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Review and Commentary |
Sarah Cannon Cancer Center, Nashville, Tennessee, USA
Correspondence: Howard A. Burris, III, M.D., Sarah Cannon Cancer Center, 250 25th Avenue North, Suite 412, Nashville, Tennessee 37203, USA. Telephone: 615-342-1725; Fax: 615-342-1745.
This issue of The Oncologist provides the reader with two useful reviews [1, 2] of the new chemotherapeutic agent topotecan, one of a class of topoisomerase I inhibitors that is being studied and incorporated into the treatment of various malignancies. Topotecan was approved for the treatment of refractory ovarian cancer in 1996 [3, 4], and has shown promising activity against a variety of solid tumors, as well as hematologic malignancies. One paper discusses clinical guidelines for managing topotecan-related hematologic toxicities, and centers on data derived from ovarian cancer studies [1]. The other focuses on the role of topotecan in the treatment of small cell lung cancer (SCLC), where it has consistently shown encouraging results and for which definitive trials are now being conducted [2]. As front-line therapy for ovarian cancer and small cell lung cancer is dominated by platinum-based regimens, the dosing guidelines and management issues discussed are pertinent for both tumor types.
Much of the interest in incorporating topotecan into combination chemotherapy regimens is based on its novel mechanism of action which leads to a scientific rationale as to how it can be used to modify patterns of resistance and hopefully improve outcomes. The cellular enzyme topoisomerase I is intricately involved in maintaining the topographic structure of DNA during translation, transcription and mitosis. Topoisomerase I covalently binds to double-stranded DNA and enables the DNA helix to uncoil during replication and RNA transcription. By causing transient single-stranded breaks, topoisomerase I relieves the torsional tension along the fork of replicating DNA. Topoisomerase inhibitors interfere with this breakage and resealing reaction by forming a ternary covalent complex of drug, enzyme, and DNA. This new class of anti-cancer agents, the topoisomerase I inhibitors, largely consists of camptothecin derivatives. Camptothecin, a natural product derived from the oriental tree Camptotheca acuminata, was noted to have anti-cancer activity, but clinical trials were halted in the early 1970s because of unpredictable toxicities including myelosuppression, gastrointestinal toxicity, and hemorrhagic cystitis. It was in the mid-1980s that the mechanism of action of camptothecin was linked to topoisomerase I inhibition, and less toxic analogs such as topotecan were developed. Because topotecan is more water soluble and less protein bound than the parent compound, the side effect profile is altered and is more predictable [5]. Irinotecan (CPT-11) is another semi-synthetic water soluble derivative of camptothecin which was approved for the treatment of 5-FU refractory colon cancer in 1996. A number of other compounds are in clinical testing and include 9-aminocamptothecin (9-AC) and GI 147211 (GG 211), among others.
Numerous phase I trials with topotecan have been performed utilizing a variety of dosing schedules [6]. In addition to single-dose and daily times five bolus schedules of administration, infusional schedules ranging from 24 hours to 21-day continuous administration were studied. Because of topotecan's relatively short half-life of approximately three to four hours, much of the focus has been on more frequent dosing schedules and/or infusional administration. Topotecan is rapidly converted from its active lactone form to its inactive carboxylate form at physiologic Ph. A number of responses were noted early on in clinical testing of the daily times five schedule, and thus the majority of phase II work was performed utilizing this particular regimen [6]. There has been much debate about the dose of topotecan to be utilized, even on the daily times five schedule, with studies being performed at doses ranging from 1.25 mg/m2 to 2 mg/m2. Furthermore, it has been shown that topotecan can be escalated with the use of colony-stimulating factors to the range of 3.0 to 4.0 mg/m2 before thrombocytopenia becomes the dose-limiting toxicity. The flexibility and/or variability of the dose of topotecan is important, and probably should be altered based on the intent and goal of the treatment utilized.
As the authors have clearly stated, the dose-limiting toxicities for topotecan largely center around myelosuppression. Varying declines in neutrophils, platelets, and red blood cells have been noted based on the dose and schedule of administration, and, maybe most importantly, the extent of prior therapy that the patients have undergone. Non-hematologic toxicities have been mild to moderate, rapidly reversible, and include alopecia, nausea and vomiting, fatigue, and stomatitis. Rarely are these toxicities of Grade III severity, and most patients receiving topotecan do not require significant antiemetic premedication. Topotecan is eliminated via both the hepatic and renal routes. Studies have been performed which show that the most important factor is renal function, and that only those patients with severe hepatic dysfunction resulting in elevated bilirubins need to be considered for dose modifications based on hepatic function [7, 8]. In contrast, patients with renal impairment are at greater risk for severe hematologic toxicities. As mentioned, with topotecan's primary current use being in the treatment of patients with ovarian and small cell lung cancer, these patients will have been previously treated with platinum-based regimens, and thus have further risk for renal impairment in addition to their age and concomitant medical problems. The authors have given very clear and reasonable dosing recommendations for patients with renal impairment based on estimated creatinine clearance. With the common-day practice of dosing carboplatin by AUC calculations, estimating creatinine clearance has become a rather routine event in the clinic, and can be quickly assessed for determining the topotecan dose [9]. The authors appropriately detail the experience of using topotecan with colony-stimulating factors, as clearly, in some settings, this would be preferential to a dose reduction. Probably because of the lack of stomatitis, the ratio of febrile neutropenia to Grade IV neutropenia has been modest. Transfusion-dependent anemia has been reported to varying degrees in topotecan clinical trials. Management practices for this toxicity certainly vary based on thresholds for administering transfusions, as well as choosing to administer prophylactic erythropoietin in some cases. Similarly, the threshold for administering platelet transfusions in those patients experiencing thrombocytopenia has complicated analyzing the severity of that particular toxicity. With the arrival of thrombopoietin and other platelet-producing growth factors, it is certain that we will see data emerging as to the role of these agents in supporting various topotecan-based regimens. Most importantly, the hematologic toxicities of topotecan are not cumulative, and thus predictable toxicity patterns can be established with various dosing regimens.
There is great interest in incorporating topotecan into the treatment of small cell lung cancer. Single agent response rates with topotecan have been similar whether the drug has been tested in front-line therapy of extensive disease patients or as second-line therapy of relapsed patients considered sensitive to the initial chemotherapy regimen. In Schiller's ECOG front-line study of extensive SCLC, the 39% response rate is similar to the 38% rate among sensitive relapses in Ardizzoni's European second-line trial [10-12]. Because topotecan is a topoisomerase I inhibitor, there has been interest in sequencing it with the various topoisomerase II inhibitors to see if resistance can be avoided or overcome. Obviously, with etoposide firmly entrenched in the management of small cell lung cancer, this has been an ideal tumor type for evaluating this principle. ECOG is in the process of completing protocol 7593 which will evaluate in a randomized fashion the effect of topotecan or observation on patients' relapse-free survival and overall survival after initially receiving four cycles of cisplatin and etoposide. Clinical trials sequencing topotecan and etoposide have already shown that, in fact, topoisomerase II levels are increased after exposure to topotecan, thus potentially making those cells more sensitive to therapy with etoposide. Similar hints of promising clinical results have been noted in trials sequencing topotecan and doxorubicin, also known to have inhibitory effects on topoisomerase II.
In addition to sequencing topotecan into regimens for small cell lung cancer, there has been data to show that synergism exists with the administration of topotecan and the platinums. Interestingly, this effect was noted preclinically in mouse models when cisplatin was given on day 1 and topotecan was given on a day 1-5 schedule. The effect was not noted when the cisplatin was given only on day 5 at the end of five days of topotecan administration. It has been postulated that part of the synergism exists because topoisomerase I is needed in cellular repair, a component to developing platinum resistance. By blocking this key repair enzyme, sensitivity to platinum is enhanced. Clinical evaluations of this sequencing have been performed, and it is clear that there is a marked difference in the toxicity patterns noted when the cisplatin is given on day 1 or day 5, with day 1 dosing being more myelosuppressive. One would suspect that the lack of myelosuppression observed when the cisplatin was given on day 5 would probably translate to less synergism in the clinic and thus lower efficacy. Synergism has also been noted between the topoisomerase I inhibitors and the taxanes, and although it is a small number of patients, the results from Jett's trial of taxol plus topotecan is certainly very promising and worthy of additional study [13]. At our own institution, we have taken this a step further and have been evaluating combinations of carboplatin, paclitaxel, and topotecan, with the carboplatin and paclitaxel each administered on day 1 and the topotecan given on a daily times three schedule. This regimen would have potential applicability to both small cell lung cancer and ovarian cancer, as well as other malignancies. Although substantial neutropenia and thrombocytopenia have been observed, a number of responses have been noted in previously treated small cell lung cancer patients who have previously failed platinum-based regimens. We are now conducting a trial utilizing this three-drug regimen in small cell lung cancer for four cycles, followed by three cycles of an oral etoposide single agent regimen. This treatment will hopefully take advantage of both the established synergism between these agents, as well as the alteration in topoisomerase enzyme levels intracellularly which should occur.
Several other exciting things are taking place with the incorporation of topotecan into chemotherapy regimens. Objective responses have been noted on topotecan phase II trials in patients with hepatoma, gastric, prostate, breast, non-small cell lung, melanoma, sarcoma, glioblastoma, and head and neck cancer, as well as a wide variety of hematologic malignancies to include acute and chronic leukemias, as well as myeloma, and lymphoma [6]. The majority of these tumor types will obviously involve developing an appropriate combination regimen, but, as previously stated, the novel mechanism of action of topotecan, and the documented synergism with certain compounds makes this a worthwhile endeavor. Topotecan is also unique in its ability to cross the blood-brain barrier, with concentrations of approximately 30% of plasma levels documented. This CSF penetration is noteworthy not only for the drug's potential use in primary central nervous system tumors, but also hopefully for decreasing the incidence of metastatic disease to the brain, a common occurrence in tumors such as small cell lung cancer.
An extensive evaluation of the oral formulations of topotecan has been performed [14-16]. Consistent bioavailability in the range of 30%-40% has been documented, and, interestingly, the half-life of topotecan is actually prolonged when given orally, increasing to the range of approximately six hours. This effect is probably due to delayed conversion from the active lactone to the inactive carboxylate form secondary to the lower Ph to the upper gastrointestinal tract. A variety of schedules including 5-, 10-, 14-, and 21-day dosing has been explored. Of note, on the more prolonged 21-day schedule, diarrhea became the dose-limiting toxicity. Early results from clinical trials looking at the efficacy of the oral formulation in ovarian cancer appear promising, and this route of delivery will certainly expand the options for developing regimens in which to utilize topotecan.
In summary, topotecan is a promising addition to our chemotherapy arsenal, both because of its unique mechanism of action, and its manageable toxicity profile. The authors have reviewed the activity of topotecan in small cell lung cancer, and have given us some ideas as to the direction in which the incorporation of topotecan into this disease is heading. Furthermore, the clinical guidelines suggested for managing the hematologic toxicity of topotecan are straightforward, and should assist in the appropriate dosing of patients with both ovarian and small cell lung cancer.
References
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