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The Oncologist, Vol. 11, No. 5, 529-531, May 2006; doi:10.1634/theoncologist.11-5-529
© 2006 AlphaMed Press

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Letter to the Editor

Topotecan Continuous Infusion: CA-125 Responses Including Patients Pretreated with Other Schedules of Topotecan

Franco Muggia, Rebecca Kosloff, Leonard Liebes, Howard Hochster

New York University Medical Center, New York, New York, USA

Correspondence: Franco Muggia, M.D., New York University Medical Center, 550 First Avenue, BCD 556, New York, New York 10016, USA. Telephone: 212-263-6485; Fax: 212-263-8210; e-mail: Muggif01{at}med.nyu.edu

Received February 20, 2006; accepted for publication April 3, 2006.

The article entitled "Hematologic Safety and Tolerability of Topotecan in Recurrent Ovarian Cancer and Small Cell Lung Cancer: An Integrated Analysis" by Armstrong et al. in the October 2005 issue of The Oncologist [1] summarizes the data from eight phase II and phase III clinical studies of topotecan (Hycamtin®; GlaxoSmithKline, Philadelphia) given to 879 patients that had stage III/IV ovarian cancer or extensive small cell lung cancer. This analysis supported the use of topotecan at 1.5 mg/m2 per day on days 1–5, every 3 weeks, and concluded that the "results suggest that topotecan may be safely administered for multiple courses" with the primary major side effect being myelosupression, which was noncumulative.

In the same issue, Markman [2] commented that the extremefatigueofthedailydosingregimenat1.5mg/m2per day cannot be overlooked and suggested that lower doses (1–1.25 mg/m2 per day) may help improve the side-effect profile. Safra et al. [3] have recently provided evidence for favorable response rates and median time on study with weekly topotecan. We would like to call attention to the tolerance and efficacy of topotecan by continuous infusion at 0.4 mg/m2 per day for 14–21 days every 4 weeks in heavily pretreated patients with ovarian cancer.

Phase I/pharmacologic and phase II studies of protracted infusion schedules of topotecan as a single agent or in combination with other agents, such as cisplatin, pegylated liposomal doxorubicin, or oxaliplatin [4–9], by our group have already been published. Moreover, we have documented the ability to combine a full 14-day infusion with cisplatin in a highly active first-line regimen [6]. Finally, we have shown that the 14-day schedule of topotecan with oxaliplatin is less toxic and is active in the pre-treated setting [9].

The preclinical background for protracted-infusion schedules was provided by Peter Houghton and coworkers [10, 11]. The logistics of such schedules have improved by theavailabilityofmore‘user-friendly’7-dayBaxterinfusers (rather than battery-run pumps) and by the use of long-acting and effective antiemetics in the HT3 family and aprepitant. Our recent clinical experience with protracted-infusion topotecan in patients with recurrent ovarian or primary peritoneal cancer, after failing multiple agents including other schedules of topotecan, may therefore be of interest.

Ten platinum-resistant patients with epithelial ovarian cancer and a median age of 60 years (Table 1Go) recently received topotecan after disease progression on several prior regimens. Six women had received topotecan administered via different schedules (weekly i.v., daily i.v. x 5 days, and oral), while the other four had been exposed to a median of two nonplatinum agents after induction. All received topotecan as a single agent in a 14-day schedule every 28 days at a dose of 0.4 mg/m2 per day, with subsequent schedule adjustments for subjective intolerance (fatigue, nausea) or myelosuppression. Grade 3 and 4 toxicities of this infusion regimen in the 10 patients included grade 3 thrombo-cytopenia in three patients and grade 3 neutropenia in three patients (two of whom also had grade 3 platelet toxicity), all without complications. Red cell transfusions were required every other cycle by three patients, five patients experienced grade 2 fatigue, and subtotal alopecia was also commonly noted. One of the longest responders, patient 1, had failed multiple agents, including carboplatin, pegylated liposomal doxorubicin, gemcitabine, and weekly topotecan, after recurring from her initial induction; she had a gradual decline in CA-125 to a nadir of <10% from the original value, relief of pelvic symptoms, and improved findings on imaging (short of a partial response by Response Evaluation Criteria in Solid Tumors criteria).


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  		Table 1. Patient characteristics and outcome

 
From this experience, we conclude that the 14-day protracted infusion of topotecan is active, even after multiple courses of chemotherapy, with noncumulative and predictable toxicity. Intriguing is the possibility that this schedule might be more effective than intermittent schedules in the presence of resistance mechanisms mediated by the ABCG2 (BCRP) transporter [12]. Negative views on protracted infusion schedules [13] might be reassessed in light of our experience [14].


   DISCLOSURES
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 Disclosures
References
 
The authors indicate no potential conflicts of interest.


   ACKNOWLEDGMENT
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This study was supported in part by The Lynne Cohen Foundation and the Chemotherapy Foundation.


   REFERENCES
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 References
 

  1. Armstrong DK, Spriggs D, Levin J et al. Hematologic safety and tolerability of topotecan in recurrent ovarian cancer and small cell lung cancer: an integrated analysis. The Oncologist 2005;10:686–694.[Abstract/Free Full Text]
  2. Markman M. Topotecan as second-line therapy for ovarian cancer: dosage versus toxicity. The Oncologist 2005;10:695–697.[Abstract/Free Full Text]
  3. Safra T, Moshe I, Levy T. Topotecan in ovarian cancer: schedules and doses, activity and toxicity. Cancer Invest 2006;24 (Suppl 1):1.[Medline]
  4. Hochster H, Liebes L, Speyer J et al. Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well-tolerated regimen. J Clin Oncol 1994;12:553–559.[Abstract]
  5. Hochster H, Wadler S, Runowicz C et al. Activity and pharmacodynamics of 21-day topotecan infusion in patients with ovarian cancer previously treated with platinum-based chemotherapy. New York Gynecologic Oncology Group. J Clin Oncol 1999;17:2553–2561.[Abstract/Free Full Text]
  6. Hochster HS, Plimack ER, Mandeli J et al. Prolonged topotecan infusion with cisplatin in the first-line treatment of ovarian cancer: an NYGOG and ECOG study. Gynecol Oncol 2006;100:324–329.[Medline]
  7. Mirchandani D, Hochster H, Leibes L et al. Prolonged oral topotecan (T): unacceptable gastrointestinal toxicity in two drug combinations. Proc Am Soc Clin Oncol 2001;2075a.
  8. Mirchandani D, Hochster H, Hamilton A et al. Phase I study of combined pegylated liposomal doxorubicin with protracted daily topotecan for ovarian cancer. Clin Cancer Res 2005;11:5912–5919.[Abstract/Free Full Text]
  9. Lu JM, Hochster H, Sorich J et al. Phase I study of oxaliplatin and topotecan infusion in patients with previously treated ovarian cancer. Proc Am Soc Clin Oncol 2003;22:463.
  10. Houghton PJ, Cheshire PJ, Myers L et al. Evaluation of 9-dimethylamino-methyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 1992;31: 229–239.[CrossRef][Medline]
  11. Santana VM, Furman WL, Billups CA et al. Improved response in high-risk neuroblastoma with protracted topotecan administration using a pharmacokinetically guided dosing approach. J Clin Oncol 2005;23:4039–4047.[Abstract/Free Full Text]
  12. Maliepaard M, van Gastelen MA, de Jong LA et al. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 1999;59:4559–4563.[Abstract/Free Full Text]
  13. Hudes G. Boosting bioavailability of topotecan: what do we gain? J Clin Oncol 2002;20:2918–2919.[Free Full Text]
  14. Muggia FM. Boosting bioavailability to topotecan: what do we gain? Correspondence. J Clin Oncol 2003;21:177; author reply 177.[Free Full Text]
  15. Rustin GJ, Marples M, Nelstrop AE et al. Use of CA-125 to define progression of ovarian cancer in patients with persistently elevated levels. J Clin Oncol 2001;19:4054–4057.[Abstract/Free Full Text]



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D. K. Armstrong
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Oncologist, May 1, 2006; 11(5): 531 - 532.
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 The OncologistHome page
M. Markman
In reply.
Oncologist, May 1, 2006; 11(5): 532 - 532.
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