For the past to decades, women with recurrent or persistent ovarian carcinoma have continued to represent an important clinical problem. The majority of patients with epithelial ovarian cancer are encountered with advanced-stage disease when the diagnosis is established. The initial responses to chemotherapy may not readily translate to improved long-term survival, but a combination of a platinum compound and an alkylating agent has been considered as the standard chemotherapy following surgical cytoreduction in the management of advanced epithelial ovarian cancer(1). Recently, the study by the Gynecologic Oncology Group (GOG) 111(2) reported that combined paclitaxel and cisplatin had resulted in a significantly higher complete response rate than cyclophosphamide/cisplatin regimens in women with advanced ovarian cancer. Similar results were also reported by the Canadian-European study (OV 10)(3).
However, cisplatin is associated with a high incidence of renal dysfunction and neurotoxic events, including ototoxicity and severe peripheral neuropathy(4,5). Until recently, carboplatin, a cisplatin analogue, had been used as a substitute because of its significantly lower nonhematological toxicity and therapeutic efficacy similar to that of cisplatin(6). Clinically, with carboplatin therapy, aggressive intravenous hydration is usually unnecessary and treatment can be performed on an outpatient basis(7,8). Because of the high hematological toxicity of paclitaxel and carboplatin(6), supplemental supports such as granulocyte colony-stimulating factor (G-CSF) are usually required(9). Thrombocytopenia attributed to carboplatin is another consideration of myelosuppression(10). Nevertheless, the reports of weekly paclitaxel administration for the treatment of advanced ovarian cancer(11) and non-small-cell lung cancer(12–14) were encouraging.
Attempts to improve the outcome of chemotherapy in women with advanced ovarian cancer have focused on attenuation of side effects, improvements in responsiveness, progressive palliation of the disease, and improvements in quality of life. The purpose of the present study is to examine whether a weekly administration of paclitaxel and carboplatin could result in greater dose intensity with lower myelotoxicity, as compared with a monthly regimen, in the management of advanced ovarian cancer of women.
Patients and methods
Study design and eligibility criteria
Our ongoing, prospective and randomized clinical study was undertaken to see whether a weekly regimen of carboplatin-paclitaxel was better tolerated than the conventional monthly administration with the respect to hematological side effects.
Women with epithelial ovarian cancer pathologically confirmed and clinically diagnosed as stages IIB-IV as defined by the International Federation of Gynecology and Obstetrics (FIGO)(15) were eligible. All patients underwent cytoreductive surgery prior to the paclitaxel-carboplatin chemotherapy. Pathological types of ovarian tumor diagnosed in Groups A and B included serous (eight and nine cases, respectively), mucinous (three and three cases, respectively), endometrioid (two cases in each group) and undifferentiated adenocarcinoma (one case in each group). Patients with borderline tumors and with progressive disease were excluded from this study. Clinical stages and Eastern Cooperative Oncology Group (ECOG) performance status(16) of each group are shown in Table 1. Responding patients continued to receive treatment in the same dosage until the development of unacceptable toxicity. Further eligibility criteria included: 1) ECOG performance ≤ 2; 2) life expectancy greater than 12 weeks; 3) adequate hematological function (absolute neutrophil count ≥ 2,000/L, platelet count ≥ 100,000), adequate hepatic function (bilirubin ≤ 1.25 × upper normal limit, aspartate aminotransferase ≤ 2.5 × upper normal limit), and adequate renal function (serum creatinine ≤ 1.5 × upper normal limit); 4) no previous chemotherapy with taxane-based drugs; and 5) no serious concomitant psychiatric or medical illness. Written informed consent was required before enrollment.
Patients eligibility and treatment
From September 1997 to September 1999, 29 patients with advanced ovarian cancer and a median age of 58 years (range 41–75 years) enrolled in this study at Kaohsiung Medical University Hospital's Department of Obstetrics and Gynecology. All patients received at least four cycles of chemotherapy with paclitaxel-carboplatin. Patients were divided into two groups by the computerized simple randomization method: Group A (n = 14) received a weekly regimen (98 cycles in total), and Group B (n = 15) a monthly regimen (102 cycles in total). For the monthly regimen, pacilitaxel (175 mg/m2) in normal saline solution was given through 1-h intravenous infusion(17–19), immediately followed by carboplatin (area under the concentration-time curve of 6 using the Calvert formula(20)) over 30 min. For the weekly regimen, paclitaxel (60 mg/m2) and carboplatin (area under the concentration-time curve of 2 using the Calvert formula) were administrated in a similar way. Premedications including dexamethasone (20 mg; 6 and 12 h before therapy), diphenhydramine (50 mg), and cimetidine (300 mg) were given before each treatment as the standard procedure.
All patient responses such as complaints, complications, and outcomes were monitored during the courses of treatment. Other unexpected events such as delayed treatment (over 7 days), unanticipated hospitalization, and G-CSF supplementation were considered for evaluation. Hematological and biochemical studies as well as physical examinations were carried out on day 1 of each cycle performed. Tumor markers such as CA 125, CEA, and TPA were evaluated monthly. Computerized tomography was performed every 6 months. The total study period was 18 months. Toxicity was assessed in every cycle using World Health Organization (WHO) criteria(21). Overall toxicity was evaluated and analyzed by Mann–Whitney U-test, statistically. P < 0.05 was considered as statistically significant.
Ninety-eight cycles of the weekly regimen (Group A, n = 14) and 102 cycles of the monthly regimen (Group B, n = 15) were completed within 18 months in this study. The median ages of patients in Groups A and B were 59 years (range 47–73 years) and 57 years (range 41–75 years), respectively. No serious hypersensitivity reactions or apparent cardiac toxicity were observed in either group. There were significantly fewer hematological toxicities in the weekly regimen than in the monthly regimen Table 2. Anemia (≥ WHO grade 2), although generally mild, was shown in a cumulative manner as treatment cycles increased; i.e., in 7.1% of the weekly and 18.6% of the monthly regimen. No case in the weekly regimen was noted to have grade 3/4 anemia, but 3.9% of patients in the monthly regimen developed anemia of this grade. Grade 3/4 of granulocytopenia occurred in 7.1% of Group A and 32.3% in Group B. Thrombocytopenia over grade 2 was found in 15.7% of Group B in comparison with none in Group A. No patient had hemorrhagic problems related to thrombocytopenia.
With respect to nonhematological toxicity, alopecia appeared to be the most common. Eight of 14 patients in Group A and 9 of 15 patients in Group B complained of grade 3 alopecia Table 3. Other side effects such as peripheral neuropathy, mucositis, nausea/vomiting, and arthralgia/myalgia did not differ significantly between the weekly and monthly regimens.
Responses were defined by either computed tomographic measurement of mass or serial decline in serum CA125 levels as described previously(22). Notably, in this preliminary study patients' outcomes from these two regimens have shown that six patients in Group A and five in Group B achieved a complete response, while four in Group A and five in Group B achieved a partial response after 18 months of follow-up. All patients were assessable during the study by CA 125 and CT. Because clinical response was not the end point for this preliminary study, however, second-look laparotomy was performed in six of 11 patients with clinical complete remission, two of them having no pathologic evidence of residual disease Table 4. To compare the incidence of unscheduled events between the two regimens during the study period, there were three and 18 cycles of delayed treatment (over 7 days) in Groups A and B, respectively. Three and 15 unanticipated hospitalizations occurred in Groups A and B, respectively. In the monthly regimen, 33 patients needed G-CSF supplementation because of severe hematological toxicity (absolute neutrophil count less than 1,000/L). However, in the weekly group, only seven patients needed such support Table 5.
The mechanism of paclitaxel action is unique; it can enhance the rate and yield of microtubular assembly and prevent microtubular depolymerization, thereby synchronizing cells at the G2/M phase of the cell cycle(23). Paclitaxel concentrations at low doses (0.05 mol/l) promote microtubular assembly in vitro (24). In humans, serum paclitaxel levels greater than 0.5 mol/l are clinically tolerable(25). However, the optimal dosage and schedule of paclitaxel remain uncertain. In pharmacokinetic and pharmacodynamic studies(26), neutropenia is associated with a duration of plasma concentrations greater than 0.05 mol/l. Thus, trials of new paclitaxel regimens should consider this agent's nonlinear disposition to rule out adverse clinical consequences, especially in a short-term infusion(27). On the other hand, carboplatin provokes fewer neurotoxic, nephrotoxic, and ototoxic side actions than cisplatin does(28,29); however, the combination of paclitaxel and carboplatin in the monthly regimens induced apparently greater myelosuppression side actions than those caused by paclitaxel plus cisplatin(30).
It is reasonable to seek an approach to chemotherapy that can not only extend survival rates with fewer complications but which also fits the demand for cost-effectiveness. In the present study, we have selected a weekly schedule and therapeutic dosage, mimicking the regimen for advanced non-small-cell lung cancer chemotherapy in other studies(12–14). Although the number of hospital visits in weekly regimens is greater than in monthly regimens, the reduced side effects resulting from chemotherapy could enhance drive and psychological strength for women in those regimens, better enabling them to cope with their advanced ovarian cancer. The patient numbers and follow-up duration in this series are small, and it is too early to judge whether the efficacy of a weekly regimen of chemotherapy using paclitaxel and carboplatin in the treatment of advanced ovarian cancer is superior to that of a monthly regimen. These preliminary results demonstrate that responses of weekly paclitaxel and carboplatin administration have achieved an outcome similar to that of a conventional monthly regimen during 18 months of follow-up study. Importantly, the advantages of a weekly paclitaxel and carboplatin regimen are tolerable toxicity, reduced myelosuppression, and diminished unscheduled events. This therefore represents a more cost-effective approach than the conventional monthly regimen.
1 McGuire WP. Primary treatment of epithelial ovarian malignancies. Cancer
2 McGuire WP, Hoskins WJ, Brady MF et al
. Cyclophosphamide and cisplatin compared with paclitaxel
and cisplatin in patients with stage III and IV ovarian Cancer
. N Engl J Med
3 Stuart G, Bertelsen K, Mangioni C et al
. Updated analysis shows a highly significant improved overall survival (OS) for cisplatin-paclitaxel
as first line treatment of advanced ovarian cancer
: mature results of the EORTC-GCCG, NO-COVA, NCIC CTG and Scottish intergroup trial. Proc Am Soc Clin Oncol
4 Daugaard G, Abildgaard U. Cisplatin nephrotoxicity. A review. Cancer Chemother Pharmacol
5 Harmers FP, Gispen WH, Neijt JP. Neurotoxic side-effects of cisplatin. Eur J Cancer
6 Canetta R, Rozencweig M, Carter SK. Carboplatin
: the clinical spectrum to date. Cancer Treat Rev
7 Swenerton K, Jeffrey J, Stuart G et al
. Cisplatin-cyclophosphamide versus carboplatin
-cyclophosphamide in advanced ovarian cancer
: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol
8 Bookman MA, McGuire WP, Kilpatrick D et al
in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group. J Clin Oncol
9 ten Bokkel Huinink W, Veenhof C, Huizing M et al
in patients with advanced ovarian cancer
: a dose-finding study. Semin Oncol
1997;24 (Suppl. 2):31–3.
10 Adams M, Kerby IJ, Rocker I et al
. A comparison of the toxicity and efficacy of cisplatin and carboplatin
in advanced ovarian cancer
. The Swons Gynaecological Cancer Group. Acta Oncol
11 Abu-Rustum NR, Aghajanian C, Barakat RR et al
. Salvage weekly paclitaxel
in recurrent ovarian cancer
. Semin Oncol
1997;24 (Suppl. 15):62–7.
12 Langer CJ, Leighton JC, Comis RL et al
in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol
13 Choy H, Akerley W, Safran H et al
. Phase I trial of outpatient weekly paclitaxel
and concurrent radiation therapy for advanced non-small-cell lung cancer. J Clin Oncol
14 Giaccone G, Huizing M, ten Bokkel Huinink W et al
. Preliminary results of two dose-finding studies of paclitaxel
(Taxol) and carboplatin
in non-small cell lung and ovarian cancers: a European Cancer Centre effort. Semin Oncol
1994;21 (Suppl. 8):34–8.
15 Staging Announcement. FIGO Cancer Committee. Gynecol Oncol
16 Menzin AW, Appendixes. In. Rubin SC. eds. Chemotherapy of Gynecologic Cancers: Society of Gynecologic Oncologists Handbook
Philadelphia: Lippincott-Raven.: 188., 1996.
17 John D, Hainsworth. F. Anthony Greco. Paclitaxel
administered by 1-hour infusion. Cancer
18 F, Anthony Greco John D, Hainsworth. One-hour paclitaxel
infusion schedules: a phase I/II comparative trial. Semin Oncol
1995;22 (Suppl. 6):118–23.
19 Corey J, Langer. John C. Leighton, Robert L. Comis et al. Paclitaxel
by 24- or 1-hour infusion in combination with carboplatin
in advanced non-small cell lung cancer: the Fox Chase Cancer experience. Semin Oncol
1995;22 (Suppl. 9):18–29.
20 Calvert AH, Newell DR, Gumbrell LA et al
dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol
21 World Health Organization. Handbook for Reporting Results of Cancer Treatment. Offset Publication 48. Geneva, Switzerland: World Health Organization, 1979.
22 Rustin GJ, Nelstrop AE, McClean P et al
. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol
23 Rowinsky EK, Cazenave LA, Donehower RC. Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst
24 Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro
by taxol. Nature
25 Forastiere A, Rowinsky EK, Chaudhry V et al
. Phase I and pharmacologic study of Taxol and cisplatin + G-CSF. Proc Am Soc Clin Oncol
26 Huizing MT, Keung AC, Rosing H et al
. Pharmacokinetics of paclitaxel
and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer
patients. J Clin Oncol
27 Gianni L, Kearns CM, Giani A et al
. Nonlinear pharmacokinetics and metabolism of paclitaxel
and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol
28 Curt GA, Grygiel JJ, Corden BJ et al
. A phase I and pharmacokinetic study of diamminecyclobutane-dicarboxylatoplatinum (NSC 241240). Cancer Res
29 Egorin MJ, Van Echo DA, Tipping SJ et al
. Pharmacokinetics and dosage reduction of cis-diammine (1,1-cyclobutanedicarboxylato) platinum in patients with impaired renal function. Cancer Res
30 du Bois A, Luck HJ, Meier W et al
as first-line chemotherapy in advanced ovarian cancer
: an interim analysis of a randomized phase III trial of the Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer
Study Group. Semin Oncol
1997;24 (Suppl. 15):15–52.
Keywords:© 2001 Blackwell Science Ltd.
carboplatin; ovarian cancer; paclitaxel; weekly regimen