Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma

Figures & data

Figure 1. Dose distributions in the sagittal and transversal plane related to treatment with (from left) 3D CRT, RapidAarc and IMPT.

Table I. Organ-specific dose objectives relating to children treated with radiation therapy.

Irradiated organ	Endpoint	Patient data	Chemo	NTCP-model	Priority	Dose objectives	Reference
Bone Marrow	Hematologic toxicity	Children	Yes	N/A	2	Dmean,non-target bone < 10 Gy	Chang et al. (2002)
Eyes	Cataract	Children	N/A	N/A	2	Dmax,eye < 20 Gy or BED (mean eye dose) < 40 Gy0.65	Kal et al. (2009)
	Dry eyes	Children	Yes	N/A			Whelan et al. (2010)
	Double vision
	Blindness
	Cataract
	Dry eyes				2	Dmean,temp. lobe < 30 Gy
	Double vision
	Blindness
	Cataract
Heart	Cardiac failure	Children	Yes	N/A	1	Dmean,heart < 3.5 Gy	Guldner et al. (2006)
	Ejection Fraction
	End Systolic Wall Stress
	Long-term cardiac mortality	Adults	Yes	Relative seriality			Gagliardi et al. (1996)
Liver	Radiation Induced Liver Disease	Adults	No	LKB	1	Dmean,liver < 10 Gy	Dawson et al. (2005)
	Radiation Induced Liver Disease		No	LKB			Xu et al. (2006)
	Radiation Induced Liver Disease
Neurocognitive effects	IQ decrease	Children	Yes	IQ-decline	2	Dmean,whole brain < 25 Gy	Merchant et al. (2008)
						Dmean,sup.tent. brain < 25 Gy
	Diffrent neurologic sequelae	Children	N/A	N/A	–	–	Goldsby et al. (2010)
Parotids	Xerostomia (75% flow rate red.)	Adults	N/A	LKB	3	EUDparotid < 14 Gy	Houweling et al. (2009)
	Xerostomia (75% flow rate red.)	Adults	N/A	LKB			Roesink et al. (2001)
	Xerostomia (50% flow rate red.)	Adults	N/A	N/A			Bussels et al. (2004)
Endocrine system	Hypothyroidism	Children	Yes	N/A	5	Dmean,thyroid < 6 Gy	Ricardi et al. (2001)
	Hypothyroidism	Adults	Y & N	N/A			Bathia et al. (1996)
	Hypothyroidism	Children	Yes	N/A	4	Dmean,pituitary < 20 Gy	Chow et al. (2009)
	Neurologic sequelae	Children	Yes	N/A	–	–	Xu et al. (2004)
	Sitting height				–
	ACTH deficiancy	Children	Yes	N/A	–	–	Rose et al. (2005)
Gynecological	Infertility	Children	Yes	N/A	3	Dmean,testis < 7.5 Gy &65: Dmean,hypothal/pituitary < 40 Gy	Green et al. (2010)
	Infertility	Children	Yes	N/A		Dmean,ovaries < 5.0 Gy & Dmean,hypothal/pituitary < 30	Green et al. (2009)
	Radiation induced menopause	Children	Yes	N/A			Chiarelli et al. (1999)
	Infertility	Children	Yes	N/A		Dmax,uterus < 10 Gy	SFRO (2008)^†
Kidneys	Chronic renal dysfunction	Children	N/A	N/A	1	BEDKidney (mean dose) < 16 Gy2.5	Kal et al. (2009)
	Renal toxicity	Children	N/A	N/A			Esiashvili et al. (2009)
Lungs	Restrictive lung function	Children	No	N/A	1	Dmean,lung < 10 Gy	Attard-Montalto et al. (1992)
	Pulmonary diffusion capacity	Children	Yes	N/A			Bossi et al. (1997)
	Pulmonary function reduced	Children	No	N/A			Weiner et al. (2006)
	Pneumonitis	Adults	Yes	Mean Lung Dose			Marks et al. (2010)
Hearing apparatus	Ototoxicity	Children	Yes	N/A	2	Dmean,cochlea < 37 Gy	Miettinen et al. (1997)
	Ototoxicity	Children	Yes	N/A			Huang et al. (2002)
Submandibular glands	Xerostomia (75% flow rate red.)	Adults	N/A	N/A	5	Dmean,submandib. glands < 19 Gy	Murdoch-Kinch et al. (2008)
Chiasm	Blindness	Children	Yes	N/A	2	Dmax,chiasm < 52 Gy & V50 < 100%	SFRO (2008)^†
Optic nerve	Blindness	Children	Yes	N/A	2	Dmax,optic nerve < 50 Gy	SFRO (2008)^†
Skin	Te langiectasia/Ep ilation	Children	Yes	N/A	5	Dmax,skin < 35 Gy	SFRO (2008)†
Brainstem	Necrosis	Children	Yes	N/A	1	Dmax,brainstem < 54 Gy	SFRO (2008)†
Esophagus	Esophagal RTOG Grade 1–4 tox	Adults	Y & N	N/A	3	Dmax, esophagus < 40 Gy	Ahn et al. (2005)
Larynx	Laryngeal edema	Adults	Y & N	LKB-EUD	3	EUDlarynx < 29 Gy	Rancati et al. (2009)

^†Referenced publication is based on the gathered clinical experience of the Société française de Radiothérapie Oncologique (SfRO), not on published clinical data, published as Guide des procedures de radiotherapie externe 2007 in 2008.

EuD, Equivalent uniform Dose, further explanation given with corresponding reference.

Inter-organ priorities were based on:

1 – Permanent, life threatening event with no possible medical substitution of organ function.

2 – Permanent, non-life threatening event with inability to lead an independent life, medical substitution not possible.

3 – Permanent effect with possibility of partial medical substitution.

4 – Permanent effect with possibility of full medical substitution but with likely complications.

5 – Permanent effect with possibility of complication free full substitution.

Table II. Radiation-related secondary cancer incidence from the lSS [34] and as adopted in this study. the incidence is given as average excess absolute risk due to external low-lEt radiation as per 10 000 person years and Sieverts equivalent dose.

	incidence (10^4 PYSv)^−1		values adopted (10^4 PYSv)^−1
Site/cancer type	Males	females	Males	females
Esophagus	0.26	0.44	0.26	0.44
Stomach	2.61	5.86	2.61	5.86
Colon	2.66	1.01	2.66	1.01
liver	0.033	0.005	0.033	0.005
lungs	2.67	5.81	2.67	5.81
Bone and connective tissue	0.38	0.12	–	–
Skin	0.89	0.72	0.89	0.72
female breast	–	6.80	–	6.80
Prostate	0.44	–	0.44	–
urinary bladder	0.84	1.02	0.84	1.02
Brain and CNS	−0.21	0.43	0.00	0.43
thyroid	0.87	2.32	0.87	2.32
Non-Hodgkin 's lymphoma	0.73	−0.20	–	–
Hodgkin's disease	0.04	0.04	–	–
Multiple myeloma	0.26	−0.08	–	–
Leukemia	3.35	2.29	–	–

Table III. Dose-response functions and corresponding model parameters utilized in the estimation of treatment-induced non-cancer adverse effects.

Studied endpoint	Model	Model parameters	References
Hypothyroidism	Logistic function*	b0 = 22.50	Bathia et al. [40]
		b1 = 0.09
Ototoxicity (Hearing loss)	Logistic function*	b0 = 27.34	Huang et al. [8]
		b1 = 0.148
Pneumonitis	Logistic function*	b0 = 23.87	Marks et al. [41]
		b1 = 0.126
Heart failure	Linear-quadratic function	α1 = 0.19	Guldner et al. [38]
	OR = 1 + α1 • Dmean + α2 • D^2mean	α2 = 0.002
Xerostomia	LKB-model^†	TD50 = 39.9 Gy	Houweling et al. [42]
		m = 0.40
		n = 1
Blindness	Linear function	–	Whelan et al. [7]
	P = 0.0028 • BED2.5, mean −0.0015
Chronic renal failure	Linear function	–	Kal et al. [43]
	P = 0.075 • BED2.5, mean −1.42

*P= e^b₀+b₁ • D_mean/1 + e^b₀+b₁ • D_mean

^†Lyman-Kutcher-Burman model, details described elsewhere [44].

Figure 2. Mean values for all 10 patients of cumulative solid secondary cancer risk as a function of attained age for the three different treatment modalities studied. Results are given for the two different prescription CSI dose levels that are relevant for this patient group. The results are shown up to an attained age of 100 years, after this the cumulative risk levels out since the probability of surviving to older ages is very low. For IMPT the results are given as including SN dose with values of the WR_neutron as proposed in ICRP publication 92, denoted IMPT_SN and values five times higher, denoted IMPT_SNx5.

Figure 3. Mean values of EAR are given for a plateau, bell shape and a linear model, normalized to the EAR of the plateau model. The estimates are given for prescribed CSI doses of a) 23.4 Gy and b) 36 Gy. The relative difference between models depends on the initial slope of the dose-response curves and at what doses the risk plateaus out/turns over. The linear model deviates somewhat from the other two, likely since it did not provide a good fit to the original input data.

Figure 4. Mean values for all 10 patients comparing long-term risks of inducing pneumonitis, heart failure, xerostomia, blindness, hypothyroidism and ototoxicity between the different treatment modalities.

Figure 5. Mean values of all 10 patients comparing the risk of heart failure for different spinal field widths in 3D CRT treatment.

Table IV. Mean values for all ten patients of target coverage parameters comparing the 3D CRT, RapidArc and IMPT plans for the 23.4 Gy craniospinal prescription dose.

Parameter	PTV craniospinal	PTV boost	CTV - Brain	CTV - Spinal
3D CRT
Dmin	13.5 Gy	45.1 Gy	21.5 Gy	21.3 Gy
Dmax	29.5 Gy	57.3 Gy	25.0 Gy	28.6 Gy
V95	96.6%	99.3%	99.9%	98.7%
V107	4.5%	0.0%	0.1%	17.1%
CI	0.61	0.61	–	–
RapidArc
Dmin	15.5 Gy	41.1 Gy	19.6 Gy	21.0 Gy
Dmax	27.8 Gy	59.4 Gy	27.7 Gy	25.9 Gy
V95	95.2%	97.8%	97.3%	98.7%
V107	6.3%	3.9%	7.5%	0.7%
CI	0.73	0.77	–	–
IMPT
Dmin	13.7 Gy	39.2 Gy	19.4 Gy	22.1 Gy
Dmax	26.5 Gy	59.0 Gy	26.3 Gy	24.8 Gy
V95	97.1%	98.6%	99.7%	99.5%
V107	0.2%	0.2%	0.2%	0.0%
CI	0.89	0.90	–	–

CI: Conformity Index. Closer to unity equals better conformity, calculation details described elsewhere [45].

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