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Recent Advances with Topotecan in the Treatment of Lung Cancer
Mary O'Brien, John Eckardt and Rodryg Ramlau
Oncologist 2007;12;1194-1204
DOI: 10.1634/theoncologist.12-10-1194

This information is current as of October 28, 2007

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 The
Oncologist ®

Lung Cancer
Recent Advances with Topotecan in the Treatment of Lung Cancer
MARY O’BRIEN,a JOHN ECKARDT,b RODRYG RAMLAUc
a
Royal Marsden Hospital, Surrey, United Kingdom; bThe Center for Cancer Care and Research, St. Louis,
Missouri, USA; cRegional Lung Disease Centre, Oncology Department, Poznan, Poland
Key Words. Lung cancer • Topotecan oral • Chemotherapy

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Disclosure: M.O’B. has acted as a consultant to Schering-Plough, Roche, and GlaxoSmithKline. J.E. has a financial interest in
Aventis and GlaxoSmithKline. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff
managers of this article.

LEARNING OBJECTIVES
After completing this course, the reader will be able to:
1. Describe phase I studies evaluating the pharmacokinetics and early safety data of single-agent oral topotecan.
2. Discuss the results and implications of clinical trials evaluating oral topotecan for small cell lung cancer (SCLC)
and non-small cell lung cancer (NSCLC).
3. Explain why topotecan is a good candidate for combination with other novel anticancer agents.
CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com

ABSTRACT
Topotecan is a semisynthetic derivative of camptothecin onstrated the activity of oral topotecan. In the first
that specifically targets topoisomerase I. It has well-estab- study of chemotherapy-naı̈ve patients with extensive-
lished antineoplastic properties and has been successfully disease SCLC, oral topotecan plus cisplatin provided ef-
combined with other antineoplastic agents with activity ficacy and safety similar to those of etoposide plus
dependent on DNA disruption, such as cisplatin and eto- cisplatin. In a second study of patients with relapsed
poside. Topotecan is indicated for the treatment of small SCLC, treatment with oral topotecan showed a statisti-
cell lung cancer (SCLC) sensitive disease after failure of cally significant and clinically meaningful longer overall
first-line chemotherapy and metastatic ovarian carcinoma survival time and improvement in dyspnea and quality
after failure of initial or subsequent chemotherapy. Since of life compared with best supportive care alone in all
the approval of topotecan for the second-line treatment of prognostic groups. Finally, in previously treated pa-
SCLC, studies have been conducted in the first-line set- tients with NSCLC, single-agent oral topotecan was
ting. Recent studies demonstrate the utility of i.v. topote- shown to be noninferior in 1-year survival rate relative
can in combination with cisplatin for untreated SCLC. to the current standard of i.v. docetaxel. In future stud-
Further, an oral formulation of topotecan is currently un- ies, oral topotecan will represent a good candidate for
der investigation and may provide added convenience for combination therapy with other i.v. or oral chemother-
patients. Oral topotecan has been studied in the first- and apy agents, monoclonal antibodies, and small molecule
second-line settings for both SCLC and non-small cell lung tyrosine kinase inhibitors. The Oncologist 2007;12:
cancer (NSCLC). Three recent phase III trials have dem- 1194 –1204

Correspondence: Mary O’Brien, M.D., FRCP, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM25JS, United Kingdom. Tele-
phone: 00442086613278; Fax: 00442086437371; e-mail: mary.o’brien@rmh.nhs.uk Received May 14, 2007; accepted for publication
August 1, 2007. ©AlphaMed Press 1083-7159/2007/$30.00/0 doi: 10.1634/theoncologist.12-10-1194

The Oncologist 2007;12:1194 –1204 www.TheOncologist.com

O’Brien, Eckardt, Ramlau 1195

INTRODUCTION settings for both SCLC and NSCLC. This paper reviews the
Lung cancer is a significant global health issue, being both role of topotecan in the treatment of lung cancer, focusing
the most commonly diagnosed cancer and the most com- on recent data with i.v. topotecan in first-line SCLC and the
mon cause of cancer-related death worldwide. Globally, new oral formulation in both SCLC and NSCLC.
lung cancer accounts for an estimated 1.4 million cancer
cases and 1.2 million deaths each year [1]. Similar inci- I.V. TOPOTECAN FOR UNTREATED SCLC
dence and mortality rates are seen in developed and devel- Median survival times from studies evaluating conven-
oping nations. The highest incidence rates occur for men in tional cisplatin plus etoposide regimens as first-line treat-
Eastern Europe and North America and for women in North ment for patients with extensive-disease (ED)-SCLC are
America and Northern Europe [1]. In the U.S., small cell approximately 9 –10 months [10 –13]. Results from studies
lung cancer (SCLC) accounts for approximately 15% of discussed below suggest that using topotecan in combina-
lung cancer cases [2]. tion regimens in this setting is an effective and well-toler-
Although surgery and radiation play integral roles in ated option.
lung cancer management, chemotherapy is the mainstay of Recent studies evaluating topotecan in first-line SCLC
treatment for SCLC and is increasingly being used in non- have primarily examined its use in combination with either

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small cell lung cancer (NSCLC). Platinum-based regimens cisplatin or etoposide. Results of a phase II study in 36 pa-
are the standard first-line strategy in both settings for either tients with limited or extensive disease suggested that se-
early-stage or advanced disease. The agents used as second- quential administration of i.v. topotecan (0.75 mg/m2 daily
line therapy vary by setting [2, 3]. for 5 days) and oral etoposide (50 mg twice daily for 7 days)
Topotecan, a semisynthetic derivative of camptothecin, as 21-day cycles is effective for SCLC [14]. The median
is a topoisomerase I inhibitor with well-established antineo- progression-free survival duration was 7.3 months and the
plastic properties. In the mid-1990s, i.v. single-agent topo- median survival time was 12.0 months. The incidences of
tecan was shown to have activity against relapsed ovarian grade 3 or 4 neutropenia and thrombocytopenia were 25%
cancer [4] and SCLC [5]. This activity led to approval by and 11%, respectively; two patients died from neutropenic
the U.S. Food and Drug Administration (FDA) of single- sepsis.
agent topotecan for the treatment of metastatic ovarian car- The topotecan– etoposide combination was compared
cinoma after failure of initial or subsequent chemotherapy, with a topotecan– cisplatin combination, with results sug-
and for the treatment of SCLC sensitive disease after failure gesting similar efficacy [15]. In that randomized phase II
of first-line chemotherapy. Most recently, topotecan, in study, 82 patients with previously untreated ED-SCLC re-
combination with cisplatin, was approved for use in stage ceived either i.v. topotecan (1.25 mg/m2 per day) on days
IV-B recurrent or persistent cervical cancer [6]. The princi- 1–5 plus cisplatin (50 mg/m2) on day 5 or i.v. topotecan
pal dose-limiting toxicity of i.v. topotecan is myelosuppres- (0.75 mg/m2 per day) on days 1–5 plus i.v. etoposide (60
sion, which is short lived, noncumulative, and reversible; mg/m2 per day) on days 1–5. Response rates and median
nonhematologic toxicities are manageable [5]. For SCLC survival times were similar in the two groups (63.4% versus
and ovarian cancer, the approved dose of i.v. topotecan is 61.0% and 9.6 months versus 10.1 months, respectively).
1.5 mg/m2 given as a 30-minute i.v. infusion, daily for five Hematologic toxicities in the topotecan– cisplatin arm ver-
consecutive days, every 21 days. However, multiple trials sus the topotecan– etoposide arm, respectively, were grade
have evaluated alternative doses and schedules, including 3 or 4 anemia (46.4% versus 20.0%) and grade 4 neutrope-
lower starting doses of 1.25 or 1.0 mg/m2 given for 5 days, nia (56.1% versus 65.0%). The incidence of sepsis was 0%
3-day schedules, and weekly bolus schedules [7–9]. i.v. to- with topotecan plus cisplatin versus 9.8% with topotecan
potecan has been used as a single agent and in combination plus etoposide. Secondary to the significant myelosuppres-
regimens for the treatment of various tumor types. Topo- sion of the topotecan– cisplatin combination, investigators
tecan is currently recommended by the National Compre- have studied shorter schedules of topotecan in combination
hensive Cancer Network as the first choice in treating with cisplatin [7, 16, 17], including a 3-day administration
chemotherapy-sensitive SCLC, specifically for disease that schedule of topotecan that appears to be comparable with
has relapsed within 2– 6 months after primary treatment [2]. the standard 5-day schedule [7]. A randomized phase II
Since the approval of topotecan for use in relapsed study in 86 patients with ED-SCLC compared a 1.0-mg/m2
SCLC, various studies have been conducted in the first-line dose of topotecan on days 1–5 with a 1.5-mg/m2 dose on
setting. An oral formulation of topotecan has been investi- days 1–3, each with cisplatin (75 mg/m2) on the last day of
gated and provided added convenience for patients. Oral to- topotecan treatment. While the efficacies were similar, the
potecan has been studied in the first- and second-line 3-day regimen may offer a more tolerable option. The me-

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1196 Topotecan in Lung Cancer Treatment

dian survival times in the 5- and 3-day arms were 8.7 pare a basis for further investigation of topotecan as a po-
months and 7.6 months, respectively. There was no signif- tential new agent in the treatment of this disease.
icant difference in overall survival (p ⫽ .68), and response
rates were 62% and 60%, respectively. Grade 3 or 4 toxic- DEVELOPMENT OF ORAL TOPOTECAN
ities in the 5- and 3-day arms, respectively, included leuko- An oral version of topotecan was developed to improve
cytopenia (64% versus 48%), anemia (43% versus 21%), convenience and accessibility for patients. Indeed, many
and thrombocytopenia (52% versus 40%). patients prefer oral chemotherapy. A 1997 survey of 103
Topotecan has been evaluated in a consolidation ap- patients with incurable cancer showed that, given a choice
proach to untreated SCLC. A randomized phase III trial by of agents with similar efficacy, most patients would prefer
the Eastern Cooperative Oncology Group (ECOG) evalu- oral agents over i.v. chemotherapy [20]. Reasons for this
ated topotecan following cisplatin plus etoposide in patients preference include convenience, problems with i.v. access
with previously untreated ED-SCLC [18]. Four cycles of or needles, having control over the environment for taking
cisplatin plus etoposide were given to 402 patients; those chemotherapy, and the need for travel to receive i.v. che-
with response or stable disease were then randomized to ei- motherapy. Compliance with oral topotecan in clinical tri-
ther continue chemotherapy with topotecan (1.5 mg/m2) als, to the extent that this can be evaluated by pill counts,

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daily for 5 days every 3 weeks for four cycles (n ⫽ 112) or has been high. In a retrospective analysis of compliance
proceed to observation alone (n ⫽ 111). The progression- data from three randomized phase III trials of oral topotecan
free survival interval was significantly longer in the topo- in lung cancer, compliance according to pill counts was in
tecan arm (median, 3.7 months with topotecan versus 2.3 the range of 90.8%–98.6% [21].
months with observation alone; p ⬍ .001). The overall sur- Quality of life is an important issue for patients with
vival duration was not significantly different between the lung cancer. In another survey of patients with advanced
two groups (median, 9.3 months with topotecan versus 8.9 NSCLC, given the choice between supportive care and che-
months with observation; p ⫽ .43). Administration of topo- motherapy, only 22% selected chemotherapy if it provided
tecan did not worsen quality of life; no significant differ- a survival benefit of 3 months, whereas 68% chose chemo-
ences occurred in Trial Outcome Index or Functional therapy if it substantially reduced symptoms without pro-
Assessment of Cancer Therapy–Lung scores. longing survival [22]. Advantages of oral agents include
Finally, a phase III trial comparing two different sched- eliminating the need for i.v. lines that cause discomfort and
ules of the cisplatin– etoposide–topotecan combination has possibly lead to infections, the potential for fewer side ef-
been completed [19]. The study employed either sequential fects than the injectable counterparts, and perhaps easier in-
administration— cisplatin (75 mg/m2) on day 1 and etopo- tegration into combination regimens.
side (100 mg/m2 per day) on days 1–3 for four cycles fol- Phase I studies evaluating the pharmacokinetics and
lowed by topotecan (1.5 mg/m2 per day) on days 1–5 for early safety data of single-agent oral topotecan have been
four cycles— or alternating administration of the same completed (Table 1) [23–31]. Single-dose studies deter-
doses of i.v. cisplatin and etoposide (cycles 1, 3, 5, and 7) mined that the absolute bioavailability of the oral formula-
and topotecan (cycles 2, 4, 6, and 8) in 284 chemotherapy- tion is 30%– 44% [23–25] and is not affected by food intake
naı̈ve patients with ED-SCLC. The preliminary analysis in- [23]. A multiple-dose study found that approximately 57%
dicated comparable activity and safety in the two of the oral dose is eliminated unchanged in the urine and
comparison groups, with no significant differences be- feces [26]. A population pharmacokinetic analysis revealed
tween groups in response, overall survival, time to progres- that renal creatinine clearance and, to a limited extent, per-
sion (TTP), or response duration. For the sequential versus formance status (PS) are factors that significantly affect
alternating groups, the overall response rates were 53% ver- oral topotecan clearance [27].
sus 55%; the median survival times were 10.2 versus 9.5 In multiple-dose phase I studies, several dosing sched-
months; the median TTP were 6.0 versus 6.8 months; and ules of single-agent topotecan were examined for toxicity
the median response durations were 5.5 versus 5.2 months, and pharmacokinetics. Together these studies suggested the
respectively. Grade 3 or 4 hematologic toxicities were neu- following recommended dosing schema: 14 mg/m2 on day
tropenia (51% and 52%), anemia (12% and 11%), febrile 1 every 21 days [25], 0.5 mg/m2 twice daily for 21 days
neutropenia (7% and 9%), and thrombocytopenia (19% and every 28 days [28], 2.3 mg/m2 per day or 4 mg/day for 5
20%). There were seven toxicity-related deaths (four in the days every 21 days [29], and 1.4 mg/m2 per day or 0.7
sequential arm and three in the alternating arm). Taken to- mg/m2 twice daily for 10 days every 21 days [30]. The dose-
gether, these studies add useful information about the use of limiting toxicity was diarrhea with the longer schedule
i.v. topotecan in the first-line treatment of SCLC and pre- (dosing for 21 days) versus hematologic toxicity (granulo-
O’Brien, Eckardt, Ramlau 1197

Table 1. Phase I studies with single-agent oral topotecan

Study n Design Topotecan dose and route Results
Bioavailability and excretion
Herben et al. (1999) [23] 18 Randomized, Period 1: oral, 2.3 mg/m2 with or Food does not affect extent
two-period without high-fat breakfast; period of absorption; mean F,
crossover, 2: oral capsules, 2.3 mg/m2 or i.v. 42% ⫾ 13%; 90% CI,
single-dose 1.4 mg/m2 37%–47%
Schellens et al. (1996) [24] 12 Crossover, Oral solution, 1.5 mg/m2 day 1, Mean F, 30% ⫾ 7.7%;
single-dose then i.v. 1.5 mg/m2 day 1 range, 21%–45%
Kuhn et al. (1995) [25] 11 Randomized, Oral solution, 14 mg/m2 or i.v. Mean F, 44%
single-dose 17.5 mg/m2
Herben et al. (2002) [26] 9 Randomized, Oral, 2.3 mg/m2 or i.v. 1.5 mg/m2, Percent unchanged in urine
crossover, each daily ⫻ 5 days and feces, 20% and 33%
multiple-dose oral, 49% and 18% i.v.
Leger et al. (2004) [27] 190 Retrospective data i.v. (n ⫽ 72) or oral (n ⫽ 118) CrCl and PS are significant
collection; population covariates affecting

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model (NONMEM) clearance
Dosing studiesa
Creemers et al. (1997) [28] 31 Prospective, 0.15–0.6 mg/m2 b.i.d. ⫻ 21 days DLT, diarrhea; MTD, 0.5
multiple-dose every 28 days mg/m2 b.i.d. ⫻ 21 days
every 28 days
Gerrits et al. (1998) [29] 29 Prospective, 1.2–2.7 mg/m2 or 4 mg daily ⫻ 5 DLT, granulocytopenia;
multiple-dose days every 21 days MTD, 2.3 mg/m2 or 4 mg
daily ⫻ 5 days every 21
days
Gerrits et al. (1998) [30] 39 Prospective, 1.0–1.6 mg/m2 daily ⫻ 10 days DLT, myelosuppression
multiple-dose every 21 days or 0.5–0.8 mg/m2 and diarrhea; MTD, 1.4
b.i.d. ⫻ 10 days every 21 days mg/m2 daily or 0.7 mg/m2
b.i.d. ⫻ 10 days every 21
days
Gerrits et al. (1999) [31] – Pharmacokinetic Daily ⫻ 5 days every 21 days (n ⫽ 5-day schedule preferred
evaluation of three 29); daily ⫻ 10 days every 21 days for future clinical trials
studies above (n ⫽ 19); b.i.d. ⫻ 10 days every 21 based on toxicity and
days (n ⫽ 20); b.i.d. ⫻ 21 days pharmacokinetic
every 28 days (n ⫽ 31) evaluation
aAlloral topotecan.
Abbreviations, b.i.d., twice daily; CI, confidence interval; CrCl, creatinine clearance; DLT, dose-limiting toxicity; F,
bioavailability; MTD, maximum-tolerated dose; NONMEM, nonlinear mixed-effects model; PS, performance status.

cytopenia) with the shorter schedule (dosing for 1 or 5 bination with other chemotherapeutic agents have identi-
days). Both diarrhea and granulocytopenia occurred with fied the maximum-tolerated dose of oral topotecan with
the 10-day schedules. These toxicities were self-limiting cisplatin, capecitabine, and carboplatin plus paclitaxel [32–
and noncumulative. Finally, a pharmacokinetic and phar- 35]. In a randomized, crossover design, 49 patients received
macodynamic comparison of the four different multiday oral topotecan at escalating doses daily for 5 days every 21
schedules using data from the patients in these studies days with i.v. cisplatin (75 mg/m2) on either day 1 or day 5
found that (a) the area under the concentration–time curve of topotecan [32]. Consistent with previously reported data
(AUC) per week and AUC per course were not significantly with i.v. topotecan and cisplatin [36], myelotoxicity was
different among the schedules, (b) the 5-day schedule had significantly more severe when cisplatin preceded topo-
the least inter- and intrapatient variability, and (c) the 10- tecan. As such, the recommended maximum-tolerated dose
and 21-day schedules were associated with unpredictable, of oral topotecan is lower in the cisplatin–topotecan se-
and sometimes severe, diarrhea [31]. Thus, the 5-day quence—topotecan (1.25 mg/m2 per day) for 5 days pre-
schedule (2.3 mg/m2 per day or 4 mg/day for 5 days every ceded by cisplatin (75 mg/m2) on day 1 once every 3 weeks
21 days) was recommended as the preferred regimen for fu- versus topotecan (2.0 mg/m2 per day) for 5 days followed
ture clinical trials [31]. by cisplatin (75 mg/m2) on day 5. Evaluation of an all-oral
Phase I trials that evaluated oral topotecan given in com- combination of topotecan and capecitabine in 19 patients

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1198 Topotecan in Lung Cancer Treatment

led to a recommended regimen of topotecan (1.5 mg/m2 per between arms (p ⫽ .48). The hazard ratio adjusted for in-
day) for 5 days on days 1–5 of each week for 2 weeks and terim analyses was 1.05 (95% confidence interval [CI],
capecitabine (1,800 mg/m2 twice daily) on days 1–14 of a 0.90 –1.24). The median survival times were 39.3 weeks
21-day cycle in future trials [34]. A study of 13 patients re- with TC versus 40.3 weeks with PE. The 1-year survival
ceiving escalating doses of topotecan on days 1–5 in com- rates were similar between TC and PE (31% in both
bination with paclitaxel (175 mg/m2) and carboplatin groups). The 95% CI for the coprimary endpoint of differ-
(AUC, 5) on day 1 found significant myelotoxicity at all ence in the 1-year survival rate between TC and PE was
dose levels of topotecan (0.75, 1.0, and 1.25 mg/m2), and ⫺6.5 to 6.5, indicating that TC was not inferior to PE in
the authors could not recommend any of the doses for fur- 1-year survival rate based on a 10% noninferiority margin.
ther study [33]. However, a subsequent phase I–II study in The median TTP for TC and PE were 24.1 weeks and 25.1
patients with ovarian cancer administered the triplet in a weeks, respectively. Response rates were 63% with TC and
“reverse schedule,” with the same doses of paclitaxel plus 69% with PE. Of grade 3 or 4 hematologic toxicities, neu-
carboplatin on day 5 of oral topotecan dosing (rather than tropenia occurred more frequently with PE (84% versus
day 1) [35]. In the phase I portion, a topotecan dose of 2.0 59%), while anemia and thrombocytopenia occurred more
mg/m2 for 5 days was reached; however, in the phase II por- frequently with TC (38% versus 21% and 38% versus 23%,

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tion, a dose reduction to 1.75 mg/m2 was required after the respectively). Fever and infection occurring within 2 days
first course as a result of febrile neutropenia. The triplet was of grade 4 neutropenia was observed in 10% of patients on
well tolerated after the dose reduction. PE versus 4% on TC. Differences between arms were ob-
served for nonhematologic toxicities. Patients on TC had a
ORAL TOPOTECAN IN SCLC higher incidence of diarrhea (33% for TC versus 18% for
Phase II and III studies have been conducted with oral to- PE), but a lower incidence of serum creatinine elevations
potecan in the first- and second-line treatment of SCLC (12% for PE versus 5% for TC) and alopecia (40% for PE
(Table 2) [10, 37– 40]. Of particular note are two recent ran- versus 24% for TC). Overall, this phase III study demon-
domized phase III trials that demonstrate the activity of oral strated similar efficacy and tolerability between oral topo-
topotecan both in a combination regimen as first-line treat- tecan plus cisplatin and the standard etoposide– cisplatin
ment and as monotherapy in the second-line treatment of combination as first-line treatment for patients with ED-
patients with SCLC [10, 40]. SCLC.

First-Line Oral Topotecan in SCLC SECOND-LINE ORAL TOPOTECAN IN SCLC

A phase II feasibility study examined oral topotecan as The rationale for evaluating oral topotecan in relapsed
first-line monotherapy in 41 patients with ED-SCLC who SCLC is based on the efficacy of the i.v. formulation in this
were ineligible for standard therapy (because of factors setting. Intravenous topotecan is the only single agent ap-
such as age or concomitant illness; 88% with PS scores of proved for second-line SCLC and is currently the agent of
1–2) [39]. Patients initially received 2.0 mg/m2 per day for choice for treatment of patients with SCLC that has re-
5 days every 3 weeks, but the dose level was reduced to 1.7 lapsed within 2– 6 months after completing first-line che-
mg/m2 per day as a result of myelosuppression. The overall motherapy [2]. This recommendation is supported by data
response rate was 30%, including one complete response. from a randomized trial in which i.v. topotecan was com-
The incidence of grade 3 or 4 neutropenia was 72% at the pared with cyclophosphamide, doxorubicin, and vincristine
2.0-mg/m2 dose and 57% at the 1.7-mg/m2 dose. These data (CAV) in 211 patients with relapsed SCLC considered sen-
suggest that oral topotecan is active in this setting. sitive to chemotherapy (defined in this trial as relapse ⱖ60
days after the end of chemotherapy) [41]. The primary end-
Phase III Trial point of difference in response rate between topotecan and
In a subsequent randomized, phase III trial, the combination CAV was 6.0% in favor of topotecan, with a 95% CI of
of oral topotecan and cisplatin was compared with the stan- ⫺5.9 to 18, indicating that, at the lower limit of the CI, to-
dard etoposide– cisplatin regimen in previously untreated potecan may be inferior to CAV by at most 5.9%. No sig-
patients with ED-SCLC [10]. Treatment consisted of oral nificant differences between i.v. topotecan and CAV were
topotecan (1.7 mg/m2 per day) for 5 days with i.v. cisplatin observed in the response rate (24.3% versus 18.3%), TTP
(60 mg/m2) on day 5 (TC, n ⫽ 389) or i.v. etoposide (100 (median, 13.3 versus 12.3 weeks; p ⫽ .552), or overall sur-
mg/m2 per day) for 3 days with i.v. cisplatin (80 mg/m2) on vival time (median, 25.0 versus 24.7 weeks; p ⫽ .795).
day 1 (PE, n ⫽ 395) every 21 days. The primary endpoint of However, several disease-related symptoms (dyspnea, fa-
the study, overall survival, was not significantly different tigue, anorexia, hoarseness, and interference with daily ac-
 Table 2. Clinical studies with oral topotecan in small cell lung cancer
Survival and Grade 3 or 4 hematologic
Study n Treatment Response rates progression toxicity
O’Brien, Eckardt, Ramlau

First-line treatment

www.TheOncologist.com
Eckardt (2001) [39], phase II 41 Oral topotecan, 1.7–2.0 mg/m2 ORR, 30%; CR, 3%; PR, 27%; NA N, 57%–72%; A, 32%–29%;
per day ⫻ 5 days every 21 SD, NA; CBR, NA T, 52%–36%
days (preliminary analysis)
Eckardt et al. (2006) [10], phase III 389 Oral topotecan, 1.7 mg/m2 per ORR, 63%; CR, 6%; PR, 57%; MST, 39.3 wks; 1-yr, N, 59%; A, 38%; T, 83%
day ⫻ 5 days, with i.v. SD, 10%; CBR, 73% 31%; TTP, 24.1 wks
cisplatin, 60 mg/m2 on day 5
every 21 days
395 i.v. etoposide, 100 mg/m2 per ORR, 69%; CR, 5%; PR, 64%; MST, 40.3 wks; 1-yr, N, 84%; A, 21%; T, 23%
day ⫻ 3 days, with i.v. SD, 12%; CBR, 81% 31%; TTP, 25.1 wksa
cisplatin, 80 mg/m2 on day 1
every 21 days
Second-line treatment
von Pawel et al. (2001) [37], 52 Oral topotecan, 2.3 mg/m2 per ORR, 23%; CR, 2%; PR, 21%; MST, 32 wks; TTP, N, 57%; A, 31%; T, 53%
phase II day ⫻ 5 days every 21 days SD, 19%; CBR, 42% 14.9 wks
54 i.v. topotecan, 1.5 mg/m2 per ORR, 15%; CR, 4%; PR, 11%; MST, 25 wks; TTP, N, 94%;b A, 30%; T, 49%
day ⫻ 5 days every 21 days SD, 30%; CBR, 45% 13.1 wks
Eckardt et al. (2007) [38], phase III 153 Oral topotecan, 2.3 mg/m2 per ORR, 18%; CR, NA; PR, NA; 1-yr, 33%; MST, 33 N, 47% (grade 4); A, 23%;
day ⫻ 5 days every 21 days SD, 18%; CBR, 36% wks T, 29% (grade 4)
151 i.v. topotecan, 1.5 mg/m2 per ORR, 22%; CR, NA; PR, NA; 1-yr, 29%; MST, 35 N, 64%; (grade 4) A, 31%;
day ⫻ 5 days every 21 days SD, 23%; CBR, 45% wks T, 18% (grade 4)
O’Brien et al. (2006) [40], phase III 71 Oral topotecan, 2.3 mg/m2 per ORR, 7%; CR, 0; PR, 7%; SD, MST, 25.9 wks; N, 61%; A, 25%; T, 38%
day ⫻ 5 days every 21 days 44%; CBR, 51% TTP, 16.3 wks
with BSC
70 BSC alone NA MST, 13.9 wksc NA
ap⫽ .02 for overall TTP versus oral topotecan.
bp⫽ .001 versus oral topotecan for grade 4 neutropenia (67% for i.v. versus 35% for oral).
cp⫽ .01 for overall survival versus oral topotecan.
Abbreviations, A, anemia; BSC, best supportive care; CBR, clinical benefit rate (CR ⫹ PR ⫹ SD); CR, complete response; MST, median survival time; N, neutropenia;
NA, not available; ORR, overall response rate; PR, partial response; SD, stable disease; T, thrombocytopenia; TTP, time to progression.
1199

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1200 Topotecan in Lung Cancer Treatment

tivity) improved to a significantly greater extent with served in the oral topotecan arm (p ⫽ .01). The unadjusted
topotecan than with CAV. Some safety advantages were hazard ratio for oral topotecan relative to BSC was 0.64
observed with topotecan as well. While grade 3 or 4 throm- (95% CI, 0.45– 0.90), indicating a 36% lower risk for death
bocytopenia and anemia occurred more frequently with to- in the oral topotecan group. The median survival time was
potecan, grade 4 neutropenia occurred less frequently than 86% longer in the topotecan arm than in the BSC arm (25.9
with CAV. Additionally, fewer dose reductions for nonhe- weeks versus 13.9 weeks). The 6-month survival rates were
matologic toxicities occurred in the topotecan arm. A sub- 49% in the topotecan arm and 26% in the BSC arm. On en-
sequent study demonstrated activity with topotecan in try, patients were stratified according to the TTP since first-
patients previously treated for SCLC who relapsed with line therapy (ⱕ or ⬎60 days). Importantly, the survival
symptomatic brain metastases [42]. Of the 30 patients in the advantage for topotecan was maintained in both strata:
single-arm phase II study, eight had prior whole-brain irra- namely, patients with resistant disease (TTP ⱕ60 days) and
diation (WBI). Responses in cerebral metastases were ob- patients with sensitive disease (TTP ⬎60 days). The overall
served in 33% of patients, including four of the eight response rate to topotecan was 7%. Importantly, an addi-
patients who had undergone WBI. These data support the tional 44% experienced stable disease. As shown in Table
current role of i.v. topotecan in relapsed SCLC and the in- 2, this clinical benefit rate of 51% (representing the sum of

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vestigation of the oral formulation in this setting. the percentages of patients experiencing an objective re-
To evaluate whether oral topotecan could alternatively sponse and stable disease) is consistent with the range of
be used in chemotherapy-sensitive SCLC, i.v. and oral to- 36%– 45% observed with oral or i.v. topotecan in other
potecan were compared in a phase II trial [37] and further phase II and III clinical trials in second-line SCLC [37, 38].
explored in a phase III trial [10] (Table 2) [10, 37– 40]. In The median TTP in the topotecan arm was 16.3 weeks. Re-
these randomized studies, patients with relapsed, sensitive sponse and progression data were not collected for the BSC
SCLC (defined as relapse ⬎90 days after the end of chemo- arm. Quality of life (measured with the EuroQoL-5 Dimen-
therapy) received second-line therapy with either oral topo- sions [EQ-5D] questionnaire) deteriorated significantly
tecan (2.3 mg/m2 per day) or i.v. topotecan (1.5 mg/m2 per faster in patients receiving BSC alone. The rate of deterio-
day) for 5 days every 21 days. Efficacy parameters indi- ration per 3-month interval in EQ-5D scores was ⫺0.20
cated similar activity between the two treatments and pos- (95% CI, ⫺0.27 to ⫺0.12) on BSC compared with ⫺0.05
sibly a lower incidence of severe neutropenia with the oral (95% CI, ⫺0.11 to 0.02) on topotecan. The difference in
formulation. From the phase III trial, response rates and me- rate of change was significant (⫹0.15; 95% CI, 0.05– 0.25).
dian survival times for oral versus i.v. topotecan were Oral topotecan also significantly improved the symptom of
18.3% versus 21.9% and 33 weeks versus 35 weeks, respec- dyspnea, clinically important in this patient population.
tively [38]. The incidences of grade 4 neutropenia were This finding is consistent with the study of i.v. topotecan
47% versus 64% for the oral and i.v. formulations, respec- versus CAV, in which dyspnea was improved to a signifi-
tively. In the phase II trial, the incidences of grade 4 neu- cantly greater extent with topotecan than with CAV [41].
tropenia were 35% versus 67% for the oral and i.v. The most common toxicities related to oral topotecan were
formulations, respectively [37]. These data suggest that oral hematological (grade 3 or 4 neutropenia, 61%; grade 3 or 4
topotecan has similar efficacy to the i.v. formulation and is thrombocytopenia, 38%; grade 3 or 4 anemia, 25%). All-
a suitable alternative to the i.v. route in patients with re- cause mortality within 30 days of starting the study was not
lapsed SCLC, with the added advantage of convenient ad- higher in the topotecan group (7% for topotecan versus 13%
ministration. for BSC). The most commonly occurring nonhematologic
toxicity was diarrhea in the topotecan group (6%) and dys-
Phase III Trial: Superior Survival in Relapsed pnea in the BSC group (9%). These data suggest that treat-
Advanced SCLC Compared with Best ment with oral topotecan should be considered for all
Supportive Care patients with relapsed SCLC, including those with resistant
The phase III trial, designed to assess whether active che- disease. Until this study, the role of chemotherapy in resis-
motherapy has a role in second-line SCLC, evaluated oral tant disease was not well defined, and some evidence pre-
topotecan versus best supportive care (BSC) in patients viously suggested that chemotherapy may not be beneficial
with relapsed SCLC [40]. In this open-label study, 141 pa- in such patients [43]. This study made an important contri-
tients were randomized to receive oral topotecan (2.3 bution by being the first to show that active chemotherapy
mg/m2 per day) for 5 days every 3 weeks plus BSC or BSC can in fact prolong survival in patients with resistant SCLC
alone. A clinically and statistically significant improve- and improve quality of life in patients with relapsed SCLC.
ment in the primary endpoint of overall survival was ob- SCLC is an aggressive and fatal disease. Novel active
O’Brien, Eckardt, Ramlau 1201

Table 3. Clinical studies with oral topotecan in non-small cell lung cancer
Survival and Grade 3 or 4
Study n Treatment Response rates progression hematologic toxicity
First-line treatment
White et al. (2000) 30 Escalated oral topotecan, ORR, 0%;a SD, 43%;a MST, 39.9 wks; N, 40%; A, 17%; T,
[48], phase II 2.3–3.1 mg/m2 day ⫻ 5 CBR, 43% 1-yr, 33%; 7%
days every 21 days TTP, 12.3 wks
Eckardt (2001) [49], 41 Oral topotecan, 1.25 ORR, 12%; CR, 0; PR, NA N, 68%; A, 18%; T,
phase II mg/m2 per day ⫻ 5 days, 12%; SD, 27%; CBR, 0%
with paclitaxel, 175 mg/ 39%
m2 on day 1 every 21
days
Second-line treatment
Ramlau et al. (2006) 414 Oral topotecan, 2.3 mg/ ORR, 5%; CR, 0; PR, MST, 27.9 wks; N, 50%; A, 26%; T,
[50], phase III m2 per day ⫻ 5 days 5%; SD, 27%; CBR, 1-yr, 25.1%; 26%
every 21 days 32% TTP, 11.3 wks

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415 i.v. docetaxel, 75 mg/m2 ORR, 5%; CR, ⬍1%; MST, 30.7 wks; N, 60%; A, 10%; T,
on day 1 every 21 days PR, 4%; SD, 36%; 1-yr, 28.7%; 7%
CBR, 41% TTP, 13.1 wksb
aWorld Health Organization criteria for tumor response.
bp ⫽ .02 for overall TTP versus oral topotecan.
Abbreviations, A, anemia; CBR, clinical benefit rate (CR ⫹ PR ⫹ SD); CR, complete response; MST, median survival
time; N, neutropenia; ORR, overall response rate; PR, partial response; SD, stable disease; T, thrombocytopenia; TTP,
median time to progression.

therapies are urgently needed in all subsets of patients with administered for five consecutive days every 3 weeks for up
this disease. Taken together, the studies with oral topotecan to six cycles. No responses were observed; however, 43%
support a role for this new agent in the treatment of SCLC. of patients achieved stable disease. The median survival
time was 39.9 weeks, the 1-year survival rate was 33%, and
ORAL TOPOTECAN IN ADVANCED NSCLC the median TTP was 12.3 weeks. Grade 3 or 4 hematologic
A doublet platinum-containing chemotherapy regimen toxicities were neutropenia (40%), anemia (17%), and
(with or without bevacizumab) is considered the standard of thrombocytopenia (7%). Disease-related symptom im-
care for the first-line treatment of advanced NSCLC [3, 44]. provement was observed in some patients for all parame-
Upon progression, established second-line agents include ters, including dyspnea (17%), cough (31%), chest pain
docetaxel, pemetrexed, and erlotinib [3]. Oral topotecan (20%), and hemoptysis (33%).
has been evaluated in phase II and III trials in NSCLC (Ta- A second phase I–II trial in untreated advanced NSCLC
ble 3). Phase II trials show activity of first-line oral topo- evaluated combination therapy with oral topotecan and i.v.
tecan, and a phase III trial in the second-line setting shows paclitaxel [49]. Results from the phase I portion determined
that oral topotecan may offer a new option in this setting. that the maximum-tolerated dose of oral topotecan was 1.25
mg/m2 per day for 5 days every 3 weeks when given in com-
First-Line Oral Topotecan for Advanced NSCLC bination with paclitaxel (175 mg/m2) on day 1. A total of 41
The rationale for studying oral topotecan in the first-line patients (six from phase I and 35 from phase II) received
setting is based on data from single-agent trials supporting topotecan at the maximum-tolerated dose. Grade 3 or 4 neu-
the activity of the i.v. formulation in previously untreated tropenia and anemia occurred in 68% and 18% of patients,
advanced NSCLC. Intravenous topotecan, dosed daily for 5 respectively. Preliminary response data for 33 patients were
days every 3 weeks, produced response rates ranging up to reported: a 12% partial response rate and a 27% stable dis-
15% and median survival times of 32–38 weeks [45– 47]. ease rate.
Two phase II trials of oral topotecan have been con-
ducted in untreated patients with NSCLC. Monotherapy Second-Line Oral Topotecan for
was evaluated in 30 patients with inoperable stage III or IV Advanced NSCLC
NSCLC and an ECOG PS score of 0 (7%), 1 (70%), or 2 Recent data from a large randomized phase III trial show
(23%) [48]. The dose of oral topotecan was escalated start- that oral topotecan is not inferior to i.v. docetaxel in the
ing with 2.3 mg/m2 per day up to 3.1 mg/m2 per day and treatment of patients with relapsed or refractory NSCLC

www.TheOncologist.com
1202 Topotecan in Lung Cancer Treatment

[50]. Patients were randomized to oral topotecan (2.3 can evade targeting by topotecan by ubiquitination, leading
mg/m2 per day) for 5 days (n ⫽ 414) or a standard regimen to downregulation of topoisomerase 1 [52]. At least in vitro,
of i.v. docetaxel (75 mg/m2) on day 1 (n ⫽ 415) every 3 this process can be inhibited by proteosome inhibitors [53],
weeks. The 1-year survival rates for oral topotecan versus suggesting that combinations with bortezomib should be
docetaxel were 25.1% versus 28.7%; the 95% CI for the pri- explored. Finally, tyrosine kinase inhibitors also inhibit
mary endpoint of difference in 1-year survival rate between breast cancer resistance protein, which pumps topotecan
oral topotecan and docetaxel was ⫺9.6 to 2.5, indicating out of cancer cells [54], suggesting that combinations with
that oral topotecan was not inferior to docetaxel in 1-year tyrosine kinase inhibitors may be particularly efficacious
survival rate based on a prespecified 10% noninferiority and worthy of future evaluation.
margin. Overall survival was in favor of docetaxel (log-
rank p ⫽ .06). The unadjusted hazard ratio was 1.16 (95% CONCLUSIONS
CI, 0.99 –1.36), indicating a 16% higher risk for death in the A growing body of data provides support for the use of to-
topotecan arm. For oral topotecan versus docetaxel, respec- potecan as a viable option in treating lung cancer. Intrave-
tively, the median survival times were 27.9 weeks versus nous topotecan is currently indicated for the treatment of
30.7 weeks, 1-year survival rates were 25.1% versus relapsed, sensitive SCLC. Recent studies demonstrate the

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28.7%, and median TTP were 11.3 weeks versus 13.1 potential utility of i.v. topotecan as first-line treatment of
weeks. The response rate was 5% in both arms. Based on SCLC.
the 1-year survival rate, oral topotecan met the criteria for An oral topotecan formulation has been developed. The
noninferiority to docetaxel in this trial. The quality of life dose-limiting toxicity of single-agent oral topotecan is
profile favored docetaxel relative to topotecan; however, grade 4 neutropenia, which appears somewhat less fre-
the magnitude of the difference was small and may not be quently than with i.v. topotecan. Oral topotecan (alone or in
clinically significant. Grade 3 or 4 toxicities differed be- combination) may be a viable option for patients with lung
tween treatments; neutropenia occurred more frequently cancer who prefer oral treatment to i.v. therapy. Three re-
with docetaxel (60% versus 50%), while anemia and throm- cent phase III trials have demonstrated the activity of oral
bocytopenia occurred more frequently with oral topotecan topotecan. In chemotherapy-naı̈ve patients with ED-SCLC,
(26% versus 10% and 26% versus 7%, respectively). This oral topotecan plus cisplatin provided efficacy and safety
study demonstrated that topotecan may provide an oral al- that were similar to those of etoposide plus cisplatin. In pa-
ternative for patients with relapsed, advanced NSCLC. tients with relapsed SCLC, treatment with oral topotecan
Together, these studies in advanced NSCLC show that oral showed a statistically significant and clinically meaningful
topotecan represents a feasible treatment option in this setting longer overall survival duration than with BSC alone, a
and offers the advantage of convenient administration. benefit maintained in subgroups of patients with either che-
motherapy-resistant or chemotherapy-sensitive disease. In
TOPOTECAN AS A CANDIDATE FOR COMBINATION that same study, oral topotecan also improved quality of life
WITH NOVEL AGENTS over that seen with BSC alone in the study population. In
Recent literature suggests that topotecan is a good candi- previously treated patients with NSCLC, single-agent oral
date for combination with additional categories of antineo- topotecan was shown to be noninferior in 1-year survival
plastic agents. The specific targeting of topoisomerase 1 by relative to the current standard of i.v. docetaxel based on a
topotecan appears to lead to a decrease in hypoxia-induc- 10% noninferiority margin.
ible factor (HIF)-1 transcriptional repression, downregula- In future studies, oral topotecan represents a good
tion of HIF-1– dependent gene expression, and inhibition of candidate for combination therapy with other i.v. or oral
vascular endothelial growth factor (VEGF) mRNA expres- chemotherapy agents, monoclonal antibodies, proteo-
sion [51], suggesting that the combination of topotecan some inhibitors, and small molecule tyrosine kinase in-
with VEGF inhibitors may be synergistic. Topoisomerase 1 hibitors.

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 Recent Advances with Topotecan in the Treatment of Lung Cancer
Mary O'Brien, John Eckardt and Rodryg Ramlau
Oncologist 2007;12;1194-1204
DOI: 10.1634/theoncologist.12-10-1194
This information is current as of October 28, 2007

Updated Information including high-resolution figures, can be found at:

& Services http://www.TheOncologist.com/cgi/content/full/12/10/1194

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