Sarcoma

Volume 2012 (2012), Article ID 749067, 4 pages

doi:10.1155/2012/749067

Research Article

Topotecan and Cyclophosphamide in Adults with Relapsed Sarcoma

P. Blanchette,¹ D. Hogg,² P. Ferguson,³ J. S. Wunder,³ C. Swallow,⁴ R. Gladdy,⁴ P. Chung,⁵ B. O’Sullivan,⁵ M. E. Blackstein,² C. Catton,⁵ and A. A. Gupta²

¹Department of Internal Medicine, University of Toronto, Toronto, Canada

²Department of Medical Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Canada

³University Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Mount Sinai Hospital, University of Toronto, Canada

⁴Division of General Surgery, Mount Sinai Hospital, University of Toronto, Canada

⁵Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Canada

Received 1 May 2012; Accepted 1 June 2012

Academic Editor: Luca Sangiorgi

Copyright © 2012 P. Blanchette et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Background. The combination of topotecan and cyclophosphamide (TC) has activity in pediatric patients with recurrent sarcoma, especially Ewing’s sarcoma (EWS). We sought to determine the toxicity of and response to TC in adults with recurrent sarcoma. Patients and Methods. Adults treated with TC from 2005 to 2010 were reviewed who received T = topotecan at 0.75 mg/m²/day (days 1–5) and C = cyclophosphamide at 250 mg/m²/day (days 1–5) every 21 days. Results. Fifteen patients, median age 31 years (range 17.5–56) had nonpleomorphic rhabdomyosarcoma (RMS, ), EWS, , synovial sarcoma (SS, ) leiomyosarcoma (LMS, ), and desmoplastic small round cell tumour (DSRCT, ). Median time to progression was 2.5 months (range 1.6–13.0). Partial responses were seen in 2/6 RMS and 1/2 SS. Stable disease was seen in 2/5 EWS, 1/2 SS and 1 DSRCT. The most common reason for stopping treatment was progressive disease 12/15, (80%). Hematologic toxicity was common; 7 (47%) patients required blood product transfusion, 5 (33%) patients had fever/neutropenia. At median follow-up time of 7.7 months, all but 1 patient had died of disease. Conclusion: TC combination is tolerable but has only modest activity in adults with recurrent sarcoma. Other regimens deserve exploration for this high-risk group of patients

1. Introduction

Approximately 13,000 patients are diagnosed with sarcoma annually in the United States, accounting for only 1% of all adult cancer diagnosis [1]. Certain sarcoma subtypes, including rhabdomyosarcoma (RMS) and Ewing sarcoma (EWS), are more common in children as well as in young adults, with adult patients having worse outcomes compared to their pediatric counterparts [1–3]. For example, almost 50% of adults with localized EWS are expected to relapse from their disease (reviewed in [4]). Even when treated with similar therapy, patients with EWS greater than age 18 relapse more frequently than younger patients [5]. Treatment strategies for relapsed sarcoma in adults are limited, and we evaluated if topotecan and cyclophosphamide chemotherapy was beneficial to this sarcoma population.

Cyclophosphamide (C) is an oxazaphosphorine alkylating agent causing 3′ nicks in DNA while topotecan (T) binds to and inhibits topoisomerase I when bound to free 3′ ends of DNA [6]. In combination, these two agents (TC) have demonstrated promising activity in children and adolescents with relapsed/refractory RMS with response rate of 67% [7]. Response to window TC therapy in newly diagnosed patients with metastatic RMS was 47% [8]. Similarly, response rate in pediatric patients with relapsed EWS was 32%–35% [7, 9]. Nonhematological toxicity was rare [7, 8]. In young patients with metastatic EWS, 57% had a partial response to TC window therapy [10]. Based on these results, TC has now been incorporated in a randomized study for patients with newly diagnosed localized EWS by The Children’s Oncology Group (COG-AEWS07P1) [11].

The promising observations in pediatric patients and the limited nonhematological toxicity of this regimen make TC an attractive option for further clinical testing among adults with relapsed sarcoma. In the current study, we report the safety and efficacy of TC in adults with relapsed sarcoma.

2. Methods

The medical records of consecutive patients with recurrent sarcoma treated with TC chemotherapy at Princess Margaret Hospital and Mount Sinai Hospital, Toronto from 2005–2010 were reviewed. Research ethics board approval was obtained for this study.

All patients received topotecan 0.75 mg/m² intravenously daily for 5 days plus cyclophosphamide 250 mg/m² intravenously daily for 5 days, on a 21 day cycle. The use of granulocyte colony stimulating factor was variable.

Radiologic response was rated according to RECIST [12]. Since this was not a formal clinical trial, systematic documentation of toxicity was not available. Need for transfusion and neutropenia associated fever was documented. Furthermore, any delay in chemotherapy and reasons for discontinuation of TC was documented.

3. Results

3.1. Patient Demographics

Fifteen adults with relapsed sarcoma received TC chemotherapy as second or third line treatment. Patient characteristics are presented in Table 1. The median age of patients was 31 years (range 17.5–56). Patients had the following diseases: nonpleomorphic RMS, 6 (40%); EWS, 5 (33%); synovial sarcoma (SS), 2 (13%); leiomyosarcoma (LMS), 1 (7%); and desmoid small round cell tumour (DSRCT), 1 (7%). Median time to first relapse was 21 months (range 9–52). All patients had metastatic disease at time of TC treatment.

Table 1: Patient characteristics.

Patient characteristics
Number ()

Total
15

Diagnosis:

    Rhabdomyosarcoma
6

    Ewing’s sarcoma
5

    Synovial sarcoma
2

    Leiomyosarcoma
1

    DSRCT
1

Gender:

    Male
8

    Female
7

Age:

    Age at diagnosis (years)
mean: 30, (range: 16–56)

    Age at relapse (years)
mean: 31, (range: 19–57)

Topotecan/cyclophosphamide

    2nd line therapy
12

    3rd line therapy
3

Time to 1st relapse (months)
mean: 21, (range: 9–52)

3.2. Treatment

TC was used as 2nd line therapy for 12 patients and 3rd line therapy for 2 patients with RMS and 1 patient with SS (Table 2). A median of 4 cycles was delivered per patient (range 2 to 9).

Table 2: Treatment and disease outcome in patients treated with topotecan/cyclophosphamide.

Patient
Age at TC treatment
Diagnosis
Time to relapse (months)
Prior therapy
TTP with TC
Best response with TC
Outcome

1
51.5
RMS
11.8
VDC
1.6
PD
DOD

2
26.3
RMS
24.8
VAC, then VDC
2.0
PD
DOD

3
31.0
RMS
15
VAC, then VDC
2.3
PD
DOD

4
29.5
RMS
47.6
VDC/IE
4.3
PR
DOD

5
23.3
RMS
16
VDC/IE
1.8*
PR
DOD

6
49.6
RMS
19
VDC/IE
2.5*
PD
DOD

7
19.0
EWS
38
VDC/IE
1.5
PD
ANED

8
43.2
EWS
35.4
VDC/IE
5.3
PD
DOD

9
23.3
EWS
14.3
VDC/IE
2.3
PD
DOD

10
17.7
EWS
13.1
VDC/IE
6.1
SD
DOD

11
56.6
EWS
13.0
VDC/IE
13*
SD
DOD

12
32.0
DSRCT
10.1
VDC/IE
7.0
SD
DOD

13
46.7
SS
14.4
Dox, then Gem
5.6
PR
DOD

14
24.8
SS
42.5
AI
5.6
SD
DOD

15
57.4
LMS
80.5
AI
1.8
PD
DOD

TTP, time to progression; RMS, rhabdomyosarcoma; EWS, Ewing’s sarcoma; DSRCT, desmoplastic small round cell tumour; PD, progressive disease; PR, partial response; SD, stable disease; DOD, dead of disease; ANED, alive no evidence of disease.

*Discontinued TC for other than disease progression.

3.3. Disease Outcome

Response rate and time to progression are listed for all patients in Table 2. Overall response rate for RMS was 33%, EWS 0%, and other sarcoma 25%. Median time to progression was 2.5 months (range 1.5–13). TC was discontinued due to disease progression in 12 (80%), toxicity in 2 (13%), and patient refusal (not related to toxicity) in 1 (7%). At a median follow-up time of 7.7 months, 14/15 (93%) patients had died of disease progression. Failing treatment with TC, one patient subsequently had a complete response (CR) to an IGF-1R antibody and remains in CR at 28 months.

3.4. Toxicity

Hematological toxicity was observed in 7 (47%) patients (Table 3). Seven patients (47%) required at least one blood transfusion and three patients (20%) required at least one platelet transfusion. Five patients (33%) had at least one episode of febrile neutropenia.

Table 3: Toxicity related to topotecan/cyclophosphamide chemotherapy.

Toxicity
Number ()
Percentage (%)

Febrile neutropenia
5
33%

Patient requiring transfusion
7
47%

    Blood
7
47%

    Platelets
3
20%

Discontinuation of therapy
2
13%

4. Discussion

This is the first paper reporting outcomes of adults with relapsed sarcoma who received salvage chemotherapy with topotecan plus cyclophosphamide. Although the combination seems tolerable, there is less activity observed in adults with relapsed EWS and RMS compared to previously reported pediatric series [7, 9]. There were no responses seen in the 5 adults with EWS.

Due to the rarity of “chemo-sensitive” sarcomas in adult oncology practices, it is difficult to design trials to systematically evaluate regimens for patients with relapsed EWS or RMS. In this regard, extrapolation from pediatric series is common; however, our data, though limited in sample size, caution against assuming equivalent outcomes across ages. There are likely differences in primary therapy delivered between patients included in this series and the previously published pediatric patients. For example, pediatric RMS patients would have likely received vincristine/actinomycin/cyclophosphamide-based chemotherapy, rather than that containing doxorubicin as in our series. Nonetheless, the 2 patients with RMS who attained a partial response to TC chemotherapy had previously received vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide and etoposide. Response to TC does not seem to correlate with prior exposure to alkylating agents [7]. TC was used as 3rd line therapy in 2 others with RMS who did not respond. In EWS, older patients more commonly present with large pelvic disease [13], and are offered local control later compared to that prescribed by pediatric protocols [3] perhaps contributing to differences in response to salvage therapies.

There is substantial interpatient variability in the pharmacokinetics of topotecan with 10-fold variability in systemic clearance of the drug [14]; however, to date there have been no studies examining pharmacokinetic targeting in patients with EWS or RMS. Cyclophosphamide pharmacokinetics are also quite variable, and age-related differences in drug handling between pediatric and adult patients may, in part, play a role in outcome of patients with sarcoma [15–19]. The haematological toxicity in this study was modest and comparable to prior studies in which there was routine use of growth factor support [7, 9].

In conclusion, topotecan plus cyclophosphamide combination is tolerable but has less activity in adults with recurrent sarcoma than previously reported in pediatric series. It may have more benefit when used as 2nd line, and its use as 3rd-line therapy should be limited. Confirmation of our preliminary data is required with larger adult series; however, patients with relapsed EWS should perhaps be offered alternative therapeutic opportunities such as temozolomide plus irinotecan [20, 21] or clinical trials exploiting novel targets.

References

I. Sultan, I. Qaddoumi, S. Yaser, C. Rodriguez-Galindo, and A. Ferrari, “Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients,” Journal of Clinical Oncology, vol. 27, no. 20, pp. 3391–3397, 2009.

H. Al-Hussaini, D. Hogg, M. E. Blackstein et al., “Clinical features, treatment, and outcome in 102 adult and pediatric patients with localized high-grade synovial sarcoma,” Sarcoma, vol. 2011, Article ID 231789, 7 pages, 2011.

A. A. Gupta, A. Pappo, N. Saunders et al., “Clinical outcome of children and adults with localized ewing sarcoma: impact of chemotherapy dose and timing of local therapy,” Cancer, vol. 116, no. 13, pp. 3189–3194, 2010.

M. Scurr and I. Judson, “How to treat the Ewing's family of sarcomas in adult patients,” Oncologist, vol. 11, no. 1, pp. 65–72, 2006.

R. B. Womer, D. C. West, M. D. Krailo, P. S. Dickman, and B. Pawel, “Randomized comparison of every-two-week v. every-three-week chemotherapy in Ewing sarcoma family tumors (ESFT),” Journal of Clinical Oncology, vol. 26, supplement, abstract 10504, no. 15S, 2008.

Y. Pommier, “Eukaryotic DNA topoisomerase I: genome gatekeeper and its intruders, camptothecins,” Seminars in Oncology, vol. 23, no. 1, supplement, pp. 3–10, 1996.

R. L. Saylors, K. C. Stine, J. Sullivan et al., “Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a pediatric oncology group phase II study,” Journal of Clinical Oncology, vol. 19, no. 15, pp. 3463–3469, 2001.

D. O. Walterhouse, E. R. Lyden, P. P. Breitfeld, S. J. Qualman, M. D. Wharam, and W. H. Meyer, “Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a children's oncology group study,” Journal of Clinical Oncology, vol. 22, no. 8, pp. 1398–1403, 2004.

A. Hunold, N. Weddeling, M. Paulussen, A. Ranft, C. Liebscher, and H. Jürgens, “Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors,” Pediatric Blood and Cancer, vol. 47, no. 6, pp. 795–800, 2006.

M. L. Bernstein, M. Devidas, D. Lafreniere et al., “Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: pediatric oncology group/children's cancer group phase II study 9457—a report from the children's oncology group,” Journal of Clinical Oncology, vol. 24, no. 1, pp. 152–159, 2006.

http://www.clinicaltrials.gov/ct2/show/NCT00618813?term=AEWS07P1&rank=1, 2011

E. A. Eisenhauer, P. Therasse, J. Bogaerts et al., “New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1),” European Journal of Cancer, vol. 45, no. 2, pp. 228–247, 2009.

S. J. Cotterill, S. Ahrens, M. Paulussen et al., “Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group,” Journal of Clinical Oncology, vol. 18, no. 17, pp. 3108–3114, 2000.

J. R. Park, J. R. Scott, C. F. Stewart, et al., “Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study,” Journal of Clinical Oncology, vol. 29, no. 33, pp. 4351–4357, 2011.

T. Macarulla, E. Rodriguez-Braun, J. Tabernero, et al., “Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of the selective aurora A kinase (AAK) inhibitor MLN8054 in patients (pts) with advanced solid tumors,” Journal of Clinical Oncology, vol. 27, no. 15S, article 2578, 2009.

J. S. McCune, A. Batchelder, H. J. Deeg et al., “Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality,” Biology of Blood and Marrow Transplantation, vol. 13, no. 7, pp. 853–862, 2007.

J. S. McCune, A. Batchelder, K. A. Guthrie et al., “Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients with hematologic malignancy,” Clinical Pharmacology and Therapeutics, vol. 85, no. 6, pp. 615–622, 2009.

J. S. McCune, D. H. Salinger, P. Vicini, C. Oglesby, D. K. Blough, and J. R. Park, “Population pharmacokinetics of cyclophosphamide and metabolites in children with neuroblastoma: a report from the children's oncology group,” Journal of Clinical Pharmacology, vol. 49, no. 1, pp. 88–102, 2009.

A. A. Gupta, J. R. Anderson, A. S. Pappo et al., “Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma: a Report From the Children's Oncology Group Soft Tissue Sarcoma Committee,” Cancer, vol. 118, no. 4, pp. 1130–1137, 2012.

D. A. Casey, L. H. Wexler, M. S. Merchant et al., “Irinotecan and temozolomide for Ewing sarcoma: the memorial sloan-kettering experience,” Pediatric Blood and Cancer, vol. 53, no. 6, pp. 1029–1034, 2009.

L. M. Wagner, N. McAllister, R. E. Goldsby et al., “Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma,” Pediatric Blood and Cancer, vol. 48, no. 2, pp. 132–139, 2007.