The International Experience With Docetaxel in the Treatment of Breast Cancer

March 1, 1997

The extensively studied agent docetaxel (Taxotere) has shown marked clinical activity in the treatment of anthracycline-resistant breast cancer. Phase I trials indicate that toxicities, such as mucositis and neutropenia, limit the administration of docetaxel to shorter perfusion schedules. Pharmacokinetic studies have shown that docetaxel's clearance by hepatic metabolism is correlated with a marked increase in risk of toxicity in patients with impaired liver function. Nevertheless, studies of docetaxel as front-line therapy for breast cancer were initiated because of its good activity against tumors in early studies and its close relationship to paclitaxel (Taxol), an agent with proven efficacy. Phase II studies have demonstrated excellent activity for docetaxel as a single agent, with an overall response rate of 61% in trials of a 100-mg/m² dose. A phase III study is currently comparing docetaxel with paclitaxel as single-agent therapy. Docetaxel is expected to provide a better response rate but a higher incidence of neutropenia. The agent shows promise in adjuvant therapy, with very high response rates in anthracycline-resistant patients. Preliminary results of tests using docetaxel in combination with doxorubicin show high objective response rates but low complete response rates; early results suggest that this combination may have some advantages over paclitaxel/doxorubicin. [ONCOLOGY 11(Suppl):38-42, 1997]

ABSTRACT: The extensively studied agent docetaxel (Taxotere) has shown marked clinical activity in the treatment of anthracycline-resistant breast cancer. Phase I trials indicate that toxicities, such as mucositis and neutropenia, limit the administration of docetaxel to shorter perfusion schedules. Pharmacokinetic studies have shown that docetaxel's clearance by hepatic metabolism is correlated with a marked increase in risk of toxicity in patients with impaired liver function. Nevertheless, studies of docetaxel as front-line therapy for breast cancer were initiated because of its good activity against tumors in early studies and its close relationship to paclitaxel (Taxol), an agent with proven efficacy. Phase II studies have demonstrated excellent activity for docetaxel as a single agent, with an overall response rate of 61% in trials of a 100-mg/m² dose. A phase III study is currently comparing docetaxel with paclitaxel as single-agent therapy. Docetaxel is expected to provide a better response rate but a higher incidence of neutropenia. The agent shows promise in adjuvant therapy, with very high response rates in anthracycline-resistant patients. Preliminary results of tests using docetaxel in combination with doxorubicin show high objective response rates but low complete response rates; early results suggest that this combination may have some advantages over paclitaxel/doxorubicin. [ONCOLOGY 11(Suppl):38-42, 1997]

Introduction

Docetaxel (Taxotere) is the second taxoid to be widely evaluated inclinical trials. It has some specific apparent advantages and disadvantagesrelative to the first described taxoid, paclitaxel (Taxol). Docetaxel hasbeen approved for the treatment of anthracycline-resistant breast cancer;in this setting, a series of trials shows it to have clinical activitythat is at least as good as and perhaps superior to any other single agent.

Paclitaxel was discovered serendipitously 34 years ago by a programscreening natural products. The recognition of abnormal stabilization ofmicrotubule assembly[1,2] as paclitaxel's mechanism of action allowed forrapid laboratory screening of related compounds.[3] Docetaxel was discoveredduring these screening programs, which were carried out in the early 1980s.

A semisynthetic product, docetaxel is derived from the European yew(Taxus baccata). Although docetaxel and paclitaxel appear to bindto the same site on microtubules, docetaxel seems to bind with higher affinity.[4]In addition, in some cell culture systems, docetaxel accumulated to higherintracellular concentrations and had slower efflux than did paclitaxel.[5]This preclinical work suggested that docetaxel would be more potent thanpaclitaxel but left open the question of whether it would have a more favorabletherapeutic index.

The next logical step in the development of docetaxel was evaluationof the agent's activity against a variety of cell lines in culture. Thesestudies showed that docetaxel had activity against cell lines from a widevariety of tumor types, including cell lines derived from breast, colon,ovarian, sarcoma, and bladder cancers.[6-8] Studies using human primarytumors showed docetaxel to have a broad range of activity and to be partiallynon-cross-resistant with paclitaxel and doxorubicin.[9,10] Preclinicalevaluation has shown that overexpression of p-glycoprotein (the productof the gene mdr-1) and tubulin alterations are two mechanisms ofresistance to docetaxel.

Docetaxel was also evaluated against a number of animal tumor models.In these studies, docetaxel had a high level of activity against many butnot all mammary tumor models. The agent also had a high level of activityin nude mice with human mammary tumor xenografts (MX-1).[11]

Phase I Trials

Docetaxel has been extensively evaluated in phase I trials. The majordose- limiting toxicities observed in these trials were mucositis and neutropenia,with mucositis more prominent in the extended regimens (Table1). For this reason, the schedule selected for phase II studies was1 hour every 3 weeks, and neutropenia was expected to be the major dose-limitingtoxicity on this schedule.

Phase II studies of docetaxel with long perfusion times have not beenconducted because of the prominent mucositis that occurs with these schedules.In the majority of phase II studies, docetaxel has been administered ata dose of 100 mg/m² IV over 1 hour every 3 weeks.

Pharmacokinetics

Extensive studies of the pharmacokinetics of docetaxel have been conducted.[17]The most important finding of these studies is the demonstration that docetaxel,like paclitaxel, is cleared by hepatic metabolism. These studies have showna markedly lower clearance of docetaxel when there was concurrent elevationof transaminases and alkaline phosphatase. The lower clearance rate ofdocetaxel in these patients has been shown to correlate with a markedlyincreased risk of toxicity (Table 2 andTable 3). Docetaxel is also more toxicin patients with elevated bilirubin levels,[18] and thus, is contraindicatedin patients with liver dysfunction.

The pharmacokinetic studies conducted in the phase I and II trials haveshown docetaxel to be largely protein bound. Values of maximum serum concentration(Cmax) and area under the curve (AUC) values were proportionalto dose. Estimates of half-life (t½b) at the 100-mg/m²dose ranged from 11.4 to 18.5 hours.

PhaseII Studies of Docetaxel in Breast Cancer Patients

Docetaxel was taken directly into front-line studies for the treatmentof breast cancer for several reasons. The drug had shown good activityagainst mammary tumors in preclinical models, and a number of responsesin breast cancer patients had been seen in phase I trials. Also, paclitaxel,a closely related agent, is known to have excellent activity in breastcancer.

Several phase II trials have been conducted using docetaxel as front-linetherapy (Table 4). These trials foundexcellent activity for docetaxel as a single agent, with an overall responserate of 61% in the trials conducted with a dose of 100 mg/m².

Docetaxelin Anthracycline-Resistant Breast Cancer

Currently, docetaxel is approved in the United States for the treatmentof anthracycline-resistant breast cancer. Approval of this indication wasbased largely on the results of three trials (Table5). In all three trials, docetaxel was used to treat patients who hadanthracycline- or anthracenedione-resistant disease, defined as diseaseprogression during administration of one of these agents (as opposed tosimple prior exposure during adjuvant therapy). The European study (study3) had the most rigorous definition of anthracycline resistance, allowingonly patients with intrinsic resistance and excluding those with acquiredresistance (ie, initial response to anthracyclines and then progression).

The overall response rate for patients in these studies was 41%. Table6 shows that for patients with evaluable disease, the response ratewas well maintained in patients with visceral disease sites, such as theliver, as well as in patients with multiple disease sites. These resultsare quite striking, given the generally low response rates of other singleagents and combinations in such patients.

Docetaxel Toxicity

The major dose-limiting toxicity of docetaxel, given at 100 mg/m²over 1 hour every 3 weeks, is neutropenia. Toxicity information for docetaxelderived from phase II studies is summarized in Tables 2 and 3. It is clearthat for patients with hepatic compromise, docetaxel at a dose of 100 mg/m²,has unacceptable toxicity. Even in patients with normal hepatic function,docetaxel caused more than 90% of patients to develop grade 4 neutropenia,but the neutropenia generally lasted less than 1 week, and only 4% of patientsper cycle developed neutropenia and fever. Other severe hematologic toxicitiesare rare in patients with normal hepatic function.

Several types of nonhematologic toxicities were noted in these trials.Acute hypersensitivity reactions and neurosensory reactions were rare.Myalgias, when they occurred, were generally mild. Some patients experiencedsevere skin reactions, with peeling of the skin particularly obvious onthe palms. Some patients developed severe asthenia, and a few developedsevere stomatitis.

A toxicity that at first seemed unique to docetaxel is a fluid retentionsyndrome. This syndrome is the result of cumulative toxicity. It is gradualin onset and reversible. In unpremedicated patients, the syndrome can becomesevere, leading to treatment discontinuation.

The fluid retention syndrome seems to be ameliorated largely by thepresent premedication regimen of dexamethasone, 8 mg bid orally, startingthe day of treatment and continuing for 5 consecutive days. Mild peripheraledema may still occur on this regimen, but it can be easily managed withoral diuretics.

Ongoing Trialsand Outstanding Questions

Which Single Agent Is Better--Docetaxel or Paclitaxel?

This question is of obvious importance, and there is an ongoing clinicaltrial to address it. The trial compares docetaxel and paclitaxel at thedoses and schedules for which they are approved in the United States (fordocetaxel, 100 mg/m² IV over 1 hour, every 3 weeks; for paclitaxel,175 mg/m² IV over 3 hours, every 3 weeks). The agents are used asfirst- or second-line therapy in women with prior anthracycline exposure(and those in whom anthracyclines would be contraindicated).

The trial end points include not only objective response rate but alsoresponse duration, survival, toxicity, and quality of life. Given the informationon the package inserts, one might expect docetaxel to have a higher responserate but a greater number of events associated with neutropenia. If thisis borne out, the issue of which single agent to use will be a matter ofphysician judgment.

For physiologically strong patients with immediately life-threateningdisease, docetaxel may be preferable. For patients with comorbidity andfor whom the goal is palliation with a lesser risk of toxicity, perhapspaclitaxel would be preferred. Such a supposition is pure con- jecturebecause the phase III study is ongoing, and given selection biases andother factors, definitive conclusions cannot be drawn by comparing phaseII studies.

A stated objection to the phase III trial is its failure to addressother possible doses and schedules of paclitaxel. This is a valid criticismbut one that is unanswerable in a practical sense, given the multiple dosesand schedules of paclitaxel that have been used or are under study.

Can Docetaxel Have a Major Effect in Adjuvant Therapy?

Several characteristics of docetaxel indicate that it may be a veryfavorable agent to use in adjuvant therapy. The very high response ratesreported in anthracycline-resistant patients suggest that docetaxel isat least partially non-cross-resistant with doxorubicin, and that it mayadd considerable efficacy to an anthracycline-based adjuvant program. Inaddition, the cumulative toxicity (fluid retention) of docetaxel wouldnot be a problem in a typical adjuvant regimen, in which only a few cyclesof drug would be given. Finally, the risk of neutropenia and fever mightbe expected to be lower in a population of patients with no prior therapyand minimal disease, and this risk might be more justifiable when the goalwas cure.

These suppositions are currently being tested in the National SurgicalAdjuvant Breast and Bowel Project (NSABP) neoadjuvant trial B-27. Thistrial compares a standard neoadjuvant regimen based on cyclophosphamide(Cytoxan, Neosar) and doxorubicin with two regimens that add four cyclesof single-agent docetaxel. If docetaxel is as non-cross-resistant withdoxorubicin in early breast cancer as it is in trials of metastatic disease,one might expect that patients receiving docetaxel would do considerablybetter than those not given the additional docetaxel.

Can Docetaxel Be Used in Combination With Other Agents?

Numerous phase I and I/II trials addressing the issue of whether docetaxelcan be used in combination with other chemotherapeutic agents. Preclinicaldata suggest that docetaxel has additive or even synergistic activity withother agents.[28]

At present, the most mature of these clinical combination studies isthat assessing the combination of docetaxel and doxorubicin.[29] This trialhas reported objective response rates of 89%, which suggests that the combinationhas great promise. This objective response rate appears to be as high asthat reported for the combination of paclitaxel and doxorubicin, althoughthe complete response rate (less than 10%) seems to be lower.

Preliminary reports of the docetaxel/doxorubicin trial suggest thatthis combination does not cause congestive heart failure at relativelylow doses of doxorubicin, a problem that has caused concern in the high-responserate trials of paclitaxel/doxorubicin.[30] Although early results suggestthat docetaxel/doxorubicin may have some advantages in comparison to paclitaxel/doxorubicin,the results must be viewed as preliminary until confirmed by a second trial.

Summary

Docetaxel is an exciting new agent for the treatment of breast cancer.It exhibits a high level of efficacy in the front-line treatment of breastcancer, and a high level of non-cross-resistance with anthracyclines, asmany patients with anthracycline-resistant disease have objective responsewhen treated with docetaxel. During this decade, phase I and II trialshave been completed. Docetaxel is now being evaluated in phase II trialsto assess how to best use it in combination with other agents, and in phaseIII trials to compare its efficacy directly with other agents and to defineits role in adjuvant therapy.

References:

1. Fuchs DA, Johnson RK: Cytologic evidence that taxol, an antineoplasticagent from Taxus brevifolia acts as a mitotic spindle poison. Cancer TreatRes 62:1219-1222, 1978.

2. Schiff PB, Horowitz SB: Taxol stabilizes microtubules in mouse fibroblastcells. Proc Natl Acad Sci USA 77:1561-1565, 1980.

3. Bissery M-C, Nohynek G, Sanderink G-J, et al: Docetaxel (Taxotere):A review of preclinical and clinical experience. Anticancer Drugs 6: 339-368,1995.

4. Ringel I, Horowitz SB: Studies with RPR 56976 (Taxotere) a semisyntheticanalogue of Taxol. J Natl Cancer Inst 83: 288-291, 1991.

5. Lavelle F, Bissery MC, Combeau C, et al: Preclinical evaluation ofdocetaxel (Taxotere). Semin Oncol 22(suppl 4):3-16, 1995.

6. Riou JF, Naudin A, Lavelle F: Effects of Taxotere on murine and humancell lines. Biochem Biophys Res Commun 187:164-170, 1992.

7. Kelland LR, Abel G: Comparative in vitro cytotoxicity of Taxol andTaxotere against cisplatin-sensitive and resistant human ovarian carcinomacell lines. Cancer Chemother Pharmacol 30:444-450, 1992.

8. Braakhuis BJM, Hill BT, Dietel M, et al: In vitro antiproliferativeactivity of docetaxel (Taxotere), paclitaxel (Taxol) and cisplatin againsthuman tumors and normal bone marrow cells. Anticancer Res 14:205-208, 1994.

9. Vogel M, Hilsenbeck SG, Depenbrock H, et al: Preclinical activityof taxotere (RP 56976, NSC 628503) against freshly explanted clonogenichuman tumour cells: comparison with taxol and conventional antineoplasticagents. Eur J Cancer 29A(14):2009-2014, 1993.

10. Hanauske AR, Degen D, Hilsenbeck SG, et al: Effects of Taxotereand taxol on in vitro colony formation of freshly explanted human tumorcells. Anticancer Drugs 3:121-124, 1992.

11. Dykes DJ, Bissery MC, Gueritte-Vogelein F, et al: Response of humantumor xenografts in athymic mice to docetaxel. Invest New Drugs 13:1-11,1995.

12. Extra J-M, Rousseau F, Bruno R, et al: Phase I and pharmacokineticstudy of taxotere (RP 56976, NSC 628503) given as a short intravenous infusion.Cancer Res 53:1037-1042, 1993.

13. Tomiak E, Piccart MJ, Kerger J, et al. Phase I study of docetaxeladministered as a 1-hour intravenous infusion on a weekly basis. J ClinOncol 12:1458-1468, 1994.

14. Burris H, Irvin R, Kuhn J, et al: Phase I clinical trial of Taxotereadministered as either a 2-hour or 6-hour intravenous infusion. J ClinOncol 11:950-958, 1993.

15. Pazdur R Newman RA, Newman BM, et al: Phase I clinical study ofTaxotere: five day schedule. J Natl Cancer Inst 84:1781-1788, 1992.

16. Bisset D, Setanoians A, Cassidy J, et al: Phase I and pharmacokineticstudy of Taxotere (RP 56976) administered as a 24 hour infusion. CancerRes 53:523-527, 1993.

17. Bruno R, Hille D, Thomas L, et al: Population pharmacokinetics/pharmacodynamicsof docetaxel (Taxotere) in phase II studies. Proc Annu Meet Am Soc ClinOncol 14:A1471, 1995.

18. Hudis CA, Seidman AD, Crown JP, et al: Phase II and pharmacologicstudy of docetaxel as initial chemotherapy for metastatic breast cancer.J Clin Oncol14:58-65, 1996.

19. Trudeau ME, Eisenhauer EA, Higgins BP, et al: Docetaxel in patientswith metastatic breast cancer: A phase II study of the national CancerInstitute of Canada Clinical Trials Group. J Clin Oncol 14:422-428, 1996.

20. Dieras V, Chevallier B, Kerbrat P, et al: A multicentre phase IIstudy of docetaxel 75 mg m-2 as first-line chemotherapy for patients withadvanced breast cancer: Report of the Clinical Screening Group of the EORTC.Br J Cancer 74:650-656, 1996.

21. ten Bokkel-Huinink WW, Prove AM, Piccart M, et al: A phase II trialwith docetaxel (Taxotere) in second line treatment with chemotherapy foradvanced breast cancer. A study of the EORTC Early Clinical Trials Group.Ann Oncol 5:527-532, 1994.

22. Hudis CA, Seidman AD, Crown JP, et al: Phase II and pharmacologicstudy of docetaxel as initial chemotherapy for metastatic breast cancer.J Clin Oncol 14:58-65, 1996.

23. Chevallier B, Fumoleau P, Kerbrat P, et al: Docetaxel is a majorcytotoxic drug for the treatment of advanced breast cancer: a phase IItrial of the Clinical Screening Co-operative Group of the EORTC. J ClinOncol 13:314-322, 1995.

24. Krakowsky I, Rios M, Fumoleau P, et al: Phase II first line chemotherapystudy with docetaxel (Taxotere) and prophylactic premedication of fluidretention in patients with metastatic or locally advanced breast cancer.EORTC Clinical Screening Group (abstract). Proc Am Soc Clin Oncol 14(87):97,1995.

25. Valero V, Holmes FA, Walters RS, et al. Phase II trial of docetaxel:a new highly effective antineoplastic agent in the management of patientswith anthracycline resistant metastatic breast cancer. J Clin Oncol 13:2886-2894, 1996.

26. Ravdin PM, Burris HA, Cook G: Phase II trial of docetaxel in advancedanthracycline-resistant or anthracenedione resistant breast cancer. J ClinOncol 13:2879-2885, 1995.

27. Guastalla JP, Bonneterre J, Fumoleau P, et al: A phase II trialof docetaxel in patients with anthracycline resistant metastatic breastcancer. 8th European Conference on Clinical Oncology and Cancer Nursing(ECCO). Paris, October 1995.

28. Bissery MC, Nohynek G, Sanderink GJ, et al: Docetaxel (Taxotere):a review of preclinical and clinical experience. Anticancer Drugs 6:339-355,363-368, 1995.

29. Kalla S, Boureois H, Gruia G: Docetaxel in combination with doxorubicinas 1st line CT of metastatic breast cancer: A phase I dose finding study--Finalresults. Ann Oncol 7:124, 1996.

30. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusionin combination with bolus doxorubicin in women with untreated metastaticbreast cancer: high anti tumor efficacy and cardiac effects in a dose-findingand sequence-finding study. J Clin Oncol 13:2688-2699,1995.