새로 진단된 중추신경계 뇌종양 - 배아세포종 중 뇌종자종의 치료 (NCI해석, 연세암병원 소아혈액종양과 역)

[한정우]

새로 진단된 중추신경계 뇌종자종의 치료 (Treatment of Newly Diagnosed Childhood CNS Germinomas)

·         Treatment Options for Newly Diagnosed Childhood CNS Germinomas

o    Radiation therapy

o    Neoadjuvant chemotherapy followed by response-based radiation therapy

·         Treatment Options Under Clinical Eval‎uation for Newly Diagnosed Childhood CNS Germinomas

Treatment Options for Newly Diagnosed Childhood CNS Germinomas

Treatment options for newly diagnosed childhood CNS germinomas include the following:

1.      Radiation therapy.

2.      Neoadjuvant chemotherapy followed by response-based radiation therapy.

Radiation therapy

배아세포종은 매우 방사선에 민감한 종양으로 전통적으로 방사선 치료 단족으로 치료하여 왔다. 역사적으로 두개척추방사선 및 원발종양부위의 부스트법이 사용되어 왔다. 이 방법은 5년 전체생존률 (OS)를 90% 이상이었다.[1]; [2][Level of evidence: 2A]; [3,4][Level of evidence: 3iA] 이 훌륭한 성적은 후기후유증을 감소 시키고자, 연구자들이 방사선치료의 용적과 강도를 줄이는데 집중하게 하였다.

[2,5,6]

용적감소 방사선 치료 (reduced volume radiation therapy, 전뇌 또는 전뇌실 방사선치료)에 대비한 두개척추방사선요법 후의 재발 양상은 두개척추방사선 치료가 국소배아세포종에 대해서는 필요하지 않다는 것을 강하게 제시하였다. [7,8] 이들 결과를 바탕으로, 국소 순수 배아세포종의 치료는 전체 두개척추축에 방사선치료를 하거나 전뇌 방사선 치료를 하는 대신에, 전체 뇌실 (24Gy)을 포함하면서 원발부위에 부스트하는 방식으로 변화하여 왔다. 이러한 변화는 나쁜 성적을 야기하지 않았고, 급성, 그리고 장기 방사선 독성을 최소화 하는 것으로 기대된다. 방사선전 항암화학요법 이후 국소 방사선 치료는, 전뇌 또는 전뇌실 방사선 치료에 비하여 나쁜 예후를 보여주므로, 추천되지 않는다.[6]

방사선전 항암화학요법 이후 반응기반 방사선 치료(Neoadjuvant chemotherapy followed by response-based radiation therapy)

항암화학요법은 방사선 치료 용량을 줄이고 관련된 신경발달 후유증을 감소시키기 위하여 연구되어 왔다. 몇몇 연구들은 좋은 생존률을 유지하면서 가능성을 확인시켜 주었지만 치료 환자의 숫자는 여전히 적다.[9-11]; [12][Level of evidence: 2A]; [13][Level of evidence: 3iiiC]

항암화학요법 약제는 cyclophosphamide, ifosfamide, etoposide, cisplatin, and carboplatin 등이 매우 효과적이라고 알려져 있다. 항암요법을 받는 환자들은 이 종양 환자에서 요붕증을 흔히 가지고 있으므로, 고용량 수액요법(e.g., cyclophosphamide, ifosfamide, and cisplatin)이 필요한 항암제를 사용할 때 치료에 어려움이 있다.

[14]

국제 연구자 그룹은 주로 연령이 어린 환아들에게 항암제 단독 방법을 연구하였다. 그들은 배아세포종을 가진 환자의 84%에서 완전 관해를 얻을 수 있었다. 그러나 이들 환자 중 50%에서 재발 또는 진행을 경험하였다; 많은 재발이 국소적이거나, 국소 및 뇌실재발, 뇌실 단독재발 그리고/또는 중추신경계 전체의 연수박 전이였고, 방사선 치료를 포함한 후속 치료가 필요하였다.[15] 후속 연구들은 항암화학요법 후 방사선 치료의 필요성을 지속적으로 보였었고, 아마도 전뇌실 (24Gy) 방사선 치료와 국소 종양부위 부스트 (전체 용량 40Gy)가 필요한 것으로 보여진다. [16][Level of evidence: 2A]; [17][Level of evidence: 3iiiA] 전이성 순수배아세포종에서 항암 치료 후 24Gy의 두개척추 방사선 치료를 시행하여 훌륭한 성적을 보임이 보고되었다.[18][Level of evidence: 2A]

2개초점 (bifocal) 병변의 적절한 치료는 아직 불분명하다. 60명의 환자를 대상으로 한 메타 분석에서 두개척추방사선 치료 단독으로 훌륭한 무진행생존률 (PFS)를 보여주었다. 항암요법 및 국한적 방사선 치료 (전뇌실방사선을 포함한) 또한 훌륭한 질병 조절률을 보여주었다.[19][Level of evidence: 3iiDiii]

Treatment Options Under Clinical Eval‎uation for Newly Diagnosed Childhood CNS Germinomas

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

Treatment options under clinical eval‎uation for newly diagnosed childhood CNS germinomas include the following:

1.      COG-ACNS1123 (NCT01602666) (Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized CNS Germ Cell Tumors [GCTs]): COG-ACNS1123은 COG협동 다기관 임상시험이다. 이 2상, 국소성 중추신경계 생식세포종에 대한 반응기반 방사선치료 임상 시험은 짧은 기간의 항암 치료 후 반응 기반의 전뇌 방사선 치료 및 원발부위 부스트법의 무사건생존률 (EFS)와 전체생존률 (OS)를 비교하는 것이다. 항암요법 후 완전 관해를 나타나낸 환자에 대해 표준 전뇌실 방사선 용량의 25% 감소 용량을 투여한다. 완전관해를 보이지 않는 환자에게는 표준 전뇌실 용량을 사용하며, 2^nd look 수술은 하거나 또는 하지 않는다.

References

1.      Shibamoto Y, Abe M, Yamashita J, et al.: Treatment results of intracranial germinoma as a function of the irradiated volume. Int J Radiat Oncol Biol Phys 15 (2): 285-90, 1988. [PUBMED Abstract]

2.      Cho J, Choi JU, Kim DS, et al.: Low-dose craniospinal irradiation as a definitive treatment for intracranial germinoma. Radiother Oncol 91 (1): 75-9, 2009. [PUBMED Abstract]

3.      Huang PI, Chen YW, Wong TT, et al.: Extended focal radiotherapy of 30 Gy alone for intracranial synchronous bifocal germinoma: a single institute experience. Childs Nerv Syst 24 (11): 1315-21, 2008. [PUBMED Abstract]

4.      Eom KY, Kim IH, Park CI, et al.: Upfront chemotherapy and involved-field radiotherapy results in more relapses than extended radiotherapy for intracranial germinomas: modification in radiotherapy volume might be needed. Int J Radiat Oncol Biol Phys 71 (3): 667-71, 2008. [PUBMED Abstract]

5.      Chen MJ, Santos Ada S, Sakuraba RK, et al.: Intensity-modulated and 3D-conformal radiotherapy for whole-ventricular irradiation as compared with conventional whole-brain irradiation in the management of localized central nervous system germ cell tumors. Int J Radiat Oncol Biol Phys 76 (2): 608-14, 2010. [PUBMED Abstract]

6.      Joo JH, Park JH, Ra YS, et al.: Treatment outcome of radiation therapy for intracranial germinoma: adaptive radiation field in relation to response to chemotherapy. Anticancer Res 34 (10): 5715-21, 2014. [PUBMED Abstract]

7.      Rogers SJ, Mosleh-Shirazi MA, Saran FH: Radiotherapy of localised intracranial germinoma: time to sever historical ties? Lancet Oncol 6 (7): 509-19, 2005. [PUBMED Abstract]

8.      Shikama N, Ogawa K, Tanaka S, et al.: Lack of benefit of spinal irradiation in the primary treatment of intracranial germinoma: a multiinstitutional, retrospective review of 180 patients. Cancer 104 (1): 126-34, 2005. [PUBMED Abstract]

9.      Kretschmar C, Kleinberg L, Greenberg M, et al.: Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: a report from the Children's Oncology Group. Pediatr Blood Cancer 48 (3): 285-91, 2007. [PUBMED Abstract]

10.  Allen JC, DaRosso RC, Donahue B, et al.: A phase II trial of preirradiation carboplatin in newly diagnosed germinoma of the central nervous system. Cancer 74 (3): 940-4, 1994. [PUBMED Abstract]

11.  Buckner JC, Peethambaram PP, Smithson WA, et al.: Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors. J Clin Oncol 17 (3): 933-40, 1999. [PUBMED Abstract]

12.  Khatua S, Dhall G, O'Neil S, et al.: Treatment of primary CNS germinomatous germ cell tumors with chemotherapy prior to reduced dose whole ventricular and local boost irradiation. Pediatr Blood Cancer 55 (1): 42-6, 2010. [PUBMED Abstract]

13.  O'Neil S, Ji L, Buranahirun C, et al.: Neurocognitive outcomes in pediatric and adolescent patients with central nervous system germinoma treated with a strategy of chemotherapy followed by reduced-dose and volume irradiation. Pediatr Blood Cancer 57 (4): 669-73, 2011. [PUBMED Abstract]

14.  Afzal S, Wherrett D, Bartels U, et al.: Challenges in management of patients with intracranial germ cell tumor and diabetes insipidus treated with cisplatin and/or ifosfamide based chemotherapy. J Neurooncol 97 (3): 393-9, 2010. [PUBMED Abstract]

15.  Balmaceda C, Heller G, Rosenblum M, et al.: Chemotherapy without irradiation--a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study. J Clin Oncol 14 (11): 2908-15, 1996. [PUBMED Abstract]

16.  da Silva NS, Cappellano AM, Diez B, et al.: Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study. Pediatr Blood Cancer 54 (3): 377-83, 2010. [PUBMED Abstract]

17.  Alapetite C, Brisse H, Patte C, et al.: Pattern of relapse and outcome of non-metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience. Neuro Oncol 12 (12): 1318-25, 2010. [PUBMED Abstract]

18.  Calaminus G, Kortmann R, Worch J, et al.: SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 15 (6): 788-96, 2013. [PUBMED Abstract]

19.  Weksberg DC, Shibamoto Y, Paulino AC: Bifocal intracranial germinoma: a retrospective analysis of treatment outcomes in 20 patients and review of the literature. Int J Radiat Oncol Biol Phys 82 (4): 1341-51, 2012. [PUBMED Abstract]

Treatment of Newly Diagnosed Childhood CNS Germinomas

·        

Treatment Options for Newly Diagnosed Childhood CNS Germinomas

o    Radiation therapy

o    Neoadjuvant chemotherapy followed by response-based radiation therapy

·         Treatment Options Under Clinical Eval‎uation for Newly Diagnosed Childhood CNS Germinomas

Treatment Options for Newly Diagnosed Childhood CNS Germinomas

Treatment options for newly diagnosed childhood CNS germinomas include the following:

1.      Radiation therapy.

2.      Neoadjuvant chemotherapy followed by response-based radiation therapy.

Radiation therapy

Germinomas are highly radiosensitive and have been traditionally treated with radiation therapy alone; historically, craniospinal irradiation with a boost to the region of the primary tumor has been utilized. This has resulted in 5-year overall survival rates of greater than 90%.[1]; [2][Level of evidence: 2A]; [3,4][Level of evidence: 3iA] These excellent survival rates have allowed investigators to focus on reducing radiation treatment volume and intensity in an attempt to decrease late effects.[2,5,6]

Patterns of relapse after craniospinal irradiation versus reduced-volume radiation therapy (whole-brain or whole-ventricular radiation therapy) have strongly suggested that craniospinal irradiation is not necessary for localized germinomas.[7,8] On the basis of these results, the treatment for patients with localized pure germinomas has been modified to cover the whole ventricular system (24 Gy) followed by a boost to the primary site, rather than to deliver radiation therapy to the entire craniospinal axis or even to the whole brain. This change has not resulted in worse outcomes and is expected to minimize the acute and long-term toxicity of radiation therapy. Focal radiation therapy after neoadjuvant chemotherapy results in inferior outcomes compared with whole-brain or whole-ventricle radiation therapy; therefore, focal radiation therapy is not recommended.[6]

Neoadjuvant chemotherapy followed by response-based radiation therapy

Chemotherapy has been explored in an effort to reduce radiation therapy doses and associated neurodevelopmental morbidity. Several studies have confirmed the feasibility of this approach for maintaining excellent survival rates, but the number of treated patients is still small.[9-11]; [12][Level of evidence: 2A]; [13][Level of evidence: 3iiiC]

Chemotherapy agents such as cyclophosphamide, ifosfamide, etoposide, cisplatin, and carboplatin are highly active in central nervous system (CNS) germinomas. Patients receiving chemotherapy agents that require hyperhydration (e.g., cyclophosphamide, ifosfamide, and cisplatin) are often quite challenging to manage because of the high preval‎ence of diabetes insipidus in this population.[14]

An international group of investigators have explored a chemotherapy-only approach primarily for younger children. They were able to achieve a complete response in 84% of patients with germinomas treated with chemotherapy alone. Fifty percent of these patients relapsed or progressed; many recurrences were local, local plus ventricular, and ventricular alone and/or with leptomeningeal dissemination throughout the CNS, which required further therapy, including radiation.[15] Subsequent studies have continued to support the need for radiation therapy after chemotherapy and the likely requirement for whole-ventricular irradiation (24 Gy) with local tumor site boost (total dose of 40 Gy).[16][Level of evidence: 2A]; [17][Level of evidence: 3iiiA] Excellent results have also been reported for patients with metastatic germinomas who received chemotherapy followed by 24 Gy of craniospinal irradiation.[18][Level of evidence: 2A]

Optimal management of bifocal lesions is unclear. A meta-analysis of 60 patients demonstrated excellent progression-free survival after craniospinal irradiation alone. Chemotherapy plus localized radiation therapy, including whole-ventricular irradiation, also resulted in excellent disease control.[19][Level of evidence: 3iiDiii]

Treatment Options Under Clinical Eval‎uation for Newly Diagnosed Childhood CNS Germinomas

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

Treatment options under clinical eval‎uation for newly diagnosed childhood CNS germinomas include the following:

1.      COG-ACNS1123 (NCT01602666) (Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized CNS Germ Cell Tumors [GCTs]): COG-ACNS1123 is a Children’s Oncology Group cooperative multi-institutional trial. This phase II trial of response-based radiation therapy for patients with localized CNS GCTs will compare the event-free survival and overall survival rates of a short course of chemotherapy followed by response-based, whole-ventricular radiation therapy, with a boost to the primary site. For patients who obtain a complete response after chemotherapy, the whole-ventricular radiation dose will be 25% lower than the standard whole-ventricular dose; for patients who have less than a complete response after chemotherapy, the standard whole-ventricular dose will be used, with or without second-look surgery.

References

1.      Shibamoto Y, Abe M, Yamashita J, et al.: Treatment results of intracranial germinoma as a function of the irradiated volume. Int J Radiat Oncol Biol Phys 15 (2): 285-90, 1988. [PUBMED Abstract]

2.      Cho J, Choi JU, Kim DS, et al.: Low-dose craniospinal irradiation as a definitive treatment for intracranial germinoma. Radiother Oncol 91 (1): 75-9, 2009. [PUBMED Abstract]

3.      Huang PI, Chen YW, Wong TT, et al.: Extended focal radiotherapy of 30 Gy alone for intracranial synchronous bifocal germinoma: a single institute experience. Childs Nerv Syst 24 (11): 1315-21, 2008. [PUBMED Abstract]

4.      Eom KY, Kim IH, Park CI, et al.: Upfront chemotherapy and involved-field radiotherapy results in more relapses than extended radiotherapy for intracranial germinomas: modification in radiotherapy volume might be needed. Int J Radiat Oncol Biol Phys 71 (3): 667-71, 2008. [PUBMED Abstract]

5.      Chen MJ, Santos Ada S, Sakuraba RK, et al.: Intensity-modulated and 3D-conformal radiotherapy for whole-ventricular irradiation as compared with conventional whole-brain irradiation in the management of localized central nervous system germ cell tumors. Int J Radiat Oncol Biol Phys 76 (2): 608-14, 2010. [PUBMED Abstract]

6.      Joo JH, Park JH, Ra YS, et al.: Treatment outcome of radiation therapy for intracranial germinoma: adaptive radiation field in relation to response to chemotherapy. Anticancer Res 34 (10): 5715-21, 2014. [PUBMED Abstract]

7.      Rogers SJ, Mosleh-Shirazi MA, Saran FH: Radiotherapy of localised intracranial germinoma: time to sever historical ties? Lancet Oncol 6 (7): 509-19, 2005. [PUBMED Abstract]

8.      Shikama N, Ogawa K, Tanaka S, et al.: Lack of benefit of spinal irradiation in the primary treatment of intracranial germinoma: a multiinstitutional, retrospective review of 180 patients. Cancer 104 (1): 126-34, 2005. [PUBMED Abstract]

9.      Kretschmar C, Kleinberg L, Greenberg M, et al.: Pre-radiation chemotherapy with response-based radiation therapy in children with central nervous system germ cell tumors: a report from the Children's Oncology Group. Pediatr Blood Cancer 48 (3): 285-91, 2007. [PUBMED Abstract]

10.  Allen JC, DaRosso RC, Donahue B, et al.: A phase II trial of preirradiation carboplatin in newly diagnosed germinoma of the central nervous system. Cancer 74 (3): 940-4, 1994. [PUBMED Abstract]

11.  Buckner JC, Peethambaram PP, Smithson WA, et al.: Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors. J Clin Oncol 17 (3): 933-40, 1999. [PUBMED Abstract]

12.  Khatua S, Dhall G, O'Neil S, et al.: Treatment of primary CNS germinomatous germ cell tumors with chemotherapy prior to reduced dose whole ventricular and local boost irradiation. Pediatr Blood Cancer 55 (1): 42-6, 2010. [PUBMED Abstract]

13.  O'Neil S, Ji L, Buranahirun C, et al.: Neurocognitive outcomes in pediatric and adolescent patients with central nervous system germinoma treated with a strategy of chemotherapy followed by reduced-dose and volume irradiation. Pediatr Blood Cancer 57 (4): 669-73, 2011. [PUBMED Abstract]

14.  Afzal S, Wherrett D, Bartels U, et al.: Challenges in management of patients with intracranial germ cell tumor and diabetes insipidus treated with cisplatin and/or ifosfamide based chemotherapy. J Neurooncol 97 (3): 393-9, 2010. [PUBMED Abstract]

15.  Balmaceda C, Heller G, Rosenblum M, et al.: Chemotherapy without irradiation--a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous System Germ Cell Tumor Study. J Clin Oncol 14 (11): 2908-15, 1996. [PUBMED Abstract]

16.  da Silva NS, Cappellano AM, Diez B, et al.: Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study. Pediatr Blood Cancer 54 (3): 377-83, 2010. [PUBMED Abstract]

17.  Alapetite C, Brisse H, Patte C, et al.: Pattern of relapse and outcome of non-metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience. Neuro Oncol 12 (12): 1318-25, 2010. [PUBMED Abstract]

18.  Calaminus G, Kortmann R, Worch J, et al.: SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 15 (6): 788-96, 2013. [PUBMED Abstract]

19.  Weksberg DC, Shibamoto Y, Paulino AC: Bifocal intracranial germinoma: a retrospective analysis of treatment outcomes in 20 patients and review of the literature. Int J Radiat Oncol Biol Phys 82 (4): 1341-51, 2012. [PUBMED Abstract]