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Phase I trial of concurrent chemoradiation with weekly nedaplatin in patients with squamous cell carcinoma of the uterine cervix
Gynecologic Oncology 104 (2007) 36 – 40 www.elsevier.com/locate/ygyno
Phase I trial of concurrent chemoradiation with weekly nedaplatin in patients with squamous cell carcinoma of the uterine cervix Kohsuke Yoshinaga a , Hitoshi Niikura a,⁎, Yoshihiro Ogawa b , Kenji Nemoto c , Satoru Nagase a , Tadao Takano a , Kiyoshi Ito a , Nobuo Yaegashi a a
Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan b Department of Radiology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan c Department of Radiology, Yamagata University School of Medicine, Sendai 980-8574, Japan Received 11 April 2006 Available online 4 August 2006
Abstract Objective. This phase I clinical trial for cervical carcinoma had three objectives: to evaluate the toxicity of a concurrent chemoradiation regimen featuring weekly nedaplatin; to determine the recommended dose of nedaplatin for a phase II concurrent chemoradiation trial; and to evaluate the formula for predicting area under the curve data for nedaplatin through pharmacokinetic studies. Patients and methods. Twelve patients with locally advanced squamous cell carcinoma of the uterine cervix were enrolled. Nedaplatin was administered once a week for 6 weeks. The starting dose of nedaplatin was 25 mg/m2/week, with increments of 5 mg/m2/week planned for each dose level. Three cases were enrolled at each of the dose levels. Radiation therapy was delivered with both external beam teletherapy and intracavitary brachytherapy with HDR-RALS. Volunteering patients underwent pharmacokinetics studies during the second course. Results. Nedaplatin at a dose of 25, 30, and 35 mg/m2 was safely administered for three cases at each dose level. At a dose of 40 mg/m2, however, all three cases had Grade 3 neutropenia. Observed area under the curve value and predicted value was closely correlated, with differences between the two area under the curve values within 25%. All 12 cases achieved a clinical complete response, as evaluated with RECIST. Conclusions. Our recommended dose for a phase II trial of concurrent chemoradiation with weekly nedaplatin is 35 mg/m2. The formula can predict unbound concentration of nedaplatin based on area under the curve within 25% error. © 2006 Elsevier Inc. All rights reserved. Keywords: Nedaplatin; Cervical cancer; Chemoradiation; Concurrent; Pharmacokinetics
Introduction Nedaplatin is a platinum derivative developed in Japan [1]. Nedaplatin causes much less nephrotoxicity than cisplatin [2]; hematologic toxicity including thrombocytopenia and neutropenia is a dose-limiting factor for nedaplatin [3]. A recent in vitro chemosensitivity test suggested that nedaplatin has equivalent or superior antitumor activity to cisplatin in cervical cancer [4]. Pharmacokinetic study has shown that the protein binding ability of nedaplatin is much lower than that of cisplatin [5]. Subsequently, the plasma concentration profile of unbound ⁎ Corresponding author. E-mail address: [email protected] (H. Niikura). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.06.034
platinum after nedaplatin infusion has been found to be close to that of total platinum, and nedaplatin has a shorter elimination half-life than cisplatin [5]. Although these pharmacokinetic characteristics of nedaplatin are similar to those of carboplatin, response rates of cervical canter to carboplatin and nedaplatin are different. The response rate of cervical cancer to carboplatin is generally considered to be 15% [6,7]. In a phase II clinical trial with single agent nedaplatin, there was a 46% response rate in 41 patients with cervical cancer [8], whereas carboplatin had a response rate less than 20%. A retrospective study with combination chemotherapy including nedaplatin showed a very high response rate against advanced cancer of the terine cervix, 84%, and a response rate of 62% for recurrent cancer of the cervix [9].
K. Yoshinaga et al. / Gynecologic Oncology 104 (2007) 36–40
Concurrent chemoradiation therapy (CCRT) is currently recommended as standard therapy for locally advanced cervical cancer [10]. Some clinical trials of CCRT with nedaplatin directed against other cancers have been published [11–15]. The most recent publication studied intraarterial nedaplatin and intravenous 5fluorouracil (5-FU) with concurrent radiation therapy for cervical cancer patients [16]. In the trial, two sessions of concurrent radiation therapy were administered every 3 weeks using a combination of 50 mg/m2 nedaplatin and 5-FU at a given dose and schedule. The process to decide the nedaplatin dose, however, was not mentioned and clinical evidence to date has not been clarified what dose should be used. Only one phase I study of CCRT with an intravenous infusion of nedaplatin against cervical cancer has been reported, at the 2002 annual meeting of the American Society of Clinical Society (ASCO) [17]. However, nedaplatin in that trial was administered for 4 weeks, whereas radiotherapy for advanced cervical cancer treatment usually continues for 6 weeks or more, and the maximally tolerated dose was 30 mg/m2. In this study, we performed a phase I clinical trial of CCRT with nedaplatin for patients with locally advanced squamous cell carcinoma of the uterine cervix. The objectives of the study were three-fold: (1) to evaluate the toxicity of concurrent nedaplatin and radiotherapy with both external beam teletherapy and HDR-RALS, (2) to determine the recommended dose of nedaplatin for a phase II CCRT trial, and (3) to evaluate the formula that predicts optimal dosage of nedaplatin by pharmacokinetic studies. Patients and methods Study design and patient selection This phase I study was designed to define the maximum tolerated dose (MTD) of nedaplatin delivered by weekly infusion for a total of 6 weeks. The starting dose of nedaplatin was 25 mg/m2/week, with planned increments of 5 mg/m2/week. Each dose of nedaplatin was reconstituted in 500 mL saline solution and administered intravenously over 180 min. Nedaplatin infusion was completed 1 h before irradiation. Three patients were enrolled at each dose level. Acute toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria, version 2.0, issued in 1998 [18]. Nedaplatin infusion was delayed if Grade 3 toxicity appeared and was discontinued if Grade 4 toxicity appeared. Dose-limiting toxicity (DLT) was defined as Grade 3 intensity of any toxicity or as a delay of 1 week or longer of nedaplatin infusion. The dose was escalated to the next level if none or one of the patients experienced DLT. If DLT was seen in two or three patients at a given dose level, dose escalation was stopped. Twelve patients with locally advanced cancer of the uterine cervix, stage IB2, II, or III (FIGO) were enrolled. Eligibility criteria were the following: (1) radiotherapy chosen as initial treatment of the cervical cancer, (2) target lesion measurable with RECIST [19], (3) histologically proven squamous cell carcinoma, (4) age 75 years or younger, (5) ECOG performance status 0 or 1, (6) no previous chemotherapy or radiotherapy, (7) leukocyte count >3000/mm3, (8) neutrophil count >2000/mm3, (9) platelet count >100,000/mm3, (10) total bilirubin <1.5 mg/dL, (11) serum creatinine < upper normal limit, and (12) AST or ALT level < twice upper normal limit. Laboratory studies, including chemistry panels and a complete blood cell count, were obtained twice a week or more frequently if clinically necessary. Use of granulocyte-colony stimulating factors confirmed to ASCO guidelines [20]. All patients received an anti-emetic drug (5-HT3 antagonist) before drug infusion in accordance with clinical guidelines
37
[21]. The study protocol was approved by the Ethical Committee of the Institutional Review Board of Tohoku University Hospital. Enrollment of patients started in 2004 and ended in 2006. All patients gave their written informed consent before entry into the trial.
Radiotherapy Radiation therapy was delivered with both external beam radiation and intracavitary brachytherapy. Methods of radiotherapy have been described in detail in previous studies of ours [22]. Briefly, external beam radiation therapy was given with 10 MV photon beams produced by a linear accelerator. Whole pelvis irradiation to a total dose of 50 Gy was delivered with a fraction size of 2 Gy via anterior–posterior and posterior–anterior parallel opposed portals. After 20 to 40 Gy had been given, we used a central shield of 4-cm width at midline. Intracavitary brachytherapy was performed with HDR-RALS with a 192Ir source as described previously [22]. The mean total dose for external teletherapy was 50 Gy. All patients received HDR-RALS with a mean dose of 24 Gy to point A. Nedaplatin was infused weekly immediately prior to external beam radiation therapy and prior to each brachytherapy application. Radiotherapy continued if Grade 3 toxicities developed, but it was suspended if Grade 4 toxicity occurred.
Measurement of platinum concentrations and calculation of AUCs Pharmacokinetic studies were performed to determine the AUC values of platinum in collected blood samples. Blood sampling was done more than five times over the course of treatment. Total platinum and free platinum concentrations were measured as described previously [23]. AUCs were calculated as the areas under the lines that connected data for samples obtained until 24 h after the beginning of nedaplatin administration. Before starting chemotherapy, each patient's 24-h creatinine clearance was determined.
Results A total of 12 patients enrolled in the trial; three with stage IB2, five with IIB, one with IIIA, and three with IIIB disease. Median age was 44.8 years (range, 31–75). Median period for radiation therapy was seven weeks (range, 6 to 9 weeks), and nedaplatin was infused 5 to 6 weeks continuously once a week from the first day of radiotherapy. Grade 3 and 4 toxicities are shown in Table 1. No grade 4 toxicity occurred. A total of six patients experienced Grade 3 toxicity. Case 2 had Grade 3 leukopenia associated with Grade 3 neutropenia at the fifth drug infusion. She recovered from leukopenia after administration of G-CSF, and her final (sixth) infusion was performed without schedule delay. Case 4 also had Grade 3 leukopenia associated with Grade 3 neutropenia at her fifth and sixth infusions, but she quickly recovered after administration of G-CSF and finished all treatment schedules without delay. The only non-hematological toxicity was Grade 3 diarrhea, which occurred for Case 9 at the dose level of 35 mg/ m2 after the fourth infusion of nedaplatin. The fifth infusion was withheld until she recovered. Nedaplatin infusion was restarted with a 6-day delay in schedule, but the fifth and sixth infusions were administered without delay. This event did not influence her radiotherapy schedule. Because diarrhea is one of the common acute toxicities with radiotherapy, we thought that this instance of Grade 3 toxicity might not be a side effect of nedaplatin. All cases at the dose of 40 mg/m2 after the sixth infusion of nedaplatin had Grade 3 neutropenia but recovered within 1 week without G-CSF administration. All 12 of our enrolled patients showed a clinical complete response as
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Table 1 Toxities, AUCs, and responses of CCRT with nedaplatin AUC a (μg/mL)
Patient no.
Dose level (mg/ mm)
Total
Unbound
Predicted b
1 2 3 4 5 6 7 8 9 10 11 12
25 25 25 30 30 30 35 35 35 40 40 40
n.p. c n.p. n.p. n.p. 4.05 3.15 6.35 8.15 8.85 n.p. n.p. n.p.
n.p. n.p. n.p. n.p. 3.50 2.40 3.85 4.05 4.25 n.p. n.p. n.p.
n.p. n.p. n.p. n.p. 3.98 2.68 5.12 5.21 3.64 n.p. n.p. n.p.
a b
c d
Toxicity (grade 3 or 4)
Neutropenia G3 Neutropenia G3
Diarrhea G3 Neutropenia G3 Neutropenia G3 Neutropenia G3
Response
CR d CR CR CR CR CR CR CR CR CR CR CR
concurrent chemoradiation with weekly nedaplatin infusion is 35 mg/m2. Another study of clinical phase I trial of CCRT with weekly nedaplatin was reported at the ASCO 2002 annual meeting [17]. Nedaplatin was administered four times, i.e., on days 1, 8, 15, and 29. Radiation therapy was scheduled to undergo external and intracavitary brachytherapy. At the dose of 35 mg/m2, two of three patients had grade 3 thrombocytopenia or grade 3 neutropenia and needed schedule delay. Nine of 12 patients showed clinical response and five patients needed additional therapy for residual lesion. Their recommendation dose of nedaplatin was 30 mg/m2. However, methods of radiation therapy have not been described in detail. We cannot know what kinds of schedule delay occurred, i.e., radiation schedule, chemotherapy schedule, or both. Use of G-CSF was not described in detail, only with the comment, “we could increase
Area under the curve. dose : Predicted AUC ¼ 0:0836 Ccr þ 3:45 Not performed. Complete response.
evaluated with RECIST. No individual schedule of radiation therapy was disturbed by weekly nedaplatin infusion. At this point, we suspended further patient enrollment to the upper dose level. There was no recurrent patient in this phase I study for 2 to 36 months of follow-up periods. Five volunteering patients of the 12 enrolled in the present study had agreed to measurements of plasma platinum concentration. Data for plasma total-platinum and free-platinum concentrations for those five patients are shown in Figs. 1A and B, respectively. Total platinum concentrations decreased under detection level at 5 h after infusion in two patients at the dose level of 30 mg/m2, and at 24 h in three patients at the dose level of 35 mg/m2. Table 1 summarizes observed AUCs measured from plasma platinum concentrations and predicted AUCs estimated with the proposed formula based on infusion dose and serum creatinine clearance (Ccr): Predicted AUC = nedaplatin infusion dose / (0.0836 × Ccr + 3.45) [24]. AUC ratios between free and total platinum concentrations were 48% to 86%, findings that are close to previously published data [5]. The data from the current study supported the hypothesis that at least 50% of nedaplatin exists as free (unbound from albumin) in plasma. Observed AUC and predicted AUC were closely correlated, with differences between the two AUCs within 25%.
Discussion To our knowledge, this is the first phase I clinical trial against cervical cancer featuring CCRT with full-course infusion of nedaplatin. Nedaplatin 35 mg/m2 could be safely administered for cervical cancer with concurrent radiotherapy delivered as HDR-RALS and external pelvic radiation therapy and seemed effective. Our recommended dose for phase II trials of
Fig. 1. Plasma platinum concentration after intravenous infusion of nedaplatin. A total of five patients gave consent for measurement of plasma concentrations. Each line represents data from one patient. (A) Total platinum concentration. (B) Unbound (not bound to protein) platinum concentration.
K. Yoshinaga et al. / Gynecologic Oncology 104 (2007) 36–40
the dose of nedaplatin with routine use of G-CSF to get higher response rate”. Usage of G-CSF may have been different between the previous trial and the present trial. Our recommendation dose, 35 mg/m2, was 5 mg/m2 above the previous study, all 12 patients showed CR, and needed no further treatments. We think the dose of 35 mg/m2 is safe and effective enough for CCRT with weekly nedaplatin. The area under the plasma platinum concentration curve (AUC) is an important predictor for effects and toxicity of platinum-derivative anti-cancer drugs such as nedaplatin [3,24]. Recently, a formula for predicting optimal dosage of nedaplatin based on renal function was proposed by Ishibashi et al. [25]. but the formula has not been verified at other institutions [25]. We confirmed validation of the formula to predict unbound AUCs of nedaplatin and found that the differences between observed AUC and predicted AUC were within 25%. In this study, an infusion dose of 35 mg/m2 was almost equal to 4.0 mg/h/mL of observed free-platinum AUCs. Because AUCs for nedaplatin empirically correlate well with toxicities [24], we suggest use of AUCs to decide infusion dose of nedaplatin as is done with carboplatin for advanced cervical cancer patients with insufficient renal function. For patients with renal dysfunction, we can set 4.0 mg/h/mL of predicted AUC as the therapeutic AUC for CCRT with nedaplatin, and this formula will help to administer an adequate nedaplatin dose safely and effectively. However, for patients with normal renal function, administration dose of nedaplatin can be decided from body surface area for its convenience. Radiation methods may differ among nations and institutions [26,27]. For example, approximately 90% of institutions in Japan use the high-dose-rate remote after loading system (HDR-RALS) for intracavitary brachytherapy as the standard treatment modality for cervical cancer. Differences in radiation modality may produce different kinds and different levels of toxic side effects associated with the CCRT regimen as a whole. Further studies may be necessary to evaluate what constitutes an adequate dose of nedaplatin for CCRT against cervical cancer.
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Acknowledgments We deeply appreciate technical helps of Shionogi and Co., LTD., for measuring plasma nedaplatin concentrations. This study was supported by Grant-in-aid from Kurosawa Cancer Research Foundation, Grant-in-aid for Scientific Research on priority area from the Ministry of Education, Science, Sports and Culture, Japan, Grant-in-aid from the Ministry of Education, Science, Sports and Culture, Japan, Grant-in-aid from the Ministry of Health, Labor and Welfare, Japan, the 21st Century COE Program Special Research Grant (Tohoku University) from the Ministry of Education Science, Sports and Culture, Japan.
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Phase I trial of concurrent chemoradiation with weekly nedaplatin in patients with squamous cell carcinoma of the uterine cervix Kohsuke Yoshinaga a , Hitoshi Niikura a,⁎, Yoshihiro Ogawa b , Kenji Nemoto c , Satoru Nagase a , Tadao Takano a , Kiyoshi Ito a , Nobuo Yaegashi a a
Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan b Department of Radiology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan c Department of Radiology, Yamagata University School of Medicine, Sendai 980-8574, Japan Received 11 April 2006 Available online 4 August 2006
Abstract Objective. This phase I clinical trial for cervical carcinoma had three objectives: to evaluate the toxicity of a concurrent chemoradiation regimen featuring weekly nedaplatin; to determine the recommended dose of nedaplatin for a phase II concurrent chemoradiation trial; and to evaluate the formula for predicting area under the curve data for nedaplatin through pharmacokinetic studies. Patients and methods. Twelve patients with locally advanced squamous cell carcinoma of the uterine cervix were enrolled. Nedaplatin was administered once a week for 6 weeks. The starting dose of nedaplatin was 25 mg/m2/week, with increments of 5 mg/m2/week planned for each dose level. Three cases were enrolled at each of the dose levels. Radiation therapy was delivered with both external beam teletherapy and intracavitary brachytherapy with HDR-RALS. Volunteering patients underwent pharmacokinetics studies during the second course. Results. Nedaplatin at a dose of 25, 30, and 35 mg/m2 was safely administered for three cases at each dose level. At a dose of 40 mg/m2, however, all three cases had Grade 3 neutropenia. Observed area under the curve value and predicted value was closely correlated, with differences between the two area under the curve values within 25%. All 12 cases achieved a clinical complete response, as evaluated with RECIST. Conclusions. Our recommended dose for a phase II trial of concurrent chemoradiation with weekly nedaplatin is 35 mg/m2. The formula can predict unbound concentration of nedaplatin based on area under the curve within 25% error. © 2006 Elsevier Inc. All rights reserved. Keywords: Nedaplatin; Cervical cancer; Chemoradiation; Concurrent; Pharmacokinetics
Introduction Nedaplatin is a platinum derivative developed in Japan [1]. Nedaplatin causes much less nephrotoxicity than cisplatin [2]; hematologic toxicity including thrombocytopenia and neutropenia is a dose-limiting factor for nedaplatin [3]. A recent in vitro chemosensitivity test suggested that nedaplatin has equivalent or superior antitumor activity to cisplatin in cervical cancer [4]. Pharmacokinetic study has shown that the protein binding ability of nedaplatin is much lower than that of cisplatin [5]. Subsequently, the plasma concentration profile of unbound ⁎ Corresponding author. E-mail address: [email protected] (H. Niikura). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.06.034
platinum after nedaplatin infusion has been found to be close to that of total platinum, and nedaplatin has a shorter elimination half-life than cisplatin [5]. Although these pharmacokinetic characteristics of nedaplatin are similar to those of carboplatin, response rates of cervical canter to carboplatin and nedaplatin are different. The response rate of cervical cancer to carboplatin is generally considered to be 15% [6,7]. In a phase II clinical trial with single agent nedaplatin, there was a 46% response rate in 41 patients with cervical cancer [8], whereas carboplatin had a response rate less than 20%. A retrospective study with combination chemotherapy including nedaplatin showed a very high response rate against advanced cancer of the terine cervix, 84%, and a response rate of 62% for recurrent cancer of the cervix [9].
K. Yoshinaga et al. / Gynecologic Oncology 104 (2007) 36–40
Concurrent chemoradiation therapy (CCRT) is currently recommended as standard therapy for locally advanced cervical cancer [10]. Some clinical trials of CCRT with nedaplatin directed against other cancers have been published [11–15]. The most recent publication studied intraarterial nedaplatin and intravenous 5fluorouracil (5-FU) with concurrent radiation therapy for cervical cancer patients [16]. In the trial, two sessions of concurrent radiation therapy were administered every 3 weeks using a combination of 50 mg/m2 nedaplatin and 5-FU at a given dose and schedule. The process to decide the nedaplatin dose, however, was not mentioned and clinical evidence to date has not been clarified what dose should be used. Only one phase I study of CCRT with an intravenous infusion of nedaplatin against cervical cancer has been reported, at the 2002 annual meeting of the American Society of Clinical Society (ASCO) [17]. However, nedaplatin in that trial was administered for 4 weeks, whereas radiotherapy for advanced cervical cancer treatment usually continues for 6 weeks or more, and the maximally tolerated dose was 30 mg/m2. In this study, we performed a phase I clinical trial of CCRT with nedaplatin for patients with locally advanced squamous cell carcinoma of the uterine cervix. The objectives of the study were three-fold: (1) to evaluate the toxicity of concurrent nedaplatin and radiotherapy with both external beam teletherapy and HDR-RALS, (2) to determine the recommended dose of nedaplatin for a phase II CCRT trial, and (3) to evaluate the formula that predicts optimal dosage of nedaplatin by pharmacokinetic studies. Patients and methods Study design and patient selection This phase I study was designed to define the maximum tolerated dose (MTD) of nedaplatin delivered by weekly infusion for a total of 6 weeks. The starting dose of nedaplatin was 25 mg/m2/week, with planned increments of 5 mg/m2/week. Each dose of nedaplatin was reconstituted in 500 mL saline solution and administered intravenously over 180 min. Nedaplatin infusion was completed 1 h before irradiation. Three patients were enrolled at each dose level. Acute toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria, version 2.0, issued in 1998 [18]. Nedaplatin infusion was delayed if Grade 3 toxicity appeared and was discontinued if Grade 4 toxicity appeared. Dose-limiting toxicity (DLT) was defined as Grade 3 intensity of any toxicity or as a delay of 1 week or longer of nedaplatin infusion. The dose was escalated to the next level if none or one of the patients experienced DLT. If DLT was seen in two or three patients at a given dose level, dose escalation was stopped. Twelve patients with locally advanced cancer of the uterine cervix, stage IB2, II, or III (FIGO) were enrolled. Eligibility criteria were the following: (1) radiotherapy chosen as initial treatment of the cervical cancer, (2) target lesion measurable with RECIST [19], (3) histologically proven squamous cell carcinoma, (4) age 75 years or younger, (5) ECOG performance status 0 or 1, (6) no previous chemotherapy or radiotherapy, (7) leukocyte count >3000/mm3, (8) neutrophil count >2000/mm3, (9) platelet count >100,000/mm3, (10) total bilirubin <1.5 mg/dL, (11) serum creatinine < upper normal limit, and (12) AST or ALT level < twice upper normal limit. Laboratory studies, including chemistry panels and a complete blood cell count, were obtained twice a week or more frequently if clinically necessary. Use of granulocyte-colony stimulating factors confirmed to ASCO guidelines [20]. All patients received an anti-emetic drug (5-HT3 antagonist) before drug infusion in accordance with clinical guidelines
37
[21]. The study protocol was approved by the Ethical Committee of the Institutional Review Board of Tohoku University Hospital. Enrollment of patients started in 2004 and ended in 2006. All patients gave their written informed consent before entry into the trial.
Radiotherapy Radiation therapy was delivered with both external beam radiation and intracavitary brachytherapy. Methods of radiotherapy have been described in detail in previous studies of ours [22]. Briefly, external beam radiation therapy was given with 10 MV photon beams produced by a linear accelerator. Whole pelvis irradiation to a total dose of 50 Gy was delivered with a fraction size of 2 Gy via anterior–posterior and posterior–anterior parallel opposed portals. After 20 to 40 Gy had been given, we used a central shield of 4-cm width at midline. Intracavitary brachytherapy was performed with HDR-RALS with a 192Ir source as described previously [22]. The mean total dose for external teletherapy was 50 Gy. All patients received HDR-RALS with a mean dose of 24 Gy to point A. Nedaplatin was infused weekly immediately prior to external beam radiation therapy and prior to each brachytherapy application. Radiotherapy continued if Grade 3 toxicities developed, but it was suspended if Grade 4 toxicity occurred.
Measurement of platinum concentrations and calculation of AUCs Pharmacokinetic studies were performed to determine the AUC values of platinum in collected blood samples. Blood sampling was done more than five times over the course of treatment. Total platinum and free platinum concentrations were measured as described previously [23]. AUCs were calculated as the areas under the lines that connected data for samples obtained until 24 h after the beginning of nedaplatin administration. Before starting chemotherapy, each patient's 24-h creatinine clearance was determined.
Results A total of 12 patients enrolled in the trial; three with stage IB2, five with IIB, one with IIIA, and three with IIIB disease. Median age was 44.8 years (range, 31–75). Median period for radiation therapy was seven weeks (range, 6 to 9 weeks), and nedaplatin was infused 5 to 6 weeks continuously once a week from the first day of radiotherapy. Grade 3 and 4 toxicities are shown in Table 1. No grade 4 toxicity occurred. A total of six patients experienced Grade 3 toxicity. Case 2 had Grade 3 leukopenia associated with Grade 3 neutropenia at the fifth drug infusion. She recovered from leukopenia after administration of G-CSF, and her final (sixth) infusion was performed without schedule delay. Case 4 also had Grade 3 leukopenia associated with Grade 3 neutropenia at her fifth and sixth infusions, but she quickly recovered after administration of G-CSF and finished all treatment schedules without delay. The only non-hematological toxicity was Grade 3 diarrhea, which occurred for Case 9 at the dose level of 35 mg/ m2 after the fourth infusion of nedaplatin. The fifth infusion was withheld until she recovered. Nedaplatin infusion was restarted with a 6-day delay in schedule, but the fifth and sixth infusions were administered without delay. This event did not influence her radiotherapy schedule. Because diarrhea is one of the common acute toxicities with radiotherapy, we thought that this instance of Grade 3 toxicity might not be a side effect of nedaplatin. All cases at the dose of 40 mg/m2 after the sixth infusion of nedaplatin had Grade 3 neutropenia but recovered within 1 week without G-CSF administration. All 12 of our enrolled patients showed a clinical complete response as
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Table 1 Toxities, AUCs, and responses of CCRT with nedaplatin AUC a (μg/mL)
Patient no.
Dose level (mg/ mm)
Total
Unbound
Predicted b
1 2 3 4 5 6 7 8 9 10 11 12
25 25 25 30 30 30 35 35 35 40 40 40
n.p. c n.p. n.p. n.p. 4.05 3.15 6.35 8.15 8.85 n.p. n.p. n.p.
n.p. n.p. n.p. n.p. 3.50 2.40 3.85 4.05 4.25 n.p. n.p. n.p.
n.p. n.p. n.p. n.p. 3.98 2.68 5.12 5.21 3.64 n.p. n.p. n.p.
a b
c d
Toxicity (grade 3 or 4)
Neutropenia G3 Neutropenia G3
Diarrhea G3 Neutropenia G3 Neutropenia G3 Neutropenia G3
Response
CR d CR CR CR CR CR CR CR CR CR CR CR
concurrent chemoradiation with weekly nedaplatin infusion is 35 mg/m2. Another study of clinical phase I trial of CCRT with weekly nedaplatin was reported at the ASCO 2002 annual meeting [17]. Nedaplatin was administered four times, i.e., on days 1, 8, 15, and 29. Radiation therapy was scheduled to undergo external and intracavitary brachytherapy. At the dose of 35 mg/m2, two of three patients had grade 3 thrombocytopenia or grade 3 neutropenia and needed schedule delay. Nine of 12 patients showed clinical response and five patients needed additional therapy for residual lesion. Their recommendation dose of nedaplatin was 30 mg/m2. However, methods of radiation therapy have not been described in detail. We cannot know what kinds of schedule delay occurred, i.e., radiation schedule, chemotherapy schedule, or both. Use of G-CSF was not described in detail, only with the comment, “we could increase
Area under the curve. dose : Predicted AUC ¼ 0:0836 Ccr þ 3:45 Not performed. Complete response.
evaluated with RECIST. No individual schedule of radiation therapy was disturbed by weekly nedaplatin infusion. At this point, we suspended further patient enrollment to the upper dose level. There was no recurrent patient in this phase I study for 2 to 36 months of follow-up periods. Five volunteering patients of the 12 enrolled in the present study had agreed to measurements of plasma platinum concentration. Data for plasma total-platinum and free-platinum concentrations for those five patients are shown in Figs. 1A and B, respectively. Total platinum concentrations decreased under detection level at 5 h after infusion in two patients at the dose level of 30 mg/m2, and at 24 h in three patients at the dose level of 35 mg/m2. Table 1 summarizes observed AUCs measured from plasma platinum concentrations and predicted AUCs estimated with the proposed formula based on infusion dose and serum creatinine clearance (Ccr): Predicted AUC = nedaplatin infusion dose / (0.0836 × Ccr + 3.45) [24]. AUC ratios between free and total platinum concentrations were 48% to 86%, findings that are close to previously published data [5]. The data from the current study supported the hypothesis that at least 50% of nedaplatin exists as free (unbound from albumin) in plasma. Observed AUC and predicted AUC were closely correlated, with differences between the two AUCs within 25%.
Discussion To our knowledge, this is the first phase I clinical trial against cervical cancer featuring CCRT with full-course infusion of nedaplatin. Nedaplatin 35 mg/m2 could be safely administered for cervical cancer with concurrent radiotherapy delivered as HDR-RALS and external pelvic radiation therapy and seemed effective. Our recommended dose for phase II trials of
Fig. 1. Plasma platinum concentration after intravenous infusion of nedaplatin. A total of five patients gave consent for measurement of plasma concentrations. Each line represents data from one patient. (A) Total platinum concentration. (B) Unbound (not bound to protein) platinum concentration.
K. Yoshinaga et al. / Gynecologic Oncology 104 (2007) 36–40
the dose of nedaplatin with routine use of G-CSF to get higher response rate”. Usage of G-CSF may have been different between the previous trial and the present trial. Our recommendation dose, 35 mg/m2, was 5 mg/m2 above the previous study, all 12 patients showed CR, and needed no further treatments. We think the dose of 35 mg/m2 is safe and effective enough for CCRT with weekly nedaplatin. The area under the plasma platinum concentration curve (AUC) is an important predictor for effects and toxicity of platinum-derivative anti-cancer drugs such as nedaplatin [3,24]. Recently, a formula for predicting optimal dosage of nedaplatin based on renal function was proposed by Ishibashi et al. [25]. but the formula has not been verified at other institutions [25]. We confirmed validation of the formula to predict unbound AUCs of nedaplatin and found that the differences between observed AUC and predicted AUC were within 25%. In this study, an infusion dose of 35 mg/m2 was almost equal to 4.0 mg/h/mL of observed free-platinum AUCs. Because AUCs for nedaplatin empirically correlate well with toxicities [24], we suggest use of AUCs to decide infusion dose of nedaplatin as is done with carboplatin for advanced cervical cancer patients with insufficient renal function. For patients with renal dysfunction, we can set 4.0 mg/h/mL of predicted AUC as the therapeutic AUC for CCRT with nedaplatin, and this formula will help to administer an adequate nedaplatin dose safely and effectively. However, for patients with normal renal function, administration dose of nedaplatin can be decided from body surface area for its convenience. Radiation methods may differ among nations and institutions [26,27]. For example, approximately 90% of institutions in Japan use the high-dose-rate remote after loading system (HDR-RALS) for intracavitary brachytherapy as the standard treatment modality for cervical cancer. Differences in radiation modality may produce different kinds and different levels of toxic side effects associated with the CCRT regimen as a whole. Further studies may be necessary to evaluate what constitutes an adequate dose of nedaplatin for CCRT against cervical cancer.
[2] [3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Acknowledgments We deeply appreciate technical helps of Shionogi and Co., LTD., for measuring plasma nedaplatin concentrations. This study was supported by Grant-in-aid from Kurosawa Cancer Research Foundation, Grant-in-aid for Scientific Research on priority area from the Ministry of Education, Science, Sports and Culture, Japan, Grant-in-aid from the Ministry of Education, Science, Sports and Culture, Japan, Grant-in-aid from the Ministry of Health, Labor and Welfare, Japan, the 21st Century COE Program Special Research Grant (Tohoku University) from the Ministry of Education Science, Sports and Culture, Japan.
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