Correspondence

Treatment of Growing Teratoma Syndrome

N Engl J Med 2009; 360:423-424January 22, 2009

Article

To the Editor:

Growing teratoma syndrome consists of an enlarging mature teratoma arising during or after chemotherapy for a nonseminomatous germ-cell tumor, with normal serum levels of alpha-fetoprotein and human chorionic gonadotropin.1 The preferred treatment is complete surgical resection2 because teratomas are resistant to chemotherapy and radiation therapy.

Although embryonal carcinomas express little or no retinoblastoma protein (pRB),3 mature teratomas express high levels of pRB. Normally, cyclin-dependent kinase 4/6 (CDK4/6) stimulates cell growth by phosphorylating pRB. The development of selective CDK inhibitors,4 including PD0332991 (Pfizer), which selectively inhibits CDK4/6, suggests a new treatment for growing teratoma syndrome.

We report on the clinical course of three men, 22 to 37 years of age, with growing teratoma syndrome who were treated in a phase 1 trial of PD0332991 for refractory solid tumors (ClinicalTrials.gov number, NCT00141297).5 This trial was sponsored and funded by Pfizer. The patients initially presented with metastatic nonseminomatous germ-cell tumors. They received four cycles of cisplatin-based chemotherapy, with normalization of serum tumor markers. Each patient underwent two or more operations for growing teratoma syndrome after chemotherapy. Subsequently, progressive disease that was not amenable to further surgery developed in all the patients. Written informed consent was obtained from the patients in this protocol, which was approved by the institutional review board of the University of Pennsylvania.

There was a strong nuclear expression of pRB in the epithelial component of the teratomas in all three patients (Figure 1A, 1B, and 1CFigure 1Immunohistochemical and Radiologic Findings in Three Patients with Growing Teratoma Syndrome after Treatment with PD0332991.). At enrollment, all patients had radiologic evidence of disease progression (Figure 1D). Patient 1 received oral PD0332991, 150 mg daily, for 21 days on an every-28-days cycle. The dose was decreased to 100 mg because of neutropenia. He had stable disease for 18 months. Patient 2 initiated treatment with PD0332991, 200 mg daily, for 14 days on an every-21-days cycle. The dose was decreased to 150 mg because of headaches and vomiting. Neutropenia also developed. He had a partial response (according to the Response Evaluation Criteria in Solid Tumors) for 22 months and continued to receive treatment. Patient 3 initiated treatment with PD0332991 at a dose of 125 mg daily for 21 days on an every-28-days cycle. He also had neutropenia. He had stable disease for 24 months and continued to receive treatment.

These preliminary data suggest that PD0332991 has therapeutic benefit in patients with growing teratoma syndrome in whom the tumor is inoperable. We suggest further evaluation of CDK inhibitors in pRB-expressing teratomas.

David J. Vaughn, M.D.
Keith Flaherty, M.D.
Priti Lal, M.D.
Maryann Gallagher, R.N.
Peter O'Dwyer, M.D.
Abramson Cancer Center, Philadelphia, PA 19104
david.vaughn@uphs.upenn.edu

Keith Wilner, M.D.
Isan Chen, M.D.
Pfizer, La Jolla, CA 92121

Gary Schwartz, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Dr. O'Dwyer reports being a consultant to and receiving grant support for clinical trials from Pfizer; and Drs. Wilner and Chen, being employees of and having equity interest in Pfizer.

No other potential conflict of interest relevant to this letter was reported.

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Citing Articles (7)

Citing Articles

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   P. J. Roberts, J. E. Bisi, J. C. Strum, A. J. Combest, D. B. Darr, J. E. Usary, W. C. Zamboni, K.-K. Wong, C. M. Perou, N. E. Sharpless. (2012) Multiple Roles of Cyclin-Dependent Kinase 4/6 Inhibitors in Cancer Therapy. JNCI Journal of the National Cancer Institute
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   G K Schwartz, P M LoRusso, M A Dickson, S S Randolph, M N Shaik, K D Wilner, R Courtney, P J O'Dwyer. (2011) Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). British Journal of Cancer 104:12, 1862-1868
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   Christine M. Veenstra, David J. Vaughn. (2011) Third-Line Chemotherapy and Novel Agents for Metastatic Germ Cell Tumors. Hematology/Oncology Clinics of North America 25:3, 577-591
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   Kemin Cai, Yu Wang, Xueli Bao. (2011) MiR-106b promotes cell proliferation via targeting RB in laryngeal carcinoma. Journal of Experimental & Clinical Cancer Research 30:1, 73
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   Roelof Koster, Alessandra di Pietro, Hetty Timmer-Bosscha, Johan H. Gibcus, Anke van den Berg, Albert J. Suurmeijer, Rainer Bischoff, Jourik A. Gietema, Steven de Jong. (2010) Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer. Journal of Clinical Investigation 120:10, 3594-3605
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   J L Dean, C Thangavel, A K McClendon, C A Reed, E S Knudsen. (2010) Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29:28, 4018-4032
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   Søren M. Johnson, Chad D. Torrice, Jessica F. Bell, Kimberly B. Monahan, Qi Jiang, Yong Wang, Matthew R. Ramsey, Jian Jin, Kwok-Kin Wong, Lishan Su, Daohong Zhou, Norman E. Sharpless. (2010) Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. Journal of Clinical Investigation 120:7, 2528-2536
   CrossRef