Keywords
213 Bismuth -
225 Actinium - endocrine - neuroendocrine neoplasms - oncology - radionuclide therapy
- radionuclide therapy - targeted alpha therapy
Introduction
Neuroendocrine neoplasms (NENs) are an uncommon heterogeneous group of neoplasms originating
from endocrine cells that secrete biogenic amines and polypeptide hormones. Data from
Europe and the USA from 1994 to 2003 demonstrate a rise in incidence, in part due
to improved awareness and detection, and is approximately 2/100,000 per year.[[1 ]] A retrospective, population-based study using nationally representative data from
the Surveillance, Epidemiology, and End Results program in the USA from 1973 to 2012
revealed that the age-adjusted annual incidence of neuroendocrine tumors (NETs) increased
from 1.09 per 100,000 in 1973 to 6.98 per 100,000 in 2012, a 6.4-fold increase.[[2 ]] Within Australia, based on the data from the Australian Institute of Health and
Welfare, there were 10,108 patients diagnosed with NEN in the 5-year period of 2012–2016.
In 2016, the age-standardized incidence rate was 15 cases per 100,000 persons, which
has shown an increase from 1982, wherein the age-standardized incidence rate was 8.9
cases per 100,000 persons.[[3 ]]
The clinical behavior of NENs is variable; they may be hormonally active or endocrinologically
nonfunctioning and range from low-grade, slow-growing tumors to highly malignant and
aggressive tumors. The current WHO/ENETs Pathologic Classification divides NENs into
well-differentiated neuroendocrine tumors (WDNETs) G1 (Ki-67 <3%), G2 (Ki-67 3%–20%),
and G3 (Ki-67 >20%), which is in turn divided into WDNET (G3 WDNET) and poorly-differentiated
neuroendocrine carcinoma (G3 PDNEC). Ki-67 is a nuclear protein which is associated
with cellular proliferation.[[4 ]],[[5 ]]
The most frequent primary sites are the gastrointestinal (GI) tract, including the
pancreas (62%–67%) and the lung (22%–27%).[[6 ]] NENs of the gastroenteropancreatic (GEP) origin (GEP-NENs) characteristically present
at the age of 50–60 years and are challenging to diagnose. GEP-NENs are subdivided
into two categories: NENs of the luminal GI tract and pancreatic NENs. Up to 90% of
NENs of the GEP origin Express somatostatin receptors (SSRs) on its cell membrane.
This forms the basis of first-line therapy with somatostatin analog (SSA) therapy
such as octreotide or lanreotide, with the CLARINET and PROMID studies, respectively,
demonstrating significantly improved progression-free survival (PFS) and longer time
to tumor progression with SSA compared to placebo.[[7 ]],[[8 ]] On further tumor progression, despite SSA therapy and ensuring eligibility criteria
are met, patients are considered for SSA-based radionuclide therapy, also known as
peptide receptor radionuclide therapy (PRRT).[[9 ]]
PRRT is an accepted option of therapy for patients with advanced, progressive NENs.
PRRT is a form of systemic radiotherapy that delivers the radionuclides directly into
tumor cells, with subsequent DNA damage and cell death through the emission of particulate
radiation. The first PRRT was carried out in Rotterdam with 111In-DTPA-octreotide
(OctreoScan®) in 2002 which demonstrated only modest disease response, wherein several
patients had significant clinical improvement in classic carcinoid symptoms.[[10 ]] The development of radionuclides led to the next generation of beta-emitting radionuclides,
specifically 90Y (with maximum energy of beta particles of 2.28 MeV) conjugated to
DOTA peptides (DOTATATE and DOTATOC), which showed further promising results.[[11 ]] However, transient hematologic toxicities and severe permanent nephrotoxicity were
experienced in a small cohort of this patient group, in turn limiting its use.[[12 ]] In recent years, the use of 177Lu has largely replaced 90Y as the radionuclide
of choice in part due to the reduction of complications such as nephrotoxicity, as
a result of lower maximum energies of emitted beta particles (<0.5 MeV).[[13 ]]
177Lu-DOTATATE has emerged as the preferred agent as supported by the NETTER-1 trial.
The NETTER-1 trial (NCT01578239) is a randomized, multicenter, open-label, active-controlled
trial in 229 patients with progressive, well-differentiated, locally advanced/inoperable,
or metastatic SSR-positive mid-gut NENs. Treatment with 177Lu-DOTATATE compared with
high-dose octreotide LAR resulted in an increase in PFS (65.2% at month 20 in the
177Lu-DOTATATE group vs. 10.8% in the control group) and a significantly higher response
rate (18% in the 177Lu-DOTATATE group vs. 3% in the control group (P < 0.001) among
patients with advanced mid-gut NETs at the data cutoff date for the primary analysis
(approximately 34 months from the date of commencement of the trial).[[14 ]] 177Lu-DOTATATE has since been approved by the FDA in January 2018 for use in GEP-NEN.[[15 ]]
Targeted alpha-particle therapy (TAT) has emerged as an alternative treatment option
to beta emitters in PRRT. The use of alpha emitters for cancer therapy has two advantages
over beta emitter PRRT. The short range of alpha particles of only a few cell diameters
(<0.1 mm) allows for selective ablation of the target cancer cells, while sparing
the surrounding healthy tissue. In addition, the higher linear energy transfer (LET),
when compared to conventional beta emitters, results in the formation of complex DNA
double-strand and DNA cluster breaks, which ultimately lead to cell death.[[16 ]]
Despite this, the evidence of TAT in the treatment of GEP-NET is sparse. The aim of
this systematic review is to evaluate the current evidence for TAT in the treatment
of GEP-NET/NENs and to identify current and potential alpha emitters that can be used
in future TAT trials.
Materials and Methods
Search strategy
We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis
guidelines. A literature search of MEDLINE, EMBASE, SCOPUS, and Cochrane Library database
from 1985 to September 2020 resulted in 2073 potentially relevant articles using the
following search string: (“peptide receptor radionuclide therapy” OR “radioisotope
therapy” OR “radionuclide therapy” OR “radiolabeled therapy” OR “alpha-emitter” OR
“212Pb” OR “213Bi OR “PRRT” “targeted alpha particle therapy” or “targeted alpha therapy”
or “225Ac” or “225-Ac”) AND (neuroendocrine OR carcinoid OR paraganglioma OR pheochromocytoma
OR neuroblastoma OR somatostatin).
In addition, corresponding search terms were used to search free text, and manual
reference checks (i.e., pearling) of included articles of previously published reviews
were performed to compliment the electronic searches.
Inclusion and exclusion criteria
All peer-reviewed original articles were examined for the use of TAT in the treatment
of GEP-NENs. Only articles in the English language were included. Articles were included
if they had reported all of the following: (i) NET or GEP-NET, (ii) the use of TAT,
and (iii) an outcome.
Studies were excluded in non-NET or non-NET patients, studies involving 177Lu, 99m Tc, 18F, Y-90, and 68Ga, those without reported outcomes, animal/in vitro studies,
case reviews, and comments/letters to the editor.
Selection of articles
A flowchart of the selection of eligible articles is shown in [Figure 1 ]]. Two authors (T.K. and G.C.) independently reviewed all titles and abstracts for
inclusion. Disagreement was resolved by discussion and reference to the full text
of the paper. If consensus could not be reached, a third author (E.B.) made a final
decision.
Figure 1 Summary of citations included in review
Data extraction
All methods for exclusion criteria, data extraction, and quality assessment were specified
in advance. However, due to the evaluated number of participants and variation in
reporting and data collection of overall survival (OS), freedom from local progression
(FFLP), progression free survival (PFS) and median survival time (MST), a systematic
analysis was not possible due to the lack of consistency. Data were, however, extracted
and tabulated to provide a clear integrative overview of the results to date for TAT
for NENs. Data extracted include pretreatment with either chemotherapy or PRRT and
outcome measures such as RECIST 1.1 staging and chromogranin A levels.[[17 ]],[[18 ]] The review protocol was not registered with any organization.
Results
Search results
Of the 2334 articles identified, 258 were duplicates. One article, an ongoing trial
on the use of TAT in GEP-NET, was included following review of current literature.[[19 ]] Of the remaining 2076 articles, a further 2065 were excluded based on the inclusion/exclusion
criteria, leaving 11 articles; of which 2 studies were original articles describing
the use of targeted alpha therapy in neuroendocrine tumours more specifically GEP-NENs.
One case report and one ongoing phase 1 prospective trial which did not meet our inclusion
criteria are discussed separately in the “Discussion” section.
Study characteristics
Only two articles were included in the study. These studies were published in 2014
and 2019, were prospective, and retrospective in design. No randomized controlled
trials were identified. The study lengths varied from 2 to 34 months. The median/mean
age of the patients in the prospective study was 52 years (range 43–61); The age of
the patients in the retrospective study was not clearly described; however, the study
cohort is assumed to be in an adult population based on the epidemiology of this disease.
All patients had metastatic NET of which more than 70% are related to GEP-NET. All
patients had also received standard first/second-line systemic therapy (including
SSA and chemotherapy) as well as treatment with PRRT using 177Lu-DOTATATE. These patients
were either stable or refractory to the standard therapy. The studies used two different
types of TAT, namely 213Bismuth (213Bi)-DOTATOC and 225Actinium (225Ac)-DOTATATE.
The administration of therapy varied between the studies with 213Bi-DOTATOC infused
intra-arterially through the common hepatic artery (1 patient of the study had 213Bi-DOTATOC
infused intravenously), while 225Ac-DOTATATE was administered intravenously. The baseline
treatment characteristics of the individual articles are described in [Table 1 ].
Table 1: Baseline treatment characteristics
Efficacy and safety of 225Actinium-DOTATATE
The therapeutic outcome of the study was objective tumor response by RECIST 1.1 criteria
and biochemical response [[Table 2 ]]. Treatment-related adverse events during 225Ac-DOTATATE therapy were assessed according
to the CTCAE V5 criteria and reported in two categories: Adverse events-related laboratory
parameters and other clinical adverse events. The median follow-up duration was 8
months (2–13 months) from the start of 225Ac-DOTATATE therapy.
Table 2: Posttreatment response and adverse events with targeted alpha-particle therapy
Thirty-two patients were recruited for the study; however, only 24 patients underwent.
interim analysis which was conducted 8 weeks after the second cycle of 225Ac-DOTATATE
therapy. The remaining 8 patients were awaiting rescanning. 62.5% (15/24) of patients
revealed partial response and the remaining 37.5% of patients showed stabilization
of disease (minimal response 6/24, stable disease [SD] 3/24) based on the RECIST 1.1
criteria. Biochemical response showed a significant decrease in CgA levels post-225Ac-DOTATATE.
Median CgA level of 326.4 ng/mL (interquartile range [IQR] 125–1055 ng/mL) was measured
before therapy. At the end of the follow-up, it was 126 ng/mL (IQR 51.6–574.4) (P
< 0.0001).
With regard to adverse effects-related laboratory parameters, no significant difference
in hemoglobin levels was seen (P = 0.5138) although a statistically significant decrease in the platelet counts was
noted (P = 0.0380). No significant biochemical complications such as grade III/IV hematological,
renal, or hepatotoxicity were documented. The most common clinical adverse events
reported was abdominal distension (100%), followed by vomiting 29/32 (90.6%), headache
25/32 (78%), and diarrhea 24/32 (75%) The most severe clinical adverse effect was
grade III/IV gastritis 7/32 (22%), and the incidence of peptic ulcer disease however
was not reported.
Efficacy and safety of 213Bismuth-DOTATOC
In this retrospective case series, eight patients were studied and followed up. The
therapeutic outcome of the study was tumor response by RECIST 1.1 criteria. A specific
time point for the analysis of the treatment outcome (i.e., following x number of
cycles after treatment) was not described. Biochemical response was not assessed.
Treatment-related adverse events during 213Bi-DOTATOC were described. The median follow-up
duration was 22.5 months (6–34 months) from the start of 213Bi-DOTATOC therapy.
25% (2/8) of the patients showed partial response, 37.5% (3/8) patients showed SD,
while 12.5% (1/8) showed complete response. 25% (2/8) of the patients did not have
a RECIST 1.1 score provided. With regard to adverse effects, 37.5% (3/8) patients
developed chronic anemia while 12.5% (1/8) developed myelodysplastic syndrome/acute
myeloid leukemia (AML). 12.5% (1/8) developed Graves' disease as thyroid cells can
also express somatostatin receptors, and as such, this is considered a treatment-related
adverse event. 12.5% (1/8) had an elevated creatinine value between 1 and 1.5 times
the upper limit of normal 2 years after therapy. No clinically significant nephrotoxicity
was described in the rest of the cohort [[Table 2 ]].
Discussion
NENs are very heterogeneous tumors which are challenging to manage given varying behavior
as well as the propensity of some NENs to produce hormones. While some patients have
indolent disease, many progress despite systemic treatment and patients may die from
progressive disease. There are limited treatment options, particularly after the failure
of 177Lu-DOTATATE (PRRT) therapy. Therefore, there is an urgent need for further-line,
well-tolerated therapies for metastatic NEN.
Alpha emitters have two distinct advantages over conventional beta emitter therapy.
First, the short range of alpha radiation in the human tissue (of only a few cells
or 40–100 μm) allows for more selective killing of targeted cancer cells while preserving
surrounding healthy tissue. Second, the high LET of alpha radiation results in dense
ionization along the particle track as compared to sparsely ionizing beta particles.
This allows for more effective cell killing via increased production of DNA double-strand
and DNA cluster breaks.[[20 ]] As such, TAT therapy can target cells which are otherwise resistant to treatment
with conventional beta and gamma particles or chemotherapeutic drugs.
Alpha particle therapy in the treatment of various cancers such as prostate, NENs,
breast, colon, myeloma, and ovarian cancer has been investigated.[[20 ]],[[21 ]] However, the safety and efficacy of TAT in the treatment of NENs have not been
clearly established in clinical studies. This is due to the lack of a well-designed
prospective randomized controlled trial and lack of well-designed safety profile trials.
This is the first systematic review performed to date to understand and identify the
clinical evidence of targeted alpha therapy in the treatment of NENs. Our systematic
review has identified two clinical studies, both of which are retrospective and prospective
case series, which meet our inclusion criteria for review. Unfortunately, due to the
limited number of studies identified and the significant heterogeneity of the intervention
and outcome measurement, a meta-analysis cannot be performed. Through this systematic
review, we also identified one case report and one ongoing phase 1 prospective trial
which did not meet our inclusion criteria but are worth discussing in this section.
Putative targeted alpha particle therapy agents in the treatment of neuroendocrine
tumors and its outcomes
225Ac-DOTATATE, 213Bi-DOTATOC, and 212Pb-octreotate have been investigated for the
treatment of NETs.[[19 ]],[[22 ]],[[23 ]],[[24 ]],[[25 ]],[[26 ]] These agents have been predominantly used in patients who have had conventional
therapy and are found to be refractory or stable on these treatments. Based on our
current review, intravenous/systemic use of 225Ac-DOTATATE shows the most promise
as a putative TAT agent. The study by Ballal et al . is a well-designed prospective case series with a well-defined patient cohort, a
systematic treatment algorithm, and a standardized measurement of outcome, with regard
to the timing of the radiological acquisition and assessment of biochemical response
with CgA. The study showed that 67.5% of its patients achieved partial remission following
two cycles of 225Ac-DOTATATE of 100 kBq/kg without any patients experiencing progressive
disease. Clinically significant adverse effects such as myelodysplasia, nephrotoxicity,
and hepatotoxicity were not documented during the initial/early follow-up period.
A similar response to 225Ac-DOTATATE has been documented in a case report with a dosage
of 9.8 MBq wherein a patient with pancreatic NEN and hepatic metastases developed
resistance to PRRT with the β-emitters 177Lu and 90Y at the 10th cycle of PRRT.[[26 ]] The patient was subsequently treated with 9.8 MBq of 225Ac-DOTATATE and achieved
partial remission according to the RECIST 1.1 and molecular imaging criteria following
the single dose of TAT. Long term follow-up of this index patient was not available
for review.
Although the study by Ballal et al . provides encouraging evidence for the use of TAT in treatment-resistant NET, the
study is limited by the small sample size of only 24 patients and the lack of functional
imaging (either 18FDG-PET or 68Ga-DOTATATE/DOTANOC) for the characterization of the
residual metabolic activity of the metastatic NET. Long-term outcome measures such
as PFS and OS were not documented due to the short-term follow-up of these patients.
The optimum number of cycles required to obtain sustained response is unknown as the
data set is only valid for two cycles of 225Ac-DOTATATE administered intravenously
at 100 kBq/kg.
Our review has found very little evidence for the use of 213Bi-DOTATOC and 212Pb-octreotate
in the treatment of metastatic NET. The retrospective case series by Kratochwil et al . reported almost a third of its patient cohort achieved either partial or complete
response.[[23 ]] However, only eight patients were involved in this study and the baseline characteristics
of the patient cohort was very heterogeneous without a reportable age. The tumor grade
of the metastatic NET was not reported while two of its patient cohort had either
neuroendocrine cancer of unknown primary or neuroendocrine prostate cancer. Treatment
administration was not standardized with 1/8 patient receiving 213Bi-DOTATOC intravenously,
while the rest received intra-arterial administration of 213Bi-DOTATOC through the
common hepatic artery. Patients also received varying doses of 213Bi-DOTATOC therapy
with one patient only receiving a single cycle of 213Bi-DOTATOC and 4/8 patients receiving
five cycles. Although the objective treatment response in this study was based on
the RECIST 1.1 criteria, the timing of the radiological acquisition was not described
or standardized within its patient cohort.
Currently, there are no published studies on the use of 212Pb-octreotate in the management
of NETs. A recent study investigating the therapeutic efficacy and safety profile
of 212Pb-octreotate was presented at the Annual Meeting of the American Association
for Cancer Research in 2020.[[27 ]] This was a phase 1, nonrandomized, open-label, dose escalation study in adult subjects
(6 men and 7 women, median age 68 [range 27–75] years) with NETs overexpressing SSRs.
Preliminary findings revealed a decrease in tumor burden and a positive impact on
quality of life in patients (n = 3) who received three cycles of 212Pb-octreotate at the highest dose, specifically
at 67.6 mCI/kg for three cycles. Partial response with 73%, 71%, and 33% decrease
in size of the index lesions, respectively, was based on the RECIST 1.1 criteria.
68Ga DOTATATE PET/CT revealed almost a complete response in two patients and a partial
response in the third. No clinically significant drug-related hematological and renal
toxicity was encountered. Results of this study are promising, and further long-term
studies are required to further assess the therapeutic efficacy and safety profile
of 212Pb-octreotate.
Adverse events related to targeted alpha particle therapy
Severe clinical adverse events such as hepatotoxicity, nephrotoxicity, and myelodysplasia
have not been found to be the dominant adverse events experienced by patients who
underwent TAT according to the reviewed studies. Kratochwil et al . reported a single case of myelodysplastic syndrome which progressed to AML 24 months
following the last treatment of intra-arterial 213Bi-DOTATOC (a total of 5 cycles
which is equivalent to 16.0 GBq); however, the occurrence of myelodysplasia may have
been confounded by prior intra-arterial PRRT with beta emitters (90Y and 177Lu).[[23 ]] Other reported adverse events across the studies include loss of appetite, nausea,
vomiting, gastritis, and chronic anemia.
Conclusion
Currently, there is limited published data on the safety and efficacy of TAT in the
treatment of NENs. However, TAT remains a promising treatment option for metastatic
and treatment-resistant NEN. 225Ac-DOTATATE has been shown to be effective in the
treatment of metastatic NEN with minimal clinically significant adverse events. Further
long-term randomized controlled trials are needed to assess the treatment outcome,
adverse events, and placement of TAT in the overall treatment algorithm for NENs.
