Abstract
Purpose:
This study aimed to assess the incidence and management of pseudoprogression after radiation therapy (RT) in patients with pediatric low-grade glioma (LGG).
Methods:
This retrospective review included patients aged 21 years or younger with intracranial LGG treated with curative-intent RT. Pseudoprogression was defined as an increase in tumor size by ≥10% in at least 2 dimensions between 2 or 3 consecutive MR imaging studies. Overall survival (OS) and event-free survival (EFS) were measured from the first day of RT. EFS was defined as survival without true progression or secondary high-grade glioma.
Results:
Sixty-two of 221 patients developed pseudoprogression, with a 10-year cumulative incidence of 29.0% (95% CI 23.0–35.2). Median time to pseudoprogression was 6.1 months after RT. Symptomatic pseudoprogression was managed with subtotal resection, shunt/Ommaya reservoir placement, or corticosteroids in 11 (18%), 7 (11%), and 2 patients (3%), respectively. The remaining tumors were observed (68%). Patients with pilocytic astrocytoma (PA) had 5.4-fold greater odds of developing pseudoprogression relative to tumors of other histology (odds ratio 95% CI 2.5–11.4, P < 0.0001). Among patients with PA (n = 127), the 10-year cumulative incidence of pseudoprogression was 42.9%. In this group, pseudoprogression was associated with improved 10-year EFS (84.5% vs. 58.5%, P = 0.008) and OS (98.0% vs. 91.2%, P = 0.03).
Conclusions:
Pseudoprogression after irradiation was common, especially in patients with pilocytic astrocytoma, and was associated with improved survival. Knowledge of the incidence and temporal course of pseudoprogression may help avoid unnecessary salvage therapy.
Keywords: glioma, magnetic resonance imaging, pediatrics, pseudoprogression, radiation effects, radiation
Introduction
Treatments for pediatric low-grade glioma (LGG) vary and may involve a combination of surgery, chemotherapy, targeted agents, and irradiation.[1] Radiation therapy (RT) plays an important role in long-term local control of LGG, with contemporary 10-year progression-free survival (PFS) or event-free survival (EFS) rates ranging from 74% to 78%.[2–4] However, irradiation can cause pseudoprogression, defined as transient tumor growth that stabilizes or resolves with time.[5–7] It is important to distinguish true tumor progression from pseudoprogression in order to document the effectiveness of irradiation and ensure that patients are appropriately selected for subsequent salvage treatment.
In published reports with small patient cohorts, the crude incidence of pseudoprogression ranges from 16% to 54%.[5, 6, 8] An awareness of pseudoprogression is important in order to prepare patients, parents, and caregivers for imaging changes, potential symptoms, and the need to consider interventions (such as steroids, a cerebrospinal fluid [CSF] shunt, or surgery). Most importantly, identifying pseudoprogression may avoid unnecessary interventions or the administration of salvage systemic therapy for a process that will resolve with time.
The purpose of the present study was to characterize the incidence of pseudoprogression after curative-intent RT for intracranial pediatric LGG. Secondary endpoints included the evaluation of the temporal dynamics and treatments for pseudoprogression, the identification of clinicopathologic factors associated with pseudoprogression, and the elucidation of the association between pseudoprogression and true progression.
Materials and Methods
This was a retrospective cohort study of all patients with pediatric LGG treated with irradiation at a single institution from 1986 to 2016. Eligible patients were aged 21 years or younger, had WHO grade I or II intracranial LGG diagnosed according to the criteria in use at the time of diagnosis, and had been treated with curative-intent RT. Patients were included based on a neuroimaging diagnosis if it was consistent with LGG (e.g. optic pathway glioma). The indications for RT were tumor progression at the time of initial diagnosis, as salvage treatment after surgery and subsequent tumor progression, or tumor progression after chemotherapy. No patient received adjuvant RT after gross total resection of their tumor. Individuals with spinal cord primary tumors (without intracranial involvement) and clinical or neuroimaging features of HGG, bithalamic tumors, gliomatosis cerebri, or diffuse infiltrating pontine gliomas with classic findings were excluded. The study was approved by the Institutional Review Board of St. Jude Children’s Research Hospital.
Data were collected from medical charts, RT records, and the institutional picture archiving and communication system. Tumor tissue, when available, was reviewed by the institutional pathology team. Follow-up neuroimaging included T1, T2, FLAIR, and contrast-enhanced T1 sequences every 3 months for 3 years after completion of RT, every 6 months through year 5 after completion, and annually thereafter, unless more frequent imaging was required to assess or monitor imaging changes or symptoms.
For this investigation, pseudoprogression was defined as an interval increase in the tumor size on brain MRI of at least 10% in at least 2 dimensions over 2 or 3 consecutive evaluations. Pseudoprogression was distinguished from true progression by the presence or occurrence of any of the following: a) the eventual stabilization of, or reduction in tumor size, without treatment; b) the growth of cystic components only, rather than solid components; c) subsequent, non-curative intervention (with steroids, CSF shunt placement, or cyst decompression/partial resection) without further treatment being required. Patients were defined as having true progression if they had persistent tumor growth after RT that required tumor-directed therapy (chemotherapy, a targeted agent, gross total resection, or repeated subtotal resections), a decline in visual acuity in patients with optic pathway tumors, if they developed new lesions outside the RT field, or if they died from tumor progression.
Statistical analysis
Clinical factors and baseline characteristics were reported descriptively; categorical variables were compared using Fisher’s exact test (for up to 3 categories) or the chi-squared test (for more than 3 categories). Cumulative incidences of pseudoprogression were reported using the method of Fine and Gray to account for competing risks of true progression or death.[9] Days were counted from the first day of RT. Patients who were alive at the last follow-up, who were lost to follow-up without observed pseudoprogression, or who developed a competing risk were censored. Overall survival (OS) was reported using the Kaplan-Meier method. Event-free survival (EFS) was defined as survival without true progression or secondary HGG. Comparisons between groups were performed using the log-rank test. Stepwise logistic regression was used to create a multivariate model to evaluate factors associated with pseudoprogression. Analyses were completed using SAS 9.4 (Cary, NC).
Results
The study included 221 eligible patients with LGG. The median follow-up time was 12.2 years. Baseline characteristics of the patients according to their pseudoprogression status are listed in Table 1. Most patients with pseudoprogression had pilocytic astrocytoma. There was no difference in the radiation dose between the 2 groups. Representative examples of pseudoprogression are shown in Supplementary Figure 1.
Table 1.
Baseline characteristics of patients stratified by occurrence of pseudoprogression
| Characteristic | Pseudoprogression (n = 62) | No pseudoprogression (n = 159) | P-value |
|---|---|---|---|
| Median age at RT start (range) | 9.4 y (1.2–18.7 y) | 8.7 y (1.2–24.9 y) | 0.35 |
| Female | 27 (43.6%) | 78 (49.0%) | 0.55 |
| NF-1 positive | 6 (9.7%) | 15 (9.4%) | 1.0 |
| Histology | 0.0002 | ||
| Pilocytic astrocytoma | 52 (83.9%) | 75 (47.2%) | |
| Astrocytoma, NOS | 2 (3.2%) | 21 (13.2%) | |
| Diffuse astrocytoma | 0 | 18 (11.3%) | |
| Ganglioglioma | 3 (4.8%) | 11 (6.9%) | |
| Pilomxyoid astrocytoma | 1 (1.6%) | 4 (2.5%) | |
| Oligodendroglioma | 0 | 3 (1.9%) | |
| Other low-grade glioma | 3 (4.8%)a | 10 (6.3%)b | |
| No surgery | 1 (1.6%) | 17 (10.7%) | |
| Cystic component at RT start | 26 (41.9%) | 40 (25.2%) | 0.021 |
| Tentorial location | 0.41 | ||
| Supratentorial | 46 (74.2%) | 110 (69.2%) | |
| Infratentorial | 15 (24.2%) | 48 (30.2%) | |
| Both | 1 (1.6%) | 1 (0.6%) | |
| Tumor location | 0.15 | ||
| Brainstem | 11 (17.7%) | 32 (20.1%) | |
| Cerebellum | 4 (6.5%) | 16 (10.0%) | |
| Optic pathway–hypothalamic | 28 (45.2%) | 68 (42.8%) | |
| Midbrain or thalamus | 16 (25.8%) | 29 (18.2%) | |
| Tectal plate | 2 (3.2%) | 1 (0.6%) | |
| Supratentorial | 0 | 12 (7.6%) | |
| Diffuse neuraxis | 1 (1.6%) | 1 (0.6%) | |
| Metastatic at diagnosis | 4 (6.5%) | 5 (3.1%) | 0.27 |
| Surgery before RT | 0.55 | ||
| GTR or NTR | 3 (9.7%) | 7 (4.4%) | |
| STR | 23 (37.1%) | 58 (36.5%) | |
| Biopsy | 32 (51.6%) | 73 (45.9%) | |
| No surgery before RT | 4 (6.5%) | 21 (13.2%) | |
| Chemotherapy before RT | 21 (33.9%) | 59 (37.1%) | 0.76 |
| Median max. tumor dimension before RT (range) | 3.3 cm (0.5–9.9 cm) | 2.7 cm (0.8–10.1 cm) | 0.12 |
| Median RT dose (range) | 54 Gy (48.9–70.2 Gy) | 54 Gy (46.8–55.8 Gy) | 0.16 |
| RT modality | 0.42 | ||
| Photon | 59 (95.2%) | 154 (96.9%) | |
| SRS | 1 (1.6%)c | ||
| Proton | 2 (3.2%) | 5 (3.1%) |
GTR = gross total resection, Gy = gray, LGG = low-grade glioma, NF-1 = neurofibromatosis type 1, NOS = not otherwise specified, NTR = near total resection, RT = radiation therapy, SRS = stereotactic radiosurgery, STR = subtotal resection
Low-grade glioma, not otherwise specified (NOS) (2), gangliocytoma (1)
Low-grade glioma, NOS (5), angiocentric glioma (1), central neurocytoma (1), oligoastrocytoma (1), optic nerve glioma, NOS (1), neurocytoma (1)
22 Gy SRS (Gamma Knife)
Pseudoprogression
Pseudoprogression was observed in 62 patients (Figure 1). The cumulative incidence was 29.0% (95% confidence interval [CI] 23.0–35.2) at 10 years. The median time to first imaging evidence of pseudoprogression, measured from the first day of RT, was 6.1 months (IQR 3.5–14.6; range, 0.9–105); 18 (29.0%) experienced onset of pseudoprogression more than 12 months after receiving RT, and 8 (12.9%) experienced onset of pseudoprogression more than 24 months after receiving RT. The one patient with pseudoprogression 105 months after RT had tumor growth suspected to represent true progression and underwent surgery; pathology was negative for malignancy but demonstrated benign intratumoral hemorrhage. 46 patients (74.2%) had tumors with more than 10% growth over 2 consecutive MR imaging studies, while the remainder (16 patients, 25.8%) experienced more than 10% growth over 3 consecutive studies.
Fig 1.
Cumulative incidence of pseudoprogression for all patients and stratified by histology. PA = pilocytic astrocytoma, All = all patients, Other = histologies other than pilocytic astrocytoma.
Among 127 patients with pilocytic astrocytoma, the cumulative incidence of pseudoprogression was 42.9% (95% CI 33.8–51.7) at 10 years, with a median time to onset of 6.1 months (IQR 3.3–14.3). For patients with tumors of histologies other than pilocytic astrocytoma, the 10-year cumulative incidence of pseudoprogression was 10.8% (95% CI 5.5–18.1). In the subgroup of patients with pilocytic astrocytoma and pseudoprogression, 30 (57.7%) had predominantly cystic-appearing pseudoprogression and 22 (42.3%) had predominantly solid-appearing pseudoprogression. Cumulative incidences of pseudoprogression by histology and the presence or absence of cystic components at initiation of RT are shown in Supplementary Figure 2.
Treatments and interventions for pseudoprogression are listed in Table 2. The median time from onset of pseudoprogression to intervention was 3.4 months (IQR 1.8–6.1). The tumor locations for patients who required intervention were thalamic (n = 5), hypothalamic (n = 5), midbrain (n = 4), or optic pathway/diencephalic (n = 4); 18 of 141 patients (12.8%) with tumors in locations surrounding the third ventricle required invasive treatment for pseudoprogression. In a high-risk subgroup of 33 patients with pilocytic astrocytoma, cystic components at the time of RT, and a tumor location near the third ventricle, 8 (24%) required an invasive intervention for symptomatic pseudoprogression. All 11 patients with pseudoprogression who required surgical resection had pilocytic astrocytoma; 10 (91%) experienced cystic pseudoprogression, and 1 (9%) had an intratumoral hemorrhage. Repeat resection pathology results were available for 10 patients, 9 of whom had evidence of residual pilocytic astrocytoma, often showing treatment-related change (gliosis or hyalinization).
Table 2.
Treatments for pseudoprogression
| Treatment | Pilocytic astrocytoma (n = 52) | Other histologies (n = 10) | Total (n = 62) |
|---|---|---|---|
| Observation | 34 (65.4%) | 8 (80.0%) | 42 (67.7%) |
| Steroids | 2 (3.8%)a | 2 (3.2%) | |
| CSF shunt | 2 (3.8%) | 2 (20.0%) | 4 (6.5%) |
| Ommaya reservoir | 3 (5.8%) | 3 (4.8%) | |
| Surgery | 11 (21.2%) | 11 (17.7%) |
CSF = cerebrospinal fluid
One patient also received bevacizumab
Observation was performed for pseudoprogression in 42 patients. Over time, 30 patients (71.4%) experienced tumor shrinkage and 11 (26.2%) showed stabilization; 1 patient remained under close observation. The median duration of pseudoprogression in the observation cohort was 6.2 months (IQR 3.2–11.7), measured from first evidence of tumor growth to tumor shrinkage or stabilization.
Factors associated with pseudoprogression are presented in Table 3. Age at irradiation, sex, neurofibromatosis type 1 (NF-1), tumor location, maximum tumor dimension at RT, prior chemotherapy, extent of resection prior to RT, and receipt of craniospinal irradiation were not independently associated with the development of pseudoprogression. The only significant factor, after adjustment for the presence of cystic components at diagnosis, was histologic subtype; pilocytic astrocytoma conferred significantly higher odds of developing pseudoprogression.
Table 3.
Factors associated with pseudoprogression
| Variable | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| OR (95% CI) | P-value | Adjusted OR (95% CI) | P-value | |
| Age at RT (per year) | 1.02 (0.96–1.09) | 0.53 | ||
| Female | 0.83 (0.46–1.5) | 0.52 | ||
| NF-1 positive | 0.86 (0.30–2.5) | 0.78 | ||
| Tumor location around 3rd ventricle | 1.7 (0.87–3.2) | 0.13 | ||
| Pilocytic astrocytoma | 5.7 (2.7–12.0) | <0.0001 | 5.4 (2.5–11.4) | <0.0001 |
| Maximum tumor dimension before RT (per cm) | 1.13 (0.94–1.36) | 0.19 | ||
| Cystic component at RT start | 2.2 (1.2–4.1) | 0.012 | 1.9 (0.98–3.6) | 0.059 |
| GTR or NTR before RT | 0.89 (0.22–3.6) | 0.87 | ||
| Chemotherapy prior to RT | 0.89 (0.48–1.7) | 0.71 | ||
| CSI given | 1.9 (0.59–6.4) | 0.27 | ||
cm = centimeter, CSI = craniospinal irradiation, GTR = gross total resection, NF-1 = neurofibromatosis type 1, NTR = near-total resection, OR = odds ratio, RT = radiation therapy
Tumor control
Ten of the patients with pseudoprogression (6 with cystic pseudoprogression, 4 with solid pseudoprogression) developed true progression after long-term follow-up. The median time from pseudoprogression to true progression was 67.8 months (IQR 53.3–85.4). Overall survival and EFS for all patients and stratified by histology are shown in Figure 2. The hazard ratios (HRs) for death and an event (death, progression, or secondary HGG) in patients with pseudoprogression were 0.097 (95% CI 0.01–0.71, P = 0.022) and 0.40 (95% CI 0.21–0.77, P = 0.006), respectively, relative to patients without pseudoprogression. Among the subgroup of patients with pilocytic astrocytoma, the HRs for death and an event were 0.14 (95% CI 0.02–1.11, P = 0.062) and 0.37 (95% CI 0.17–0.79, P =0.011), respectively. Among patients with non-pilocytic astrocytoma histology, the HR for an event was 0.50 (95% CI 0.12–2.1, P = 0.34); HR for death in this subgroup was not reportable because there were no deaths among the patients with pseudoprogression. There was no difference in OS or EFS between patients with cystic versus non-cystic pseudoprogression (Supplementary Figure 3).
Fig 2.
OS and EFS plots for all patients (a, b), for patients with pilocytic astrocytoma (c, d), and for patients with tumors of non–pilocytic astrocytoma histology (e, f).
The conditional probability of true progression at the time of tumor growth was 49.1% for the entire cohort (44 patients with true progression out of 106 with true progression and/or pseudoprogression). In patients with pilocytic astrocytoma, the conditional probability of true progression at the time of tumor growth was 29.7% (22 out of 74), whereas in those patients with non-pilocytic astrocytoma, it was 68.8% (22 out of 32). A hazard plot displaying the risk of true progression versus pseudoprogression over time (as a first event after RT) is shown in Supplementary Figure 4. The highest risk of pseudoprogression is within the first 4 years of irradiation, while the risk of true progression persists more than 10 years post-irradiation.
In a sensitivity analysis, all 11 patients who had undergone surgery for symptomatic pseudoprogression were treated as having had true progression at the time of surgery. The associations between pseudoprogression and OS and EFS were unchanged (Supplementary Figure 5). In the subgroup of patients with pilocytic astrocytoma, the occurrence of pseudoprogression was no longer significant for OS (HR 0.26, 95% CI 0.032–2.1, P = 0.20), but it remained significant for EFS (HR 0.26, 95% CI 0.11–0.61, P = 0.002). Statistically significant variables predictive of pseudoprogression remained unchanged (Supplementary Table 1).
Discussion
In this study of pediatric LGG, the incidence, risk factors, temporal course, management, and prognostic implications of pseudoprogression were described. Pseudoprogression was common, particularly for pilocytic astrocytoma, but occurred in fewer than 50% of patients. Pseudoprogression was more common in patients with pilocytic astrocytoma due to the frequent presence of cystic components that can enlarge after RT. The time course of pseudoprogression can be prolonged, with almost 30% of patients having onset of pseudoprogression more than 1 year after RT, and nearly one-quarter of patients needing more than 1 year for the pseudoprogression to stabilize or reverse. In most cases, the management of pseudoprogression did not require invasive intervention. Those patients who required invasive intervention for symptomatic pseudoprogression tended to have pilocytic astrocytoma, with all their tumors being in locations surrounding the third ventricle (the hypothalamus, thalamus, midbrain, or optic pathway). In a high-risk subgroup for intervention (patients with pilocytic astrocytoma, cystic components at diagnosis, and tumor locations surrounding the third ventricle), only 24% of patients required an invasive intervention; for such patients, close observation is recommended rather than prophylactic intervention.
Pseudoprogression in pediatric LGG was associated with improved OS and EFS. This association has not been well studied in pediatric LGG, whereas the link between disease control and pseudoprogression is well-established in adults with glioblastoma.[10] Pseudoprogression in glioblastoma is associated with MGMT methylation, which is a strong positive prognostic and predictive factor in patients treated with RT and temozolomide.[11] Pseudoprogression in adults with glioblastoma is also independently associated with improved OS, even after accounting for MGMT methylation.[11] In contrast, among adults with LGGs and anaplastic gliomas, pseudoprogression—when defined as increasing enhancement post-RT—is associated with 1p19q-intact tumors and tumors with wild-type IDH1. In the subgroup of patients with 1p19q-intact tumors, pseudoprogression was not associated with improved OS (P = 0.16).[12, 13] These survival outcomes are consistent with earlier findings that wild-type IDH1 and the lack of 1p19q co-deletion are both poor prognostic factors.[14, 15] The new WHO classification now incorporates molecular information in histopathologic diagnosis; tumors that are 1p19q-intact are classified as diffuse or anaplastic astrocytoma, with a higher incidence of pseudoprogression and poorer prognosis as compared to tumors with 1p19q co-deletion.[12, 16, 17]
Definition of pseudoprogression
One challenge with regard to differentiating true progression from pseudoprogression in clinical trials is the lack of a universally accepted definition of pseudoprogression.[18] In HGG, the Response Assessment in Neuro-Oncology (RANO) Working Group established accepted criteria for true progression.[19] In their response criteria, true progression (an increase of at least 25% in the product of the perpendicular diameters of the tumor) cannot be defined within 12 weeks of RT unless there is pathologic confirmation or new out-of-field enhancement. However, pseudoprogression can occur more than 12 weeks after RT, particularly with LGG, which limits the applicability of the RANO criteria in the setting of pediatric LGG. Other authors have defined pseudoprogression as any increase in tumor size on axial imaging[5] or an increase in tumor size, edema, or enhancement within 6 to 12 months of RT.[6, 12, 13, 20]
The working definition of pseudoprogression used in this study, i.e., a 10% growth threshold (rather than just any growth), is intended to represent the point of uncertainty in day-to-day clinical care, where one may suspect either pseudoprogression or true progression. Increased contrast enhancement only was not included as a criterion for pseudoprogression in this study; although increased gadolinium uptake may be seen in both pseudoprogression and true progression,[5, 6] one would generally not act upon post-RT enhancement changes alone without observing a corresponding change in the patient’s clinical symptoms or in the size of the tumor. Quantifying changes in tumor enhancement can also be challenging with pilocytic astrocytomas, which often enhance avidly on MR sequences with gadolinium.[21]
Prior studies
There have been few studies of pseudoprogression in pediatric LGG. Chawla et al. examined the incidence of pseudoprogression in 181 pediatric brain tumors treated with surgery, chemotherapy, and/or radiation; 64 were low-grade tumors, and most were treated with RT.[6] Pseudoprogression was defined as “patients … whose MRI scans demonstrated an increase in tumor size, edema, and/or contrast enhancement on any post-therapy scan within 1 year after completing therapy.” Almost all cases of pseudoprogression in their study cohort were in patients with LGG. The incidence of pseudoprogression was 27% for all LGGs and was associated with patients treated with radiation. Cases of pseudoprogression occurring more than 1 year after RT were not described.
The second study reported on 24 children with LGG treated with irradiation.[5] In that study, “…increase[d] mass effect and/or increased enhancement were considered to have pseudo-progression” without true progression on follow-up. Of the 24 children, 54% developed pseudoprogression, with maximal enlargement being recorded at a median of 8 months post-irradiation. No patient in the small dataset required intervention for pseudoprogression. Possible associations with pseudoprogression, although not statistically significant, were larger tumor size and infratentorial tumors (versus optic pathway gliomas). A third report, by Mannina et al., described 15 patients with juvenile pilocytic astrocytoma, in whom a crude pseudoprogression rate of 20% was observed.[8] The authors of that study noted that pseudoprogression peaked between 3 and 8 months post-irradiation and resolved by 18 months. Lastly, Bakardjiev et al. reported upon 28 children treated from 1992 to 1994 with stereotactic fractionated RT.[7] Eleven patients (39%) experienced an increase in their tumor size or cystic growth after treatment, with typical onset between 9–12 months after RT.
To our knowledge, our present report represents the largest study to date of pseudoprogression in pediatric LGG. Almost all of our patients received frequent, high-quality, contrast-enhanced MR imaging after radiation, enabling accurate determination of the incidence and temporal dynamics of pseudoprogression. The median follow-up period for our patient cohort was more than 10 years.
Limitations of this study include the retrospective nature of the data collection. There was no available data on genetic/molecular biomarkers (BRAF alterations) to elucidate the association of such markers with pseudoprogression. Misclassification of pseudoprogression is possible, although our findings were robust to a sensitivity analysis in which cases of pseudoprogression requiring surgery were treated as true progression. Finally, there is the possibility of immortal time bias, which may have favored increased survival in the pseudoprogression subgroup, given that patients who died could not have subsequently developed pseudoprogression. However, the time to onset of pseudoprogression was short (median, 6.1 months) and the median follow-up time was long, thereby reducing the impact of this source of bias.
The Children’s Oncology Group ACNS0221 protocol was a phase II study of conformal radiation therapy for pediatric LGG (NCT00238264). The study closed to accrual on December 20, 2010, after enrolling more than 75 patients, but the results have not yet been reported. Follow-up imaging data for eventual central review were only required to be submitted at the pre-treatment stage, at mid-treatment, at the first follow-up after the patient received RT, and at the time of a patient’s removal from the study (as a result of progression). No definition of, or allowance for pseudoprogression was incorporated into the study protocol. Therefore, it is possible that pseudoprogression occurred in patients who were removed early from the study as a result of their tumor showing presumed true progression.
Conclusions
In this study of 221 pediatric patients with pediatric low-grade glioma, the cumulative incidence of pseudoprogression after treatment with fractionated irradiation was 29% for all patients and 43% for patients with pilocytic astrocytoma. More than 25% of patients experienced the onset of pseudoprogression more than 1 year after they received RT, and in nearly 30% of patients it took more than 1 year for the pseudoprogression to stabilize or reverse. Most patients were observed after experiencing pseudoprogression. Those who required invasive treatment tended to have pilocytic astrocytoma and cystic components at diagnosis, and all had a tumor location near the third ventricle; the crude incidence of symptomatic pseudoprogression requiring intervention in this subgroup was 24%. One factor strongly associated with pseudoprogression was histologic subtype (pilocytic astrocytoma). In patients with pilocytic astrocytoma, the conditional probability of true progression at the time of tumor growth was 29.7%; in those with non-pilocytic astrocytoma it was 68.8%. Pseudoprogression was associated with increased overall survival and event-free survival. The new information derived from this study should assist clinicians in their patient evaluations and facilitate an accurate ascertainment of disease progression, as well as inform clinical trial design in future studies of pediatric LGG.
Supplementary Material
Funding:
This work was supported by the American Cancer Society [grant number: SPAMM-15-210-01-COUN] and by the American Lebanese Syrian Associated Charities (ALSAC). The authors thank Keith A. Laycock, PhD, for scientific editing of the manuscript.
Footnotes
Conflict of interest: None to declare.
References
- 1.Qaddoumi I, Sultan I, Gajjar A (2009) Outcome and prognostic features in pediatric gliomas: a review of 6212 cases from the Surveillance, Epidemiology, and End Results database. Cancer 115: 5761–5770 doi: 10.1002/cncr.24663 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Merchant TE, Kun LE, Wu S, Xiong X, Sanford RA, Boop FA (2009) Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 27: 3598–3604 doi: 10.1200/JCO.2008.20.9494 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Laack NN, Schomas DA, Schomberg PJ, Brown PD Pediatric, Intracranial, Low-Grade Glioma; 20-year Experience With Long-Term Follow-up at the Mayo Clinic. International Journal of Radiation Oncology • Biology • Physics 69: S34–S35 doi: 10.1016/j.ijrobp.2007.07.064 [DOI] [Google Scholar]
- 4.Gnekow AK, Falkenstein F, von Hornstein S, Zwiener I, Berkefeld S, Bison B, Warmuth-Metz M, Driever PH, Soerensen N, Kortmann RD, Pietsch T, Faldum A (2012) Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology. Neuro Oncol 14: 1265–1284 doi: 10.1093/neuonc/nos202 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Naftel RP, Pollack IF, Zuccoli G, Deutsch M, Jakacki RI (2015) Pseudoprogression of low-grade gliomas after radiotherapy. Pediatr Blood Cancer 62: 35–39 doi: 10.1002/pbc.25179 [DOI] [PubMed] [Google Scholar]
- 6.Chawla S, Korones DN, Milano MT, Hussain A, Hussien AR, Muhs AG, Mangla M, Silberstein H, Ekholm S, Constine LS (2012) Spurious progression in pediatric brain tumors. J Neurooncol 107: 651–657 doi: 10.1007/s11060-011-0794-z [DOI] [PubMed] [Google Scholar]
- 7.Bakardjiev AI, Barnes PD, Goumnerova LC, Black PM, Scott RM, Pomeroy SL, Billett A, Loeffler JS, Tarbell NJ (1996) Magnetic resonance imaging changes after stereotactic radiation therapy for childhood low grade astrocytoma. Cancer 78: 864–873 doi: [DOI] [PubMed] [Google Scholar]
- 8.Mannina EM, Bartlett GK, McMullen KP (2016) Extended Volumetric Follow-up of Juvenile Pilocytic Astrocytomas Treated with Proton Beam Therapy. International Journal of Particle Therapy 3: 291–299 doi: 10.14338/ijpt-16-00020.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Fine JP, Gray RJ (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94: 496–509 doi:Doi 10.2307/2670170 [DOI] [Google Scholar]
- 10.Kruser TJ, Mehta MP, Robins HI (2013) Pseudoprogression after glioma therapy: a comprehensive review. Expert Rev Neurother 13: 389–403 doi: 10.1586/ern.13.7 [DOI] [PubMed] [Google Scholar]
- 11.Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, Bertorelle R, Bartolini S, Calbucci F, Andreoli A, Frezza G, Leonardi M, Spagnolli F, Ermani M (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 26: 2192–2197 doi: 10.1200/JCO.2007.14.8163 [DOI] [PubMed] [Google Scholar]
- 12.Lin AL, White M, Miller-Thomas MM, Fulton RS, Tsien CI, Rich KM, Schmidt RE, Tran DD, Dahiya S (2016) Molecular and histologic characteristics of pseudoprogression in diffuse gliomas. J Neurooncol 130: 529–533 doi: 10.1007/s11060-016-2247-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Lin AL, Liu J, Evans J, Leuthardt EC, Rich KM, Dacey RG, Dowling JL, Kim AH, Zipfel GJ, Grubb RL, Huang J, Robinson CG, Simpson JR, Linette GP, Chicoine MR, Tran DD (2014) Codeletions at 1p and 19q predict a lower risk of pseudoprogression in oligodendrogliomas and mixed oligoastrocytomas. Neuro Oncol 16: 123–130 doi: 10.1093/neuonc/not142 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Cairncross G, Wang M, Shaw E, Jenkins R, Brachman D, Buckner J, Fink K, Souhami L, Laperriere N, Curran W, Mehta M (2013) Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol 31: 337–343 doi: 10.1200/JCO.2012.43.2674 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, Coons S, Ricci P, Bullard D, Brown PD, Stelzer K, Brachman D, Suh JH, Schultz CJ, Bahary JP, Fisher BJ, Kim H, Murtha AD, Bell EH, Won M, Mehta MP, Curran WJ Jr. (2016) Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. The New England journal of medicine 374: 1344–1355 doi: 10.1056/NEJMoa1500925 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M, Neurooncology Working Group of the German Cancer S (2016) Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol 18: 1529–1537 doi: 10.1093/neuonc/now133 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131: 803–820 doi: 10.1007/s00401-016-1545-1 [DOI] [PubMed] [Google Scholar]
- 18.Parvez K, Parvez A, Zadeh G (2014) The diagnosis and treatment of pseudoprogression, radiation necrosis and brain tumor recurrence. Int J Mol Sci 15: 11832–11846 doi: 10.3390/ijms150711832 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28: 1963–1972 doi: 10.1200/JCO.2009.26.3541 [DOI] [PubMed] [Google Scholar]
- 20.Lassen-Ramshad Y, Petersen JB, Tietze A, Borghammer P, Mahajan A, McGovern SL (2015) Pseudoprogression after proton radiotherapy for pediatric low grade glioma. Acta Oncol 54: 1701–1702 doi: 10.3109/0284186X.2015.1078498 [DOI] [PubMed] [Google Scholar]
- 21.Chourmouzi D, Papadopoulou E, Konstantinidis M, Syrris V, Kouskouras K, Haritanti A, Karkavelas G, Drevelegas A (2014) Manifestations of pilocytic astrocytoma: a pictorial review. Insights Imaging 5: 387–402 doi: 10.1007/s13244-014-0328-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
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