Pineoblastoma is a rare, embryonic tumor with sparse data in literature about the outcome and prognostic factors affecting the survival. Some studies support that patients with pineoblastomas have a worse outcome compared to other primitive neuroectodermal tumors (sPNETs) [13]. In this study, younger patients had significantly low EFS and OS. The impact of age on outcome is mostly due to different molecular subgroups that affected the response to treatment and metastases occurrence. Recent studies proved that there are four molecular subgroups in pineoblastoma (A, B, B-like, and FOXR2) exist. Group A occurs in infants, and B and B-like groups occur in older age with 50% and 0% incidence of metastases, respectively [8]. The COG ACNS0332 trial reported a 5-year EFS of 62.8% in pineoblastoma patients older than 3 years, which is better than our results [14]. A pooled analysis from 11 centers under the umbrella of SIOP reported 5-year PFS rates of 63% and 11% for patients older and younger than 4 years of age, respectively [15].
The presence of the metastatic disease did not affect survival in our study. Gururangan S et al. reported a surprisingly higher survival rate of 75% for metastatic and localized diseases. These unexpected results may be attributed to high-dose chemotherapy administration, which nullified the negative impact of metastatic disease [9]. The SIOP multicentric work proved that metastatic disease was an independent adverse prognostic factor, and using HDCTH did not improve survival [15]. Contrarily, Jakacki RI et al. reported that metastatic disease had no significant impact on survival [16]. In our study, there was no significant impact of age on the outcome of metastatic disease. However, it was apparent that young patients with metastatic disease showed a much lower cure rate, where 85% of the younger patients died from progressive disease compared to 56% in the older age group. In our study, the 3-year OS of older patients with M + ve disease was 50% compared to 5-year OS of 60.3% in the SJMB03 trial. The SJYC07 trial reported a 2-year OS of 0% for infantile patients with M + ve disease, comparable with our results (10% survival) [8]. The common element between our study and the SJYC07 trial is that neither used mega therapy in infants. In this study, the extent of resection did not affect the outcome as in the SIOP data but this is not conclusive in our study due to small number of patients who underwent GTR [15]. Low number of gross total resection was due to reluctance of the neurosurgeon to pursue this risky procedure with no clear evidence of the impact of GTR on the outcome.
However, St. Jude’s report concluded that GTR was significantly associated with a better outcome for patients over 3 years (PFS, P = 0.005, OS, P = 0.008) with no impact on the younger age group [8]. Another St. Jude report concluded that there was no outcome difference between GTR and STR, but when controlling for age, 80% of the GTR group and 50% of the STR/biopsy group were alive without evidence of progression [10]. Adjuvant therapy was a significant predictor of the outcome in our study. All patients who did not receive adjuvant CTH/RTH (due to guardians’ refusal), died. This emphasizes that pineoblastoma is an aggressive disease that cannot be treated by surgery alone. CSI showed a more positive impact on survival than focal irradiation, taking in consideration that all older patients received CSI while most of the younger patients received focal RTH. The better results with CSI may be due to the impact of the age group and the related molecular subtypes.
Patients younger than 3 years of age were assigned for focal radiotherapy for fear of developmental, intellectual and toxicity which may be encountered by CSI. Patients close to or older than 3 years of age were assigned to CSI as they can better tolerate CSI with less side effects aiming to improve the outcome.
Mynarek M et al. concluded that radiation therapy was the most important prognostic factor where most of the patients received CSI. Five non-metastatic young patients achieved cure with focal radiotherapy and HDCTH [15]. Focal RTH delivery may explain young patients’ unfortunate outcomes in our study (even the non-metastatic ones), as they were offered focal RTH without mega therapy. In this study, most of the failures (15/19) occurred distally, regardless of their metastatic state upfront. These results pointed out that focal RTH is not efficient in treating pineoblastoma, especially in infants who initially have a high potential for metastatic disease and recurrence. Perrault et al. reported the same recurrence pattern in which all relapses were metastatic [17]. The radiological response was associated with a substantial impact on the outcome. The survival of patients with objective responses (CR and PR) was significantly better than those with MR, SD, and PD, which raises the importance of intensifying induction by CTH/RTH to achieve a better outcome. Mynarek M et al. concluded that the more intensified the chemotherapy induction (even without transplant), the better the remission status [15]. The 3-year OS and EFS for all cases were 46.7% and 44.4%, respectively. This survival was inferior compared to the survival reported by Liu et al. (5-year PFS and OS of 60.7 ± 6.6% and 61.0 ± 6.8%, respectively) [8]. In our study, the 3-year OS of M0 patients in the older group was 74% compared to 100% for the same group in the SJMB03 study; the high-dose chemotherapy used may be the cause of their better survival in older patients [9]. SIOP data concluded that the impact of HDCTH on survival is limited, but it was more evident in older patients [8]. The children oncology group (COG 99701) trial reported a much better 5-year OS and PFS of 81 ± 9% and 62 ± 11% [15]. The survival discrepancy between our study and the COG 99701 may be attributed to our center’s lack of chemotherapy dose intensity policy. In this study, the better infant survival in the M + ve group compared to the M0 group may be due to CSI administration to the only surviving patient. Mynarek et al. reported that 3/5 patients treated with focal RTH and transplant and 3/16 treated with CSI were cured in the younger age group [15]. RCT is needed to evaluate the real impact of mega therapy in pineoblastoma, especially in young patients. There is great need to classify pineoblastoma molecularly based on copy number, whole exome sequencing analysis to label patients with poor prognostic molecular groups (MYC, RB) who need intensified therapy, and those with excellent survival who harbored post-transcriptional regulators endonucleases mutations as DROSHA, DGCR8, and DICER1 with survival up to 100% [18]. The present study limitations were its retrospective design, relatively small number of patients, low number of patients with GTR, lack of molecular subtyping to detect patients with high risk for relapse, inability to offer transplant especially in infants due to long waiting list and lack of adoption of chemotherapy dose intensity policy .