Preliminary Results of Combined Therapy with Topotecan and Carboplatin in Advanced Non-Small-Cell Lung Cancer

Abstract

Topotecan is a topoisomerase I inhibitor and an analogue of camptothecin with demonstrated activity in small-cell lung cancer. However, less is known about the potential role of topotecan in advanced non-small-cell lung cancer (NSCLC). Platinum-based combination therapy is currently recommended in NSCLC patients presenting with good performance status. Because topotecan demonstrates a novel mechanism of action, its investigation in platinum combinations is warranted. In phase I/II trials of topotecan given as part of a cisplatin-based regimen, significant antitumor activity has been observed, providing the rationale for conducting further studies aimed at assessing survival benefit. However, this combination exhibits sequence dependence, with increasing hematologic toxicity observed when cisplatin is administered on day 1 of a 5-day topotecan course. Cisplatin has been associated with dose-limiting nonhematologic toxicities. Carboplatin exhibits a different toxicity profile compared with cisplatin, which makes it an attractive agent to study in combination. A hypothesis can be made that carboplatin in combination with newer agents such as topotecan might compare favorably with classic cisplatin-based regimens, particularly with respect to efficacy:toxicity ratio. Therefore, a phase II study was initiated to determine the efficacy, toxicity, and safety of carboplatin-topotecan combination in advanced NSCLC. Preliminary results reported here show that topotecan with carboplatin is generally well tolerated with manageable hematologic toxicity. Indirect comparison with cisplatin-topotecan combination suggests a lower incidence of dose-limiting nonhematologic toxicity. Whether or not the carboplatin-topotecan regimen is able to offer tumor response and survival benefit comparable to those observed with cisplatin-based combinations remains to be established.

Topotecan Dosing Guidelines in Ovarian Cancer: Reduction and Management of Hematologic Toxicity

“…Topotecan (Hycamtin of recurrent epithelial ovarian cancer [3] and relapsed small cell lung cancer [4], and has also demonstrated activity in hematologic malignancies [5][6][7] and solid tumors including non-small cell lung [8,9], cervical [10][11][12], and colon cancers [13]. In ovarian cancer, topotecan has demonstrated activity in both platinum-and paclitaxel-resistant tumors, with response rates ranging from 12%-33% [14][15][16][17][18][19].…”

A Phase I Study of Weekly Topotecan in Combination with Pemetrexed in Patients with Advanced Malignancies

“…The demographics of the patient population are outlined in Table 2. These patients were treated with 120 cycles of therapy, including five patients who received 8,8,10,12, and 17 cycles without dose reductions, confirming a lack of cumulative myelosuppression. Four patients were dosed at level 5-topotecan, 4.0 mg/m 2 , and pemetrexed, 500 mg/m 2 -but experienced two DLTs, one each of febrile neutropenia and grade 4 thrombocytopenia.…”

Update on the Role of Topotecan in the Treatment of Non-Small Cell Lung Cancer

“…Recent studies of topotecan-based combination therapies are summarized in Table 2 [14][15][16][29][30][31][32][33].…”

“…Thus, topotecan has also been investigated in combination with carboplatin. In a phase II study, Pujol et al [16] enrolled 47 patients with unresectable stage III or IV NSCLC. Patients received i.v.…”

“…Therefore, agents with novel mechanisms of action and superior safety profiles need to be investigated in this patient population. Topotecan (Hycamtin ® ; GlaxoSmithKline), a topoisomerase I inhibitor, is currently approved for the treatment of relapsed small cell lung cancer (SCLC) and has recently shown activity in the NSCLC setting [14][15][16]. This review summarizes the recent findings on topotecan in the treatment of these patients and explores the potential role of topotecan in the treatment of patients with NSCLC.…”