Topotecán en el tratamiento de niños con tumores sólidos refractarios o recidivantes

Pérez Martínez, A.; Contra, T.; Scaglione, C.; Díaz Pérez, M.A.; Madero López, L.

doi:10.1016/S1695-4033(03)78738-4

Información del artículo

Antecedentes

Topotecán es un quimioterápico alcaloide derivado de la planta Camptotheca acuminata (originaria de China) con capacidad de inhibir la enzima topoisomerasa I y de reciente uso en el tratamiento del cáncer pediátrico.

Objetivos

Evaluar nuestra experiencia preliminar con el topotecán en el tratamiento de segunda línea de tumores sólidos refractarios en la edad pediátrica.

Pacientes y métodos

Estudio retrospectivo de 10 pacientes con tumores sólidos refractarios o recidivantes a la primera línea de tratamiento que reciben topotecán en monoterapia o en asociación con otros agentes quimioterápicos.

Resultados

Se incluyeron 10 pacientes con tumores sólidos refractarios o recidivantes al tratamiento convencional (dos neuroblastomas, tres rabdomiosarcomas, dos tumores neuroectodérmicos primitivos (PNET)/Ewing, un astrocitoma anaplásico, un tumor desmoplásico y un sarcoma sinovial). Obtuvieron respuesta favorable 5 pacientes (dos remisiones completas, dos remisiones parciales y un estabilización de la enfermedad). En 5 pacientes no se consiguió ninguna respuesta. Todos los pacientes presentaron toxicidad hematológica de grado III-IV.

Conclusiones

En nuestra experiencia, topotecán sería beneficioso en determinados tumores sólidos refractarios o recidivantes, sobre todo neuroblastomas y sarcomas de partes blandas, con una aceptable tolerancia a la toxicidad hematopoyética con el uso de factores estimulantes de colonias granulocíticas. Los pacientes en remisión completa de su enfermedad tras topotecán podrían beneficiarse de una intensificación de quimioterapia con rescate autólogo de progenitores hematopoyéticos.

Palabras clave:

Glioma de tronco

Neuroblastoma

PNET

Rabdomiosarcoma

Sarcoma sinovial

Topotecán

Tumor desmoplásico

Tumores sólidos refractarios

Background

Topotecan is a cytotoxic drug isolated from the Camptotheca acuminata tree (from China). It is able to block the enzyme DNA topoisomerase I and has recently been used in the treatment of pediatric cancer.

Objectives

To evaluate our preliminary experience with topotecan in the second line treatment of refractory solid tumors in the pediatric age group.

Patients and methods

We performed a retrospective study of 10 patients with various recurrent solid tumors resistant to first line treatment who were treated with topotecan alone or in association with other chemotherapeutic agents.

Results

Ten patients with recurrent solid tumors or tumors that were refractory to conventional treatment (two neuroblastomas, three rhabdomyosarcoma, two PNET/Ewing's sarcoma, one anaplastic astrocytoma, one soft tissue sarcoma and one synovial sarcoma) were included. Five patients showed favorable responses (two had complete responses, two had partial responses and one had stable disease). Five patients showed no response. All patients showed grade II-IV hematological toxicity.

Conclusions

In our experience, topotecan is beneficial in some refractory or recurrent solid tumors, especially neuroblas-tomas and soft tissue sarcomas. Myelosuppression was tolerable with the use of granulocyte colony-stimulating factors. Patients with a complete response to topotecan could benefit from high-dose chemotherapy and autologous stem cell rescue therapy.

Key words:

Brainstem glioma

Neuroblastoma

PNET/Ewing's sarcoma

Rhabdomyosarcoma

Soft tissue sarcoma

Synovial sarcoma

Topotecan

Recurrent and refractory pediatric solid tumors

El Texto completo está disponible en PDF

Bibliografía

[1.]

C. Rodríguez-Galindo, K. Radomski, F. Clinton, W. Furman, V. Santana, P. Houghton.

Clinical use of topoisomerase I inhibitors in anticancer treatment.

Med Pediatr Oncol, 35 (2000), pp. 385-402

Medline

[2.]

R. Saylors, C. Stine, J. Sullivan, J. Kepner, D. Wall, M. Bernstein, et al.

Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: A pediatric oncology group phase II study.

J Clin Oncol, 19 (2001), pp. 3463-3469

http://dx.doi.org/10.1200/jco.2001.19.15.3463 | Medline

[3.]

U. Athale, C. Stewart, J. Kuttesch, A. Maghrabi, W. Meyer, C. Pratt, et al.

Phase I study of combination topotecan and carboplatin in pediatric solid tumors.

J Clin Oncol, 20 (2002), pp. 88-95

http://dx.doi.org/10.1200/jco.2002.20.1.88 | Medline

[4.]

R. Wells, J. Reid, M. Ames, W. Mares, M. Krailo, N. Seibel, et al.

Phase I trial of cisplatin and topotecan in children with recurrent solid tumors: Children's cancer group study 0942.

J Pediatr Hematol/Oncol, 24 (2002), pp. 89-93

[5.]

B. Kushner, K. Kramer, P. Meyers, N. Wollner, N. Cheung.

Pilot study of topotecan and high. Dose cyclophosphamide for resistant pediatric solid tumors.

Med Pediatr Oncol, 35 (2000), pp. 468-474

Medline

[6.]

R. Nietschke, J. Parkhusrst, J. Sullivan, M. Harris, M. Bernstein, C. Pratt.

Topotecan in pediatric patients with recurrent and progressive solid tumors: A pediatric oncology group Phase II study.

J Pediatr Hematol/Oncol, 20 (1998), pp. 315-318

[7.]

G.J. Greemers, G. Bolis, M. Gore, G. Scarfone, A.J. Lacave, J.P. Guastalla, et al.

Topotecan an active drug in the second line treatment of epithelial ovarian cancer: Results of a large European Phase II study.

J Clin Oncol, 14 (1996), pp. 3056-3061

http://dx.doi.org/10.1200/jco.1996.14.12.3056 | Medline

[8.]

J. Schillrer, K. Kim, P. Hutson.

Phase II study of topotecan in patients with extensive stage small cell carcinoma of the lung: An Eastern Cooperative Oncology Group trial.

J Clin Oncol, 14 (1996), pp. 2342-2352

[9.]

C. Pratt, C. Stewart, V. Santana, L. Bowman, W. Furman, J. Ochs, et al.

Phase I study of topotecan for pediatric patients with malignant solid tumors.

J Clin Oncol, 12 (1994), pp. 539-543

http://dx.doi.org/10.1200/jco.1994.12.3.539 | Medline

[10.]

C. Stewart, S. Baker, R. Heideman, D. Jones, W. Crom, C. Pratt.

Clinical pharmacodynamics of continuous infusion topotecan in children: Systemic exposure predicts hematologic toxicity.

J Clin Oncol, 12 (1994), pp. 1946-1954

http://dx.doi.org/10.1200/jco.1994.12.9.1946 | Medline

[11.]

H. Frangoul, M. Ames, R. Mosher, J. Reid, M. Krailo, N. Seibel, et al.

Phase I study of topotecan administered as a 21-day continuous infusion in children with recurrente solid tumors: A report from the children's cancer group.

Clin Canc Res, 5 (1999), pp. 3956-3962

[12.]

R. Saylors, C. Stewart, W.C. Zamboni, D. Wall, B. Bell, K.C. Stine, et al.

Phase I study of topotecan in combination with cyclophosphamide in pedoatric patients with malignant solid tumors: A Pediatric Oncology Group study.

J Clin Oncol, 16 (1998), pp. 945-952

http://dx.doi.org/10.1200/jco.1998.16.3.945 | Medline

[13.]

S.B. Lansky, M.A. List, L.L. Lansky, C. Ritter-Sterr, D. Miller.

The measurement of performance in childhood cancer patients.

Cancer, 60 (1987), pp. 1651-1656

Medline

[14.]

A. Trotti, R. Byhardt, J. Stetz, C. Gwede, B. Corn, K. Fu, et al.

Common toxicity criteria: Version 2.0 an improved reference for grading the acute effects of cancer treatment: Impact of radiotherapy.

Int J Radiat Oncol Biol Phys, 47 (2000), pp. 13-47

Medline

[15.]

R. Kadota, C. Stewart, M. Horn, J. Kuttescs, P. Burger, J. Kepner, et al.

Topotecan for the treatment of recurrent or progressive centra nervous system tumors –a pediatric oncology group phase II study.

J Neuro-oncol, 43 (1999), pp. 43-47

[16.]

D. Tubergen, C. Stewart, C. Pratt, W. Zamboni, N. Winick, Z. Dryer, et al.

Phase I trial and pharmacokinetic and pharmacodynamics study of topotecan using a five-day course in children with refractory solid tumors: A pediatric oncology group study.

J Pediatr Hematol Oncol, 18 (1996), pp. 352-361

Medline

[17.]

S. Blaney, F. Balis, D. Cole, C. Craig, J. Reid, M. Ames, et al.

Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion.

Cancer Research, 53 (1993), pp. 1032-1036

Medline

[18.]

A. Pappo, E. Lyden, J. Breneman, E. Wiener, L. Teat, J. Meza, et al.

Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: An intergroup rhabdomyosarcoma study.

J Clin Oncol, 19 (2001), pp. 213-219

http://dx.doi.org/10.1200/jco.2001.19.1.213 | Medline

[19.]

J. Park, J. Slattery, T. Gooley, D. Hawkins, K. Lindsley, J. Villablanca, et al.

Phase I topotecan preparative regimen for high-risk neuroblastoma, high-grade glioma, and refractory/recurrent pediatric solid tumors.

Medical and Pediatric Oncology, 35 (2000), pp. 719-723

Medline

[20.]

A. Langler, A. Christaras, K. Abshagen, K. Krauth, B. Hero, F. Berthold.

Topotecan in the treatment of refractory neuroblastoma and other malingnant tumors in childhood-a phase II study.

Klin Pediatr, 214 (2002), pp. 153-156

[21.]

B. Kushner, N. Cheung, K. Kramer, I. Dunkel, E. Calleja.

Topotecan combined with myeloablatie doses of thiotepan an d carboplantin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults.

Bone Marrow Trasplantation, 28 (2001), pp. 551-555

[22.]

S. Blaney, M. Needle, A. Gillespie, J. Sato, G. Reaman, S. Berg, et al.

Phase II trial of topotecan administered as a 72-hour continuous infusion in children with refractory solid tumors: A collaborative pediatric branch, national cancer institute, and children's cancer group study.

Clin Can Res, 4 (1998), pp. 357-360

[23.]

W. Furman, C. Stewart, M. Kirstein, J. Kepner, M. Bernstein, F. Kung, et al.

Protracted Intermittent shedule of topotecan in children with refractory acute leukemia: A pediatric oncology group study.

J Clin Oncol, 6 (2002), pp. 1617-1624

[24.]

S. Baker, R. Heideman, W. Crom, J. Kuttesch, A. Gajjar, C. Stewart.

Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors.

Cancer Chemother Pharmacol, 37 (1996), pp. 195-202

Medline

[25.]

W. Zamboni, L. Bowman, M. Tan, V. Santana, P. Houghton, W. Meyer, et al.