients who developed irreversible grade 3 or 4 toxicity were removed from treatment. Patients were considered assessable for response if they completed the first 8 weeks of therapy and were re-evaluated. All patients were assigned a response category according to standard definitions. Complete response required the total disappearance of clinically and radiologically detectable disease for at least 4 weeks. Partial response required at least a 50% reduction in the size of all measurable lesions as measured by the product of the greatest length and maximum width, with no new lesions appearing. Stable disease was defined by a reduction of less than 50% or an increase of less than 25% in the size of existing lesions, with no new lesions appearing. Patients had progressive disease if any new lesion appeared or if any existing lesion increased by 25% or more. Patients who were removed from the trial during the first 8 weeks as a result of rapid tumor progression were considered nonresponders. Survival and time to progression were measured from the first day of docetaxel therapy. Actuarial survival curves were constructed using the method of Kaplan and Meier.11 All patients who received at least one dose of docetaxel were included in the toxicity evaluation. The characteristics of the 41 patients included in this phase II trial are listed in Table 1. The median age was 74 years; 27 patients (66%) were older than 70 years of age. The six patients who were younger than age 65 were included in this trial for the following reasons: severe coexisting medical illness (two); poor performance status (one); and poor tolerance to previous chemotherapy (three). Thirty patients (73%) had metastases in one or more visceral sites. Twenty patients (49%) had received previous chemotherapy. Fourteen patients (34%) had received previous adjuvant therapy, and 10 patients (25%) had received one previous regimen for metastatic disease. Seven patients (17%) had received previous doxorubicin as part of either adjuvant therapy (six) or treatment for metastatic disease (one).
Thirty-two patients (78%) completed the first course of treatment (8 weeks) and were evaluated for response. Four of the nine patients who did not complete 8 weeks of treatment were removed from the trial as a result of rapid progression of metastatic breast cancer and were considered nonresponders. The remaining five patients were considered inassessable for response. One of the remaining five patients had unacceptable fatigue and requested removal from treatment. Two patients were removed from the trial as a result of exacerbations of pre-existing conditions thought to be unrelated to weekly docetaxel (worsening congestive heart failure, one patient; frequent episodes of supraventricular tachycardia, one patient). The final two patients requested withdrawal from trial for unclear reasons; one had achieved a partial response after five doses, and one was stable after three doses. Twenty-six (81%) of 32 patients who completed the first course of therapy received all of the intended docetaxel doses. During the first course, 156 (81%) of 194 doses were administered at full dose, six doses (3%) were given at 75%, and 32 doses (16%) were omitted. Dose reductions remained uncommon in subsequent courses. Responses to treatment with weekly docetaxel are summarized in Table 2. Twelve (33%) of 36 assessable patients had objective response to treatment when restaged after 8 weeks of treatment (partial response, 11 patients; complete response, one patient). Fourteen additional patients (39%) had either stable disease or minor response at the time of first re-evaluation and continued treatment with weekly docetaxel. One of these patients subsequently achieved a partial response with continued treatment. Therefore, a total of 13 patients (36%) had objective responses, and 72% had either objective response or stable disease. Ten patients (28%) had progressive breast cancer either at the 8-week restaging or before completing the first 8 weeks of treatment. Twelve (46%) of the 26 assessable patients with visceral metastasis had objective responses. All 13 major responses were seen in patients receiving first-line treatment for metastatic breast cancer.
Patients with objective response or stable disease received a median of 12 doses (ie, two 8-week courses) of docetaxel therapy (range, three to 23 doses). Eight of these 26 patients were removed from therapy at the time of disease progression. Nine patients discontinued weekly docetaxel because of poor tolerance (usually fatigue), while nine had treatment discontinued for other reasons. The median response duration in patients with objective response was 8 months (range, 6 to 27 months). In the 13 patients with stable disease, median time to progression was 5 months (range, 3 to 21 months); seven of these 13 patients had stable disease for 24 weeks. The median survival time for the entire group was 13 months, with 1- and 2-year actuarial survival rates of 61% and 29%, respectively (Fig 1).
Treatment-related toxicity is summarized in Table 3. In general, weekly docetaxel was well tolerated by this group of elderly patients with advanced breast cancer. Severe leukopenia was uncommon, and only two patients required omission of scheduled doses on this basis. Thrombocytopenia did not occur, and anemia requiring RBC transfusions was observed in only two patients. Fatigue and asthenia were the most common nonhematologic treatment-related toxicities; severe (grade 3) fatigue occurred in eight patients (20%), but less severe symptoms were reported by 30 additional patients (73%; grade 1, 16 patients; grade 2, 14 patients). In many of these elderly patients with advanced breast cancer, the distinction between cancer-related and treatment-related fatigue was difficult. Other nonhematologic toxicities were uncommon, as indicated in Table 3. There were no treatment-related deaths.
The results of this phase II trial document a high level of activity for weekly docetaxel in the treatment of metastatic breast cancer. In this group of elderly patients, a 36% major response rate was achieved, and 72% of patients had stable disease or better at the time of re-evaluation. The median response duration of 8 months is comparable to response durations produced by various combination regimens. Response rates were similar in patients with visceral and nonvisceral sites of metastases. The elderly and poor-performance status nature of this patient population is reflected in the small percentage who had received previous anthracycline therapy, currently considered a part of standard adjuvant therapy in our practice. Because this trial contained a selected subset of patients with metastatic breast cancer, comparisons of the efficacy of weekly docetaxel versus docetaxel administered every 3 weeks are difficult. However, the results of this study further substantiate the activity of the weekly schedule of docetaxel. Similar efficacy of weekly docetaxel has been recently reported by other investigators, although not specifically in an elderly patient population. Burstein et al12 treated 29 women with docetaxel 40 mg/m2 administered weekly for 6 out of 8 weeks and observed a 41% objective response rate (58% if stable patients are also included) with modest toxicity. Preliminary information from other phase I and phase II trials using weekly docetaxel (35 to 40 mg/m2) have also documented major response rates of approximately 40% in patients with advanced breast cancer.13-15 Although both schedules of docetaxel are efficacious in the treatment of breast cancer, the toxicities of these two schedules differ markedly. With weekly docetaxel, only two patients (5%) developed grade 3/4 leukopenia, and only one patient required hospitalization for treatment of neutropenia and fever. Dose reductions were uncommon. Therefore, the average docetaxel dose rate was 27 mg/m2/wk (factoring in the 2 weeks of every 8 with no treatment). In contrast, 90% to 95% of patients with advanced breast cancer who received docetaxel 100 mg/m2 every 3 weeks developed grade 3 or 4 leukopenia (grade 4, 72%), and 24% required hospitalization for treatment of infections.1,2 Although the calculated docetaxel dose using the every 3-week dosing schedule was 33 mg/m2/wk, a substantial percentage of patients required dose reductions, so the actual dose rate achieved was less than this calculated dose. Nonhematologic toxicity was reduced with weekly administration of docetaxel. Specifically, peripheral neuropathy, edema, and gastrointestinal toxicity were uncommon with weekly docetaxel. Although skin and nail toxicity has been reported by others, we did not observe any patients with severe toxicity of this type. Alopecia is also less common with weekly docetaxel. Although 20 patients (49%) in this trial developed alopecia, we have not observed any alopecia with a slightly lower docetaxel dose (30 mg/m2/wk). The only common toxicity with weekly docetaxel was treatment-related fatigue. This toxicity was cumulative and resulted in premature discontinuation of treatment in nine patients who were stable or responding to treatment. Not surprisingly, the incidence of this toxicity in these elderly patients was higher than observed in younger patients with advanced breast cancer.12 In our experience, the severity of treatment-related fatigue with weekly docetaxel increases sharply with increasing weekly dose. A slightly lower weekly dose (eg, 30 mg/m2) would probably be far more easily tolerated. Alternatively, weekly administration for 3 consecutive weeks and then 1 week without treatment may minimize this toxicity. Weekly administration of paclitaxel has also been evaluated in the treatment of metastatic breast cancer and seems to have activity at least comparable to that of paclitaxel administered every 3 weeks. Seidman et al10 reported a response rate of 53% in a group of 30 women receiving either first- or second-line therapy for metastatic breast cancer. With a median weekly paclitaxel dose of 91 mg/m2/wk actually delivered, myelosuppression was uncommon, and dose reductions were rarely required. Severe nonhematologic toxicity was also uncommon when weekly doses were kept below 100 mg/m2. However, grade 1/2 peripheral neuropathy developed in 59% of patients, and grade 1/2 arthralgia/myalgia was reported in 52%. In a preliminary report of a large, community-based trial with weekly paclitaxel (80 mg/m2), Perez et al16 reported 27 responses in 113 assessable patients (24%), and another 42% experienced stable disease. Using an intensive induction schedule of weekly paclitaxel (175 mg/m2/wk), Sikov et al17 reported a high response rate of 78%. However, myelosuppression and peripheral neuropathy became substantial at this dose. At present, it is difficult to compare the efficacy of weekly paclitaxel versus weekly docetaxel; however, high levels of efficacy have been reported with both drugs. Weekly paclitaxel produces more peripheral neuropathy, arthralgias, and myalgias than does weekly docetaxel. Fatigue is probably more common with weekly docetaxel. Weekly docetaxel, therefore, provides an attractive additional option for the treatment of metastatic breast cancer. The response rates of approximately 40% observed in several phase II trials are similar to those obtained with numerous combination regimens, with substantially less toxicity. Several other new antineoplastic agents, including vinorelbine, gemcitabine, and capecitabine, have also shown substantial activity with favorable toxicity profiles in the treatment of metastatic breast cancer, although single-agent response rates are somewhat lower than seen with the taxanes. Sequential single-agent treatment with these well-tolerated drugs provides an attractive strategy for palliative treatment of metastatic breast cancer, particularly since this approach has produced similar survival rates when compared with treatment with more toxic combination regimens.6 The high level of activity and minimal myelosuppression seen with weekly docetaxel also provides attractive possibilities for the development of combination chemotherapy regimens incorporating this schedule. Preliminary data indicate that gemcitabine or vinorelbine can be safely used with docetaxel, and it is likely that the dose-intensity of docetaxel can be better preserved with weekly scheduling than with combination regimens incorporating the every 3-week schedule. Weekly administration of docetaxel with trastuzumab in patients who overexpress Her2 may also optimize the synergy between these two agents. Further exploration of this well-tolerated docetaxel schedule is therefore indicated and may well result in further improvements in the therapy of advanced breast cancer.
Minnie Pearl Cancer Research Network Participating Sites: Tennessee Oncology, PLLC, Nashville, TN; Upstate Carolina, Community Clinical Oncology Program, Spartanburg, SC; Consultants in Blood Disorders and Cancer, Louisville; Graves-Gilbert Clinic, Bowling Green; and Oncology Associates of Western Kentucky, Paducah, KY; Oncology/Hematology Group of South Florida, Miami, FL; Oncology and Hematology of Southwest Virginia, Roanoke, VA; Northeast Alabama Regional Medical Center, Anniston; and Alabama Oncology, LLC, Montgomery, AL; Phoebe Cancer Center, Albany, GA; The Medical Oncology Group, PA, Gulfport, MS; Louisiana Oncology Associates, Lafayette, LA.
Supported in part by Aventis Pharmaceuticals, Bridgewater, NJ, and the Minnie Pearl Foundation, Nashville, TN.
1. Valero V, Holmes FA, Walters RS, et al: Phase II trial of docetaxel: A new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 13: 2886-2894, 1995[Abstract] 2. Ravdin PM, Burris HA, Cook G, et al: Phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. J Clin Oncol 13: 2879-2885, 1995[Abstract] 3. Seidman AD, Tiersten A, Hudis C, et al: Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol 13: 2575-2581, 1995[Abstract]
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Nabholtz JM, Mackey JR, Smylie M, et al: Phase II study of docetaxel, doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer. J Clin Oncol 19: 314-321, 2001 5. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13: 2688-2699, 1995[Abstract] 6. Sledge GW Jr, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin versus paclitaxel versus doxorubicin plus paclitaxel as first-line therapy for metastatic breast cancer. Proc Am Soc Clin Oncol 16: 1a, 1997 (abstr 2) 7. Nabholtz JM, Falkson G, Campos D, et al: A phase III trial comparing doxorubicin and docetaxel to doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 18: 127a, 1999 (abstr 485) 8. Hainsworth JD, Burris HA, Erland JB, et al: Phase I trial of docetaxel administered by weekly infusion in patients with advanced refractory cancer. J Clin Oncol 16: 2164-2168, 1998[Abstract]
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Fennelly D, Aghajanian C, Shapiro F, et al: Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 15: 187-192, 1997 10. Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16: 3353-3361, 1998[Abstract] 11. Kaplan ZL, Meier P: Non–parametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958
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Burstein HJ, Manola J, Younger J, et al: Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 18: 1212-1219, 2000 13. Loeffler T, Droege C, Hausamen TU, et al: Dose dense weekly docetaxel (Taxotere) in metastatic breast cancer. Breast Cancer Res Treat 57: 125, 1999 (abstr 527) 14. Rittershaus A, Luck H, Sholz U, et al: Weekly docetaxel in pretreated patients with metastatic breast cancer. Breast Cancer Res Treat 57: 126, 1999 (abstr 552) 15. Fornasiero A, Daniele O, Ghiotto C, et al: Weekly docetaxel for metastatic breast cancer: A phase II trial. Breast Cancer Res Treat 57: 127, 1999 (abstr 534) 16. Perez EA, Irwin DH, Patel R, et al: A large phase II trial of paclitaxel administered as a weekly one hour infusion in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 18: 126a, 1999 (abstr 480) 17. Sikov W, Akerley W, Strenger R, et al: Weekly high-dose paclitaxel demonstrates significant activity in advanced breast cancer. Proc Am Soc Clin Oncol 17: 112a, 1998 (abstr 432) Submitted February 13, 2001; accepted April 26, 2001.
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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
