Summary: survival, progression, and mortality

Long-term overall survival in pLGG is high, and tumor-related mortality is uncommon. In 4,040 children in SEER (1973 to 2008), 20-year overall cancer-specific survival was 87% and the 20-year cumulative incidence of death due to glioma was 12%, falling to 7% after age 22 years. In a population-based Ontario cohort of 1,202 children, 93 deaths (7.7%) occurred over a median of 12.73 years, with 20-year overall survival of 90.1%. Upfront radiotherapy was associated with higher late mortality in both cohorts (hazard ratios 3.9 and 3.3).

Progression is frequent among children who need systemic therapy. In COG A9952 (274 randomized children younger than 10 years), 5-year event-free survival was 39% with carboplatin and vincristine and 52% with TPCV, and was 19% in children younger than 1 year. In SIOP-LGG 2004 (497 randomized non-NF1 patients), 5-year progression-free survival was 46% with vincristine and carboplatin and 45% with added etoposide. In HIT-LGG-1996, 10-year progression-free survival after chemotherapy was 44%. Approximately 40% to 50% of children require subsequent chemotherapy lines.

Molecular subtype modifies prognosis. In the Toronto cohort, 5-year progression-free survival was 69% for KIAA1549-BRAF and 52% for BRAF p.V600E tumors. BRAF V600E tumors had 10-year progression-free survival of 27% versus 60.2% for wild-type tumors, and 5-year progression-free survival after first-line chemotherapy of 30.4%. BRAF p.V600E with CDKN2A deletion was associated with 10-year progression-free survival of 0% and 10-year overall survival of 41%. Low-risk tumors (fusions or germline NF1) often stop growing, with few progressions after 10 years. Malignant transformation was observed in fewer than 1% of the HIT-LGG-1996 cohort.

Long-term overall survival and tumor-related death: SEER cohort of 4,040 children

“The 20-year OS was 87% ± 0.8% and the 20-year cumulative incidence of death due to glioma was 12% ± 0.8%. The incidence of death after transition to adulthood (age greater than 22 years) was slightly lower, with 20-year cumulative incidence of disease death of 7% ± 1.8%.” (opens the source at this quote in a new tab)
“The 30-year OS of the 4,040 patients was 74.8% ± 2%, including all causes of death.” (opens the source at this quote in a new tab)
“Of the 4,040 patients, 347 patients died as a result of PLGG and 78 patients died of other causes.” (opens the source at this quote in a new tab)
“We performed a multivariate Cox model analysis (Table II) and identified an increased risk of cancer-specific death in children who were treated with radiation therapy (HR = 3.9, P < 0.0001).” (opens the source at this quote in a new tab)

Long-term survival and late mortality: Ontario population-based cohort

“At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%.” (opens the source at this quote in a new tab)
“Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood.” (opens the source at this quote in a new tab)
“For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001)” (opens the source at this quote in a new tab)
“In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes.” (opens the source at this quote in a new tab)

Survival by extent of resection and progression rates in a molecularly profiled cohort

“If complete surgical resection is possible, 10-year progression-free survival (PFS) exceeds 85%, but drops below 50% if there is radiologically visible residual tumor” (opens the source at this quote in a new tab)
“Importantly, only 7.5% of patients succumbed to their disease (median time to death=3.9 years, median OS follow-up=15.9 years) despite 33% experiencing tumor progression (median time to progression=2.3 years, median PFS follow-up=5.9 years) (Figure 1F).” (opens the source at this quote in a new tab)

Outcome after first-line chemotherapy: COG A9952 carboplatin and vincristine versus TPCV

“Of 274 randomly assigned patients who met eligibility requirements, 137 received CV and 137 received TPCV. The 5-year event-free survival (EFS) and overall survival (OS) rates for all eligible patients were 45% ± 3.2% and 86% ± 2.2%, respectively. The 5-year EFS rates were 39% ± 4% for CV and 52% ± 5% for TPCV (stratified log-rank test P = .10; cure model analysis P = .007).” (opens the source at this quote in a new tab)
“Five-year EFS was 19% ± 7% for patients younger than age 1 year, 51% ± 4% for those age 1 to 5 years, and 64% ± 4% for those older than 5 years.” (opens the source at this quote in a new tab)

Outcome after first-line chemotherapy: SIOP-LGG 2004 vincristine and carboplatin with or without etoposide

“Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS.” (opens the source at this quote in a new tab)

Outcome after first-line chemotherapy: HIT-LGG-1996 long-term follow-up

“Following a median observation of 9.3 years, 10-year overall survival (OS) was 0.94 and 10-year event-free survival (EFS) was 0.47. Ten-year progression-free survival was 0.62 following radiotherapy and 0.44 following chemotherapy.” (opens the source at this quote in a new tab)
“Supporting other reports, satisfactory PFS in the first years steadily declined without plateau (Fig. 4A), in contrast to an OS of 0.88 at 10 years (Table 3).” (opens the source at this quote in a new tab)
“Following first or further progressions, 61 (28.2%) of 216 patients eventually received radiotherapy.” (opens the source at this quote in a new tab)

Chronic course with multiple recurrences and subsequent lines of therapy

“In previously untreated patients with sporadic pLGG, most chemotherapies have 5-year progression-free survival (PFS) rates ranging from 45% to 55%. However, approximately 50% of children will require alternative second-line chemotherapy.” (opens the source at this quote in a new tab)
“Since many children will have multiple recurrences throughout childhood with numerous chemotherapy interventions, alternative therapies are needed.” (opens the source at this quote in a new tab)

“Around 40-50% of PLGG patients require subsequent chemotherapy lines.” (opens the source at this quote in a new tab)

“Although pLGG is a low-grade tumor with an excellent 10-year overall survival (OS) rate of 94%, the 10-year progression-free survival (PFS) rate in case of an indication for systemic treatment with standard of care (SoC) chemotherapy is only 44%” (opens the source at this quote in a new tab)
“Therefore, pLGG may be considered a chronic disease in patients whose tumors are unresectable or cannot be completely resected, who will often require several treatment lines throughout life” (opens the source at this quote in a new tab)
“In addition, these chemotherapy regimens appear even less effective in infants with pLGG” (opens the source at this quote in a new tab)

Risk factors for progression in a UK population-based cohort

“The 5-year overall survival and progression-free survival in the whole cohort were 94.6% and 69.4%, respectively.” (opens the source at this quote in a new tab)
“Multivariate analysis identified young age, fibrillary astrocytoma, and extent of surgical resection as significant independent risk factors for progression. Hypothalamic/chiasmatic tumors demonstrated the most sustained tendency to progress.” (opens the source at this quote in a new tab)
“This discrepancy underlines the chronic nature of the clinical course for patients with these tumors, which threaten life infrequently, yet continue to be at a sustained risk for progression when unresectable.” (opens the source at this quote in a new tab)

Prognosis by molecular alteration: rearrangement-driven versus SNV-driven tumors

“Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared to SNV-driven tumors.” (opens the source at this quote in a new tab)
“This pattern is evident in BRAF, where tumors with KIAA1549-BRAF have superior outcome to BRAF p.V600E (5-year PFS of 69% for KIAA1549-BRAF versus 52% for BRAF p.V600E, p=0.0058, log-rank test).” (opens the source at this quote in a new tab)

Prognosis by molecular alteration: low-, intermediate-, and high-risk groups

“pLGG harboring gene fusions or germline NF1 mutations comprise the low risk group. These tumors progress less frequently and often eventually stop growing with very few progressions seen after 10 years and almost no deaths at 20 years follow-up (10-year PFS of 67% and OS of 98%, 20-year PFS and OS of 58% and 96%, respectively) (Figure 7B–C).” (opens the source at this quote in a new tab)
“Intermediate risk tumors had a 10-year PFS and OS of 35% and 90%, respectively (Figure 7B–C). However, in contrast to the low risk tumors, these tumors continue to progress with a 20-year PFS of 27% and 20-year OS of 81%.” (opens the source at this quote in a new tab)
“High risk pLGG include those with H3.3 p.K27M, or BRAF p.V600E with CDKN2A deletion. These tumors almost invariably progress (10-year PFS of 0%) and these patients often succumb to their disease (10-year OS of 41%) (Figure 7B,C).” (opens the source at this quote in a new tab)

Prognosis by molecular alteration: BRAF V600E and CDKN2A deletion

“Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001).” (opens the source at this quote in a new tab)
“Thirty-two percent of patients with BRAF V600E-mutant received chemotherapy. Five-year PFS after first-line chemotherapy was 30.4% (95% CI, 13.3% to 47.5%; Appendix Fig A1B).” (opens the source at this quote in a new tab)
“PFS in children with BRAF V600E PLGG was 24.0% (95% CI, 1.9% to 46.1%) and 68.7% (95% CI, 52.8% to 70.2%) for the CDKN2A deleted and balanced tumors, respectively, at 5 years and 0% and 45.9% (95% CI, 21.6% to 70.2%), respectively, at 10 years (P = .005; Fig 2C).” (opens the source at this quote in a new tab)
“Of importance, late deaths related to tumor progression were observed in BRAF V600E PLGG even at 25 years of follow-up.” (opens the source at this quote in a new tab)

Spontaneous stabilization, growth arrest, and regression

“PLGGs have been reported to spontaneously stabilize or regress” (opens the source at this quote in a new tab)

“Incompletely resected or unresected tumors may progress, remain stable, or even spontaneously involute.” (opens the source at this quote in a new tab)

“The tumors are characterized by a slow growth rate and may show periods of growth arrest.” (opens the source at this quote in a new tab)

“Numerous individual reports describe NF1-OPG in young children undergoing periods of rapid growth, prolonged quiescence, and rare spontaneous regression” (opens the source at this quote in a new tab)

Quiescence in adulthood

“These populations of senescent cells may provide clues to the mechanisms underlying pLGG quiescence upon transition to adulthood” (opens the source at this quote in a new tab)

“Because many pLGGs undergo senescence when patient ages reach their 20s, the goal of therapy is to maximize tumor control while minimizing treatment-associated toxicities from surgery, chemotherapy, and radiation.” (opens the source at this quote in a new tab)

Malignant transformation

“Importantly this highlights that PLGGs are very unlikely to undergo malignant transformation resulting in tumor-related death, which contrasts with the natural history of ALGGs” (opens the source at this quote in a new tab)

“Malignant transformation is highlighted postradiotherapy, has been observed even without prior treatment, and is not restricted to the older age group or initial astrocytoma grade II. The frequency of <1% in our cohort is lower than incidence rates in smaller series.” (opens the source at this quote in a new tab)

“Tumors harboring both BRAF p.V600E and CDKN2A deletion comprise a distinct clinical subtype of pLGG prone to transformation into secondary HGG” (opens the source at this quote in a new tab)

Mortality: late mortality among 5-year survivors of childhood CNS tumors in the Childhood Cancer Survivor Study

“Among all eligible 5-year survivors (n = 2821), cumulative late mortality at 30 years was 25.8% (95% confidence interval [CI] = 23.4% to 28.3%), due primarily to recurrence and/or progression of primary disease.” (opens the source at this quote in a new tab)
“All-cause mortality at 30 years was higher in 5-year survivors of ependymoma (29.5%) and medulloblastoma (29.0%) than in 5-year survivors of astrocytoma and glial tumors (23.9%; P < .001 for both comparisons) (Figure 1, B).” (opens the source at this quote in a new tab)

Mortality: brain and CNS tumor deaths in United States children and adolescents

“Overall, 2,589 deaths were attributed to primary malignant brain and other CNS tumors. This represents an annual average age-specific mortality rate of 0.62 per 100,000 population and an average of 518 deaths per year caused by primary malignant brain and other CNS tumors.” (opens the source at this quote in a new tab)

Causes of early and late death and standardized mortality ratio in a population-based cohort

“Despite the excellent overall outcomes, late deaths occurred up to 23 years after the initial diagnosis, and overall SMR was 16.1 (95% CI, 13.0-19.6).” (opens the source at this quote in a new tab)
“Overall, 55 of 803 patients died during the study period (Table 3).” (opens the source at this quote in a new tab)
“Importantly, although 37% of early deaths (<5 years after the diagnosis) were due to tumor progression, none of the late deaths was attributed to PLGG, and most could be attributed to late effects of therapy.” (opens the source at this quote in a new tab)

Subgroups with inferior long-term survival in the Ontario cohort

“In contrast, patients with brainstem and thalamic tumors had significantly lower survival than patients with tumors in the rest of the locations (P < .001; Fig. 1D).” (opens the source at this quote in a new tab)
“Importantly, most of these children who died had received upfront radiotherapy.” (opens the source at this quote in a new tab)
“In contrast, less than half of patients with pleomorphic xanthoastrocytoma in our study were long-term survivors.” (opens the source at this quote in a new tab)
“Children younger than 3 years with OPG also emerge as a distinct subgroup with poorer outcomes.” (opens the source at this quote in a new tab)

Multivariable analysis of late mortality and the factors adjusted for

“In a multivariate analysis adjusted for the age of diagnosis, upfront radiation treatment was the most significant factor associated with late overall deaths and tumor-related deaths (P = .012 and P = .014, respectively; Table 2).” (opens the source at this quote in a new tab)
“Finally, to assess the association of all factors simultaneously, Cox proportional regression was used to estimate hazard ratios (HRs) after adjustments for the age of diagnosis, tumor location, pathology, and radiation.” (opens the source at this quote in a new tab)

Leading cause of death and when deaths occurred

“Transformation to malignant glioma (n = 26) was the most common cause of death, and almost half of all deaths occurred in the first 5 years after the diagnosis (29 of 55 or 52.7%).” (opens the source at this quote in a new tab)

Overall survival at 10, 20, and 30 years in the Ontario population-based cohort

“There were a total of 93 deaths (7.7%) with 10-, 20-, and 30-year OS rates of 93.1% ± 0.8%, 90.1% ± 1.1%, and 88% ± 1.5%, respectively (Fig. 1A).” (opens the source at this quote in a new tab)

Overall survival by tumor location

“Patients with posterior fossa tumors had an excellent 20-year OS rate of 96.8% ± 1.1%, which was similar to the rates for patients with cerebral hemispheric tumors (89.1% ± 2.7%), OPG (90.6% ± 2.2%), and spinal tumors (89.7% ± 2.7%).” (opens the source at this quote in a new tab)

Overall survival by histological subtype

“Pilocytic astrocytoma was the most common histological subtype, and these patients exhibited excellent 20-year OS of 95.5% ± 1.7% (Fig. 1C); no significant differences were observed for most histological subgroups (astrocytoma ganglioglioma, mixed glioma, and low-grade astrocytoma not otherwise specified).” (opens the source at this quote in a new tab)
“whereas pleomorphic xanthoastrocytoma patients (n = 10) had significantly lower survival (10-year OS, 42.9% ± 20.8%; P < .001; Fig. 1C)” (opens the source at this quote in a new tab)

Optic pathway glioma: survival by age at diagnosis and by neurofibromatosis type 1 status

“Young children with OPG diagnosed when they were 3 years old or younger had inferior outcomes in comparison with older children (20-year OS, 80.4% ± 6.1% vs 97.9% ± 1%; P = .007; Supporting Fig. 2 [see online supporting information]).” (opens the source at this quote in a new tab)
“Children with NF1 and tumors affecting the optic pathway had excellent survival outcomes (20-year OS, 95.1% ± 2.4%; SMR, 8.9; 95% CI, 2.3-19.7; Supporting Fig. 3A [see online supporting information]), but they were not significantly better than those of OPG patients without NF1 (20-year OS, 88.7% ± 3.6%; SMR, 17.5; 95% CI, 7.9-30.7; P = .06; Supporting Fig. 3B [see online supporting information]).” (opens the source at this quote in a new tab)

Tovorafenib (DAY101)

Natural history, survival, and mortality