Expert Commentary

Anthony Greco, MD, Oncology and Internal Medicine Physician, Tennessee Oncology; Clinical Researcher and Director of Sarah Cannon Cancer Center, Co-director, Minnie Pearl Research Network, Nashville, Tennessee

Small cell lung cancer (SCLC) is a tumor that is difficult to cure and control, however, chemotherapy usually produces responses and results in rapid improvement in cancer-related symptoms and length of survival. Despite such responses to first-line therapy, however, median survival is still only 9 to 10 months with chemotherapy (12 to 16 months for patients with limited disease), and the vast majority of patients relapse and progress within a year from the end of treatment. In this setting, the efficacy of standard chemotherapeutic agents diminishes significantly leaving little in the way of treatment options. However, there is evidence that topotecan, a topoisomerase I inhibitor, is an active drug producing tumor responses and symptom control in some patients as second-line therapy. Topotecan, in fact, is the only FDA-approved chemotherapeutic agent for relapsed SCLC.

Topotecan is an established treatment in recurrent SCLC, with tumor response rates of about 20% reported in extensive disease patients with good performance status (PS).^1-5 Topotecan is particularly beneficial in patients with sensitive relapse with overall tumor response rates ranging from 11% to 31% with symptomatic improvement, whereas in the more difficult to treat refractory relapse patients overall response rates have ranged from 2% to 7%.^1-5

Emerging data in ovarian cancer patients support a new weekly administration of topotecan that not only maintains its efficacy but also largely overcomes the severe and frequent hematologic toxicity (myelosuppression) that can be associated with the conventional intravenous administration of topotecan 1.5 mg/m² daily for 5 days on a 21-day cycle. Studies of weekly topotecan in previously treated SCLC patients are in progress, and early data shows less myelosuppression than the standard schedule and some activity. Other data presented at this meeting showed that even with the standard 5-day schedule, PS 2 is not a sole reason to exclude patients from topotecan in the relapsed setting, as a study by Treat et al⁶ found comparable antitumor activity and tolerability in PS 2 and PS 0/1 patients.

Furthermore, a new oral form of topotecan currently under investigation will offer benefits in terms of patient convenience, without sacrificing efficacy, according to a study by Gralla et al⁷ reported at this meeting.

Topotecan is one of the most extensively studied chemotherapy agents in the second-line SCLC setting and the only drug with this specific indication. Studies such as those presented at the 10th World Conference on Lung Cancer give oncologists a level of confidence for the various treatment options and emerging data involving topotecan in SCLC.

Topotecan in the Treatment of Relapsed SCLC

Relapse following treatment for SCLC is a common clinical problem. Relapses are seen in 95% of all SCLC 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.

David J. Stewart, MD, Professor of Medicine and Chief, Section of Lung Cancer Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, described the challenge of treating relapsed SCLC at a symposium held during this meeting,⁸ focusing on the treatment options provided by topotecan.

Topotecan (Hycamtin) was the first chemotherapy agent approved in the United States and Canada for the treatment of relapsed SCLC. Before the introduction of topotecan, "state of the art" treatment was based mainly on retrospective data and no one regimen was adopted as the standard. Based on minimal evidence, the CAV regimen (cyclophosphamide, Adriamycin, vincristine) was the most widely used, along with re-induction or single-agent etoposide.

Studies of single-agent topotecan in the late 1990s showed activity for this agent, particularly in platinum-sensitive relapse. Ardizzoni et al (1997) found a 38% relapse rate and 7 months median survival in 45 sensitive patients, though reponse rates in refractory patients remained low.³ When given as first-line therapy to patients with extensive-stage SCLC, single-agent topotecan produced a 39% response rate.⁹ Von Pawel et al showed the comparability of single-agent topotecan to CAV in a study of 211 patients.¹ In that study, topotecan 1.5 mg/m² daily for 5 days on a 21-day cycle yielded a 24% response rate, compared to 18% for CAV, with median time to progression of 13 and 12 weeks, respectively, and median survival of 25 weeks in each. Toxicity was relatively mild, and topotecan was superior in terms of symptom control of all cancer-related symptoms, Dr. Stewart noted.

"Topotecan has activity as a front-line and second-line agent for small cell lung cancer and non-small cell lung cancer, and is a worthwhile option for your patients," Dr. Stewart said.

Preclinical synergism has been shown between topotecan and other chemotherapy agents, including the taxanes, vinca alkaloids, platinums, topoisomerase II inhibitors, 5-fluorouracil and others. Synergism has also been demonstrated with molecules that are not part of mainstream chemotherapy treatment, including decitabine (a DNA methyltransferase inhibitor), buthionine sulfoximine (GSH depletion), PARP-1 inhibitors (DNA repair enzyme), CD95 ligand, TRAIL, Erb cell signaling pathway antagonists, and more. It is possible that by manipulating other pathways or affecting gene expression through such agents, treatment effects may be enhanced, Dr. Stewart predicted.

The clinical use of topotecan, therefore, in combination with other agents has also been explored for the second-line treatment of SCLC, and benefits have been demonstrated with some combinations. Recently, Ardizzoni et al (2003) found a 29% response rate and median survival of 6.4 months in platinum-sensitive relapse patients given topotecan and cisplatin, and a 24% response in resistant patients.¹⁰ Jett et al found a 29% rate and 6.9-month survival for the combination of topotecan and paclitaxel, and a 9% response in resistant patients.¹¹ Overall responses have been somewhat less with vincristine, and generally poor with epirubicin or gemcitabine in combination with topotecan, Dr. Stewart noted.

Topotecan is also being combined sequentially or alternating with paclitaxel, etoposide, carboplatin, or combinations of paclitaxel plus carboplatin or cisplatin in phase I and II studies, yielding response rates and survival times similar to those with other standard chemotherapy approaches.

A significant improvement in survival was seen in a randomized study comparing the topoisomerase I inhibitor irinotecan to etoposide when combined with cisplatin in patients with chemo-naпve extensive stage SCLC.¹² The irinotecan plus cisplatin arm in this study produced an 84% response rate, a median survival of 12.8 months, and 2-year survival of 19.5%, Dr. Stewart reported.

"This study provided a glimmer of hope that the topoisomerase I inhibitors may prove superior to the topoisomerase II inhibitors," noted Dr. Stewart. To evaluate this possibility, there is an ongoing study (the HOPE study) that will compare oral topotecan plus cisplatin to etoposide plus cisplatin, advised Dr. Stewart.

Topoisomerase Inhibitors In NSCLC

In the treatment of non-small cell lung cancer (NSCLC), single-agent topotecan has typically produced relatively low response rates in the first-line setting, however, "response rates may not be the most important factor," Dr. Steward offered. Stable disease rates in numerous studies have been very high, 35 to 55%, with up to 40% of patients experiencing symptomatic improvement. Survival times of 6 to 9 months match or exceed those seen with many other standard single agents in NSCLC. "The studies are not direct comparisons but they suggest similar efficacy for topotecan and other agents," Dr. Stewart said.

Similarly, topotecan combinations in the first-line NSCLC setting are also comparable in efficacy to other regimens. Phase I and II studies combining topotecan with cisplatin with or without gemcitabine or with vinorelbine have resulted in response rates of 17% to 42%, median survival durations of 7.6 to 13 months, and 1-year survival rates of over 30%. Such results suggest that topotecan may be comparable to other agents when used in combination, despite modest single-agent activity, according to Dr. Stewart.

Topotecan Effective and Tolerable in Poor-Performance Patients

SCLC patients with poor-PS status are often considered questionable or unsuitable for chemotherapy, but a study presented at this meeting by Joseph Treat, MD, of Fox Chase-Temple Cancer Center, Philadelphia, Pennsylvania,⁶ provided support for topotecan regimens in this population.

The study was a retrospective analysis of data from five clinical trials of topotecan (1.5 mg/m² daily for 5 days on a 21-day cycle) in 479 SCLC patients (381 with PS 0/1 and 98 with PS 2). A total of 1,874 courses were administered, including 1,533 in patients with a PS 0/1 and 341 in patients with PS 2.

"Treatment of performance status 2 patients has been discussed a lot at this meeting, and this is one of the first times I have seen an analysis broken down by performance status. Patients you see in actual practice are very likely to be performance status 2 and not the good-performance patients you see in the clinical trials," noted co-investigator Jeremy Levin, MD.

Topotecan was well tolerated in both patient groups. With the exception of grade 3 or 4 anemia, grade 3 or 4 hematological toxicities were no higher in the PS 2 patients. Hematologic toxicity was non-cumulative and reversible. The most common non-hematologic toxicities were dyspnea, asthenia, nausea and vomiting, the incidence was similar for poor- and good-PS groups. In one of the individual studies, topotecan-treated patients with PS 2 achieved significantly greater improvements in fatigue and interference with daily activity, compared with patients receiving CAV, Dr. Treat reported.

The antitumor activity was also comparable for patients with poor- or good-PS. PS 2 patients had an overall response rate of 17%, compared with 13% for PS 0/1 patients.

Dr. Levin said the findings provide support for extending chemotherapy to patients who are often judged unsuitable. "A lot of patients in this setting have compromised performance status. Oncologists often question whether they should be treated, or treated with a lesser dose. Obviously attenuating the dose will diminish efficacy. We showed that topotecan at 1.5 mg/m² daily for 5 days can be given safely and effectively in these patients," stated Dr. Levin.

In an interview, Corey Langer, MD, Professor of Medicine at Fox Chase Cancer Center, Philadelphia, Pennsylvania, who has conducted a number of studies in elderly and poor-PS patients, commented on the value of evaluating PS 2 patients separately from PS 0/1. "Oncologists should not automatically apply data that are generated in performance status 0/1 patients to their performance status 2 patients, but data that comes from performance status 2 patients can be extrapolated [for use in the clinical setting]," stated Dr. Langer.

Dr. Langer added, "Performance status is probably the most critical prognostic factor and it determines tolerance as well. Unfortunately, many people are of the mindset that performance status 2 patients should not receive chemotherapy," but recent clinical trials, including an abstract presented by Dr. Langer at this meeting¹³ show that patients who are traditionally considered unsuitable can respond to and tolerate combination therapy. "If you use caution and monitor patients carefully, they can receive treatment," stated Dr. Langer.

Benefits Emerging for Weekly Topotecan

While approximately 20% of patients with SCLC have an objective response to topotecan on the 1.5 mg/m² daily for 5 days schedule, 70% will also experience grade 3 or 4 neutropenia. The myelosuppression associated with the 5-day schedule can preclude topotecan's full-dose administration in patients with poor-PS or associated co-morbidities, as well as its use in combination with other cytotoxic agents. Recent in vitro data demonstrated that a single dose of topotecan can substantially inhibit topoisomerase I for 4 to 6 days. Additionally, clinical studies in ovarian cancer patients have shown comparable outcomes to those achieved with standard administration of the drug.¹⁴ With these studies as the foundation, weekly topotecan is being explored in the second-line SCLC setting with good results, according to John Eckardt, MD, Director of the Clinical Research Program, The Center for Cancer Care and Research, St. Louis, Missouri.15

"Topotecan works in lung cancer, but it can be accompanied by significant myelosuppression," Dr. Eckardt said. "What we want is a better dosing schedule that produces high response rates and less toxicity, and is more convenient and can be combined with other agents."

Preclinical Rationale for Weekly Dosing

Topotecan is an S-phase-specific drug, which supports repeated dosing schedules. "Preclinical studies of topotecan have demonstrated activity on an every-fourth day or even every-seventh day schedule. Topoisomerase I remains suppressed for up to 7 days after a single dose of a topoisomerase inhibitor", stated Dr. Eckardt.

"When you give a dose of topotecan, you can see that within twelve hours the target topoisomerase levels are suppressed, and it can take six days to bring them back to baseline levels," Dr. Eckardt noted, citing a study by Bence et al¹⁶ that showed downregulation of topoisomerase I is transient and reversible, with levels returning to near baseline 6 days after drug removal.

Further support came from an older study of intermittent dosing in a murine tumor model.¹⁷ Subcutaneous topotecan given weekly x 2 was curative in "virtually" all mice with Lewis lung carcinoma receiving the maximum tolerated dose, which was comparable to the effect of topotecan by other schedules: intravenous topotecan on Days 1, 5, and 9 produced 90% tumor volume reduction on Day 13, and intraperitoneal topotecan on Days 2 and 6 was associated with a 183% increase in lifespan of mice implanted with L1210 lymphocytic leukemia.

Three schedules of weekly topotecan have been evaluated: a weekly 24-hour continuous infusion, a weekly 72-hour continuous infusion, and a weekly bolus schedule. The 24-hour infusion schedule produced somewhat disappointing results,¹⁸ however, in a study by Rose et al,¹⁹ a 72-hour weekly infusion was used providing longer exposure. This study found a 9% response rate and 27% rate of stable disease, with low toxicity: 13% grade 3 neutropenia, 17% grade 3 anemia, and 9% grade 3 thrombocytopenia.

"These rates were much lower than we were used to seeing with topotecan, and the response rates were not far from our expectations for this setting, however, wearing a pump for 3 days was difficult for the patients," Dr. Eckardt said. The next approach, therefore, was weekly bolus, which has produced encouraging results.

"Because of the convenience and potential to combine with other weekly agents, the weekly bolus schedule has gained a lot of favor," Dr. Eckardt told listeners. "There is a lot of enthusiasm about this approach."

In the phase I study by Homesley et al²⁰ in relapsed ovarian cancer, weekly bolus topotecan in doses at least 2 mg/m² yielded 4 responses in 32 patients, and 6 patients had stable disease. In a dose escalation trial by Tan et al²¹ involving 48 heavily pretreated patients with advanced malignancies, topotecan given at 3 mg/m² as a 30-minute bolus intravenous infusion was well tolerated.

These initial results led to the refinement of topotecan 4 mg/m² weekly by 30-minute infusion, and at The American Society of Clinical Oncology (ASCO) 2003 meeting, Morris et al¹⁴ reported very encouraging outcomes and minimal toxicity in their phase II study of sensitive relapsed ovarian cancer patients. Their study included 28 patients to date (25 evaluable) who received a total of 430 weekly treatments (82% on schedule). Overall response was 28% and stable disease was demonstrated by 52% of patients. The progression-free interval was 23 weeks, rising to 32 weeks for responders.

Remarkably, grade 3/4 hematologic toxicity was rare: neutropenia occurred in only 1.4% of treatments, anemia in 1%, and thrombocytopenia in 1.6%. Severe diarrhea and fatigue was equally uncommon.

"This study provided definitive evidence of clinical activity on the weekly schedule, and a significant change in the toxicity profile of topotecan," Dr. Eckhardt said.

While Morris et al gave topotecan weekly without a break, Dr. Eckhardt believes treating 3 weeks out of 4 provides the same efficacy with less occurrence of fatigue.

Weekly Topotecan in SCLC

Based on the preclinical rationale and the encouraging results in relapsed ovarian cancer, weekly topotecan is being evaluated in SCLC. A report by Anthony Greco, MD, Oncology and Internal Medicine Physician, Tennessee Oncology; Clinical Researcher and Director of Sarah Cannon Cancer Center, Co-director, Minnie Pearl Research Network, Nashville, Tennessee, presented at this meeting provided the first results of this approach.²²

The study evaluated topotecan 4.0 mg/m² via 30-minute intravenous infusion given weekly as second-line therapy to 29 patients with sensitive-relapsed or refractory-relapsed SCLC. Only 17 patients to date were evaluable for response (having 3 or more weekly treatments). Of the 11 patients with sensitive-relapsed disease, one had a partial response (9%) and two had stable disease (18%). In the refractory group, one patient (17%) had stable disease. The drug was well tolerated, with the incidence of grade 3/4 fatigue being only 10% and grade 3/4 myelosuppression occurring in only 14 to 17%.

"This trial is still too early to give an estimate of response as secondary therapy in small cell lung cancer," Dr. Greco noted.

Weekly Topotecan in Combination

The better therapeutic ratio seen with weekly topotecan has prompted investigations of weekly combination treatment in ovarian cancer and SCLC. In a phase II study from the Southern Italy Cooperative Oncology Group²³ of 37 chemonaпve extensive-disease SCLC patients, an overall response rate of 81% was achieved with a weekly regimen of cisplatin, paclitaxel and topotecan (2.25 mg/m²), including a 22% complete response rate. Median overall survival was 12.5 months, 1-year projected survival was 55%, and 2-year projected survival was 21%. Despite combining three agents, the hematologic toxicity was quite low.

In extensive-stage NSCLC, several phase I studies have examined front-line topotecan in combination with gemcitabine. Guarino et al²⁴ achieved a 39% response rate and 1-year survival of 33% with topotecan, gemcitabine, and cisplatin.

"These are very good data, and they show that it is feasible to combine weekly topotecan with other agents," Dr. Eckardt commented.

Citing studies of topotecan combinations in ovarian cancer as well, in which topotecan has been combined with cisplatin, paclitaxel, carboplatin and oxaliplatin, Dr. Eckardt added, "We are definitely seeing the activity of this weekly combination."

Phase I studies in SCLC are evaluating regimens of weekly topotecan 2.5 mg/m² in combination with cisplatin 30 mg/m², carboplatin AUC 2, or oxaliplatin 40 mg/m² weekly x 3 every 28 days (giving a 1-week break), and topotecan 2.5 mg/m² in combination with temozolamide 50 mg/m² daily for 21 days.

Commenting on combination options, Dr. Stewart added, "If, like irinotecan, ongoing randomized studies show topotecan to be superior to etoposide when combined with cisplatin in the front-line therapy of small cell lung cancer, topotecan might well become the preferred topoisomerase I inhibitor in this setting, since it is easier to use and less toxic than irinotecan."

Oral Topotecan

A new oral formulation of topotecan can preserve efficacy and meet the patients' needs for convenience, said Richard J. Gralla, MD, of the New York Lung Cancer Alliance, who described the emerging use of this agent in lung cancer.⁷

"Use of oral topotecan instead of intravenous topotecan effectively addresses several patient-expressed chemotherapy concerns. It greatly decreases venipuncture, time spent at the clinic, and family time off work, and positively influences several dimensions of quality of life," stated Dr. Gralla.

In a study by Liu et al,²⁵ 89% of oncology patients said they would prefer an oral agent if it provided equal survival and response as an intravenous agent. Women primarily cited the desire to eliminate venipuncture, while men stated convenience as the primary concern.

While there were problems with absorption with the oral versions of older agents, including etoposide and methotrexate, the new oral drugs—topotecan, capecitabine, and vinorelbine—have good bioavailability, Dr. Gralla indicated. "These are all reliable," noted Dr. Gralla.

At this meeting, Dr. Gralla presented the results of an international phase III study⁷ that assessed quality of life with single-agent oral topotecan versus intravenous topotecan in patients with SCLC. The study randomized SCLC patients to topotecan 2.3 mg/m²/day orally or 1.5 mg/m²/day intravenously for 5 consecutive days on a 21-day cycle. Quality of life was measured by the Functional Assessment of Cancer Therapy—Lung (FACT-L) questionnaire at baseline and prior to each course of therapy.

The overall response rates for oral and intravenous topotecan were 18.3% and 21.9%, respectively, and survival curves were similar. Both treatment arms were generally well-tolerated. There were no significant differences between treatment groups in change from baseline in total FACT-L scores or any individual FACT-L dimension; symptom scores were also similar.

"Single-agent oral topotecan or intravenous topotecan in small cell lung cancer both offer similar efficacy and provide oncologists and patients with convenient treatment alternatives," Dr. Gralla concluded. He said that while oral drugs are more convenient, this alone is not enough to represent changes on quality of life scales. The benefits seen with the oral form generally do not affect the symptoms of the disease to a greater extent than does the intravenous form, though there were significant benefits in the social domain of the phase III study, explained Dr. Gralla.

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