The impact of low dose methotrexate on cerebral complications in acute lymphoblastic leukemia treatment Original Article

Abstract

Aim: The aim of this study is to determine the possible side effects of central nervous system CNS prophylactic treatment in childhood leukemia by using cranial imaging techniques Material and Method: Data collected from records of 90 patients diagnosed as acute lymphoblastic leukemia ALL and treated according to BFM 90 or TR ALL 2000 protocols which used lowered dose of methotrexate between January 1991 and December 2004 Gender age at diagnosis immunophenotype cranial radiation doses risk groups intrathecal treatment modalities neurological and electroencephalography EEG findings imaging interval and techniques were recorded These variables were analyzed for their role in cranial lesions Patiens with CNS leukemia and mature B cell phenotype were excluded Results: Ninety patients were enrolled in the study Sixty three patients had up to 18 Gy cranial radiation whereas in 27 patients radiation was not utilized Eleven doses of Intrathecal methotrexate were administered to 77 patients and 13 patients had more intensive regimen No patients demonstrated cortical atrophy or calcifications Mild white matter changes WMC were observed in eight patients Only one patient had moderate changes Eight of the nine patients with WMC had radiotherapy but no significant correlation was found p gt;0 05 There were also no significant relation of WMA with gender age at diagnosis treatment protocol risk groups intrathecal therapy neurologic symptoms EEG finding and imaging techniques p gt;0 05 Conclusions: Intrathecal treatment does not cause cortical atrophy White matter changes are not influenced by systemic methotrexate dose but radiotherapy may have an additive effect Short interval between CNS prophylaxis and imaging can be responsible for the limitation of our study at detecting the late effects of radiotherapy A new study aiming at investigating the late effects of radiotherapy by performing late imaging studies may be more informative Turk Arch Ped 2009; 44: 62 7 Key words: Acute leukemia pediatric treatment complication imaging

Keywords

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Akut lenfoblastik lösemi tedavisinde düşük dozda metotreksatın beyin komplikasyonlarına etkisi Orijinal Araştırma

Öz

Amaç: Çocukluk çağı lösemilerinde koruyucu tedavinin olası yan etkilerinin kraniyal görüntüleme teknikleriyle incelenmesi amaçlanmıştır Gereç ve Yöntem: Çalışmaya Ocak 1991 ile Aralık 2004 tarihleri arasında akut lenfoblastik lösemi ALL tanısı ile izlenen ve sistemik metotreksat dozu azaltılmış BFM 90 ve TR ALL 2000 tedavi protokolü uygulanan hastalar alındı Hastaların cinsiyeti tanı yaşı ALL tiplendirmesi risk grubu uygulanan tedavi protokolü kraniyal ışınlama dozu ek intratekal tedavi şekli tedavi sırasında saptanan merkezi sinir sistemi bulguları elektroansefalografi değerlendirmeleri görüntüleme yöntemi ve tarihi değerlendirildi Hastalar görüntülemelerinde saptanan lezyonlara göre gruplanarak yukarıdaki değişkenlerle aralarındaki ilişki araştırıldı Tanı anında merkezi sinir sistemi tutulumu saptanan veya B ALL tanısı alanlar çalışma dışı bırakıldı Bulgular: Çalışma grubunu 90 hasta oluşturdu Hastaların 63’üne radyoterapi uygulanmıştı İntratekal tedavi 77 hastaya sadece metotreksatla 11 doz diğerlerine daha yoğun olarak yapılmıştı Hastalarda kortikal atrofi ve kraniyal kalsifikasyon saptanmadı Demiyelinizasyona bağlı değişik yoğunlukta lezyonlar ise dokuz hastada saptandı Olguların sekizinde hafif derecede lezyon saptanırken birinde orta derecede lezyon saptandı Lezyon saptanan olguların sekizine radyoterapi uygulanmış olmakla beraber anlamlı ilişki saptanmadı p gt;0 05 Değişik yoğunluktaki lezyonların cinsiyet tanı yaşı tedavi protokolü risk grubu intratekal tedavi yöntemi nörolojik bulgu elektroansefalografide bozulma ve görüntüleme yöntemleri ile anlamlı ilişkileri bulunmadı p gt;0 05 Çıkarımlar: Bu bulgular kortikal atrofinin intratekal tedaviyle ilişkili olmadığını ve beyaz madde lezyonlarından sorumlu tutulan sistemik metotreksatın dozunun belirleyici olmadığını göstermektedir Lezyon saptanan hastaların çoğuna ışın tedavisi uygulanmış olması nedeniyle radyoterapinin metotreksata bağlı beyaz madde lezyonlarının oluşmasına katkı sağlayabileceğini düşünüyoruz Çalışmamızda radyoterapinin geç etkilerini saptamamamız tedavi ile görüntülemeler arasındaki sürenin kısa olmasına bağlı olabilir Radyoterapi alan hastalarımıza görüntülemelerin geç dönemde planlandığı bir çalışma bu durumu açıklamak için uygun olacaktır Türk Ped Arş 2009; 44: 62 7 Anahtar kelimeler: Akut lösemi pediatrik tedavi komplikasyon görüntüleme

Anahtar Kelimeler

• Akut lösemi, pediatrik, tedavi, komplikasyon, görüntüleme

References

1. Asato R, Akiyama Y, Ito M, et al. Nuclear magnetic resonance abnormalities of the cerebral white matter in children with acute lymphoblastic leukaemia and malignant lymphoma during and after central nervous system prophylactic treatment with intrat- hecal methotrexate. Cancer 1992; 7: 1997-2003.
2. Iuvone L, Mariotti P, Colosimo C, Guzetta F, Ruggiero A, Riccar- di R. Long-term cognitive outcome, brain computed tomography scan and magnetic resonance ımaging in children cured for acu- te lymphoblastic leukemia. Cancer 2002; 12: 2562-70.
3. Ramu-Peylan N, Poplack GD, Pizzo AP, Adornato TB, Chiro G. Abnormal CT scans of the brain in asymptomatic children with acute lymphocyctic leukemia after prophylactic treatment of the central nervous system with radiation and intrathecal chemothe- rapy. N Engl J Med 1978; 298: 815-8.
4. Prassopoulos P, Cavouras D, Golfinopoulos S. et al. Quantitati- ve assesment of cerebral atrophy during and after treatment in children with acute lymphoblasic leukemia. İnvest Radiol 1996; 12: 749-54.
5. Pim B, Riccardo R, Paul F, Poplack GD. Long-term neuropsy- chologic sequelae of childhood leukemia: correlation with CT brain scan abnormalities. J Pediatr 1985; 5: 723-8.
6. Duffner P, Cohen EM, Brecher M, et al. CT abnormallities and al- tered methotrexate clearence in children with CNS leukemia. Ne- urology 1984;34:229-33.
7. Ochs J, Berger P, Brecher LM, et al. Computed tomography bra- in scans in children with acute lymphocyctic leukemia receiving methotrexate alone as central nervous system prophylaxis. Can- cer 1980; 45: 2274-8.
8. Sağlamer L, Ulukutlu L, Yıldız İ. Modifiye BFM protokolları ile ço- cuklarda akut lenfoblastik lösemi tedavisi; 1993; (4): 65-72.

9. Wilson AD, Nitschke R, Bowman EM, Chaffin JM, Sexauer LC, Prince RJ. Transient white matter changes on MR images in chil- dren undergoing chemotherapy for acute lymphoblastic leukemi- a: correlation with neuropsychologic deficiencies. Radiology 1991; 180: 205-9.
10. Hertzberg H, Huk JW, Ueberall AM, et al. CNS late effects after ALL therapy in childhood. Part 1: Neuroradiological findings in long term survivors of childhood ALL-an evaluation of the inter- ferences between morphology and neuropsychological perfor- mance. Med Pediatr Oncol 1997; 28: 387-400.
11. Riccardi R, Brouwers P, di Chiro G, Poplack GD. Abnormal com- puted tomography brain scans in children with acute lymphoblas- tic leukemia: serial long-term follow-up. J Clin Oncol 1985; 1: 12-8.
12. Reddick EW, Shan YZ, Glass OJ. Smaller white-matter volumes are associated with larger deficits in attention and learning among long-tem survivors of acute lymphoblastic leukemia. Cancer 2006; 106: 941-9.
13. Ochs JJ, Rivera G, Aur JR, Hutsu OH, Berg R, Simone VJ. Cen- tral nervous system morbidity following an initial isolated central nervous system relapse and its subsequent therapy in childhood acute lymphoblastic leukemia. J Clin Oncol 1985; 5: 622-6.
14. Winnie CW, Ki-wai C, Yu-leung C, et al. White Matter and cerebrl metabolite changes in children undergoing treatment for acute lymphoblastic leukemia: longitudinal study with MR imaging and HMR spectroscopy. Radiology 2003; 3: 659-69.
15. Harila-Saari AH, Pääkkö EL, Vainionpää LK, Pyhtinen J, Lanning BM. A longitudinal magnetic resonance imaging study of the bra- in in survivors of childhood acute lmphoblastic leukemia. Cancer 1998; 12: 2608-17.
16. Pääkkö E, Harila-Saari A, Vanionpää L, Himanen S, Pyhtinen J, Lanning M. White matter changes on MRI during treatment in children with acute lymphoblastic leukemia: correlation with neu- ropsychological findings. Med Pediatr Oncol, 2000; 35; 456-61.
17. Haykin ME, Gorman M, Van Hoff J, Fulbright RK, Baehring JM. Diffusion-weighted MRI correlates of subacute methotrexate- related neurotoxicity. J Neurooncol 2006; 76: 153-7.
18. Corn WB, Yousem MD, Scott BC, et al. White matter changes are correlated significantly with radiation dose. Cancer 1994; 10: 2828-35.
19. Fouladi M, Chintagumpala M, Laningham HF. White matter lesi- ons detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 2004; 22: 4551- 60.
20. Aytaç S, Yetgin S, Tavil B. Acute and long-term neurologic complications in children with acute lymphoblastic leukemia. Turk J Pediatr 2006;48:1-7.
21. Korinthenberg R, Scheuring B, Boos J, Niemeyer C. On the ori- gin of EEG-slowing and encephalopathy during induction treat- ment of acute lymphoblastic leukemia. Med Pediatr Oncol 2002; 39: 566-72.
22. Ueberall AM, Skirl G, Strassburg MH, et al. Neurophysiological findings in long-term survivors of acute lymphoblastic leukemia in childhood treated with BFM protocol 81 SR-A/B. Eur J Pediatr 1997; 156: 727-33.
23. Ueberall AM, Wenzel D, Hertzbeg H, et al. CNS late effects after ALL therapy in childhood. Part 2: Conventional EEG recordings in asymptomatic long term survivors of childhood ALL-an evalu- ation of the interferences between neurophysiology, neurology, psychology, an CNS morphology. Med Pediatr Oncol 1997; 29: 121-31.
24. Campbell WH. The use of electroencephalography in forensic evaluations. Am Acad Pychiatr LAW 2002: 27.
25. Smith D, Bartolo R, Pickles MR, Tedman MB. Requests for elec- troencephalography in a district general hospital: retrospective and prospective audit. BMJ 2001; 322: 954-7.