Docetaxel in the Treatment of Ovarian Cancer

June 1, 2002

Docetaxel (Taxotere) has extended the armamentarium of agents with significant activity in the treatment of ovarian cancer. As a single agent in advanced ovarian cancer patients previously treated with a platinum agent, docetaxel at 100 mg/m² every 3 weeks yields a 30% overall response rate and a 6-month duration of response.

ABSTRACT: Docetaxel (Taxotere) has extended the armamentarium of agents with significant activity in the treatment of ovarian cancer. As a single agent in advanced ovarian cancer patients previously treated with a platinum agent, docetaxel at 100 mg/m² every 3 weeks yields a 30% overall response rate and a 6-month duration of response. In vitro data demonstrate a lack of complete cross-resistance between docetaxel and paclitaxel. As a result, antitumor activity has also been demonstrated in patients refractory to a paclitaxel-containing regimen. In both platinum- and paclitaxel-pretreated patients, the highest response rates were obtained in patients with the longest interval of time since receipt of prior chemotherapy. Docetaxel has been successfully combined with the platinum salts for the first-line treatment of ovarian cancer patients. In combination with cisplatin, response rates of 69% were reported. In an effort to minimize hematologic toxicities and asthenia associated with the cisplatin/docetaxel combination, investigators have substituted carboplatin (Paraplatin) for cisplatin. Several phase II studies and the Scottish Randomized Trial in Ovarian Cancer (SCOTROC), a large phase III randomized trial, of the docetaxel/carboplatin combination have been completed. The most frequent toxicity noted is neutropenia, which is generally of brief duration, predictable, and manageable. The docetaxel/carboplatin combination has a notably low rate of neurotoxicity. Therefore, the SCOTROC comparative trial, demonstrating equivalent overall response rates and progression-free survival rates, suggests that the docetaxel/carboplatin combination may represent a new alternative to paclitaxel/carboplatin as first-line chemotherapy for advanced ovarian cancer. [ONCOLOGY 16(Suppl 6):73-81, 2002]

Epithelial ovarian cancer is a major source ofmortality of women in the United States. It is the leading cause of gynecologiccancer death.[1] The disease is unusual in women below the age of 40, andgradually increases to a peak rate of 57 per 100,000 in the 8th decade. Themedian age of diagnosis is 63 years of age.[2] Although genetic factors havebeen noted, approximately 90% of the cases do not have an identifiable geneticpredisposition. There are no early signs or symptoms of the disease, and mostpatients are diagnosed in an advanced state. Following surgical bulk reduction,chemotherapy is generally given. The prognostic factors for the disease remainthe nature of the histology, the amount of residual disease following primarysurgery, and the stage of the disease.[3] The disease is staged according to theInternational Federation of Gynecology and Obstetrics (FIGO) nomenclature.

Chemotherapy for advanced ovarian cancer has evolved over the years intocombination regimens that generally included cisplatin or carboplatin(Paraplatin). The introduction of paclitaxel/platinum-based chemotherapy hasresulted in a prolongation of the median progression-free survival and overallsurvival of patients. In the benchmark trial, Gynecologic Oncology Group (GOG)-111,the taxane/cisplatin arm had a median survival of 38 months vs 24 months (P <.001) for the cisplatin/cyclophosphamide arm. Superiority of thepaclitaxel/cisplatin regimen over the cisplatin/cyclophosphamide regimen interms of both progression-free survival and overall survival were laterconfirmed in a European trial.[4]

The long-term impact on survival is not yet known. The cisplatin/paclitaxelcombination has the major side effects of myelosuppression and neuropathy. Thesubstitution of carboplatin for cisplatin has generally lessened, but does noteliminate, neuropathy. Furthermore, depending on the administration schedule ofpaclitaxel, hematologic toxicities may be less frequent.[5] Taken together, thetrial results indicate that the more convenient paclitaxel/carboplatincombination is generally better tolerated than paclitaxel/cisplatin and appearsto be equally efficacious.

When used as a 3-hour infusion, paclitaxel is associated with significantneurotoxicity, however, and questions remain about the possibility that longerschedules of paclitaxel may be somewhat more efficacious as first-line therapy.As a result of this ambiguity, and based upon the results of docetaxel (Taxotere)in preclinical and clinical trials, numerous studies have investigated thesubstitution of docetaxel for paclitaxel in combined use with the platinum saltsin the treatment of ovarian carcinoma. The remainder of this article will reviewpreclinical and clinical trials of docetaxel in ovarian cancer, concluding withthe preliminary results of a large, phase III randomized trial comparingdocetaxel- and paclitaxel-based regimens in the first-line setting.

Preclinical Data

The relative activity of paclitaxel vs docetaxel in ovarian cancer cell lineshas been the subject of several studies. Aapro et al compared the in vitrosensitivities of paclitaxel and docetaxel in bone marrow, head and neck,sarcoma, colon, and ovarian cancer cell lines.[6] In a sulforhodamine ortetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)assay, 13 ovarian cancer lines were two- to fourfold more sensitive to docetaxelas compared with paclitaxel and up to 6,500-fold more potent than cisplatin.

Alberts et al conducted an in vitro study comparing the relativecytotoxicities of paclitaxel and docetaxel against 50 fresh ovarian cancersobtained at surgery prior to chemotherapy.[7] A human tumor cloning assay wasused to evaluate the degree of drug-induced inhibition of tumor colony formation(TCF) from the ovarian cancers. The achievable and median IC50 values (ie, 50%inhibition of TCF compared with control) were 47.8% achievable and 19.0 µMmedian IC50 for paclitaxel vs 48.5% achievable and 3.28 µM median IC50 fordocetaxel. On the basis of this data, it was concluded that docetaxel had atleast equivalent cytotoxicity to paclitaxel against fresh ovarian cancers.

Hanauske et al compared the antiproliferative action of docetaxel andpaclitaxel against a variety of freshly explanted human tumor specimens using anin vitro soft agar cloning system.[8] Cytotoxicity was observed against breast,lung, ovarian, colorectal cancer, and melanoma tumor colony-forming units. In ahead-to-head comparison, 29 specimens were found more sensitive to docetaxelthan paclitaxel, while only 13 were more sensitive to paclitaxel than docetaxel.At 10 µg/mL, significant cytotoxicity was observed in 41% of specimens testedwith docetaxel and 33% of specimens tested with paclitaxel. The authorsconcluded that cross-resistance between the two agents was incomplete, and that,on a concentration basis, docetaxel was more cytotoxic than paclitaxel in themajority of human primary tumor specimens evaluated.

Silverstrini et al compared paclitaxel and docetaxel in three establishedcell lines and in 19 primary cultures of ovarian neoplasms.[9] The assay usedwas clonogenic with a proliferative index based on tritiated thymidineincorporation. Both docetaxel and paclitaxel were more potent than cisplatin ordoxorubicin in all three established cell lines. In addition, docetaxel was twoto four times more cytotoxic than paclitaxel in two of the established celllines and showed similar activity in one cell line. In primary culture systems,however, the taxanes were less active than cisplatin and doxorubicin. Cell linesthat were sensitive to the taxanes generally had a higher labeling index (ie,higher proliferative activity) than those observed in resistant cultures. Theauthors suggested that preclinical determination of the inherent sensitivity ofindividual tumors to taxanes and of the tumor cell population proliferation ratecould be useful in identifying patients who could benefit from taxane treatment.

Untch et al used the adenosine triphosphate cell viability assay in 14 celllines, including 12 gynecologic and 2 breast cancer cell lines.[10] On aconcentration basis, docetaxel was more active than paclitaxel in 5 cell linesand paclitaxel was the more active drug in 6 cell lines. Of interest, totalcross-resistance to cell lines between the taxanes was not demonstrated. Theauthors concluded that both compounds were quite active and showed partial non-cross-resistance.The authors indicated that paclitaxel and docetaxel appear to have a differentspectrum of activity in gynecologic and breast cancers, both of which arediseases where tumor heterogenicity remains a challenging therapeutic problem.

Nicoletti et al reviewed the activity of both taxanes in human ovariancarcinoma xenografts.[11] Intravenous drug was given once every 4 days for threeconsecutive doses in the nude mouse model. Xenografts were transplantedsubcutaneously or intraperitoneally. Both taxanes cured all animals in earlystage peritoneal implantation of HOC22 tumor lines. Of note, both docetaxel andpaclitaxel were more effective than cisplatin, which was used as the referencecompound. The authors concluded that both docetaxel and paclitaxel were highlyeffective in four human ovarian carcinoma xenograft models.

In summary, both taxanes have been found to be extremely active in a varietyof human ovarian cancer models. Docetaxel and paclitaxel demonstrated varyingdegrees of activity in preclinical ovarian carcinoma models and did notdemonstrate total cross-resistance. The research indicates that human tumor celllines that are resistant to paclitaxel are not necessarily resistant todocetaxel. Taken together, the information provided an interesting avenue forthe clinical investigation of docetaxel in ovarian carcinoma.

Docetaxel in Refractory, Platinum-Pretreated Ovarian Cancer

The role of docetaxel in the treatment of refractory or recurrent ovariancancer has been well described.[12-16] Four major trials of single-agentdocetaxel have been conducted in advanced, pretreated ovarian cancer patients. Atotal of 340 patients were treated in two European and two US trials (Table1).[12-16] The dose of docetaxel used in these studies was 100 mg/m² every 3weeks. All patients had received prior platinum salt-based therapy. The timeinterval from previous platinum therapy, as well as the definition of"platinum resistance," was variable in the trials. When analyzedtogether, the overall response rate in the four phase II studies combined was30% among 315 evaluable patients (95% confidence interval[CI]: 25%-36%) asshown in Table 2.[12-16] This level of antitumor activity was maintained amongthe 155 patients who had the most refractory disease (defined as atreatment-free interval of less than 4 months), where the overall response ratewas 28% (95% CI: 19%-36%).

The most common side effects were grade 4 neutropenia and fluid retention.The incidence of febrile neutropenia among patients varied from 8% to 44%. Thesestudies confirmed the activity of docetaxel in platinum-pretreated patients. Inaddition, there was a trend demonstrating that longer treatment-free intervalsand platinum-free intervals were associated with higher response rates. It wasalso noteworthy that even the most refractory cases demonstrated a significantresponse rate to docetaxel.

Docetaxel in the Treatment of Paclitaxel-Resistant Patients

As discussed above, preclinical data indicated a lack of completecross-resistance between docetaxel and paclitaxel; however, informationconcerning their clinical cross-resistance in epithelial ovarian cancer waslacking. Anecdotally, it had been reported that patients may respond to thealternative taxane upon relapse. Still, the characteristics and nature of thesepatients, along with the duration of the response, have not been welldocumented. A provocative paper published by Verschraegen et al partiallyaddressed this question.[17]

Thirty-two patients with ovarian carcinoma were treated with docetaxel at 100mg/m² (n = 27) or 75 mg/m² (n = 5) after having failed paclitaxel-based therapy.The definition of paclitaxel failure was progression while on therapy orevidence of persistent disease after four courses of paclitaxel-based therapy(absolute paclitaxel resistance) or clinical remission followed by relapsewithin 6 months of completing paclitaxel-based therapy (relative paclitaxelresistance). Patients demonstrating paclitaxel resistance did not necessarilyreceive docetaxel treatment immediately and, in fact, may have been treatedfirst with other, potentially non-cross-resistant regimens. Although thelargest subgroup of patients (14/30) had received just one prior chemotherapyregimen, nine patients had received two prior regimens, five patients hadreceived three prior regimens, three patients had received four prior regimens,and one patient had received five prior chemotherapy regimens.

In 30 assessable patients, an overall response rate of 23% was documented,with 1 complete and 6 partial responses. An additional 6 patients demonstratedstable disease. Of the 19 patients who had disease progression while onpaclitaxel (absolute paclitaxel resistance), 11% responded to docetaxel therapy.Docetaxel responders had a median taxane-free interval of 73 weeks, comparedwith 19 weeks in nonresponders (Table 3).[17] The implication of this report isthat taxane resistance, similar to platinum resistance, may be a time-dependentphenomena. One criterion for analysis of taxane re-treatment studies, therefore,should be the time interval from prior taxane therapy. It is possible thatre-treatment with taxanes is not necessarily schedule- or dose-dependent but maybe most influenced by time from previous therapy. Further confirmation of thisobservation will be necessary.

The authors concluded that docetaxel had definite antitumor activity inpaclitaxel-resistant ovarian carcinoma—findings supported by previouspreclinical observations as well as data concerning docetaxel sensitivity inpaclitaxel-refractory breast cancer.[18] The authors indicated that docetaxelappears to be at least as effective as other approved second-line treatments forrecurrent ovarian cancer (ie, topotecan [Hycamtin], liposomal doxorubicin[Doxil]), and its level of activity, ease of administration, and known safetyprofile warrant serious consideration in the first-line setting.

The Role of Docetaxel as Primary Therapy for Ovarian Carcinoma

Docetaxel/Cisplatin Combination Therapy

In untreated ovarian cancer, docetaxel has been investigated in dose-findingcombination studies and in fixed-dose combinations aimed at identifying activityin larger patient populations. Two of the most notable dose-finding studiesinvolved combinations of docetaxel with cisplatin and with carboplatin.

The largest study combining docetaxel with cisplatin was published by Vaseyet al.[19] A total of 100 patients with FIGO stage IC to IV epithelial cancerwere divided into two cohorts for treatment with docetaxel, 75 mg/m² or 85 mg/m², plus cisplatin, 75mg/m², every 3 weeks, with an anticipated total numberof six cycles. All patients received premedication with oral dexamethasone 8 mgtwo times per day for 5 days, starting the day prior to chemotherapy. Theprimary end point of the study was incidence of severe fluid retention thatnecessitated treatment withdrawal. Additional objectives were to gather data onthe potential efficacy of the combination in terms of objective tumor responses,duration of response, progression-free survival, and overall survival.

In the first cohort, 49 patients received 258 cycles of therapy withcisplatin, 75 mg/m², and docetaxel, 75 mg/m². In the second cohort, 51 patientsreceived 254 cycles with cisplatin, 75 mg/m², and docetaxel, 85 mg/m². Activitywas notable, with an overall response rate of 69% and a clinical completeresponse rate of 38% in 39 patients assessable for response after three and sixcycles. In 85 patients assessable by the serum marker CA-125, 73% demonstrated aresponse. Median progression-free survival for the group was 12 months (95% CI:10-14 months).

Results demonstrated that no patients were taken off study because of fluidretention. On the other hand, only 66 patients received the planned six cyclesof therapy, and 16 patients withdrew from therapy early because of toxicity.Patients in cohort 2 experienced more profound nadir neutropenia and morefrequent fatigue/lethargy compared with cohort 1 (Table4).[19] In both cohortscombined, grade 2 or 3 neuropathy was reported in 17% and 6% of patients,respectively. There were five treatment-related deaths, all occurring in cohort2. Three patients died of neutropenic complications and two patients died as aresult of upper gastrointestinal hemorrhage related to premedication with the5-day corticosteroid regimen. The authors concluded that the combination ofdocetaxel and cisplatin can be safely administered at doses of 75 mg/m² per druggiven every 3 weeks, but they did not recommend increasing the dose of docetaxelto 85 mg/m² because of unacceptable hematologic complications and poorlytolerated fatigue/lethargy. In an effort to attenuate cisplatin-inducedtoxicities, the investigators subsequently investigated the substitution ofcarboplatin for cisplatin in combination with docetaxel.

Docetaxel/Carboplatin Combination Therapy

Vasey et al combined docetaxel and carboplatin as first-line therapy forovarian cancer patients in a prospective, nonrandomized feasibility study.[20]The aim was to establish whether patterns of toxicity differed from thoseexperienced with paclitaxel/carboplatin, with particular reference tomyelotoxicity and neurotoxicity. One hundred and thirty-nine eligible patientswith FIGO stage IC to IV epithelial ovarian cancer received a total of 750cycles of chemotherapy in five cohorts at varying dose levels of carboplatin (atan area under the concentration-time curve [AUC] of 5-7) and docetaxel (60-85mg/m²) every 3 weeks. Patients received a 3-day prophylactic regimen of oraldexamethasone 8 mg twice a day. In total, 110 patients received all six plannedcycles of docetaxel and carboplatin for a 79% completion rate, and only 12% ofpatients came off therapy early because of toxicity.

Toxicities included grade 4 neutropenia in 75% of patients; however, febrileneutropenia was reported in only 4% of patients. Significant nonhematologictoxicities were infrequently reported. Although fatigue or lethargy werereported in more than 50% of patients, it was grade 3 in only five patients(4%). Also notable was the especially low incidence of significantneurotoxicity. Thirty-six patients (26%) experienced a treatment-relatedneuropathy; however, it was grade 1 in the vast majority (20%). No patientsstopped protocol therapy because of neurotoxicity, and no significant neuromotortoxicity was reported. Overall, the clinical response rate was 66%, with aCA-125 response of 75%. The median progression-free interval was 16.6 months(95% CI: 13.3-19.1 months), and the estimated 1-year overall survival rate was84%.

The authors concluded that the tolerable dose was carboplatin at an AUC of 5and docetaxel, 75 mg/m² every 3 weeks. It is pertinent that carboplatin wasdosed according to the Calvert formula, where the glomerular filtration rate wasmeasured by 51CrEDTA. If clearance is calculated mathematically by the Cockcroft-Gaultformula, then carboplatin at an AUC of 6 is recommended. At this recommendeddose, 91% of patients completed six cycles of therapy. Although myelosuppressionwas commonly observed, complications were rare, and neither prophylacticantibiotics nor growth factors were required routinely. The authors reportedevidence of a platelet-sparing effect with the docetaxel/carboplatincombination. Another interesting observation was the relative lack ofsignificant neurotoxicity. The authors suggested that these findings mayrepresent a toxicity advantage for docetaxel plus carboplatin, which may beparticularly important for longer treatment durations.

The group from the Cleveland Clinic also conducted a study of combinationcarboplatin/docetaxel for malignancies of the ovary and fallopian tube andprimary carcinoma of the peritoneum.[21] Eligible patients were those with noprior chemotherapy or a treatment-free interval of more than 2 years. The doseschosen for study were docetaxel, 60 mg/m², and carboplatin at an AUC of 6 (Cockcroft-Gaultformula) once every 3 weeks for a maximum planned number of six cycles oftreatment. Prophylactic medication was given with oral dexamethasone 8 mg twicedaily beginning 24 hours before chemotherapy and continuing for a total of fivedoses. Prophylactic oral antibiotics were allowed if the clinician thought thatgrade 4 neutropenia would last more than 3 days.

A total of 50 patients were entered in the study, with all but three patients(6%) having received no prior chemotherapy for their malignancy. Among the totalpatient population, 67% received all six planned treatment courses. Similar toother studies was the report of severe, but usually brief, neutropenia.Thrombocytopenia was distinctly uncommon, and there were no episodes of grade IVnonhematologic toxicities. Hypersensitivity reactions occurred in approximatelyone-third of patients—higher than the incidence reported in other clinicaltrials of the combination. In all cases, however, patients were able to continuetherapy without further incidence by utilizing a protocol of diphenhydramine (50mg IV) and hydrocortisone (50 mg IV) after discontinuation of the initialinfusion. The chemotherapy was continued upon resolution of the hypersensitivityreaction and the administration of prophylactic compounds. It is also ofinterest that there was only a 6% incidence of grade 2 peripheral neuropathy,with no cases of grade 3 neuropathy observed.

In 42 patients assessable for response, 32 patients (81%) were consideredobjective responders. At the time of the report, the median duration ofprogression-free survival had not been reached; it would exceed 16 months. Theauthors concluded that the combination of carboplatin at an AUC of 6 anddocetaxel at 60 mg/m² was a highly active regimen with manageablehypersensitivity reactions and a very low incidence of neurotoxicity.

Docetaxel/Carboplatin vs Paclitaxel/Carboplatin Therapy

The largest trial of docetaxel in the first-line treatment of ovarian cancerhas been the phase III SCOTROC trial comparing the docetaxel/carboplatincombination with the paclitaxel/carboplatin combination.[22] The preliminaryresults of the study were presented at the 2001 annual meeting of the AmericanSociety of Clinical Oncology. Eligible patients had FIGO stage IC to IVepithelial ovarian cancer and primary peritoneal cancer, an Eastern CooperativeOncology Group (ECOG) performance status of 0 to 2, and had received no priorchemotherapy or radiotherapy. The primary end point of the study wasprogression-free survival, and secondary end points were overall survival,toxicity, quality of life, and response rate.

The treatment programs randomized 1,077 patients to either docetaxel at 75 mg/m²plus carboplatin at an AUC of 5 (Calvert formula) or paclitaxel at 175 mg/m² over 3 hours plus carboplatin at an AUC of 5(Figure 1). Treatment courseswere repeated every 3 weeks for up to six cycles. Patient characteristics werewell balanced in terms of median age, ECOG performance status, FIGO stage, andpostoperative residual disease. In a total of 586 patients evaluable forclinical response, the response rates were similar in both arms, with an overallresponse rate of 65% in the docetaxel/carboplatin arm (n = 297) and 62% in thepaclitaxel/carboplatin arm (n = 289) (Table 5). Using CA-125 serum marker as acriterion of response, there was a 75% response rate in thedocetaxel/carboplatin arm (n = 354) and 76% response in thepaclitaxel/carboplatin arm (n = 355). There was no significant difference inprogression-free survival or overall survival at the time of this report.

A major issue of discussion concerning the trial has been the incidence ofhematologic vs nonhematologic toxicities. The incidence of hematologictoxicities was higher in the docetaxel/carboplatin arm, although thecomplications were manageable and patients usually completed therapy as planned.Importantly, there were no differences between the arms in incidence of septicmortality or treatment discontinuations as a result of neutropenic complications(Table 6).[22] In contrast, the paclitaxel/carboplatin arm was associated with agreater incidence of neurologic toxicities that led to early treatmentdiscontinuation. The overall rates of peripheral neuropathy were significantlyhigher for the paclitaxel/carboplatin arm (77% vs 45%, P < .001), and theincidence of grades 2 to 4 peripheral neuropathy also was significantly higherin the paclitaxel/carboplatin arm (30% vs 11%, P < .001) as compared with thedocetaxel/carboplatin arm. Similarly, the paclitaxel/carboplatin arm had asignificantly higher incidence of motor neuropathy, both overall (17% vs 8%, P< .001) and for grades 2 to 4 (8% vs 3%, P < .001), in comparison with thedocetaxel/carboplatin arm (Table 7).[22] Finally, a much greater percentage ofpatients in the docetaxel/carboplatin arm did not develop neurotoxicity (Figure2).

The preliminary conclusion of this large randomized trial was that thedocetaxel/carboplatin and paclitaxel/carboplatin combinations were equallyeffective in regards to clinical and CA-125 response. Further analyses will benecessary to determine whether there is any difference in progression-free andoverall survival between the study arms. The docetaxel/carboplatin arm wasassociated with a higher incidence of neutropenia, which did not result in ahigher incidence of discontinuation of therapy or treatment-related deaths,however, and was generally managed on an outpatient basis. In contrast, thepaclitaxel/carboplatin arm had significantly more neurotoxicity that led toearly treatment discontinuation. To date, the findings suggest that docetaxelmay represent a new alternative to paclitaxel for combination with carboplatinas first-line chemotherapy for advanced ovarian cancer.

Conclusions

Docetaxel has unequivocal and definite activity in platinum-refractoryovarian cancer patients, with a response rate of 30% and a response duration of6 months. The activity of docetaxel in platinum-pretreated patients is relatedto the treatment-free interval, with higher response rates being reported inpatients with longer treatment-free intervals. The currently available clinicaldata do not support a conclusion about whether docetaxel or paclitaxel is asuperior drug in treating patients who have had prior therapy, particularlyplatinum-based therapy. However, it has been demonstrated in a phase III trialthat docetaxel has activity equal to paclitaxel as first-line therapy, as wellas activity in patients who have had prior paclitaxel-based chemotherapy. Theevidence suggests that the longer the taxane-free interval, the more likely theresponse to docetaxel. Because of our lack of understanding about the mechanismsof resistance to taxanes in the clinic, the optimum drug, dosing, or schedulefor a taxane reinduction strategy remains unclear.

Several studies combining docetaxel with the platinum salts have beenconducted. The combination of cisplatin and docetaxel yields high antitumoractivity. However, as was reported with the paclitaxel/cisplatin combinations,neurotoxicity and fatigue limit therapy. In contrast, the docetaxel/carboplatinregimen is a functional combination when used in doses of carboplatin at an AUCof 5 (51CrEDTA determination) or 6 (Cockcroft-Gault formula) and docetaxel dosesranging from 60 to 75 mg/m². This combination has been well tolerated when givenevery 3 weeks for six cycles. Of interest, the combination of docetaxel andcarboplatin suggests a platelet-sparing effect in terms of the cumulativetoxicity of carboplatin and a low incidence of neurotoxicity.

The results of the large SCOTROC randomized trial comparingdocetaxel/carboplatin with paclitaxel/carboplatin demonstrated that thedocetaxel/carboplatin combination therapy had a significantly lower incidence oftreatment-limiting neuropathy. Although the docetaxel/carboplatin combinationdemonstrated a higher incidence of neutropenia, this side effect was manageableand did not result in early treatment discontinuation. Preliminary results showsimilar overall response and survival rates, and the data await furtheranalyses. In combination with carboplatin, docetaxel may represent a newalternative to paclitaxel as first-line chemotherapy for advanced ovariancancer.

References:

1. Landis SH, Murray T, Bolden S, et al: Cancer Statistics, 1999. CA Cancer JClin 49:8, 1999.

2. Yancik R, Ries LG, Yates JW: Ovarian cancer in the elderly: An analysis ofsurveillance. Am J Obstet Gynecol 154:639-647, 1986.

3. Ozols RF, Rubin SC, Thomas GM, et al: Epithelial Ovarian Cancer, in,Hoskins WJ, Perez CA, Young RC (eds): Principles and Practice of GynecologicOncology, 3rd ed, pp 981-1057. Philadelphia, Lippincott Williams & Wilkins,2000.

4. Piccart MJ, Bertelsen K, James K, et al: Randomized intergroup trial ofcisplatin/paclitaxel vs cisplatin/cyclophosphamide in women with advancedepithelial ovarian cancer: Three-year results. J Natl Cancer Inst 92:699-708,2000.

5. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatincompared with paclitaxel and cisplatin in patients with stage III and stage IVovarian cancer. N Engl J Med 334:1-6, 1996.

6. Aapro M, Braakhuis B, Dietel M, et al: Superior activity of Taxotere overTaxol in vitro (abstract 3086). Proc Am Assoc Cancer Res 33:516, 1992.

7. Alberts DS, Arcia D, Fanta P, et al: Comparative cytotoxicities of Taxoland Taxotere in vitro against fresh ovarian cancers (abstract 719). Proc Am SocClin Oncol 11:226a, 1992.

8. Hanauske AT, Degen D, Hilsenbeck GS, et al: Effects of Taxotere and Taxolon in vitro colony formation of freshly explanted human tumor cells. AnticancerDrugs 3:121-124, 1992.

9. Silverstrini R, Zaffaroni N, Orlandi L, et al: In vitro cytotoxic activityof Taxol and Taxotere on primary cultures and established cell lines of humanovarian cancer. Stem Cells 11:528-535, 1993.

10. Untch M, Untch A, Sevin BU, et al: Comparison of paclitaxel and docetaxel(Taxotere) in gynecologic and breast cancer cell lines with the ATP-cellviability assay. Anticancer Drugs 5:24-30, 1994.

11. Nicoletti MI, Lucchini V, D’Incalci M, et al: Comparison of paclitaxeland docetaxel activity on human ovarian carcinoma xenografts. Eur J Cancer30A:691-696, 1994.

12. Kaye SB, Piccart M, Aapro M, et al: Phase II Trials of docetaxel (Taxotere)in advanced ovarian cancer: An updated overview. Eur J Cancer 33:2167-2170,1997.

13. Francis P, Schneider J, Hann L, et al: Phase II trial of docetaxel inpatients with platinum-refractory advanced ovarian cancer. J Clin Oncol12:2301-2308, 1994.

14. Kavanagh JJ, Kudelka AP, de Leon CG, et al: Phase II study of docetaxelin patients with epithelial ovarian carcinoma refractory to platinum. ClinCancer Res 2:837-842, 1996.

15. Kaye SB, Piccart M, Aapro M, et al: Docetaxel in advanced ovarian cancer,preliminary results from three phase II trials. Eur J Cancer 31A (suppl 4):S14-S17, 1995.

16. Piccart MT, Gore M, Huinink WTB, et al: Docetaxel, an active new drug fortreatment of advanced epithelial ovarian cancer. J Natl Cancer Inst 87:676-681,1995.

17. Verschraegen C, Sittisomwong T, Kudelka A, et al: Docetaxel for patientswith paclitaxel-resistant Müllerian carcinoma. J Clin Oncol 18:2733-2739, 2000.

18. Valero V, Jones SE, Von Hoff DD, et al: A phase II study of docetaxel inpatients with paclitaxel-resistant metastatic breast cancer. J Clin Oncol16:3362-3368, 1998.

19. Vasey PA, Birt PA, Junor EJ, et al: Docetaxel and cisplatin incombination as first-line chemotherapy for advanced epithelial ovarian cancer. JClin Oncol 17:2069-2080, 1999.

20. Vasey PA, Atkinson R, Coleman R, et al: Docetaxel-carboplatin asfirst-line chemotherapy for epithelial ovarian cancer. Br J Cancer 84:170-178,2001.

21. Markman M, Kennedy A, Webster K, et al: Combination chemotherapy withcarboplatin and docetaxel in the treatment of cancers of the ovary and fallopiantube and primary carcinoma of the peritoneum. J Clin Oncol 19:1901-1905, 2001.

22. Vasey P: Preliminary results of the SCOTROC trial: A phase III comparisonof paclitaxel-carboplatin (PC) and docetaxel-carboplatin (DC) as first linechemotherapy for stage IC-IV epithelial ovarian cancer (abstract 804). Proc AmSoc Clin Oncol 20:202a, 2001.