Normal-Tissue Tolerance to Radiopharmaceutical Therapies, the Knowns and the Unknowns

Richard L. Wahl; George Sgouros; Amir Iravani; Heather Jacene; Daniel Pryma; Babak Saboury; Jacek Capala; Stephen A. Graves

doi:10.2967/jnumed.121.262751

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TABLE 1

Summary of Normal-Tissue Dose Limits by Organ Tissue and Toxicity Endpoint for External-Beam Radiotherapy (EBRT) and Radiopharmaceutical Therapy (RPT)

Tissue	Toxicity endpoint	Toxicity rate	EBRT limits*	RPT limits^†	References
Brain	Symptomatic Necrosis	5%	D_max = 72 Gy	Unknown	(25)^‡
Optic nerve/chiasm	Optic neuropathy	5%	D_max = 55–60 Gy	Unknown	(25)
Brain stem	Permanent cranial neuropathy or necrosis	5%	D_max = 54 Gy (small volume)	Unknown	(25)
		5%	D_max = 59 Gy (1–10 cc)
		5%	D_max = 64 Gy (<1 cc)
Spinal cord	Myelopathy	5%	D_max = 55–60 Gy	Unknown	(25)
Cochlea	Sensory-neural hearing loss (measured @ 4 kHz)	30%	D_mean = 45 Gy	Unknown	(25)
Parotid-salivary glands	Long-term salivary function reduced to < 25% of pre–radiation therapy level	20%	D_mean = 25 Gy (bilateral)	9.2–33 Gy as single dose caused 25% incidence of transient xerostomia and 1 case of transient mucositis (4%) ¹³¹I-NaI has been reported to cause symptomatic xerostomia at doses as low as 5 Gy.	(25,72,76)
Larynx	Vocal dysfunction	20%	D_max = 66 Gy	Unknown	(25)
	Aspiration	30%	D_mean = 50 Gy	Unknown	(25)
	Edema	20%	D_mean = 44 Gy	Unknown	(25)
Pharynx	Symptomatic dysphagia and aspiration	20%	D_mean = 50 Gy	Unknown	(25)
Thyroid	Clinical Hypothyroidism	8%	D_mean = 45 Gy	Hypothyroidism common in ¹³¹I-MIBG and ¹³¹I-tositumomab therapies, but dose delivered unclear	(6)
Lungs	Symptomatic pneumonitis	5%	D_mean = 7 Gy	D_mean > 30 Gy from single ⁹⁰Y-microsphere^¶ Tx (33% toxicity rate; n = 3); D_mean > 50 Gy cumulative from ⁹⁰Y-microsphere Tx (50% toxicity rate; n = 2) D_mean > 27 Gy from ¹³¹I-radioimmunotherapy	(25,86,87)
		< 20%	V₂₀ < 30% (volume receiving > 20 Gy less than 30% of total lung volume)
Heart	Pericarditis	15%	D_mean = 26 Gy	Unknown	(25)
	Long-term cardiac mortality	< 1%	V₂₅ < 10%	Unknown
Esophagus	Grade > = 3 acute esophagitis	5%–20%	D_mean = 34 Gy	Unknown	(25)
		< 30%	Various dose volume constraints, ranging up to V₇₀ < 20%
Liver	Classical RILD	5%	D_mean = 30–32 Gy	Data at the 5% toxicity rate level is inconclusive, but perhaps suggestive of D_mean = ∼35–50 Gy (glass ⁹⁰Y-microspheres) and D_mean = ∼20–40 Gy (resin ⁹⁰Y-microspheres). Package insert allows 80–150 Gy. Microsphere tolerance appears higher than agents targeting hepatocytes, but data limited. ⁹⁰Y-ibirtumomab hepatic MTD > 28.5 Gy MIBG, approx. 30 Gy results in < 10% transient liver toxicity	(25,51–55,112)
		50%	D_mean = 42 Gy	D_mean > 70 Gy (glass ⁹⁰Y-microspheres) D_mean = 52 Gy (resin ⁹⁰Y-microspheres)
Stomach	Ulceration	5%–7%	Uniform dose of ∼45 Gy	Unknown	(25)
Small bowel	Grade > = 3 acute toxicity	< 10%	V₁₅ < 120 cc	Unknown	(25)
Spleen	Sepsis, Pneumonia	—	Data inconclusive, but suggestive of ∼20% chance of infection event after mean dose of 40 Gy to spleen	Unknown	(113)
Kidneys	End-stage renal disease	5%	D_mean = 18 Gy (∼38 Gy BED)	23–26 Gy (∼36 Gy BED)	(7,25)
		50%	D_mean = 28 Gy (∼44 Gy BED)	34–38 Gy (∼44 Gy BED)
Bladder	Grade > =3 late toxicity (RTOG grading)	< 6%	D_max < 65 Gy	Unknown	(25)
Penile bulb	Severe erectile dysfunction	35%	D_mean = 50 Gy	Unknown	(25)
Rectum	Grade 2+ late rectal toxicity	< 15%	Various dose volume constraints ranging from V₅₀ < 50% up to V₇₅ < 15%	Unknown	(25)
Bone marrow	Moderate to severe hematopoietic syndrome	—	Acute WB exposure 2–5 Gy	D_mean > 2–3 Gy (¹³¹I-NaI, radioimmunotherapy, ⁹⁰Y-DOTATOC, ¹³¹I-MIBG)	(36,85,88,114,115)
	Hematopoietic syndrome w/anemia from GI syndrome	—	Acute WB exposure 6–7 Gy (LD50/60 with antibiotic and transfusion support)	—	(46)
	Pretransplant myeloablation	—	12.0–13.5 Gy in ∼1.5 Gy WB exposures over 4–4.5 d	D_mean = ∼15 Gy (4.6–32.0 Gy; ¹³¹I-Iomab-B)	(89)
Whole body	Moderate to severe hematopoietic syndrome	—	(See “Bone Marrow”)	MTD of ¹³¹I-Tositumomab determined to be 75 cGy the MTD for pretreated patients. MTD for patients who had HSC transplants = 65 cGy. MTD for patients with no prior therapy = 85 cGy	(92,93)

*EBRT limits are for conventional fractionation unless otherwise stated.
↵^†RPT limits are specified for β-emitting agents (i.e., ¹⁷⁷Lu, ⁹⁰Y, ¹³¹I).
^‡Reference is provided for the QUANTEC summary article, for further details readers are referred to the tissue-specific QUANTEC documents.
↵^¶Although ⁹⁰Y-microspheres are typically treated as medical devices rather than radiopharmaceuticals under regulatory purview, they are included herein for completeness.