Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
    • CME
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CCR Focus Archive
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Breast Cancer
      • Clinical Trials
      • Immunotherapy: Facts and Hopes
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Clinical Cancer Research
Clinical Cancer Research
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
    • CME
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CCR Focus Archive
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Breast Cancer
      • Clinical Trials
      • Immunotherapy: Facts and Hopes
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Clinical Trials

Pharmacological Analysis of Etoposide in Elderly Patients with Lung Cancer

Masahiko Ando, Hironobu Minami, Yuichi Ando, Shuzo Sakai, Yohei Shimono, Seiji Sugiura, Hideo Saka, Kaoru Shimokata and Yoshinori Hasegawa
Masahiko Ando
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hironobu Minami
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuichi Ando
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shuzo Sakai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yohei Shimono
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Seiji Sugiura
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hideo Saka
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kaoru Shimokata
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yoshinori Hasegawa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI:  Published July 1999
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

To analyze the pharmacological characteristics of etoposide in elderly patients, we conducted a Phase I trial of a 14-day administration of oral etoposide on 12 chemotherapy-naive patients, ages 75 years or older, with lung cancer. The pharmacological profiles of etoposide in elderly patients were compared with those of younger patients in our previous studies (H. Minami et al., J. Clin. Oncol., 11: 1602–1608, 1993; H. Minami et al., J. Clin. Oncol., 13: 191–199, 1995; Y. Ando et al., Jpn. J. Cancer Res., 87: 200–205, 1996). The sigmoid Emax model and logistic regression model were used for pharmacodynamic analysis. The maximum tolerated dose for elderly patients was 75 mg/body/day. The apparent oral clearance in elderly patients was 37 ± 10 (mean ± SD) ml/min, which was not different from that in younger patients (44 ± 12 ml/min). The area under the concentration-versus-time curve of etoposide over the treatment period (total AUC) that produced a 50% decrease in absolute neutrophil counts was significantly different between elderly and younger patients, 14.3 ± 2.5 and 21.6 ± 2.7 mg·min/ml, respectively (P = 0.048). The incidence of grade 3 or 4 neutropenia at total AUC of 30 mg·min/ml (corresponding to a plasma concentration of 1.5 μg/ml for 14 days) was 81% in elderly patients but only 48% in younger patients. Although there was no pharmacokinetic difference between elderly and younger patients, equivalent exposure to etoposide resulted in severer myelosuppression in elderly patients. These findings suggest that prolonged etoposide administration with plasma concentration maintained at 1–2 μg/ml may cause severe myelotoxicity in elderly patients.

INTRODUCTION

Etoposide is a semi-synthetic derivative of podophyllotoxin and is efficacious against small cell lung cancer, malignant lymphoma, leukemia, and probably non-small cell lung cancer (1 , 2) . Etoposide works through a reversible interaction with topoisomerase II (3 , 4) , and its efficacy has been shown to be cell cycle-dependent (5) and related to the duration of drug exposure in vitro(6, 7, 8) . Clinical studies have demonstrated that etoposide has a schedule-dependent effect (9 , 10) , and that five consecutive daily infusions of divided doses were more effective than a 24-h infusion of the same total dose. More prolonged administration of etoposide was also extensively studied (11 , 12) . Some investigators have suggested that a plasma etoposide concentration of 2–3 μg/ml may be associated with hematological toxicity, whereas a 1–2 μg/ml may be associated with antitumor activity (10 , 13, 14, 15) .

In a previous study (16) , we showed that a thrice daily dose (25-mg capsule) of etoposide could achieve a stable plasma concentration, with the mean concentration of etoposide ranging from 0.5 to 2.0 μg/ml. However, it is well known that elderly patients have an increased risk in both the frequency and the severity of adverse reactions to anticancer drugs (17 , 18) . Such adverse reactions are often related to changes in drug disposition that result from age-related changes in body composition and organ-system functions and to an age-related decline in plasma albumin concentration (19, 20, 21) . Another explanation for the increase in adverse drug reactions in elderly patients is a greater pharmacodynamic response to drug exposure (20) . Thus far, there have been only a few studies focusing on the exposure-effect relationship of anticancer drugs in elderly patients (22) . The retrospective analysis of our trials of continuous infusion of etoposide found that the percentage decrease in absolute neutrophil counts became severer in proportion to age despite the absence of a correlation between age and AUC3 of etoposide; all three of the patients, ages 75 years or more, experienced more than an 80% decrease in absolute neutrophil counts, although such a small number of patients prevented any detailed analysis of the effect of aging on hematological toxicities ,(23 , 24) .

In the present study, we performed a Phase I trial of a 14-day administration of oral etoposide on 12 chemotherapy-naive patients, ages 75 years or older, with lung cancer to see whether multiple dosing with oral etoposide would achieve desirable plasma etoposide concentrations in elderly patients and to clarify the differences in the pharmacokinetic and/or pharmacodynamic profiles of etoposide between elderly and younger patients.

PATIENTS AND METHODS

Patients and Treatment in Phase I Trial.

The eligibility criteria for our Phase I trial were as follows: (a) WHO performance status ≤ 2; (b) estimated life expectancy ≥ 8 weeks; (c) leukocyte count ≥ 3500/μl; (d) platelet count ≥ 100 × 103/μl; (e) serum creatinine level ≤ 2.0 mg/dl; and (f) serum bilirubin level ≤ 2.0 mg/dl. Pretreatment evaluation included a complete history and a physical examination as well as the following laboratory tests: (a) complete blood cell counts; (b) differential smear; (c) serum electrolytes; (d) total protein; (e) albumin; (f) total bilirubin; (g) aspartate aminotransferase; (h) alanine aminotransferase; (i) alkaline phosphatase; (j) lactate dehydrogenase; (k) creatinine; (l) urea nitrogen; (m) creatinine clearance; and (n) urinalysis. During the study, a complete blood cell count with differential smear was obtained two to three times per week, and the other laboratory tests were repeated weekly. Toxicities were reported using the Japan Clinical Oncology Group grading system (25) . At level 1 in the Phase I study, the etoposide dose was set at 50 mg/body/day, and a 25-mg capsule (Nippon Kayaku Co., Tokyo) was administered twice daily at 7:00 a.m. and 7:00 p.m.. At level 2, the etoposide dose was increased to 75 mg/body/day, and a 25-mg capsule was administered thrice daily at 7:00 a.m., 1:00 p.m., and 7:00 p.m.. This time schedule of etoposide administration was the same as that in our previous study (16) . Etoposide was discontinued if the leukocyte count decreased to less than 2000/μl, if the platelet count decreased to less than 75 × 103/μl, or if there was a grade 2 or greater nonhematological toxicity other than alopecia or emesis. At least three patients were to be entered at each dose level; and, when any of them developed hematological toxicities reaching grade 3 or nonhematological toxicities other than alopecia and nausea reaching grade 2, three additional patients were to be entered. The maximum tolerated dose was defined as the dose level producing any of the following: (a) hematological toxicities reaching grade 3 or nonhematological toxicities reaching grade 2 in two-thirds or more of the patients; or (b) grade 4 hematological toxicities in one-third or more of the patients. This Phase I study was approved by the ethical committee of the Nagoya University School of Medicine, and written informed consent was obtained from all of the patients.

Pharmacokinetic Analysis.

Blood sampling was performed on days 3 and 10 in the first cycle of chemotherapy. At dose level 1, heparinized blood samples were obtained at 7:00 a.m., 7:30 a.m., 8:00 a.m., 9:00 a.m., 10:00 a.m., 1:00 p.m., and 7:00 p.m. corresponding, respectively, to before and 0.5, 1, 2, 3, 6, and 12 h after administration; and at dose level 2, blood samples were drawn at 1:00 p.m., 1:30 p.m., 2:00 p.m., 3:00 p.m., 4:00 p.m., and 7:00 p.m., which were before and 0.5, 1, 2, 3, and 6 h after administration, respectively. Plasma was immediately separated by centrifugation and frozen at −20°C until analysis. The etoposide concentration was determined by high-performance liquid chromatography (26) . The detection limit of the assay was less than 0.02 μg/ml. The intra- and interassay coefficients of variation were less than 3 and 10%, respectively. The mean concentration of etoposide was calculated by AUC divided by sampling hours as follows: (a) dividing AUC from 7:00 a.m. to 7:00 p.m. by 12 h at level 1; and (b) dividing AUC from 1:00 p.m. to 7:00 p.m. by 6 h at level 2. The apparent oral clearance of etoposide was calculated as follows, and compared with that obtained from 16 younger patients who had been treated with 75 mg/body/day of oral etoposide for inoperable lung cancer previously in our hospital (16) : Math

Pharmacodynamic Analysis.

In the pharmacodynamic analysis of prolonged etoposide administration, data obtained from six patients, ages 75 years or older, in two previous studies were incorporated as follows: from three patients in a Phase I study of a 14-day infusion of etoposide (23) and from three in a pharmacological study of a 21-day administration of oral etoposide (16) . These data were combined with those from 12 patients in this Phase I trial and then compared with those from 23 younger patients (ages, 62 ± 8 years) in our previous studies (16 , 23 , 24) . Patients who had been treated with chemotherapy before the prolonged administration of etoposide were excluded from the analysis, and blood sampling was performed during the first cycle of chemotherapy. The mean concentration of etoposide between days 3 and 10 were comparable, which suggested that there was no evidence of an accumulation of etoposide or an alternation of its metabolism (Table 4)<$REFLINK> . The interday coefficients of variation in the present study (1–32%; median, 8%) are similar to those reported in studies of infusional etoposide (3–33%; Ref. 23 , 27 ). Accordingly, total AUC during the treatment period was calculated as follows: Math where AUCday 3 or AUCday 10 was calculated as follows: Math

View this table:
  • View inline
  • View popup
Table 1

Demographic characteristics of patients entered in the present Phase I study and our previous studies of long-term administration of infusional or oral etoposide

In our previous study of oral etoposide, total AUC was calculated in the same way. When etoposide was administered i.v. in our previous study, total AUC was calculated by the trapezoidal method with extrapolation to infinity (23) . The pharmacodynamic analysis was focused on neutropenia because this toxicity became dose-limiting in the present study. The relationship between total AUC and the percentage decrease in absolute neutrophil counts was analyzed using a sigmoid Emax model. EAUC50 of elderly patients was compared with that of younger patients using a z statistic for normal distribution. The effect of age as a continuous variable on pharmacodynamics was analyzed using a stepwise logistic regression model; other factors such as total AUC, total AUC of unbound etoposide, gender, performance status (0, 1, 2), serum albumin (g/dl), total bilirubin (mg/dl), neutrophil count before chemotherapy (per μl), and types of treatment were also evaluated. The unbound fraction of etoposide was estimated from serum albumin and total bilirubin concentration (28) .

RESULTS

Toxicities and Responses in Phase I Trial.

Patient characteristics were different in age, gender and histology between the current and previous studies (Table 1)<$REFLINK> .

At dose level 1 (50 mg/body/day), one patient experienced grade 3 thrombocytopenia, and an additional three patients were entered (Table 2)<$REFLINK> . Because two of the six patients suffered grade 3 neutropenia, the dose was then increased. At dose level 2 (75 mg/body/day), one of the first three patients experienced grade 4 neutropenia, and an additional three patients were entered. Among these, one patient experienced grade 4 neutropenia on day 11 and was taken off etoposide but died of pneumonia on day 19. Another patient at this dose level developed fever associated with grade 4 neutropenia and received i.v. antibiotics. We decided that the maximum tolerated dose in this trial was 75 mg/body/day because three patients experienced grade 4 neutropenia including one toxic death at that level. We observed no dose-limiting nonhematological toxicities (Table 3)<$REFLINK> . Overall, 38 courses of chemotherapy were administered (1–8 courses; median, 2 in each patient). The median nadir neutrophil count for all of the courses was 1360/μl (range, 0–3040). There was no evidence of cumulative hematological toxicities. In five patients with small cell lung cancer, one complete response and three partial responses were observed; the mean concentration of etoposide in responders ranged from 0.6 to 1.4 μg/ml. No response was observed in seven patients with non-small cell lung cancer.

View this table:
  • View inline
  • View popup
Table 2

Hematological toxicity in elderly patientsa in the first cycle of Phase I trial of oral etoposide

View this table:
  • View inline
  • View popup
Table 3

Nonhematological toxicity in elderly patientsa in the first cycle of Phase I trial of oral etoposide

Pharmacokinetics.

All of the patients were treated as inpatients and took all of the capsules at the planned time. The plasma concentration versus time curve during the dosing interval is shown in Fig. 1<$REFLINK> . The apparent oral clearance in 12 elderly patients in this study was 37 ± 10 (mean ± SD) ml/min, which was not different from that in 16 younger patients treated with 75 mg/body/day of oral etoposide (44 ± 12 ml/min; P = 0.200 by Mann-Whitney test; Ref. 16 ). There was no difference in the mean concentration of etoposide between the 6 elderly patients at level 2 (75 mg/body/day) and the 16 younger patients, who were all treated with the same dosing schedule (1.4 ± 0.3 μg/ml and 1.3 ± 0.3 μg/ml, respectively). There were no significant interday differences in the mean concentration of etoposide within any individual patient (Table 4)<$REFLINK> .

Fig. 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 1.

The plasma concentration versus time curve of etoposide. At dose level 1, blood samples were obtained at 7:00 a.m., 7:30 a.m., 8:00 a.m., 9:00 a.m., 10:00 a.m., 1:00 p.m. (13:00 h), and 7:00 p.m. (19:00 h); and at dose level 2, blood samples were drawn at 1:00 p.m. (13:00 h), 1:30 p.m. (13:30 h), 2:00 p.m. (14:00 h), 3:00 p.m. (15:00 h), 4:00 p.m. (16:00 h), and 7:00 p.m. (19:00 h), respectively.

View this table:
  • View inline
  • View popup
Table 4

Pharmacokinetic data (mean ± SD) in the Phase I trial of 14-day administration of oral etoposide in elderly patients

Pharmacodynamics.

Because 17 of 18 patients, ages 75 years or older, were male and 10 of the 23 younger patients were female (Table 1)<$REFLINK> , we first confirmed that gender did not affect the pharmacokinetics or pharmacodynamics of etoposide in younger patients. Total AUC for male patients (32.9 ± 8.1 mg·min/ml) was the same as that for female patients (34.0 ± 8.1 mg·min/ml). Similarly, the percentage decreases in absolute neutrophil counts for male and female patients were 72 ± 24% and 71 ± 24%, respectively. Estimated EAUC50 ± SD of elderly patients was 14.3 ± 2.5 mg·min/ml and significantly lower than that of younger patients (21.6 ± 2.7 mg·min/ml; P = 0.048; Fig. 2<$REFLINK> ). Because the inclusion of the 6 elderly patients from the previous studies might have led to some bias, we conducted a further analysis using the 12 patients without the 6 patients from the previous study. The resultant EAUC50 (13.4 ± 2.4 mg·min/ml, mean ± SD) remained significantly lower than that of the younger patients (P = 0.023). In a stepwise logistic regression analysis, total AUC was significantly correlated with the incidence of grade 3 or 4 neutropenia (P < 0.001), and there was a trend toward a greater risk of neutropenia as a patient got older (P = 0.066). In elderly patients, a more rapid increase in the incidence of grade 3 or 4 neutropenia was observed; at total AUC 30 mg·min/ml, which corresponded to a 14-day administration of etoposide to keep the plasma concentration at 1.5 μg/ml, the estimated incidence was 81% in elderly patients in contrast to only 48% in younger patients (Fig. 3)<$REFLINK> .

Fig. 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 2.

Relationship between percentage decrease in absolute neutrophil counts and total AUC of etoposide. ▪, 12 patients in the present Phase I study; •, 6 patients, ages 75 or older, in our previous studies (16 , 23) ; ○, 23 younger patients in our previous studies (16 , 23 , 24) . Correlation coefficient for elderly and younger patients were 0.59 and 0.63, respectively.

Fig. 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
Fig. 3.

Relationship between incidence of grade 3 or 4 neutropenia and total AUC of etoposide. ▪, patients, ages 75 or older, who suffered neutropenia; □, patients, ages 75 or older, who did not suffer neutropenia; •, younger patients who suffered neutropenia; ○, younger patients who did not suffer neutropenia.

When total AUC of unbound etoposide was calculated by multiplying the total AUC by the unbound fraction, it failed to improve correlation coefficients of sigmoid Emax models in either elderly (r = 0.55) or younger patients (r = 0.33) and was not selected in a stepwise logistic regression in any of the 41 patients.

DISCUSSION

Our results showed that elderly patients had pharmacokinetics for long-term administration of oral etoposide similar to younger patients but showed greater pharmacodynamic sensitivity. Although the results of our study should be interpreted carefully because the elder and younger patients were evaluated in separate studies, the study conducted by Fujiwara et al.(29) also supported our conclusion, which showed that there was no meaningful pharmacokinetic difference for etoposide between elderly (ages 75 years or older) and younger patients.

The narrow therapeutic range of cytotoxic anticancer drugs makes dose optimization for individual patients necessary, and chemotherapy in elderly patients can be considered as a good example of the need for this optimization. However, the pharmacological characteristics of anticancer agents in elderly patients, which should be a basis for dose optimization in the population, have rarely been investigated (30) . In the present study, the mean concentration of etoposide in elderly patients was within the range observed in younger patients treated with 75 mg/body/day of oral etoposide (0.5–2.0 μg/ml; Ref. 16 ), and 8 of 12 elderly patients had a mean concentration between 1 and 2 μg/ml, which was considered to be “therapeutic range.” However, an equivalent exposure to etoposide brought severer myelosuppression in elderly patients as demonstrated by a pharmacodynamic analysis using a sigmoid Emax model and a logistic model. This suggests that prolonged administration of etoposide to maintain a plasma etoposide concentration of 1 to 2 μg/ml would pose a toxic risk for elderly patients.

High toxicities were observed in elderly patients in many studies of chemotherapy. In a retrospective review of the data from nonprotocol settings and clinical trials, the attenuation of chemotherapy by dose reduction or omission occurred more frequently in elderly patients (31 , 32) , which suggested that aging and its consequences indeed influenced chemotherapy dose delivery. Our study demonstrated that, for patients ages 75 years or older, a thrice daily dose of 25 mg etoposide for 14 days was toxic but caused minimal toxicity in younger patients (16) . This was explained by the pharmacodynamic alterations in elderly patients rather than by any change in pharmacokinetics related to aging. The greater sensitivity of hematopoietic cells to anticancer drugs may be responsible for severer neutropenia in elderly patients (33 , 34) .

Previous investigators (35 , 36) have demonstrated the importance of unbound etoposide as a pharmacokinetic parameter to delineate the exposure-effect relationship. We do not believe that a greater fraction of unbound etoposide can explain the greater sensitivity in the elderly patients in our study because the estimated unbound fraction was not correlated with age (r = 0.23), and the total AUC of unbound etoposide did not improve the predictability of neutropenia. Reasons for the poor relationship between the total AUC of unbound etoposide and neutropenia may lie in the narrow range of total bilirubin (0.2–1.5 mg/dl) and greater age compared with the study reported by Stewart et al.(28) , which included patients (ages 37–72 years; median, 61) with hyperbilirubinemia and excluded elderly patients. Additional studies should continue to scrutinize the importance of unbound etoposide.

Recently, two randomized trials of the palliative treatment of unfit patients with small cell lung cancer demonstrated that oral etoposide was inferior to i.v. combination chemotherapy (37 , 38) . In addition to a small disadvantage in survival, oral etoposide was associated with increased hematological toxicity. In these studies, a total of 1000 mg of etoposide was administered over a period of 5–10 days, which was a standard dose of oral etoposide and might have been overdosing for unfit patients. In the present study, we showed that increased hematological toxicity in elderly patients was brought on by an altered exposure-effect relationship rather than by any change in the pharmacokinetics of etoposide. Our pharmacological analysis did not justify a dose reduction to alleviate hematological toxicity in elderly patients because that would involve decreased exposure to etoposide and an additional reduction in antitumor activity. These findings argue against the long-term administration of oral etoposide in elderly patients.

Despite the relatively small number of patients, the present study could detect a 27% difference in the apparent oral clearance with a statistical power of 80% when compared with that of the 16 younger patients. Therefore, we consider that the present study could detect a clinically important difference in pharmacokinetics.

We conclude that the exposure-effect relationship of etoposide in elderly patients is different from that in younger patients, whereas the pharmacokinetics of long-term administration of oral etoposide is not. Additional studies of the difference in exposure-effect relationship should include biological studies of the mechanism of this difference.

Acknowledgments

We thank Dr. Kazumitsu Nakashima for the helpful discussions and review of the manuscript.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • ↵1 This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan.

  • ↵2 To whom requests for reprints should be addressed, at First Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan. Phone: 81-52-744-2153; Fax: 81-52-744-2157; E-mail: yhasega{at}tsuru.med.nagoya-u.ac.jp

  • ↵3 The abbreviations used are: AUC, area under the plasma concentration-versus-time curve; EAUC50, total AUC that produced half of the maximal effect.

    • Accepted April 14, 1999.
    • Received October 29, 1998.
    • Revision received April 13, 1999.

References

  1. ↵
    Fleming R. A., Miller A. A., Stewart C. F. Etoposide: an update. Clin. Pharmacol., 8: 274-293, 1989.
    OpenUrlPubMed
  2. ↵
    Radice P. A., Bunn P. J., Ihde D. C. Therapeutic trials with VP-16–213 and VM-26: active agents in small cell lung cancer, non-Hodgkin’s lymphomas, and other malignancies. Cancer Treat. Rep., 63: 1231-1239, 1979.
    OpenUrlPubMed
  3. ↵
    Loike J. D., Horwitz S. B. Effect of VP-16–213 on the intracellular degradation of DNA in HeLa cells. Biochemistry, 15: 5443-5448, 1976.
    OpenUrlCrossRefPubMed
  4. ↵
    Long B. H., Musial S. T., Brattain M. G. Single- and double-strand DNA breakage and repair in human lung adenocarcinoma cells exposed to etoposide and teniposide. Cancer Res., 45: 3106-3112, 1985.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Drewinko B., Barlogie B. Survival and cycle-progression delay of human lymphoma cells in vitro exposed to VP-16–213. Cancer Treat. Rep., 60: 1295-1306, 1976.
    OpenUrlPubMed
  6. ↵
    Dombernowsky P., Nissen N. I. Schedule dependency of the antileukemic activity of the podophyllotoxin-derivative VP 16–213 (NSC-141540) in L1210 leukemia. Acta Pathol. Microbiol. Scand. [A], 81: 715-724, 1973.
    OpenUrlPubMed
  7. ↵
    Roed H., Vindelov L. L., Christensen I. J., Spang T. M., Hansen H. H. The effect of the two epipodophyllotoxin derivatives etoposide (VP-16) and teniposide (VM-26) on cell lines established from patients with small cell carcinoma of the lung. Cancer Chemother. Pharmacol., 19: 16-20, 1987.
    OpenUrlCrossRefPubMed
  8. ↵
    Wolff S. N., Grosh W. W., Prater K., Hande K. R. In vitro pharmacodynamic evaluation of VP-16–213 and implications for chemotherapy. Cancer Chemother. Pharmacol., 19: 246-249, 1987.
    OpenUrlPubMed
  9. ↵
    Cavalli F., Sonntag R. W., Jungi F., Senn H. J., Brunner K. W. VP-16–213 monotherapy for remission induction of small cell lung cancer: a randomized trial using three dosage schedules. Cancer Treat. Rep., 62: 473-475, 1978.
    OpenUrlPubMed
  10. ↵
    Slevin M. L., Clark P. I., Joel S. P., Malik S., Osborne R. J., Gregory W. M., Lowe D. G., Reznek R. H., Wrigley P. F. A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J. Clin. Oncol., 7: 1333-1340, 1989.
    OpenUrlAbstract
  11. ↵
    Johnson D. H., Greco F. A., Strupp J., Hande K. R., Hainsworth J. D. Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer: a Phase II trial. J. Clin. Oncol., 8: 1613-1617, 1990.
    OpenUrlAbstract
  12. ↵
    Waits T. M., Johnson D. H., Hainsworth J. D., Hande K. R., Thomas M., Greco F. A. Prolonged administration of oral etoposide in non-small-cell lung cancer: a Phase II trial. J. Clin. Oncol., 10: 292-296, 1992.
    OpenUrlAbstract
  13. ↵
    Clark P. I., Slevin M. L., Joel S. P., Osborne R. J., Talbot D. I., Johnson P. W., Reznek R., Masud T., Gregory W., Wrigley P. F. A randomized trial of two etoposide schedules in small-cell lung cancer: the influence of pharmacokinetics on efficacy and toxicity. J. Clin. Oncol., 12: 1427-1435, 1994.
    OpenUrlAbstract
  14. ↵
    Greco F. A. Chronic etoposide administration: overview of clinical experience. Cancer Treat. Rev., 19 (Suppl. C): 35-45, 1993.
  15. ↵
    Miller A. A., Tolley E. A., Niell H. B., Griffin J. P., Mauer A. M. Pharmacodynamics of prolonged oral etoposide in patients with advanced non-small-cell lung cancer. J. Clin. Oncol., 11: 1179-1188, 1993.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Minami H., Ando Y., Sakai S., Shimokata K. Clinical and pharmacologic analysis of hyperfractionated daily oral etoposide. J. Clin. Oncol., 13: 191-199, 1995.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Hurwitz N. Predisposing factors in adverse reactions to drugs. Br. Med. J., 1: 536-539, 1969.
  18. ↵
    Oshita F., Kurata T., Kasai T., Fakuda M., Yamamoto N., Ohe Y., Tamura T., Eguchi K., Shinkai T., Saijo N. Prospective evaluation of the feasibility of cisplatin-based chemotherapy for elderly lung cancer patients with normal organ functions. Jpn. J. Cancer Res., 86: 1198-1202, 1995.
    OpenUrlCrossRefPubMed
  19. ↵
    Schmucker D. L. Age-related changes in drug disposition. Pharmacol. Rev., 30: 445-456, 1978.
    OpenUrlPubMed
  20. ↵
    Greenblatt D. J., Sellers E. M., Shader R. I. Drug therapy: drug disposition in old age. N. Engl. J. Med., 306: 1081-1088, 1982.
    OpenUrlPubMed
  21. ↵
    Schmucker D. L. Aging and drug disposition: an update. Pharmacol. Rev., 37: 133-148, 1985.
    OpenUrlPubMed
  22. ↵
    Egorin M. J. Cancer pharmacology in the elderly. Semin. Oncol., 20: 43-49, 1993.
    OpenUrlPubMed
  23. ↵
    Minami H., Shimokata K., Saka H., Saito H., Ando Y., Senda K., Nomura F., Sakai S. Phase I clinical and pharmacokinetic study of a 14-day infusion of etoposide in patients with lung cancer. J. Clin. Oncol., 11: 1602-1608, 1993.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Ando Y., Minami H., Saka H., Ando M., Sakai S., Shimokata K. Therapeutic drug monitoring of etoposide in a 14-day infusion for non-small-cell lung cancer. Jpn. J. Cancer Res., 87: 200-205, 1996.
    OpenUrlCrossRefPubMed
  25. ↵
    Tobinai K., Kohno A., Shimada Y., Watanabe T., Tamura T., Takeyama K., Narabayashi M., Fukutomi T., Kondo H., Shimoyama M., Suemasu K. Toxicity grading criteria of the Japan Clinical Oncology Group. The Clinical Trial Review Committee of the Japan Clinical Oncology Group. Jpn. J. Clin. Oncol., 23: 250-257, 1993.
    OpenUrlFREE Full Text
  26. ↵
    Allen L. M. Analysis of 4′-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-β-rdr-glucopyranoside) by high-pressure liquid chromatography. J. Pharm. Sci., 69: 1440-1441, 1980.
    OpenUrlCrossRefPubMed
  27. ↵
    Minami H., Horio Y., Sakai S., Saka H., Shimokata K. Pharmacokinetics of an etoposide infused over three days: concomitant infusion with cisplatin. Jpn. J. Clin. Oncol., 21: 400-405, 1991.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Stewart C. F., Arbuck S. G., Fleming R. A., Evans W. E. Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J. Clin. Oncol., 8: 1874-1879, 1990.
    OpenUrlAbstract
  29. ↵
    Fujiwara Y., Ohune T., Niitani K., Okusaki K., Sumiyoshi H., Ohashi N., Egusa Y., Elisna S., Oguri T., Takahashi T., Yamaoka N., Tsuya T., Yamakido M. Clinical pharmacological profile of etoposide in the elderly. Proc. Am. Soc. Clin. Oncol., 15: 174 1996.
    OpenUrl
  30. ↵
    Bonetti A., Franceschi T., Apostoli P., Cetto G. L., Recaldin E., Molino A., Leone R. Cisplatin pharmacokinetics in elderly patients. Ther. Drug Monit., 16: 477-482, 1994.
    OpenUrlPubMed
  31. ↵
    Shepherd F. A., Amdemichael E., Evans W. K., Chalvardjian P., Hogg-Johnson S., Coates R., Paul K. Treatment of small cell lung cancer in the elderly. J. Am. Geriatr. Soc., 42: 64-70, 1994.
    OpenUrlPubMed
  32. ↵
    Siu L. L., Shepherd F. A., Murray N., Feld R., Pater J., Zee B. Influence of age on the treatment of limited-stage small-cell lung cancer. J. Clin. Oncol., 14: 821-828, 1996.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    Lipschitz D. A. Age-related declines in hematopoietic reserve capacity. Semin. Oncol., 22: 3-5, 1995.
    OpenUrlPubMed
  34. ↵
    Sundman-Engberg B., Tidefelt U., Paul C. Toxicity of cytostatic drugs to normal bone marrow cells in vitro. Cancer Chemother. Pharmacol., 42: 17-23, 1998.
    OpenUrlCrossRefPubMed
  35. ↵
    Stewart C. F., Arbuck S. G., Fleming R. A., Evans W. E. Relation of systemic exposure to unbound etoposide and hematologic toxicity. Clin. Pharmacol. & Ther., 50: 385-393, 1991.
    OpenUrlPubMed
  36. ↵
    Ratain M. J. Therapeutic relevance of pharmacokinetics and pharmacodynamics. Semin. Oncol., 19: 8-13, 1992.
    OpenUrlPubMed
  37. ↵
    Girling D. J. Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet, 348: 563-566, 1996.
    OpenUrlCrossRefPubMed
  38. ↵
    Souhami R. L., Spiro S. G., Rudd R. M., Ruiz de Elvira M. C., James L. E., Gower N. H., Lamont A., Harper P. G. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J. Natl. Cancer Inst., 89: 577-580, 1997.
    OpenUrlFREE Full Text
View Abstract
PreviousNext
Back to top
July 1999
Volume 5, Issue 7
  • Table of Contents

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Clinical Cancer Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Pharmacological Analysis of Etoposide in Elderly Patients with Lung Cancer
(Your Name) has forwarded a page to you from Clinical Cancer Research
(Your Name) thought you would be interested in this article in Clinical Cancer Research.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Pharmacological Analysis of Etoposide in Elderly Patients with Lung Cancer
Masahiko Ando, Hironobu Minami, Yuichi Ando, Shuzo Sakai, Yohei Shimono, Seiji Sugiura, Hideo Saka, Kaoru Shimokata and Yoshinori Hasegawa
Clin Cancer Res July 1 1999 (5) (7) 1690-1695;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Pharmacological Analysis of Etoposide in Elderly Patients with Lung Cancer
Masahiko Ando, Hironobu Minami, Yuichi Ando, Shuzo Sakai, Yohei Shimono, Seiji Sugiura, Hideo Saka, Kaoru Shimokata and Yoshinori Hasegawa
Clin Cancer Res July 1 1999 (5) (7) 1690-1695;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • INTRODUCTION
    • PATIENTS AND METHODS
    • RESULTS
    • DISCUSSION
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Abstract B32: RADIANCE: An open-label, nonrandomized, prospective biomarker study to assess analytic concordance between noninvasive testing and tissue testing for EGFR T790M mutation detection in patients with non-small cell lung cancer
  • Abstract B33: Expansion study of pegylated arginine deiminase (ADI-PEG20), pemetrexed, and cisplatin in patients with ASS1-deficient non-squamous non-small cell lung cancer (TRAP)
  • Abstract B34: Safety and activity of the IL-15/sIL-15Rα complex ALT-803 in combination with the anti-PD1 mAb nivolumab in metastatic non-small cell lung cancer
Show more Clinical Trials
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • CCR Focus Archive
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Clinical Cancer Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Clinical Cancer Research
eISSN: 1557-3265
ISSN: 1078-0432

Advertisement