Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy

Figures & data

Table I. Patient, tumor, and preradiotherapy characteristics (N = 313).

Characteristics	Value
Patient and tumor characteristics
Age
Median patient age	5.9 y (range 0.5–17.9 y)
< 5 y at time of radiotherapy	130 pts
Sex
Male	168 pts
Female	145 pts
Race
White	214 pts
Black	41 pts
Hispanic	27 pts
Asian	4 pts
Histologies
Ependymoma	73 pts
Craniopharyngioma	68 pts
Low-grade glioma	66 pts
Medulloblastoma/primitive neuroectodermal tumor	38 pts
Parameningeal rhabdomyosarcoma	13 pts
Other	55 pts
Site
Supratentorial	164 pts
Posterior fossa	114 pts
Skull base	35 pts
Pre-RT treatment details
Operations prior to RT
1	213 pts
2	76 pts
> 2	18 pts
Treatment based on radiographic characteristics alone, without biopsy	6 pts
Gross total or near total resection^1	109 pts
History of hydrocephalus	182 pts
Extended or permanent shunting to manage hydrocephalus	73 pts
Disease-specific chemotherapy	155 pts
Intrathecal or high-dose intravenous methotrexate	48 pts

CGE, Cobalt Gray equivalent; mo, months; pt, patient; RT, radiotherapy; y, years.

¹At the time of radiotherapy.

Note: A more detailed table is included with the supplemental materials as Supplementary Table I to be found online at http://informahealthcare.com/doi/abs/10.3109/0284186X.2014.957414.

Table II. Clinical and dosimetric variables potentially associated with brainstem toxicity.

		Percent toxicity rate
Variables	Factor	if factor was present	if factor was absent	p-Value
Clinical variables
Focal vs. craniospinal (CSI) radiotherapy	CSI	2.6%	3.6%	> 0.5
Radiotherapy modality	Mixed	3.2%	3.5%	> 0.5
Sex	Male	2.4%	4.8%	> 0.1
Race	Non-white	5.6%	2.9%	> 0.1
Age	< 5 y/o	6.9%	1.1%	0.01
Anesthesia	Yes	5.7%	0.7%	> 0.1
Hydrocephalus	Yes	5.0%	1.5%	> 0.1
Tumor location	Posterior fossa	10.7%	0%	<< 0.001
Number of operations	> 1	2%	4.1%	> 0.5
CSF shunt needed	Yes	1.4%	4.2%	> 0.1
Degree of resection	GTR/NTR	7.3%	1.5%	> 0.1
Chemotherapy	Any given	5%	2.5%	> 0.1
Type of chemotherapy	IT or HD methotrexate-based	6.3%	3.0%	> 0.1
Dosimetric variables
Mean dose	< 44.2 Gy	0.0%	9.0%	0
D10%	< 55.4 Gy	0.9%	10.3%	0
D50%	< 52.4 Gy	0.0%	10.5%	0
V40 Gy	< 71.3%	0.5%	8.5%	0
V45 Gy	< 67.5%	0.0%	9.6%	0
V50 Gy	< 61.7%	0.5%	9.6%	0
V55 Gy	< 17.7%	1.3%	10.5%	< 0.01
V60 Gy	0	2.5%	14.8%	0.01
Max dose* to brainstem	< 56.6 Gy	1.6%	10.6%	< 0.01
Max dose* to brainstem surface	< 56.1 Gy	1.5%	13.2%	< 0.01
Max dose* to brainstem core	< 56.6 Gy	1.6%	11.1%	< 0.01

Percentages are 2-year Kaplan-Meier point estimates; p-values are based on the log-rank test statistic.

Dx, minimum dose received by the ‘‘hottest’’ x% of the brainstem; GTR/NTR, gross total resection/near total resection; HD, high dose; IT, intrathecal; Mixed, proton-based radiotherapy with a photon component; Vx, the volume of the brainstem receiving ≥× Gy.

*To 0.1 cm³.

Figure 1. A comprehensive dose-volume histogram (DVH) including each patient's DVH curve. The colored curves correspond with the 11 patients who experienced toxicities outlined in Table III as follows:

1;

2;

3;

4;

5;

6;

7;

8;

9;

10;

11. The inset provides a magnified view of the high-dose range.

Table III. Patient, tumor, and treatment characteristics for patients who experienced brainstem toxicity.

			Brainstem
Patient no.	Age	Diagnosis	Prescription dose (Gy)	Mean dose (Gy)	D50%	Time to toxicity (mos.)	Toxicity	Grade	Intervention	Current status
1	4.4	Posterior fossa ependymoma	52.2	52.2	55.6 Gy	3	Hemiparesis; dysmetria; CNVII palsy; lower CN palsy; respiratory difficulty	3	Steroids, IV gamma- globulin	Stable; ataxia, dysmetria, unilateral CNVI palsy
2	2.1	Posterior fossa ATRT	50.4	52.1	52.4 Gy	3	Seizure; ataxia; quadraparesis; lower CN palsy respiratory difficulty	4	Steroids, bevacizumab, irinotecan	Stable; seizures, CNXII palsy, tracheostomy, quadraparesis
3	3.5	Posterior fossa ependymoma	54	44.2	55.2 Gy	4	Ataxia	2	Steroids	Stable; mild unilateral foot drop
4	3.2	Posterior fossa ependymoma	59.4	54.4	56.7 Gy	3	Ataxia	2	Steroids	Stable; unilateral LE weakness, sleep apnea
5	2.6	Posterior fossa ependymoma	54	51.5	55.3 Gy	3	Ataxia, lower CN palsy	2	Steroids, HBOT	Stable; neurologically intact
6	7.5	Posterior fossa ependymoma	59.4	51.1	59.1 Gy	4	Ataxia, CNVII palsy, lower CN palsy, respiratory difficulty	5	Steroids, HBOT, bevacizumab	Dead
7	2.3	Posterior fossa ependymoma	59.4	47	55.0 Gy	3	Ataxia; CNVII palsy, lower CN palsy	2	Steroids, HBOT	Stable; mild ataxia, sleep apnea
8	4.3	Posterior fossa ependymoma	59.4	51.5	55.2 Gy	4	Ataxia, lower CN palsy	2	Steroids	Stable; neurologically intact
9	15.8	Medulloblastoma	54	49.3	53.4 Gy	12	Ataxia, lower CN palsy, respiratory difficulty	4	Steroids, HBOT, bevacizumab, pentoxifylline	Respiratory difficulty
10	4.4	Cerebellar low-grade glioma	54	48.9	54.2 Gy	2	Ataxia	2	Steroids	Stable; mild ataxia
11	3.4	Posterior fossa ependymoma	54	52.8	53.5 Gy	4	Ataxia, CNVII palsy	2	Steroids	Stable; mild ataxia

ATRT, atypical teratoid rhabdoid tumor; CN, cranial nerve; HBOT, hyperbaric oxygen therapy; LE, lower extremity.