Japanese Journal of Clinical Oncology 32:128-134 (2002)
© 2002 Foundation for Promotion of Cancer Research
A Phase I/II Study of Carboplatin and Paclitaxel in Patients with Epithelial Ovarian Cancer
1 Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Sapporo, 2 Kohnan Hospital, Sapporo, 3 Sapporo Kohsei Hospital, Sapporo, 4 Sapporo City Hospital, Sapporo, 5 Teine Keijinkai Hospital, Sapporo, 6 Obihiro Kohsei Hospital, Obihiro, 7 Kushiro Red Cross Hospital, Kushiro, 8 Hakodate National Hospital, Hakodate and 9 Asahikawa City Hospital, Asahikawa, Hokkaido, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: This study was conducted to investigate the recommended dose of paclitaxel for use in combination with a fixed dose of carboplatin and to evaluate the toxicity and efficacy of carboplatin–paclitaxel combination chemotherapy in patients with epithelial ovarian cancer.
Methods: One hundred and ten patients were enrolled in the Phase I/II study and 97 patients were evaluated for further analysis, excluding 13 ineligible patients or patients with infringement of protocol: 15 patients for the Phase I and 82 for the Phase II study. In the Phase I trial, we studied dose escalation using a carboplatin dose of AUC 5 and paclitaxel levels of 150, 175 and 200 mg/m2. The grades of toxicity of the regimen of all patients enrolled in the Phase II study (n = 82), the progression-free survival time (PFS) of optimal-debulked patients and complete responders (n = 62) and the response rate of suboptimal-debulked patients (n = 39) were investigated.
Results: After observing grade 4 neutropenia in four of six patients in the paclitaxel 200 mg/m2 administration group, we chose 175 mg/m2 as the recommended dose of paclitaxel in this regimen. At this dose, the median of PFS and response rate were 432 days (range, 19–907 days) and 66.7%, respectively.
Conclusion: Combination chemotherapy using paclitaxel 175 mg/m2 and carboplatin AUC 5 is very well tolerated and highly effective for the treatment of ovarian cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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In theory, to obtain the maximum effect of anticancer agents, it is best to administer them while there are as few resistant cells as possible. Adjuvant chemotherapy is a therapy intended to eradicate possible micrometastasis. Combination chemotherapy with a cyclophosphamide–doxorubicine–platinum agent (cisplatin or carboplatin) was widely used as an effective adjuvant chemotherapy for ovarian cancer until the efficacy of paclitaxel was confirmed. However, in the treatment of recurrent ovarian cancer, just as with cancers of other organs, chemotherapy has rarely been successful.
Paclitaxel has been reported to be an effective agent for platinum-resistant ovarian cancer (1,2). A number of reports have been published in Western countries regarding the safety and recommended dosage of carboplatin–paclitaxel combination chemotherapy for ovarian cancer (2–6), but similar comprehensive studies have not been carried out in Japan.
In this study, we conducted a Phase I and Phase II multicenter investigation using a fixed carboplatin dose of AUC 5 (6). The Phase I study attempted to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose (RD) of paclitaxel in Japanese patients receiving carboplatin–paclitaxel combination chemotherapy. The Phase II study attempted to confirm the efficacy and safety of carboplatin–paclitaxel combination chemotherapy using the RD determined in Phase I.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The protocol was approved by the institutional review board of each participating institution in June 1997. All patients gave their written informed consent and this study was monitored independently by the committee.
Eligibility Criteria
All patients included in the study had histologically proven epithelial ovarian cancer. Other criteria for inclusion were as follows: chemonaivety, a performance status (ECOG) of 0–2, age of between 15 and 75 years, leukocytes >4.0 x 109/l and <12.0 x 109/l, platelet count >100 x 109/l, Hgb >9.0 g/dl, total bilirubin <1.5 mg/dl, serum creatinine <1.5 mg/dl, serum GOT/GPT <2x upper limit of normal, 24 h creatinine clearance >60 ml/min, absence of cardiovascular disease, life expectancy of at least 3 months and absence of any past or current history of other neoplasma.
The number of suboptimal-debulked patients required to reject the null hypothesis that the response rate was 
30% was calculated to be 34, based on an alternative response rate of 50%, a one-sided test with 
= 0.10 and ß = 0.20 (7). We planned to enroll 40 patients for suboptimal-debulked cases and the same number of patients for optimal-debulked cases.
Treatment Protocol
Paclitaxel diluted in 500 ml of physiological saline was administered at a dose of 150, 175 or 200 mg/m2 as a 3 h intravenous infusion followed by 30 min of intravenous infusion of carboplatin (AUC 5, diluted in 250 ml of physiological saline). All patients were premedicated with intravenous dexamethasone (20 mg) at 12–14 h and 6–7 h before paclitaxel administration and intravenous ranitidine hydrochloride (50 mg) and oral diphenhydramine (50 mg) were administered 30 min before paclitaxel. A 3 mg amount of granisetron hydrochloride in 100 ml of physiological saline as a 30 min intravenous infusion was administered 30 min after paclitaxel.
Phase I Study
Phase I study subjects had been histologically diagnosed with epithelial ovarian cancer after an examination by laparotomy or radical surgery at one of four institutes between January and June of 1998 and were indicated for first-line chemotherapy. Nineteen patients were registered for the Phase I study and four of these were subsequently excluded (one with gastric cancer, one with performance status 3, two with infringement of protocol). The median age of the investigated patients was 53 years (range, 30–67 years) and the median performance status (ECOG) was 0 (range, 0–2), as indicated in Table 1. After obtaining written informed consent from the patients, we set the carboplatin dose at AUC 5 (6) and the three paclitaxel levels at 150, 175 and 200 mg/m2 in the dose-escalation study. We calculated the carboplatin dose with Calvert’s equation (8), assuming that the mean of the 24 h creatinine clearance with two measurements or more was GFR. The maximum dose of carboplatin was set at 800 mg/body. Paclitaxel and carboplatin were administered according to the dosage protocols and an analgesic was administered only if clinically indicated. We followed the National Cancer Institute Common Toxicity Criteria (NCI-CTC Version 2, January 30, 1998) for grading side effects. Nonhematological toxicities of grade 3 or higher, except in cases of nausea, fatigue or alopecia or hematological toxicities of a grade 4 platelet count (<25 x 109/l), a 4 day or longer grade 4 leukocyte count (<1.0 x 109/l) and a 4 day or longer grade 4 neutrophil count (<0.5 x 109/l) were defined as dose-limiting toxicities (DLT). If DLT was not observed in the three patients registered at a particular dose level, we advanced to the next-higher dose level. However, if we observed DLT in even one of the three cases, we added three more cases at that dose level. Then, if DLT was observed in less than three of the total of six cases, we advanced to the next-higher level. However, if we observed DLT in three or more cases, we regarded that dose level as the MTD and the dose level one step lower as the RD.
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DLT was judged up to the second course in every patient. We injected granulocyte colony-stimulating factor (G-CSF) only when the leukocyte count was <1.0 x 109/l or the neutrophil count was 0.5 x 109/l. We prohibited administration of other anticancer agents and biological response modifier (BRM) to patients. If leukocyte levels were <3.0 x 109/l or platelet levels were <100 x 109/l at 3 weeks after administration, we postponed the next course of chemotherapy. If leukocytes were not recovered to 3.0 x 109/l or higher and platelets were not 100 x 109/l or higher at 6 weeks after administration, we canceled the next dosage cycle. If a hematological DLT was observed, we reduced the next paclitaxel dose by 25 mg/m2 and set the target carboplatin AUC at 4. If the hematological toxicity re-emerged despite the reduced dosage, we canceled all plans for further administration. We also stopped this course of chemotherapy if an apparent adverse change had progressed or the general state of the patient had worsened.
Phase II Study
For the Phase II study, 91 patients from nine institutes were registered between June 1998 and October 2000. Nine patients were excluded from or dropped out of the study (one with death in 2 months, eight with infringement of protocol) and 43 optimal-debulked patients (remaining tumor diameter <0.5 cm) and 39 suboptimal-debulked patients (
0.5 cm), 82 patients in total, were investigated. The median age of the investigated patients was 53 years (range, 26–72 years) and the median performance status was 0 (range, 0–2) (Table 1). We administered the recommended dose of paclitaxel as determined in the Phase I study, 175 mg/m2, every 3 weeks to both optimal-debulked and suboptimal-debulked patients. The target number of therapy courses was three to six. If, after completing six courses, the response was judged to be pathological based on a second-look operation, then it was recommended that the patient continue with cyclic chemotherapy every 3 months for 3 years. To ensure the safety of the Phase II trial better, we injected G-CSF after verifying that leukocyte counts were <2.0 x 109/l or neutrophil counts were <1.0 x 109/l, while following the guidelines of the Phase I study for other anticancer agents and BRM. Based on the ‘Direct Effect Evaluation Standards of Gynecological Chemotherapy’ of the Japan Society for Cancer Therapy, we studied the response rate (RR) of 39 suboptimal-debulked patients and the progression-free survival time (PFS) of optimal-debulked patients and complete responders (n = 62), as well as the overall tolerance of this regimen. The starting point of PFS was defined as the day of optimal-debulked surgery or the day of confirmation of an absence of residual tumor by second-look operation. The rate of relapse and the efficacy of the chemotherapy were explored by using tumor markers, ultrasound testing and/or a chest radiograph every 2 weeks and/or a computed tomography (CT) scan or magnetic resonance imaging (MRI) study every 3 months during the combination chemotherapy. The following criteria of response established by the Japan Society for Cancer Therapy were used. Complete response (CR) was defined as the disappearance of all clinical evidence of a tumor based on clinical examinations at intervals of 4 weeks or less. Partial response (PR) was defined as a 50% or greater decrease in the sum of products of measured indicator lesions with no simultaneous increase in the size of any lesion or appearance of new lesions based on clinical examinations at intervals of 4 weeks or less. No change (NC) was defined as a less than 50% response, steady-state response or less than 25% progression based on clinical examinations at intervals of 4 weeks or less. Progressive disease (PD) was defined as an unequivocal increase of at least 25% in the product of measured lesions.
Statistical Analysis
Statistical significance was determined by the Mann–Whitney U-test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Phase I Study
In all three patients of the paclitaxel 150 mg/m2 group, DLT was not observed during the first or second course. Throughout the total of 13 courses administered to each member of this group, no non-hematological toxicities of grade 3 or greater or hematological toxicities of grade 4 were observed. In the paclitaxel 175 mg/m2 group, three patients were added because grade 3 febrile neutropenia (lowest neutrophil counts = 0.1 x 109/l, fever = 39.0°C) was observed in one patient and grade 3 pelvic pain in another. We observed no DLT in the other patients. In the paclitaxel 200 mg/m2 group, three patients were added because one patient with grade 3 myalgia, another with grade 3 neuropathy and two with grade 4 neutropenia were observed. Grade 4 neutropenia lasting
4 days was observed in four of six patients of the paclitaxel 200 mg/m2 groups. The paclitaxel MTD in carboplatin–paclitaxel combination chemotherapy was thus taken as 200 mg/m2. We also determined that 175 mg/m2, one dose step lower, was the paclitaxel RD in this combination chemotherapy (Table 2).
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Phase II Study
There was only one recurrence among the 43 optimal-debulked patients enrolled in the Phase II study. This occurred in a patient with a mixed epithelial adenocarcinoma of the ovary in the Ic stage [FIGO staging system (9)]. Tables 3 and 4 show the response rate in the suboptimal-debulked patients on the basis of clinical stage and histological type, respectively. The response rate of suboptimal-debulked patients (n = 39) was 66.7%. Each CR case (n = 19) was confirmed pathologically by second-look operation. However, cases of PR (n = 7), NC (n = 3) and PD (n = 10) were evaluated by tumor markers, ultrasound testing, chest radiograph, CT scan and/or MRI study. The median PFS of optimal-debulked patients and complete responders (n = 62) was 432 days (range, 19–907 days).
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Tables 5 and 6 show the non-hematological toxicities and hematological toxicities, respectively, of the 82 patients (420 courses in total) enrolled in the Phase II study. The non-hematological toxicities resulted in no severe side effects other than one case of grade 3 pelvic pain and another of febrile neutropenia. Both patients achieved remission after hospitalization, administration of analgesics and/or intravenous administration of antibiotics.
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Table 6 shows changes in the leukocyte, neutrophil and platelet counts. The medians of the lowest leukocyte counts during the fourth, fifth and sixth courses were 2.0 x 109/l (range, 1.2–3.7 x 109/l), 1.9 x 109/l (range, 1.1–5.9 x 109/l) and 2.0 x 109/l (range, 0.8–4.6 x 109/l), significantly lower than the median value of 2.3 x 109/l (range, 1.1–7.1 x 109/l) obtained at the first course. The median number of days required to reach the lowest leukocyte count was 9.5 days in the fifth course (range, 2–22 days), significantly lower than the 11 days (range, 3–21 days) required in the first course of therapy. There were no significant differences among the other courses of therapy with respect to the number of days required to reach the lowest leukocyte count.
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The median values for the lowest neutrophil counts during the third and fourth courses were 0.5 x 109/l (range, 0.0–2.4 x 109/l) and 0.4 x 109/l (range, 0.1–1.5 x 109/l), respectively, significantly lower than the median value of 0.8 x 109/l (range, 0.1–2.3 x 109/l) during the first course. The median numbers of days required to reach the lowest neutrophil count were 10 (range, 3–17) and 9.5 (range, 3–15) for the fifth and sixth courses, respectively and both of these values were significantly lower than that of 12 days (range, 2–18 days) for the first course. There were no significant differences among the other courses of therapy with respect to the number of days required to reach the lowest neutrophil count.
The median values for the lowest platelet counts during the second and sixth courses were 160 x 109/l (range, 20–350 x 109/l) and 140 x 109/l (range, 28–265 x 109/l), significantly lower than the valued of 190 x 109/l (range, 80–350 x 109/l) at the first course. As for the number of days required to reach the lowest platelet count, we did not observe any significant differences among the courses of chemotherapy.
The median paclitaxel dosage administered to patients of the Phase II study during the 1st course of therapy was 240 mg/body (range, 200–318 mg/body). The median carboplatin dosage administered to patients of the Phase II study during the first course of therapy was 550 mg/body (range, 370–750 mg/body). The median number of treatment courses was 6 (range, 1–12). The median paclitaxel dosage administered to patients during the final course of therapy was 240 mg/body (range, 200–318 mg/body). The median carboplatin dosage administered to patients during the final course of therapy was 545 mg/body (range, 370–750 mg/body), with no statistically significant difference between the first and final dosage.
Table 7 shows changes in the measured values of the serum tumor markers CA125 (normal value, <35.0 U/ml), CA19-9 (<37.0 U/ml), CA72-4 (<4.0 U/ml) and CEA (<6.5 ng/ml). These were measured before and after the carboplatin–paclitaxel combination chemotherapy and were evaluated on a histological-type basis when it was possible to examine eight or more patients. The median value of serum CA125 decreased significantly from 1100 U/ml (range, 16.0–12 000 U/ml) before serous adenocarcinoma therapy to 13.7 U/ml (range, 2.9–190.0 U/ml) after and that of serum CA72-4 decreased significantly from 3.8 U/ml (range, 1.2–364.4 U/ml) before to 2.7 U/ml (range, 1.0–5.5 U/ml) after therapy. The median values of serum CA125, CA19-9 and CA72-4 decreased significantly from 171.8 U/ml (range, 29.0–1500 U/ml) to 10.2 U/ml (range, 1.0–37.0 U/ml), from 376.3 U/ml (range, 6.7–14 406 U/ml) to 5.0 U/ml (range, 2.0–29.3 U/ml) and from 3.6 U/ml (range, 2.7–73.0 U/ml) to 2.4 U/ml (range, 0.7–3.6 U/ml), respectively, between before and after mucinous adenocarcinoma therapy. The median value of serum CA125 decreased significantly from 58.6 U/ml (range, 10.1–8 800 U/ml) to 10.1 U/ml (range, 3.0–279.7 U/ml) between before and after clear cell adenocarcinoma therapy. The median value of serum CA125 decreased significantly from 134.5 U/ml (range, 13.0–8 784 U/ml) before endometrioid adenocarcinoma therapy to 7.1 U/ml (range, 2.0–27.0 U/ml) after and that of serum CA72-4 decreased significantly from 17.3 U/ml (range, 3.0–45.5 U/ml) before to 2.8 U/ml (range, 1.6–3.0 U/ml) after therapy.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The standard chemotherapy regimen for ovarian cancer in the last two decades has been cyclophosphamide–cisplatin ± adriamycin combination chemotherapy. However, as a result of study 111 of the Gynecologic Oncology Group (GOG), it was found that a combination therapy of paclitaxel (135 mg/m2, 24 h DIV) and cisplatin has a significantly better response rate and PFS than that of cyclophosphamide–cisplatin (10). In 1994, a European and Canadian multicenter joint research project was conducted targeting relapsed ovarian cancer (1). Using a 3 h intravenous paclitaxel infusion, side effects such as bone marrow suppression were significantly reduced. An allergic reaction to paclitaxel was also controlled by premedication. This joint research group reported that in the comparative test between the carboplatin–paclitaxel 175 mg/m2 (3 h DIV) chemotherapy and the cyclophosphamide–cisplatin chemotherapy, the PFS was extended significantly in the former, verifying the GOG 111 study. The subjects were 680 ovarian cancer patients, including patients who had previously been treated with other regimens. They concluded that carboplatin–paclitaxel therapy was highly effective for the treatment of ovarian cancer (10).
A number of studies on combination chemotherapies of platinum agents and paclitaxel have been carried out in Western countries (2–6,11). The rationale behind the current use of carboplatin in this combination chemotherapy is as follows. (i) Carboplatin alone is as effective as cisplatin alone for the treatment of ovarian cancer (12,13). (ii) Carboplatin is significantly less nephrotoxic than cisplatin (14). Hydration is not necessary when administering carboplatin, unlike with cisplatin. (iii) The non-hematological toxicity of carboplatin is less than that of cisplatin; this is important because there is concern about the anxiety produced by the peripheral nervous toxicity in cisplatin–paclitaxel combination chemotherapy (15). (iv) Using the carboplatin dose obtained from AUC and GFR by Calvert's equation, it is possible to control platelet reduction (8,15).
The results of the present study suggest that the RD of paclitaxel is 175 mg/m2 (3 h DIV) for Japanese patients, similar to or slightly lower than the dosage recommended in Western countries (2–6), in this combination chemotherapy with carboplatin AUC 5.
With regard to non-hematological toxicities, all but two patients who received a combination of carboplatin AUC 5 plus paclitaxel 175 mg/m2 in a 3 h infusion showed a non-hematological toxicity grade of 2 or lower. Even in the two patients who showed grade 3 toxicity, remission was achieved in response to analgesic administration through hospitalization and intravenous administration of antibiotics.
As for the decrease in leukocytes and neutrophils, it became difficult to interpret the results because the G-CSF limit was set less severely than in the Phase I study. We were able to observe that the lowest leukocyte value for each course decreased significantly once the number of courses exceeded four. However, although the number of days to reach the nadir was significantly reduced in the fifth course, in the sixth course it was again identical with that in the first course. As for neutrophils, the numbers of days required to reach the lowest value of neutrophils in the third and fourth courses were clearly lower than that in the first course. In the fifth and sixth courses, the neutrophil nadir was reached very quickly and often G-CSF was administered from an early period. Thus the lowest neutrophil counts in the first, fifth and sixth courses were roughly identical.
With regard to the accumulation of hematological toxicity on bone marrow, the significant decrease in the lowest count of platelets during the sixth course can be easily explained. Although platelets showed a significant decrease in the lowest count in the second course, there was no decrease between the third and fifth courses. As for the number of days required to reach the nadir, there was absolutely no change from the first to the sixth course. Although the number of patients examined was small in the Phase I study, with regard to platelets, the number of days required to reach the nadir in the 200 mg/m2 paclitaxel administration group was significantly smaller than that of 150 mg/m2 administration group. As for the lowest count of platelets, the difference between these two groups was not significant, although the 200 mg/m2 paclitaxel administration group did show a decreasing trend (data not shown).
Based on the above, we believe that the decrease in the platelet counts in this combination chemotherapy was possibly dose dependent. However, since the entire process is fairly complicated, especially regarding the disorder of bone marrow function for platelet reproduction and the recovery mechanism of bone marrow function when suppressed by anticancer agents multiple times, further examination is necessary, including examination of involvement of the platelet-sparing effect.
The examination of tumor markers of ovarian cancer on a histological basis revealed that the median values of serum CA125 before treatment were significantly higher than the normal range in every histological type of ovarian cancer. Clear changes before and after chemotherapy were also visible. Thus the results verified that serum CA125 is the most useful tumor marker for establishing the extent of the tumor burden before treatment and for monitoring the response to therapy for ovarian cancer. However, the serum CEA was within the normal range before therapy in every histological type of ovarian cancer and no changes were caused by the chemotherapy. As such, serum CEA was not found to be effective as a tumor marker for ovarian cancer.
Although the present study was somewhat limited in that the longest follow-up from the start of initial therapy was less than 3 years, we observed no recurrence of tumor in 43 of 44 patients in whom optimal-debulked surgery was possible. The overall response rate was a favorable 66.7% and the same dose used in the first course could also be used in the sixth course. We therefore conclude that this combination chemotherapy using paclitaxel 175 mg/m2 and carboplatin AUC 5 is well tolerated and highly effective in the treatment of ovarian cancer.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This study was supported in part by a grant from Bristol-Myers Squibb, Sapporo. We acknowledge the excellent advice of Hirotaka Seto, Supervisor, Scientific Promotions, Oncology Marketing, Bristol-Myers Squibb, Japan. We thank all the pathologists and clinician teams of the different centers who actively participated in this study.
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FOOTNOTES |
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+ For reprints and all correspondence: Ritsu Yamamoto, Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-8638, Japan. E-mail: rityam@med.hokudai.ac.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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2
Guastalla JP, Lauraine EP, Weber B, Curé H, Orfeuvre H, Mousseau M, et al. Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma. Ann Oncol 1998;9:37–43.
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10
McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1–6.
11
Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al. Randomized intergroup trial of cisplatin–paclitaxel versus cisplatin–cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000;92:699–708.
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15
Kjorstad K, Harris A, Bertelsen K, Slevin M, Schultz H, Hellman K, et al. A multicenter phase II study of carboplatin in advanced ovarian carcinoma: final report. Ann Oncol 1992;3:217–22.
Received October 25, 2001; accepted January 22, 2002
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