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The Oncologist, Vol. 6, Suppl 3, 26-29, June 2001
© 2001 AlphaMed Press

SUPPLEMENT

Weekly Docetaxel in Breast Cancer: Applying Clinical Data to Patient Therapy

Jose Baselga, Josep M. Tabernero

Vall d'Hebron University Hospital, Barcelona, Spain

Correspondence: Jose Baselga, M.D., Vall d'Hebron University Hospital, Servicio de Oncologia, P. Vall D'Heron 119-129, Barcelona 08035, Spain. Telephone: 34-93-274-6077; Fax: 34-93-274-6059; e-mail: baselga{at}hg.vhebron.es


   ABSTRACT
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 Abstract
Introduction
 Phase II Studies of...
 Ongoing Randomized Studies
 Discussion
 References
 
The use of weekly 35-40 mg/m2 docetaxel, typically on a schedule of 6 weeks of therapy followed by a 2-week break, has produced response rates ranging from 33%-50% in patients with advanced breast cancer, the majority of whom have already received chemotherapy. These encouraging levels of response are seen across disease sites and in patients with prior anthracycline exposure. Importantly, the weekly administration of docetaxel allows prolonged treatment to a high cumulative dose: the weekly regimen is minimally myelotoxic, and neuropathy and other adverse events are infrequent. Weekly single-agent docetaxel may be a useful therapy in particular groups of patients such as those with reduced bone marrow reserve. It may also be a helpful means of delivering a highly active cytotoxic drug in combination with radiation therapy, other proven chemotherapy agents such as doxorubicin, and new, highly promising biological agents such as Herceptin.

Key Words. Advanced breast cancer • Docetaxel • Weekly schedule • Doxorubicin • Herceptin


   INTRODUCTION
Top
 Abstract
 Introduction
Phase II Studies of...
 Ongoing Randomized Studies
 Discussion
 References
 
Although consensus quickly emerged that the clinical development of docetaxel should concentrate on administration of the drug at 75-100 mg/m2 over 1 hour every 3 weeks, early work showed the drug to be active in metastatic breast cancer when used at a variety of doses and with a range of infusion schedules [1-3]. Subsequently, experience with paclitaxel indicated that weekly use of the drug might maintain efficacy while reducing toxicity when compared with schedules that used larger doses at less frequent intervals [4-6]. The suggestion that this might also be true with docetaxel was a natural corollary and has produced considerable interest: weekly regimens may enhance dose density and also have potential for use in combination with radiation therapy and new biological agents such as the anti-HER-2 and anti-epidermal growth factor receptor agents.

Initial work with weekly docetaxel involved patients with a variety of advanced malignancies and produced encouraging evidence of reduced hematological toxicity [7-9]. In the trial of Hainsworth et al., 58 patients received a total of 284 treatments with weekly docetaxel at doses ranging from 20 mg/m2/week to 52 mg/m2/week [7]. Treatment was administered for 6 weeks, followed by a 2-week rest. No cases of grade 2, 3, or 4 thrombocytopenia occurred; and no cases of grade 2 or greater neutropenia were seen with doses of less than 43 mg/m2/week. In addition to causing minimal hematotoxicity, phase I data showed that weekly docetaxel was likely to be associated with a very low incidence of the other acute toxicities.


   PHASE II STUDIES OF WEEKLY DOCETAXEL IN ADVANCED BREAST CANCER
Top
 Abstract
 Introduction
 Phase II Studies of...
Ongoing Randomized Studies
 Discussion
 References
 
These encouraging data were followed by a number of phase II trials, several of which are now reasonably mature and have reported similar response rates (RR) [10-13]. Thus Burstein et al. found an RR of 41% in a population of 29 patients (37% of whom were receiving first-line therapy) treated with weekly 40 mg/m2 docetaxel i.v. administered over 1 hour [10]. The RR was 47% in 14 second-line (or more extensively pretreated) patients who received weekly 35 mg/m2 docetaxel over 1 hour [11]. In a similar population of 43 patients, Loeffler et al. found an RR of 50% following weekly treatment with 40 mg/m2 docetaxel given over 15-30 minutes [12, 13]. In all three studies, treatment was administered weekly for 6 weeks, followed by a 2-week rest (Table 1Go).


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  		Table 1. Weekly docetaxel in advanced breast cancer: phase II studies [10-13]
 
In the Burstein study, the median number of weeks on protocol was 22, and the median cumulative dose of docetaxel administered was 720 mg/m2 (range 80-1,440+ mg/m2) [10]. This is approximately twice the figure that is typically achieved using the classic q 3-week schedules. The median dose intensity of 30 mg/m2/week seen in this trial was close to that predicted. Dose reductions were needed in 8 of the 29 patients studied, but occurred late (after a median of 16 cycles). The need for dose reduction (which in five cases was due to fatigue) reflects the emergence after prolonged therapy of a pattern of toxicity which is different from that seen with 3-weekly schedules.

Interestingly, the overall 41% RR in this study was consistent across disease sites, being the same in patients with lung and liver metastases as in the total population. Importantly, the RR was maintained in patients with prior exposure to anthracyclines (in whom the RR was 44%). Of the 12 responses, five occurred after the first cycle of 6 weeks of treatment, and seven after the second cycle. It is also worth noting that disease was stabilized for 6 months or more in an additional 17% of the overall population of 29 patients.

Hematological toxicity in this study was minimal. Grade 3 neutropenia occurred in 14% of patients, and grade 4 neutropenia in none. There were no cases of grade 3 or 4 anemia or thrombocytopenia of any grade. As a criterion for entry into the study, patients had to have a platelet level greater than 100,000. However, given the absence of thrombocytopenia, this weekly docetaxel regimen may well be worth exploring in patients with a much reduced marrow reserve.

In the trial by Loeffler et al., the overall 50% RR seen in the 43 patients treated included a complete response (CR) in 12% [12, 13]. Responses were seen among those patients who had received prior anthracycline therapy: of 23 patients exposed to epirubicin, three had a CR and eight a partial response (PR). Overall in the study, the median duration of remission was 8.8 months (range 2-12+ months). Median survival is 12.8 months or longer. The median dose intensity achieved, at 36 mg/m2 docetaxel per week, was similar to the 30 mg/m2 figure reported in the study of Burstein et al. [10].

The hematological and nonhematological toxicities seen in the two studies are summarized in Table 2Go. Along with the low incidence of hematological adverse events, these data are striking for the absence of diarrhea and the low incidence of grade 3/4 neuropathy. Fatigue/asthenia may occur with prolonged therapy, as may fluid retention, although at a higher cumulative dose than is seen with 3-weekly schedules. A new toxicity of frequent tearing and visual problems, which is generally mild and manageable, may also occur after substantial total exposure to weekly docetaxel.


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  		Table 2. Grade 3/4 toxicities in two phase II studies of 40 mg/m2 weekly docetaxel in advanced breast cancer [10, 12, 13]
 
Recently, confirmation of consistently encouraging RRs and low rates of neutropenia following weekly docetaxel has come from four further studies (Table 3Go) [14-17]. In the study by Jackisch et al., 60 patients (53 of them second-line) received 35-40 mg/m2 docetaxel per week [14]. The RR was 33%, and grade 3-4 neutropenia complicated 3.5% of therapy cycles. Kim et al. used 40 mg/m2 docetaxel given for 3 weeks followed by a 1-week rest in 36 patients, one-third of whom had previously been exposed to anthracyclines [15]. The RR was 36% and the incidence of grade 3-4 neutropenia 16%. Ramos et al. used a 40 mg/m2 docetaxel dose but repeated treatment for 6 weeks, followed by a 2-week break [16]. The RR in 31 patients (all anthracycline exposed) was 42% and the incidence of neutropenia 20%. In the study by Stemmler et al., a schedule of 6 weeks of therapy using 35 mg/m2 weekly docetaxel and then a 2-week rest was followed by 3 weeks of treatment and a 2-week break [17]. Of the 35 patients treated, 32 had previously received anthracyclines, and in five cases a taxane had been used. The RR was 34%, and a total of 83% had disease control. The incidence of grade 3-4 neutropenia was 9%.


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  		Table 3. Recent trials with weekly docetaxel in metastatic breast cancer: ASCO 2000 update [14-17]
 

   ONGOING RANDOMIZED STUDIES
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 Abstract
 Introduction
 Phase II Studies of...
 Ongoing Randomized Studies
Discussion
 References
 
Which Docetaxel Schedule in Advanced Breast Cancer?
The efficacy and toxicity data obtained in phase II studies of weekly docetaxel are sufficiently good for such a schedule to be compared with the conventional schedule for administering the drug. In the Spanish Co-operative Group's SOLTI trial, patients with metastatic breast cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of two or less who have received one prior chemotherapy regimen (in either the adjuvant or advanced setting) are being randomized to the classical schedule of docetaxel 100 mg/m2 q 3 weeks or 40 mg/m2 docetaxel weekly for 6 weeks, followed by a 2-week pause.

The primary purpose of the study is to determine whether there is a significant difference between the two regimens in the incidence of grade 3-4 toxicities. Secondary endpoints include RR, duration of response, the survival rate at 1 year and dose density delivered.

Which Taxane and Schedule for Adjuvant Therapy?
Weekly and conventional schedules for administering the taxanes are to be compared directly in the planned ECOG 1199/Intergroup trial in which approximately 5,000 patients will be randomized to four arms. Following four cycles of treatment with doxorubicin plus cyclophosphamide, patients will receive either paclitaxel 80 mg/m2 weekly for 12 weeks, paclitaxel 175 mg/m2 q 3 weeks x 4, docetaxel 35 mg/m2 weekly for 12 weeks, or docetaxel 100 mg/m2 q 3 weeks x 4. Disease-free and overall survival and toxicity are the primary endpoints of the trial.

Weekly Docetaxel in Combination
A particular advantage of any less toxic drug regimen, such as weekly docetaxel, is its potential for use in combination with other agents. One provocative study in this context is that of Manga et al. who entered 62 patients with locally advanced or metastatic breast cancer into a trial in which they were treated with doxorubicin 50 mg/m2 on day 1 and docetaxel 36 mg/m2 on days 1, 8, and 15 [18]. Cycles were repeated monthly.

Among the 15 evaluable patients with locally advanced disease, there were 5 CRs and 9 PRs, giving an overall RR of 93%. In the 28 patients with metastatic breast cancer, the overall RR was 64% (with 4 CRs and 14 PRs). G-CSF was not routinely administered, yet grade 3-4 neutropenia was seen in only 7% of cycles, and febrile neutropenia affected only 4%.

A rather different docetaxel combination is under investigation by Nicholson et al. who are comparing docetaxel 75 mg/m2 q 3 weeks plus herceptin against herceptin plus weekly docetaxel at a dose of 35 mg/m2 [19]. Data are extremely preliminary but out of 16 evaluable patients in the conventional docetaxel arm, there has been an RR of 44% while the RR is 54% among 16 patients assigned to herceptin plus weekly docetaxel.


   DISCUSSION
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 Abstract
 Introduction
 Phase II Studies of...
 Ongoing Randomized Studies
 Discussion
References
 
The value of weekly docetaxel lies not just in its activity and tolerability per se but in the fact that such a regimen increases the options available to patients and clinicians alike. In different contexts, and with different types of patients, it should be increasingly possible to tailor therapy to individual needs. The same is true in focusing our research efforts on strategies likely to be most effective. Figure 1Go presents a proposed algorithm based on our current understanding.



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  		Figure 1. Docetaxel: proposed algorithm for systemic treatment in advanced disease.

 
For patients who are HER-2-positive, there needs to be a concentration on clinical development programs that combine agents such as docetaxel (weekly or 3-weekly) with platinum compounds and herceptin. For HER-2-negative women, an obvious initial approach would be combinations such as docetaxel plus anthracyclines. Those less able to withstand such therapy could be considered for treatment with weekly docetaxel regimens, possibly in combination with other agents such as vinorelbine, gemcitabine, and capecitabine.


   REFERENCES
Top
 Abstract
 Introduction
 Phase II Studies of...
 Ongoing Randomized Studies
 Discussion
 References
 

  1. Ravdin PM. Treatment of patients resistant to anthracycline therapy. Anticancer Drugs 1996;7(suppl 2):13-16.
  2. Nabholtz J-M, Tonkin K, Smylie M et al. Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer? Exp Opin Pharmacother 2000;1:187-206[CrossRef][Medline]
  3. Crown J. Evolution in the treatment of advanced breast cancer. Semin Oncol 1998;25(suppl 12):12-17.
  4. Seidman AD, Hudis CA, Albanel J et al. Dose-dense therapy with weekly one-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 1998;16:3353-3361.[Abstract]
  5. Klaasen U, Wilke H, Strumberg D et al. Phase I study with a weekly one-hour infusion of paclitaxel in heavily pre-treated patients with metastatic breast and ovarian cancer. Eur J Cancer 1996;32A:547-549.
  6. Briasoulis E, Tzamakou E, Nicolaides C et al. Long-term weekly administration of paclitaxel in chemotherapy-naive patients, phase I study. Proc Am Soc Clin Oncol 1997;16:811a.
  7. 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 1998;16:2164-2168.[Abstract]
  8. Briasoulis E, Karavasilis V, Anastasopoulos D et al. Weekly docetaxel in minimally pretreated cancer patients: a dose escalation study focused on feasibility and cumulative toxicity of long-term administration. Ann Oncol 1999;10:701-706.[Abstract/Free Full Text]
  9. Lück HJ, Donnè S, Glaubitz M et al. Phase I study of weekly docetaxel (Taxotere) in heavily pretreated breast cancer patients. Eur J Cancer 1997;33(suppl 8):S158a.
  10. Burstein HJ, Manola J, Younger J et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000;18:1212-1219.[Abstract/Free Full Text]
  11. Climent MA, Ruiz A, Llombart-Cussac A. Weekly docetaxel in patients with advanced malignancies. Toxicity profile and activity results. Proc Am Soc Clin Oncol 1999;18:453a.
  12. Loeffler T. Is there a place for "dose-dense" weekly schedules of the taxoids? Semin Oncol 1999;25:32-34.
  13. Loeffler TM, Freund W, Hausamen TU. Activity of weekly Taxotere (TXT) in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 1998;17:113a.
  14. Jackisch C, Eibach HW, Knuth A et al. Phase-II trial of docetaxel weekly as dose dense treatment in metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 2000;19:417a.
  15. Kim Y, Takatsuka Y, Tanigawara Y et al. Weekly docetaxel for patients with recurrent breast cancer: clinical results and pharmacokinetic/pharmacodynamic assessment. Proc Am Soc Clin Oncol 2000;19:436a.
  16. Ramos M, Gonzalez-Ageitos A, Vicente J. Weekly docetaxel (D) for metastatic breast cancer (MBC) progressing after anthracyclines treatment. Proc Am Soc Clin Oncol 2000;19:445a.
  17. Stemmler J, Gutschow K, Sommer H et al. Taxotere weekly in metastatic breast cancer: evaluation of response and toxicity. Proc Am Soc Clin Oncol 2000;19:455a.
  18. Manga PG, Lopez P, Sancho JF et al. Phase II study of weekly docetaxel (TXT) and doxorubicin (D) as first line treatment of locally advanced or metastatic breast cancer (BC): preliminary results. Proc Am Soc Clin Oncol 2000;19:407a.
  19. Nicholson BP, Thor AD, Goldstein LJ et al. Weekly docetaxel (D) and rhumabher2 (H) combination therapy as first- or second-line treatment for metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 2000;19:549a.
Received February 6, 2001; accepted for publication March 6, 2001.




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