Current Clinical Practices for Ovarian Cancers

Peter Harper

Ovarian cancer is one of the most aggressive gyneco-logic cancers. It shows its symptoms late and is conse-quently often diagnosed at an advanced stage. Thesearch for a more effective chemotherapy regimen,therefore, is of great importance. Since 1996, the com-bination of cisplatin and paclitaxel has been proven toprolong survival in comparison with older regimenscontaining cisplatin and cyclophosphamide. In addition,the introduction of carboplatin in combination withpaclitaxel showed similar efficacy but preferable toxic-ity profiles when compared with cisplatin in combina-tion with paclitaxel. Representative studies evaluatingpaclitaxel combination therapies as well as new trendsin the treatment of ovarian cancer are summarized inthis article.Semin Oncol 29 (suppl 8):3-6. Copyright 2002, ElsevierScience (USA). All rights reserved.

SURVIVAL rates in ovarian cancer dependgreatly on the times of diagnosis and treat-

ment. If diagnosed and treated early, the survivalrate is 95%; however, only approximately 25% ofall cases of ovarian cancer are detected at thelocalized stage.1 Unfortunately, ovarian cancerdoes not commonly show any signs or symptomsuntil late in its development, a factor that delaysthe early treatment necessary for increasing sur-vival rates.

Ovarian cancer is one of the most lethal gyne-cologic cancers when not detected at an earlystage. Despite initial response rates of 60% to 80%with platinum-based chemotherapy, more than75% of women affected will die of complicationsassociated with this malignancy.2 Even though animprovement in 5-year survival rates for all diseasestages has been observed, ovarian cancer has es-sentially become a chronic disease associated withsignificant morbidity.3 Therefore, the search fornew chemotherapeutic approaches has become apressing need.

A meta-analysis of 37 trials including 5,667patients with advanced ovarian cancer concludedthat platinum-based regimens were superior tononplatinum-based regimens. In addition, thisanalysis showed that carboplatin was as effective ascisplatin, and platinum-based combination che-motherapy, including paclitaxel, was superior tosingle-agent chemotherapy.4

PACLITAXEL IN COMBINATIONCHEMOTHERAPY

In combination chemotherapy, paclitaxel hasbecome the agent of choice with or without plat-inum-based compounds.5 Paclitaxel is approved bythe US Food and Drug Administration for first-line therapy in patients with advanced ovariancancers; the role of paclitaxel in advanced ovariancancer was evaluated in four large, phase III studiesdiscussed below.

The Gynecologic Oncology Group 111 trialcompared cyclophosphamide/cisplatin with pacli-taxel/cisplatin in patients with stage III subopti-mally debulked disease or stage IV disease.6 A totalof 410 women were randomly assigned to thetreatment groups. Significantly higher responserates were observed among patients receiving pac-litaxel (135 mg/m2 administered over 24 hours)followed by cisplatin (75 mg/m2) compared withthose receiving cyclophosphamide (750 mg/m2)followed by cisplatin (75 mg/m2) (73% v 60%,respectively; P � .01). Additionally, progression-free survival and overall survival were significantlylonger in the paclitaxel/cisplatin study arm whencompared with the cyclophosphamide/cisplatinarm (median of 18 months v 13 months, respec-tively, and 38 months v 24 months, respectively;P � .001 for both). However, the use of paclitaxelin combination with cisplatin led to significantlyhigher toxicity (P � .05). Overall, the incidenceof neutropenia, febrile neutropenia, alopecia, andperipheral neurotoxicity was higher in the cispla-tin/paclitaxel study arm.

A subsequent randomized European-Canadianstudy compared the same regimen of cyclophos-phamide/cisplatin with a 3-hour paclitaxel infu-sion (175 mg/ m2) followed by cisplatin in previ-

From the Medical Oncology Department, Guy’s Hospital, Lon-don, UK.

Dr Harper has received honoraria from Janssen-Cilag and OrthoBiotech.

Address reprint requests to Peter Harper, MD, Guy’s Hospital,Saint Thomas Street, London SE19RT UK.

Copyright 2002, Elsevier Science (USA). All rights reserved.0093-7754/02/2903-0802$35.00/0doi:10.1053/sonc.2002.33525

3Seminars in Oncology, Vol 29, No 3, Suppl 8 (June), 2002: pp 3-6

ously untreated patients with ovarian cancer.7This study confirmed the superiority of the pacli-taxel/cisplatin regimen over cyclophosphamide/cisplatin regarding overall response rates (59% v45%, respectively; P � .01) and complete clinicalremission rates (41% v 27%, respectively; P � .01).At a median follow-up of 38.5 months, despite ahigh rate of crossover from the cyclophosphamidearm to the paclitaxel arm (48%), a longer progres-sion-free survival (median 15.5 months v 11.5months; log-rank P � .0005) and a longer overallsurvival (median of 35.6 months v 25.8 months;log-rank P � .0016) was observed in the pacli-taxel/cisplatin group when compared with the cy-clophosphamide/cisplatin group.

Another trial, the Arbeitsgemeinschaft Gyna-kologische Onkologie study evaluating patientswith stages IIB�IV disease, randomized patients toreceive either paclitaxel/cisplatin or paclitaxel/carboplatin.8 This study showed that carboplatin isnot inferior to cisplatin in patients with optimalstage III disease, and the paclitaxel/carboplatinregimen had a favorable toxicity profile whencompared with paclitaxel/cisplatin. Neuropathywas much less prevalent in the paclitaxel/carbo-platin regimen than in the cisplatin group (8% v19%, respectively). This neuropathy was persis-tent; 41% of the total cisplatin/paclitaxel grouphad neuropathy at 12 months and 13% at 24months. This trial also reported on quality of life,which was worse overall for patients treated with

the cisplatin-based regimen. There was no differ-ence in survival rates between the two groups.Results of the these trials are summarized in Table 1.

Finally, the second International CollaborativeOvarian Neoplasm Study compared cyclophos-phamide/doxorubicin/cisplatin (CAP) with single-agent carboplatin in previously untreated patientswith ovarian cancer.9 The goal of the study was torecruit 2,000 patients worldwide and administereither cyclophosphamide (500 mg/m2)/doxorubi-cin (50 mg/m2)/cisplatin (50 mg/m2) or carbopla-tin (minimum dose of an area under the curve[AUC] of 5). Chemotherapy was administered ev-ery 3 weeks for a total of six cycles. In 1996, aninterim report was presented including 1,526 pa-tients. The absolute difference regarding progres-sion-free interval and overall survival at 2 yearswas 2% in favor of the CAP regimen. Overalltoxicity was higher in the CAP arm when com-pared with the cisplatin arm (leukopenia: 34% v10%, respectively; alopecia: 70% v 3%, respec-tively; nausea and vomiting: 20% v 9%, respec-tively; mucositis: 21% v 0%, respectively). Theinterim conclusion was that CAP, despite beingmore toxic, may slightly improve progression-freesurvival.10

Based on the results from the second Interna-tional Collaborative Ovarian Neoplasm study, thethird International Collaborative Ovarian Neo-plasm trial was initiated.11 In this study, previouslyuntreated patients requiring chemotherapy (stages

Table 1. Phase III Trials of Paclitaxel in Ovarian Cancer

Study Disease Stage Regimen

Progression-Free Survival

(mos)

OverallSurvival(mos) Neurotoxicity

Gynecologic Oncology Group 1116 III debulkedor IV

Cyclophosphamide (750 mg/m2)/Cisplatin (75 mg/m2)

13 24 20% (grade 1–4*)

Paclitaxel (135 mg/m2 over 24hrs)/Cisplatin (75 mg/m2)

18 38 28% (grade 1–4*)

European/Canadian Study7 IIB, IIC, III, orIV

Cyclophosphamide (750 mg/m2/Cisplatin (75 mg/m2)

11.5 25.8 1% (grade 3–4*)

Paclitaxel (175 mg/m2 over 3hrs)/Cisplatin (75 mg/m2)

15.5 35.6 19.6% (grade 3–4*)

Arbeitsgemeinschaft GynakologischeOnkologie8

IIB-IV Paclitaxel (185 mg/m2 over 24hrs)/Cisplatin (75 mg/m2)

17.25 NA* 19%

Paclitaxel (185 mg/m2 over 3hrs)/Carboplatin (AUC 6†)

18.25 NA* 8%

* National Cancer Institute Common Toxicity Criteria.† AUC 6, area under the concentration-time curve 6, calculated.

4 PETER HARPER

I to IV) were enrolled in the trial; half the patientshad residual disease. Patients were randomized to acontrol arm of carboplatin or CAP, with a test armof carboplatin (AUC 6) and paclitaxel (175mg/m2 over 3 hours). Interim results showed sim-ilar rates of progression-free survival and mediansurvival for the control arm and the paclitaxel-based combination. Overall survival differed by 2to 3 months. Results of this study are shown inTable 2.

A separate Gynecologic Oncology Group 132trial comparing cisplatin/paclitaxel and CAP wasdesigned to further evaluate the role of paclitaxelin patients with stage III suboptimally debulkedand stage IV disease, but it failed to confirm theexpected benefits of paclitaxel. It has been sug-gested that the failure was due to early crossover.12

CHEMOTHERAPY ANDMYELOSUPPRESSION

In light of the myelosuppressive effect of che-motherapy regimens, such as paclitaxel/cisplatin orpaclitaxel/carboplatin combination treatments,the evaluation of concomitant administration ofrecombinant human erythropoietin (rHuEPO,epoetin alfa) may be a consideration in futuretrials concerning ovarian cancer and paclitaxel-containing regimens. Grade 1 to 4 anemia, forinstance, was present in 61% of patients receivingcyclophosphamide/cisplatin and in 67% of pa-tients receiving paclitaxel/cisplatin.6 Several trialshave already proven that epoetin alfa is effectiveand safe in ameliorating symptoms of anemia andimproving overall quality of life.13-17 These trialsincluded patients suffering from various malignan-cies who were receiving platinum- and nonplati-num-based chemotherapy regimens.

NEW COMBINATION REGIMEN

Many new agents have shown substantial activ-ity in advanced and relapsed disease and require

further study to determine how they best fit into acombination regimen. Triplet studies based on theactivity of carboplatin and paclitaxel are beingconsidered. Oral etoposide, for instance, was testedin a phase I trial conducted by Rose et al.18 Pac-litaxel (175 mg/m2) was given to 52 patients over3 hours in combination with carboplatin (AUC 5)on day 1 followed by oral etoposide (50 mg/m2)beginning on day 2. The number of days of eto-poside therapy was escalated based on toxicity.Chemotherapy cycles were repeated every 21 daysfor a maximum of six courses. Twenty-nine pa-tients were in the first stage of accrual; dose-lim-iting toxicity occurred at day 8 of oral etoposideadministration, making the maximum tolerabledose that of 6 days of etoposide treatment. For the23 patients entered into the second stage of ac-crual, dose-limiting toxicity occurred at day 12 ofadministration of oral etoposide, making the max-imum tolerable dose that of 10 days of etoposidetherapy. Three patients developed acute myeloidleukemia 16, 27, and 35 months after receiving acumulative dose of 200, 1,200, and 2,400 mg/m2 ofetoposide, respectively. The paclitaxel/carbopla-tin/etoposide combination therapy was tolerablefor 10 days without supportive therapy. While itwas not a primary focus of this phase I study, it wasinteresting to note that 79% of the patients withadvanced-stage disease achieved complete clinicalremission.18 However, the leukemogenic potentialof this etoposide/paclitaxel/carboplatin combina-tion therapy is of concern, limiting its use as afirst-line treatment in ovarian cancer.

Epirubicin, which was evaluated in a phase IItrial,19 is also being considered for combinationtherapy with carboplatin/paclitaxel. Forty patientswith optimally (n � 7) or suboptimally (n � 33)debulked advanced ovarian cancer were treatedwith a combination of paclitaxel (135 mg/m2 overa 3-hour infusion), cisplatin (75 mg/m2), and epi-

Table 2. Results of the International Collaborative Ovarian Neoplasm (ICON) 3 Trial: A Carboplatin orCyclophosphamide/Doxorubicin/Cisplatin Regimen versus a Carboplatin/Paclitaxel Combination Regimen11

RegimenMedian Progression-Free

Survival (mos)1-Year Progression-Free

Survival2-Year Progression-Free

SurvivalOverall Survival

(mos)

Carboplatin or CAP(control group) 16.2 60% 62% 36.0

Carboplatin/paclitaxel 16.8 61% 64% 38.7

Abbreviation: CAP, cyclophosphamide/doxorubicin/cisplatin.

CURRENT CLINICAL PRACTICES FOR OVARIAN CANCERS 5

rubicin (50 mg/m2 intravenously every 3 weeks onan outpatient basis). This combination therapywas well tolerated and objective response was ob-served in 86% of patients.

A proposed randomized global study intends toenroll patients with stage II to IV optimal andsuboptimal ovarian cancer. Patients will be equallyassigned to carboplatin/paclitaxel combinationregimens additionally containing gemcitabine ordoxorubicin. Primary endpoints will be progres-sion-free survival, overall survival, and responserates. The outcomes of this study are eagerlyawaited.

CONCLUSIONS

In summary, the addition of paclitaxel to plati-num-based chemotherapy regimens prolongs pro-gression-free and overall survival. The carboplatin/paclitaxel combination was better tolerated andcaused less neurotoxicity than the cisplatin/pacli-taxel regimen with no loss of efficacy. It is sug-gested that the carboplatin/paclitaxel combinationbecome the standard therapy, with possibly a thirdagent added for improved survival rates. Addi-tional trials including greater numbers of patientsare required to explore the efficacy and safety ofthese new combination therapies.

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