새로 진단된 뇌종양 (수모세포종, medulloblastoma)의 치료, 출처 NCI, 연세암병원 소아혈액종양과 역

[한정우]

새로 진단된 소아 수모세포종의 치료 (accessed 20151201)

·         Treatment Modalities

o    Surgery

o    Radiation therapy

o    Chemotherapy

·         Children Older Than 3 Years with Average-Risk Medulloblastoma

o    Standard treatment options

·         Children Older Than 3 Years with High-Risk Medulloblastoma

o    Standard treatment options

o    Treatment options under clinical eval‎uation

·         Children Aged 3 Years and Younger

o    Standard treatment options

o    Treatment options under clinical eval‎uation

·         Current Clinical Trials

치료의 방법

수술

수술은 종양 형태의 조직학적 확인과 예후 향상의 수단으로서 표준적인 치료의 부분이다. 전절제 또는 NTR (near total resection)은 만약 안전하게 행해질 수만 있다면, 적절한 것으로 생각된다.[1]

수술 후, 환자는 유의미한 신경학적 이상을 가질 수 있다. 이러한 이상은 수술 전 종양 관련 뇌 손상, 수두증 또는 수술 관련 뇌 손상 때문에 발생한다.[2][Level of evidence: 3iC] 상당한 수의 수모세포종 환자는 소뇌실어증후군 (cerebellar mutism syndrome)을 나타낸다. 증상은 다음과 같다.

n  말을 꺼내는 것의 지연 (발화지연)

n  Suprabulbar palsies. (식사 및 삼킴곤란, 침흘림, 발음이상)

l  실조증 (Ataxia.)

l  저긴장증 (Hypotonia.)

l  감정적 취약상태 (Emotional lability.)

소뇌실어증후군의 원인은 잘 알려져있지 않다. 소뇌의 충부 (vermian) 손상 그리고/또는 소뇌-뇌피질 tract의 손상 등이 가능한 원인으로 거론된다.[3,4]; [5][Level of evidence: 3iC] 2개의 소아암그룹연구에서 표준 및 고위험군 수모세포종 환자들을 분석한 결과, 이 중후군은 환자의 약 25%에서 관찰된다.[4-6]; [7][Level of evidence: 3iiiC] 대략 50%의 환자들이 장기간의, 영구적인 신경학적, 신경인지적 후유증을 남긴다.[5,7]

방사선치료

원발 종양 부위의 방사선 치료는 대개 54 Gy to 55.8 Gy 정도의 범위로 조사된다. 이것은 보통 1~2 cm 정도의 여유부위를 포함하며 위상 기술 (conformal technique)을 사용한다. 3~4세 이상의 모든 수모세포종 환자에게 두개척추방사선조사 (craniospinal radiation therapy)는 위험 인자에 따라 즉, 진단 당시의 침범 범위에 따라 23.4 Gy and 36 Gy 정도의 범위로 조사된다. 항암 치료는 방사선 치료의 도중 및 방사선 치료 이후 보통 투여된다.

3세 미만의 소아에서 방사선 치료를 생략하거나 지연시키는 노력이 행해져 왔다. 방사선이 이 연령의 환자에게 심각한 영향을 주기 때문이다. 모든 연령의 소아는 뇌 발달에 있어서 방사선 치료의 나쁜 영향에 민감하다. 신경학/인지적 발달, 성장, 내분비 기능에 흔히 나쁜 영향이 특히 어린 소아에서 관찰된다. 독성을 줄이는 양성사치료의 사용은 현재 연구 중이다. [8-12]

항암약물요법

보통 방사선 치료 중 또는 그 이후 투여되는 항암요법은 수모세포종이나 또는 다른 배아형 종양을 가진 좀더 연령이 높은 환자들에게 표준 요법이다. 항암약물요법은 비전이성 수모세포종을 가진 3~4세 미만의 소아 중 20~40%에서 때때로 방사선 치료의 필요성을 없애거나, 방사선 치료를 지연시키는데 사용된다.

[13,14]; [12][Level of evidence: 3iiiC]

3세 이상의 표준위험군 수모세포종

표준 치료 옵션

3세 이상의 새로 진단된 표준위험군 수모세포종의 치료는 다음과 같다.

1.      수술 Surgery.

2.      보조치료 Adjuvant therapy.

o    방사선 Radiation therapy.

o    항암약물치료 Chemotherapy.

수술

가능하다면 전절제 또는 near-total removal 을 시행한다.[1]

보조 치료

방사선 치료는 보통 수술 이후에 시행하며, 동시 항암요법을 하거나 하지않거나 한다.[15-17]

보조방사선치료

1.      수모세포종의 가장 좋은 생존 결과는 방사선 치료가 수술 이후 4~6주 이내에 시행되었을 때 얻어진다.[15-18]; [19][Level of evidence: 1iA]

2.      표준위험군수모세포종의 방사선 치료 용량은 54 Gy to 55 Gy 를 후두개와 (posterior fossa) 또는 국소종양부위 (local tumor bed)에 투여하고 23.4 Gy 를 전체신경축에 투여하는 것이다. (즉 전뇌 및 척추).[15-17,20]

o    방사선 치료 단독으로, 5년 event-free survival (EFS) 은 50% 에서 65% 까지 얻을 수 있다. (비전이성의 경우).[16,17]

o    종양 조절에 필요한 최소 두개척추방사선 용량은 알려져 있지 않다. 두개척추방사선의 용량을 항암치료 없이, 23.4Gy까지 낮추려는 시도는 독립적 (isolated) 연수막 재발이 증가하는 결과를 초래하였다.[20]

o    만약 방사선 치료 후 항암약물치료를 추가한다면, 23.4Gy 의 두개척추방사선치료는 효과적인 용량이라고 보여져 왔다.[21-23] 방사선 용량을 더 낮추는 시도는 현재 진행 중이다.

3.      수모세포종에서 표준 boost를 전체 후두개와에 시행하는 것이 치료 실패 패턴에 관한 자료를 보면, 방사선 치료를 전체 후두개와 대신 종양이 있던 부위 (tumor bed)에만 시행해도 동등하게 효과적이고, 독성을 낮출 수 있다는 것을 시사한다.[24,25]

보조항암요법 (Adjuvant chemotherapy)

항암약물요법은 표준위험군 수모세포종의 치료에 표준적인 부분이다..

1.      전향적 무작위 배정 임상시험과, 단일 arm 임상시험 등은 방사선치료 도중 및 이후 보조항암요법을 시행하는 것이 표준위험군 수모세포종의 전체 생존률 (OS)을 향상시킨다는 것을 시사한다..[7,15-19]

o    방사선 및 항암약물치료는 5년EFS  70% to 85%를 보여준다.[15-17]; [26][Level of evidence: 2A]

2.      신경축 방사선 용량을 23.4 Gy까지 낮추고, 항암요법을 병용하는 방법은 85%의 환자에서 질병조절을 달성하고, 장기 신경인지 후유증을 낮추는 결과를 보였다. [21-23,27]

3.      다양한 항암화학요법이 성공적으로 사용되어 왔고, the combination of cisplatin, lomustine, and vincristine 또는 the combination of cisplatin, cyclophosphamide, and vincristine 이 투여되어 왔다. [15,16,27,28] 추가적으로, 방사선치료 후, 고용량항암요법 및 말초조혈모세포구제법이 비슷한 생존률을 보였다.[29]

4.      수모세포종은 주로 항암요법에 민감하지만, 방사선치료 전 항암화학요법은 방사선 치료 및 추후 항암요법의 방법에 비하여 생존률 향상을 보여주지 못하였다. 몇몇 전향적 연구에서 방사선치료 전 항암화학요법은 더 낮은 생존률과 관계되어 있다.

5.      .[16-19]

3세 이상, 고위험군 수모세포종

표준 치료 옵션Standard treatment options

3세 이상, 새로 진단된 수모세포종이, 전이성 질환을 갖고 있거나 subtotal 절제 된 경우 다음의 표준 치료 옵션이 있다.:

1.      수술 Surgery.

2.      보조치료 Adjuvant therapy.

o    방사선 치료.

o    항암약물요법.

수술

표준위험군에 대해 가능하다면 육안적완전절제 (gross total resection)를 시도하는 것이 적절하다.[1] 진단시 전이성 질환 환자에 대해, 절제의 정도는 치료 결과의 독립적인 예측 인자로서 보여지지는 않아 왔다.[30]

보조 치료

고위험군 환자에서, 많은 연구 결과들은 다학제적 (multimodal) 치료가 질병조절 기간을 늘리고 DFS를 향상시킴을 보여주었다.[29,31] 대략 50~65%의 고위험군 환자들이 장기 질환 조절을 경험한다.[15,29,31-33]; [34][Level of evidence: 1iiA]

보조 방사선요법

1.      표준위험군 치료와 달리, 두개척추방사선 조사의 량은 일반적으로 36 Gy 이다.

보조 항암약물요법

1.      표준위험군 치료에 효과가 있다고 알려져있는 약과 고위험군 치료에 광범위하게 쓰이는 약은 같다. cisplatin, lomustine, cyclophosphamide, etoposide, and vincristine 등이다.[34]

2.      방사선 치료 후 고용량, 비골수억제 항암요법 후 말초 조혈모세포 이식술은 5년 무진행생존률 (PFS) 약 60% 정도를 나타내었다.[29]

임상연구중인 치료옵션

다음은 국가, 국제적 임상 시험의 예이다.

1.      COG-ACNS0332 (NCT00392327) (Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma or Supratentorial Primitive Neuroectodermal Tumor): 3세 이상 소아의 수모세포종 또는 천막상부 PNET에서 방사선 치료에 vincristine, carboplatin을 사용하고, 이후 통상적인 보조항암요법 및 isotretinoin을 투여하는 유지 요법을 진행함.

3세 이하의 소아

표준 치료 옵션

수모세포종을 가진 어린 소아의 5년 DFS rates 는 30~70% 사이에 위치하며, 전이가 없고 완전 절제 되었으며, desmoplasia의 조직 소견을 가진 대부분의 장기 생존자들은 항암치료 단독으로 성공적인 치료가 된다. [13,35,36]

3~4세 이하의 새로 진단된 수모세포종 환자들의 치료는 지속적으로 발전되어 왔다. 치료의 접근법은 미성숙한 신경계에 해로운 효과를 나타내는 두개척추방사선치료의 사용을 지연시키거나, 몇몇 경우에는 완전히 피하는 것이다. 성적들은 다양하였으며, 연구 결과들을 비교해 보는 것은 어려운데, 왜냐하면, 치료의 방식이 연구마다 다르고, 두개척추 및 국소 방사선 요법을 항암치료 종료시 또는 몇몇 연구에서는 3세에 도달할 때 진행하는 등의 차이들 때문이다..

3세 이하 소아의 새로 진단된 수모세포종 표준 치료 옵션은 다음과 같다.:

1.      수술 Surgery.

2.      보조항암약물요법Adjuvant chemotherapy.

수술

가능하다면, 종양의 완전 절제가 적절한 치료이다. 수술적 절제가능여부는 조직에 따라 다른데, desmoplastic 수모세포종 또는 extensive nodularity를 가진 수모세포종 (MBEN)은 완전 절제율이 다른 전통적 수모세포종 환자에 비해 높다..[37,38]

보조항암약물요법

1.      어린 소아의 수모세포종 치료에는 다양한 항암약물요법을 포함한다. 약제는 cyclophosphamide, etoposide, cisplatin, and vincristine, with or without concomitant high-dose intravenous methotrexate 그리고/또는 척추강내 methotrexate or mafosfamide, 그리고/또는 뇌실내 등을 포함한다.[13,35,36,38-40]; [41][Level of evidence: 2A]; [42][Level of evidence: 2B]

2.      몇몇 연구에서 desmoplasia의 조직 소견 (desmoplastic 수모세포종 이나 MBEN에서 관찰되는)은 전통적 수모세포종이나 large cell/anaplastic 수모세포종에 비하여 유의하게 좋은 예후를 보여주었다.[37,38,43-45]; [46][Level of evidence: 2A]

o    Desmoplasia 는 독일 HIrnTumor (HIT) 2000 multicenter trial 에서 EFS에 있어서 독립적인 양호 예후인자 였다. 이 임상시험에서 19명의 desmoplastic MB 또는 MBEN은 5-year EFS rates 이 90% ± 7% 였고 OS rates 는100% ± 0% 였으며 모든 환자들은 수술 후, 항암약물요법 단독으로 치료 받았다. (intraventricular methotrexate 포함) (질환 진행되기 전까지) [38]

o    반면에, 전통적 MB를 가진 환자들의 EFS and OS rates 는 HIT 2000 trial 에서 유의하게 낮았다. (EFS, 30% ± 11%; OS, 68% ± 10%).[38]

o    The COG clinical trial CCG-9921 또한, desmoplastic MB (MBEN 포함)은 좋은 생존률을 보여주었다. EFS of 77% ± 9%  및 OS of 85% ± 8% for the desmoplastic group. Nondesmoplastic 그룹은 EFS of 17% ± 5% 및 OS of 29% ± 6% 였다. (P < .0001 for both EFS and OS comparisons).[13] 이 연구에서, desmoplastic 종양 환자들은 질병진행 전에는 방사선 치료를 받지 않았다.

3.      desmoplastic또는 MBEN 소아와 달리, 다른 조직형 환자들의 치료 성적은 좋지 않다.

o    강력한 항암화학요법과 뇌실내/척추강내/정맥주입 MTX 의 치료, 그리고 고용량항암화학요법 및 조혈모세포이식 에도 불구하고, EFS rates 는 40% 이하이다.[13,38]

o    치료의 성적은 전이성 질환일 때 특히 나쁘다. 전이성 질환의 환자에게 방사선 치료를 언제, 얼마나 투여하고, 방사선 치료 연령을 어떻게 정할것인지에 대해 아직 consensus가 없다. [13,35,36]

3세 이하 환자들의 또다른 치료 옵션은 항암 치료 후 자가조혈모세포 이식 요법이다. 고용량, 골수억제 요법 및 조혈모세포 이식을 사용하는 임상시험의 결과들은 역시,  3세 이하 수모세포종 환자들의 일부에서 항암치료 단독으로 치료 가능함을 보여주었다..[14,47][Level of evidence: 2A]

임상연구중인 치료 옵션

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.

1.      COG-ACNS0334 (NCT00336024) (Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma): 3세 이하 고위험군 질환자 (즉 전이성 그리고/또는 subtotal 절제 환자 또는 8개월 미만의 소아이면서 표준위험군 양상을 보일 때)를 대상으로 한다. PNET나 pineoblastoma 환자도 또한 등록 가능하다. 완료된 임상시험인 COG 99703과 같이 항암요법을 진행한다. 이후 thiotepa 기반의 고용량, 골수억제 항암요법 및 조혈모세포이식을 진행한다. 환자들은 정맥내 고용량 MTX를 받는 군과 받지 않는 군으로 무작위 배정된다.

.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with untreated childhood medulloblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References

1.      Albright AL, Wisoff JH, Zeltzer PM, et al.: Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group. Neurosurgery 38 (2): 265-71, 1996. [PUBMED Abstract]

2.      Stargatt R, Rosenfeld JV, Maixner W, et al.: Multiple factors contribute to neuropsychological outcome in children with posterior fossa tumors. Dev Neuropsychol 32 (2): 729-48, 2007. [PUBMED Abstract]

3.      Pollack IF, Polinko P, Albright AL, et al.: Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology. Neurosurgery 37 (5): 885-93, 1995. [PUBMED Abstract]

4.      Robertson PL, Muraszko KM, Holmes EJ, et al.: Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children's Oncology Group. J Neurosurg 105 (6): 444-51, 2006. [PUBMED Abstract]

5.      Wells EM, Khademian ZP, Walsh KS, et al.: Postoperative cerebellar mutism syndrome following treatment of medulloblastoma: neuroradiographic features and origin. J Neurosurg Pediatr 5 (4): 329-34, 2010. [PUBMED Abstract]

6.      Gudrunardottir T, Sehested A, Juhler M, et al.: Cerebellar mutism: review of the literature. Childs Nerv Syst 27 (3): 355-63, 2011. [PUBMED Abstract]

7.      Wolfe-Christensen C, Mullins LL, Scott JG, et al.: Persistent psychosocial problems in children who develop posterior fossa syndrome after medulloblastoma resection. Pediatr Blood Cancer 49 (5): 723-6, 2007. [PUBMED Abstract]

8.      Ris MD, Packer R, Goldwein J, et al.: Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study. J Clin Oncol 19 (15): 3470-6, 2001. [PUBMED Abstract]

9.      Packer RJ, Sutton LN, Atkins TE, et al.: A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. J Neurosurg 70 (5): 707-13, 1989. [PUBMED Abstract]

10.  Johnson DL, McCabe MA, Nicholson HS, et al.: Quality of long-term survival in young children with medulloblastoma. J Neurosurg 80 (6): 1004-10, 1994. [PUBMED Abstract]

11.  Walter AW, Mulhern RK, Gajjar A, et al.: Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital. J Clin Oncol 17 (12): 3720-8, 1999. [PUBMED Abstract]

12.  Laughton SJ, Merchant TE, Sklar CA, et al.: Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol 26 (7): 1112-8, 2008. [PUBMED Abstract]

13.  Geyer JR, Sposto R, Jennings M, et al.: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 23 (30): 7621-31, 2005. [PUBMED Abstract]

14.  Chi SN, Gardner SL, Levy AS, et al.: Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma. J Clin Oncol 22 (24): 4881-7, 2004. [PUBMED Abstract]

15.  Packer RJ, Sutton LN, Elterman R, et al.: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81 (5): 690-8, 1994. [PUBMED Abstract]

16.  Bailey CC, Gnekow A, Wellek S, et al.: Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 25 (3): 166-78, 1995. [PUBMED Abstract]

17.  Kortmann RD, Kühl J, Timmermann B, et al.: Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys 46 (2): 269-79, 2000. [PUBMED Abstract]

18.  Taylor RE, Bailey CC, Robinson KJ, et al.: Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0-M1 medulloblastoma. Int J Radiat Oncol Biol Phys 58 (4): 1184-93, 2004. [PUBMED Abstract]

19.  von Hoff K, Hinkes B, Gerber NU, et al.: Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT'91. Eur J Cancer 45 (7): 1209-17, 2009. [PUBMED Abstract]

20.  Thomas PR, Deutsch M, Kepner JL, et al.: Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol 18 (16): 3004-11, 2000. [PUBMED Abstract]

21.  Oyharcabal-Bourden V, Kalifa C, Gentet JC, et al.: Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study. J Clin Oncol 23 (21): 4726-34, 2005. [PUBMED Abstract]

22.  Merchant TE, Kun LE, Krasin MJ, et al.: Multi-institution prospective trial of reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma. Int J Radiat Oncol Biol Phys 70 (3): 782-7, 2008. [PUBMED Abstract]

23.  Packer RJ, Gajjar A, Vezina G, et al.: Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24 (25): 4202-8, 2006. [PUBMED Abstract]

24.  Fukunaga-Johnson N, Sandler HM, Marsh R, et al.: The use of 3D conformal radiotherapy (3D CRT) to spare the cochlea in patients with medulloblastoma. Int J Radiat Oncol Biol Phys 41 (1): 77-82, 1998. [PUBMED Abstract]

25.  Huang E, Teh BS, Strother DR, et al.: Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 52 (3): 599-605, 2002. [PUBMED Abstract]

26.  Carrie C, Grill J, Figarella-Branger D, et al.: Online quality control, hyperfractionated radiotherapy alone and reduced boost volume for standard risk medulloblastoma: long-term results of MSFOP 98. J Clin Oncol 27 (11): 1879-83, 2009. [PUBMED Abstract]

27.  Packer RJ, Goldwein J, Nicholson HS, et al.: Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. J Clin Oncol 17 (7): 2127-36, 1999. [PUBMED Abstract]

28.  Nageswara Rao AA, Wallace DJ, Billups C, et al.: Cumulative cisplatin dose is not associated with event-free or overall survival in children with newly diagnosed average-risk medulloblastoma treated with cisplatin based adjuvant chemotherapy: report from the Children's Oncology Group. Pediatr Blood Cancer 61 (1): 102-6, 2014. [PUBMED Abstract]

29.  Gajjar A, Chintagumpala M, Ashley D, et al.: Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 7 (10): 813-20, 2006. [PUBMED Abstract]

30.  Taylor RE, Bailey CC, Robinson K, et al.: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study. J Clin Oncol 21 (8): 1581-91, 2003. [PUBMED Abstract]

31.  Verlooy J, Mosseri V, Bracard S, et al.: Treatment of high risk medulloblastomas in children above the age of 3 years: a SFOP study. Eur J Cancer 42 (17): 3004-14, 2006. [PUBMED Abstract]

32.  Gandola L, Massimino M, Cefalo G, et al.: Hyperfractionated accelerated radiotherapy in the Milan strategy for metastatic medulloblastoma. J Clin Oncol 27 (4): 566-71, 2009. [PUBMED Abstract]

33.  Evans AE, Jenkin RD, Sposto R, et al.: The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 72 (4): 572-82, 1990. [PUBMED Abstract]

34.  Jakacki RI, Burger PC, Zhou T, et al.: Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group Phase I/II study. J Clin Oncol 30 (21): 2648-53, 2012. [PUBMED Abstract]

35.  Grill J, Sainte-Rose C, Jouvet A, et al.: Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 6 (8): 573-80, 2005. [PUBMED Abstract]

36.  Rutkowski S, Bode U, Deinlein F, et al.: Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352 (10): 978-86, 2005. [PUBMED Abstract]

37.  Rutkowski S, von Hoff K, Emser A, et al.: Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 28 (33): 4961-8, 2010. [PUBMED Abstract]

38.  von Bueren AO, von Hoff K, Pietsch T, et al.: Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirm‎ing the prognostic impact of histology. Neuro Oncol 13 (6): 669-79, 2011. [PUBMED Abstract]

39.  Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993. [PUBMED Abstract]

40.  Ater JL, van Eys J, Woo SY, et al.: MOPP chemotherapy without irradiation as primary postsurgical therapy for brain tumors in infants and young children. J Neurooncol 32 (3): 243-52, 1997. [PUBMED Abstract]

41.  Grundy RG, Wilne SH, Robinson KJ, et al.: Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial. Eur J Cancer 46 (1): 120-33, 2010. [PUBMED Abstract]

42.  Blaney SM, Kocak M, Gajjar A, et al.: Pilot study of systemic and intrathecal mafosfamide followed by conformal radiation for infants with intracranial central nervous system tumors: a pediatric brain tumor consortium study (PBTC-001). J Neurooncol 109 (3): 565-71, 2012. [PUBMED Abstract]

43.  Leary SE, Zhou T, Holmes E, et al.: Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group. Cancer 117 (14): 3262-7, 2011. [PUBMED Abstract]

44.  Giangaspero F, Perilongo G, Fondelli MP, et al.: Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91 (6): 971-7, 1999. [PUBMED Abstract]

45.  Garrè ML, Cama A, Bagnasco F, et al.: Medulloblastoma variants: age-dependent occurrence and relation to Gorlin syndrome--a new clinical perspective. Clin Cancer Res 15 (7): 2463-71, 2009. [PUBMED Abstract]

46.  Rutkowski S, Gerber NU, von Hoff K, et al.: Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol 11 (2): 201-10, 2009. [PUBMED Abstract]

47.  Dhall G, Grodman H, Ji L, et al.: Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the "Head Start" I and II protocols. Pediatr Blood Cancer 50 (6): 1169-75, 2008. [PUBMED Abstract]

< Previous section
Treatment Option Overview for CNS Embryonal Tumors

출처 : http://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq#section/_29

Treatment of Newly Diagnosed Childhood Medulloblastoma

·         Treatment Modalities

o    Surgery

o    Radiation therapy

o    Chemotherapy

·         Children Older Than 3 Years with Average-Risk Medulloblastoma

o    Standard treatment options

·         Children Older Than 3 Years with High-Risk Medulloblastoma

o    Standard treatment options

o    Treatment options under clinical eval‎uation

·         Children Aged 3 Years and Younger

o    Standard treatment options

o    Treatment options under clinical eval‎uation

·         Current Clinical Trials

Treatment Modalities

Surgery

Surgery is considered a standard part of treatment for histologic confirmation of tumor type and as a means to improve outcome. Total or near-total resections are considered optimal, if they can be performed safely.[1]

Postoperatively, children may have significant neurologic deficits caused by preoperative tumor-related brain injury, hydrocephalus, or surgery-related brain injury.[2][Level of evidence: 3iC] A significant number of patients with medulloblastoma will develop cerebellar mutism syndrome. Symptoms of cerebellar mutism syndrome include the following:

·         Delayed onset of speech.

·         Suprabulbar palsies.

·         Ataxia.

·         Hypotonia.

·         Emotional lability.

The etiology of cerebellar mutism syndrome remains unclear, although cerebellar vermian damage and/or disruption of cerebellar-cortical tracts has been postulated as the possible cause for the mutism.[3,4]; [5][Level of evidence: 3iC] In two Children’s Cancer Group studies eval‎uating children with both average-risk and high-risk medulloblastoma, the syndrome has been identified in nearly 25% of patients.[4-6]; [7][Level of evidence: 3iiiC] Approximately 50% of patients with this syndrome manifest long-term, permanent neurologic and neurocognitive sequelae.[5,7]

Radiation therapy

Radiation therapy to the primary tumor site is usually in the range of 54 Gy to 55.8 Gy. This is usually given with a 1 cm to 2 cm margin around the primary tumor site, preferably by conformal techniques. For all medulloblastomas in children older than 3 or 4 years at diagnosis, craniospinal radiation therapy is given at doses ranging between 23.4 Gy and 36 Gy, depending on risk factors, such as extent of disease at diagnosis. Chemotherapy is routinely administered during and after radiation therapy.

For children younger than 3 years, efforts are made to omit or delay radiation, given the profound impact of radiation at this age. Children of all ages are susceptible to the adverse effects of radiation on brain development. Debilitating effects on neurologic/cognitive development, growth, and endocrine function have been frequently observed, especially in younger children.[8-12] The use of proton-beam therapy to reduce toxicity is under investigation.

Chemotherapy

Chemotherapy, usually given during and after radiation therapy, is a standard component of treatment for older children with medulloblastoma and other embryonal tumors. Chemotherapy can be used to delay and sometimes obviate the need for radiation therapy in 20% to 40% of children younger than 3 to 4 years with nondisseminated medulloblastoma.[13,14]; [12][Level of evidence: 3iiiC]

Children Older Than 3 Years with Average-Risk Medulloblastoma

Standard treatment options

Standard treatment options for children older than 3 years with newly diagnosed average-risk medulloblastoma include the following:

3.      Surgery.

4.      Adjuvant therapy.

o    Radiation therapy.

o    Chemotherapy.

Surgery

If deemed feasible, total or near-total removal of the tumor is considered optimal.[1]

Adjuvant therapy

Radiation therapy is usually initiated after surgery with or without concurrent chemotherapy.[15-17]

Adjuvant radiation therapy

4.      The best survival results for children with medulloblastoma have been obtained when radiation therapy is initiated within 4 to 6 weeks postsurgery.[15-18]; [19][Level of evidence: 1iA]

5.      The radiation dose for patients with average-risk medulloblastoma is 54 Gy to 55 Gy to the posterior fossa or local tumor bed and 23.4 Gy to the entire neuraxis (i.e., the whole brain and spine).[15-17,20]

o    With radiation therapy alone, 5-year event-free survival (EFS) rates range between 50% and 65% in those with nondisseminated disease.[16,17]

o    The minimal dose of craniospinal radiation needed for disease control is unknown. Attempts to lower the dose of craniospinal radiation therapy to 23.4 Gy without chemotherapy have resulted in an increased incidence of isolated leptomeningeal relapse.[20]

o    If chemotherapy is added after radiation therapy, 23.4 Gy of craniospinal radiation therapy has been shown to be an effective dose.[21-23] Lower doses are being eval‎uated.

6.      Although the standard boost in medulloblastoma is to the entire posterior fossa, failure data patterns suggest that radiation therapy to the tumor bed instead of the entire posterior fossa would be equally effective and may be associated with reduced toxicity.[24,25]

Adjuvant chemotherapy

Chemotherapy is now a standard component of the treatment of children with average-risk medulloblastoma.

6.      Prospective randomized trials and single-arm trials suggest that adjuvant chemotherapy given during and after radiation therapy improves overall survival (OS) for children with average-risk medulloblastoma.[7,15-19]

o    Radiation therapy and chemotherapy given during and after surgery has demonstrated 5-year EFS rates of 70% to 85%.[15-17]; [26][Level of evidence: 2A]

7.      A lower radiation dose of 23.4 Gy to the neuraxis when coupled with chemotherapy has been shown to result in disease control in up to 85% of patients and may decrease the severity of long-term neurocognitive sequelae.[21-23,27]

8.      A variety of chemotherapeutic regimens have been successfully used, including the combination of cisplatin, lomustine, and vincristine or the combination of cisplatin, cyclophosphamide, and vincristine.[15,16,27,28] In addition, postradiation, high-dose chemotherapy supported by peripheral stem cell rescue has resulted in similar survival rates.[29]

9.      Although medulloblastoma is often sensitive to chemotherapy, preradiation chemotherapy has not been shown to improve survival compared with treatment with radiation therapy and subsequent chemotherapy. In some prospective studies, preradiation chemotherapy has been related to a poorer rate of survival.[16-19]

Children Older Than 3 Years with High-Risk Medulloblastoma

Standard treatment options

Standard treatment options for children older than 3 years who are newly diagnosed with medulloblastoma and have metastatic disease or have had a subtotal resection include the following:

3.      Surgery.

4.      Adjuvant therapy.

o    Radiation therapy.

o    Chemotherapy.

Surgery

As for those with average-risk disease, attempt at gross-total resection is considered optimal, if deemed feasible.[1] In those with disseminated disease at diagnosis, the degree of resection has not been shown to be an independent predictor of outcome.[30]

Adjuvant therapy

In high-risk patients, numerous studies have demonstrated that multimodality therapy improves the duration of disease control and overall disease-free survival (DFS).[29,31] Studies show that approximately 50% to 65% of patients with high-risk disease will experience long-term disease control.[15,29,31-33]; [34][Level of evidence: 1iiA]

Adjuvant radiation therapy

2.      In contrast to standard-risk treatment, the craniospinal radiation dose is generally 36 Gy.

Adjuvant chemotherapy

3.      The drugs that have been found to be useful in children with average-risk disease are the same drugs that have been used extensively in children with high-risk disease, including cisplatin, lomustine, cyclophosphamide, etoposide, and vincristine.[34]

4.      Postradiation, high-dose, nonmyeloablative chemotherapy supported by peripheral stem cell rescue has also been utilized and has resulted in 5-year progression-free survival rates of approximately 60%.[29]

Treatment options under clinical eval‎uation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.

2.      COG-ACNS0332 (NCT00392327) (Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma or Supratentorial Primitive Neuroectodermal Tumor): This COG phase III trial for children older than 3 years is eval‎uating the efficacy of adding carboplatin to radiation therapy with vincristine, followed by maintenance chemotherapy with conventional adjuvant chemotherapy and isotretinoin.

Children Aged 3 Years and Younger

Standard treatment options

Five-year DFS rates for young children with medulloblastoma have ranged between 30% and 70%, with most long-term survivors successfully treated with chemotherapy alone, having nondisseminated, totally resected tumors and histologic evidence of desmoplasia.[13,35,36]

The treatment of children younger than 3 to 4 years with newly diagnosed medulloblastoma continues to evolve. Therapeutic approaches have attempted to delay and, in some cases, avoid the use of craniospinal radiation therapy because of its deleterious effects on the immature nervous system. Results have been variable, and comparison across studies has been difficult because of differences in drug regimens used and the utilization of craniospinal and local boost radiation therapy at the end of chemotherapy or when children reached age 3 years in some studies.

Standard treatment options for children aged 3 years and younger with newly diagnosed medulloblastoma include the following:

3.      Surgery.

4.      Adjuvant chemotherapy.

Surgery

If deemed feasible, complete surgical resection of the tumor is the optimal treatment. Surgical resectability is associated with histology, as patients with desmoplastic medulloblastoma or medulloblastoma with extensive nodularity (MBEN) have a higher rate of complete resection than do patients with classic medulloblastoma.[37,38]

Adjuvant chemotherapy

4.      Therapies for younger children with medulloblastoma have included the use of multiagent chemotherapeutic approaches, including drugs such as cyclophosphamide, etoposide, cisplatin, and vincristine, with or without concomitant high-dose intravenous methotrexate and/or intrathecal methotrexate or mafosfamide, and/or intraventricular methotrexate.[13,35,36,38-40]; [41][Level of evidence: 2A]; [42][Level of evidence: 2B]

5.      Several studies have observed that the histologic finding of desmoplasia, seen in patients with desmoplastic medulloblastoma or MBEN, connotes a significantly better prognosis compared with outcome for patients with classic or large cell/anaplastic medulloblastoma.[37,38,43-45]; [46][Level of evidence: 2A]

o    Desmoplasia was an independent predictor of favorable EFS rates in the German HIrnTumor (HIT) 2000 multicenter trial in which 19 patients with desmoplastic medulloblastoma or MBEN had 5-year EFS rates of 90% ± 7% and OS rates of 100% ± 0%, with all patients being treated with postoperative chemotherapy alone (including intraventricular methotrexate) prior to progression.[38]

o    By contrast, EFS and OS rates for children with classic medulloblastoma in the HIT 2000 trial were significantly lower (EFS, 30% ± 11%; OS, 68% ± 10%).[38]

o    The COG clinical trial CCG-9921 also observed a favorable outcome for children with desmoplastic medulloblastoma (including MBEN), with an EFS of 77% ± 9% and an OS of 85% ± 8% for the desmoplastic group compared with an EFS of 17% ± 5% and OS of 29% ± 6% for patients in the nondesmoplastic group (P < .0001 for both EFS and OS comparisons).[13] In this study, patients with desmoplastic tumors did not receive radiation prior to progression.

6.      In contrast to children with desmoplastic medulloblastoma or MBEN treated with current intensive chemotherapy regimens, children with other histologic subtypes fare less well.

o    EFS rates are below 40% despite the use of intensive chemotherapy supplemented with methotrexate (intravenous, intrathecal, and intraventricular) and the use of high-dose chemotherapeutic regimens supported with stem cell rescue.[13,38]

o    Outcome is particularly poor when these patients have disseminated disease, and there is no consensus on when and how much radiation therapy should be given and at what age radiation therapy should be instituted in patients with disseminated disease.[13,35,36]

Another treatment option for children younger than 3 years at diagnosis is chemotherapy followed by autologous stem cell rescue. Results of trials utilizing higher-dose, marrow-ablative chemotherapeutic regimens supported by stem cell rescue have also demonstrated that a subgroup of patients with medulloblastoma who are younger than 3 years at the time of diagnosis can be treated with chemotherapy alone.[14,47][Level of evidence: 2A]

Treatment options under clinical eval‎uation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.

2.      COG-ACNS0334 (NCT00336024) (Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma): This COG trial is open for children aged 3 years or younger at diagnosis with high-risk disease, which is defined as those with disseminated and/or subtotally resected tumors, or those younger than 8 months with otherwise standard-risk disease. Patients with cortical primitive neuroectodermal tumors or pineoblastomas are also eligible.

This study is eval‎uating chemotherapy as given in the completed COG study COG-99703, which used multiagent chemotherapy followed by thiotepa-based, higher-dose, marrow-ablative chemotherapy and peripheral stem cell rescue, and randomly assigns patients to treatment with or without intravenous high-dose methotrexate.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with untreated childhood medulloblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References

48.  Albright AL, Wisoff JH, Zeltzer PM, et al.: Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group. Neurosurgery 38 (2): 265-71, 1996. [PUBMED Abstract]

49.  Stargatt R, Rosenfeld JV, Maixner W, et al.: Multiple factors contribute to neuropsychological outcome in children with posterior fossa tumors. Dev Neuropsychol 32 (2): 729-48, 2007. [PUBMED Abstract]

50.  Pollack IF, Polinko P, Albright AL, et al.: Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology. Neurosurgery 37 (5): 885-93, 1995. [PUBMED Abstract]

51.  Robertson PL, Muraszko KM, Holmes EJ, et al.: Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children's Oncology Group. J Neurosurg 105 (6): 444-51, 2006. [PUBMED Abstract]

52.  Wells EM, Khademian ZP, Walsh KS, et al.: Postoperative cerebellar mutism syndrome following treatment of medulloblastoma: neuroradiographic features and origin. J Neurosurg Pediatr 5 (4): 329-34, 2010. [PUBMED Abstract]

53.  Gudrunardottir T, Sehested A, Juhler M, et al.: Cerebellar mutism: review of the literature. Childs Nerv Syst 27 (3): 355-63, 2011. [PUBMED Abstract]

54.  Wolfe-Christensen C, Mullins LL, Scott JG, et al.: Persistent psychosocial problems in children who develop posterior fossa syndrome after medulloblastoma resection. Pediatr Blood Cancer 49 (5): 723-6, 2007. [PUBMED Abstract]

55.  Ris MD, Packer R, Goldwein J, et al.: Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study. J Clin Oncol 19 (15): 3470-6, 2001. [PUBMED Abstract]

56.  Packer RJ, Sutton LN, Atkins TE, et al.: A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. J Neurosurg 70 (5): 707-13, 1989. [PUBMED Abstract]

57.  Johnson DL, McCabe MA, Nicholson HS, et al.: Quality of long-term survival in young children with medulloblastoma. J Neurosurg 80 (6): 1004-10, 1994. [PUBMED Abstract]

58.  Walter AW, Mulhern RK, Gajjar A, et al.: Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital. J Clin Oncol 17 (12): 3720-8, 1999. [PUBMED Abstract]

59.  Laughton SJ, Merchant TE, Sklar CA, et al.: Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol 26 (7): 1112-8, 2008. [PUBMED Abstract]

60.  Geyer JR, Sposto R, Jennings M, et al.: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 23 (30): 7621-31, 2005. [PUBMED Abstract]

61.  Chi SN, Gardner SL, Levy AS, et al.: Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma. J Clin Oncol 22 (24): 4881-7, 2004. [PUBMED Abstract]

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Treatment Option Overview for CNS Embryonal Tumors

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