Abstract
Purpose:
In patients with high-risk neuroblastoma, there is an increased recognition ofrelapse in the central nervous system (CNS). Craniospinal irradiation (CSI) has been an effective treatment butcarries significant long-term complications. It is unclear whether reducing the CSI dose from 21Gy to 18Gy can achieve similar CNS tumor control.
Patients and methods:
A retrospective review of pediatric patients with CNS-relapsedneuroblastoma treated with CSI and boost to parenchymal lesions between 2003 and 2019 was performed. The goal was to assess CNS controlcomparing 18Gy and 21Gy regimens.
Results:
94 patients withCNS-relapsed neuroblastoma were treated with CSIfollowed by intraventricular compartmental radioimmunotherapy. Median age at the time of CNS diseasewas 4 years (range 1–13 years). Forty-one patients (44%) received 21Gy CSI prior to an institutional decision to lower the dose; 53 patients (56%) received 18Gy CSI. 79 patients (84%) received additional boosts. With a median follow-up of 4.1 years for surviving patients, 2-year CNS-relapse free survival was 74% for 18Gy group vs. 77% for 21Gy group, and 5-year CNS-relapse free survival was 66% for 18Gy vs. 72% for 21Gygroup, respectively (p=0.40). 5-year overall survival rate was 43% in 18Gy group vs. 47% in 21Gy group (p=0.72).
Conclusion:
For patients with CNS-relapsed neuroblastoma, CNS disease control is comparable between 18Gy and 21Gy CSI dose regimens, in conjunction with radioimmunotherapy and CNS penetrating chemotherapy. More than 65% of the patients remain CNS-disease free after 5 years. The findingssupport 18Gy as the new standard CSI dose for CNS-relapsed neuroblastoma.
Keywords: cerebrospinal irradiation, neuroblastoma, central nervous system metastasis
Introduction
More than half of children with neuroblastoma present with distant metastasis at diagnosis. The most common sites include bone, bone marrow, liver, and skin. Intraparenchymal brain metastasis and leptomeningeal disease arerare on presentation and typically a manifestation of end-stage disease. However, as a result of improved overall survival from multimodality therapy and modern therapeutic techniques, there is an increased recognition of central nervous system (CNS) metastasis1.
When neuroblastoma relapses in the CNS, the entire neuroaxis is at risk due to the tendency of leptomeningeal spread by the neuroblastoma cells. Standard treatment for CNS-relapsed neuroblastoma at our institution has been surgical resection of the gross disease if feasible, followed by craniospinal irradiation (CSI)with boost to the site of CNS relapse, chemotherapy with irinotecan and temozolomide, and intraventricular compartmental radioimmunotherapy (RIT)2. The treatment regimen likely varies across the nation and internationally due to limited availability of RIT, though this novel treatment is in a pivotal international trial (NCT03275402). Croog et al. has previously described early experience in achieving durable CNS remission and improved survival withCSIcompared to focal radiation and conventional therapies3.
CSI carries detrimental consequences that correlate with increasing dose and decreasing patient age. Until recently, our standard CSI dosehas been 21Gy with a boost to 30Gy for resection cavities, 36Gy for unresectable lesions. We decided to reduce the dose of CSI from 21Gy to 18Gy unless there is bulky leptomeningeal disease. The rationale for reducing CSI dose to 18Gy is based on studies showing improvement in neurocognitive outcomes4,5 and endocrine outcomes with lower CSI dosing6.To date, there is no report on whether 18Gy CSI is as effective as standard dose (21Gy) CSI in patients with CNS-relapsed neuroblastoma. This study aims to retrospectively review the outcomes of CNS control with 18Gy versus 21Gy CSI in CNS-relapsed neuroblastoma patients who received subsequent care at a single institution.
Methods
Patient selection
A retrospective review of patients with CNS-relapsedneuroblastoma treated at a single institution between 2003and 2019 was performedwith the approval of Institutional Review Board (IRB #16–1184). Patients were excluded if CSI was not delivered, CSI dose was other than 18Gy or 21Gy, or if RIT was not delivered. CNS relapse after CSI was defined by disease recurrence involving brain or spinal cord parenchyma, subarachnoid space, or leptomeninges. The diagnosis of CNS relapse was based on MRI imaging. Lumbar puncture was not routinely performed to minimize the risk of disease spread in cerebrospinal fluid.
Treatment
CSI was considered for patients who were age one year or older. CSI was delivered with either photon or proton therapy based on the availability of proton therapy. CSI was delivered with daily fractions of 1.5Gy or 1.8Gy. Additional boost radiation up to 36Gy in total was optional and given to the site of CNS relapse. Most patients received a course of irinotecan for 5 days during radiation therapy.Following CSI, all patients received RIT with 131I-8H9 (Omburtamab) or 131I-3F8 as previously described2.
Statistical analysis
The primary objective was to compareCNS relapse-free survival between standard dose (21Gy) and reduced-dose (18Gy) CSI. Additional analyses were performed to compare overall survival between the two groups. CNS relapse-free interval was calculated as the time from end of CSI to a new CNS relapse event. Kaplan-Meier method was used to estimate CNS-relapse free survivaland overall survival7.
Results
A total of 172 patients with a diagnosis of CNS-relapsed neuroblastoma were identified (Figure 1).Patients were excluded for not receiving CSI (n=44), receiving CSI doses other than 18Gy or 21Gy (n=11), or not receiving radioimmunotherapy (n=19). Final analysis included 94 patients who were treated with CSI 18Gy or 21Gyand RIT between 2003and 2019.Demographic and clinical characteristics of patients are detailed in Table 1. Median age of patient at diagnosis of CNS relapse was 4 years and age ranged from 1 year to 13 years. Median follow-up was 23 months for all patients and 49 months for surviving patients.
Figure 1.
Flow chart of patient selection.
TABLE 1.
Baseline characteristics of patients with CNS-relapsed neuroblastoma who had received CSI and RIT.
| Total | 18Gy | 21Gy | |
|---|---|---|---|
| Patients | 94 | 53 (56%) | 41 (44%) |
| Age (years) | |||
| Median (Range) | 4 (1–13) | 4 (1–13) | 4 (1–11) |
| Sex | |||
| Male | 61 (65%) | 36 (68%) | 25 (61%) |
| Female | 33 (35%) | 17 (32%) | 16 (39%) |
| CSI | |||
| Year delivered (median, range) | 2013 (2003–2019) | 2014 (2007–2019) | 2009 (2003–2019) |
| Boost | |||
| Yes | 79 (84%) | 47 (89%) | 32 (78%) |
| No | 11 (12%) | 4 (8%) | 7 (17%) |
| Unknown | 4 (4%) | 2 (4%) | 2 (5%) |
| Total dose (Gy) after boost (median, range) | 30.6 (21.6–45) | 30.6 (21.6–45) | 30.6 (23.4–36) |
| RT Modality | |||
| Photon | 78 (83%) | 41 (77%) | 37 (90%) |
| Proton | 15 (16%) | 11 (21%) | 4 (10%) |
| Unknown | 1 (1%) | 1 (2%) | 0 (0%) |
Abbreviations
CSI: Craniospinal irradiation
RT: Radiation therapy
Among 94 patients, 53 (56%) received 18Gy CSI while 41 (44%)received 21Gy. Additional boosts to the site(s) of initial CNS relapse were given to 79 patients (84%) for total focal doses ranging from 21.6Gy to 45Gy. All patients had received RIT with 131I-8H9 or 131I-3F8.
23 (24%) patients developed another CNS relapse after receiving CSI, of whom14patients (26%) were in the 18Gy group, and 9patients (22%) were in the 21Gy group. A total of 32 patients (34%) developed systemic metastases after CSI, 15 patients in the 18Gy group compared to 17 patients in the 21Gy group. Of the patients who developed CNS recurrence, 11 (48%) had co-recurrence of disease outside of CNS, 8 patients (35%) had recurrent or persistent leptomeningeal disease after CSI. The median CNS-relapse free survival was not reached in either the18Gy group or 21Gy group (Figure 2). The 2-year CNS-relapse free survival was 74% for 18Gy groupvs. 77% for21Gy group. The 5-year CNS-relapse free survival was 66% for 18Gy group vs. 72% for 21Gy group (p=0.40).
Figure 2.
CNS relapse-free survival in patients with CNS-relapsed neuroblastoma who received either 18Gy CSI (red) vs. 21Gy CSI (black). Shaded areas represent 95% confidence interval of the Kaplan-Meier curve.
Median overall survival was 35.9 months in the 18Gy group and 55.0 months for the 21Gy group (Figure 3). At 2 years, overall survival rate was 65% for 18Gy group vs. 74% for 21Gy group. At 5 years, the overall survival rate was 43% for 18Gy group vs. 47% for 21Gygroup. There was no significant difference in overall survival rates between thegroups (p=0.72).
Figure 3.
Overall survival in patients with CNS-relapsed neuroblastoma who received either 18Gy CSI (red) vs. 21Gy CSI (black). Shaded areas represent 95% confidence interval of the Kaplan-Meier curve.
Discussion
The CNS is a sanctuary site for neuroblastoma cells as many chemotherapy and immunotherapy agents do not cross the blood-brain barrier. Historically, CNS involvement in neuroblastoma has been rare and a manifestation of end-stage disease8–13. However, its incidence has been steadily rising in the modern era, likely due to advances in multimodality approach and improved overall survival in patients withhigh-risk neuroblastoma. Kramer et al. had recognizedand reported an increasing incidence of CNS spread from 1.7% in patients treated on older protocols, to 11.7% in patients treated on more recent protocols1. Prior to the development and adoption of CNS-specific therapies, CNS relapse was universally fatal. In addition, the likelihood of developing CNS relapse could not be lessened by the intensification of systemic therapy. We reported on a myeloablative regimen comprising topotecan, thiotepa, and carboplatin, designed to consolidate remission and to prevent CNS relapse. Despite the enhanced CNS penetration, CNS relapse remained a major problem14.
Neuroblastoma cells are sensitive to radiation. External beam radiation in combination with compartmental RIT has becomepart of our standard salvage program for patients with CNS relapse. A retrospective analysis of 29 patients with neuroblastoma treated for CNS relapse included 16 treated with CSI (median dose 21.6Gy) and 13 treated with focal RT. At a median follow-up of 28 months, 12 patients (75%) in the CSI group were alive without CNS disease while all 13 patients treated with focal RT had died3. The study suggests that when neuroblastoma recurs in the CNS, the entire neuroaxis is at risk. This finding agrees with early observations of frequent leptomeningeal disease seen on neuroimaging and neuroblastoma cells found in cerebrospinal fluid duringautopsies1,11,15.
CSI carries significant long-term riskssuch as neurocognitive deficit, endocrine dysfunction, and increased risk of secondary malignancy. Theseverity of neurocognitive deficit is proportional to the dose of CSI delivered16–18. In children with acute lymphoblastic leukemia, the reduction of cranial radiation dose from 24Gy to 18Gy was associated with improvement in neurocognitive outcomes including higher scores on verbal intelligence quotient and achievement tests of reading, spelling, and mathematics19. In another study, children treated with 18Gy CSI for medulloblastoma had statistically greater adult heights and sitting heights compared to a group treated with conventional doses of CSI (23 to 39Gy). Notably, the adult heights of the 18Gy group were not different from themidparental heights6. Furthermore, studies have shown the relative risk of developing a secondary malignancy after irradiation follows a linear relationship20–22. This linear increase in secondary malignancy is seen from4Gy to 40Gy in breast cancer risk after radiation for Hodgkin’s lymphoma20. In addition to long-term effects, cranial radiation can also cause somnolence syndrome characterized by sleepiness, irritability, and anorexia. It generally occurs subacutely (1 to 6 months after RT), resolves in 2–8 weeks with steroids treatment, and does not predict any subsequent long-term brain injury23.
The current study is the largest cohort of patients with CNS-relapsed neuroblastoma and the first to show that in conjunction with compartmental RIT and systemic chemotherapy, reduced-dose CSI of 18Gy is equally effective in CNS disease control compared to 21Gy CSI regimen. The 2-year CNS disease-free survival of the 18Gy CSI group is 74%, which is not significantly different from the 21Gy CSI group, and comparable to previously reported CNS control of 75% (12/16 patients) with 21Gy CSI3. Notably, more than 65% to the patients were able to achieve durable remission for at least 5 years after treatment.The study has several limitations. The dose reduction from 21Gy to 18Gy was based on an institutional decision and not part of a randomized trial, therefore unmeasured confounding biases may exist. In addition, patients in this study has received radioimmunotherapy which is not readily available at other institutions. Radioimmunotherapy and CSI are both integral components of the salvage regimen for CNS-relapsed neuroblastoma at our institution. According to the published initial experience, the addition of radioimmunotherapy to surgery, CSI, and chemotherapy extended the median survival by approximately 6 months compared to historic control2. In the 21 patients included in the study, 17 patients remained CNS-disease free at 7–74 months after CNS relapse. However, it is unclear if CSI dose was a factor in this series because majority of the patients (16 out of 21) received 21Gy CSI and 3 patients who received 18Gy CSI all achieved CNS-disease remission. Another disadvantage is that because patients were not part of a clinical trial, detailed toxicity and formal neuropsychological evaluationswere not performed to the assess long-term neurocognitive effects of reduced versus standard CSI doses.
The successful tumor control with 18Gy CSI raises the possibility that the dose can be further reduced to minimize radiation toxicities. Dose de-escalation in neuroblastoma is under investigation as part of initial therapy. A recent prospective study has shown that 18Gy hyperfractionated radiation to the primary tumor site after gross total resectiondoes not compromise local control or survival outcomes compared to 21Gy in patients with high-risk neuroblastoma24. The protocol is currently studying 15Gy as the next reduced dose level. As 18Gy CSI is deemed an acceptable dose level, we believe it is reasonable to consider a lower dose as the next step in further decreasing the long-term morbidity.
Conclusion
The pattern of relapse in high-risk neuroblastoma is shifting as a result of advances in multimodality approach and improved survival outcome. CSI for CNS relapse has been effective, but carries significant long-term morbidity. The study shows that CNS disease control is comparable between 18Gy and 21Gy CSI dose regimens,in conjunction with compartmental RIT and CNS-penetrating chemotherapy.
Conflict of Interest Statement
N.K. Cheung (NKC) reports: receiving commercial research grants from Y-mAbs Therapeutics and Abpro-Labs Inc.; holding ownership interest/equity in Y-mAbs Therapeutics Inc., holding ownership interest/equity in Abpro-Labs, and owning stock options in Eureka Therapeutics. NKC is the inventor and owner of issued patents licensed by MSK to Y-mAbs Therapeutics, Biotecpharmacon, and Abpro-labs. NKC is a consultant/advisory board member for Abpro-Labs and Eureka Therapeutics. Kim Kramer and Shakeel Modak are consultants to Y-mAbs Therapeutics Inc. Omburtamab was licensed to Y-mAbs Therapeutics in 2015. No potential conflicts of interest were disclosed by other authors.
Abbreviation Key
- CNS
Central nervous system
- CSI
Cerebrospinal irradiation
- RIT
Radioimmunotherapy
- RT
Radiation therapy
Footnotes
Data availability statement: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
References
- 1.Kramer K, Kushner B, Heller G, Cheung NK. Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer. 2001;91(8):1510–1519. [PubMed] [Google Scholar]
- 2.Kramer K, Kushner BH, Modak S, et al. Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neurooncol. 2010;97(3):409–418. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Croog VJ, Kramer K, Cheung NK, et al. Whole neuraxis irradiation to address central nervous system relapse in high-risk neuroblastoma. Int J Radiat Oncol Biol Phys. 2010;78(3):849–854. [DOI] [PubMed] [Google Scholar]
- 4.Smibert E, Anderson V, Godber T, Ekert H. Risk factors for intellectual and educational sequelae of cranial irradiation in childhood acute lymphoblastic leukaemia. Br J Cancer. 1996;73(6):825–830. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Schreiber JE, Gurney JG, Palmer SL, et al. Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma. Neuro Oncol. 2014;16(8):1129–1136. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Xu W, Janss A, Packer RJ, Phillips P, Goldwein J, Moshang T Jr. Endocrine outcome in children with medulloblastoma treated with 18 Gy of craniospinal radiation therapy. Neuro Oncol. 2004;6(2):113–118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Journal of the American statistical association. 1958;53(282):457–481. [Google Scholar]
- 8.Astigarraga I, Lejarreta R, Navajas A, Fernandez-Teijeiro A, Imaz I, Bezanilla JL. Secondary central nervous system metastases in children with neuroblastoma. Med Pediatr Oncol. 1996;27(6):529–533. [DOI] [PubMed] [Google Scholar]
- 9.Blatt J, Fitz C, Mirro J Jr. Recognition of central nervous system metastases in children with metastatic primary extracranial neuroblastoma. Pediatr Hematol Oncol. 1997;14(3):233–241. [DOI] [PubMed] [Google Scholar]
- 10.Hu H, Zhang W, Huang D, et al. Clinical characteristics, treatment and prognosis of paediatric patients with metastatic neuroblastoma to the brain. Clin Neurol Neurosurg. 2019:105372. [DOI] [PubMed] [Google Scholar]
- 11.Kellie SJ, Hayes FA, Bowman L, et al. Primary extracranial neuroblastoma with central nervous system metastases characterization by clinicopathologic findings and neuroimaging. Cancer. 1991;68(9):1999–2006. [DOI] [PubMed] [Google Scholar]
- 12.Matthay KK, Brisse H, Couanet D, et al. Central nervous system metastases in neuroblastoma: radiologic, clinical, and biologic features in 23 patients. Cancer. 2003;98(1):155–165. [DOI] [PubMed] [Google Scholar]
- 13.Paulino AC, Nguyen TX, Barker JL Jr. Brain metastasis in children with sarcoma, neuroblastoma, and Wilms’ tumor. Int J Radiat Oncol Biol Phys. 2003;57(1):177–183. [DOI] [PubMed] [Google Scholar]
- 14.Kushner BH, Kramer K, Modak S, et al. Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system. Bone Marrow Transplant. 2006;37(3):271–276. [DOI] [PubMed] [Google Scholar]
- 15.de la Monte SM, Moore GW, Hutchins GM. Nonrandom distribution of metastases in neuroblastic tumors. Cancer. 1983;52(5):915–925. [DOI] [PubMed] [Google Scholar]
- 16.Mulhern RK, Palmer SL, Merchant TE, et al. Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol. 2005;23(24):5511–5519. [DOI] [PubMed] [Google Scholar]
- 17.Palmer SL, Goloubeva O, Reddick WE, et al. Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis. J Clin Oncol. 2001;19(8):2302–2308. [DOI] [PubMed] [Google Scholar]
- 18.Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM. Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol. 2001;19(15):3470–3476. [DOI] [PubMed] [Google Scholar]
- 19.Moore IM, Kramer JH, Wara W, Halberg F, Ablin AR. Cognitive function in children with leukemia. Effect of radiation dose and time since irradiation. Cancer. 1991;68(9):1913–1917. [DOI] [PubMed] [Google Scholar]
- 20.Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. 2003;290(4):465–475. [DOI] [PubMed] [Google Scholar]
- 21.Berrington de Gonzalez A, Gilbert E, Curtis R, et al. Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship. Int J Radiat Oncol Biol Phys. 2013;86(2):224–233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Svahn-Tapper G, Garwicz S, Anderson H, et al. Radiation dose and relapse are predictors for development of second malignant solid tumors after cancer in childhood and adolescence: a population-based case-control study in the five Nordic countries. Acta Oncol. 2006;45(4):438–448. [DOI] [PubMed] [Google Scholar]
- 23.Butler JM, Rapp SR, Shaw EG. Managing the cognitive effects of brain tumor radiation therapy. Curr Treat Options Oncol. 2006;7(6):517–523. [DOI] [PubMed] [Google Scholar]
- 24.Casey DL, Kushner BH, Cheung NV, et al. Reduced-Dose Radiation Therapy to the Primary Site is Effective for High-Risk Neuroblastoma: Results From a Prospective Trial. Int J Radiat Oncol Biol Phys. 2019;104(2):409–414. [DOI] [PMC free article] [PubMed] [Google Scholar]