Tumor Response to Radiopharmaceutical Therapies: The Knowns and the Unknowns

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FIGURE 1.
Tumor dose–response relationship in PRRT for 13 patients treated with ⁹⁰Y-DOTATOC (A) and 24 patients treated with ¹⁷⁷Lu-DOTATATE (B). (Adapted from Pauwels et al. (102) and Ilan et al. (103).)

TABLE 1

Summary of Tumor-Absorbed Dose vs. Response from EBRT

Cancer	Prescribed tumor dose/fraction number	Comments	Reference
Breast	40 or 43.5 Gy/15	2.67–2.9 Gy/fraction	118,119
Prostate	76–82 Gy/38–41; 64.6 Gy/19; 60 Gy/20	2, 3.4, or 3 Gy/fraction	120,121
Head and neck cancers	70 Gy/35	2 Gy/fraction	122
Hepatocellular carcinoma	66 Gy/10	Proton therapy, 109-Gy biologically effective dose (α/β = 10 Gy)	123
Lung (stage I, non–small cell lung carcinoma)	54 Gy/3	Stereotactic body radiotherapy, 18 Gy/fraction	124
Lymphoma	30 Gy	Median, 30 Gy (overall range, 24–52 Gy)	125
Oligometastatic disease	30–60 Gy/3–8; 16 Gy/1, 24 Gy/1 to CNS metastases	1–3 vs. 4–5 metastases	126

TABLE 2

Studies Reporting on Tumor-Absorbed Dose vs. Response in Microsphere Radioembolization of Hepatic Malignancies

Study	n	Disease	Lesion size (cm)	Device	Imaging	Endpoint	Threshold mean dose (Gy)
Garin (92,127,128)	36, 71, 71	HCC	7.1 ± 3.3	⁹⁰Y glass	^99mTc-MAA SPECT	PFS, EASL	205
Mazzaferro (129)	52	HCC		⁹⁰Y glass	^99mTc-MAA SPECT	EASL (PR + CR)	500
Chiesa (130)	52	HCC	4.9 (1.8–10.3)	⁹⁰Y glass	^99mTc-MAA SPECT	EASL (PR + CR) 50% TCP	390
Chan (131)	35	HCC	7.3 (3.0–17.9)	⁹⁰Y glass	⁹⁰Y PET/CT	mRECIST (PR + CR)	200
Ho (132)	62	HCC		⁹⁰Y glass	^99mTc-MAA SPECT/CT	¹⁸F-FDG, ¹¹C PET res. > 50%	170
Kappadath (110)	34	HCC	4.1 (2.6–12.3)	⁹⁰Y glass	⁹⁰Y SPECT/CT	mRECIST 50% TCP	160
Dewaraja (111)	28	HCC and metastases	2.7 (1.6–11.7)	⁹⁰Y glass	⁹⁰Y PET/CT	mRECIST 50% TCP	290
Lau (133)	18	HCC	NA	⁹⁰Y resin	^99mTc-MAA planar	CT volume + AFP	120
Strigari (134)	73	HCC	5.8 (1.6–15.6)	⁹⁰Y resin	⁹⁰Y SPECT	50% TCP (PR + CR)	150
Flamen (135)	8	Colorectal	781 mL (95% CI, 332–1,230)	⁹⁰Y resin	^99mTc-MAA SPECT	¹⁸F-FDG PET res. > 50%	46
Song (136)	23	HCC and metastases	467 mL (5–1,400)	⁹⁰Y resin	⁹⁰Y PET/CT	PFS, RECIST	200
Chansanti (97)	15	NET	3.9 (±2.3)	⁹⁰Y resin	^99mTc-MAA SPECT/CT	mRECIST (PR + CR)	191
Allimant (137)	38	HCC	5 (2.8–11.4)	⁹⁰Y resin	⁹⁰Y PET/CT	PFS, mRECIST	Area under DVH > 61 Gy
Hermann (138) (SARAH trial)	121	HCC	152 cm (IQR, 46.4–399.5)	⁹⁰Y resin	^99mTc-MAA SPECT/CT	RECIST	100

HCC = hepatocellular carcinoma; MAA = macroaggregated albumin; PFS = progression-free survival; EASL = European Association for the Study of the Liver; PR = partial response; CR = complete response; res. = response; TCP = tumor control probability measure of tumor control (typically a radiobiologically derived parameter based on linear quadratic model that accounts for nonuniformity in absorbed dose within tumor and effect this has on likelihood of tumor control; can also be obtained using statistical data–driven models [MIRD Primer and International Commission on Radiation Units and Measurements report 96]); AFP = α-fetoprotein; NA = not applicable; DVH = dose-volume histogram; IQR = interquartile range.
Data in parentheses are ranges.

TABLE 3

Studies Reporting Tumor Dose–Response Relationship in Other RPTs

Study	Disease	Therapy	n	Lesion size	Dosimetry method	Endpoint	Threshold
Maxon (139)	Thyroid cancer metastases	¹³¹I radioiodine	76		Planar conjugate views	Response on ¹³¹I planar scans	80 Gy for metastases; 300 Gy for remnants
Wierts (140)	Thyroid cancer remnants and metastases	¹³¹I radioiodine	47	>0.15 cm³	¹²⁴I PET + OLINDA sphere model	CR on ¹³¹I SPECT or ¹²⁴I PET	40 Gy for metastases; 90 Gy for remnants
Pauwels (102)	NET	⁹⁰Y-DOTATOC PRRT	13	NA	⁸⁶Y-DOTATOC PET + MIRDOSE sphere model	Volume shrinkage > 30% on CT	∼150 Gy for >30% shrinkage
Ilan (103)	NET	¹⁷⁷Lu-DOTATATE PRRT	24 (24 tumors)	>2.2 cm	SPECT/CT + OLINDA sphere model	RECIST best response > 30%	∼150 Gy
Matthay (141)	Neuroblastoma	¹³¹I-metaiodobenzylguanidine	27		Planar conjugate view + MIRDOSE	Volume shrinkage > 50% on CT	70 Gy
Dewaraja (16)	Non-Hodgkin lymphoma	¹³¹I-radioimmunotherapy	39 (130 tumors)	Median, 20 cm³	Multi-SPECT/CT + Monte Carlo	Progression-free survival	200 cGy

TABLE 4

List of Unknowns

No.	Description
1	How does inflammation- or immune-mediated effects influence dose-vs.-response relationship?
2	Does negative theranostic imaging preclude patient benefit from RPT?
3	What are radiobiologic parameter values for RPT? Do those from EBRT apply?
4	Do genomic approaches to assessing individual patient or tumor radiosensitivity (e.g., genomic-adjusted radiation dose) apply to RPT?
5	To what extent do differences in dosimetry methods vs. other factors (radiosensitivity, patient population) explain variability in dose vs. response?
6	How do immunooncologic agents such as immune checkpoint inhibitors impact RPT?
7	How do patient-specific differences (kinetics, size and distribution of lesions, overall tumor burden) impact tumor response to RPT? Can these differences be accounted for by calculating tumor-absorbed dose?
8	How does hypoxia affect response to RPT?
9	What is best formalism or approach for relating RPT to EBRT dose response ?