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ORIGINAL ARTICLE

Int J Clin Oncol (2003) 8:343347 The Japan Society of Clinical Oncology 2003DOI 10.1007/s10147-003-350-8

Yoshimitsu Niwa Toru Nakanishi Kazuo Kuzuya

Akihiro Nawa Shigehiko Mizutani

Salvage treatment with docetaxel for recurrent epithelial ovarian cancer

Received: November 21, 2002 / Accepted: July 17, 2003

Y. Niwa T. Nakanishi (*) K. Kuzuya A. NawaDepartment of Gynecology, Aichi Cancer Center Hospital,1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, JapanTel. 81-52-762-6111; Fax81-52-763-5233e-mail: trnakans@aichi-cc.jp

S. MizutaniDepartment of Obstetrics and Gynecology, Nagoya UniversityGraduate School of Medicine, Nagoya, Japan

Abstract

Background. We investigated the clinical usefulness andtoxicity of salvage treatment with docetaxel (70mg/m2) in-

fused at 3-week intervals in patients with recurrent ovariancancer.Methods.Retrospectively, we reviewed the clinical recordsof 24 patients diagnosed with recurrent ovarian cancer whohad received the salvage treatment.Results.A total of 128 courses (median, 5.5 courses; range,28 courses) were administered to the 24 patients. Themean number of prior chemotherapy courses in the patientswas 16.4 (range, 435 courses); they had already beentreated heavily. The tumor response was evaluable at theend of the treatment in 20 patients, with the overall re-sponse rate being 15.0%. Using the criterion of serum car-bohydrate antigen (CA)125 level, the response rate was

13.0%. By the time of the final docetaxel treatment, all 24patients had relapsed and 19 had died of the disease. Themedian progression-free interval was 4.6 months (range,1.37.8 months), and the median overall survival time was13.7 months (range, 2.127.0 months). While hematologicaltoxicity was not severe, 20.8% of patients experiencedgrade 3 asthenia/fatigue, and 5 patients refused furthertreatments with docetaxel because of this toxicity.Conclusion.Salvage treatment using docetaxel (70mg/m2)was somewhat effective for recurrent ovarian cancer, al-though severe asthenia/fatigue was frequently observed.Docetaxel provides sufficient palliation of disease-relatedsymptoms and some improvement in the length of life in

patients with recurrent ovarian cancer, when asthenia/fatigue is mild.

Key words Docetaxel Ovarian cancer Salvage treatment

Introduction

Because the probability of a response to second-line chemo-therapy following platinum-based treatments is mainlyrelated to the platinum-free interval, platinum agentsare important drugs in the treatment of recurrent ovariancancer, as well as in primary chemotherapy.14 For somepatients whose platinum-free interval is longer than 24months, re-treatment with a platinum agent is the most

appropriate choice, and both a sufficient effect and an ad-equate disease-free survival period can be expected. How-ever, many patients who suffer from tumor progressionor recurrence within 6 months after primary therapy areconsidered to be resistant to platinum.36Generally, thesepatients would not be considered curable, and the mainoption is salvage treatment, performed for the palliation ofdisease-related symptoms and the improvement of qualityand length of life.5,6

Several treatments have been reported to be effec-tive for recurrent ovarian cancer resistant to platinumplus paclitaxel, such as weekly single-agent paclitaxel;7

docetaxel;811 oral etoposide;12 irinotecan;13 topotecan;14

gemcitabine;15and liposomal doxorubicin.16While the anti-tumor effects of these drugs would be much weaker thanthose of the primary chemotherapy, the treatment would berepeated until evidence of disease progression was con-firmed, or severe adverse effects threatened the life of apatient. Although the effects on the quality and length oflife of patients should be considered as the more importanteffects of salvage treatment, it is the response rates of thesetreatments that have been reported most frequently.

In the current study, we focused on the salvage effects oftreatment in which docetaxel was administered successivelyat 3-week intervals in patients with recurrent ovarian

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cancer. We hoped to determine whether the treatmentwould be useful for the improvement of the quality andlength of life in these patients.

Patients and methods

The treatment records of patients with recurrent ovariancancer treated at our hospital from May 2000 to October2001 were reviewed. Recurrent disease was diagnosed byhistological, radiological, or biochemical methods. The cri-terion of the carbohydrate antigen (CA)125 level was usedto define progression,17and this level was used for the diag-nosis of biochemical recurrence. All patients had normalrenal function (serum creatinine, 0.79mg/dl); normal he-patic function (serum bilirubin,1.0mg/dl; serum glutamic-oxaloacetic transaminase, alanine aminotransferase, andalkaline phosphatase less than two times the upper limitsof institutional normal levels), adequate bone marrowreserves (WBC 4000 cells/ml and platelets 100000/ml),

performance status (Eastern Cooperative OncologyGroup) less than or equal to 2, a life expectancy enablingcompletion of at least two courses of therapy, and no recent(within at least 28 days) cytotoxic chemotherapy or wide-field radiation therapy. We found 24 patients who met theinclusion criteria, and they received docetaxel as a salvagetreatment. No exclusions were made based on the numberof previous regimens undergone by the patients. Measur-able (indicator) lesions were assessed by clinical examina-tion (nodes and subcutaneous nodules), and computedtomography/magnetic resonance imaging scans (hepatic,pelvic, or abdominal masses).

The starting dose of docetaxel in the 24 patients was

70mg/m2

. All patients were hospitalized for each treatmentcourse, which involved a 1-h intravenous infusion every 3weeks. They were premedicated with 8mg of dexametha-sone, given orally every 12h for 3 days, commencing beforethe initiation of each infusion. The calculated dose ofdocetaxel was delivered as a 1-h infusion diluted in 250ml of5% glucose in sterile water. Complete blood counts andplatelet counts were done at least weekly after discharge.Repeat courses of docetaxel were administered every 21days as long as there was no evidence of tumor progressionand blood counts had returned to pretreatment levels. Thetreatment was repeated until patients suffered disease pro-gression and/or a severe adverse effect.

Tumor evaluations were repeated at minimum intervalsof 6 weeks (after two courses). In the present study, theresponse to evaluable disease was classified according to theWorld Health Organization (WHO) criteria, by which amore than 50% reduction in the product of the largest twoperpendicular tumor diameters is considered to be a partialresponse, and total disappearance of the disease is regardedas a complete response. Patients were also classified as as-sessable if they satisfied the criterion of CA125 definition ofprogression.17This marker of assessable disease was mea-sured at least at 4-week intervals, and a response was de-fined as one showing a 50% decrease in the marker level,

while disease progression was defined according to the cri-terion of CA125 definition of progression.17 Toxic effectswere graded according to the WHO criteria.

The progression-free interval was calculated from thefirst day of treatment until the day of documented diseaseprogression. Overall survival was calculated from the initia-tion of chemotherapy. The progression-free interval andoverall survival of patients were calculated by the method

of Kaplan and Meier, using SPSS (Chicago, IL, USA) soft-ware, version 11.5.

Results

The characteristics of the patients are summarized inTable 1. The mean age at initiation of docetaxel treatmentwas 59.0 years (range, 42.9 to 74.0 years), and the medianfollow-up time of surviving patients was 21.7 months. Mostpatients included in this study had already been treatedheavily; 19 (79.2%) of them had received more than ten

courses of chemotherapy before the docetaxel treatment.All patients had received paclitaxel, 23 had been treatedwith platinum drugs, and 21 had previously received chemo-therapy with paclitaxel plus a platinum regimen at sometime in the course of their disease. In total, in the presentstudy, 128 courses (median, 5.5 courses; range, 28 courses)were administered to the 24 patients. Although no dosemodification was performed, 5 patients refused furthertreatment because of asthenia/fatigue. Treatments in theother patients were interrupted by progression of disease.

The tumor response was evaluable in 20 patients. Three(15.0%) achieved a partial response, while stable diseasewas noted in 8 (40.0%), and progression in another 9

(45.0%) (Table 2). Although the other 4 patients did nothave evaluable disease, they did have carcinomatous perito-nitis. Twenty-three patients were assessable using the serumCA125 level. In the course of the docetaxel treatment, the

Table 1. Patient characteristics

Total no. of patients 24

Age (years) Mean 59.0Range 42.974.0

WHO performance status 0 81 122 4

Histology Serous 20Endometrioid 3Mucinous 1

Number of prior regimens 1 52 123 7

Number of prior chemotherapy Median 16courses Range 435

Treatment interval from the Median 1.3last chemotherapy (months) Range 0.511.1

Site of lesion Pelvic 9Peritoneal 8Lymph node 3Marker 4

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Table 3 summarizes the toxicity data from this study.Hematological toxicity was not severe, while febrile neutro-penia was observed in 8 patients (33.3%). Although grade 4neutropenia was observed in 18 (75.0%) patients, it lastedno more than 3 days, and they recovered immediatelywhether granulocyte-colony-stimulating factor (G-CSF)was used or not. Severe thrombocytopenia or anemia wasnot observed in any patient. Dose reductions were not pre-

scribed for any patient. Although 5 patients did not experi-ence any asthenia/fatigue, the other 19 (79.2%) complainedof this symptom throughout treatment, of whom 5 hadgrade 3. The asthenia/fatigue in most patients worsened asthe infusions of docetaxel were repeated, and 5 patientswho experienced severe asthenia/fatigue refused furtherdocetaxel treatments. Nail change was observed in 18(75.0%) patients, and in 2 of these patients this was accom-panied by pain. There were rare episodes of severe nausea/vomiting, diarrhea, stomatitis, fluid retention/peripheraledema, myalgia/arthralgia, neuropathy, and hypersensitiv-ity reaction, none of which were clinically significant.

Table 2. Response to docetaxel and survival

Number of patients 24

Measurable disease 20Complete response 0

Partial response 3Stable disease 8Disease progression 9Response rate 15.0%

Measurable marker 23Response 3Stable 10Progression 10Response rate 13.0%

Fig. 1. Progression-free intervaland overall survival curve

CA125 of 9 (45.0%) patients showed a 50% decrease for atime, although this marker in 6 of them increased afteradditional treatments. Finally, only 3 (13.0%) patientsachieved a response at the end of the docetaxel treatment,while 10 (43.5%) showed stable disease and another 10(43.5%) satisfied the criterion of the CA125 definition ofprogression17 at the end of the treatment (Table 2). Thismarker level in the 1 remaining patient was within the nor-

mal range before treatment, although she had evaluabledisease. No significant difference was observed in analysesof responses compared between patients whose treatmentinterval from the last chemotherapy was less than 3 monthsand those with an interval of more than 3 months.

By the time of the final docetaxel treatment, all 24 pa-tients had relapsed disease, and 19 had died of the diseasedespite the successive treatments. The median progres-sion-free interval was 4.6 months (range, 1.37.8 months)(Fig. 1). The estimated 3-month progression-free survivalrate was 79.2%, while at 6 months it was 19.1%. The medianoverall survival time was 13.7 months (range, 2.127.0months) (Fig. 1), and the 6-month estimated overall survival

rate was 74.6%, while for 12 months this rate was 60.8%,and this rate was 33.8% for 18 months. No significant differ-ence was observed in analyses of prognoses comparedbetween patients with a treatment interval from the lastchemotherapy of less than 3 months and those with a treat-ment interval of more than 3 months.

Table 3. Adverse effects

WHO grade 0 1 2 3 4 34 (%)

HematologicalAnemia 7 4 7 5 1 25.0Thrombocytopenia 20 3 1 0 0 0.0Leucopenia 3 1 3 8 9 70.8Neutropenia 3 0 1 2 18 83.3

NonhematologicalAsthenia/fatigue 5 6 8 5 0 20.8Nausea/vomiting 5 9 8 2 0 8.3Diarrhea 19 3 2 0 0 0.0

Fluid retention/edema 16 6 2 0 0 0.0Alopecia 0 22 2 0 0 0.0Myalgia/arthralgia 14 8 2 0 0 0.0Neuropathy 11 10 3 0 0 0.0Nail change 6 16 2 Hypersensitivity reaction 20 3 1 0 0 0.0Mucositis 20 1 3 0 0 0.0Hypesthesia of gustation 17 7 0 0 0 0.0Febrile neutropenia 16 8 0 33.3

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Discussion

The prognosis of patients with recurrent ovarian cancer isextremely poor.36 Although many antitumor agents havebeen produced and examined for their efficacy, the survivalrates of patients with recurrent ovarian cancer have notsufficiently improved.316For these reasons, the important

aims of salvage treatments for recurrent ovarian cancershould be the palliation of disease-related symptoms, exten-sion of the platinum-free interval, and improvement of thequality and longevity of life.36Therefore, salvage treatmentmust demonstrate more antitumor effects as well as feweradverse effects. Fortunately, several antitumor agents havebeen reported as demonstrating sufficient beneficial effectson recurrent ovarian cancer,316 and docetaxel has beendescribed as one of the best.811

In this study, the response rate of recurrent ovariancancer to docetaxel seemed to be extremely low comparedto previous studies.811Because we examined the data retro-spectively, the responses were evaluated at the end of the

treatments, which were repeated until either the diseaseprogressed or a severe adverse effect was confirmed. Whilemost patients in this study had previously been heavilytreated using platinum compounds and/or paclitaxel, treat-ments using 70mg/m2of docetaxel were repeated for a totalof 128 courses in 24 patients. In spite of these conditions, themedian progression-free interval in this study (4.6 months)was no less than that in previous studies,811and the medianoverall survival time (13.7 months) was rather longer. Theseresults suggested that docetaxel is suitable for the salvagetreatment of recurrent ovarian cancer, and sufficient resultscould be expected in terms of the palliation of symptomsand longer life.

Hematological toxicities constituted the most frequentadverse effect in the current study. Although most patientswere heavily treated, these toxicities were mostly transientand tolerable. Although fluid retention and peripheraledema have been reported to be common adverse effects ofdocetaxel, mild peripheral edema was observed in onlyeight patients, and no fluid retention was observed. Hyper-sensitivity reaction has also been reported frequently, butno patient suffered from a reaction of more than grade 2in this study. These results suggested that the severe fluidretention, peripheral edema, and hypersensitivity reactionto docetaxel could be prevented by using a recommendedpremedication, such as the oral administration of 8mg

dexamethasone every 12h for 3 days.Though other toxicities were generally mild and toler-

able, asthenia/fatigue was the most severe and trouble-some toxicity in this study. While only 20.8% of patientssuffered from grade 3 asthenia/fatigue, five patients refusedfurther treatment because of this toxicity. Of these patients,two with evaluable disease achieved a partial response,and the serum CA125 level of the other three patientsshowed a 50% decrease at the time of their refusal. Theseresults suggested that asthenia/fatigue is the most impor-tant toxicity, and that the use of docetaxel treatmentcould be ruled out because the toxicity would also threaten

the patients quality of life. In such cases, docetaxeltreatment should be discontinued in favor of treatmentalternatives.

While asthenia/fatigue has been reported to be causedprincipally by the toxicity of docetaxel infused weekly,18,19ahigh level of toxicity has rarely been encountered in treat-ments with docetaxel infused every 3 weeks.811Because thedocetaxel infusion in the present study was repeated until

either disease progression or a severe adverse effect wasconfirmed, 70.8% (17/24) of the patients were thus treatedmore than five times. Considering that the asthenia/fatiguein most patients was exacerbated as the number ofdocetaxel infusions increased, it follows that the toxicitywould also become more severe for the same reason. Thissuggests that docetaxel would not be suitable for treatmentwhen administered repeatedly, and that further studiesshould be performed to reduce the asthenia/fatigue indocetaxel treatment.

In conclusion, the overall response rate to single-agentdocetaxel treatment for recurrent ovarian cancer was15.0%, the median progression-free interval was 4.6 months,

and the median overall survival time was 13.7 months.Though these results suggested that salvage treatment withdocetaxel for recurrent ovarian cancer patients would besufficiently effective, severe asthenia/fatigue was frequentlyobserved; 20.8% of patients experienced severe asthenia/fatigue and five refused further treatment because of thistoxicity. Docetaxel, therefore, is one of the appropriate op-tions for the relief of disease-related symptoms and forimprovement in the length of life in patients with recurrentovarian cancer whenever quality of life is not compromisedby severe asthenia/fatigue.

References

1. Piccart MJ, Lamb H, Vermorken JB (2001) Current and futurepotential roles of the platinum drugs in the treatment of ovariancancer. Ann Oncol 12:11951203

2. Covens A, Carey M, Bryson P, et al. (2002) Systematic review offirst-line chemotherapy for newly diagnosed postoperative patientswith stage II, III, or IV epithelial ovarian cancer. Gynecol Oncol85:7180

3. Gadducci A, Conte P, Cianci C, et al. (2001) Treatment options inpatients with recurrent ovarian cancer. Anticancer Res 21:35573564

4. Latorre A, De Lena M, Catino A, et al. (2002) Epithelial ovariancancer: second and third line chemotherapy. Int J Oncol 21:179186

5. Patnaik A, Doyle C, Oza AM (1998) Palliative therapy in ad-vanced ovarian cancer: balancing patient expectations, quality oflife and cost. Anticancer Drugs 9:869878

6. Garcia AA (1999) Salvage therapy for ovarian cancer. Curr OncolRep 1:6470

7. Markman M, Hall J, Spitz D, et al. (2002) Phase II trial of weeklysingle-agent paclitaxel in platinum/paclitaxel-refractory ovariancancer. J Clin Oncol 20:23652369

8. Francis P, Schneider J, Hann L, et al. (1994) Phase II trial ofdocetaxel in patients with platinum-refractory advanced ovariancancer. J Clin Oncol 12:23012308

9. Noda K, Terajima Y, Ogita Y, et al. (1994) Phase II clinical studyof RP56976 (docetaxel) in patients with carcinoma ovarii or carci-noma colli uteri (in Japanese). Gan To Kagaku Ryoho (Jpn JCancer Chemother) 21:24712477

7/26/2019 uuuuuu.pdf

5/6

347

10. Kavanagh JJ, Kudelka AP, de Leon CG, et al. (1996) Phase IIstudy of docetaxel in patients with epithelial ovarian carcinomarefractory to platinum. Clin Cancer Res 2:837842

11. Katsumata N, Tsunematsu R, Tanaka K, et al. (2000) A phase IItrial of docetaxel in platinum pre-treated patients with advancedepithelial ovarian cancer: a Japanese Cooperative Study. AnnOncol 11:15311536

12. Rose PG, Blessing JA, Mayer AR, et al. (1998) Prolonged oraletoposide as second-line therapy for platinum-resistant andplatinum-sensitive ovarian carcinoma: a Gynecologic OncologyGroup study. J Clin Oncol 16:405410

13. Takeuchi S, Dobashi K, Fujimoto S, et al. (1991) A late phase IIstudy of CPT-11 on uterine cervical cancer and ovarian cancer.Research Groups of CPT-11 in Gynecologic Cancers (inJapanese). Gan To Kagaku Ryoho (Jpn J Cancer Chemother) 18:16811689

14. Kudelka AP, Tresukosol D, Edwards CL, et al. (1996) Phase IIstudy of intravenous topotecan as a 5-day infusion for refractoryepithelial ovarian carcinoma. J Clin Oncol 14:15521557

15. Friedlander M, Millward MJ, Bell D, et al. (1998) A phase II studyof gemcitabine in platinum pre-treated patients with advancedepithelial ovarian cancer. Ann Oncol 9:13431345

16. Gordon AN, Granai CO, Rose PG, et al. (2000) Phase II study ofliposomal doxorubicin in platinum- and paclitaxel-refractory epi-thelial ovarian cancer. J Clin Oncol 18:30933100

17. Rustin GJ, Marples M, Nelstrop AE, et al. (2001) Use of CA-125 todefine progression of ovarian cancer in patients with persistentlyelevated levels. J Clin Oncol 19:40544057

18. Burstein HJ, Manola J, Younger J, et al. (2000) Docetaxel admin-istered on a weekly basis for metastatic breast cancer. J Clin Oncol18:12121219

19. Aihara T, Kim Y, Takatsuka Y (2002) Phase II study of weeklydocetaxel in patients with metastatic breast cancer. Ann Oncol 13:286292

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