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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

From the Departments of Radiotherapy and Oncology and Gynecology, Turku University Hospital, and Department of Biostatistics, University of Turku, Turku, Finland.

Address reprint requests E. Salminen, MD, Department of Radiotherapy and Oncology, Turku University Hospital, Kiinamyllynk 4-8, 20520 Turku, Finland; email eeva.kaarina.salminen{at}utu.fi

	ABSTRACT

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PURPOSE: Patients with metastatic breast cancer, especially those with progression after several prior chemotherapy treatments, need efficient chemotherapy. This study investigates the efficacy and toxicity of docetaxel in metastatic breast cancer patients with previous chemotherapy for metastatic disease.

PATIENTS AND METHODS: Thirty-one women (median age, 52 years; range, 40 to 65 years) treated for metastatic breast cancer with docetaxel were included. Eleven patients had one metastatic site, 10 patients had two, and 10 patients had three or more. The planned dose of docetaxel per course was the standard treatment of 100 mg/m² (or 75 mg/m² if liver enzyme levels were abnormal) every 3 weeks, given for six or eight cycles.

RESULTS: The overall response rate was 48% (three complete responses [CR] and 11 partial responses [PR] ), and the median duration of response was 7 months (range, 2 to 16 months). Twenty patients (65%) experienced fatigue, and 27 patients (87%) had alopecia. Fifteen cases (48%) of grade 4 leukopenia were observed. Edema with a weight gain of 2 to 15 kg was seen in 12 patients (39%), and mucositis occurred in 20 patients (65%). Twenty-three patients (74%) interrupted treatment before reaching the planned number of courses, nine patients owing to progression of cancer and 14 owing to toxicity. Dose reduction was required in 18 (61%) of the patients. Only two patients were able to receive the planned eight courses without dose reduction.

CONCLUSION: Docetaxel is highly active in metastatic breast cancer, even as a third-line treatment, and can be considered as an efficient standard option in second-line treatment. The standard recommended dose level of 100 mg/m² is not feasible in heavily pretreated patients; therefore, for such patients, an initial dose level not exceeding 75 mg/m² is recommended.

	INTRODUCTION

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BREAST CANCER IS the most common cancer in women in the Western world, affecting one in every 12 women. Fifty percent of all breast cancer patients eventually develop metastases, and breast cancer is the primary cause of cancer mortality among women, contributing to 13% of cancer deaths.¹ In the United States, breast cancer is the leading cause of mortality for women between the ages of 40 and 55 years. Once metastases have been documented, the mean survival of patients is approximately 2 years.² Chemotherapy is the preferred treatment for women of any age with rapidly growing breast cancer, massive liver involvement, or lung or skin involvement with lymphangitic metastases, disease-free survival less than 2 years, and no hormonal activity of the cancer.³

During the past decade, new chemotherapeutic agents have become available for the treatment of metastatic breast cancer. Until the introduction of taxoids (docetaxel and paclitaxel), anthracyclines were recognized as the best single agents for the treatment of breast cancer.⁴ Docetaxel is a synthetic taxane isolated from the needles of the European yew tree (Taxus baccata). Docetaxel promotes abnormal polymerization of tubulin and arrests depolymerization of microtubule elements necessary for the proper functioning of the mitotic spindle and other microtubule-based structures⁵ (data on file, Rhône-Poulenc Rorer, Antony, France). In cell culture studies, the activity of docetaxel has also exceeded that of other taxanes.⁶ Docetaxel has been reported to have considerable activity in advanced breast cancer as first-line chemotherapy^7,8 and as second-line chemotherapy.⁹ In palliation, the efficacy must be carefully evaluated in relation to toxicity to estimate the benefit of the given treatment for the patient. This phase II study investigated the efficacy and safety (feasibility) of docetaxel in metastatic breast cancer patients pretreated with chemotherapy.

	PATIENTS AND METHODS

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Patients
A total of 31 patients were enrolled from April 1996 to May 1998. Eligible patients were women age 18 to 70 years with histologically confirmed metastatic breast cancer. Prior chemotherapy, except high-dose treatment with stem-cell support in an adjuvant or metastatic setting, and prior hormonal therapy or radiotherapy were permitted. Eligibility requirements included the presence of progressive measurable and assessable disease, with a performance status of 2 or lower, WBC count over 3,000/mm³, platelet count of 130,000/mm³ or more, and liver functions of less than three times the normal value. Patients with clinical or radiologic evidence of brain metastases, as well as patients with evidence of active infection, were excluded.

The study was conducted according to the ethical standards described in the Helsinki declaration. Approval for the protocol was given by the ethical committee of Turku University Hospital.

Docetaxel Dose
The docetaxel dose per course was the standard recommended 100 mg/m² (or 75 mg/m² if liver enzyme levels were abnormal) every 3 weeks, given as a 1-hour intravenous infusion, as recommended by the manufacturer (Rhône-Poulenc Rorer, Antony, France). The treatment was preceded by dexamethasone 8 mg orally, given the previous night; dexamethasone 8 mg bid was continued for 4 days. Dose modification was based on observed toxicities and frequently was needed. If the patients gave evidence of progressive disease at the first evaluation after the fourth cycle, the treatment was changed (nine patients, 31%). The aim was to give six to eight cycles to responding patients. Dose reduction was necessary in 18 patients (61%) owing to cytopenia (eight patients, 26%), elevated liver enzymes (three patients, 10%), or other toxicity (six patients, 20%). Seven patients received eight cycles, six patients received seven cycles, six patients received six cycles, and two patients received five cycles of docetaxel.

Monitoring
Before beginning the treatment, all patients had a complete physical examination, including measurement of tumor lesions, complete blood cell count, serum chemistry, chest X-ray, computed tomography or ultrasound examination of the liver, ECG, and bone scintigraphy if clinically indicated. A blood cell count was required before each treatment. Assessment of tumor response was repeated after every three or four cycles of therapy, and no more than eight treatments were recommended. Maintenance treatment of the physician's choice was permitted.

After the treatment, follow-up studies included physical examination, performance scale assessment, blood cell count, and serum chemistry, as well as assessment of the size of target lesions.

Response
Tumor response was evaluated after the third or fourth and eighth cycle of therapy according to World Health Organization criteria, and 29 of the 31 patients were assessable for response. After the first dose, one patient, who previously had had psoriasis, developed an infectious skin rash and pustulous psoriasis requiring several months of specific care; further treatment with docetaxel was deferred, and she was evaluated only for toxicity. Another patient developed an ileal occlusion after the second cycle and therefore was not evaluated for response.

Toxicity
Toxicity to chemotherapy was evaluated using World Health Organization criteria.¹⁰ Hematologic counts were performed on the day before treatment, and midcycle counts were taken if clinically indicated.

	RESULTS

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Patient characteristics are listed in Table 1. The median age was 52 years. Breast cancer was initially diagnosed in the left breast in 19 patients and in both breasts in four patients. Nineteen patients were estrogen receptor– and progesterone receptor–positive, and 12 patients were hormone receptor–negative.

The number of metastasis sites was one in 11 patients, two in 10 patients, and three or more in 10 patients. Lymph nodes (14), bone (14), liver (13), lung (six), bone marrow (three), and skin (seven) were most frequently affected. All patients had assessable disease. Docetaxel was given as first-line chemotherapy for metastatic cancer (after adjuvant chemotherapy) in five patients, second-line in 17 patients, third-line in six patients, and fourth-line in three patients.

Response
The overall response rate was 48% (three complete responses [CR] and 11 partial responses [PR]). Responses were seen at all sites of disease and in patients with more than three sites of disease involvement (four patients). A CR was observed in patients with skin or lymph node involvement only. Although the shortest responses were of only 2 months' duration, long-lasting responses were also observed (CR, 13 months; PR, 14 months). Ten patients had stable disease, and five patients progressed during treatment.

The response was not dependent on the number of previous treatments with chemotherapy (Table 2). No correlation between the extent of disease, number of metastatic sites, and response was seen in these patients.

The median duration of response for the 14 patients with CR and PR was 7 months (range, 2 to 16 months). Five of the responding patients (one CR, four PR) were treated after docetaxel with antiestrogens, and two patients (both PR) were given a low-dose methotrexate and fluorouracil combination as maintenance therapy until progression. The median duration of response was 8 months for these patients and 5 months for patients who did not receive further treatment.

Toxicity
Hematologic toxicity is shown in Table 3, and nonhematologic chemotherapy-associated toxicity is summarized in Table 4. Toxic events were common, and most patients experienced fatigue during treatment. Fluid retention and/or weight gain was observed in 12 patients (39%). Significant edema and weight gain of more than 3 kg occurred only after the third cycle. In two patients, it was so extensive (9 and 15 kg) that treatment had to be discontinued at the patient's request. After treatment, the edema abated within 7 weeks. Dose reductions were frequent, owing to objective or subjective toxicity. Only two patients received eight cycles without dose reduction. Dose reduction was 50% in two patients, 30% in nine patients, 25% in four patients, 20% in two patients, and 10% in one patient. The number of cycles and reasons for dose reductions are listed in Table 5. The reason for dose reduction was cytopenia in eight patients, elevated liver enzymes in three patients, nonhematologic toxicity (neuropathy, neurologic symptoms, erythrodermia, low albumin and ascites, and edema [x2]) in six patients, and other reasons in two patients.

	DISCUSSION

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Of the current anticancer agents available, taxanes produce the highest response rates in breast cancer patients.¹¹ As a single agent used in first-line chemotherapy for patients with metastatic breast cancer, docetaxel 75 to 100 mg/m², administered as a 1-hour intravenous infusion once every 3 weeks, has demonstrated significant antitumor activity in metastatic breast cancer,¹² exceeding that reported with both older agents and newer ones, such as vinorelbine, edatrexate, and gemcitabine. It is important to observe, however, that comparative studies with these newer agents have not yet been reported.

We observed significant efficacy of docetaxel in patients treated even as second- or third-line therapy for metastatic breast cancer. Our results in patients with multiple sites of cancer and visceral metastases confirms the high response rate reported earlier,¹³ even for patients with previous chemotherapy treatments.¹⁴ However, our analysis of the dose levels and toxicity shows the toxic limitations of docetaxel when used in the later phases of breast cancer. Only two patients were able to tolerate the full planned regimen. Toxicity seriously decreased the patients' quality of life. Despite the good response, some patients were unable to continue receiving docetaxel because of toxicity, although only six to eight treatments were planned for the entire regimen. Despite this need for dose reduction, our response rate remained similar to those reported in other studies.

The relatively low incidence of fever and infections among our patients is certainly due to dose reduction. Because the patients were treated for palliative indications, the policy was to avoid jeopardizing their quality of life, and therefore the dose was reduced when significant subjective or objective toxicity was observed. The feasibility of weekly docetaxel has been recently reported in phase I studies,¹⁵ and this approach may also provide a less toxic alternative in advanced breast cancer.

Among our patients, the occurrence of severe fluid retention was less frequent than is usually reported for docetaxel.¹⁶ The likely explanation is dose reduction and the early interruption required for several of our patients. The cumulative dose of docetaxel has been shown to be the most important predictor of fluid retention, along with other, less significant factors, such as drug exposure at the first course and treatment duration.

Although dose reduction was common, the observed responses were similar to those reported in previous series, in which higher doses have been used.^11,17 This important finding is in agreement with the results of studies using docetaxel at a dose of 60 mg/m², resulting in a 44% response rate,¹⁵ or 75 mg/m², resulting in a 50% response rate.¹⁸ As in our study, in the series of Archer et al,¹⁴ more than half of the patients who were heavily pretreated needed a significant dose reduction of 25% to 45%. On the basis of these earlier results and our experience, we suggest a dose level lower than 100 mg/m² for patients with several prior chemotherapy regimens and extensive metastases. We have changed our recommendation of an initial dose of 75 mg/m², even for patients with normal liver function, when docetaxel is prescribed as second- or further-line treatment. It is also important to explore new methods for defining the optimal dose level for the individual patient.¹⁹ With regard to docetaxel, preliminary studies²⁰ have indicated that such a method could be the determination of serum alpha-1-acid glycoprotein at baseline and its correlation with docetaxel toxicity and efficacy.

The need for quality-of-life assessment during treatment with taxanes has been pointed out recently.¹⁴ On the basis of our experience with docetaxel as the last effective treatment in the series of treatments for patients with metastatic breast cancer, we believe that defining the optimal way of using docetaxel in breast cancer is needed. This drug has great potential in the treatment of breast cancer. Responses have been observed even after several previous treatments. If toxicity can be avoided, patients can benefit more from this effective drug when it is used earlier, as an adjuvant or as first-line treatment for metastatic disease. Studies addressing this issue are under way.²¹

Our aim was to give a maximum of eight treatments, but achievement of this goal was rarely possible, owing to toxicity. However, responses were obtained and maintained for a significant time with a dose level lower than initially planned. With respect to the currently available clinical data on docetaxel, we conclude that the standard dose level recommended (100 mg/m²) is significantly toxic for breast cancer patients treated on a second- or third-line basis. We recommend an initial dose level not exceeding 75 mg/m² every three weeks, especially for patients receiving earlier treatments for palliative indications.

In conclusion, docetaxel is highly active in breast cancer patients previously treated with chemotherapy, even as third-line treatment; however, it has significant toxicity. Individual dose adjustment according to toxicity does not decrease response in a palliative setting, and the initial dose level should not exceed 75 mg/m² for pretreated patients.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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2. Mouridsen H: Systemic therapy of advanced breast cancer. Drugs 44:17-28, 1992

3. Harris J, Morrow M, Bonadonna G: Cancer of the breast. In De Vita VT Jr, Hellman S, Rosenberg S (eds): Cancer: Principles and Practice of Oncology (ed 4). Philadelphia, PA, Lippincott, 1993, pp 1264-1332

4. Ravdin P: Docetaxel (Taxotere) for the treatment of anthracycline-resistant breast cancer. Semin Oncol 24:S10-18-S10-21, 1997 (suppl 10)

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6. Vogel M, Hilsenbeck S, Depenbrock H, et al: Preclinical activity of Taxotere against freshly explanted clonogenic human tumour cells: Comparison with Taxol and conventional antineoplastic agents. Eur J Cancer 29A:2009-2014, 1993

7. Chevallier B, Fumoleau P, Kerbrat P, et al: Docetaxel is a major cytotoxic drug for the treatment of advanced breast cancer: A phase II trial of the Clinical Screening Cooperative Group of the European Organization for Research and Treatment of Cancer. J Clin Oncol 13:314-322, 1995[Abstract/Free Full Text]

8. Hortobagyi G: Docetaxel: Today's results and tomorrow's promises. Oncology (Huntingt) 8:11-14, 1997 (8 suppl 8)

9. ten Bokkel Huinink WW, Prove AM, Piccart M, et al: A phase II trial with docetaxel (Taxotere) in second line treatment with chemotherapy for advanced breast cancer: A study of the EORTC Early Clinical Trials Group. Ann Oncol 5:527-532, 1994[Abstract/Free Full Text]

10. World Health Organization: Handbook for Reporting Results of Cancer Treatment: WHO publication no. 48. Geneva, Switzerland, World Health Organization, 1979

11. Clemons M, Leahy M, Valle J, et al: Review of recent trials of chemotherapy for advanced breast cancer: The taxanes. Eur J Cancer 33:2183-2193, 1997

12. Trudeau M: First line treatment of metastatic breast cancer. Anticancer Drugs 7:9-12, 1996 (suppl 2)

13. 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]

14. Archer CD, Lowdell C, Sinnett HD, et al: Docetaxel: Response in patients who have received at least two prior chemotherapy regimens for metastatic breast cancer. Eur J Cancer 34:816-819, 1998

15. Hainsworth J, Burris H, Erland J, 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]

16. 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[Abstract/Free Full Text]

17. Adachi I, Watanabe T, Takshima S, et al: A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer. Br J Cancer 73:210-216, 1996[Medline]

18. Dieras V, Chevallier B, Kerbrat P, et al: A multicentre phase II study of docetaxel 75 mg/m² 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]

19. Ratain M: Body-surface area as a basis for dosing of anticancer agents: Science, myth, or habit? J Clin Oncol 16:2297-2298, 1998[Medline]

20. Bruno R, Olivares R, Berille E, et al: Alpha-1-acid glycoprotein is an independent predictor of efficacy and survival in NSCLC patients treated with docetaxel. Proceedings Am Soc Clin Oncol 16:471a, abstract 1812, 1998

21. Piccart M, Di Leo A: Future perspectives of docetaxel (Taxotere) in front-line therapy. Semin Oncol 24:S10-27-S10-33, 1997 (suppl 10)

Submitted July 14, 1998; accepted December 22, 1998.

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