Critical Reviews in Oncology / Hematology 123 (2018) 7–20

Contents lists available at ScienceDirect

Critical Reviews in Oncology / Hematology

journal homepage: www.elsevier.com/locate/critrevonc

Global comparison of targeted alpha vs targeted beta therapy for cancer: In T

vitro, in vivo and clinical trials
⁎
Loredana Marcua,b, Eva Bezakb,c, Barry J. Allend,
a
Department of Physics, Faculty of Science, 1 Universitatii street, University of Oradea, 410087, Romania
b
Sansom Institute for Health Research and the School of Health Sciences, University of South Australia, GPO Box 247, Adelaide SA 5001, Australia
c
Department of Physics, University of Adelaide, Adelaide, SA 5005, Australia
d
School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith NSW 2751, Australia

A R T I C L E I N F O A B S T R A C T

Keywords: Targeted therapy for cancer is a rapidly expanding and successful approach to the management of many in-
Systemic cancer tractable cancers. However, many immunotherapies fail in the longer term and there continues to be a need for
Targeted alpha therapy improved targeted cancer cell toxicity, which can be achieved by radiolabelling the targeting vector with a
Targeted beta therapy radioisotope.
Clinical trials
Such constructs are successful in using a gamma ray emitter for imaging. However, traditionally, a beta
emitter is used for therapeutic applications. The new approach is to use the short range and highly cytotoxic
alpha radiation from alpha emitters to achieve improved efficacy and therapeutic gain.
This paper sets out to review all experimental and theoretical comparisons of efficacy and therapeutic gain for
alpha and beta emitters labelling the same targeting vector. The overall conclusion is that targeted alpha therapy
is superior to targeted beta therapy, such that the use of alpha therapy in clinical settings should be expanded.

1. Introduction improved targeted cancer cell toxicity, which can be achieved by

Anti-cancer treatment, such as surgery, radiotherapy and che-
motherapy are considered standard of care in today’s oncology. While
the advances in science and technology have led to developments in all
these therapeutic areas, the global cancer burden is expected to nearly
double by 2030 and will continue to be the leading cause of death in
both developed and less developed countries (American Cancer Society,
2015).
New therapies are needed to increase systemic cancer control and to
diminish normal tissue side effects. These should be more targeted and
patient specific. Targeted therapy for cancer is a rapidly expanding and
successful approach to the management of many intractable cancers.
For example, monoclonal antibodies to target specific antigens or re-
ceptors have been used effectively to control the progression of dif-
ferent cancers. Immuno-modulators such as Rituximab (MabThera®) for
lymphoma, Trastuzumab (Herceptin®) for breast cancer, Alemtuzumab
(Campath-1H®) for chronic lymphocytic leukemia, Cetuximab
(Erbitux®) for colorectal cancer and Bevacizumab (Avastin®) for color-
ectal and lung cancers have been used clinically with significant suc-
cess. However, cancer specific antibodies alone can be insufficient to
control cancer progression and there continues to be a need for
radiolabelling the targeting vector with a radioisotope.
Monoclonal antibodies (Mabs) labeled with radionuclides form so-
called radio-immunoconjugates (RIC), which deliver high dose radia-
tion directly to the cancer cell (Allen 2011). Traditionally, beta emitters
(i.e. electrons) have been used for therapeutic applications. FDA ap-
provals have been granted for targeted radio-immunotherapy for non-
Hodgkin’s lymphoma using 131I-tositumomab (Bexxar®) and 90Y-ibri-
tumomab tiuxetan (Zevalin®) to target CD20 (Kang et al., 2013). More
recently, the short-range beta-emitting conjugate 177Lu-J591 has been
used with encouraging results in a phase 2 clinical trial for castrate
resistant prostate cancer, where it targets metastases in both the bone
and soft tissues and survival time has almost doubled (Tagawa et al.,
2013). These beta-emitting conjugates do enhance cytotoxicity to tu-
mours. However, the long range of betas is a double edged sword. On
one hand, the long range electrons can travel through several cancer
cells thus increasing the average dose to a tumour. On the other hand,
the long range of electrons also results in a larger dose to surrounding
healthy tissue. Additionally, the low ionisation capacity of electrons
(i.e. low linear energy transfer (LET)) means that beta radiation cannot
deliver a lethal dose to a targeted single cancer cell (Marcu et al., 2012).
The new approach is to use the short range and highly cytotoxic

⁎
Corresponding author.
E-mail address: bja1940b@outlook.com (B.J. Allen).

https://doi.org/10.1016/j.critrevonc.2018.01.001
Received 19 July 2017; Received in revised form 11 November 2017; Accepted 9 January 2018
1040-8428/ © 2018 Elsevier B.V. All rights reserved.
L. Marcu et al. Critical Reviews in Oncology / Hematology 123 (2018) 7–20

alpha radiation from alpha emitters to achieve improved efficacy and
therapeutic gain. This new field of targeted radio therapy is gaining
clinical interest, with a number of clinical trials around the world either
being completed, underway or under development (Allen et al., 2016).
The important advantage of alpha radiation is the high LET to targeted
cancer cells over a short range of several cell diameters (Mulford et al.,
2005). Furthermore, the formation of complex DNA lesions by alpha
emitters can be explained by the energy distribution at the nanoscale
level, though it is likely that the cell membrane and mitochondria are
also sensitive targets of alpha irradiation (Pouget et al., 2015).
As such, alpha radiation is better suited to the treatment of micro-
scopic or small-volume disease since their short range and high energies
potentially offer more efficient and specific killing of tumour cells,
while sparing distant normal cells (Allen et al., 2007).
Nevertheless, most clinical trials continue to use beta emitters ra-
ther than alpha emitters. This paper sets out to review all experimental
comparisons of cytotoxicity, efficacy and therapeutic gain for alpha and
beta emitters labelling, where possible, the same targeting vector with
the aim to identify the therapeutic benefit of both modalities.
2. Biophysical and radiobiological comparison of alpha and beta
radiations
The several cell categories that must be considered when employing
TAT as a curative therapeutic modality are: (1) isolated or in transit
cancer cells; (2) targeted cancer cell clusters and tumours (3) non-tar-
geted contiguous cancer cells and (4) cancer stem cells. While TAT has a
powerful effect on contiguous non-targeted cancer cells, this property is
inexistent with beta-emitters.
2.1. Monte Carlo calculations
The different properties of radiations from alpha and beta emitting
radioisotopes are apparent from the results of Monte Carlo calculations.
Random event probabilities are calculated by Monte Carlo to build up
the specific energy spectrum in the targeted cell nucleus (Huang et al.,
2012). The mean nuclear specific energy (Gy) for different radio-
isotopes is shown in Fig. 1 for multiple alpha emissions, single alpha
emissions and beta emissions from the designated radioisotopes on the
surface of a cell. 223Ra and 225Ac have about 4 times the specific energy
of the single alpha emitters 211At and 213Bi. However, the specific en-
ergies for beta emitters are approximately two orders of magnitude
lower than for 213Bi and three orders below 225Ac.
2.2. Physical and radiobiological properties
These specific energies, coupled with the short range of alphas as
shown in Table 1, means that alphas exhibit a much greater toxicity to
targeted cells than betas.
Table 1
Physical and radiobiological properties of alpha and beta radiation.
Properties Alpha radiation Beta radiation
Tissue range (μm) 20–80 2000–11500
Linear energy transfer (keV/ ∼100 ∼0.3
μm)
RBE (external beam) (Section 5 1
3.1)
RBE (internal) (section 3.2) > 100 1
Pharmacokinetics (half-life) 1 h–10 d 7 h–7 d
Decay behaviour One step and One-step decay to stable
multiple alpha nuclide
decays
The high LET and short range means that alphas are preferred to kill
isolated cells. If the AIC diffuses into the nucleus, the toxicity increases
markedly which is not the case for betas. The exception is Auger elec-
tron-emitting radioisotopes, such as 77Br, 111In, 123I and 125I, which are
potential therapeutic agents, given the fact that when combined with
suitable molecular carriers, these isotopes have proven high LET cell-
killing efficiency (Adelstein et al., 2003).
The long-range crossfire effect gives beta radiation some advantage
over other targeted therapy candidates as the consequences of hetero-
geneous uptake of the beta-immunoconjugate (BIC) in the tumour are
reduced. With alpha-emitters, this problem can be overcome with in-
tralesional injections with AICs (Allen et al., 2005) or by tumour anti-
vascular alpha therapy (TAVAT) (Allen et al., 2007), the latter property
being inexistent with beta-emitters (Table 2).
The bystander effect could contribute to cell kill in both beta and
alpha radioimmunotherapy. While several aspects regarding the by-
stander effect are still under investigation, it is known that cells that
have not been traversed by radiation but are located in the vicinity of
irradiated cells, can present signs of radiation damage, similar to cells
affected by ionising radiation (such as chromosomal damage, muta-
tions, apoptosis) or even radio-adaptation (Pouget et al., 2015). These
effects occur at low dose and dose rates and in targeted therapy can be
particularly relevant due to the non-uniform distribution of radio-
activity that influences risk estimation and clinical outcome in general.
Abscopal effects, which are distant bystander effects that inhibit distant
tumours after local irradiation, are also potential players in cell kill
through distant cellular signaling. Alpha radioimmunotherapy com-
bined with adoptive T cell therapy to stimulate the immune system was
shown to be a successful treatment for multiple myeloma in mice
models, potentially mediated by abscopal effects (Ménager et al., 2015).
The antigen expression of cancer stem cells remains uncertain.
Failure to kill these stem cells means that the cancer cannot be con-
trolled. However, if these cells are either isolated or in transit, they can
only be eliminated by alpha rays if their antigenic expression is known.
This may be the case for beta emitters such as 131I and 90Y, used in
combination with monoclonal antibodies for the treatment of non-
Hodgkin’s lymphoma, 177Lu for prostate cancer and 153Sm and 89Sr for
the palliation of bone metastases. Other possible candidates for clinical
studies are 166Ho, 67Co, 186Re and 188Re. While efficacious, none of
these radioisotopes have been curative.

Table 2
Comparative effects of alpha and beta radiation (Allen, 1999).

Cancer Type Alpha particles Beta particles

Isolated cells Yes No

Contiguous non-targeted cells Yes No
stem cells Yes No
Fig. 1. The mean nuclear specific energy (Gy) for different alpha and beta emitting Antivascular effect Yes No
DNA localization effect Yes No
radioisotopes located on the cell membrane are shown for the multiple and single alpha
Clusters Yes Yes
emitters, in comparison with that for the beta emitting radioisotopes (courtesy (Huang
Tumor crossfire No Yes
et al., 2012)).

8
L. Marcu et al.
Fig. 2. Log-survival curves, obtained by clonogenic assay, for A549 cells and endothelial
cells (EC) exposed to X-rays or alpha particles (courtesy (Riquier et al., 2013)).
3. In vitro cytotoxicity
There are substantial differences between the radiobiological
properties of radioisotopes. These relate to the linear energy transfer
(LET) of the emitted particles, radiochemistry and elemental properties.
Barendsen et al. (1960) was the first to study the survival of cells under
alpha, beta and gamma external radiation beams.
3.1. External X-ray and alpha particle irradiation on a human cancer and
endothelial cells
Barendson compared the effect of external photon beams and alpha
radiation (Barendsen et al., 1960) in terms of cell survival after single or
multiple exposures of X and alpha radiation. The relative biological
effect for alphas vs X-rays was estimated to be around 3 for 1–10%
survival.
Another experiment looking at the effect of external photon beams
and alphas on two cell lines was undertaken by Riquier et al. (2013).
Survival curves are shown in Fig. 2 for A549 cells and endothelial cells
(EC) exposed to x-rays or alpha particles, which were obtained by
clonogenic assay. The survival curves are fitted with the Linear Quad-
ratic model. The high LET radiation gave a linear curve on the log plot,
while the low LET radiation a shoulder curve. The relative biological
effect is seen to be close to 5 for 1–10% survival (Riquier et al., 2013).
3.2. Cancer cell survival studies after in vitro incubation of
radioimmunoconjugates
3.2.1. Melanoma
In a study reported by Rizvi et al., the 9.2.27 monoclonal antibody,
which targets the MCSP antigen expressed by most melanoma cells, was
investigated. MM138 cells were incubated in different activities of the
same mAb labeled with either 213Bi (alpha) or 152Tb (positron). The
survival of melanoma cells is shown in Fig. 3 (Rizvi et al., 2000).
Note that the half-lives are 213Bi = 46 m for vs 18.5 h for 152Tb.
After a 1 h incubation time, the cells were washed. However, attached
152
Tb conjugates can remain on or in the cell, causing additional cy-
totoxicity over the 24 h counting time. A half-life correction has not
been made. The RBE for 37% survival (Do) is 120, after correction for
branching ratios. This first result showed the marked difference in
targeted alpha cytotoxicity compared with the beta label.
3.2.2. Leukaemia
Acute myeloid leukemia cells (HL-60) express the CD33 antigen,
which is targeted by the WM53 monoclonal antibody. The WM53 Mab
9
Critical Reviews in Oncology / Hematology 123 (2018) 7–20
Fig. 3. Comparative melanoma cell log-survival for alpha (Bi213) and beta (Tb152) la-
beled 9.2.27 mAb (Courtesy (Rizvi et al., 2000)).
was labeled with radioisotopes with > 90% labelling efficiency high
stability (< 20% leaching) of the radio-immunoconjugate. The HL-60
cells were incubated over 24 h with WM53 Mab being unlabelled or
labeled with 153Sm(β), 152Tb(β+) and 213Bi(α) labels (Rizvi et al.,
2002).
Cytotoxicity relative to unlabelled antibody was determined for
DNA synthesis using tritium labeled thymidine incorporation and cell
survival using the MTS method. A correction has not been made for the
different half-lives of the radioisotopes for the 24 h incubation (Fig. 4).
For either method, only the 213Bi −WM53 conjugate was effective in
killing targeted cancer cells. Free 213Bi was as ineffective as the targeted
beta emitting WM-53 conjugates (Rizvi et al., 2002).
3.2.3. Prostate cancer
In an experiment reported by Li et al. (2002a), cells originating from
prostate cancer were treated with varying concentrations of AIC in-
cubated over 24 h and cell survival measured by MTS assay and ex-
pressed as a mean percent ± SD of control plates containing a non-
specific antibody only (Li et al., 2002a). The survival curves for prostate
cancer cells (LN3) incubated with a specific 213Bi −J591 conjugate and
a non-specific 213Bi conjugate are shown in Fig. 5. Each point represents
a mean of three experiments with each experimental point having tri-
plicate wells. This result clearly demonstrates that the alphas are only
effectively cytotoxic to cancer cells when they are targeted and at-
tached to those cells. The cytotoxicity of alpha labeled specific targeting
vector is very much greater (10–100 times) than the cross fire generated
at these uCi activity incubations. However, if the vector is truly non-
specific or is unlabeled, then it is not directly cytotoxic to the cancer
cells.
4. Preclinical in vivo studies
In vivo studies use human cancer xenografts in immune-in-
competent mice to test pharmacokinetics, efficacy and the maximum
tolerance dose of radiolabelled targeting vectors. While single cell
radiobiology is determined in vitro studies, in vivo studies are much
more complex, involving physiological properties such as bioavail-
ability, clearance, tumour capillary density and permeability and im-
mune response. The objective is to observe efficacy within the max-
imum tolerance dose (MTD), efficacy meaning the ability of the therapy
to stop tumour formation, retard tumour growth or partial or complete
tumour regression after subcutaneous, intraperitoneal or intravenous
inoculation of cancer cells. Table 3 is a compilation of in vivo studies
directly comparing the efficacy and toxicity of α-RIT vs β-RIT.
4.1. Ovarian ascites
The first attempt to compare the effectiveness of alpha- versus beta-
emitting radioisotopes was related to the treatment of malignant
ovarian ascites in mice (Bloomer et al., 1984). The efficacy of the alpha-
L. Marcu et al.
Fig. 5. Comparative prostate cancer cell log-survival for the 213Bi labeled specific
(square) and non-specific mAbs (triangle) (Courtesy (Li et al., 2002b)).
emitter 211
At-tellurium colloid was compared with the beta-emitting
colloids 32P, 165Dy and 90Y. Radiocolloids of beta emitters were not
curative, irrespective of the doses used, whereas the 211At-tellurium
colloid was shown to be curative for doses of 925 MBq. The increased
therapeutic efficacy of the alpha-emitting radioisotope was ascribed to
its densely ionising character.
4.2. Colon cancer
Since this pioneering study, the following experimental investiga-
tion in solid tumours that showed a therapeutic advantage of α-RIT
after a direct comparison with β-RIT was reported by Behr et al. (1999).
Using monovalent antibody fragments (Fab’) of the Mab CO17-A1, the
group has evaluated the tumoricidal and normal tissue effects of RIT
with an alpha emitter (213Bi/213Po) and a beta emitter (90Y) in a human
colon cancer model in nude mice. The advantageous physical properties
of 213Bi, such as the high mean LET of 100 keV/μm as compared to only
0.2 keV/μm of 90Y as well as its short range in tissue (0.1 mm vs
3.96 mm) lead to a therapeutically superior outcome with α-RIT,
through a 2–3 fold higher radiobiological effectiveness in the tumour
(Behr et al., 1999).
4.3. Neuroendocrine tumours
Alpha-emitting isotopes have shown improvement over beta emit-
ters (Miederer et al., 2008). Over the last two decades, peptide receptor
radionuclide therapy has been developed for these tumours. Given their
high-level expression of somatostatin receptors, somatostatin analogues
having high affinity to these receptors have been studied in the context
of metastasized neuroendocrine tumours. Most commonly, beta-emit-
ting isotopes have been employed (90Y or 177Lu-DOTATOC), that
showed a minimum 50% tumour regression in up to 50% of patients
(Kam et al., 2012; Waldherr et al., 2001). As demonstrated by pre-
clinical studies, the somatostatin receptor radiotherapy can be im-
proved by replacing low LET beta emitting isotopes with high LET alpha
emitters, such as 225Ac (Miederer et al., 2008). A comparative study on
the effectiveness of 177Lu-DOTATOC and 225Ac-DOTATOC showed a
10
Critical Reviews in Oncology / Hematology 123 (2018) 7–20
Fig. 4. Log of DNA uptake and cell survival studies with alpha
versus beta targeted therapy, free radioisotopes and non-specific
radio-labeled conjugates (Courtesy (Rizvi et al., 2002)). Only the
Bi213 labeled WM53 MAb showed high cytotoxicity.
therapeutic window in favour of the alpha-emitting isotope that could
be further pursued in clinical settings.
4.4. Ovarian peritoneal carcinoma
The effect of alpha-RIT was investigated using monoclonal huma-
nised anti-CD138 antibody radiolabeled with 213Bi. The effect of RIT
was compared with the outcome after hyperthermic intraperitoneal
chemotherapy, an accredited treatment with new research protocols
(Derrien et al., 2015). The mice undergoing alpha-RIT outlived those
that were treated with chemotherapy (median survival 37.5 days).
Median survival rates for the RIT group could not be calculated as over
50% of mice were still alive after study completion (at 90 days).
4.5. Breast cancer lung metastases
The efficacy of the 225Ac and 90Y radiolabels were compared in a
mouse model of breast cancer metastases (Song et al., 2009). A single
administration of 225Ac (14.8 kBq)–labeled anti-rat HER-2/neu mono-
clonal antibody (7.16.4) completely eradicated breast cancer lung mi-
crometastases in ∼67% of HER-2/neu transgenic mice and led to long-
term survival of these mice for up to 1 year. 225Ac was significantly
more effective than the 90Y- (4.44 MBq; median survival of 50 days;
P < .001) as well as untreated control (median survival of 41 days;
P < .0001).
225
Ac treated metastases received a total dose of 9.6 Gy, sig-
nificantly higher than 2.0 Gy from 213Bi and 2.4 Gy from 90Y.
Biodistribution studies revealed that 225Ac daughters, 221Fr and 213Bi,
accumulated in kidneys and probably contributed to the long-term
renal toxicity observed in surviving mice. These data suggest 225Ac
labeled anti–HER-2/neu monoclonal antibody could significantly pro-
long survival in HER-2/neu–positive metastatic breast cancer patients.
4.6. Prostate cancer
A novel 213Bi-labeled peptide, DOTA-PEG4-bombesin (DOTA-PESIN)
was compared with 177Lu-labeled DOTA-PESIN in a human androgen-
independent prostate carcinoma xenograft model (PC-3 tumour) (Wild
et al., 2011). Animals were injected with 213Bi or 177Lu-DOTA-PESIN to
determine the MTD, biodistribution and dosimetry of each agent; con-
trols were left untreated or were given nonradioactive 175Lu-DOTA-
PESIN.
The MTD of 213Bi-DOTA-PESIN is 25 MBq (25.16 MBq) and for the
177
Lu conjugate is 112 MBq (111 MBq). Alpha therapy with 213Bi-
DOTA-PESIN was clearly superior to the treatment with 177Lu-DOTA-
PESIN at the MTD, although the tumour uptake was not significantly
different between the 2 tracers. 213Bi-DOTA-PESIN treatment resulted
in a highly significant increase in life span to 30 weeks when compared
with nontreated controls (P < .0004; log-rank test) and 177Lu-DOTA-
PESIN (P = .043). The median survival of animals treated with
4 × 28 MBq 177Lu-DOTA-PESIN was 12.9 weeks, which was not sig-
nificantly longer than that of untreated controls (P = 0.085). Both
177
Lu and 213Bi conjugates showed minimal to slight kidney damage
20–30 weeks post-treatment. These preclinical data indicate that α-RIT
is more efficacious than β-RIT. Furthermore, 213Bi-DOTA-PESIN
L. Marcu et al. Critical Reviews in Oncology / Hematology 123 (2018) 7–20

Table 3
in vivo studies directly comparing the efficacy and toxicity of α-RIT vs β-RIT.

Cancer type [ref] α-RIT β-RIT Observations Conclusion

Colon cancer (Behr 213

Bi-labeled CO-1A 90
Y-labeled CO-1A 90
Y more nephrotoxic. α-RIT is more effective than β-
213
et al., 1999) Fab′ (dose from 3.7 Fab′ (dose from 3.7 Bi-Fab′ was therapeutically superior to 90Y-Fab′ at RIT (tumour RBE is 2–3 fold
MBq) MBq) each dose. higher).
Neuro-endocrine 225
Ac-DOTATOC 177
Lu-DOTATOC Activities up to 20 kBq have no toxic effects in mice. α-RIT with 225Ac improves
(Miederer et al., (10–130 kBq) (450 kBq-2MBq) outcome compared with177Lu.
2008)
At 20 kBq, Ac reduced tumour growth more effectively
than Lu.
Multiple myeloma 213
Bi-labeled 9E7.4 Lu-labeled 9E7.4 Median survival with α-RIT compared to control: α-RIT superior to β-RIT in both
(Fichou et al., anti-CD138 mAb mAb (18.5 MBq) 80 days vs 37 days; 45% mice cured. tumour control and survival.
2015) (3.7 MBq)
Median survival with β-RIT com-pared to control:
54 days vs 37 days; no mice cured.
Breast cancer lung 225
Ac-7.16.4 anti-rat 90
Y-7.16.4 anti-rat 225
Ac completely eradicated lung micro-metastases in α-RIT markedly superior to β-
metastases HER-2/neu 14.8 kBq HER-2/neu 4.44 ∼67% of mice; with long-term survival up to 1 year. RIT in both tumour control and
(Song et al., 2009) MBq survival.
Significantly more effective than 90Y with median
survival 50 days; untreated controls had a median
survival of 41 days.
Prostate cancer (Wild 213
Bi-DOTA-PESIN 177
Lu-DOTA-PESIN LD40 at the MTD was ∼30 weeks for 225Ac vs 13 weeks α-RIT superior to β-RIT in
et al., 2011) 25 MBq 112 MBq for 177Lu. survival.
213 177
Peritoneal carcino- Bi-d9MAb 1.85 Lu-d9MAb 1.85 Comparable efficacy. But only 177Lu caused As 213Bi-RIT has no toxicity for
matosis (Seidl MBq Over MBq Over lymphoblastic lymphoma, proliferative the same efficacy, it is the
et al., 2011) 24 h = 2.05 MBq·h 24 h = 42.2 MBq·h glomerulonephritis and hepatocarcinoma. preferred treatment.

represents a new approach for use in peptide-receptor TAT for recurrent
prostate cancer.
4.7. Peritoneal carcinomatosis
Nude mice received intraperitoneal inoculation of HSC45-M2 gas-
tric cancer cells expressing d9-E-cadherin and were treated in-
traperitoneally 1 or 8 days later with different activities of specific
177
Lu-d9MAb immunoconjugates targeting d9-E-cadherin or with non-
specific 177Lu-d9MAb (Seidl et al., 2011). Therapeutic efficacy was
evaluated by monitoring survival for up to 250 days. For evaluation of
toxicity, both biodistribution of 177Lu-d9MAb and blood cell counts
were determined at different time points and organs were examined
histopathologically.
For similar therapeutic efficacies, the intraperitoneal injection re-
quired 825-times more 177Lu-RICs than 213Bi-RICs. Thus, one α-particle
was as cytotoxic as approximately 1000 β-particles. The markedly dif-
ferent half-lives cause the cumulative activity over 24 h post- admin-
istration of 1.85 MBq 177Lu to be 42.2 MBq·h and that for 213Bi to be
2.05 MBq·h.
Treatment on day 1 after tumour cell inoculation was more effective
than treatment on day 8, and specific 177Lu-d9MAb conjugates were
superior to nonspecific 177Lu-d8MAb. Treatment with 7.4 MBq of 177Lu-
d9MAb was most successful, with 90% of the animals surviving longer
than 250 days. However, treatment with therapeutically effective ac-
tivities of 177Lu-d9MAb was not free of toxic side effects. In some ani-
mals, lymphoblastic lymphoma, proliferative glomerulonephritis and
hepatocarcinoma were seen but were not observed after treatment with
213
Bi-d9MAb at comparable therapeutic efficacy. The therapeutic effi-
cacy of 177Lu-d9MAb is impaired by toxic side effects. Myelotoxicity
was observed after intraperitoneal administration of 177Lu-d9MAb as
lymphoblastic lymphoma in some animals. However, chronic myelo-
toxicity could never be observed following treatment of animals with
213
Bi-d9MAb. As therapy with 213Bid9MAb revealed comparable
therapeutic efficacy without toxicity, it should be preferred for the
treatment of peritoneal carcinomatosis.
Using 212Pb as an alpha emitter for the management of small vo-
lume peritoneal carcinomatosis, a comparison was undertaken between
internalizing anti-HER2 mAbs (trastuzumab) and non-internalizing
anti-CEA mAbs (35A7) in alpha-RIT (Boudousq et al., 2013). Athymic
nude mice bearing 2–3 mm tumour xenografts were intraperitoneally
injected with 370, 740 and 1480 kBq; 37 MBq/mg 212Pb-labeled 35A7,
trastuzumab or nonspecific mAbs, or with unlabeled mAbs/NaCl. The
results indicated that 212Pb-mAb RIT warrants further investigations as
a post-surgery adjuvant therapy in patients with peritoneal carcino-
matosis.
Promising results with 212Pb in tumour xenografts were obtained
when combining 212Pb-trastuzumab with paclitaxel in order to in-
vestigate the molecular basis of enhanced cell killing by alpha emit-
ters. Yong et al. have investigated the impact of targeted alpha therapy
on gene expression in a pre-clinical model for disseminated peritoneal
disease and observed that the alpha emitter-drug duo inhibits growth
arrest and suppresses proliferation through regulation of genes that are
involved in DNA damage repair and apoptosis (Yong et al., 2014).
Similar molecular mechanisms were identified when 212Pb-trastu-
zumab was administered in combination with gemcitabine, demon-
strating a great therapeutic potential in pre-clinical models (Yong
et al., 2016).
5. Clinical studies
5.1. Radioisotopes and maximum tolerance dose (MTD)
Radioisotopes used in clinical trials include, from short to long
range betas, are 177Lu, 131I, 188Re, 166Ho and 90Y. 177Lu emits a low
energy beta (150 keV) with an effective range of ∼ 300 μm (Gledhill,
1973). Alpha emitting radioisotopes and their respective half-lives are
211
At (7 h), 212Bi (60 min), 213Bi (67 min), 223Ra, 225Ac (10 d).

11
L. Marcu et al.
The linear energy transfer (LET) to targeted cancer cells from 177Lu
is only ∼0.5 keV/μm so cancer cell toxicity would also be very low. On
the other hand, 213Bi is an alpha emitting radioisotope with alpha en-
ergy of ∼8 MeV, a range of 80 μm and LET ∼100 keV/μm. This is 200
times the LET for 177Lu. This means that if 213Bi is used to label the
vector, then cancer cell cytotoxicity will be very much greater than for
177
Lu. Further, normal tissue exposure will be less because of the much
shorter range. However, the short half-life of 46 min compares with 6.7
d for Lu177 and argues against 213Bi infusion into established tumours.
225
Ac has a 10 day half-life with 4 alpha emissions. A comparative study
shows that on all aspects, 225Ac is equal or superior to 213Bi (Allen,
2017). Post-androgen deprivation therapy shows a nadir in PSA value.
At this stage tumour may be absent but cells insensitive to androgen
deprivation are present. This is the ideal time for targeted short range
and high LET alpha radiation to delay the onset of lethal castration
resistant prostate cancer.
While animal models offer some guidance regarding tolerance doses
for humans they cannot replace phase I trials. Toxicity may depend
both on the radioisotope and the character of the targeting vector
(murine or humanised). MTDs are given in terms of body weight, as-
sumed to be 70 kg in humans, when not stated. The MTD value reported
for 213Bi in humans is 37 MBq/kg (Jurcic et al., 2002). The long half-life
of 225Ac renders the injected activities to be lower than 213Bi by
570 kBq/kg (Kratochwil et al., 2015); 225Ac PSMA617 in humans with
metastatic CRPC: 100 kBq/kg per fraction (Kratochwil et al., 2016a),
and 225Ac lintuzumab in humans with relapsed/refractory AML:
111 kBq/kg (Jurcic et al., 2011).
5.2. Hematologic malignancies
The first clinical studies designed to target the CD33 antigen that is
expressed by most myeloid leukemias have used the murine M195 or
the humanised HuM195 antibody as anti-CD33 RI Scheinberg et al.
(1991) reported the first pilot trial using beta-RIT with 131I-M195 in 10
patients with AML (Scheinberg et al., 1991). While the study showed
rapid tumour targeting and internalization of 131I-M195 by the blasts,
no tumour control has been achieved with the trialed doses. Conse-
quently, a dose-escalation trial (1.85–7.7 GBq/m2) followed in 24 pa-
tients, showing sufficient depletion of leukemia in 8 patients to permit
bone marrow transplant (Schwartz et al., 1993).
Radiolabeled anti-CD45 mAb (CD45 antigen is expressed on all
leukocytes) has also been investigated in a number of trials, mainly in
combination with 131I. The first phase I trial using 131I-BC8 mAb in
combination with cyclophosphamide and 12 Gy total body irradiation
enrolled 44 patients with refractory AML or ALL, or myelodysplastic
syndrome (Matthews et al., 1999). Thirty-four patients received a
therapeutic dose of 131I-BC8 mAb that delivered an estimated absorbed
dose to the liver (the dose limiting organ) between 3.5 Gy and 12.25 Gy.
The maximum tolerated dose was 10.5 Gy. The radiation doses deliv-
ered to marrow were 2.3-fold greater than liver and spleen doses.
Disease free survival after a median of 65 months among the 25 AML
patients was 28%, while 3 out of 9 ALL patients presented with disease
free survival up to 66 months post-transplant (Matthews et al., 1999).
More recent studies support the evidence whereby 131I-anti-CD45
added to conventional treatment for acute AML improve survival
(Mawad et al., 2014). Furthermore, the promising results due to RIT has
stimulated the development of alpha-radiolabeled anti-CD45 mAb, with
the aim to further intensity treatment and diminish side effects.
188
Re and 90Y are two other beta-emitting radioisotopes tested for
RIT in conjugation with anti-CD66, the carcinoembryonic antigen ex-
pressed on granulocytes and epithelial cells. While the two radio-
isotopes have very similar ranges in tissue (2.4 mm vs 2.7 mm), yttrium
provides the higher bone marrow dose that results in the higher ther-
apeutic efficacy (Ringhoffer et al., 2005).
As already mentioned above, to overcome some of the limitations
imposed by beta-RIT (such as normal tissue toxicity and radiation risk
12
Critical Reviews in Oncology / Hematology 123 (2018) 7–20
for staff/family), alpha-emitting radioisotopes are seen to be more ap-
propriate for AML therapy.
The first clinical trial using targeted alpha therapy was designed for
acute myelogenous leukemia. Within the trial 18 patients with relapsed
and refractory acute or chronic myeloid leukemia were accrued and
treated with 213Bi-AIC of an anti-CD33 mAb (Jurcic et al., 2002). The
213
alpha-immunoconjugate Bi-CHX-A”-HuM195 (Bi-lintuzumab),
showed feasibility, safety and anti-leukemic activity in all patients.
Dose escalation from 10.36 to 37 MBq/kg of AIC was tested. It was
showed that alpha-immunoconjugate uptake by the leukemic cells oc-
curs within 5 min of systemic injection. While all 17 evaluable patients
developed myelosuppression, with 22 days median recovery time, no
significant extramedullary cytotoxicity was observed. Regarding tu-
mour control, 93% of patients showed reductions in circulating blasts
and 78% had reductions in bone marrow leukemic cells 7–10 days after
treatment.
Previous studies by the same group employing beta-emitting radio-
immunoconjugates (131I-M195, 131I-HuM195, 90Y-HuM195) allowed a
dosimetric comparison between the alpha- and beta-emitters (Caron
et al., 1994; Jurcic et al., 2000; Schwartz et al., 1993). It was showed
that the absorbed dose ratios between the bone marrow, liver, spleen
and the whole body were about 1000 times higher for 213Bi-HuM195
than for the beta emitters. This result was mainly due to the high target
dose and the considerably reduced whole body dose for 213Bi as com-
pared to 90Y and 131I.
While this first clinical trial using Bi-lintuzumab showed great po-
tential in tumour control, the large tumour burden (up to 1012 leukemia
cells) did not allow complete remission. Consequently, a phase I/II trial
was conducted at Memorial Sloan Kettering Cancer Center using partial
cyto-reduction with cytarabine followed by 18.5 MBq to 46.3 MBq per
kg of AIC. The dose limiting toxicity was myelosuppression, which set
the maximum tolerated dose to 37 MBq. Clinical response was achieved
in 24% of patients at doses ≥ 37 MBq/kg (Rosenblat et al., 2010).
These results confirmed the ability of 213Bi-lintuzumab to trigger re-
mission in patients with high-risk AML, therefore justifying the use of
alpha-emitting radioisotopes for hematological malignancies (see
Table 4).
The major shortcoming of Bi-lintuzumab is the short half-life of
213
Bi and the necessity for an on-site Bi generator. Since the efficacy of
alpha-RIT could be increased even more with longer lasting activity a
second generation RIT was developed represented by 225Ac. In addition
to its longer half-life (10 days), 225Ac emits 4 alpha particles with a
cytotoxicity 1000 times greater than the cytotoxic effect of 213Bi. To
investigate its clinical potential, a phase I trial that accrued 18 AML
patients was conducted (Jurcic et al., 2011). Doses delivered ranged
between 18.5–150 kBq/kg of 225Ac-lintuzumab, setting the maximum
tolerated dose to 110 kBq/kg. Peripheral blasts were eliminated in 63%
of patients, while reduction in bone marrow blast was achieved in 67%.
More studies are underway investigating the effect of fractionated
225
Ac-lintuzumab with low-dose cytarabine in previously untreated
older patients (Jurcic and Rosenblat, 2014).
RIT is a promising treatment for hematological malignancies.
Radiolabeled monoclonal antibodies are good candidates and the re-
sults of clinical studies warrant further research. While beta-RIT is
suitable for the treatment of large tumour burden, alpha-RIT has the
advantage of a more focused targeting which makes it ideal for isolated
tumour cells and residual disease (Bodet-Milin et al., 2016). The un-
biased advantage of alpha therapy could only be determined via a well-
designed large randomized clinical trial, comparing alpha-RIT with
beta-RIT labeled to the same targeting agent.
5.3. Metastatic melanoma
The first report of a clinical trial using RIT for metastatic melanoma
was published in 1985 (Larson et al., 1985). I-131 labeled Fab frag-
ments of the high molecular weight antigen (HMWA) (melanoma
L. Marcu et al. Critical Reviews in Oncology / Hematology 123 (2018) 7–20

Table 4
A compilation of representative beta-RIT and alpha-RIT trials for AML and ALL.

Trial/study Vector Target Conclusions/observations

Beta emitter
Phase I study for AML (Scheinberg et al., 1991) M195 CD33 antigen I-131 Rapid tumour targeting with 131I-M195 without complete response.
131
Phase I/II study for AML(Schwartz et al., 1993) M195 CD33 antigen I-131 I-M195 could be considered as a treatment alternative prior to
bone marrow transplant
131
Phase I study for AML or ALL (Matthews et al., 1999) BC8 mAb CD45 antigen I-131 I-BC8 mAb for advanced AML/ALL was feasible, safe and
warranted further investigations.
Phase I/II study for AML or ALL (Ringhoffer et al., anti-CD66 CD66 antigen Y-90 Overall survival at 12 months – 70%; at 30 months 17%. Higher
2005) Re-188 relapse rate in the rhenium group.

Alpha emitter
Phase I study for AML (Jurcic et al., 2002) MAb lintuzumab CD33 antigen Bi-213 Bi-lintuzumab was shown to be safe, feasible and efficient therapy.
Phase II study for post-chemotherapy of AML MAb lintuzumab CD33 antigen Bi-213 One quarter of patients achieved clinical response, without
(Rosenblat et al., 2010) significant toxicity.
Phase I study for AML (Jurcic et al., 2011; Jurcic and MAb lintuzumab CD33 antigen Ac-225 Ongoing trial
Rosenblat, 2014) Clinical trial NCT01756677 (2015)

Table 5
A compilation of representative beta-RIT and alpha-RIT trials for metastatic melanoma.

Trial/study Vector Target Conclusions/observations

Beta emitter
131
Phase I trial for metastatic melanoma (Larson anti-HMWA HMWA I-131 I-HMWA showed good tumour localization; larger doses resulted in > 50% tumour
et al., 1985) Fab reduction and disease stabilization for 3 months.
188
Phase I trial for metastatic melanoma (Klein MAb 6D2 melanin Re-188 Re-6D2 treatment for advanced metastatic melanoma patients resulted in median
et al., 2013) overall survival of 13 months with no dose-limiting toxicities.

Alpha
emitter
213
Phase I trial for intralesional melanoma cDTPA-9.2.27 MCSP Bi-213 Bi-cDTPA-9.2.27 is an efficient agent without added normal tissue toxicity. Further
(Allen et al., 2005) studies are warranted.
213
Phase I trial of systemic melanoma (Allen cDTPA-9.2.27 MCSP Bi-213 Bi-cDTPA-9.2.27 showed very good response in a select group of patients. There was
et al., 2011; Raja et al., 2007) no evidence of a dose dependence. Several tumour-related factors might influence
response to alpha-RIT, thus more studies are needed.

−associated proteoglycan) was used in the trial that enrolled 10 pa-
tients. The administered doses ranged from 185 MBq to 481 MBq. All
patients with lesions greater than 1 cm showed good localization of the
agent is one or more lesions. The patient receiving the highest dose
showed a greater than 50% reduction in tumour size as well as disease
stabilization for a three-month time period. Despite these promising
results, RIT was not pursued for the treatment of unresectable mela-
nomas until more recently (Table 5).
A novel approach to beta-RIT of metastatic melanoma is by means
of melanin targeting with radiolabeled monoclonal antibodies (such as
6D2 mAb). Experiments with tumour-bearing nude mice showed some
therapeutic effect without significant toxicities with 166Ho-6D2 and
188
Re-6D2, but not with 90Y (Dadachova et al., 2008; Thompson et al.,
2014). The results of two open-label phase I trials investigating safety
and efficacy of 188Re-6D2 showed good tolerance and tumour activity
(Klein et al., 2013). Beside pharmacokinetics, safety and antitumour
activity, the first phase I trial (phase Ia, 13 patients) aimed to determine
the effect of unlabeled mAb on biodistribution of 188Re-6D2, whereas
phase Ib (7 patients) investigated the effect of dose escalation. The fast
clearance and relative short half-life of Re (17 h) resulted in good tol-
erability with maximum doses delivered (3.7 GBq). Median survival
was about 13 months, which is longer than the median 8.5 months after
standard melanoma treatment. These results warrant further in-
vestigations with 166Ho-6D2 and 188Re-6D2.
Targeted alpha therapy for intralesional metastatic melanoma was
aimed to establish a new systemic therapy for this neoplasm. The alpha-
immunoconjugate designed for this treatment was 213Bi-cDTPA-9.2.27,
exhibiting 120 times greater cytotoxicity to melanoma cells than beta-
emitting radioisotopes (Allen et al., 2001; Rizvi et al., 2000). The 9.2.27
mAb is specific for the 250 kDa cell-surface antigen, human melanoma
chondroitin sulphate proteoglycan (MCSP), antigen that is expressed in
over 90% of melanoma cells lines (Bumol and Reisfeld, 1982). The first
human trial investigating this agent enrolled 16 patients with meta-
static skin melanoma that were positive to the monoclonal antibody
9.2.27 (Allen et al., 2005). Intralesional TAT was found to be efficient at
a dose of 22 MBq and safe up to 50 MBq. As shown by melanoma in-
hibiting activity, apoptosis and Ki67 proliferation marker tests 213Bi-
cDTPA-9.2.27 is a promising agent in the management of unresectable
secondary melanomas.
The same alpha-immunoconjugate was employed for the treatment
of metastatic melanoma based on a single bolus intravenous TAT in-
jection. The open-labeled phase I dose escalation trial aimed to estab-
lish the effective dose of 213Bi-cDTPA-9.2.27 in a group of 38 patients,
treated with doses ranging from 46 MBq to 925 MBq (Allen et al., 2011;
Raja et al., 2007). Both superficial and internal lesion regression have
been achieved at fairly low activities, from 148 to 259 MBq. Median
survival time for patients with stable disease or partial response (10% of
patients) was 612 days, significantly higher than the median survival
time of 266 days among the overall study population (Allen et al.,
2011). Since there were no adverse events, the maximum tolerated dose
was not achieved in this trial. While among the responders the results
were above expectations, only a small fraction of patients showed po-
sitive outcome. This might be due to several factors such as tumour size,
variations of the vascular structures, size and frequency of fenestrations
and also the expression of targeted receptors. However, tumour anti-
vascular alpha therapy (TAVAT) is considered to be the main re-
sponsible factor for the positive results obtained in the small group of
patients (Allen et al., 2007).
5.4. Bone metastases
Bone metastasis is still a clinical challenge in prostate and breast
cancer and has a significant impact on the quality of life. While there is
no conclusive therapy to control bone metastasis, bone-seeking

13
L. Marcu et al.
Table 6
A compilation of representative beta-RIT and alpha-RIT trials for bone metastases.
Trial/study
Phase II randomized trial in advanced androgen-independent prostate cancer (Tu
et al., 2001)
Phase III trial comparing the effect of 89Sr vs external beam radiotherapy for bone
metastasis of hormone-resistant prostate cancer (Porter et al., 1993)
Phase III trial comparing the effect of 89Sr vs external beam radiotherapy in
metastatic prostate cancer (Quilty et al., 1994)
Phase III trial comparing the effect of 89Sr vs external beam radiotherapy for bone
metastasis of hormone-resistant prostate cancer (Oosterhof et al., 2003)
Phase III randomized trial for bone metastasis (Serafini et al., 1998)
Phase I/II trial for bone metastases (Nilsson et al., 2007; Nilsson et al., 2005)
Phase III trial for prostate cancer and symptomatic bone metastases with or without
previous docetaxel (ASYMPCA trial) (Hoskin et al., 2014; Sartor et al., 2014)
Phase I: Safety, biodistribution, radiation dosimetry and pharmacokinetics study of
BAY88-8223 in Japanese patients (Yoshida et al., 2016)
Phase III: Asian population study in the treatment of CRPC patients with bone
metastasis (completion 2016)
Phase I/II: Re-treatment safety of Ra-223 dichloride in CRPC with bone metastases
(completion 2017)
Randomized open-label phase II study evaluating the efficacy/safety of Ra-223 in
combination with abiraterone acetate or enzalutamide in patients with CRPC
and bone metastases (completion 2022)
radioisotopes, both beta and alpha emitters, are under clinical in-
vestigation. Of the beta-emitting radioisotopes, 89Sr and 153Sm have
been widely investigated and approved for palliative treatment.
Nevertheless, the results of phase II/III trials conducted to date are
inconclusive, as while some failed to demonstrate improvement in
progression-free or overall survival (Oosterhof et al., 2003; Porter et al.,
1993; Quilty et al., 1994), others showed higher effectiveness in the
radionuclide arm (Oosterhof et al., 2003; Porter et al., 1993; Quilty
et al., 1994; Tu et al., 2001). Nevertheless, the vast majority of these
trials showed some improvement in the quality of life through pain
palliation (see main conclusions in Table 6).
As a calcium mimetic, the bone-seeking alpha emitter, 223Ra was
shown to have potential for palliating cancer patients affected by bone
metastases. Nilsson et al. (2005) reported on the first clinical experience
with radium-223 within a phase I trial that enrolled 15 hormone re-
fractory prostate cancer patients and 10 breast cancer patients, with
bone metastasis (Nilsson et al., 2005). The aim of the trial was to assess
the safety and tolerability of 223Ra and also to evaluate pain palliation.
Radium was well tolerated within the administered range (50–250 kBq/
kg). Treatment efficacy was confirmed by the significant reduction in
serum alkaline phosphatase (ALP) and improved pain control, with pain
relief reported by 52%, 60%, and 56% of patients after 7 days, 4 weeks
and 8 weeks, respectively. Side effects were acceptable without dose
limiting toxicity. Further investigations followed driven by the positive
results. Thus, a randomized, double blind, placebo controlled, multi-
centre phase II study examined the effect of multiple doses of Ra-223 in
patients with hormone-refractory prostate cancer (Nilsson et al., 2007).
Similar end-points were set as in the previous phase I trial, such as the
reduction in bone-specific alkaline phosphatase concentration and also
time to occurrence of skeletal-related events.
The trial enrolled 64 patients needing external beam radiotherapy,
Critical Reviews in Oncology / Hematology 123 (2018) 7–20
Conclusions/observations
Beta
emitter
Sr-89 Patients randomized to receive doxorubicin with/without 89Sr. Median
survival in the 89Sr group was 27.7 months vs 16.8 months of chemo-only
group.
Sr-89 No significant difference in overall survival or pain relief at the index site.
Progression of pain as measured by sites of new pain showed better outcome
in the 89Sr arm. Quality of life analysis showed superiority of strontium in
pain relief.
Sr-89 There was no significant difference in median survival. Both treatment
provided pain relief sustained to 3 months in 63.6% after radiotherapy and
66.1% after 89Sr.
Sr-89 89
Sr vs palliative local field radiotherapy showed a borderline statistically
significant difference in overall survival for the radiotherapy group. No
difference in progression-free survival or toxicity.
Sm-153 Double-blind placebo-controlled trial of 153Sm-EDTMP in patients with bone
metastasis. Significant pain relief observed in the Sm group in up to 72%
patients during the first 4 weeks. Mild bone marrow suppression.
Alpha
emitter
Ra-223 Median relative change in bone-ALP was −66% in the 223Ra group vs 9.3% in
the placebo group. Median overall survival was 65 weeks for 223Ra vs 46
weeks for placebo. No significant Ra-induced toxicity.
Ra-223 High efficacy of radium. Median overall survival of patients treated with
223
Ra was 14.9 months as compared with the 11.3 months of the placebo
group.
Ra-223 Initial bone uptake was 52%, with maximum activity of Ra in the bone within
2 h of injection and no signs of activity in other organs.
Ra-223 Ongoing trial
Clinical trial NCT01810770 (2013)
Ra-223 Ongoing trial
Clinical trial NCT01934790 (2013)
Ra-223 Ongoing trial
Clinical trial NCT02034552 (2013)
of which 33 were assigned to receive four intravenous injections of
223
Ra every four weeks, with an activity of 50 kBq/kg. Patients were
monitored for survival and long term toxicity over 24 months. The
223
Ra group had significant reductions in all five markers of bone for-
mation and bone balance such as bone-ALP, total-ALP, serum type 1
procollagen, collagen fragment CTX-1 and ICTP. Also, substantial dif-
ferences were observed with changes in PSA from baseline to 4 weeks,
PSA decreasing by 24% in the 223Ra group and increasing by 45% in the
placebo group. Median time to PSA progression was 26 weeks for 223Ra
vs 8 weeks for placebo (P = .04). Treatment with 223Ra was well tol-
erated and no patients discontinued treatment.
The success of the phase II trial has encouraged the wider use of
223
Ra. Therefore, Radium-223 dichloride (Xofigo®) has recently been
approved for the treatment of castration-resistant prostate cancer
(CRPC) patients with symptomatic bone metastases, due to its effi-
ciency in bone-targeting and increased patient survival (Nilsson, 2014).
The Alpharadin in Symptomatic Prostate Cancer Patients
(ALSYMPCA) is a large, multicenter, randomized, double-blind, pla-
cebo-controlled trial targeting CRPC patients which enrolled 921 pa-
tients with bone metastases (Hoskin et al., 2014; Parker et al., 2013;
Sartor et al., 2014). Prior randomization, patients were stratified as a
function of: baseline ALP, previous/no use of docetaxel and current/no
use of a bisphosphonate. Treatment with 223Ra consisted of 6 in-
travenous injections at 4-week intervals delivering a dose of 50 kBq/kg.
The primary endpoint was overall survival, whereas the main sec-
ondary endpoints targeted the changes in biomarker levels for PSA and
ALP as well as the symptomatic bone-related effects. The results of the
ALSYMPCA trial confirmed the high efficacy of radium as indicated by
previous phase I/II trials. The median overall survival of patients
treated with 223Ra was 14.9 months as compared with the 11.3 months
of the placebo group (HR = 0.70, 95% CI). Additionally, the time delay
14
L. Marcu et al.
to an increase in ALP level in the 223Ra group was 7.4 months compared
with the placebo group that had only 3.8 months (HR = 0.17, 95% CI)
(Hoskin 2014). Overall radium-223 was found to be effective and safe
in patients with CRPC and symptomatic bone metastases.
The positive clinical outcome of the previous trials led to the design
of several studies with 223Ra. Table 6 is a compilation of the completed
and ongoing worldwide trials in patients with CRPC and bone metas-
tases.
5.5. Ovarian carcinoma
Several beta-emitters have been investigated in the past for in-
traperitoneal administration in ovarian cancer patients, such as 90Y,
131
I, 177Lu, some with promising results (Epenetos et al., 2000;
Rosenblum et al., 1999). However, a large, multinational randomized
phase III trial for epithelial ovarian cancer that aimed to compare Y-90
labeled murine HMFG1 administered with standard therapy versus
standard treatment alone showed neither survival benefit nor extension
of time to relapse from the addition of 90Y-based radio-immunotherapy
(Verheijen et al., 2006). These results are partly due to the biophysical
properties of beta-emitting isotopes, as their long range in tissue led to
suboptimal irradiation of tumour clusters to eradicate micrometastases,
and also due to the half-life which is long enough (64 h) to result in
normal tissue damage (red marrow irradiation). Given the failure of
beta-RIT in treating residual cell clusters, alpha-emitting radioisotopes
are under clinical investigation, due to their promising results in vitro.
A phase I trial reported by Andersson et al. (2009) employed 211At
labeled to MX35 F(ab’)2 for recurrent ovarian carcinoma in 9 patients
with the aim to assess pharmacokinetics, dosimetry and tolerance doses
(Andersson et al., 2009). The highest agent concentration administered
was 100 MBq/L. The median follow-up was 23 months, during which
no late toxicities were recorded. While the bone marrow is the main
dose limiting organ in RIT, the largest absorbed dose measured was
0.01 Gy, thus about 2.5% of the estimated tolerable dose. Three patients
remained in clinical remission during the follow-up period.
Next to 211At, there is a growing interest towards the clinical po-
tential of 212Pb (Table 7), the parental radionuclide of 212Bi, which has
a more optimal half-life for RIT application (10.6 h vs 61 min).
Meredith et al. (2014) reported the results of a Phase I trial that in-
cluded three ovarian cancer patients after failing all prior therapies
(Meredith et al., 2014). Patients were treated with 212Pb-TCMC-tras-
tuzumab that accumulated preferentially inside the peritoneal cavity, as
showed by imaging studies. Patient follow-up (> 6 months) showed no
treatment-related side effects, which correlates with the good phar-
macokinetic and dosimetric results. The results justified the accrual of a
larger number of patients to be treated with 212Pb-based RIT. A recent
report by the same group has shown the successful administration of
212
Pb-TCMC-trastuzumab in 18 patients that were monitored for safety
and outcome for a year (Meredith et al., 2016). Six dose levels were
studied starting from 7.4 MBq/m up to 27.4 MBq/m which was con-
sidered the upper safety limit. There were no late renal, liver or cardiac
toxicities reported. Tumour marker studies showed a reduction in
Table 7
A compilation of representative beta-RIT and alpha-RIT trials for ovarian carcinomas.
Trial/study Vector
Phase III trial of intraperitoneal therapy with beta-RIT with/ muHMFG1
without standard treatment (Verheijen et al., 2006)
Phase I trial of intraperitoneal TAT for ovarian cancer MX35 F(ab’)2
(Andersson et al., 2009)
Phase I trial of intraperitoneal TAT for ovarian cancer TCMC-trastuzumab
(Meredith et al., 2014)
Critical Reviews in Oncology / Hematology 123 (2018) 7–20
tumour-associated glycoprotein 72 and tumour growth with increasing
radioactivity administered.
5.6. Glioma/glioblastoma (GBM)
A highly targeted treatment approach implemented over the last
couple of decades in order to increase local tumour control in malignant
brain tumours with poor prognosis is the administration of radiolabeled
monoclonal antibodies into the surgically resected cavity. In this way,
local irradiation of the residual cancer cells by means of beta- or alpha-
RIT can potentially increase response rate and survival (Table 8).
Beta-RIT has been trialed in the late 1990s using 131I or 90Y labeled
to anti-tenascin mAb (Bigner et al., 1998; Riva et al., 1999). Tenascin is
a glycoprotein overexpressed in gliomas and glioblastomas, that in-
creases in level with advancing tumour grade (Leins et al., 2003) thus
can serve as a target in malignant brain tumours.
In a phase I trial of previously irradiated patients with recurrent or
metastatic brain tumours, 131I-labeled anti-tenascin monoclonal anti-
body 81C6 was administered in 34 patients, with doses up to 4.4 GBq
(Bigner et al., 1998). The maximum tolerated dose was reached at 3.7
GBq. Dose-limiting toxicity occurred in the form of neurologic and
hematologic toxicity. The estimated median survival for glioblastoma
patients was 56 weeks. The same beta-RIT was administered within a
phase II trial that accrued 33 previously untreated patients with ma-
lignant glioma (Reardon et al., 2002). Median survival was longer than
in the previously reported phase I trial (Bigner et al., 1998) (Bigner
1998): 79.4 and 86.7 weeks for GBM and all patients, respectively. On
third of patients remained alive at a median follow-up of 93 weeks.
Toxicity was mainly reversible, though one patient required reopera-
tion for radionecrosis (Reardon et al., 2002).
Twenty previously treated patients with high-grade malignant
glioma were administered 90Y-labeled Mab conjugates (BC-4, a te-
nascin-affine murine MAb) within a phase I clinical trial (Riva et al.,
1999). Dose escalation from 185 to 1110 MBq was performed and the
maximum tolerated dose was determined to be 925 MBq. The agent
showed a good biodistribution in the tumour area, without any diffu-
sion into the normal brain or healthy organs. Due to the advanced
stages of all patients, there was no clinical response recorded in this
trial.
The first clinical trial using an alpha-immunoconjugate injection
into the surgically resected cavity for recurrent brain malignancies,
employed 211At-human antimouse chimeric anti-tenascin mAb 81C6
(Zalutsky et al., 2008). The activities used ranged from 74 to 347 MBq,
however the maximum tolerated dose was not reached. The median
survival for glioblastoma patients was 52 weeks as compared to 23
weeks for a placebo group. While no patient experienced dose-limiting
toxicity, 6 of 17 patients developed grade 2 neurotoxicity. Despite the
fact that the normal liver and spleen have high levels of tenascin, there
was no measurable 211At uptake outside the treated area. Overall, local
administration of 211At-ch81C6 was found to be safe and efficacious.
Another alpha-emitting radioisotope that has been recently trialed
in recurrent GBM patients is 213Bi-213 (Morgenstern et al., 2014).
Target Conclusions/observations
Beta emitter
90
MUC1 Y-90 Y-muHMFG1 did not extend patient survival
Alpha
emitter
NaPi2b At-211 Administration of 211At-MX35 F(ab’)2 allows good tumour uptake
in order to achieve therapeutic doses without significant toxicities.
Her2 Pb-212 Very good accumulation in tumour. No side effects. Has potential
for increased therapeutic ratio as compared to beta-RIT.
15
L. Marcu et al. Critical Reviews in Oncology / Hematology 123 (2018) 7–20

Table 8
A compilation of representative beta-RIT and alpha-RIT trials for recurrent brain malignancies.

Trial/study Vector Target Conclusions/observations

Beta emitter
131
Phase I trial of recurrent malignant gliomas Mab 81C6 tenascin I-131 I-labeled 81C6 seems safe and feasible for patients refractory to other therapies.
(Bigner et al., 1998) Median survival for GBM was 56 weeks and for all patients was 60 weeks.
131
Phase II trial in newly diagnosed malignant MAb 81C6 tenascin I-131 I-labeled 81C6 administered to previously untreated glioma patients resulted in a
gliomas (Reardon et al., 2002) 86.7 weeks median survival for all patients and 79.4 weeks for GBM patients. One
patient (3%) patients developed radionecrosis.
Phase I trial of high-grade malignant gliomas (Riva MAb tenascin Y-90 Good biodistribution, without any diffusion into normal tissues. No systemic toxicity.
et al., 1999) Clinical response was not recorded due to very advanced disease stage.

Alpha
emitter
211
Phase I trial of recurrent brain malignancies (74% MAb 81C6 tenascin At-211 At-ch81C6 was found to be feasible, safe and with promising antitumour activity. 2
glioblastoma) (Zalutsky et al., 2008) of 14 glioblastoma patients survived for nearly 3 years after alpha-RIT. No
radionecrosis was observed.
Pilot trial of glioma (Cordier et al., 2010) DOTA-SP NK1R Bi-213 Critically located gliomas were treated with 213Bi-DOTA-substance P for which 90Y
was not suitable due to long range. Well localised and tolerated treatment, without
additional neurotoxicity.
Pilot trial of glioblastoma (Morgenstern et al., DOTA-SP NK1R Bi-213 The first clinical study using 213Bi-SP for recurrent GBM. Median survival was 18
2014) months compared to 15 months with standard therapy. Safe treatment.

Patients were treated via intracavitary or intratumoral delivery of 213Bi- 177

labeled DOTA-substance P (213Bi-SP) with a maximum dose of 11 GBq
delivered in 2 GBq fractions. The peptide carrier substance P targets NK
1 receptors that are overexpressed on GMB cells, thus they represent a
good therapeutic target. The median survival of the 20 evaluable pa-
tients was 18 months as compared to 15 months after standard therapy
alone. There was no significant normal tissue toxicity. Although the
patient group enrolled in the trial was small to state definite conclu-
sions, a possible dose-response effect was observed, since those patients
that received multiple doses of 213Bi-SP showed better tumour control.
The neurokinin type-1 receptor (NK1R) which is overexpressed in
primary malignant gliomas could potentially be used as a target for the
treatment of glial brain tumours. A novel targeting vector was devel-
oped in this sense at the University of Basel, in the form of a diffusible
peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-
triacetic acid-substance P (DOTAGA) (Kneifel et al., 2006). A clinical
pilot study was designed to assess biodistribution, short and long-term
toxicity, as well as clinical and radiological responses in 20 patients
with grade 2–4 gliomas. Radio-conjugates were prepared with the high
energy beta emitter 90Y, the low energy beta emitter 177Lu and the high
energy alpha emitter 213Bi. Injected activities into the resection cavity
ranged from 2.25 to 7.5 GBq for 90Y, 1.125-6.375 GBq for 177Lu and
375–825 MBq for 213Bi. The outcome in all cases was positive and
without significant toxicity. For invasive tumour cells beyond visible
tumour margins alpha-RIT may be best suited (Kneifel et al., 2006).
One shortcoming of 90Y beta radiation is the relatively large range
in tissue (maximum of 12 mm), which could produce collateral damage
to the normal brain. This outcome could be overcome by the use of
Lu (beta range 1.5 mm) and 213Bi (alpha range 80 μm). In a pilot trial
reported by Cordier et al. (2010), 213Bi has been tested for functionally
critically located gliomas that are not eligible for standard treatment
(Cordier et al., 2010). 213Bi-DOTA-SP was locally injected in 5 patients
with grade 2–4 gliomas and, without local or systemic toxicity. The
study showed that alpha-RIT with 213Bi is safe, and might have the
great advantage to allow post-treatment resection for otherwise un-
resectable gliomas.
While beta-RIT studies show promising results in recurrent brain
malignancies, alpha-RIT has important physical and radiobiological
advantages. Given that brain malignancies are usually hypoxic, the
oxygen enhancement ratio of nearly 1 for alpha-emitters show a
minimal dependence on the oxygenation status which leads to efficient
cell kill in a hypoxic environment.
5.7. Neuroendocrine tumours
Neuroendocrine tumours express somatostatin receptors that enable
targeting with high affinity peptides. Radiopeptides that target soma-
tostatin receptors in these tumours have therefore been investigated
over the last decade. Most commonly, octreotide analogue peptides
(DOTATOC, DOTATATE) are labeled with beta emitters such as 90Y or
177
Lu, and show clinical response in up to 30% of patients
(Kwekkeboom et al., 2008; Waldherr et al., 2001).
Based on the promising results obtained in a phase II trial (Waldherr
et al., 2001) (see Table 9), the Swiss group has extended the in-
vestigations with 90Y DOTATOC on 116 patients with metastatic neu-
roendocrine tumours. Patients were treated with 5.9–7.4 GBq/m2 body

Table 9
A compilation of representative beta-RIT and alpha-RIT trials for neuroendocrine tumours.

Trial/study Vector Target Conclusions/observations

Beta
emitter
90
Phase II trial in neuroendocrine tumours DOTATOC Somatostatin Y-90 Y-Dotatoc led to 24% overall response rate, with complete remission rate of
(Waldherr et al., 2001) receptor 2%. Well tolerated treatment.
Phase III randomized trial for midgut DOTATATE Somatostatin Lu-177 The estimated rate of progression free survival at 20 months was 65.2% vs
neuroendocrine tumours (Strosberg et al., receptor 10.8% for the trial arm treated with 177Lu-Dotatate vs control group
2017) (octreotide alone). Manageable toxicity.

Alpha
emitter
Phase I trial in neuroendocrine tumours DOTATOC Somatostatin Bi-213 The first study with 213Bi-DOTATOC in patients refractory to 90Y/177Lu-
(Kratochwil et al., 2014) receptor DOTATOC showed good stability and pharmacokinetics leading to high
efficacy. Good treatment tolerability without kidney failure.

16
L. Marcu et al.
surface. Significant symptom reduction was achieved in 83% of pa-
tients, with complete remission in 4%, partial remission in 23% and
stabilization in 62% (Forrer et al., 2006).
Kwekkeboom et al. (2008) reported on treatment efficacy and
toxicity with 177Lu-octreotate in 504 patients. Treatment efficacy was
assessable in 310 patients. Among these, tumour response rate, in-
cluding complete, partial and minimal response was 46%
(Kwekkeboom et al., 2008). The most common acute adverse events
were nausea (25% patients), vomiting (10%), abdominal pain or dis-
comfort (10%), temporary hair loss (62%). Serious delayed toxicities,
such as liver or renal toxicity were rare.
An interim report of a phase III randomized trial enrolling 229 pa-
tients with midgut neuroendocrine tumours which employed
177
Lu-DOTATATE (7.4 GBq every 8 weeks in 4 cycles) vs octreotide
alone showed significantly higher response rate (18% vs 3%) and longer
progression-free survival (65.2% vs 10.8% at 20 months) in the
177
Lu-DOTATATE arm (Strosberg et al., 2017). While the control arm
experienced no hematological toxicities, in the beta-RIT group these
side effects occurred in about 10% of patients. There was no evidence of
renal toxicity during the reported follow-up period. While these pre-
liminary results clearly show a survival benefit with 177Lu-DOTATATE,
a confirmation will be required by the final trial report.
A critical aspect that has been demonstrated in regards to the
therapeutic effects of radiolabelled DOTATOC concerns the improved
tumour to non-tumour uptake achieved after intra-arterial administra-
tion in liver metastatic neuroendocrine tumours (Kratochwil et al.,
2011). Nevertheless, this approach has a shortcoming, as patients with
recurrences are usually refractory to further treatment with beta ra-
diation therapy.
Perhaps one of the greatest advantages of alpha-RIT for neu-
roendocrine tumours consist of its success in overcoming beta re-
sistance, as an additional treatment line.
The first human study with alpha-RIT was reported by Kratochwil
et al. (2014) and employed 213Bi-DOTATOC in seven patients with
progressive advanced neuroendocrine liver metastases, which was re-
fractory to treatment with 90Y/177Lu-DOTATOC beta emitters. 213Bi-
DOTATOC was given in increasing activities in cycles every 2 months
(between 1 and 4 GBq/cycle). Both chronic kidney toxicity and acute
hematotoxicity were moderate, and even less pronounced than with the
preceding beta therapies. The duration of tumour control with the
earlier 90Y or 177Lu-DOTATOC therapy was up to 3 years and the
follow-up in patients receiving 213Bi-DOTATOC was reported to be 2
years (Kratochwil et al., 2014).
Apart from the physical advantages of alpha-emitting isotopes, the
molecular mechanisms of tumour damage linked to TAT seem to be an
added reason for their success. A recent study aimed to compare the
alpha-emitting 225Ac- and beta emitter 177Lu-labeled somatostatin
analogue DOTATOC regarding DNA damage induction and the level of
cell death (Graf et al., 2014). The group determined the level of γH2AX
as an indicator of DNA double-strand breaks and apoptosis in a neu-
roendocrine cell line. Tumours treated with 225Ac-DOTATOC (40 kBq)
showed a higher fraction of cells with γH2AX foci than those treated
with 177Lu-DOTATOC (30 MBq). The comparative cytotoxicity analysis
between the two agents resulted in a factor of 700, which translates into
a radiobiological effectiveness of about 5 (Graf et al., 2014).
5.8. Radio-immunotherapy for castrate resistant prostate cancer (CRPC)
An important development in prostate cancer therapy has been the
completion of a phase 2 trial of radio-immunotherapy for CRPC patients
using a single dose of the 177Lu-J591 conjugate (Akhtar et al., 2012;
Tagawa et al., 2010; Tagawa et al., 2013). The monoclonal antibody
J591 (Ananias et al., 2009; Bostwick et al., 1998; Mannweiler et al.,
2009) targets an epitope on the prostate specific membrane antigen
(PSMA), which is an integral cell-surface membrane protein expressed
by most prostate cancer cells.
17
Critical Reviews in Oncology / Hematology 123 (2018) 7–20
PSMA expression increases progressively in higher-grade cancers,
metastatic and castration-resistant disease (Bostwick et al., 1998; Israeli
et al., 1993, 1994; Sweat et al., 1998; Wright et al., 1996). Although
first thought to be prostate-specific (Israeli et al., 1993), PSMA ex-
pression has been identified in cells of the small intestine, proximal
renal tubules and salivary glands (Troyer et al., 1995), albeit at levels
100–1000-fold than in tumours (Sokoloff et al., 2000). PSMA is ex-
pressed in most prostate tumours and associated neovasculature, but
not on normal vasculature (Chang et al., 1999). This makes it the ideal
target for TAT, where alpha radiation with its short range has far
greater endothelial cell toxicity, compared to beta radiation, within the
dose tolerance restriction (Allen et al., 2007; Huang et al., 2012).
The humanised J591 antibody demonstrates high-affinity binding to
PSMA-expressing cells in culture and is rapidly internalized (Liu et al.,
1997, 1998). J591 demonstrates excellent specificity for prostate
cancer xenografts (LNCaP) in mice and for prostate tumours in human.
PSMA is further upregulated in LNCaP xenografts following MDV3100
androgen deprivation therapy (ADT), making PSMA the ideal target
post-ADT Moreover, PET (89Zr-J591) can be used effectively for se-
quential monitoring of xenograft growth and regression, using 89Zr-
J591 before and after androgen deprivation (Holland et al., 2010). The
J591 antibody against PSMA demonstrates excellent specificity in the
clinic for prostate cancer metastases in humans.
177
Lu emits a low energy beta (150 keV) with an effective range of
∼300 μm (Gledhill, 1973). The trial achieved major decreases in PSA
for 67% of subjects, with survival time almost doubling from 12 to 22
months at the maximum tolerance dose of 2.6 GBq/m2. Overall, a single
dose of 177Lu-J591 was efficacious and well tolerated with reversible
myelosuppression.
These results are at the limits of adverse events and do not allow
higher activities to be administered. Alpha therapy is expected to be
more efficacious within the tolerance dose. The alpha emitter 213Bi-
J591 AIC has been tested successfully in vitro and in vivo (Li et al.,
2002b), but not in clinical trial. However, alpha and beta RICs have
been compared in CRPC patients using the PSMA617 ligand as the
targeting vector (Table 10).
5.8.1. 68Ga-PSMA-617
Patients with at least 1 lesion suspected of being a prostate cancer
tumour were injected with this conjugate (Afshar-Oromieh et al.,
2015). At 3 h post-injection, the kidneys and salivary glands showed the
highest uptake in 14 of 19 patients (74%) of the 53 representative tu-
mour lesions at 3 h post-injection. The mean tumour-to-background
ratio for maximum standardized uptake value was 20 ± 17 (range,
2.3–84) at 1 h post-injection and 38 ± 39 (range, 3.6–154) at 3 h post-
injection. 68Ga-PSMA-617 shows lesions with high contrast. Images
obtained between 2 and 3 h after injection seem to be the best option
for radiotracer uptake and tumour contrast.
5.8.2. 225Ac vs 177Lu-PSMA-617
The Heidelberg trial began in 2014 for prostate cancer patients
using either 225Ac or 177Lu labeled PSMA ligand (PSMA617) with pre &
post-PSMA imaging with 68Ga. 50 patients were administered 130
therapies. This trial is ongoing, but early results show superior efficacy
for 225Ac, for which several patients are achieving complete remission,
some of whom had PSA values > 3000 ng/ml (Kratochwil et al.,
2016a,b).
Patients are stratified for treatment with those with the worst
prognosis, e.g. bone marrow involvement, visceral and bone metas-
tases, being assigned to the 225Ac group, while the better patients pri-
marily received 177Lu-PSMA.
The most significant adverse response was xerostomia. The salivary
glands express this PSMA epitope, with 225Ac causing more damage
than 177Lu. This is a serious and incurable effect, and tends to rule out
the use of 225Ac for earlier applications, such as pre-hormonal therapy.
This glandular damage is reduced with 177Lu, but so is the cytotoxicity
L. Marcu et al.
Table 10
Summary of beta-RIT and alpha-RIT trials for CRPC.
Trial/study Vector Target
Phase 2 for CRPC (Akhtar et al., 2012; J591 PSMA
Tagawa et al., 2010; Tagawa et al.,
2013)
Completed
Phase 2 for CRPC (Kratochwil et al., 2016a; PSMA617 PSMA617
Kratochwil et al., 2016b). ligand
Ongoing
Phase 2 for CRPC (Kratochwil et al., 2016a; PSMA617 PSMA617
Kratochwil et al., 2016b) Ongoing ligand
of targeted cancer cells (Kratochwil et al., 2016b). The PSMA617 ligand
targets a different epitope and has a different biodistribution compared
with J591, which spares the salivary glands.
6. Conclusions
This work is a review of the radiobiology, in vitro and in vivo stu-
dies of targeted alpha versus beta therapies. In vitro studies and cal-
culations demonstrate the fundamental principles for alpha cytotoxi-
city: are high specific energy and short range, meaning that cells must
be targeted for effective cancer cell kill. While the RBE for 37% survival
for external alpha vs beta irradiation is ∼ 5, the RBE for internal tar-
geted alphas relative to betas and non-targeted alphas is close to 120.
The difference is given by the fact that the range of alphas is very much
smaller than for betas, such that most targeted cancer cells receive a
large fraction of the short-range alpha energy but a very, very small
fraction of the long-range beta energy.
Comparing the biological effects of alpha and beta radio-
immunotherapy is not a straightforward task, as various factors such as:
dose rate, protracted irradiation, associated emission by daughter
radionuclides, chelator stability, etc. may interfere with the analysis
(Brady et al., 2013; Pouget et al., 2015). Nevertheless, the physical and
radiobiological properties of α-RIT, as well as clinical trials demon-
strate an advantage of the alpha emitting isotopes:
(1) in a hypoxic environment, due to minimal dependence on the
oxygenation status of alpha particles,
(2) overcoming treatment resistance to beta targeted therapy,
(3) of a more focused targeting which makes it ideal for isolated cancer
cells and residual disease,
(4) in anti-vascular targeted therapies.
While the number of preclinical and clinical studies to date is rather
small, α-RIT or β-RIT studies for the above cancers and tumour sites
show that in all the reviewed cases, α-RIT is superior to β-RIT in terms
of efficacy within the tolerance dose.
References
Adelstein, S., Kassis, A., Bodei, L., Mariani, G., 2003. Radiotoxicity of iodine-125 and
other Auger-electron-emitting radionuclides: background to therapy. Cancer Biother.
Radiopharm. 18, 16.
Afshar-Oromieh, A., Hetzheim, H., Kratochwil, C., Benesova, M., Eder, M., Neels, O.C.,
Eisenhut, M., Kubler, W., Holland-Letz, T., Giesel, F.L., Mier, W., Kopka, K.,
Haberkorn, U., 2015. The theranostic PSMA ligand PSMA-617 in the diagnosis of
prostate cancer by PET/CT: biodistribution in humans, radiation dosimetry, and first
evaluation of tumor lesions journal of nuclear medicine: official publication. Soc.
Nucl. Med. 56 (11), 1697–1705.
Critical Reviews in Oncology / Hematology 123 (2018) 7–20
Conclusions/observations
Beta
emitter
Lu-177 Major decrease in PSA for 67% of subjects, with survival time increasing from 12 to
22 months at the MTD of 2.6 GBq/m2. Overall, a single dose of 177Lu-J591 was
efficacious and well tolerated with reversible myelosuppression at the limits for
adverse events.
Lu-177 Patients selected with better prognosis.
Reduced efficacy cf Ac225.
Minimal xerostomia in salivary glands.
Alpha
emitter
Ac-225 Patients selected with the worst prognosis, e.g. bone marrow involvement, visceral
and bone metastases. Several patients are achieving complete remission, some of
whom had PSA values > 3000 ng/ml
Major xerostomia in salivary glands.
Akhtar, N.H., Pail, O., Saran, A., Tyrell, L., Tagawa, S.T., 2012. Prostate-specific mem-
brane antigen-based therapeutics. Adv. Urol. 2012, 973820.
Allen, B., Rizvi, S., Tian, Z., 2001. Preclinical targeted alpha therapy for subcutaneous
melanoma. Melanoma Res. 11 (2), 175–182.
Allen, B.J., Raja, C., Rizvi, S., Li, Y., Tsui, W., Graham, P., Thompson, J., Reisfeld, R.,
Kearsley, J., Morgenstern, A., 2005. Intralesional targeted alpha therapy for meta-
static melanoma. Cancer Biol. Ther. 4 (12), 1318–1324.
Allen, B.J., Raja, C., Rizvi, S., Song, E.Y., Graham, P., 2007. Tumour anti-vascular alpha
therapy: a mechanism for the regression of solid tumours in metastatic cancer. Phys.
Med. Biol. 52 (13), L15.
Allen, B.J., Singla, A.A., Rizvi, S.M.A., Graham, P., Bruchertseifer, F., Apostolidis, C.,
Morgenstern, A., 2011. Analysis of patient survival in a Phase I trial of systemic
targeted α-therapy for metastatic melanoma. Immunotherapy 3 (9), 1041–1050.
Allen, B., Marcu, L., Bezak, E., 2016. Targeted alpha therapy for cancer. In: Godfrey, D.J.,
VanDyk, J., Das, S.K., Curran, B.H., Wolbarst, A.A. (Eds.), Advances in Medical
Physics. Medical Physics Publishing.
Allen, B., 1999. Can alpha-immunotherapy succeed where other systemic modalities have
failed? Nucl. Med. Commun. 20, 3.
Allen, B., 2017. A comparative evaluation of Ac225 vs Bi213 as therapeutic radioisotopes
for targeted alpha therapy. Aust. Phys. Eng. Sci. Med. 40 (4). http://dx.doi.org/10.
1007/s13246-017-0534-6.
American Cancer Society, I., 2015. Global Cancer Facts & Figures, 3rd edition. American
Cancer Society, Inc., Atlanta.
Ananias, H.J., van den Heuvel, M.C., Helfrich, W., de Jong, I.J., 2009. Expression of the
gastrin-releasing peptide receptor, the prostate stem cell antigen and the prostate-
specific membrane antigen in lymph node and bone metastases of prostate cancer.
Prostate 69 (10), 1101–1108.
Andersson, H., Cederkrantz, E., Bäck, T., Divgi, C., Elgqvist, J., Himmelman, J., Horvath,
G., Jacobsson, L., Jensen, H., Lindegren, S., 2009. Intraperitoneal α-particle radio-
immunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of
211At-MX35F (abα) 2′a phase I study. J. Nucl. Med. 50 (7), 1153–1160.
Barendsen, G., Beusker, T., AJ, V., Budke, L., 1960. Effects of different ionizing radiations
on human cells in tissue culture: II. Biological experiments. Rad. Res. 13 (6),
841–849.
Behr, T.M., Behe, M., Stabin, M.G., Wehrmann, E., Apostolidis, C., Molinet, R., Strutz, F.,
Fayyazi, A., Wieland, E., Gratz, S., Koch, L., Goldenberg, D.M., Becker, W., 1999.
High-linear energy transfer (LET) alpha versus low-LET beta emitters in radio-
immunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of
213Bi- versus 90Y-labeled CO17-1A Fab' fragments in a human colonic cancer model.
Cancer Res. 59 (11), 2635–2643.
Bigner, D.D., Brown, M.T., Friedman, A.H., Coleman, R.E., Akabani, G., Friedman, H.S.,
Thorstad, W.L., McLendon, R.E., Bigner, S.H., Zhao, X.G., Pegram, C.N., Wikstrand,
C.J., Herndon 2nd, J.E., Vick, N.A., Paleologos, N., Cokgor, I., Provenzale, J.M.,
Zalutsky, M.R., 1998. Iodine-131-labeled antitenascin monoclonal antibody 81C6
treatment of patients with recurrent malignant gliomas: phase I trial results. J. Clin.
Oncol. 16 (6), 2202–2212.
Bloomer, W.D., McLaughlin, W.H., Lambrecht, R.M., Atcher, R.W., Mirzadeh, S., Madara,
J.L., Milius, R.A., Zalutsky, M.R., Adelstein, S.J., Wolf, A.P., 1984. 211At radiocolloid
therapy: further observations and comparison with radiocolloids of 32P, 165Dy, and
90Y. Int. J. Radiat. Oncol. Biol. Phys. 10 (3), 341–348.
Bodet-Milin, C., Kraeber-Bodéré, F., Eugène, T., Guérard, F., Gaschet, J., Bailly, C., 2016.
Radioimmunoterapy for treatment of acute leukemia. Semin. Nucl. Med. 46 (2),
135–146.
Bostwick, D.G., Pacelli, A., Blute, M., Roche, P., Murphy, G.P., 1998. Prostate specific
membrane antigen expression in prostatic intraepithelial neoplasia and adenocarci-
noma: a study of 184 cases. Cancer 82 (11), 2256–2261.
Boudousq, V., Bobyk, L., Busson, M., Garambois, V., Jarlier, M., Charalambatou, P., et al.,
2013. Comparison between internalizing anti-HER2 mAbs and non-internalizing anti-
CEA mAbs in alpha-radioimmunotherapy of small volume peritoneal carcinomatosis
using 212Pb. PLoS One 8 (7 (Jul 29)), e69613.
18
L. Marcu et al.
Brady, D., O'Sullivan, J.M., Prise, K.M., 2013. What is the role of the bystander response
in radionuclide therapies? Front. Oncol. 3 (Aug 19), 215.
Bumol, T., Reisfeld, R., 1982. Unique glycoprotein-proteoglycan complex defined by
monoclonal antibody on human melanoma cells. Proc. Natl. Acad. Sci. 79 (4),
1245–1249.
Caron, P., Jurcic, J., Scott, A., Fin, R., Digvi, C., Graham, M., Jureidini, I., Sgouros, G.,
Tyson, D., Old, L., 1994. A phase IB trial of humanized antibody M195 (anti-CD33) in
myeloid leukemia: specific targeting without immunogenicity. Blood 83, 1760–1768.
Chang, S.S., Reuter, V.E., Heston, W.D., Bander, N.H., Grauer, L.S., Gaudin, P.B., 1999.
Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm
PSMA expression in tumor-associated neovasculature. Cancer Res. 59 (13),
3192–3198.
Cordier, D., Forrer, F., Bruchertseifer, F., Morgenstern, A., Apostolidis, C., Good, S.,
Müller-Brand, J., Mäcke, H., Reubi, J., Merlo, A., 2010. Targeted alpha-radionuclide
therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8, Met (O2)
11]-substance P: a pilot trial. Eur. J. Nucl. Med. Mol. Imaging 37 (7), 1335–1344.
Dadachova, E., Revskaya, E., Sesay, M.A., Damania, H., Boucher, R., Sellers, R.S., Howell,
R.C., Burns, L., Thornton, G.B., Natarajan, A., Mirick, G.R., DeNardo, S.J., DeNardo,
G.L., Casadevall, A., 2008. Pre-clinical evaluation and efficacy studies of a melanin-
binding IgM antibody labeled with 188Re against experimental human metastatic
melanoma in nude mice. Cancer Biol. Ther. 7 (7), 1116–1127.
Derrien, A., Gouard, S., Maurel, C., Gaugler, M.H., Bruchertseifer, F., Morgenstern, A.,
Faivre-Chauvet, A., Classe, J.M., Cherel, M., 2015. Therapeutic efficacy of alpha-RIT
using a (213)Bi-Anti-hCD138 antibody in a mouse model of ovarian peritoneal car-
cinomatosis. Front. Med. (Lausanne) 2, 88.
Epenetos, A.A., Hird, V., Lambert, H., Mason, P., Coulter, C., 2000. Long term survival of
patients with advanced ovarian cancer treated with intraperitoneal radio-
immunotherapy. Int. J. Gynecol. Cancer 10 (S1), 44–46.
Fichou, N., Gouard, S., Maurel, C., Barbet, J., Ferrer, L., Morgenstern, A., Bruchertseifer,
F., Faivre-Chauvet, A., Bigot-Corbel, E., Davodeau, F., 2015. Single-dose anti-CD138
radioimmunotherapy: bismuth-213 is more efficient than lutetium-177 for treatment
of multiple myeloma in a preclinical model. Front. Med. 2.
Forrer, F., Waldherr, C., Maecke, H.R., Mueller-Brand, J., 2006. Targeted radionuclide
therapy with 90Y-DOTATOC in patients with neuroendocrine tumors. Anticancer
Res. 26 (1B), 703–707.
Gledhill, J., 1973. The range-energy relation for 0.1-600 keV electrons. J. Phys. A: Math.
Nucl. Gen. 6 (9), 1420.
Graf, F., Fahrer, J., Maus, S., Morgenstern, A., Bruchertseifer, F., Venkatachalam, S.,
Fottner, C., Weber, M.M., Huelsenbeck, J., Schreckenberger, M., Kaina, B., Miederer,
M., 2014. DNA double strand Breaks as predictor of efficacy of the alpha-particle
emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted
radiotherapy. PLoS One 9 (2), e88239.
Holland, J., Divilov, V., Bander, N., Smith-Jones, P., Larson, S., Lewis, J., 2010. Zr-89-dfo-
j591 for immuno-PET of prostate-specific membrane antigen expression in vivo. J.
Nucl. Med. 51 (8), 1193–1230.
Hoskin, P., Sartor, O., O'Sullivan, J.M., Johannessen, D.C., Helle, S.I., Logue, J.,
Bottomley, D., Nilsson, S., Vogelzang, N.J., Fang, F., 2014. Efficacy and safety of
radium-223 dichloride in patients with castration-resistant prostate cancer and
symptomatic bone metastases, with or without previous docetaxel use: a prespecified
subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial.
Lancet Oncol. 15 (12), 1397–1406.
Huang, C.-Y., Oborn, B.M., Guatelli, S., Allen, B.J., 2012. Monte Carlo calculation of the
maximum therapeutic gain of tumor antivascular alpha therapy. Med. Phys. 39 (3),
1282–1288.
Israeli, R.S., Powell, C.T., Fair, W.R., Heston, W.D., 1993. Molecular cloning of a com-
plementary DNA encoding a prostate-specific membrane antigen. Cancer Res. 53 (2),
227–230.
Israeli, R.S., Powell, C.T., Corr, J.G., Fair, W.R., Heston, W.D., 1994. Expression of the
prostate-specific membrane antigen. Cancer Res. 54 (7), 1807–1811.
Jurcic, J.G., Rosenblat, T.L., 2014. Targeted alpha-particle immunotherapy for acute
myeloid leukemia. American Society of Clinical Oncology educational book/ASCO.
Am. Soc. Clin. Oncol. Meet. e126–e131.
Jurcic, J., Divgi, C., McDevitt, M., 2000. Potential for myeloablation with yttrium-90-Hu
(anti-CD33) in myeloid leukemia. Proc. Am. Soc. Clin. Oncol. 19 (8), M195.
Jurcic, J.G., Larson, S.M., Sgouros, G., McDevitt, M.R., Finn, R.D., Divgi, C.R., Ballangrud,
Å.M., Hamacher, K.A., Ma, D., Humm, J.L., 2002. Targeted α particle im-
munotherapy for myeloid leukemia. Blood 100 (4), 1233–1239.
Jurcic, J., Rosenblat, T., McDevitt, M., 2011. Phase I trial of the targeted alpha-Particle
nano-Generator actinium-225(225Ac)-Lintuzumab (anti-CD33; HuM195) In acute
myeloid leukemia (AML). Blood 2011, 1.
Kam, B.L., Teunissen, J.J., Krenning, E.P., de Herder, W.W., Khan, S., van Vliet, E.I.,
Kwekkeboom, D.J., 2012. Lutetium-labelled peptides for therapy of neuroendocrine
tumours. Eur. J. Nucl. Med. Mol. Imaging 39 (Suppl 1), S103–112.
Kang, H., Lee, S., Byun, B., Kim, K., Lim, I., Choi, C., Suh, C., Kim, W., Nam, S., Lee, S.,
Eom, H., Shin, D., Lim, S., 2013. Repeated radioimmunotherapy with (131)I-ritux-
imab for patients with low-grade and aggressive relapsed or refractory B cell non-
Hodgkin lymphoma. Cancer Chemother. Pharmacol. 71 (4), 945–953.
Klein, M., Lotem, M., Peretz, T., Zwas, S.T., Mizrachi, S., Liberman, Y., Chisin, R.,
Schachter, J., Ron, I.G., Iosilevsky, G., Kennedy, J.A., Revskaya, E., de Kater, A.W.,
Banaga, E., Klutzaritz, V., Friedmann, N., Galun, E., Denardo, G.L., Denardo, S.J.,
Casadevall, A., Dadachova, E., Thornton, G.B., 2013. Safety and efficacy of 188-
rhenium-labeled antibody to melanin in patients with metastatic melanoma. J. Skin
Cancer 828329.
Kneifel, S., Cordier, D., Good, S., Ionescu, M.C., Ghaffari, A., Hofer, S., Kretzschmar, M.,
Tolnay, M., Apostolidis, C., Waser, B., 2006. Local targeting of malignant gliomas by
the diffusible peptidic vector 1, 4, 7, 10-tetraazacyclododecane-1-glutaric acid-4, 7,
19
Critical Reviews in Oncology / Hematology 123 (2018) 7–20
10-triacetic acid-substance P. Clin. Cancer Res. 12 (12), 3843–3850.
Kratochwil, C., López-Benítez, R., Mier, W., Haufe, S., Isermann, B., Kauczor, H.-U.,
Choyke, P.L., Haberkorn, U., Giesel, F.L., 2011. Hepatic arterial infusion enhances
DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases.
Endocr. Relat. Cancer 18 (5), 595–602.
Kratochwil, C., Giesel, F., Bruchertseifer, F., Mier, W., Apostolidis, C., Boll, R., Murphy,
K., Haberkorn, U., Morgenstern, A., 2014. 213Bi-DOTATOC receptor-targeted alpha-
radionuclide therapy induces remission in neuroendocrine tumours refractory to beta
radiation: a first-in-human experience. Eur. J. Nucl. Med. Mol. Imaging 41 (11),
2106–2119.
Kratochwil, C., Bruchertseifer, F., Giesel, F., Apostolidis, C., Haberkorn, U., Morgenstern,
A., 2015. Ac-225-DOTATOC – an empiric dose finding for alpha particle emitter
based radionuclide therapy of neuroendocrine tumors. J. Nucl. Med. 56, 1232.
Kratochwil, C., Bruchertseifer, F., Giesel, F.L., Weis, M., Verburg, F.A., Mottaghy, F.,
Kopka, K., Apostolidis, C., Haberkorn, U., Morgenstern, A., 2016a. 225Ac-PSMA-617
for PSMA-Targeted alpha-Radiation therapy of metastatic castration-Resistant pros-
tate cancer journal of nuclear medicine: official publication. J. Nucl. Med. Off. Publ.
Soc. Nucl. Med. 57 (12), 1941–1944.
Kratochwil, C., Giesel, F., Rius, M., Apostolidis, C., Haberkorn, U., Morgenstern, A.,
2016b. Ac-225-PSMA617 – a single center experience of 40 patients receiving PSMA-
targeted alpha therapy. Deutsche Gesellschaft Fur Nuklearmedizin V68.
Kwekkeboom, D.J., de Herder, W.W., Kam, B.L., van Eijck, C.H., van Essen, M., Kooij,
P.P., Feelders, R.A., van Aken, M.O., Krenning, E.P., 2008. Treatment with the
radiolabeled somatostatin analog [177Lu-DOTA0, Tyr3] octreotate: toxicity, efficacy,
and survival. J. Clin. Oncol. 26 (13), 2124–2130.
Larson, S.M., Carrasquillo, J.A., Mcguffin, R.W., Krohn, K.A., Ferens, J.M., Hill, L.D.,
Beaumier, P.L., Reynolds, J.C., Hellstrom, K.E., Hellstrom, I., 1985. Use of I-131 la-
beled, murine fab against a high molecular-weight antigen of human-melanoma –
preliminary experience. Radiology 155 (2), 487–492.
Leins, A., Riva, P., Lindstedt, R., Davidoff, M.S., Mehraein, P., Weis, S., 2003. Expression
of tenascin-C in various human brain tumors and its relevance for survival in patients
with astrocytoma. Cancer 98 (11), 2430–2439.
Li, Y., Rizvi, S., Ranson, M., Allen, B., 2002a. 213Bi-PAI2 conjugate selectively induces
apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in
a xenograft animal model. Brit. J. Cancer 86 (7), 1197–1203.
Li, Y., Tian, Z., Rizvi, S., Bander, N., Allen, B., 2002b. In vitro and preclinical targeted
alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against
the prostate specific membrane antigen. Pros Ca Pros Dis 5, 36–46.
Liu, H., Moy, P., Kim, S., Xia, Y., Rajasekaran, A., Navarro, V., Knudsen, B., Bander, N.H.,
1997. Monoclonal antibodies to the extracellular domain of prostate-specific mem-
brane antigen also react with tumor vascular endothelium. Cancer Res. 57 (17),
3629–3634.
Liu, H., Rajasekaran, A.K., Moy, P., Xia, Y., Kim, S., Navarro, V., Rahmati, R., Bander,
N.H., 1998. Constitutive and antibody-induced internalization of prostate-specific
membrane antigen. Cancer Res. 58 (18), 4055–4060.
Ménager, J., Gorin, J.B., Maurel, C., Drujont, L., Gouard, S., Louvet, C., et al., 2015.
Combining é-Radioimmunotherapy and adoptive t cell therapy to potentiate tumor
destruction. PLoS One 10 (6), e0130249.
Mannweiler, S., Amersdorfer, P., Trajanoski, S., Terrett, J.A., King, D., Mehes, G., 2009.
Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate
carcinoma with distant metastasis. Pathol. Oncol. Res. 15 (2), 167–172.
Marcu, L., Bezak, E., Allen, B.J., 2012. Biomedical Physics in Radiotherapy for Cancer.
Csiro publishing.
Matthews, D.C., Appelbaum, F.R., Eary, J.F., Fisher, D.R., Durack, L.D., Hui, T.E., Martin,
P.J., Mitchell, D., Press, O.W., Storb, R., Bernstein, I.D., 1999. Phase I study of (131)I-
anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced
acute leukemia and myelodysplastic syndrome. Blood 94 (4), 1237–1247.
Mawad, R., Gooley, T.A., Rajendran, J.G., Fisher, D.R., Gopal, A.K., Shields, A.T.,
Sandmaier, B.M., Sorror, M.L., Deeg, H.J., Storb, R., Green, D.J., Maloney, D.G.,
Appelbaum, F.R., Press, O.W., Pagel, J.M., 2014. Radiolabeled anti-CD45 antibody
with reduced-intensity conditioning and allogeneic transplantation for younger pa-
tients with advanced acute myeloid leukemia or myelodysplastic syndrome. Biol.
Blood Marrow Transplant. 20 (9), 1363–1368.
Meredith, R.F., Torgue, J., Azure, M.T., Shen, S., Saddekni, S., Banaga, E., Carlise, R.,
Bunch, P., Yoder, D., Alvarez, R., 2014. Pharmacokinetics and imaging of 212Pb-
TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients.
Cancer Biother. Radiopharm. 29 (1), 12–17.
Meredith, R.F., Torgue, J.J., Rozgaja, T.A., Banaga, E.P., Bunch, P.W., Alvarez, R.D.,
Straughn Jr., J.M., Dobelbower, M.C., Lowy, A.M., 2016. Safety and outcome mea-
sures of first-in-Human intraperitoneal alpha radioimmunotherapy with 212Pb-
TCMC-Trastuzumab. Am. J. Clin. Oncol. http://dx.doi.org/10.1097/COC.
0000000000000353. (epub ahead of print).
Miederer, M., Henriksen, G., Alke, A., Mossbrugger, I., Quintanilla-Martinez, L.,
Senekowitsch-Schmidtke, R., Essler, M., 2008. Preclinical evaluation of the alpha-
particle generator nuclide 225Ac for somatostatin receptor radiotherapy of neu-
roendocrine tumors. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 14 (11),
3555–3561.
Morgenstern, A., Krolicki, L., Kunikowska, J., Koziara, H., Krolicki, B., Jakucinski, M.,
Apostolidis, C., Bruchertseifer, F., 2014. Targeted alpha therapy of glioblastoma
multiforme: first clinical experience with 213Bi-substance P. J. Nucl. Med. 55 (Suppl.
1), 390.
Mulford, D., Scheinberg, D., Jurcic, J., 2005. The promise of targeted (American Cancer
Society)-particle therapy Journal of nuclear medicine: official publication. Soc. Nucl.
Med. 46 (Suppl. 1), 199S–204S.
Nilsson, S., Larsen, R.H., Fosså, S.D., Balteskard, L., Borch, K.W., Westlin, J.-E., Salberg,
G., Bruland, Ø.S., 2005. First clinical experience with α-emitting radium-223 in the
L. Marcu et al.
treatment of skeletal metastases. Clin. Cancer Res. 11 (12), 4451–4459.
Nilsson, S., Franzén, L., Parker, C., Tyrrell, C., Blom, R., Tennvall, J., Lennernäs, B.,
Petersson, U., Johannessen, D.C., Sokal, M., 2007. Bone-targeted radium-223 in
symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, pla-
cebo-controlled phase II study. Lancet Oncol. 8 (7), 587–594.
Nilsson, S., 2014. Alpha-emitter radium-223 in the management of solid tumors: current
status and future directions. American Society of Clinical Oncology educational
book/ASCO. Am. Soc. Clin. Oncol. Meet. e132–e139.
Oosterhof, G.O., Roberts, J.T., de Reijke, T.M., Engelholm, S.A., Horenblas, S., von der
Maase, H., Neymark, N., Debois, M., Collette, L., 2003. Strontium(89) chloride versus
palliative local field radiotherapy in patients with hormonal escaped prostate cancer:
a phase III study of the European Organisation for Research and Treatment of Cancer,
Genitourinary Group. Eur. Urol. 44 (5), 519–526.
Parker, C.C., Pascoe, S., Chodacki, A., O'Sullivan, J.M., Germá, J.R., O’Bryan-Tear, C.G.,
Haider, T., Hoskin, P., 2013. A randomized, double-blind, dose-finding, multicenter,
phase 2 study of radium chloride (Ra 223) in patients with bone metastases and
castration-resistant prostate cancer. Eur. Urol. 63 (2), 189–197.
Porter, A.T., McEwan, A.J., Powe, J.E., Reid, R., McGowan, D.G., Lukka, H.,
Sathyanarayana, J.R., Yakemchuk, V.N., Thomas, G.M., Erlich, L.E., Crook, J., 1993.
Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 ad-
juvant to local field external beam irradiation in the management of endocrine re-
sistant metastatic prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 25 (5), 805–813.
Pouget, J.P., Lozza, C., Deshayes, E., Boudousq, V., Navarro-Teulon, I., 2015. Introduction
to radiobiology of targeted radionuclide therapy. Front. Med. (Lausanne) 17 (2), 12.
Quilty, P.M., Kirk, D., Bolger, J.J., Dearnaley, D.P., Lewington, V.J., Mason, M.D., Reed,
N.S., Russell, J.M., Yardley, J., 1994. A comparison of the palliative effects of
strontium-89 and external beam radiotherapy in metastatic prostate cancer.
Radiother. Oncol. 31 (1), 33–40.
Raja, C., Graham, P., Rizvi, S., Song, E., Goldsmith, H., Thompson, J., Bosserhoff, A.,
Morgenstern, A., Apostolidis, C., Kearsley, J., 2007. Interim analysis of toxicity and
response in phase 1 trial of systemic targeted alpha therapy for metastatic melanoma.
Cancer Biol. Ther. 6 (6), 846–852.
Reardon, D., Akabani, G., Coleman, R., Friedman, A., Friedman, H., Herndon, J., 2002.
Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 ad-
ministered into surgically created resection cavities of patients with newly diagnosed
malignant gliomas. J. Clin. Oncol. 20 (5), 1389–1397.
Ringhoffer, M., Blumstein, N., Neumaier, B., Glatting, G., von Harsdorf, S., Buchmann, I.,
Wiesneth, M., Kotzerke, J., Zenz, T., Buck, A., Schauwecker, P., Stilgenbauer, S.,
Döhner, H., Reske, S., Bunjes, D., 2005. 188Re or 90Y-labelled anti-CD66 antibody as
part of a dose-reduced conditioning regimen for patients with acute leukaemia or
myelodysplastic syndrome over the age of 55: results of a phase I-II study. Br. J.
Haematol. 130 (4), 604–613.
Riquier, H., Wera, A., Heuskin, A., Feron, O., Lucas, S., Michiels, C., 2013. Comparison of
X-ray and alpha particle effects on a human cancer and endothelial cells: survival
curves and gene expression profiles. Radiother. Oncol. 106, 397–403.
Riva, P., Franceschi, G., Frattarelli, M., 1999. Loco-regional radioimmunotherapy of high-
grade malignant gliomas using specific monoclonal antibodies labeled with 90Y: a
phase I study. Clin. Cancer Res. 5 (Suppl), 3275s–3280s.
Rizvi, S., Sarkar, S., Goozee, G., Allen, B., 2000. Radioimmunoconjugates for targeted
[alpha] therapy of malignant melanoma. Melanoma Res. 10 (3), 281–289.
Rizvi, S., Henniker, A., Goozee, G., Allen, B., 2002. In vitro testing of the leukaemia
monoclonal antibody WM-53 labeled with alpha and beta emitting radioisotopes.
Leuk. Res. 26 (1), 37–43.
Rosenblat, T.L., McDevitt, M.R., Mulford, D.A., Pandit-Taskar, N., Divgi, C.R., Panageas,
K.S., Heaney, M.L., Chanel, S., Morgenstern, A., Sgouros, G., Larson, S.M.,
Scheinberg, D.A., Jurcic, J.G., 2010. Sequential cytarabine and alpha-particle im-
munotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia.
Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 16 (21), 5303–5311.
Rosenblum, M.G., Verschraegen, C.F., Murray, J.L., Kudelka, A.P., Gano, J., Cheung, L.,
Kavanagh, J.J., 1999. Phase I study of 90Y-labeled B72. 3 intraperitoneal adminis-
tration in patients with ovarian cancer: effect of dose and EDTA coadministration on
pharmacokinetics and toxicity. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 5 (5),
953–961.
Sartor, O., Coleman, R., Nilsson, S., Heinrich, D., Helle, S.I., O'Sullivan, J.M., Fosså, S.D.,
Chodacki, A., Wiechno, P., Logue, J., 2014. Effect of radium-223 dichloride on
symptomatic skeletal events in patients with castration-resistant prostate cancer and
bone metastases: results from a phase 3, double-blind, randomised trial. Lancet
Oncol. 15 (7), 738–746.
Scheinberg, D.A., Lovett, D., Divgi, C.R., Graham, M.C., Berman, E., Pentlow, K., Feirt, N.,
Finn, R.D., Clarkson, B.D., Gee, T.S., et al., 1991. A phase I trial of monoclonal an-
tibody M195 in acute myelogenous leukemia: specific bone marrow targeting and
internalization of radionuclide. J. Clin. Oncol. 9 (3), 478–490.
Schwartz, M.A., Lovett, D.R., Redner, A., Finn, R.D., Graham, M.C., Divgi, C.R., Dantis, L.,
Gee, T.S., Andreeff, M., Old, L.J., et al., 1993. Dose-escalation trial of M195 labeled
with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory
myeloid leukemias. J. Clin. Oncol. 11 (2), 294–303.
Seidl, C., Zockler, C., Beck, R., Quintanilla-Martinez, L., Bruchertseifer, F., Senekowitsch-
20
Critical Reviews in Oncology / Hematology 123 (2018) 7–20
Schmidtke, R., 2011. Lu-177-immunotherapy of experimental peritoneal carcino-
matosis shows comparable effectiveness to Bi-213-immunotherapy, but causes toxi-
city not observed with Bi-213. Eur. J. Nucl. Med. Mol. 38 (2), 312–322.
Serafini, A.N., Houston, S.J., Resche, I., Quick, D.P., Grund, F.M., Ell, P.J., Bertrand, A.,
Ahmann, F.R., Orihuela, E., Reid, R.H., Lerski, R.A., Collier, B.D., McKillop, J.H.,
Purnell, G.L., Pecking, A.P., Thomas, F.D., Harrison, K.A., 1998. Palliation of pain
associated with metastatic bone cancer using samarium-153 lexidronam: a double-
blind placebo-controlled clinical trial. J. Clin. Oncol. 16 (4), 1574–1581.
Sokoloff, R.L., Norton, K.C., Gasior, C.L., Marker, K.M., Grauer, L.S., 2000. A dual-
monoclonal sandwich assay for prostate-specific membrane antigen: levels in tissues,
seminal fluid and urine. Prostate 43 (2), 150–157.
Song, H., Hobbs, R.F., Vajravelu, R., Huso, D.L., Esaias, C., Apostolidis, C., Morgenstern,
A., Sgouros, G., 2009. Radioimmunotherapy of breast cancer metastases with alpha-
particle emitter 225Ac: comparing efficacy with 213Bi and 90Y. Cancer Res. 69 (23),
8941–8948.
Strosberg, J., El-Haddad, G., Wolin, E., Hendifar, A., Yao, J., Chasen, B., Mittra, E., Kunz,
P.L., Kulke, M.H., Jacene, H., Bushnell, D., O'Dorisio, T.M., Baum, R.P., Kulkarni,
H.R., Caplin, M., Lebtahi, R., Hobday, T., Delpassand, E., Van Cutsem, E., Benson, A.,
Srirajaskanthan, R., Pavel, M., Mora, J., Berlin, J., Grande, E., Reed, N., Seregni, E.,
Oberg, K., Lopera Sierra, M., Santoro, P., Thevenet, T., Erion, J.L., Ruszniewski, P.,
Kwekkeboom, D., Krenning, E., Investigators, N.-T., 2017. Phase 3 trial of 177Lu-
Dotatate for midgut neuroendocrine tumors. N. Engl. J. Med. 376 (2), 125–135.
Sweat, S., Pacelli, A., Murphy, G., Bostwick, D., 1998. Prostate-specific membrane antigen
expression is greatest in prostate adenocarcinoma and lymph node metastases.
Urology 52 (4), 637–640.
Tagawa, S.T., Beltran, H., Vallabhajosula, S., Goldsmith, S.J., Osborne, J., Matulich, D.,
Petrillo, K., Parmar, S., Nanus, D.M., Bander, N.H., 2010. Anti-prostate-specific
membrane antigen-based radioimmunotherapy for prostate cancer. Cancer 116 (4
Suppl), 1075–1083.
Tagawa, S.T., Milowsky, M.I., Morris, M., Vallabhajosula, S., Christos, P., Akhtar, N.H.,
Osborne, J., Goldsmith, S.J., Larson, S., Taskar, N.P., 2013. Phase II study of lutetium-
177?Labeled anti-Prostate-Specific membrane antigen monoclonal antibody J591 for
metastatic castration-Resistant prostate cancer. Clin. Cancer Res. 19 (18),
5182–5191.
Thompson, S., Ballard, B., Jiang, Z., Revskaya, E., Sisay, N., Miller, W.H., Cutler, C.S.,
Dadachova, E., Francesconi, L.C., 2014. 166Ho and 90Y labeled 6D2 monoclonal
antibody for targeted radiotherapy of melanoma: comparison with 188Re radiolabel.
Nucl. Med. Biol. 41 (3), 276–281.
Troyer, J.K., Beckett, M.L., Wright Jr., G.L., 1995. Detection and characterization of the
prostate-specific membrane antigen (PSMA) in tissue extracts and body fluids. Int. J.
Cancer 62 (5), 552–558.
Tu, S.M., Millikan, R.E., Mengistu, B., Delpassand, E.S., Amato, R.J., Pagliaro, L.C.,
Daliani, D., Papandreou, C.N., Smith, T.L., Kim, J., Podoloff, D.A., Logothetis, C.J.,
2001. Bone-targeted therapy for advanced androgen-independent carcinoma of the
prostate: a randomised phase II trial. Lancet 357 (9253), 336–341.
Verheijen, R.H., Massuger, L.F., Benigno, B.B., Epenetos, A.A., Lopes, A., Soper, J.T.,
Markowska, J., Vyzula, R., Jobling, T., Stamp, G., Spiegel, G., Thurston, D., Falke, T.,
Lambert, J., Seiden, M.V., 2006. Phase III trial of intraperitoneal therapy with yt-
trium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial
ovarian cancer after a surgically defined complete remission. J. Clin. Oncol. 24 (4),
571–578.
Waldherr, C., Pless, M., Maecke, H., Haldemann, A., Mueller-Brand, J., 2001. The clinical
value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of
neuroendocrine tumours: a clinical phase II study. Ann. Oncol. 12 (7), 941–945.
Wild, D., Frischknecht, M., Zhang, H., Morgenstern, A., Bruchertseifer, F., Boisclair, J.,
Provencher-Bolliger, A., Reubi, J.C., Maecke, H.R., 2011. Alpha- versus beta-particle
radiopeptide therapy in a human prostate cancer model (213Bi-DOTA-PESIN and
213Bi-AMBA versus 177Lu-DOTA-PESIN). Cancer Res. 71 (3), 1009–1018.
Wright Jr., G.L., Grob, B.M., Haley, C., Grossman, K., Newhall, K., Petrylak, D., Troyer, J.,
Konchuba, A., Schellhammer, P.F., Moriarty, R., 1996. Upregulation of prostate-
specific membrane antigen after androgen-deprivation therapy. Urology 48 (2),
326–334.
Yong, K.J., Milenic, D.E., Baidoo, K.E., Brechbiel, M.W., 2014. Impact of α-targeted ra-
diation therapy on gene expression in a pre-clinical model for disseminated perito-
neal disease when combined with paclitaxel. PLoS One 9 (Sep 30), e108511.
Yong, K.J., Milenic, D.E., Baidoo, K.E., Brechbiel, M.W., 2016. Cell killing mechanisms
and impact on gene expression by gemcitabine and 212Pb-Trastuzumab treatment in
a disseminated i.p. tumor model. PLoS One 11 (7 (Jul 28)), e0159904.
Yoshida, K., Kaneta, T., Takano, S., Sugiura, M., Kawano, T., Hino, A., Yamamoto, T.,
Shizukuishi, K., Kaneko, M., Zurth, C., Inoue, T., 2016. Pharmacokinetics of single
dose radium-223 dichloride (BAY 88–8223) in Japanese patients with castration-re-
sistant prostate cancer and bone metastases. Ann. Nucl. Med. 30 (7), 453–460.
Zalutsky, M.R., Reardon, D.A., Akabani, G., Coleman, R.E., Friedman, A.H., Friedman,
H.S., McLendon, R.E., Wong, T.Z., Bigner, D.D., 2008. Clinical experience with α-
particle?emitting 211At: treatment of recurrent brain tumor patients with 211At-la-
beled chimeric antitenascin monoclonal antibody 81C6. J. Nucl. Med. 49 (1), 30–38.