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Foreword—New Directions for Topotecan in Lung Cancer Treatment

The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Correspondence: David J. Stewart, M.D., F.R.C.P.C., The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Room FC-9-3062, Houston, Texas 77030, USA. Telephone: 713-792-6363; Fax: 713-796-8655; e-mail: dstewart{at}mdanderson.org

Key Words. Non-small cell lung cancer • Small cell lung cancer • Topotecan • Quality of life

With an estimated 1.2 million new cases worldwide, lung cancer remains the most common cancer in the world. An estimated 1.1 million people succumbed to lung cancer in 2000, and tobacco consumption continues to increase in developing nations [1]. Both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are aggressive tumors, making up approximately 85% and 15% of lung cancer cases, respectively [2]. The majority of patients with lung cancer present with advanced disease, and the majority of tumors are unresectable. Although platinum-based chemotherapy regimens have been associated with significant antitumor activity, the vast majority of patients relapse and die from their disease. In addition, because the majority of patients are >60 years of age and may have comorbidities or poor performance status (PS) scores, quality of life (QOL) is of major concern. In response to these concerns, investigators have been in search of novel treatment options with superior antitumor activities and safety profiles.

One agent that has been introduced during the last decade is topotecan (HYCAMTIN^®; GlaxoSmithKline; Philadelphia, PA), a novel topoisomerase I inhibitor with a broad spectrum of antitumor activity. Topotecan is currently approved for the treatment of patients with relapsed SCLC and those with recurrent ovarian cancer, and it has demonstrated activity in a variety of other solid and hematologic malignancies. This special issue of The Oncologist is devoted to reviewing and updating the clinical data related to the use of topotecan in the treatment of lung cancer. The articles herein were derived, in part, from presentations delivered at the 10th World Conference on Lung Cancer in August 2003 in Vancouver, British Columbia. In addition to providing an update on the role of topotecan in relapsed SCLC, a number of other important topics are reviewed, including the use of topotecan at first relapse, alternative topotecan dosing schedules, the use of topotecan in the first-line treatment of SCLC and in patients with NSCLC, and the potential QOL benefit with topotecan therapy.

The supplement begins with an overview of the data supporting the use of topotecan in patients with SCLC. Andrea Ardizzoni reviews the literature and builds a compelling case for the use of topotecan at first relapse in patients with SCLC [3]. Although other novel agents, including paclitaxel (Taxol^®; Bristol-Myers Squibb; Princeton, NJ), docetaxel (Taxotere^®; Aventis Pharmaceuticals Inc.; Bridgewater, NJ), gemcitabine (Gemzar^®; Eli Lilly and Company; Indianapolis, IN), and irinotecan (Camptosar^®; Pfizer Pharmaceuticals; New York, NY), have also reported antitumor activity in relapsed SCLC, results are mostly based on single institution phase II trials, whereas topotecan was compared, in a large, randomized, phase III trial, with the widely used cyclophosphamide, doxorubicin (Adriamycin^®; Bedford Laboratories; Bedford, OH), and vincristine (Oncovin^®; Eli Lilly and Company; Indianapolis, IN), CAV, regimen [4]. Therefore, topotecan should be considered the standard first-choice single agent for the treatment of relapsed SCLC. In addition, Dr. Ardizzoni reviews the activity of lower-dose regimens, the use of topotecan in combination therapy, and the use of topotecan in patients with poor PS scores. Preliminary data suggest that topotecan is an effective treatment in patients with poor PS scores and that it should be considered in this patient population, the members of which might otherwise not receive chemotherapy.

Although the standard 5-day topotecan regimen is active in patients with relapsed SCLC, alternate treatment regimens have been investigated to reduce the complications associated with hematologic toxicities. Several schedules of weekly topotecan have been evaluated, including a weekly 24-hour continuous infusion, a weekly 72-hour continuous infusion, and a weekly bolus schedule. John Eckardt [5] reviews the weekly bolus schedule, which, because of its convenience and potential for combination with other agents administered on weekly schedules, has been the most studied. Dr. Eckardt presents data showing that, compared with the 5-day regimen, weekly topotecan is generally well tolerated in patients who have relapsed SCLC, with less hematologic toxicities, and severe nonhematologic toxicities are rare. In addition, he reviews studies that have investigated combination regimens of weekly topotecan, paclitaxel, and cisplatin (Platinol^®; Bristol-Myers Squibb) in previously untreated patients with SCLC.

In patients with limited survival expectations, symptom palliation and QOL are especially important. Symptom palliation appears to correlate with QOL and survival duration. Therefore, the potential clinical benefit of chemotherapy in patients with SCLC should not be ignored. Yet, because of worsening clinical symptoms and comorbidities, some patients with SCLC are often unable to tolerate aggressive chemotherapy regimens at relapse. As a result, patient compliance is sometimes a challenge in the treatment of these patients. An increased emphasis on patient compliance and convenience has resulted in an increased interest in oral chemotherapy agents. Oral chemotherapy agents, which can be administered at home, may decrease concerns about effects on the family and transportation issues and may also eliminate frequent venipuncture. Richard Gralla reviews the QOL considerations in patients with advanced lung cancer and discusses the advantages of oral chemotherapy [6]. Dr. Gralla uses topotecan, the only single agent shown to provide symptom palliation in patients with relapsed SCLC, to demonstrate the relationship between symptom palliation and QOL. He argues that an oral formulation of topotecan, which appears to have an equivalent efficacy profile and a superior safety profile to the i.v. formulation, may allow treatment of patients who otherwise would not receive therapy.

Although SCLC is typically responsive to first-line therapy, the vast majority of patients eventually relapse. In addition, many first-line regimens are associated with cumulative toxicities, such as nephrotoxicity and peripheral neuropathy. Consequently, there is still a need for first-line therapy that demonstrates superior efficacy and that consists of agents with nonoverlapping toxicities. Topotecan has proven efficacy in relapsed SCLC and has a predictable and generally manageable safety profile, making it a practical agent to investigate in the first-line setting. The author reviewed the various doublet and triplet regimens containing topotecan that have been recently studied [7]. Although some combinations have been associated with either lower efficacies or higher toxicities, some regimens show promise. Alternating and sequential regimens are also being explored, including consolidation and induction topotecan therapy. Because some elderly and poor PS patients cannot tolerate combination regimens, single-agent topotecan as first-line therapy has been studied in those patients with good results. Taken together, these trials demonstrate that topotecan-based combination regimens are active in the first-line SCLC setting and that single-agent topotecan may provide an alternative treatment option for elderly and poor PS patients for whom there are few treatment options.

Finally, NSCLC is an aggressive disease associated with a poor prognosis. Patients with NSCLC currently receive a platinum-based regimen as the standard of care. However, many of these regimens are associated with severe and often cumulative hematologic and nonhematologic toxicities. Because of its success in relapsed SCLC, topotecan has also been investigated in the treatment of patients with NSCLC. The author reviewed studies with single-agent topotecan and topotecan-based combination regimens in both the first- and second-line treatment of NSCLC [8]. Topotecan, in combination with a number of established and novel antitumor agents, has demonstrated antitumor activity in patients with NSCLC and allows for the reduction of the dose intensity of other agents, and thereby the potential nonhematologic toxicities associated with those agents. Some of the more encouraging responses have been obtained when topotecan was combined with vinorelbine (Navelbine^®; GlaxoSmithKline) or gemcitabine, with mild to moderate toxicities. In contrast, when topotecan was combined with etoposide (Vepesid^®; Bristol-Myers Squibb), a high degree of schedule dependency was indicated, and antitumor activity was less promising at the doses and schedules studied. In addition, toxicities were problematic when topotecan was combined with platinum or taxanes. The ideal regimen combining topotecan with other agents has yet to be defined. In the future, in vitro studies investigating dose-response relationships and identifying resistance mechanisms may help to select agents, doses, and schedules for combination therapy to maximize the therapeutic index.

In summary, because patients with SCLC often have poor prognoses and deteriorate rapidly, they often have less tolerance to chemotherapy. Yet, despite limitations with chemotherapy and the potential challenges associated with its delivery, there is an overwhelming consensus that chemotherapy offers patients the best chance of improved symptom control and prolongation of survival. After relapse, palliative care and QOL are increasingly important. In this broad context, it is my hope that you find this special issue of The Oncologist to be an important educational resource that provides an up-to-date synopsis of the various studies that have investigated topotecan in the treatment of lung cancers.

	ACKNOWLEDGMENT

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Supported by GlaxoSmithKline, Philadelphia, PA. Presented in part at a satellite symposium entitled "New Horizons in the Management of Small Cell Lung Cancer" held during the British Columbia, 10th World Conference on Lung Cancer, Vancouver, Canada, August 10–14, 2003.

	REFERENCES

Top References

 

1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533–543. Erratum in: Lancet Oncol 2001;2:596.[CrossRef][Medline]
2. American Cancer Society. Cancer Facts and Figures 2004. http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdf, accessed 08/02/04.
3. Ardizzoni A. Topotecan in the treatment of recurrent small cell lung cancer: an update. The Oncologist 2004;9(suppl 6):4–13.[Abstract/Free Full Text]
4. von Pawel J, Schiller JH, Shepherd FA et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small cell lung cancer. J Clin Oncol 1999;17:658–667.[Abstract/Free Full Text]
5. Eckardt JR. Emerging role of weekly topotecan in recurrent small cell lung cancer. The Oncologist 2004;9(suppl 6):25–32.[Abstract/Free Full Text]
6. Gralla RJ. Quality-of-life considerations in patients with advanced lung cancer: effect of topotecan on symptom palliation and quality of life. The Oncologist 2004;9(suppl 6):14–24.[Abstract/Free Full Text]
7. Stewart DJ. Topotecan in the first-line treatment of small cell lung cancer. The Oncologist 2004;9(suppl 6):33–42.[Abstract/Free Full Text]
8. Stewart DJ. Update on the role of topotecan in the treatment of non-small cell lung cancer. The Oncologist 2004;9(suppl 6):43–52.[Abstract/Free Full Text]

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