Principle of Peptide Receptor Radionuclide Therapy
Peptide receptor radionuclide therapy (PRRT) is a molecular targeted receptor-based
radiopeptide therapy for metastatic/advanced neuroendocrine neoplasms (NENs), delivered
through an intravenously administered unsealed radioisotope source (mostly lutetium
octreotate or 177 Lu-DOTATATE).[1 ] The fundamental principle is targeting somatostatin receptors (SSTRs), a family
of G-protein-coupled receptors comprising five distinct subtypes (SSTR1 to SSTR5),
of which subtype 2 (SSTR2 ) has been of the major target in PRRT, in view of its overexpression and dominance
in the NENs.
The therapy is based on the principle of “Theranostics” (”Treat what you see and See
what you treat”), which is defined by integrating a diagnostic testing (in this case,
diagnostic agent and modality: 68 Ga-DOTA-TOC/NOC/TATE for positron emission tomography [PET] imaging and 99m Tc-HYNIC-TOC as single-photon emission computed tomography [SPECT] imaging where the
former is not available) for the presence of a molecular target (in this case, SSTR2),
for which a specific treatment/drug is intended (mostly lutetium octreotate or 177 Lu-DOTATATE).
Metastatic and unresectable neuroendocrine tumors that demonstrate high-grade uptake
(semi-quantitative Krenning score 3 or 4) on SSTR-based 68 Ga-DOTA-TOC/TATE PET-computed tomography (PET-CT) and 99m Tc-HYNIC-TOC SPECT-CT are the ones being considered for PRRT. Such patients typically
encompass well-differentiated and moderately differentiated NENs (NEN Grade 1 or 2
according to the World Health Organization 2017 classification, with Ki-67/MIB-1 labeling
index (LI) up to 20%, though some guidelines European Society for Medical Oncology
(ESMO) recommend considering patients up to Ki67 of 30%.[2 ]
[3 ] The Krenning score is a semi-quantitative scoring system used to grade the uptake
intensity of metastatic NEN lesions on SSTR-based imaging.[4 ] The usual setting has been disease progression on cold somatostatin analogs (SSAs),
though the application of PRRT has been steadily growing and sometimes being considered
upfront in patients with large-bulk disease on diagnostic study.
Finer points on extended indications
While the aforementioned has been a typical indication for PRRT in NENs, there have
been a number of “stretching the boundaries” beyond the typical indication in view
of the excellent tolerability of PRRT and gratifying results in improving the quality
of life in this group of patients, as follows:
PRRT in NENs with MIB-1 (Ki-67) LI between 20% and 30%: This is a “gray zone” and
frequently, these group of tumors demonstrate high uptake on 68 Ga-DOTATATE PET-CT and has been an area where PRRT has been advocated successfully.[5 ] In addition, this group usually demonstrates high uptake of fluorodeoxyglucose (FDG)
(on dual-tracer PET-CT), and thus combined chemo-PRRT is now an available option with
encouraging results (detailed later). As previously mentioned, the ESMO clinical practice
guidelines for gastroenteropancreatic (GEP)-NENs advocate PRRT up to Ki-67 of 30%[3 ]
[5 ]
Beyond GEP-NENs: While GEPNENs have been the major and classical indications of PRRT,
there are a number of other areas where this therapy has been frequently considered
and advocated. We do have a fair amount of clinical experience in these “beyond GEP-NEN”
applications in our setting which include the following (in decreasing order of frequency):
Metastatic/inoperable Bronchopulmonary and Mediastinal/Thymic NENs,[6 ]
[7 ]
** Metastatic/inoperable Medullary thyroid carcinoma,
Non-131I-MIBG concentrating metastatic Paraganglioma and Pheochromocytoma
**Non-iodine concentrating metastasis of differentiated thyroid carcinoma (TENIS:
only 15-20% of this patient subgroup demonstrates enough uptake to justify PRRT),[8 ]
Other tumors with neuroendocrine tumor differentiation/characterization: We have experience
in metastatic Merkel Cell carcinoma, Menigioma and recurrent/inoperable Phosphaturic
Mesenchymal Tumor.[9 ]
[10 ]
[11 ]
** In these '**' marked case scenarios, PRRT has been considered even though there
was a lesser degree of uptake (Krenning score 2) on SSTR based scanning, esp due to
alternative regimens were either potentially toxic/experimental with less-than-modest
efficacy/expensive.
Decision-Making Workup Scans for 177 Lu-Dotatate Peptide Receptor Radionuclide Therapy
The first decision-making scan to judge the suitability of PRRT is SSTR-2 targeting
68 Ga-DOTATATE PET-CT (alternatively, other SSTR-based ligands, e.g., 68 Ga-DOTA-TOC/NOC PET-CT has also been used with equivalent diagnostic performance).
The (i) superior resolution of PET-CT and (ii) the ability of quantification of uptake
make 68 Ga-DOTATATE PET-CT the choice for evaluating NENs.[12 ]
[13 ]
However, in the Indian setting, 68 Ga-DOTATATE PET-CT may not be available to all centers (though the situation is rapidly
changing), either due to (i) nonavailability of PET or (ii) nonavailability of 68 Ge- 68 Ga generator which are mandatory components for the aforementioned scan. In centers
where 68 Ga-DOTATATE PET-CT is not available, 99m Tc-HYNIC-TOC SPECT is the preferred scan possible with conventional gamma camera.
The kit formulation method and indigenous production at Bhabha Atomic Research Centre
and Board of Radiation and Isotope Technology have made it readily available. The
widespread employment of 99m Tc-HYNIC-TOC possible at many peripheral centers without PET-CT is less known to many
practitioners, who should ask this from their nuclear medicine colleagues. We must
mention here that in our setup, in the initial years of PRRT development, 99m Tc-HYNIC-TOC planar and SPECT imaging had served reasonably well (though quantification
and the superior resolution of 68 Ga-DOTATATE PET-CT make it the preferred option); the message is where PET-CT is not
available, 99m Tc-HYNIC-TOC can be used for the decision-making [Figure 1 ].[14 ]
Figure 1: Comparison among 68 Ga-DOTA-TATE positron emission tomography/computed tomography, 99 mTc-HYNIC-Tyr3-octreotide single-photon emission-computed tomography, and posttreatment
177 Lu-DOTA-octreotate single-photon emission-computed tomography for the detection of
particular lesions. Arrows of the same color indicate the same lesion
Dual-Tracer Positron Emission Tomography-Computed Tomography: Important Value of Adding
Fluorodeoxyglucose-Positron Emission Tomography/computed Tomography To The Management
Algorithm and Reading it Side-By-Side Somatostatin Receptor-Based Imaging for Personalized
Decision-Making
The relative uptake of 68 Ga-DOTATATE and FDG in the tumor has evolved as a powerful indicator of assessing
the dynamic tumor biology of NENs on a continuous scale.[15 ]
[16 ]
[17 ]
[18 ] This parameter has been well recognized in most active PRRT centers, and the medical
oncologists at our setup are quite accustomed to interpretation of these studies.
Along with the tumor Ki-67/MIB-1, 68 Ga-DOTATATE/FDG relative uptake forms an additional parameter to depict the tumor
phenotype. The dual-tracer PET-CT results forms a scientific basis for personalizing
therapy in NENs between SSA/PRRT vis-a-vis chemotherapy vis-a-vis chemo-PRRT. The
latter is considered when there is high uptake on both scans and typically can be
observed in Ki-67 between 20% and 30%, but can also be observed on occasional cases
in tumors with Ki-67 LI between 10% and 20%.
We have started understanding that the dual-tracer PET-CT forms a valuable complementary
to provide the subtle impression on tumor biology that cannot be discerned by the
Ki-67 discrete value alone. In addition, in a real-world scenario, discordance can
be occasionally observed between the dual-tracer PET-CT impression and that by the
Ki-67 LI, when the former is frequently assigned more weightage by oncologists for
taking decisions. Furthermore, due to intratumoral heterogeneity, the Ki-67 index
of a biopsy specimen may not be representative of the entire tumor; thus in case of
discordance between biopsy and imaging, the molecular imaging can result in better
depiction of the tumor biology. In our experience, in day-to-day practice in a busy
setting, even tumors <5% can demonstrate these characteristics. The emerging role
of dual scans has shown heterogeneous behavior in many of the previously considered
well-differentiated NENs.
Thus, areas where this can be of potential help in deciphering the tumor biology are:
(i) tumors in the intermediate level of Ki-67 LI, for example, 10%–20%; (ii) tumors
with Ki-67 LI between 20% and 30% (plays important and robust role for deciding between
PRRT, chemo-PRRT, and chemotherapy); and (iii) cases showing discordance between Ki-67
and the dual-tracer PET-CT findings.[15 ]
[16 ]
Treatment Schedule and Brief Description
Typically, the PRRT cycles are administered at 8–12 weeks' interval, with an average
of 150–200 mCi (5.55–7.4 GBq) in each cycle. In our setting, we usually keep (a) high-end
dose (200 mCi) for a patient undergoing PRRT in a neoadjuvant setting with a short
time interval (8 weeks between two cycles), whereas in the (b) multiple metastatic
setting, a patient receives a mean of 150 mCi per cycle at 3-month intervals. On an
average, a patient receives 4–5 cycles. While in the conventional fixed-dose regimen,
a cumulative dose of 800 mCi is maintained (which is much within safe limits); it
needs to be mentioned that with the dosimetric protocol, it is conveniently possible
to administer further doses in most patients – this is to be factored into while considering
“salvage PRRT” in case of progression/recurrence in the follow-up period or considering
adding stereotactic body radiation therapy. The hematological and renal parameters
can serve as good indirect guide for this.
The other point is that there is no randomized evidence for using neoadjuvant PRRT
at present; good cytoreduction can be observed with PRRT in isolated patients as per
our practice which can be used in the neoadjuvant setting on a case-to-case basis
or in the research setting.
Renal protection is carried out with a mixed amino-acid infusion (1000 ml), infused
over 8 h in addition to 200 ml prior to the 177 Lu-DOTATATE administration of the treatment. While many nephroprotection protocols
exist (ranging from 3 h infusion of basic amino acids to 2-day or 3-day protocol),
in our experience, this envisaged protocol has given excellent results in addition
to being convenient in a busy PRRT setting.
Contraindications and adverse effects and their management
First of all, PRRT is a well-tolerated therapy with minimal side effects, which is
one of the reasons for its gaining popularity over the years among patients and the
attending oncologists alike. One dose-limiting toxicity of PRRT has been nephrotoxicity
at higher doses owing to the uptake of radiolabeled SSAs in the proximal tubule cells
through megalin/cubulin system. The renal toxicity has been more often described in
the context of 90 Y-DOTATATE due to its stronger beta energy, whereas with 177 Lu-DOTATATE, this adverse effect is substantially lower in incidence. The proposed
cumulative absorbed dose to the kidney is limited to <23 Gy, which the standard PRRT
protocols had hardly ever attained. Nonetheless, we keep watching over the following
three particular group of patients: patients already having renal compromise due to
(i) hypertension, (ii) diabetes mellitus, and/or (iii) prior chemotherapy. To achieve
kidney protection, co-administration of basic amino acids through the other hand is
undertaken as a routine in PRRT, which interferes with the reabsorption pathway. In
our experience on a very large number of patients, we find excellent safety profile
of 177 Lu-DOTATATE, including patients with a single functioning kidney.[19 ]
[20 ]
The other adverse effects are minimal: nausea and vomiting (primarily due to the amino
acid co-infusion rather than the radiopharmaceutical per se ) which, during or soon after the therapy, can be well managed with dexamethasone-ondansetron
pretreatment or with aprepitant. Adequate blood counts (red blood cell, white blood
cell, and platelets) are ensured prior to PRRT in order to prevent isolated incidences
of long-term myelosuppression, specifically when combining with chemotherapy.
Efficacy results in metastatic settings
Probably, the most gratifying result is that in >90% of patients (esp. those with
functioning NENs even uncontrolled with octreotide LAR), there is remarkable symptomatic
improvement and better quality of life (QoL). The biochemical response in terms of
reduction of serum CgA/urinary 5-HIAA is noted in 60%–70% of patients. On imaging,
there were partial objective responses in around 30% of patients (complete response
in 2%–6%) [Figure 2 ], whereas disease stabilization was achieved in nearly 60% who had otherwise demonstrated
progressive disease on octreotide or lanreotide.[21 ]
[22 ]
[23 ]
[24 ]
[25 ]
Figure 2: Excellent response obtained with 177 Lu-DOTATATE peptide receptor radionuclide therapy in a 70 -year-old male, diagnosed as primary NET of body and tail of pancreas with multiple
hepatic metastasis, MIB-1 index: 12% and no previous surgical intervention. Dual-tracer
positron emission tomography-computed tomography 68 Ga-DOTATATE positron emission tomography (a) and fluorodeoxyglucose-positron emission
tomography (b) demonstrating Krenning Grade IV uptake on baseline 68 Ga-DOTATATE positron emission tomography (upper-left image) with relatively low-grade
fluorodeoxyglucose (lower-left image). Following three cycles of 177 Lu-DOTATATE peptide receptor radionuclide therapy, the metastatic lesion in both scans
showed excellent response, whereas the primary tumor showed partial response which
was then considered for surgery. (Reproduced with permission from Basu et al.[14 ])
In addition to the remarkable improvement in QoL even in patients with bulky disease,
the other parameter of interest is the prolonged progression-free survival (PFS) achieved
with PRRT. A Phase III multicentric international study (NETTER-1) in patients with
inoperable, progressive, SSR-positive, midgut carcinoid tumors documents extremely
promising results demonstrating a PFS of approximately 40 months versus 8.4 months
for octreotide LAR. This appears to be substantially superior to other systemic treatment
modalities available for metastatic NENs.[26 ]
There is some tumor-specific trend that can be observed: best objective responses
can be seen in GEP-NENs, and similar response rates have been achieved in bronchopulmonary
NENs, while relatively less favorable results are seen in thymic NENs and medullary
thyroid carcinoma, when objective partial responses are concerned. However, for both
of the latter, we have observed prolonged PFS, halting and stabilizing the disease.[6 ]
[7 ] Thus, there has been encouragement in recent times to advocate PRRT in these tumors
if they demonstrate good uptake in the diagnostic study.
Strong points of peptide receptor radionuclide therapy vis-a-vis the newer targeted
agents
The treatment options available for the advanced and metastatic NEN include systemic
therapies such as SSAs, molecular targeting therapies, chemotherapy, and PRRT. The
strong points of PRRT vis-a-vis the newer targeted agents (sunitinib and everolimus)
include (a) targeted biological action/rationale of PRRT as well as limited side effect
profile versus the toxicity of the new drugs, (b) the very convenient treatment schedule
of PRRT (completed in few discrete 1-day cycles) versus requirement to be on these
agents till disease progression, and (c) cost difference and expense (particularly
related to our setting in view of indigenous production of the radiopharmaceutical).
Special case scenarios
”Sandwich” chemo-peptide receptor radionuclide therapy regimen in neuroendocrine neoplasms
with high 68 Ga-DOTATATE and 18 F-fluorodeoxyglucose uptake on dual-tracer positron emission tomography/computed
tomography
Inoperable and metastatic NENs with low Ki-67 index (usually positive for SSTR imaging
with low/absent FDG uptake) are treated with SSA and PRRT, whereas NENs with high
Ki67 index (that are usually negative on SSTR-based imaging and show high uptake on
FDG-PET) are treated with chemotherapy. However, there exists an intermediate gray
zone with the tumor demonstrating both high 68 Ga-DOTATATEand 18 F-FDG uptake on dual-tracer PET/CT, where a combined approach of
PRRT plus chemotherapy appears a logical and rational approach.[27 ]
[28 ] In this regimen, two cycles of CAPTEM chemotherapy are sandwiched between two PRRT
cycles of 177 Lu-DOTATATE. Thus, a typical schedule is PRRT followed by two cycles of CAPTEM followed
by PRRT. In our setup, standard CAPTEM regimen comprising of oral capecitabine, 750
mg/m 2 twice daily for 14 days (D1–D14), and oral temozolomide 200 mg/m 2, once daily
for 5 days (D10–D14) is followed by 2-week rest period and another CAPTEM cycle given
for a total of 28 days is followed by the next cycle of PRRT at around 3 months. The
response evaluation involves standard procedure, i.e., assessment in three scales
namely (a) symptomatic scale, (b) biochemical tumor marker responses (serum CgA),
and (c) imaging response with 68 Ga-DOTATATE PET/CT and 18 F-FDG PET/CT. In our preliminary experience in a total of
38 aggressive metastatic NEN patients treated with chemo-PRRT, we found encouraging
results with partial response in around 45%, stable disease in 39%, and progressive
disease in 16% on RECIST 1.1 (unpublished data). The “chemoPRRT” regimen procedure
was well tolerated in all the 38 patients, with no Grade III/IV hematological and
renal toxicity in any of these patients.
Neoadjuvant peptide receptor radionuclide therapy
Similar to other oncological settings, neoadjuvant PRRT therapy has been examined
for its ability to reduce the size of tumor in GEP-NENs to the point where an initially
unresectable tumor becomes operable. PRRT as a neoadjuvant therapy was initiated in
our setting to treat locally advanced GEP-NENs using the National Comprehensive Cancer
Network criteria defined for borderline resectable pancreatic ductal adenocarcinoma.
In our preliminary experience, the inoperable disease became operable in around 26%
of patients in a population of 57 patients following PRRT. The PRRT was well tolerated
in all the 57 patients, without any major hematologic or renal toxicity in any of
these patients. We believe that this area needs further exploration, and surgeons
must be encouraged to undertake studies which would be important to know the tumor
characteristics that would be amenable to such intervention and to decide on its optimal
protocol.
Resistant functioning neuroendocrine neoplasm with carcinoid syndrome
While PRRT is an excellent and effective therapeutic modality in functioning NENs
in controlling the symptoms of carcinoid syndrome that are resistant to conventional
therapies (e.g., octreotide/lanreotide), the effect, at times, may take 2–3 cycles,
especially those with bulky hepatic metastases;[29 ] thus, it is needed to continue varying combinations of long-acting and short-acting
octreotide to be administered in the interim months between the cycles (long-acting
formulation intramuscularly) and just prior to therapy (short-acting formulation subcutaneously
daily, which can be continued till 1 day prior to a 68 Ga-DOTATATE scan or PRRT). The patient preparation is quite important in these cases
to prevent carcinoid crisis following PRRT (a rare but possible condition), which
can be well obviated by good preparation.[30 ] In our setting, in a patient with symptomatic carcinoid syndrome, we advocate short-acting
octreotide injections (subcutaneous) till 1 day before administering PRRT and start
back the next day following PRRT and continue till 10–14 days after therapy. Furthermore,
in a patient with bulky hepatic metastases, priming with antiserotonergic agent (e.g.,
cyproheptadine) is regularly undertaken.
Which radionuclide: 177 Lu, 90 Y, or alpha emitters?
PRRT has been traditionally performed with the following two beta emitters: yttrium-90
(90 Y) and lutetium-177 (177 Lu).[2 ] The radionuclides differ in their physical characteristics, which has a bearing
on their efficacy and toxicity.[2 ]
90 Y possess a higher beta particle energy (Eβmax = 2.28 MeV) than 177 Lu (Eβmax = 0.497 MeV), and thus may be more suited to treating larger tumor masses but has
more toxicity such as renal toxicity with 90 Y.[2 ] The recorded significant permanent renal toxicity from a Swiss study in over 1000
patients was documented quite high with 90 Y-DOTATOC at 9%.[31 ] This is one major reason why 177 Lu-DOTATATE has been and being adopted in most PRRT centers across the world, which
has demonstrated an excellent safety profile in thousands of patients. We believe
that combining 1–2 cycles of 90 Y-DOTATATE to the traditional 177 Lu-DOTATATE could be a reasonable approach for patients with large-sized heterogeneous
tumors, although this needs to be examined in future trials. Recently, alpha emitter
therapy (with 225 Ac-DOTATATE) has been introduced in the parlance of PRRT, which
is theoretically promising in view of its (i) high linear energy transfer, implying
delivery of “more powerful” radiation, and (ii) lesser penetration to the surrounding
normal tissues (thus lesser toxicity), though the clinical results are awaited to
prove this impression.
Cost factor and expense of peptide receptor radionuclide therapy
The PRRT service in this country has been a remarkable example of indigenization:
at the start of our PRRT program, 177 Lu-DOTATATE PRRT at the Radiation Medicine Centre used to cost between Rs. 20,000
and 22,000. In 2019, the cost of one cycle of 177 Lu-DOTATATE PRRT at this center costs around Rs. 8000–10,000 with virtually all steps
of production and radiolabeling procedures indigenized at the center. Thus, five cycles
of PRRT are completed at a convenient and much affordable cost of Rs. 50,000 for a
patient. Compared to this, the cost of the imported 177 Lu-DOTATATE per cycle would cost around Rs. 150,000/cycle (nearly 15 times more).
We have been satisfied with the indigenous product which has produced excellent results
in a large number of patients who underwent the treatment procedure at our institute.
Declaration of patient consent
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