Journal of Thoracic Oncology:
Letters to the Editor
Zauderer, Marjorie MD; Krug, Lee M. MD; Pietanza, M. Catherine MD; O'Rourke, Denise RN
Thoracic Oncology Service; Department of Medicine; Memorial Sloan-Kettering Cancer Center; New York, New York
Disclosure: M. Catherine Pietanza, MD, receives research funding from Schering-Plough (now Merck). The other authors declare no conflicts of interest.
Address for correspondence: Lee M. Krug, MD, Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. E-mail: firstname.lastname@example.org
To the Editor:
Leptomeningeal spread of small cell lung cancer (SCLC) is extremely difficult to treat. Symptoms typically progress rapidly, and the prognosis is poor with a median survival of 1.3 months.1 Temozolomide, a nonclassic oral alkylating agent with penetration into the central nervous system, is a standard therapy for glioblastoma multiforme and refractory astrocytoma. Herein, we report two patients with leptomeningeal metastases from SCLC who received temozolomide and had dramatic improvement of their disease.
A 53-year-old man, former 37 pack-year smoker, was diagnosed with SCLC after presenting with limbic encephalitis. He received six cycles of etoposide and cisplatin with concurrent radiation therapy to the thorax. A brain metastasis was irradiated and then resected because of increased symptoms. Subsequent imaging revealed new brain lesions and plaque-like leptomeningeal spread. Temozolomide was started at 75 mg/m2 for 21 days of a 28-day cycle and modified to 125 mg/m2 for 5 days because of grade 4 thrombocytopenia. Imaging 10 weeks after starting temozolomide showed significant interval improvement. Unfortunately, an magnetic resonance imaging of the spine 6 weeks later showed progression.
A 61-year-old woman, former 44 pack-year smoker, was diagnosed with SCLC after presenting with postobstructive pneumonia. She received five cycles of carboplatin and etoposide and radiation to alleviate left main stem bronchus obstruction. She also received whole brain radiation for a lesion on the third ventricle. Imaging 4 months later revealed extensive leptomeningeal disease (Figure 1A). She started temozolomide 150 mg/m2 for 5 days every 21 days. Repeat imaging after 7.5 weeks showed significant improvement (Figure 1B). Follow-up magnetic resonance imagings showed maintained response at 6 weeks but progression at 18 weeks.
For over 40 years, alkylating agents have demonstrated efficacy in SCLC. Alkylators produce specific DNA lesions that, when left unrepaired, lead to cytotoxicity and apoptosis. The MGMT (O6-methyl-guanine-DNA methyltransferase) gene encodes a DNA-repair protein that is irreversibly inactivated with each repair of alkylator-induced damage. Availability of MGMT may therefore be an important determinant of treatment failure with alkylators.2 In addition, methylation of the MGMT promoter may affect sensitivity to alkylating agents,2 and aberrant methylation of MGMT is found in SCLC.
To better characterize temozolomide activity in SCLC, we are conducting a phase II trial of temozolomide as second- or third-line therapy for SCLC. Patients with brain metastases are eligible but leptomeningeal disease is excluded because of the poor prognosis. Preliminary data were presented at the International Association for the Study of Lung Cancer meeting in 2009. Of note, regression of brain metastases in three patients previously treated with cranial radiation was observed.3
Herein, we reported the dramatic responses of SCLC leptomeningeal disease to temozolomide in two patients. The responses may not be durable, but this treatment clearly improved survival for these patients. Based on these robust responses and the preliminary data from our ongoing trial, we are hopeful that temozolomide will prove a useful addition to the arsenal of agents with efficacy in SCLC.
Marjorie Zauderer, MD
Lee M. Krug, MD
M. Catherine Pietanza, MD
Denise O'Rourke, RN
Thoracic Oncology Service
Department of Medicine
Memorial Sloan-Kettering Cancer Center
New York, New York
1.Seute T, Leffers P, ten Velde GP, et al. Leptomeningeal metastases from small cell lung carcinoma. Cancer
2.Gerson SL. Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol
3.Pietanza MC, Periera L, Dunne M, et al. Phase II study of temozolomide for relapsed sensitive or refractory small cell lung cancer. J Thorac Oncol