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Carboplatin and Topotecan Combination and Myelosuppression

Centro di Riferimento Oncologico, National Cancer Institute, Aviano, Italy

To the Editor:In the January 1, 2002, issue of the Journal of Clinical Oncology, Athale et al¹ published a phase I study of the topotecan (TOPO) and carboplatin (CARBO) combination in pediatric solid tumors. A fixed dose of CARBO at an area under the concentration-time curve of 6.5 was given on day 1 followed by escalated TOPO as a 72-hour continuous infusion from the starting dose of 0.50 mg/m²/d. The severe myelosuppression allowed only a modest (20%) increment of the dose.¹ The authors indicated several possible explanations for this additive toxicity but excluded a relationship with an alteration in the pharmacokinetics of TOPO. Finally, because of the objective responses seen in that trial, they suggested further investigations using alternative sequences and schedules of administration (ie, topoisomerase inhibitors followed by platinum agents). The findings of the authors agree with other studies of the TOPO/CARBO combination for the treatment of patients with relapsed ovarian cancer. Bookman et al² reported the Gynecologic Oncology Group experience, and the recommended doublet was TOPO on days 1 to 3 and CARBO on day 3 because the reverse sequence exhibited excessive toxicity.

DNA topoisomerase I is the target of TOPO, which produces DNA cleavage by stabilization of the covalent enzyme-DNA complex, determining DNA strand cleavage and apoptosis. A decrease in the level of topoisomerase I confers resistance to the agents targeting the enzyme. Conversely, an increase in the intracellular topoisomerase I mRNA expression level enhances the cytotoxic activity of antitopoisomerase I agents.³ We have analyzed the topoisomerase I mRNA expression level in peripheral-blood mononuclear cells (PBMCs) from 20 patients with ovarian cancer treated with CARBO (area under the concentration-time curve, 4 to 5) as a single agent. Topoisomerase I RNA was detected by the method of reverse transcriptase polymerase chain reaction (RT-PCR) at the baseline level, immediately before CARBO administration, and 24 hours afterward. Glucose-6-phosphate dehydrogenase was used as a control. PCR products were quantified on ethidium bromide–stained gels using a digital image analyzer, and the ratio of topoisomerase I to glucose-6-phosphate dehydrogenase was used to determine the relative topoisomerase expression level.

We observed a significant (P = .004 by paired t test) increase in the topoisomerase I mRNA level 24 hours after exposure to CARBO compared with the basal levels. The PBMC mRNA value (obtained from the average of a minimum of two separate PCR reactions within the linear amplification range) was 2.44 ± 2.40 times greater (median, 1.83; minimum, 0.42; maximum, 9.43).

The effect of platinum derivatives on the topoisomerase I level is actually under debate. In our opinion, the CARBO-induced effect on topoisomerase I mRNA expression in PBMCs must be considered in explaining the severe myelotoxicity of the CARBO/TOPO sequence. On these grounds, it would be crucial to ascertain at what time topoisomerase I mRNA expression increases in PBMCs after administration of CARBO and what the effect is on mRNA expression at the tumor level. Simpson et al⁴ performed two phase I trials of CARBO/TOPO, with CARBO on day 1 and TOPO either on days 1 to 5 or days 8 to 12. Interestingly, they reported responses with both schedules, but the delayed TOPO administration (days 8 to 12) was associated with lower toxicity.

In conclusion, we think that not only should alternative sequences to that reported in the study of Athale et al (ie, TOPO before CARBO) be considered but also that the sequence of CARBO before TOPO should be used with the antitopoisomerase I agent administered later than the 3 to 5 days usually utilized. A monitoring of the kinetics of mRNA topoisomerase I expression could be warranted to design the optimal schedule.

REFERENCES

1. Athale UH, Stewart C, Kuttesch JF, et al: Phase I study of combination topotecan and carboplatin in pediatric solid tumors. J Clin Oncol 20: 88-95, 2002[Abstract/Free Full Text]

2. Bookman MA: Developmental chemotherapy in advanced ovarian cancer: Incorporation of topoisomerase-I inhibitors and perspective of the Gynecologic Oncology Group. Int J Gynecol Cancer 11: 42-51, 2001 (suppl 1)

3. Kotoh S, Naito S, Yokomizo A, et al: Increased expression of DNA topoisomerase I gene and collateral sensitivity to camptothecin in human cisplatin-resistant bladder cancer cells. Cancer Res 54: 3248-3252, 1994[Abstract/Free Full Text]

4. Simpson A, Twelves C, Boddy A, et al: Schedule dependency of carboplatin and topotecan: Phase I and pharmacokinetic studies. Proc Am Soc Clin Oncol 17: 204a, 1998 (abstr 785)

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Toffoli, G. Articles by Boiocchi, M. Search for Related Content PubMed PubMed Citation Articles by Toffoli, G. Articles by Boiocchi, M. Social Bookmarking                            What's this?