Expert Commentary

Eric Rowinsky, MD, Institute for Drug Development, Cancer Therapy and Research Center; Clinical Professor of Medicine, University of Texas Health Science Center, San Antonio, Texas

According to the results of studies presented at the 40^th Annual Meeting of the American Society of Clinical Oncology (ASCO), chemotherapy with topotecan improves performance status (PS) in patients with small cell lung cancer who exhibit poor PS at baseline.¹ Moreover, studies investigating once weekly administration of topotecan in patients with small cell lung cancer have shown promising results with minimal toxicity.^2-4

Lung cancer is the leading cause of cancer-related death in the United States.⁵ Small cell lung cancer accounts for 20% of all cases of lung cancer and is characterized by an aggressive, invasive course. Relapse following treatment for small cell lung cancer is a common clinical problem. Relapses are seen in 95% of all small cell lung cancer patients and 99% of those with extensive disease. Patients with limited disease fare only slightly better, with relapse rates of 75% to 90%. Relapsed patients have a short life expectancy, only 4 to 6 months, and are often highly symptomatic. Whether these patients are candidates for second-line chemotherapy depends primarily on their duration of response to prior chemotherapy (3 months or longer), and their PS. Many patients with small cell lung cancer are elderly, frail, have significant comorbidities, and exhibit poor PS.

Poor PS has been associated with reduced survival in patients with small cell lung cancer.^6-8 Topotecan has been well tolerated in small cell lung cancer patients with poor PS (= 2) while providing similar benefits, antitumor response rates and symptom palliation as with PS 0/1 patients.⁹ Emerging evidence presented at ASCO suggests that use of topotecan in small cell lung cancer patients with poor PS at baseline may actually improve PS.¹

This Oncology Express Report^TM reviews important data presented/ published at ASCO that demonstrate new approaches to improving survival and reducing toxicity in small cell lung cancer patients receiving chemotherapy.

Association between Topotecan and Improvement in Performance Status

Results of a study presented by Rogerio Lilenbaum, MD, Clinical Associate Professor of Medicine, Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida, indicate that topotecan administered in the standard dose and schedule of 1.5 mg/m²/day on 5 consecutive days of a 21-day cycle provides clinical benefit to a significant proportion of small cell lung cancer patients with PS 2.¹ Moreover, the improvement in PS that occurred within the initial 1 to 2 courses of topotecan chemotherapy, suggests that PS may be an early surrogate for benefit from therapy.

Dr. Lilenbaum presented a retrospective analysis of five clinical trials^10-14 which investigated the use of topotecan in patients (N = 479) with relapsed small cell lung cancer. The objective of the analysis was to investigate whether treatment with topotecan was associated with an improvement in PS as assessed by the frequency of conversion from PS 2 to PS 0/1. All patients received intravenous administration of topotecan 1.5 mg/m²/day on Days 1 through 5 of a 21-day cycle.

Of 479 patients in the analysis, there were 98 patients with PS 2 at baseline. Of those 98 patients, 32 patients (33%) experienced improvement in PS during topotecan chemotherapy (Figure 1). Twenty-four of these patients experienced improvement in PS for 2 or more cycles of chemotherapy. Approximately two thirds of the 32 patients experienced improvement in PS after only 1 course of topotecan chemotherapy.

Further analysis of these data demonstrated that improvement in PS was associated with high antitumor activity, whereas lack of improvement in PS was associated with disease progression. The overall response to topotecan was 46% in those patients who experienced PS conversion compared with 8% in patients who had no improvement (Table 1).

Additionally, median overall survival was 37 weeks (95% Confidence Interval [CI], 29.6-44.6 weeks) in patients with PS 2 who showed an improvement in PS, compared with 11.6 weeks (95% CI, 9.0-15.6 weeks) in patients with PS 2 showing no improvement in PS. Transition from PS 2 to PS 0/1 was associated with a higher incidence of stable disease as best response compared with patients who did not transition to improved PS (29% vs 9%, respectively). The toxicity profile of topotecan chemotherapy was comparable between patients with poor PS and those with PS 0/1.

Investigators concluded that a significant proportion of small cell lung cancer patients with poor PS at baseline experience PS improvement after treatment with topotecan. In essence, topotecan was well tolerated by these patients whose poor performance reflects the status of their disease and not necessarily other inherent factors. Moreover, these results suggest that improvement in PS may be an early surrogate for benefit from topotecan therapy.

According to Dr. Lilenbaum, "These results suggest that patients with chemo-sensitive small cell lung cancer and poor perfor-mance status should not be denied the option of treatment with topotecan."

Weekly Bolus Topotecan as First-line Therapy for Extensive Stage Small Cell Lung Cancer

Preliminary results from an ongoing phase II study designed to evaluate the toxicity and response rate of weekly bolus topotecan in patients with previously untreated extensive stage small cell lung cancer who were elderly (>65 years), poor PS, or had severe coexistent medical illness were published at ASCO.² According to investigators, 17 of a required 40 patients have been enrolled thus far in the study. Patients were to receive a weekly intravenous bolus of topotecan 4 mg/m² administered over 30 minutes for 12 consecutive weeks, with dosage adjustments based on observed toxicity. Patients were evaluated for response after 4 weeks, with at least 3 weekly treatments required for evaluation. An additional 15 patients will soon be evaluable, according to the published results. Investigators noted that severe myelo-suppression was seen less often with weekly topotecan admin-istration compared to the standard schedule of 1.5 mg/m² for 5 consecutive days of a 21-day cycle. These findings suggest that weekly topotecan in combination with other active cyto-toxic agents should be considered for patients with extensive stage small cell lung cancer.

Weekly Bolus Topotecan as Secondary Therapy in Extensive Stage Small Cell Lung Cancer

Interim data from an ongoing phase II trial of weekly topotecan as a second-line therapy for relapsed small cell lung cancer were also published at ASCO.³

The dose of weekly topotecan was 4 mg/m² administered intravenously over 30 minutes for 12 consecutive weeks, with dosage adjustments as necessary based on observed toxicity. The interim data was from the first 30 evaluable patients of the anticipated 100-patient enrollment. Of the 30 evaluable patients, 19 patients had chemo-sensitive relapse, one patient achieved a partial response, 7 patients had stable disease, and 11 patients had progressive disease. The remaining 11 evaluable patients were chemo-resistant, with no partial responses; 3 patients had stable disease and 8 patients had progressive disease. The responses were comparable to those seen with the standard 5-day administration of topotecan. There were 25 weeks of treatment delay with 8.5% dosage adjustments.

Grade 3/4 neutropenia was observed in 17.5% of patients; grade 3/4 thrombocytopenia in 5% of patients; and grade 3/4 fatigue in 17.5% of patients.

As in other studies of weekly topotecan chemotherapy, investigators observed myelosuppression was reduced with weekly administration of topotecan compared with the standard topotecan regimen of 1.5 mg/m² for 5 consecutive days of a 21-day cycle.

Weekly Topotecan in Recurrent Small Cell Lung Cancer

Vijay Kasturi, MD, of the Dartmouth Hitchcock-Keene Kingsbury Center for Cancer Care, Keene, New Hampshire, presented a preliminary analysis of a retrospective study of weekly topotecan in patients with recurrent small cell lung cancer.⁴ The objective of the analysis was to investigate the tolerability and potential treatment benefit of weekly topotecan in patients with recurrent small cell lung cancer.

A review of patients treated with weekly topotecan after failure of first-line therapy with platinum/etoposide was conducted. All patients who received topotecan were evaluated for toxicity. Tumor response was determined for those patients who received ≥8 weeks of topotecan chemotherapy. Eleven eligible patients were identified (all but one had extensive disease). Weekly topotecan was given at a median dose of 4 mg/m²/week (range, 2.5-4 mg/m²/week), and a median of 4 cycles (3 weeks on, 1 week off; range, 1-16 cycles).

Of 9 patients treated with ≥2 cycles of weekly topotecan, 5 patients achieved a partial response, 2 patients had stable disease, and 2 patients had progressive disease. Two of the partial responses were achieved in patients with platinum-resistant disease, Dr. Kasturi noted. Median duration of partial response was 26 weeks. Median duration for response in the 2 patients with stable disease was 20 and 25 weeks.

Dr. Kasturi stated that weekly topotecan was generally well tolerated. Of 11 patients, grade 3 leukopenia and anemia occurred in 6 and 4 patients, respectively. Erythropoietin and granulocyte-colony stimulating factor (G-CSF) were used in 10 and 2 patients, respectively. One case of grade 4 neutro-penia was observed. Nonhematologic toxicity was limited to grade 3 fatigue in 4 patients.

Dr. Kasturi concluded that weekly topotecan was well tolerated and appeared to exhibit improved tolerability compared to the standard 5-day topotecan administration and that future studies of weekly topotecan (as single agent and in novel combinations) are warranted in patients with recurrent small cell lung cancer.

References

1. Levin J, Lilenbaum RC, Masters GA, Lane SR, Treat J. Association of topotecan with improved performance status (PS) in relapsed small cell lung cancer (SCLC) patients with poor PS at baseline. Proc Am Soc Clin Oncol. 2004;23:665. Poster Presentation - Abstract 7208.
2. Patton JF, Hainsworth JD, Spigel DR, et al. Weekly bolus topotecan as first-line therapy for extensive stage small cell lung cancer in patients who are elderly, poor performance status, or have severe coexistent illness: a Minnie Pearl Cancer Research Network phase II trial. Proc Am Soc Clin Oncol. 2004;23:681. Abstract 7275.
3. Peacock NW, Hainsworth JD, Switzer AB, et al. Weekly bolus topotecan as secondary therapy in extensive stage small cell lung cancer: a Minnie Pearl Cancer Research Network phase II trial. Proc Am Soc Clin Oncol. 2004;23:682. Abstract 7278.
4. Kasturi VK, Eckardt JR, Greco FA. A preliminary retrospective analysis of weekly topotecan in recurrent small-cell lung cancer. Proc Am Soc Clin Oncol. 2004;23:702. Abstract 7359.
5. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8-29.
6. Spiegelman D, Maurer LH, Ware JH, et al. Prognostic factors in small-cell carcinoma of the lung: an analysis of 1,521 patients. J Clin Oncol. 1989;7:344-354.
7. Kusumoto S, Koga K, Tsukino H, Nagamachi S, Nishikawa K, Watanabe K. Comparison of survival of patients with lung cancer between elderly (greater than or equal to 70) and younger (70 greater than) age groups. Jpn J Clin Oncol. 1986;16:319-323.
8. Osterlind K, Andersen PK. Prognostic factors in small cell lung cancer: multivariate model based on 778 patients treated with chemotherapy with or without irradiation. Cancer Res. 1986;46:4189-4194.
9. Treat J, Huang CH, Lane SR, Levin J. Topotecan in the treatment of relapsed small cell lung cancer patients with poor performance status. Oncologist. 2004;9:173-181.
10. Ardizzoni A, Hansen H, Dombernowsky P, et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol. 1997;15:2090-2096.
11. Depierre A, von Pawel J, Hans K, et al. Evaluation of topotecan (Hycamtin^TM) in relapsed small cell lung cancer (SCLC). A multicentre phase II study. Lung Cancer. 1997;18(suppl 1):35.
12. Eckardt J, Gralla R, Palmer MC, et al. Topotecan as second-line therapy in patients with SCLC: a phase II study. Ann Oncol. 1996;7(suppl 5):107.
13. 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.
14. von Pawel J, Gatzemeier U, Pujol JL, et al. Phase II comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol. 2001;19:1743-1749.

Disclosure

Eric Rowinsky, MD: Grant/Research Support-Abgenix, Amgen, AstraZeneca, OSI Pharmaceuticals, Inc., Pfizer; Consultant-Abgenix, Amgen, AstraZeneca, OSI Pharmaceuticals, Inc., Pfizer.

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