The Current Status of Docetaxel in Solid Tumors

June 1, 2002

In less than a decade, docetaxel (Taxotere) has progressed from initial studies in anthracycline-refractory metastatic breast cancer to several large, phase III randomized trials evaluating its efficacy as adjuvant, neoadjuvant, and first-line therapy for metastatic breast cancer, non-small-cell lung cancer (NSCLC), and ovarian cancer. In other tumor types, including prostate, head and neck, gastric, and bladder cancer, ongoing phase III trials are comparing docetaxel-containing regimens to previously established regimens. For the seven tumor types reviewed in this supplement, phase III study information for docetaxel or docetaxel-based combinations are presented. Impressive results have been consistently demonstrated in the trials reported to date.

ABSTRACT: In less than a decade, docetaxel (Taxotere) has progressed from initial studies in anthracycline-refractory metastatic breast cancer to several large, phase III randomized trials evaluating its efficacy as adjuvant, neoadjuvant, and first-line therapy for metastatic breast cancer, non-small-cell lung cancer (NSCLC), and ovarian cancer. In other tumor types, including prostate, head and neck, gastric, and bladder cancer, ongoing phase III trials are comparing docetaxel-containing regimens to previously established regimens. For the seven tumor types reviewed in this supplement, phase III study information for docetaxel or docetaxel-based combinations are presented. Impressive results have been consistently demonstrated in the trials reported to date. In early-stage and metastatic breast cancer, NSCLC, and ovarian cancer, randomized trials have shown that docetaxel-containing therapies are superior to or as effective as established standard chemotherapeutic regimens and are often associated with an improved safety profile. Trials of docetaxel as adjuvant and neoadjuvant therapy for breast cancer are under way or have been completed. Docetaxel has demonstrated a survival benefit in many settings that previously had not achieved such a benefit. For example, a survival benefit was demonstrated in anthracycline-resistant breast cancer and second-line NSCLC cancer phase III comparative trials. [ONCOLOGY 16(Suppl 6):9-16, 2002]

The taxanes may be the most important addition to the cancer chemotherapeuticarmamentarium.[1] Due to its substantial antitumor activity, the clinicaldevelopment of docetaxel (Taxotere) has moved rapidly from the salvagemetastatic breast cancer setting to front-line investigation in several solidtumor types, for which randomized phase III trials have been completed or areunder way. In addition, docetaxel is being evaluated in numerous adjuvant andneoadjuvant clinical trials where its use in early-stage disease is likely tohave the greatest impact on patient outcome.

Breast Cancer

Docetaxel became commercially available in 1995 due to its efficacy inanthracycline-resistant metastatic breast cancer as demonstrated in two phase IIclinical trials, one of which was performed by Dr. Vicente Valero and colleaguesat The University of Texas M. D. Anderson Cancer Center (MDACC).[2,3] Impressive overall response ratesof 53% and 57% were achieved in this setting.[2,3] An expanded indication forsingle-agent docetaxel in the treatment of patients with locally advanced ormetastatic breast cancer after failure of prior chemotherapy was granted basedon the results of two large, phase III comparative trials. One studydemonstrated a significantly higher objective response rate for docetaxel vsdoxorubicin (48% vs 33%, P = .008) in patients who had failed prior therapy withan alkylating agent.[4] This landmark trial was the first and only comparativetrial in which another single agent was shown to be more active thandoxorubicin.[5,6]

A second phase III trial of single-agent docetaxel vs the combination ofmitomycin C (Mutamycin) and vinblastine in patients who had failed prioranthracycline therapy demonstrated a survival benefit (11.4 months vs 8.7months, P = .01) as well as higher objective response rates (30% vs 11.6%, P< .0001) for docetaxel.[7] Based on this trial, docetaxel is currently theonly agent to show a survival benefit in anthracycline-resistant metastaticbreast cancer. Two additional phase III trials in this patient populationdemonstrated improved response rates and time to progression with single-agentdocetaxel vs combination chemotherapy with the fluorouracil (5-FU)/methotrexateand 5-FU/vinorelbine (Navelbine) regimens.[8,9]

Docetaxel Combinations for Metastatic Breast Cancer

As reviewed by Dr. Francisco Esteva in this supplement, docetaxel continuesto be investigated in various combinations and schedules for the management ofmetastatic breast cancer. An overall benefit to therapy was reported in a largephase III trial in metastatic breast cancer for the combination of docetaxel (Taxotere)and doxorubicin (Adriamycin) (AT) compared to a previously established standardregimen of doxorubicin and cyclophosphamide (Cytoxan, Neosar) (AC). The ATcombination achieved a higher overall response rate (60% vs 47%, P = .012) withimproved time to progression (37.1 weeks vs 31.9 weeks, P = .015) compared tothe AC combination.[10]

Another phase III trial demonstrated improvement in overall response rates(55% vs 42%) for the docetaxel-based TAC regimen(docetaxel/doxorubicin/cyclophosphamide) vs the FAC regimen(5-FU/doxorubicin/cyclophosphamide).[11] A randomized phase II trialdemonstrated that the docetaxel/epirubicin (Ellence) (ET) combination appears tobe superior to 5-FU/epirubicin/cyclophosphamide (FEC) in terms of overallresponse rate (63% vs 34.3%) and time to progression (7.8 vs. 5.9 months).[12]In a large phase III trial in patients pretreated with an anthracycline, thecombination of docetaxel and capecitabine (Xeloda) resulted in improved time toprogression (6.1 vs 4.2 months, P = .0001) and overall survival (14.1 vs 11.1months, P = .0112) over docetaxel alone.[13]

Weekly dosing of docetaxel has been shown to maintain a high level ofefficacy with the advantage of a lower rate of myelosuppressive side effects.The weekly administration schedule has opened additional avenues for combinedregimens with drugs that are routinely administered on a weekly basis, such asgemcitabine (Gemzar), vinorelbine, and trastuzumab (Herceptin). From MDACC, Dr.Esteva has recently reported the results of a trial combining weekly docetaxelplus trastuzumab in metastatic breast cancer patients whose tumors overexpressthe HER2/neu oncoprotein.[14]

Adjuvant Therapy With Docetaxel

As discussed by Dr. Gabriel Hortobagyi, evidence of docetaxel’s high levelof activity in metastatic disease led to its swift entry into clinical trials inthe adjuvant setting. In this setting, in the treatment of early-stage breastcancer patients, docetaxel is anticipated to have an even greater impact onpatient outcome and overall survival. Worldwide, most of the ongoing clinicaltrials of adjuvant chemotherapy include a taxane-related question. Thedocetaxel-containing regimens currently being investigated follow one of threeimportant strategies: (1) sequential therapy, with administration of docetaxeladded to existing, commonly used combinations; (2) combination therapy, with theaddition of docetaxel to an existing regimen; and (3) combination therapy, withthe substitution of docetaxel for one of the drugs included in standardcombinations.

These three approaches are currently under investigation in many large,multicenter, phase III prospective randomized clinical trials being conductedaround the globe. It is believed that the results of these trials will establishthe use of docetaxel in the curative treatment of breast cancer and willdetermine the optimal method for the incorporation of docetaxel into standardadjuvant therapy.

Docetaxel as Neoadjuvant Therapy

Another role for docetaxel currently under investigation is in thepreoperative, neoadjuvant setting, as discussed by Dr. VicenteValero. To date,the results of two phase III randomized studies of single-agent docetaxeladministered following an anthracycline-based regimen have demonstratedimprovement in terms of complete clinical and pathologic response rates, withnearly a doubling of these two end points in the docetaxel arm.[15,16] In onestudy for which long-term results are available, these findings translated intosignificantly improved 3-year disease-free and overall survival rates.[15]

Additional randomized studies have evaluated docetaxel in combination withthe anthracyclines, doxorubicin, and epirubicin. The preliminary resultsachieved in the docetaxel-containing arm demonstrate improvement over thosereported for the non-taxane-containing regimen.[17] Docetaxel has also beensuccessfully combined with cisplatin in the neoadjuvant setting, with highclinical and pathologic response rates, and a tolerable side-effect profile.[18]A trial of docetaxel combined with cisplatin and trastuzumab in patients withHER2/neu-positive tumors demonstrated a high rate of pathologic completeresponses and axillary node clearance at the time of surgery.[19]

Non-Small-Cell Lung Cancer

The clinical development of docetaxel as therapy for non-small-cell lungcancer (NSCLC) parallels its development in breast cancer, with initial trialsconducted in the second-line metastatic setting, followed quickly by itsintroduction into the front-line setting.

As discussed in the article by Dr. Frank Fossella, docetaxel is the onlyFDA-approved agent for use in locally advanced or metastatic NSCLC patientsafter failure of prior platinum-based chemotherapy. This indication was approvedafter a randomized phase III trial demonstrated a survival benefit in patientstreated with docetaxel who had failed prior platinum-containing chemotherapy.Two large, randomized phase III trials were conducted in this setting, withparticipation by MDACC as the lead institution for one of the studies.[20,21]Results showed significantly improved response rates, time to progression,survival, and quality of life for docetaxel compared to vinorelbine orifosfamide (Ifex) in one trial,[20] and compared to best supportive care in asecond trial.[21]

Dr. Fadlo Khuri reviewed the results of clinical trials ofdocetaxel-containing combinations in the first-line NSCLC setting. Docetaxel hasbeen successfully combined with both cisplatin and carboplatin (Paraplatin). Alarge, comparative four-arm trial conducted by the Eastern Cooperative OncologyGroup (ECOG) established docetaxel/cisplatin as a reasonable option forfirst-line treatment of NSCLC.[22]

Phase III data establishing the combination of docetaxel and carboplatin as asafe and active regimen for first-line treatment of NSCLC were recentlyreported, with investigators at MDACC again serving as the lead institution.This randomized phase III trial compared docetaxel/cisplatin ordocetaxel/carboplatin to vinorelbine/cisplatin.[23] Patients in thedocetaxel/cisplatin arm achieved superior overall and 2-year survivals. Thedocetaxel/platinum regimens demonstrated safety and quality-of-life benefitsover vinorelbine/cisplatin.

Docetaxel has also been successfully combined with gemcitabine in multipletrials in NSCLC patients with impressive response and survival rates and anacceptable toxicity profile. Therapeutic equivalence and fewer toxicities werenoted for the docetaxel/gemcitabine combination compared to thedocetaxel/cisplatin combination in a large comparative trial.[24] Thedocetaxel/gemcitabine combination therefore holds promise as a viable non-platinum-containingregimen for first-line treatment of NSCLC. Other combinations that have beeninvestigated in NSCLC include docetaxel with vinorelbine and docetaxel withirinotecan (CPT-11, Camptosar).[25,26] Further assessment of these combinationsis necessary to determine their role in the first-line management of NSCLC.

Hormone-Refractory Prostate Cancer

Dr. Christopher Logothetis reviews the data showing that docetaxel-basedchemotherapy regimens are among the most effective treatment options forpatients with advanced prostate cancer. As reviewed in his article, compellingresults achieved with docetaxel in phase I and II studies provided the rationalefor the large, phase III randomized trials in hormone-refractory prostatecancer.[27-30] The cooperative research groups, Cancer and Leukemia Group B (CALGB),North Central Cancer Treatment Group (NCCTG), and the Southwest Oncology Group (SWOG)are conducting an intergroup comparative study (SWOG 9916) of an every-3-weekschedule of docetaxel/estramustine (Emcyt) vs mitoxantrone(Novantrone)/prednisone.[31] The primary end point of the study is survival.

A second, randomized phase III trial has three arms: the control arm ofmitoxantrone plus prednisone is being compared to an every-3-week schedule ofdocetaxel plus prednisone, or weekly docetaxel plus prednisone.[32] Survivalagain is the primary end point in this trial. The results of these studies willbetter define the role of docetaxel-based therapy in hormone-refractory prostatecancer.

Investigational studies of docetaxel in the treatment of earlier stages ofprostate cancer are also being pursued. Docetaxel is being evaluated in patientswith rising prostate-specific antigen (PSA) levels after definitive localtherapy (ie, biochemical recurrence). Preliminary results of studiesincorporating docetaxel show promise in the setting of biochemical recurrence,where the optimal treatment of prostate cancer patients has not yet beenestablished.[33,34]

Two neoadjuvant studies of weekly single-agent docetaxel followed by radicalprostatectomy in high-risk prostate cancer patients have been reported.[35,36]Preliminary results demonstrated that the weekly schedule of docetaxel was welltolerated, with the majority of treated patients showing decreases in theirserum PSA levels. Continued analysis of these and other neoadjuvant studyresults for high-risk prostate cancer patients will determine the effect ofdocetaxel on the pathologic end points.

Ovarian Cancer

Dr. John Kavanagh discusses how docetaxel has extended the armamentarium ofactive agents in ovarian cancer. Data compiled from four phase II studies, oneof which was conducted by Kavanagh et al at MDACC in patients previously treatedwith a platinum agent, demonstrated a combined overall response rate of 30% anda 6-month duration of response to docetaxel.[37] Yet another study conducted atMDACC demonstrated the activity of docetaxel in patients withpaclitaxel-resistant disease.[38]

In the setting of first-line therapy for ovarian cancer, docetaxel has beensuccessfully combined with both cisplatin and carboplatin.[39,40] A large, phaseIII randomized trial (Scottish Randomized Trial in Ovarian Cancer [SCOTROC])that compared docetaxel/carboplatin to paclitaxel/carboplatin resulted inequivalent overall response rates and progression-free survivals.[40]Hematologic toxicities were more prominent with the docetaxel/carboplatincombination; however, they did not result in treatment delays or earlydiscontinuation of treatment.

In contrast, a higher rate of clinically significant neurotoxicity wasreported with the paclitaxel/carboplatin combination, and was associated withthe need for significantly more dose reductions and treatment discontinuations.In addition, neurotoxicity persisted longer in patients after they went offstudy. Therefore, the docetaxel/carboplatin regimen may represent a viablealternative to paclitaxel/carboplatin as first-line chemotherapy for advancedovarian cancer.

Squamous Cell Carcinoma of the Head and Neck

The current status of docetaxel in the management of squamous cell carcinomaof the head and neck is reviewed by Dr. BonnieGlisson. As a single agent,docetaxel has demonstrated an overall response rate of 24% to 45% in patientswith recurrent squamous cell carcinoma of the head and neck.[41-44] Thesefindings led to the investigation of docetaxel-based doublets and triplets inboth the recurrent and neoadjuvant setting. When combined with cisplatin (plusor minus 5-FU) in the treatment of recurrent disease, response rates of 33% to44% have been observed with median survivals ranging from 9.6 to 11months.[45-47]

Representing MDACC, Dr. Glisson participated in a phase I/IImulti-institution trial that demonstrated the feasibility and safety of the TPFregimen (docetaxel/cisplatin/5-FU) as induction therapy.[48] The response andhistologic complete response rates were equivalent to or better than thosereported in a randomized trial of cisplatin/5FU. Currently, thedocetaxel/cisplatin combination is being compared to cisplatin/5-FU in arandomized phase III trial in patients with recurrent or metastatic squamouscell carcinoma of the head and neck.[49]

In the neoadjuvant setting, response rates with docetaxel-based regimens havetypically been greater than 90%, with promising disease-free and overallsurvival results.[50-53] Consequently, randomized trials are currently under wayto assess the value of docetaxel-based therapy relative to that of the standardcombinations used in the neoadjuvant treatment of squamous cell carcinoma of thehead and neck. The TPF regimen is being compared to the combination ofcisplatin/5-FU (PF) in a randomized, phase III trial in patients with locallyadvanced, curable squamous cell carcinoma of the head and neck.[54] The resultswill determine if the TPF regimen offers a therapeutic advantage over standardPF, and the trial provides a model for future comparisons of sequentialchemotherapy with chemoradiotherapy regimens.

Gastric Cancer

As discussed by Dr. Jaffer Ajani, docetaxel has been successfully used in thetreatment of advanced gastroesophageal tumors both as a single agent and incombination. Phase II results of single-agent docetaxel demonstrate an overallresponse rate of 17% to 24%, with complete responses being achieved in a tumorfor which complete responses are rare.[55-58] As a result, docetaxel isconsidered among the most active agents in gastrointestinal carcinoma. Otherresearch initiatives in gastric cancer have evaluated combinations of docetaxelwith agents traditionally used for the treatment of the disease, such ascisplatin and 5-FU. Results of phase II studies of docetaxel-based combinationsdemonstrate response and progression-free survival rates comparable to thoseachieved with established three- and four-drug regimens.[59,60]

From MDACC, Ajani et al reported the results of a phase II study inpreviously untreated patients randomized to treatment with either TC(docetaxel/cisplatin), or TCF (docetaxel/cisplatin/5-FU).[61] The three-drugregimen resulted in a slightly higher incidence of nonhematologic toxicities;however, it also resulted in a higher overall response rate (52% vs 45%). TheTCF regimen was, therefore, chosen as the experimental arm of an ongoing phaseIII trial comparing it to the widely used control arm of 5-FU/cisplatin.[62]

Another ongoing phase III trial is comparing the combination of docetaxel andcisplatin to 5-FU/cisplatin.[63] It is anticipated that the addition of theindividually active docetaxel to established standard agents will ultimatelyimprove palliation and possibly the survival of patients with gastroesophagealtumors.

Combined-Modality Therapy With Docetaxel and Radiation

Drs. Edward Kim and Fadlo Khuri summarize the results of studiesinvestigating docetaxel as a component of combined-modality therapy. Docetaxelhas been studied in combination with radiation for the treatment of NSCLC, headand neck cancer, and esophageal cancer.[64-66] Trials in patients with NSCLChave evaluated the combination of docetaxel and platinum agents with radiation,and early results show promising activity and acceptable toxicity.[67,68]Generally, esophagitis or mucositis are the dose-limiting toxicities. Currenttrials are evaluating different design schedules, including concurrentchemotherapy with radiation followed by consolidation docetaxel. Additionaltrials of docetaxel-based chemoradiotherapy in the neoadjuvant and adjuvantsettings in early NSCLC are warranted.

Transitional Cell Carcinoma of the Urothelium

Drs. Christopher Logothetis and Randall Millikan review the clinical data ondocetaxel use in transitional cell carcinoma of the urothelium. In advanced ormetastatic transitional cell carcinoma of the urothelium, docetaxel yieldedpromising results in previously treated and chemotherapy-naive patients, as wellas in patients with renal impairment who were unable to receive cisplatin-basedregimens.[69-71] Docetaxel has been combined with cisplatin for bladder cancer,resulting in response rates of 52% to 60% and median overall survivals of 8 to13.6 months.[72-74] Triple-drug combinations based on the docetaxel/platinumregimen have been investigated, and the addition of an anthracycline(doxorubicin or epirubicin) or of gemcitabine has proven feasible, with theresult being favorable efficacy findings.[75-77]

Non-platinum-containing regimens such as docetaxel/gemcitabine are beingstudied, and preliminary results suggest that the combination is feasible andactive.[78] Randomized phase III trials of a docetaxel-containing regimencompared with the established MVAC regimen (methotrexate, vinblastine,doxorubicin, cisplatin) are ongoing. Additional studies are warranted todetermine if the overall long-term survival of patients with transitional cellcarcinoma of the urothelium can be improved.

Conclusions

Docetaxel has been logically and progressively developed over the past decadein several tumor types. Randomized phase III trial results have produced awealth of information on its safety and efficacy as both a single agent and incombination in the treatment of the many solid tumors discussed here.Investigators at MDACC have had the foresight to investigate docetaxel in avariety of oncologic settings, and have participated in many landmark trialsthat have brought docetaxel to the forefront of the care of cancer patients. Therecent availability of results from large, phase III randomized trials inneoadjuvant breast cancer and front-line therapy of metastatic breast cancer,NCSLC, and ovarian cancer demonstrate the superiority or at least equivalence ofdocetaxel-containing regimens over previously established regimens for thesetumor types. The findings indicate that docetaxel-based regimens may representthe new standard of care based on therapeutic index and patient benefits.

The results of ongoing phase III trials of docetaxel-based regimens forprostate, head and neck, gastric and bladder cancer are eagerly awaited tofurther define their role in the therapy of these diseases. Furthermore, thefindings from ongoing trials of docetaxel in the adjuvant and neoadjuvantsettings are anticipated in regard to their potential impact on patient outcome,and ultimately, survival in several tumor types. The next decade will likely beconcerned with investigation of the recently identified taxane mechanisms ofaction, as molecular biological capabilities and the prognostic significance ofmolecular markers are refined. The development of additional taxane drugcombinations, schedules, and regimens with newly available therapies holdpromise for the future in the management of solid tumors.

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