새로 진단된 소아청소년 중추신경계 비종자종성 배아세포종의 치료 (출처 NCI). 연세암병원 소아청소년암센터 소아혈액종양과 역

[한정우]

새로 진단된 소아청소년 중추신경계 비종자종성 배아세포종의 치료 (Treatment of Newly Diagnosed Childhood CNS Nongerminomatous Germ Cell Tumors)

·         Treatment Options for Newly Diagnosed Childhood CNS NGGCTs

o    Chemotherapy followed by radiation therapy

o    Surgery

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

중추신경계 NGGCT (비종자종성 배아세포종, nongerminomatous germ cell tumors)는 뇌종자종 (germinoma)에 비해 생존률이 낮다. 그러나 이러한 차이는 최근의 다학제적 치료법 추가에 따라 감소하고 있다. 현재의 치료 방법으로 10년 전체 생존률 (OS)는 70~80%이다..[1,2] NGGCTs 는 방사선치료에 민감하지만 표준 두개척추방사선 단독치료 후의 생존률은 좋지 않아서 5년 OS 20~45% 정도이다. 재발성 NGGCT는 보통 18개월 이내에 가장 많이 재발한다.

새로 진단된 소아청소년 중추신경계 NGGCTs의 치료 옵션 (Treatment Options for Newly Diagnosed Childhood CNS NGGCTs)

새로 진단된 소아청소년 중추신경계 NGGCT의 치료 옵션은 다음을 포함한다.:

1.      항암치료 후 방사선치료 Chemotherapy followed by radiation therapy.

2.      치료에 반응하지 않는 종양이나, 치료 후 크기가 증가되는 종양 (growing teratoma syndrome 가능성)에 대한 수술

CNS NGGCT의 적합한 치료 방침은 아직 불확실하다.

항암치료 후 방사선 치료Chemotherapy followed by radiation therapy

사용되어 왔던 항암제는 carboplatin, etoposide, bleomycin, ifosfamide, 과 vinblastine 등의 다른 조합이었다. 방사선 치료 전 항암화학요법사용은 생존률을 증가시켜왔다. 그러나 특정 항암화학요법 regimen, 치료의 길이, 적합한 방사선 치료 부위, 시점, 용량등은 여전히 연구 중이다.[1,3,4]

몇몇 연구자들은 비전이성 NGGCT환자에 대해 방사선 치료의 범위를 두개척추방사선 (CSI, CSR)보다 더 작게 하는 것을 제안하여 왔다 (예 – 전뇌실 방사선치료 및 국소 종양 부위 boost).

항암치료 및 국소 방사선치료를 한 환자에서 재발의 패턴에 대해서는 서로 이견이 존재한다.[1,2,5,6]

A COG study (ACNS0122 [NCT00047320]) 는 국소 NGGCT에서 신보조항암요법 후 방사선 치료를 평가 하였다. [7] Carboplatin/etoposide와 ifosfamide/etoposide를 번갈아 6회차 투여하는 신보조항암요법을 하였다. 항암치료 완료 후, 반응이 좋은 환자에서는 36Gy의 두개척추 방사선과 54Gy의 종양부위 방사선 치료를 하였고, 중앙센터리뷰 결과 86%의 환자들이 부분반응 (PR)또는 완전관해 (CR)을 보였다. 102명의 환자에서 5년 무사건생존률 (EFS)는 84% ± 4%, 였고 OS는  93% ± 3%. 였다. 관해요법 후 또는 second look수술에서 암세포가 확인되지 않는 환자에서는 3년째 the EFS는 92% 였고 the OS 는 98% 였다..

수술 Surgery

흔하게,항암요법을 받는 환자들은 종양표지자가 정상이 되지만, 영상학적으로 반응이 완전관해 되지 않는 경우가 있다. 2차 수술 (second look surgery)는 남아있는 종괴가 기형종 (teratoma), 섬유화 (fibrosis) 또는 잔존 NGGCT를 갖는지 결정하는데 도움을 줄 수 있다.[2,8] 만약 2차 수술이 성숙 기형종 또는 섬유화 변화를 항암치료 후에 보여 주었다면, 일반적으로는 환자가 항암치료 후 완전관해에 도달한 것과 유사한 방사선 치료를 진행한다. 만약 살아있는 종양 부분이 관찰된다면 일반적으로 다른 치료방법을 고려한다. [7]

때때로 종양 표지자는 정상화 되었더라도 종양 크기가 지속적으로 증가하는데 growing teratoma syndrome에 의한 것으로 생각되고 NGGCT 부위의 치료 실패는 아니라고 본다.[7,9,10] 이와 같은 경우 수술은 일반적으로, 종양감축술 (debulking) 및 조직학적 확인을 위하여 필요하다.

Treatment Options Under Clinical Eval‎uation for Newly Diagnosed Childhood CNS NGGCTs

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 NGGCTs include the following:

1.      COG-ACNS1123 (NCT01602666) (Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized Central Nervous System [CNS] 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 OS rates of a short course of chemotherapy followed by response-based, whole-ventricular radiation, 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.      Robertson PL, DaRosso RC, Allen JC: Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neurooncol 32 (1): 71-80, 1997. [PUBMED Abstract]

2.      Baranzelli M, Patte C, Bouffet E, et al.: Carboplatin-based chemotherapy (CT) and focal irradiation (RT) in primary germ cell tumors (GCT): A French Society of Pediatric Oncology (SFOP) experience (meeting abstract). [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-538, 140A, 1999.

3.      Matsutani M; Japanese Pediatric Brain Tumor Study Group: Combined chemotherapy and radiation therapy for CNS germ cell tumors--the Japanese experience. J Neurooncol 54 (3): 311-6, 2001. [PUBMED Abstract]

4.      Calaminus G, Bamberg M, Jürgens H, et al.: Impact of surgery, chemotherapy and irradiation on long term outcome of intracranial malignant non-germinomatous germ cell tumors: results of the German Cooperative Trial MAKEI 89. Klin Padiatr 216 (3): 141-9, 2004 May-Jun. [PUBMED Abstract]

5.      Aoyama H, Shirato H, Ikeda J, et al.: Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol 20 (3): 857-65, 2002. [PUBMED Abstract]

6.      Kim JW, Kim WC, Cho JH, et al.: A multimodal approach including craniospinal irradiation improves the treatment outcome of high-risk intracranial nongerminomatous germ cell tumors. Int J Radiat Oncol Biol Phys 84 (3): 625-31, 2012. [PUBMED Abstract]

7.      Goldman S, Bouffet E, Fisher PG, et al.: Phase II Trial Assessing the Ability of Neoadjuvant Chemotherapy With or Without Second-Look Surgery to Eliminate Measurable Disease for Nongerminomatous Germ Cell Tumors: A Children's Oncology Group Study. J Clin Oncol 33 (22): 2464-71, 2015. [PUBMED Abstract]

8.      Oya S, Saito A, Okano A, et al.: The pathogenesis of intracranial growing teratoma syndrome: proliferation of tumor cells or formation of multiple expanding cysts? Two case reports and review of the literature. Childs Nerv Syst 30 (8): 1455-61, 2014. [PUBMED Abstract]

9.      Yagi K, Kageji T, Nagahiro S, et al.: Growing teratoma syndrome in a patient with a non-germinomatous germ cell tumor in the neurohypophysis--case report. Neurol Med Chir (Tokyo) 44 (1): 33-7, 2004. [PUBMED Abstract]

10.  Kim CY, Choi JW, Lee JY, et al.: Intracranial growing teratoma syndrome: clinical characteristics and treatment strategy. J Neurooncol 101 (1): 109-15, 2011. [PUBMED Abstract]

Treatment of Newly Diagnosed Childhood CNS Nongerminomatous Germ Cell Tumors

·         Treatment Options for Newly Diagnosed Childhood CNS NGGCTs

o    Chemotherapy followed by radiation therapy

o    Surgery

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

The prognosis for children with CNS nongerminomatous germ cell tumors (NGGCTs) remains inferior to germinomas, but the differential is diminishing with the recent addition of multimodality therapy. With the current treatment regimens, the 10-year overall survival (OS) for NGGCTs is between 70% and 80%.[1,2] NGGCTs are radiosensitive, but survival after standard craniospinal irradiation alone has been poor, ranging from 20% to 45% at 5 years. Of the patients with NGGCTs who relapse, most relapse within 18 months.

Treatment Options for Newly Diagnosed Childhood CNS NGGCTs

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

1.      Chemotherapy followed by radiation therapy.

2.      Surgery, for tumors that do not respond to treatment or for tumors that increase in size after therapy (possible growing teratoma syndrome).

The optimal treatment regimen for CNS NGGCTs remains unclear.

Chemotherapy followed by radiation therapy

Anticancer agents that have been used include carboplatin, etoposide, bleomycin, ifosfamide, and vinblastine in different combinations. The use of chemotherapy before radiation therapy has increased survival rates, but the specific chemotherapy regimen and length of therapy and the optimal radiation field, timing, and dose remain under investigation.[1,3,4] Some investigators have proposed radiation therapy fields that are smaller than craniospinal irradiation (e.g., whole ventricular with boost radiation therapy to the local tumor site) for nondisseminated NGGCT patients. Controversy exists over the pattern of relapse for patients treated with chemotherapy and focal radiation.[1,2,5,6]

A COG study (ACNS0122 [NCT00047320]) eval‎uated neoadjuvant chemotherapy followed by radiation therapy for children with localized NGGCTs.[7] Neoadjuvant chemotherapy consisted of six courses using carboplatin/etoposide alternating with ifosfamide/etoposide. After chemotherapy was completed, responding patients received 36 Gy of craniospinal radiation therapy, with 54 Gy to the tumor bed. On the basis of central review, 87% of patients showed either partial response (PR) or complete response (CR). For the 102 eligible patients in the study, 5-year event-free survival (EFS) was 84% ± 4%, and OS was 93% ± 3%. At 3 years, the EFS was 92% and the OS was 98% for all patients who achieved CR or PR either after induction chemotherapy or with absence of malignant elements documented during second-look surgery.

Surgery

Commonly, patients treated with chemotherapy may have normalization of tumor markers with a less-than-complete radiographic response. A second-look surgery can help determine if the residual mass contains teratoma, fibrosis, or residual NGGCT.[2,8] If second-look surgery finds mature teratoma or fibrosis after chemotherapy, the general approach is to proceed with radiation therapy as if the patient had achieved a CR to chemotherapy. However, if active tumor is observed, then alternative treatment approaches are generally considered.[7]

Occasionally, a mass continues to expand in size even though tumor markers may have normalized; this expansion may be caused by the growing teratoma syndrome and not a failure to treat the NGGCT component.[7,9,10] In such circumstances, surgery is usually required for debulking and histologic confirmation.

Treatment Options Under Clinical Eval‎uation for Newly Diagnosed Childhood CNS NGGCTs

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 NGGCTs include the following:

1.      COG-ACNS1123 (NCT01602666) (Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized Central Nervous System [CNS] 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 OS rates of a short course of chemotherapy followed by response-based, whole-ventricular radiation, 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.      Robertson PL, DaRosso RC, Allen JC: Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neurooncol 32 (1): 71-80, 1997. [PUBMED Abstract]

2.      Baranzelli M, Patte C, Bouffet E, et al.: Carboplatin-based chemotherapy (CT) and focal irradiation (RT) in primary germ cell tumors (GCT): A French Society of Pediatric Oncology (SFOP) experience (meeting abstract). [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-538, 140A, 1999.

3.      Matsutani M; Japanese Pediatric Brain Tumor Study Group: Combined chemotherapy and radiation therapy for CNS germ cell tumors--the Japanese experience. J Neurooncol 54 (3): 311-6, 2001. [PUBMED Abstract]

4.      Calaminus G, Bamberg M, Jürgens H, et al.: Impact of surgery, chemotherapy and irradiation on long term outcome of intracranial malignant non-germinomatous germ cell tumors: results of the German Cooperative Trial MAKEI 89. Klin Padiatr 216 (3): 141-9, 2004 May-Jun. [PUBMED Abstract]

5.      Aoyama H, Shirato H, Ikeda J, et al.: Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol 20 (3): 857-65, 2002. [PUBMED Abstract]

6.      Kim JW, Kim WC, Cho JH, et al.: A multimodal approach including craniospinal irradiation improves the treatment outcome of high-risk intracranial nongerminomatous germ cell tumors. Int J Radiat Oncol Biol Phys 84 (3): 625-31, 2012. [PUBMED Abstract]

7.      Goldman S, Bouffet E, Fisher PG, et al.: Phase II Trial Assessing the Ability of Neoadjuvant Chemotherapy With or Without Second-Look Surgery to Eliminate Measurable Disease for Nongerminomatous Germ Cell Tumors: A Children's Oncology Group Study. J Clin Oncol 33 (22): 2464-71, 2015. [PUBMED Abstract]

8.      Oya S, Saito A, Okano A, et al.: The pathogenesis of intracranial growing teratoma syndrome: proliferation of tumor cells or formation of multiple expanding cysts? Two case reports and review of the literature. Childs Nerv Syst 30 (8): 1455-61, 2014. [PUBMED Abstract]

9.      Yagi K, Kageji T, Nagahiro S, et al.: Growing teratoma syndrome in a patient with a non-germinomatous germ cell tumor in the neurohypophysis--case report. Neurol Med Chir (Tokyo) 44 (1): 33-7, 2004. [PUBMED Abstract]

10.  Kim CY, Choi JW, Lee JY, et al.: Intracranial growing teratoma syndrome: clinical characteristics and treatment strategy. J Neurooncol 101 (1): 109-15, 2011. [PUBMED Abstract]