Expert Commentary

Howard A. Burris, III, MD, Director of Drug Development, Sarah Cannon Cancer Center, Nashville, Tennessee

Relapsed ovarian cancer and small cell lung cancer are frequently treated with topotecan in a standard intravenous administration of 1.5 mg/m² daily for 5 consecutive days every 3 weeks. Clinical experience has demonstrated that this dose and schedule may be unduly toxic for some patients with these diseases, posing a high risk of myelosuppression. Recently, a number of clinical trials have begun evaluating the feasibility and efficacy of topotecan given weekly. Early results suggest this approach maintains the antitumor activity of topotecan while yielding much less toxicity. From the patient's perspective, weekly topotecan offers greater convenience and quality of life. From the oncologist's perspective, weekly topotecan offers the potential to combine topotecan with other cytotoxic agents.

Several presentations at the recently concluded Chemotherapy Foundation Symposium XXI highlighted the encouraging results from clinical trials of topotecan. Dr. Anthony Greco updated attendees on the promising initial results of weekly topotecan first presented at the 10th World Congress on Lung Cancer in August 2003.¹ It is well established that topotecan is active in ovarian cancer, small cell lung cancer, and several other malignancies, but administering topotecan for 5 consecutive days results in myelosuppression in a number of patients. With weekly administration of topotecan, although the total cumulative amount of topotecan received over 6 to 8 weeks is greater, as is the peak concentration with a single dose, you avoid the repetitive marrow toxicity seen with standard topotecan administration.

Dr. Joseph Treat reported that topotecan, even with standard administration, can be given to poor-Performance Status (PS) patients, yielding outcomes and levels of toxicity similar to those found in patients with higher PS. Dr. Treat showed that all patients could benefit from receiving topotecan, regardless of PS.

This data is encouraging for oncologists. When we are able to give PS 2 patients a chemotherapeutic agent with an improved toxicity profile, we can substantially reduce the potential risks and concentrate on delivering the benefits of chemotherapy. This improved therapeutic ratio will benefit all patient types, perhaps more so in the seriously ill patients. Additionally, offering an agent that reduces the burden of associated quality of life issues, which are of great importance to our cancer patients.

Dr. David Spriggs discussed the optimal duration of treatment with topotecan. The relatively low cumulative toxicity profile of topotecan suggests that topotecan may lend itself well to extended periods of treatment, which we are beginning to employ in our responding patients. We have found that patients on extended treatment welcome a periodic break in treatment; therefore, we treat for 3 weeks with the fourth week off. Not only does this schedule provide a much-needed psychological break for the patient, but also it reduces some of the non-hematologic toxicity, such as fatigue.

The purpose of this Oncology Express Report is to review these presentations in greater detail. I hope you find this information relevant, timely and beneficial in treating your cancer patients.

Weekly Topotecan Showing Promise in Solid Tumors

The standard 5-day administration of topotecan is often associated with severe myelosuppression, which makes topotecan difficult to use in combination with other cytotoxic agents. A weekly regimen of topotecan was designed to reduce the toxicity associated with its administration, and data are emerging that support the benefit of this approach, advised F. Anthony Greco, MD, Director of the Sarah Cannon Cancer Center, Nashville, Tennessee.² Dr. Greco discussed the use of weekly topotecan in solid tumors.

From a historical perspective, Dr. Greco indicated that initial studies of weekly topotecan (4 mg/m²) in relapsed ovarian cancer showed a 13% response rate in platinum-resistant patients with stable disease achieved in 19% of patients, with very little myelosuppression observed.³ At approximately the same time, studies in non-small cell lung cancer cell lines showed that topoisomerase I levels could be diminished by topotecan for at least 72 hours, requiring nearly seven days to return to near baseline.⁴ These data suggested a rationale for weekly dosing of topotecan, Dr. Greco stated.

More recently, Morris et al reported an update of a phase II trial of topotecan in 28 chemosensitive relapsed ovarian cancer patients and documented partial responses in 7 of 25 evaluable patients (28%), and stable disease in 12 (48%) patients.⁵ Patients were treated with topotecan at 4 mg/m² weekly and only 8% of the patients required dose delays or omissions due to hematologic toxicity. Grade 3 and 4 neutropenia occurred following only 6 treatments (1.7%). "These results indicate that topotecan is apparently quite active in platinum-sensitive ovarian cancer," observed Dr. Greco.

"These results are fairly typical of the marked reduction in myelosuppression associated with the weekly schedule of topotecan," noted Dr. Greco. "It is encouraging that the response rate appears to be comparable to the more toxic schedule given five consecutive days."

Studies are currently being conducted of weekly topotecan in various solid tumors, including advanced endometrial carcinoma. Finkler et al⁶ evaluated weekly topotecan 2.5-3.5 mg/m² in patients with advanced endometrial cancer and achieved a 23% partial response rate with Grade 3 and 4 neutropenia of 39%, reducing by over half the degree of neutropenia seen with the standard administration of topotecan, Dr. Greco noted.

Non-small cell lung cancer and small cell lung cancer may also lend themselves to weekly topotecan administration. Dr. Greco indicated that the Sarah Cannon Cancer Center is evaluating weekly topotecan 4 mg/m² as secondary therapy in patients with small cell lung cancer in both refractory and sensitive relapses. Preliminary findings in 29 evaluable patients show the same reduced toxicity profile that is being reported in other studies of weekly topotecan. Grade 3 and 4 hematologic toxicity has been seen in only 15 to 20% of patients, Dr. Greco reported. Additionally, Sarah Cannon Cancer Center is also studying weekly topotecan as primary therapy in elderly and poor-PS patients with small cell lung cancer.

"The main issue is this: does weekly topotecan provide equivalent or approximately equivalent responses to its standard five-day administration? It appears to be true in ovarian cancer, and I suspect it is probably true in small cell lung cancer," stated Dr. Greco. "The other issue is that if topotecan is active in a weekly schedule with reduced myelosuppression, the opportunity to combine weekly topotecan with other active cytotoxic agents is greatly enhanced as suggested by studies with docetaxel^[7], paclitaxel^[8], carboplatin and gemcitabine^[9], paclitaxel and cisplatin^[10], and cisplatin and gemcitabine^[11]."

Topotecan Beneficial in Relapsed Small Cell Lung Cancer Patients with Poor-Performance Status

"The generally favorable toxicity and efficacy profiles of topotecan make this agent a suitable treatment for patients with relapsed small cell lung cancer and poor-Performance Status," stated Joseph Treat, MD, Vice Chairman of Oncology at Fox Chase-Temple Cancer Center, Philadelphia, Pennsylvania who based his remarks on the findings from a retrospective analysis of topotecan treatment in these patients.¹²

Poor-PS is associated with reduced survival in small cell lung cancer,^13-15 since patients may not tolerate intensive chemotherapy. However, the question of poor-PS in relation to tolerance outcomes has not been previously analyzed. A retrospective analysis was performed of 5 randomized trials (N = 479) investigating the feasibility of topotecan in the treatment of relapsed small cell lung cancer patients with a PS 2. The analysis included 98 patients with PS 2 (381 patients with PS 0/1) who received 341 courses of chemotherapy (median 2; range, 1 to 14 courses), offering "a fairly extensive look at this issue," added Dr. Treat.

The regimen in the 5 clinical trials was topotecan 1.5 mg/m²/day on Days 1 through 5 of a 21-day course. This is the FDA-approved dose and schedule for topotecan, though in the words of Dr. Treat, "This strategy is arguably not the best, and certainly is not the least toxic way to administer topotecan. The toxicity data will, therefore, be tainted by this somewhat antiquated dose and schedule."

Myelosuppression has been the primary concern with topotecan utilization and one of the key questions in the analysis was how extensively PS 2 patients would be affected by this adverse event. Dr. Treat noted, however, "Much of the neutropenia is tied to the original dose and schedule of topotecan, which many clinicians have moved away from."

The retrospective analysis showed that administration of topotecan in the standard dose and schedule was well tolerated in patients with baseline PS 0/1 and PS 2. With the exception of Grade 3 and 4 anemia, the incidence of leukopenia, neutropenia, and thrombocytopenia was not statistically different between PS 0/1 and PS 2 patients. Hematologic toxicity was noncumulative and reversible. Although anemia occurred in 30% of PS 0/1 patients and 44% of PS 2 patients (P = .009), Dr. Treat attributed this relatively high rate to restricted use of erythropoietin in one of the trials.

"For Performance Status 2 and Performance Status 0/1 patients, the toxicities were very much the same, even with the standard schedule of topotecan. There is really no difference in myelosuppressive effects," observed Dr. Treat.

Tumor response was also comparable for PS 2 patients (overall response 17%) as for PS 0/1 (overall response 14%), as was stable disease (14% vs 22%, respectively), indicating that poor-PS patients received the same clinical benefit as the higher PS patients. There was, however, a difference in survival time: median time-to-progression was 8.7 weeks (95% Confidence Interval (CI), 7.3-12.4) for PS 2 patients, 11.3 weeks (95% CI, 9.1-12.1) for PS 1 patients, and 12.6 weeks (95% CI, 11.1-15.3) for PS 0 patients (P<.046 for PS 2 vs PS 0/1). Dr. Treat indicated that these results are consistent with the large database of Eastern Cooperative Oncology Group (ECOG) patients with small cell lung cancer and in patients with non-small cell lung cancer in ECOG.

Perhaps the key finding from the retrospective analysis was that PS 2 patients demonstrated improvement in symptoms (eg, dyspnea, cough, chest pain, anorexia, insomnia as assessed by symptom scales), as did PS 0/1 patients. Also, PS actually improved in PS 2 patients treated with topotecan (defined as improvement over 2 courses of therapy). Both the PS improvement and symptom improvement with topotecan usually occurred early in treatment, often after the first cycle, indicated Dr. Treat. The improvement in PS may be associated with improved survival. For those PS 2 patients who improved to PS 0/1, the median overall survival was 37 weeks (95% CI, 29.6-44.6) as compared to 27.6 weeks in PS 0/1 patients (95% CI, 25.1-30.4). In those PS 2 patients who not show improvement in PS, the median survival was 11.6 weeks (95% CI, 9.0-15.6).

The analysis concluded that PS 2 and PS 0/1 patients were similar in their ability to tolerate topotecan, in their antitumor response, and in their ability to derive improvement in symptoms and baseline PS as the result of topotecan treatment. There was, however, as might be expected, a difference in survival time, with poor-PS patients faring less well.

Duration of Therapy for Ovarian Cancer: How Long is Enough?

The question of duration of treatment in patients with relapsed ovarian cancer has not been studied in prospective randomized trials and remains unresolved. In many studies, patients have typically been treated for up to one year with further treatment left to the discretion of the study investigator.

A recent Southwest Oncology Group/Gynecologic Oncology Group (SWOG/GOG) investigation (GOG 178) of maintenance therapy in advanced ovarian cancer demonstrated that 12 cycles of paclitaxel given every 28 days to patients in clinically complete remission resulted in a 7-month improvement in median progression-free survival as compared to 3 cycles (28 vs 21 months; P<.0028), though overall survival was not statistically different.¹⁶ With either treatment arm, discontinuation of therapy resulted in a fairly rapid disease progression, according to David Spriggs, MD, Chief, Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, New York, New York.¹⁷

The treatment for relapsed ovarian cancer is typically divided into chemosensitivity groups, based on the treatment-free interval. Patients with stable or progressing disease on platinum/taxane-based regimens are classed as refractory. Complete responders in the 0 to 12-month treatment-free group are intermediate in sensitivity to platinum, while patients not recurring within 12 to 18 months are highly platinum-sensitive. In patients with platinum-sensitive disease, retreatment with carboplatin is a reasonable option, though treatment beyond 6 to 8 cycles is associated with progressive myelosuppression and treatment delays. The combination of paclitaxel and platinum has been shown to improve survival and progression-free survival in patients with relapsed platinum-sensitive ovarian cancer, but sustained treatment with this regimen remains very difficult, Dr. Spriggs noted.

For refractory disease, placing relapsed patients on a second-line agent with a milder toxicity profile, such as topotecan, which is not known to have cumulative toxicity, is often a sound approach, Dr. Spriggs indicated. Additionally, patients who achieve stable disease on topotecan have an enhancement in survival nearly as great as patients who have an objective partial response, Dr. Spriggs advised. In his opinion, extended treatment with topotecan is generally feasible.

Extended treatment with either topotecan or liposomal doxorubicin was demonstrated as feasible in a large phase III randomized international study of 474 patients with relapsed ovarian cancer who failed first-line platinum-based therapy.¹⁸ Patients were randomized to topotecan 1.5 mg/m² for 5 consecutive days every 3 weeks or to liposomal doxorubicin 50 mg/m² every 4 weeks. Since the study allowed patients to remain on treatment for over one year, the observation was made that "there are certainly patients who have received substantial benefit from these agents beyond the typical 6-month treatment period," noted Dr. Spriggs.

With topotecan, chronic toxicities in the study appear to have been limited, with essentially no neuropathy, minimal gastrointestinal toxicity, modest alopecia, and no progressive neutropenia. "Though patients often need an initial dose adjustment, there is no strong evidence of cumulative myelosuppression associated with topotecan," stated Dr. Spriggs.

According to Dr. Spriggs, the data are more limited with respect to extended treatment with liposomal doxorubicin. There appears to be less cardiotoxicity than is seen with the conventional formulation of doxorubicin, however, it is likely there is residual toxicity that deserves monitoring. In the same study, 3 of 61 patients had at least a 20% decrease in left ventricular ejection fraction. Palmar plantar erythrodysethesia also occurs as a function of dose and treatment interval with doxorubicin.

In response to a question concerning extended treatment with topotecan, Howard A. Burris, III, MD, Director of Drug Development, Sarah Cannon Cancer Center, Nashville, Tennessee agreed that topotecan lends itself to this schedule. "I have had patients receive topotecan on various dosing and frequency schedules for more than a year. There is little cumulative toxicity and no neuropathy. I have had patients on weekly topotecan for prolonged periods, and this may turn out to be a schedule that we can give as maintenance therapy. Maintenance therapy is being explored, in fact, in small cell lung cancer and ovarian cancer because of the high rates of relapse observed in those patients. Topotecan may lend itself well to those clinical scenarios."

References

1. Greco FA, Erland J, Burris HA, et al. Weekly topotecan in the second-line treatment of small-cell lung cancer: a Minnie Pearl Cancer Research Network Trial. Lung Cancer. 2003;41(suppl 2):S237. Abstract P-576.
2. Greco FA, Jones S, Burris HA, Hainsworth JD. An update on weekly topotecan (Hycamtin(r)) in solid tumors. Presented at Chemotherapy Foundation Symposium XXI: Innovative Cancer Therapy for Tomorrow, November 12-15, 2003, New York, New York. Abstract 39.
3. Homesley HD, Hall DJ, Martin DA, et al. A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients. Gynecol Oncol. 2001;83:394-399.
4. Bence AK, Mattingly CA, Desimone PA, et al. Evaluation of topotecan cytotoxicity and topoisomerase I levels in non-small cell lung cancer cells. Proc Am Assoc Cancer Res. 2002;43:247. Abstract 1227.
5. Morris R, Alvarez RD, Andrews S, Malone J, Bryant C, Munkarah A. Topotecan weekly bolus chemotherapy for potentially chemosensitive relapsed ovarian and peritoneal cancer-an update. Proc Am Soc Clin Oncol. 2003;22:459. Abstract 1846.
6. Finkler NJ, Holloway RW. Phase I/II trial of weekly topotecan in the treatment of advanced recurrent metastatic endometrial carcinoma. Proc Am Soc Clin Oncol. 2002;21:171b. Abstract 2504.
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16. Markman M, Liu PY, Wilczynski S, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003;21:2460-2465.
17. Spriggs D. Duration of therapy for ovarian cancer: how long is enough? Presented at Chemotherapy Foundation Symposium XXI: Innovative Cancer Therapy for Tomorrow, November 12-15, 2003, New York, New York. Abstract 32.
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