- Email: [email protected]
A Phase II Study of Higher Dose Weekly Topotecan in Relapsed Small-Cell Lung Cancer
Original Study
A Phase II Study of Higher Dose Weekly Topotecan in Relapsed Small-Cell Lung Cancer David R. Spigel,1,2 F. Anthony Greco,1,2 Howard A. Burris III,1,2 Dianna L. Shipley,2 Bobby L. Clark,1 Robert C. Whorf,3 Edward R. Arrowsmith,4 John D. Hainsworth1,2 Abstract Background: Five-day topotecan is approved by the US Federal Drug Administration (FDA) for sensitive relapsed small-cell lung cancer (SCLC). We previously found that 4 mg/m2 intravenous (I.V.) weekly dosing resulted in low-grade 3/4 toxicity but an overall response rate (ORR) ⬍ 10%. We hypothesized that higher topotecan dosing could improve ORR without significantly increasing toxicity. Patients and Methods: This multicenter phase II trial sought a 25% ORR (␣ ⫽ 0.04;  ⫽ 0.20). Eligible patients (sensitive or refractory relapsed SCLC; Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1; measurable disease) received weekly topotecan (6 mg/m2 I.V. for 6 weeks) and were restaged every 8 weeks. Results: Baseline characteristics were N ⫽ 38, enrolled 5/2006-10/ 2007; median age 64 years (range, 35-82), 47% female, 74% ECOG PS 1, 50% refractory relapsed SCLC. The median follow-up was 15 months (range, 12-24 months). No patients received all planned therapy; only 1 patient was able to receive all planned treatment in cycle 1 because of hematologic toxicity and progressive disease (PD). Among all patients, ORR was 8% (95% confidence interval [CI], 2%-21%), 24% had stable disease, and disease in 47% progressed. Among sensitive relapsed patients ORR was 16% (95% CI, 3%-40%) with no complete responses; median response duration was 3.3 months. Five (26%) patients had stable disease; 8 (42%) patients had PD. Among sensitive relapsed patients, the median time to progression (TTP) and overall survival (OS) was 2.5 months and 8.6 months, respectively. Among refractory relapsed patients there were no ORRs, and median TTP and OS were 1.5 months and 3.7 months, respectively. Grade 3/4 toxicities (⬎ 10%) included neutropenia (53%), leukopenia (42%), thrombocytopenia (37%), anemia (13%), fatigue (13%), and pain (13%). There were no treatment-related deaths. Conclusion: Weekly topotecan (6 mg/m2 I.V.) is not feasible because of hematologic toxicity and does not improve efficacy in patients with relapsed SCLC. Clinical Lung Cancer, Vol. 12, No. 3, 187-91 © 2011 Published by Elsevier Inc. Keywords: Hematologic toxicity, Higher dose, Phase II, Small-cell lung cancer, Topotecan, Weekly
Introduction Topotecan is a DNA topoisomerase I inhibitor and is the only US Food and Drug Administration (FDA)-approved therapy for patients with sensitive relapsed (disease that progresses after 60-90 days of first-line therapy) small-cell lung cancer (SCLC). The approved dose and schedule is 1.5 mg/m2 intravenously (I.V.) days 1-5 every 3 1
Sarah Cannon Research Institute, Nashville, TN Tennessee Oncology, PLLC, Nashville, TN 3 Florida Cancer Specialists, Ft. Myers, FL 4 Chattanooga Oncology and Hematology Associates, Chattanooga, TN 2
Submitted: Jul 24, 2010; Revised: Oct 5, 2010; Accepted: Nov 9, 2010 Address for correspondence: David R. Spigel, MD, Sarah Cannon Research Institute, 250 25th Avenue North, Ste 110, Nashville, TN 37203 Fax: 615 986-0029; e-mail contact: [email protected]
1525-7304/$ - see frontmatter © 2011 Published by Elsevier Inc. doi: 10.1016/j.cllc.2011.03.016
weeks. The response rate (24%) and survival rate (25 weeks) associated with this regimen proved equivalent to CAV (cyclophosphamide, Adriamycin [doxorubicin], and vincristine) in a randomized trial in patients with sensitive relapsed SCLC; however, quality of life and symptom control were improved with topotecan.1 Notably, 5-day topotecan was associated with severe neutropenia (grade 4, 38%), thrombocytopenia (grade 4, 10%) and anemia (grade 3/4, 18%). Weekly scheduling of topotecan has been investigated with the dual aims of improving treatment safety and patient convenience. Studies in ovarian cancer have demonstrated that 4 mg/m2 can be safely delivered once weekly.2-11 This schedule has been studied at our center in patients with relapsed SCLC and as first-line therapy in patients with poor performance status.12,13 In general this schedule was associated with relatively low severe hematologic toxicity; how-
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187
Higher Dose Weekly Topotecan in SCLC Figure 1 Schema
CR, PR or Stable
*Course:
Continue treatment untill progression for up to 2 additional courses.
1
Week:
1
2
3
4
5
6
Day:
1
28
15
22
29
36
T
T
T
T
T
T
Restage (weeks 7-8)
(Restage every 8 weeks)
Disease Progression Off study
* For each therapeutic course, topotecan (T) 6 mg/m2 I.V. administered weekly for 6 consecutive weeks, followed by a 2-week restaging break
Abbreviations: CR ⫽ complete response; I.V. ⫽ intravenous; PR ⫽ partial response.
ever, response rates were low (⬍ 10%). We hypothesized that a higher topotecan dose could improve the response rate without significantly increasing toxicity. In this article we report on a multicenter phase II trial in which higher dose weekly topotecan was administered to patients with sensitive and refractory relapsed SCLC.
Patients and Methods This trial was initiated in May 2006. Participating centers included the Sarah Cannon Research Institute and select sites from the Sarah Cannon Oncology Research Consortium, a national community-based research network.
Patients Patients with SCLC who had progressed after 1 previous chemotherapy or chemotherapy/radiation regimen were enrolled. Patients who had disease that progressed on primary therapy or that relapsed within 3 months of the most recent chemotherapy were considered refractory relapsed patients. Patients who had progressive tumor or relapsed more than 3 months after chemotherapy were considered sensitive relapsed patients. Patients had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST).14 Other eligibility criteria included age ⱖ 18 years, presence of untreated brain metastases, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1, adequate organ function (defined as absolute neutrophil count [ANC] ⱖ 1.5 ⫻ 109/L and platelet count ⱖ 100 ⫻ 109/L). Exclusion criteria included pregnancy or lactation, clinically significant cardiovascular disease, or other active malignancy. All patients provided written informed consent before enrollment.
Pretreatment Evaluation Before treatment patients were evaluated by history, physical examination, and laboratory testing. Baseline tumor staging was per-
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formed using computed tomography (CT) of the chest and abdomen, CT or magnetic resonance imaging of the brain, and bone scan or positron emission tomography.
Treatment Plan All patients received I.V. topotecan 6 mg/m2 weekly ⫻ 6 weeks every 8 weeks (Figure 1). Routine antiemetic agents were used. Patients were restaged with CT scans every cycle or every 8 weeks (per RECIST). If there was no evidence of disease progression or significant toxicity, patients received up to 3 total cycles (24 weeks). Dose modifications were based on blood counts obtained weekly during therapy. Doses were not increased once modified. No adjustments were required if the ANC was ⬎ 1.0 ⫻ 109/L and the platelet count was ⬎ 100 ⫻ 109/L. If the ANC was ⱖ 0.5 - ⱕ 1.0 ⫻ 109/L or the platelet count was ⱖ 75 - ⱕ 100 ⫻ 109/L, chemotherapy was reduced 1 dose level (first episode 4.5 mg/m2, second episode 3 mg/m2). If the ANC was ⬍ 0.5 ⫻ 109/L or the platelet count was ⬍ 75 ⫻ 109/L, chemotherapy was held until recovery and then reduced 1 dose level. Patients requiring hospitalization for neutropenia and fever had dose reductions. Chemotherapy was also reduced for severe nonhematologic toxicity. Toxicity assessments were made according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 3.0). Cytokines were not administered with the first course of treatment; however, for patients experiencing febrile neutropenia, prophylactic granulocyte colony-stimulating factor was permitted at the discretion of the treating physician and was not to substitute for mandated dose reductions. This trial was approved by the institutional review boards of all participating institutions and was conducted in accordance with FDA Good Clinical Practices and local ethical and legal requirements. Topotecan was provided by GlaxoSmithKline.
David R. Spigel et al Definition of Response All patients were evaluated for response by RECIST. The final response category assigned represented the best response obtained during treatment.
Statistical Methods The primary objective of this study was to determine the overall response rate (ORR). Secondary objectives were to assess toxicity, time to progression (TTP), duration of response, and overall survival (OS). If the weekly administration of higher dose I.V. topotecan failed to provide efficacy that was at least comparable to the average experience of 5-day single-agent I.V. topotecan (ie, 25%) in sensitive relapsed SCLC, there would not be further interest in developing this regimen in this population. This trial used a 2-stage design. If there were 3 or more responders in the first 22 patients enrolled, another 18 patients would be treated. The total sample size was N ⫽ 40. The ␣ level of this design was 0.04; and the power was 0.8. TTP was defined as the interval between the start date of treatment and the date of occurrence of progressive disease (PD). OS was measured from the date of study entry until the date of death. If there was intolerable toxicity or discontinuation of treatment secondary to toxicity, the patient was considered assessable but was classified as a treatment failure. If other antitumor therapy was initiated before PD occurred, the patient was censored on the date the other therapy began. If a patient was lost to follow-up, the patient was censored on the date of last contact. Survival curves were estimated using the Kaplan–Meier method.15 Toxicity was assessed after the first 10 patients were treated. If grade 4 cytopenias were observed in more than 4 of the first 10 patients, further accrual would be stopped and a dose reduction considered.
Table 1 Patient Characteristics (N ⴝ 38) Characteristic
Number of Patients (%)
Median age, years (range)
64 (35-82)
Sex Male
20 (53%)
Female
18 (47%)
ECOG PS 0
10 (26%)
1
28 (74%)
Relapsed Category Resistant
19 (50%)
Sensitive
19 (50%)
Previous Radiation Therapy Chest
17 (45%)
Prophylactic cranial irradiation
15 (39%)
Metastatic sites Bone
12 (32%)
Liver
21 (55%)
Lymph nodes
17 (45%)
Pleural effusion
8 (21%)
Central nervous system
2 (5%)
Other
17 (45%)
Site of Treatment Tennessee Oncology
19 (50%)
Network sites
19 (50%)
Abbreviation: ECOG PS ⫽ Eastern Cooperative Oncology Group performance status.
Results Patient Characteristics Thirty-eight patients were enrolled from May 2006 to October 2007, 50% from our middle Tennessee site and 50% from other consortium sites. Baseline characteristics for all patients are described in Table 1. The median age was 64 years (range, 35-82 years). Eighteen (47%) patients were female and 20 patients were male. ECOG PS was 0 in 10 (26%) patients, and 1 in 28 (74%) patients. Nineteen (50%) patients had refractory relapsed SCLC, and 19 patients had sensitive disease. Metastatic sites included liver (55%), lymph nodes (45%), and bone (32%), among other sites.
Treatment Received The median follow-up was 15 months (range, 12-24 months). Two (8%) patients were not evaluable for response because of treatment-related toxicity (dyspnea and pancytopenia). These patients were included in the efficacy analyses. No patients were able to receive all planned therapy (95% of patients did not make it to cycle 3). This was primarily because of PD. Only 1 patient was able to receive all of cycle 1 planned treatment (ie, no missed doses or dose reductions). Thirty-four (89%) patients either missed planned doses and/or had reduced doses during cycle 1 because of hematologic toxicity. The average weekly dose delivered over 6 weeks, after adjusting for dose reductions and breaks, was 3.7 mg/m2.
Table 2 Response Rates (N ⴝ 38) Number of Patients (%) Best Response CR
ORR Refractory Relapsed Sensitive Relapsed Overall SCLC SCLC Group 0
0
0
PR
3 (8)
0
3 (16)
SD
9 (24)
4 (21)
5 (26)
PD
18 (47)
10 (53)
8 (42)
UE
8 (21)
5 (26)
3 (16)
Abbreviations: CR ⫽ complete response; ORR ⫽ overall response rate; PD ⫽ progressive disease; PR ⫽ partial response; SD ⫽ stable disease; UE ⫽ unevaluable.
Response Thirty-eight patients were included in the response analysis (Table 2). Eight patients were not evaluable because of clinical progression (2), death (2), treatment-related toxicity (2), patient request (1), and physician discretion (1). Among all patients the ORR was 8% (95% CI, 2%-21%). Twenty-four percent of patients had stable disease and 47% had PD. Among sensitive re-
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Higher Dose Weekly Topotecan in SCLC Figure 2 Time to Progression (TTP)
Survival Probability
1
Resistant Relapse Sensitive Relapse
0.8 Median TTP (95% CI) Resistant Relapse: 1.5 months (1.45–2.56 months) Sensitive Relapse: 2.53 months (1.58–4.47 months)
0.6 0.4 0.2 0 0
10
20
30
Time (Months)
Figure 3 Overall Survival (OS)
Survival Probability
1
Median OS (95% CI) Resistant Relapse: 3.65 months (2.33–4.86 months) Sensitive Relapse: 8.64 months (5.39–14.0 months)
0.8 0.6 0.4
Resistant Relapse Sensitive Relapse
0.2 0 0
10
20
30
Time (Months)
lapsed patients, the ORR was 16% (95% CI, 3%-40%). There were no complete responses. Three sensitive relapsed patients among the first 22 patients accrued to stage 1 achieved a partial response; the trial was thus expanded to the protocol-specified target accrual. However none of the additional patients responded to treatment. The median response duration was 3.3 months. Five (26%) patients had stable disease and 8 (42%) patients had PD. There were no ORRs among refractory relapsed patients. Four (21%) patients had stable disease and 10 (53%) patients had PD.
Time to Progression and Survival Among sensitive relapsed patients, the median TTP and OS were 2.5 months and 8.6 months, respectively (Figures 2 and 3). Among refractory relapsed patients, the median TTP and OS were 1.5 months and 3.7 months, respectively.
Treatment-related Toxicity Treatment-related toxicity is summarized in Table 3. Toxicity was generally similar between sensitive and refractory relapsed cohorts. Neutropenic fever occurred in 2 (5%) patients overall. The most
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common (⬎ 5%) grade 3/4 toxicities were neutropenia (53%), leukopenia (42%), thrombocytopenia (37%), anemia (13%), fatigue (13%), pain (13%), and pneumonia (8%). There were no treatmentrelated deaths.
Discussion Caring for patients with relapsed SCLC is challenging. Patients are often symptomatic from advanced disease and toxicity from first-line therapy, and available therapies offer limited benefits. Topotecan is commonly used in the relapsed setting, but 5-day I.V. scheduling is inconvenient and myelosuppressive. Our gynecologic oncology colleagues recognized these issues early on and began investigating a more convenient weekly schedule.2-11 In that setting, 4 mg/m2 could be safely administered with less hematologic toxicity. Our group previously studied weekly scheduling (4 mg/m2 I.V. weekly) in 2 phase II trials in patients with relapsed SCLC and as upfront therapy in patients with poor PS.12,13 Although treatment could be delivered safely, the low response rates were disappointing. Higher doses have been studied in patients with ovarian cancer with acceptable safety.6 We hypothesized that a higher dose of weekly topotecan might improve efficacy while maintaining patient convenience and safety. We were not able to achieve our intended goal of delivering a higher weekly dose of therapy in this study. The average weekly dose delivered was less than 4 mg/m2. This was primarily because of hematologic toxicity and PD. The response rate was low in the sensitive relapsed cohort, although the CIs were wide for the small sample size. To not see any response in the refractory cohort was not entirely unexpected but nonetheless disappointing. Hematologic toxicity accounted for many missed treatments and dose reductions; however, neutropenic fever and anemia were uncommon, perhaps because of supportive measures, including the use of growth factor support. Severe neutropenia was common and appeared similar to that in 5-day scheduling. Severe thrombocytopenia was notably worse than in 5-day scheduling. Nonhematologic toxicity was relatively low, but this may have been due to decreased treatment delivery. This trial had several limitations. First, both refractory and sensitive relapsed patients were included in the ORR analysis. In retrospect, these 2 cohorts should have been kept separate in the primary statistical analysis because of the expected disparate outcomes. Second, the sample size of each cohort was probably too small to adequately provide sufficient data in terms of TTP and OS. Finally, it is possible that an alternative schedule (2 out of every 3 weeks, or 3 out of 4) would have been a more feasible strategy to improve treatment delivery. In summary, higher dose weekly I.V. topotecan administered at 6 mg/m2 ⫻ 6/8 weeks is not feasible as a treatment for relapsed SCLC. Significant hematologic toxicity and limited efficacy jeopardized patient safety without improving disease control. Additional study of more intensive topotecan dosing is not warranted in our opinion. A recently approved oral formulation of topotecan appears to offer a more convenient treatment alternative to 5-day I.V. scheduling with acceptable safety and similar efficacy.11 This formulation and schedule may be the optimal chemotherapy platform for future studies with newer agents.
David R. Spigel et al Table 3 Grade 3/4 Treatment-related Toxicity (N ⴝ 38; 49 treatment cycles) Number of Patients (%) Toxicity
Resistant Relapsed (n ⴝ 19)
Sensitive Relapsed (n ⴝ 19)
Total (N ⴝ 38)
Grade 3
Grade 4
Grade 3
Grade 4
Grade 3
Grade 4
3 (15%)
0
2 (10%)
0
5 (13%)
0
Hematologic Anemia Leukopenia
7 (37%)
1 (5%)
6 (32%)
2 (10%)
13 (34%)
3 (8%)
Neutropenia
4 (21%)
5 (26%)
5 (26%)
6 (32%)
9 (24%)
11 (29%)
Thrombocytopenia
4 (21%)
4 (21%)
4 (21%)
2 (10%)
8 (21%)
6 (16%)
Neutropenic fever
1 (5%)
0
0
1 (5%)
1 (3%)
1 (3%)
1 (5%)
0
4 (21%)
0
5 (13%)
0
Pain
5 (13%)
0
Pneumonia
3 (8%)
Nonhematologic Fatigue
Acknowledgments ClinTrials.gov Identifier: NCT00294190 (SCRI LUN 120)
Disclosures Supported in part by a grant from GlaxoSmithKline, Philadelphia, PA. This work was presented in part at the 2008 American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2008; Chicago, IL.
References 1. 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; 17:658-67. 2. Bhoola SM, Coleman RL, Herzog T, et al. Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer. Gynecol Oncol 2004; 95:564-9. 3. Frasci G, Panza N, Comella P, et al. Cisplatin-topotecan-paclitaxel weekly administration with G-CSF support for ovarian and small-cell lung cancer patients: a dose-finding study. Ann Oncol 1999; 10:355-8. 4. Gelderblom H, Sparreboom A, de Jonge MJ, et al. Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer. Br J Cancer 2001; 85:1124-9. 5. Homesley H, Benigno B, Williams J, et al. A phase I study of weekly topotecan and paclitaxel in previously treated epithelial ovarian carcinoma patients. Gynecol Oncol 2002; 87:171-7.
6. 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: 394-9. 7. Largillier R, Valenza B, Ferrero JM, et al. Haematological evaluation of weekly therapy with topotecan for the treatment of recurrent ovarian cancer resistant to platinum-based therapy. Oncology 2007; 73:177-84. 8. Levy T, Inbar M, Menczer J, et al. Phase II study of weekly topotecan in patients with recurrent or persistent epithelial ovarian cancer. Gynecol Oncol 2004; 95: 686-90. 9. Morris RT. Weekly topotecan in the management of ovarian cancer. Gynecol Oncol 2003; 90:S34-8. 10. Rose PG, Smrekar M, Haba P, et al. A phase I/II trial of weekly topotecan and carboplatin in potentially platinum-sensitive relapsed ovarian and peritoneal carcinoma. Gynecol Oncol 2005; 99:714-9. 11. Stathopoulos GP, Malamos NA, Aravantinos G, et al. Weekly administration of topotecan-paclitaxel as second-line treatment in ovarian cancer. Cancer Chemother Pharmacol 2006; 60:123-8. 12. Shipley DL, Hainsworth JD, Spigel DR, et al. Topotecan: weekly intravenous (IV) schedule similar to standard 5-day IV schedule as second-line therapy for relapsed small cell lung cancer (SCLC)—A Minnie Pearl Cancer Research Network phase II trial. J Clin Oncol 2006; 24:7083. 13. Shipley D, Spigel DR, Hainsworth JD, et al. Phase II trial of high-dose weekly topotecan in patients with relapsed small-cell lung cancer (SCLC). J Clin Oncol 2008; 26(suppl) abstract 19073. Available at www.asco.org. Accessed April 14, 2011. 14. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205-16. 15. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81.
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A Phase II Study of Higher Dose Weekly Topotecan in Relapsed Small-Cell Lung Cancer David R. Spigel,1,2 F. Anthony Greco,1,2 Howard A. Burris III,1,2 Dianna L. Shipley,2 Bobby L. Clark,1 Robert C. Whorf,3 Edward R. Arrowsmith,4 John D. Hainsworth1,2 Abstract Background: Five-day topotecan is approved by the US Federal Drug Administration (FDA) for sensitive relapsed small-cell lung cancer (SCLC). We previously found that 4 mg/m2 intravenous (I.V.) weekly dosing resulted in low-grade 3/4 toxicity but an overall response rate (ORR) ⬍ 10%. We hypothesized that higher topotecan dosing could improve ORR without significantly increasing toxicity. Patients and Methods: This multicenter phase II trial sought a 25% ORR (␣ ⫽ 0.04;  ⫽ 0.20). Eligible patients (sensitive or refractory relapsed SCLC; Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1; measurable disease) received weekly topotecan (6 mg/m2 I.V. for 6 weeks) and were restaged every 8 weeks. Results: Baseline characteristics were N ⫽ 38, enrolled 5/2006-10/ 2007; median age 64 years (range, 35-82), 47% female, 74% ECOG PS 1, 50% refractory relapsed SCLC. The median follow-up was 15 months (range, 12-24 months). No patients received all planned therapy; only 1 patient was able to receive all planned treatment in cycle 1 because of hematologic toxicity and progressive disease (PD). Among all patients, ORR was 8% (95% confidence interval [CI], 2%-21%), 24% had stable disease, and disease in 47% progressed. Among sensitive relapsed patients ORR was 16% (95% CI, 3%-40%) with no complete responses; median response duration was 3.3 months. Five (26%) patients had stable disease; 8 (42%) patients had PD. Among sensitive relapsed patients, the median time to progression (TTP) and overall survival (OS) was 2.5 months and 8.6 months, respectively. Among refractory relapsed patients there were no ORRs, and median TTP and OS were 1.5 months and 3.7 months, respectively. Grade 3/4 toxicities (⬎ 10%) included neutropenia (53%), leukopenia (42%), thrombocytopenia (37%), anemia (13%), fatigue (13%), and pain (13%). There were no treatment-related deaths. Conclusion: Weekly topotecan (6 mg/m2 I.V.) is not feasible because of hematologic toxicity and does not improve efficacy in patients with relapsed SCLC. Clinical Lung Cancer, Vol. 12, No. 3, 187-91 © 2011 Published by Elsevier Inc. Keywords: Hematologic toxicity, Higher dose, Phase II, Small-cell lung cancer, Topotecan, Weekly
Introduction Topotecan is a DNA topoisomerase I inhibitor and is the only US Food and Drug Administration (FDA)-approved therapy for patients with sensitive relapsed (disease that progresses after 60-90 days of first-line therapy) small-cell lung cancer (SCLC). The approved dose and schedule is 1.5 mg/m2 intravenously (I.V.) days 1-5 every 3 1
Sarah Cannon Research Institute, Nashville, TN Tennessee Oncology, PLLC, Nashville, TN 3 Florida Cancer Specialists, Ft. Myers, FL 4 Chattanooga Oncology and Hematology Associates, Chattanooga, TN 2
Submitted: Jul 24, 2010; Revised: Oct 5, 2010; Accepted: Nov 9, 2010 Address for correspondence: David R. Spigel, MD, Sarah Cannon Research Institute, 250 25th Avenue North, Ste 110, Nashville, TN 37203 Fax: 615 986-0029; e-mail contact: [email protected]
1525-7304/$ - see frontmatter © 2011 Published by Elsevier Inc. doi: 10.1016/j.cllc.2011.03.016
weeks. The response rate (24%) and survival rate (25 weeks) associated with this regimen proved equivalent to CAV (cyclophosphamide, Adriamycin [doxorubicin], and vincristine) in a randomized trial in patients with sensitive relapsed SCLC; however, quality of life and symptom control were improved with topotecan.1 Notably, 5-day topotecan was associated with severe neutropenia (grade 4, 38%), thrombocytopenia (grade 4, 10%) and anemia (grade 3/4, 18%). Weekly scheduling of topotecan has been investigated with the dual aims of improving treatment safety and patient convenience. Studies in ovarian cancer have demonstrated that 4 mg/m2 can be safely delivered once weekly.2-11 This schedule has been studied at our center in patients with relapsed SCLC and as first-line therapy in patients with poor performance status.12,13 In general this schedule was associated with relatively low severe hematologic toxicity; how-
Clinical Lung Cancer May 2011
187
Higher Dose Weekly Topotecan in SCLC Figure 1 Schema
CR, PR or Stable
*Course:
Continue treatment untill progression for up to 2 additional courses.
1
Week:
1
2
3
4
5
6
Day:
1
28
15
22
29
36
T
T
T
T
T
T
Restage (weeks 7-8)
(Restage every 8 weeks)
Disease Progression Off study
* For each therapeutic course, topotecan (T) 6 mg/m2 I.V. administered weekly for 6 consecutive weeks, followed by a 2-week restaging break
Abbreviations: CR ⫽ complete response; I.V. ⫽ intravenous; PR ⫽ partial response.
ever, response rates were low (⬍ 10%). We hypothesized that a higher topotecan dose could improve the response rate without significantly increasing toxicity. In this article we report on a multicenter phase II trial in which higher dose weekly topotecan was administered to patients with sensitive and refractory relapsed SCLC.
Patients and Methods This trial was initiated in May 2006. Participating centers included the Sarah Cannon Research Institute and select sites from the Sarah Cannon Oncology Research Consortium, a national community-based research network.
Patients Patients with SCLC who had progressed after 1 previous chemotherapy or chemotherapy/radiation regimen were enrolled. Patients who had disease that progressed on primary therapy or that relapsed within 3 months of the most recent chemotherapy were considered refractory relapsed patients. Patients who had progressive tumor or relapsed more than 3 months after chemotherapy were considered sensitive relapsed patients. Patients had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST).14 Other eligibility criteria included age ⱖ 18 years, presence of untreated brain metastases, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1, adequate organ function (defined as absolute neutrophil count [ANC] ⱖ 1.5 ⫻ 109/L and platelet count ⱖ 100 ⫻ 109/L). Exclusion criteria included pregnancy or lactation, clinically significant cardiovascular disease, or other active malignancy. All patients provided written informed consent before enrollment.
Pretreatment Evaluation Before treatment patients were evaluated by history, physical examination, and laboratory testing. Baseline tumor staging was per-
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formed using computed tomography (CT) of the chest and abdomen, CT or magnetic resonance imaging of the brain, and bone scan or positron emission tomography.
Treatment Plan All patients received I.V. topotecan 6 mg/m2 weekly ⫻ 6 weeks every 8 weeks (Figure 1). Routine antiemetic agents were used. Patients were restaged with CT scans every cycle or every 8 weeks (per RECIST). If there was no evidence of disease progression or significant toxicity, patients received up to 3 total cycles (24 weeks). Dose modifications were based on blood counts obtained weekly during therapy. Doses were not increased once modified. No adjustments were required if the ANC was ⬎ 1.0 ⫻ 109/L and the platelet count was ⬎ 100 ⫻ 109/L. If the ANC was ⱖ 0.5 - ⱕ 1.0 ⫻ 109/L or the platelet count was ⱖ 75 - ⱕ 100 ⫻ 109/L, chemotherapy was reduced 1 dose level (first episode 4.5 mg/m2, second episode 3 mg/m2). If the ANC was ⬍ 0.5 ⫻ 109/L or the platelet count was ⬍ 75 ⫻ 109/L, chemotherapy was held until recovery and then reduced 1 dose level. Patients requiring hospitalization for neutropenia and fever had dose reductions. Chemotherapy was also reduced for severe nonhematologic toxicity. Toxicity assessments were made according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 3.0). Cytokines were not administered with the first course of treatment; however, for patients experiencing febrile neutropenia, prophylactic granulocyte colony-stimulating factor was permitted at the discretion of the treating physician and was not to substitute for mandated dose reductions. This trial was approved by the institutional review boards of all participating institutions and was conducted in accordance with FDA Good Clinical Practices and local ethical and legal requirements. Topotecan was provided by GlaxoSmithKline.
David R. Spigel et al Definition of Response All patients were evaluated for response by RECIST. The final response category assigned represented the best response obtained during treatment.
Statistical Methods The primary objective of this study was to determine the overall response rate (ORR). Secondary objectives were to assess toxicity, time to progression (TTP), duration of response, and overall survival (OS). If the weekly administration of higher dose I.V. topotecan failed to provide efficacy that was at least comparable to the average experience of 5-day single-agent I.V. topotecan (ie, 25%) in sensitive relapsed SCLC, there would not be further interest in developing this regimen in this population. This trial used a 2-stage design. If there were 3 or more responders in the first 22 patients enrolled, another 18 patients would be treated. The total sample size was N ⫽ 40. The ␣ level of this design was 0.04; and the power was 0.8. TTP was defined as the interval between the start date of treatment and the date of occurrence of progressive disease (PD). OS was measured from the date of study entry until the date of death. If there was intolerable toxicity or discontinuation of treatment secondary to toxicity, the patient was considered assessable but was classified as a treatment failure. If other antitumor therapy was initiated before PD occurred, the patient was censored on the date the other therapy began. If a patient was lost to follow-up, the patient was censored on the date of last contact. Survival curves were estimated using the Kaplan–Meier method.15 Toxicity was assessed after the first 10 patients were treated. If grade 4 cytopenias were observed in more than 4 of the first 10 patients, further accrual would be stopped and a dose reduction considered.
Table 1 Patient Characteristics (N ⴝ 38) Characteristic
Number of Patients (%)
Median age, years (range)
64 (35-82)
Sex Male
20 (53%)
Female
18 (47%)
ECOG PS 0
10 (26%)
1
28 (74%)
Relapsed Category Resistant
19 (50%)
Sensitive
19 (50%)
Previous Radiation Therapy Chest
17 (45%)
Prophylactic cranial irradiation
15 (39%)
Metastatic sites Bone
12 (32%)
Liver
21 (55%)
Lymph nodes
17 (45%)
Pleural effusion
8 (21%)
Central nervous system
2 (5%)
Other
17 (45%)
Site of Treatment Tennessee Oncology
19 (50%)
Network sites
19 (50%)
Abbreviation: ECOG PS ⫽ Eastern Cooperative Oncology Group performance status.
Results Patient Characteristics Thirty-eight patients were enrolled from May 2006 to October 2007, 50% from our middle Tennessee site and 50% from other consortium sites. Baseline characteristics for all patients are described in Table 1. The median age was 64 years (range, 35-82 years). Eighteen (47%) patients were female and 20 patients were male. ECOG PS was 0 in 10 (26%) patients, and 1 in 28 (74%) patients. Nineteen (50%) patients had refractory relapsed SCLC, and 19 patients had sensitive disease. Metastatic sites included liver (55%), lymph nodes (45%), and bone (32%), among other sites.
Treatment Received The median follow-up was 15 months (range, 12-24 months). Two (8%) patients were not evaluable for response because of treatment-related toxicity (dyspnea and pancytopenia). These patients were included in the efficacy analyses. No patients were able to receive all planned therapy (95% of patients did not make it to cycle 3). This was primarily because of PD. Only 1 patient was able to receive all of cycle 1 planned treatment (ie, no missed doses or dose reductions). Thirty-four (89%) patients either missed planned doses and/or had reduced doses during cycle 1 because of hematologic toxicity. The average weekly dose delivered over 6 weeks, after adjusting for dose reductions and breaks, was 3.7 mg/m2.
Table 2 Response Rates (N ⴝ 38) Number of Patients (%) Best Response CR
ORR Refractory Relapsed Sensitive Relapsed Overall SCLC SCLC Group 0
0
0
PR
3 (8)
0
3 (16)
SD
9 (24)
4 (21)
5 (26)
PD
18 (47)
10 (53)
8 (42)
UE
8 (21)
5 (26)
3 (16)
Abbreviations: CR ⫽ complete response; ORR ⫽ overall response rate; PD ⫽ progressive disease; PR ⫽ partial response; SD ⫽ stable disease; UE ⫽ unevaluable.
Response Thirty-eight patients were included in the response analysis (Table 2). Eight patients were not evaluable because of clinical progression (2), death (2), treatment-related toxicity (2), patient request (1), and physician discretion (1). Among all patients the ORR was 8% (95% CI, 2%-21%). Twenty-four percent of patients had stable disease and 47% had PD. Among sensitive re-
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Higher Dose Weekly Topotecan in SCLC Figure 2 Time to Progression (TTP)
Survival Probability
1
Resistant Relapse Sensitive Relapse
0.8 Median TTP (95% CI) Resistant Relapse: 1.5 months (1.45–2.56 months) Sensitive Relapse: 2.53 months (1.58–4.47 months)
0.6 0.4 0.2 0 0
10
20
30
Time (Months)
Figure 3 Overall Survival (OS)
Survival Probability
1
Median OS (95% CI) Resistant Relapse: 3.65 months (2.33–4.86 months) Sensitive Relapse: 8.64 months (5.39–14.0 months)
0.8 0.6 0.4
Resistant Relapse Sensitive Relapse
0.2 0 0
10
20
30
Time (Months)
lapsed patients, the ORR was 16% (95% CI, 3%-40%). There were no complete responses. Three sensitive relapsed patients among the first 22 patients accrued to stage 1 achieved a partial response; the trial was thus expanded to the protocol-specified target accrual. However none of the additional patients responded to treatment. The median response duration was 3.3 months. Five (26%) patients had stable disease and 8 (42%) patients had PD. There were no ORRs among refractory relapsed patients. Four (21%) patients had stable disease and 10 (53%) patients had PD.
Time to Progression and Survival Among sensitive relapsed patients, the median TTP and OS were 2.5 months and 8.6 months, respectively (Figures 2 and 3). Among refractory relapsed patients, the median TTP and OS were 1.5 months and 3.7 months, respectively.
Treatment-related Toxicity Treatment-related toxicity is summarized in Table 3. Toxicity was generally similar between sensitive and refractory relapsed cohorts. Neutropenic fever occurred in 2 (5%) patients overall. The most
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common (⬎ 5%) grade 3/4 toxicities were neutropenia (53%), leukopenia (42%), thrombocytopenia (37%), anemia (13%), fatigue (13%), pain (13%), and pneumonia (8%). There were no treatmentrelated deaths.
Discussion Caring for patients with relapsed SCLC is challenging. Patients are often symptomatic from advanced disease and toxicity from first-line therapy, and available therapies offer limited benefits. Topotecan is commonly used in the relapsed setting, but 5-day I.V. scheduling is inconvenient and myelosuppressive. Our gynecologic oncology colleagues recognized these issues early on and began investigating a more convenient weekly schedule.2-11 In that setting, 4 mg/m2 could be safely administered with less hematologic toxicity. Our group previously studied weekly scheduling (4 mg/m2 I.V. weekly) in 2 phase II trials in patients with relapsed SCLC and as upfront therapy in patients with poor PS.12,13 Although treatment could be delivered safely, the low response rates were disappointing. Higher doses have been studied in patients with ovarian cancer with acceptable safety.6 We hypothesized that a higher dose of weekly topotecan might improve efficacy while maintaining patient convenience and safety. We were not able to achieve our intended goal of delivering a higher weekly dose of therapy in this study. The average weekly dose delivered was less than 4 mg/m2. This was primarily because of hematologic toxicity and PD. The response rate was low in the sensitive relapsed cohort, although the CIs were wide for the small sample size. To not see any response in the refractory cohort was not entirely unexpected but nonetheless disappointing. Hematologic toxicity accounted for many missed treatments and dose reductions; however, neutropenic fever and anemia were uncommon, perhaps because of supportive measures, including the use of growth factor support. Severe neutropenia was common and appeared similar to that in 5-day scheduling. Severe thrombocytopenia was notably worse than in 5-day scheduling. Nonhematologic toxicity was relatively low, but this may have been due to decreased treatment delivery. This trial had several limitations. First, both refractory and sensitive relapsed patients were included in the ORR analysis. In retrospect, these 2 cohorts should have been kept separate in the primary statistical analysis because of the expected disparate outcomes. Second, the sample size of each cohort was probably too small to adequately provide sufficient data in terms of TTP and OS. Finally, it is possible that an alternative schedule (2 out of every 3 weeks, or 3 out of 4) would have been a more feasible strategy to improve treatment delivery. In summary, higher dose weekly I.V. topotecan administered at 6 mg/m2 ⫻ 6/8 weeks is not feasible as a treatment for relapsed SCLC. Significant hematologic toxicity and limited efficacy jeopardized patient safety without improving disease control. Additional study of more intensive topotecan dosing is not warranted in our opinion. A recently approved oral formulation of topotecan appears to offer a more convenient treatment alternative to 5-day I.V. scheduling with acceptable safety and similar efficacy.11 This formulation and schedule may be the optimal chemotherapy platform for future studies with newer agents.
David R. Spigel et al Table 3 Grade 3/4 Treatment-related Toxicity (N ⴝ 38; 49 treatment cycles) Number of Patients (%) Toxicity
Resistant Relapsed (n ⴝ 19)
Sensitive Relapsed (n ⴝ 19)
Total (N ⴝ 38)
Grade 3
Grade 4
Grade 3
Grade 4
Grade 3
Grade 4
3 (15%)
0
2 (10%)
0
5 (13%)
0
Hematologic Anemia Leukopenia
7 (37%)
1 (5%)
6 (32%)
2 (10%)
13 (34%)
3 (8%)
Neutropenia
4 (21%)
5 (26%)
5 (26%)
6 (32%)
9 (24%)
11 (29%)
Thrombocytopenia
4 (21%)
4 (21%)
4 (21%)
2 (10%)
8 (21%)
6 (16%)
Neutropenic fever
1 (5%)
0
0
1 (5%)
1 (3%)
1 (3%)
1 (5%)
0
4 (21%)
0
5 (13%)
0
Pain
5 (13%)
0
Pneumonia
3 (8%)
Nonhematologic Fatigue
Acknowledgments ClinTrials.gov Identifier: NCT00294190 (SCRI LUN 120)
Disclosures Supported in part by a grant from GlaxoSmithKline, Philadelphia, PA. This work was presented in part at the 2008 American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2008; Chicago, IL.
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