PRRT, Changing role of somatostatin receptor targeted drugs in NET: Nuclear Medicine’s view Vikas Prasad 1, S. Fetscher 2, and Richard P. Baum (click title)

One of the best articles on NET/Carcinoid Imaging, treatment options, & PRRT Therapy.

http://www.ualberta.ca/~csps/JPPS10_2/19/19.pdf

Changing role of somatostatin receptor targeted drugs in NET: Nuclear Medicine’s view

Vikas Prasad 1, S. Fetscher 2, and Richard P. Baum 1 Department of Nuclear Medicine, Center for PET/CT, Zentralklinik Bad Berka, Germany, 2 Department ofHematology and Oncology, Sana Kliniken Lübeck, Germany

THIS IS A MUST READ ARTICLE FOR ANYONE WHO IS BATTLING THIS DISEASE AND INTERESTED IN GA68 IMAGING AND PRRT TREATMENT. ONE OF THE BEST WRITTEN ARTICLES I HAVE READ. PRINT IT OUT AND READ IT A FEW TIMES AND BRING IT TO YOUR MD....

LEARNING ABOUT THIS OPTION IS IMPORTANT...AND THIS IS ONE OF THE DOCUMENTS YOU NEED TO STUDY!

To help, I documented a "cheat sheet" of some of the important items for PRRT on the study below with some of my comments added- (but please read the entire study link!):

PRRT

Based on the success achieved by SRS,somatostatin analogues were labeled with particle emitters such as 90Y, 177Lu, 111In and used for therapy. These three radionuclides differ significantly in their physical properties.

>111In emits auger electron and conversion electrons which have a path length in tissue of only 0.02-10 and 200-500μm, respectively. Studies demonstrating the internalization of 111In DTPA-octreotide in tumor
cells have clearly shown that the therapeutic effect of this radionuclide is due to the auger electrons andChanging role of somatostatin
receptor targeted drugs in NET:Nuclear Medicine’s view
Vikas Prasad 1, S. Fetscher
1 Department of Nuclear Medicine, Center for PET/CT,
Zentralklinik Bad Berka, Germany, 2 Department of
Hematology and Oncology, Sana Kliniken Lübeck,
Germany
http://www.ualberta.ca/~csps/JPPS10_2/19/19.pdf
not to the conversion electrons. The low tissue penetration path-length of auger electrons results in

reduced tissue toxicity, however, in our mind it is not sufficient for achieving a satisfactory therapeutic effect due to lack of a ‘cross fire’ effect whereby non SSTR positive cells could also receive lethal radiation damage.

The limitation in the therapeutic utility of 111In DTPA-octreotide led to tagging of SSTR analogues with beta particle emitting radionuclides such as 90Y and 177Lu. Numerous studies have documented that the tumor shrinking capacity of 90Y and 177Lu labeled SSTR analogues is much higher than that achieved with 111In labeled SSTR agents. The most important physical properties of these three
radionuclides are presented in Table 6 (38). Based upon a mathematical model for determining

tumor curability in relation to tumor size (38), de Jong et al. (39,40) have demonstrated in a rat model

that 90Y is more effective in killing bulky tumors, (11mm kill range) whereas 177Lu is more effective in small tumors; (2mm kill range) and combination of both radionuclides resulted in better control of both, small and large tumors.


The clinical efficacy of different radiolabeled somatostatin analogues varies from tumor to tumor because of their affinity to different SSTR subtypes. As can be seen from Table 4, unlabeled octreotide (‘cold’) has highest affinity for sstr2, binds with somewhat lower affinity to sstr3 and 5 and does not bind to sstr1 and sstr4. In contrast, 111In-Octreotide binds with lower affinity to sstr2, sstr3 and sstr5.

Since most of the metastatic tumors express sstr2, the decreased binding affinity of 111In-octreotide to all SSTR subtypes does not affect the scintigraphic results (41,42).


Several other studies have also documented that for PRRT it is primarily more important to have the

somatostatin analogue with the highest affinity for sstr2. In fact we found that 90Y-DOTA-NOC, which has higher affinity for sstr3 and sstr5, is more toxic than 90Y-DOTA-TATE (DOTA-Octreotate),

probably because of the higher uptake in normal tissues. Therefore DOTA-NOC is no longer used

for PRRT at our centre.

Selection criteria for PRRT

Because of the potential for renal and hematologic toxicity associated with PRRT, it is important to

define patient subgroups that will most likely benefit from this specialized therapy. A recent

article, based upon the survey of phase I and phase II clinical trials conducted so far, provided the

following selection criteria for gastroenteropancreatic neuroendocrine tumors:

Inclusion criteria

1. Intense SSTR expression of the tumor/metastases (as demonstrated by SRS or SR-PET/CT, Figure 3) -Oscan and or Pet/Ga68- (NOTE- IF YOU DO NOT HAVE SSTR RECEPTORS (OR WEAK), PRRT WILL PROBABLY NOT BE AN EFFECTIVE THERAPY. THIS IS REVIEWED/DETERMINED PRIOR TO THERAPY)


2. Hemoglobin, WBC and platelet count should be ≥ 6 mmol/L, 4 x 109/L and 100 x 109/L, respectively.


3. Serum creatinine should ≤ 110 μmol/L or creatinine clearance ≥ 50 mL/min.
In view of the authors,wherever there is a possibility to determine the glomerular filtration rate (GFR) by using 99mTc-DTPA (or using plasma clearance methods), it is advisable to do so. In addition, the tubular extraction rate (TER) should be determined by dynamic renal scintigraphy using 99mTc-MAG3 before and serially after PRRT. (these tests are done in Bad Berka)


4. Karnofsky Index ≥ 50


5. Average life expectancy should be > 6 months

Exclusion criteria

1. Pregnancy/lactation


2. Chemotherapy within 6 weeks prior to the PRRT


3. Second malignancies with short term survival (e.g.  metastatic melanoma).


A part from this, patients should not be on cold octreotide therapy at least 6 weeks prior to therapy
as it has been shown that there is a competitive inhibition of radiolabeled somatostatin analogues

with cold octreotide for SSTR and PRRT. The authors have also shown that there is a significant

reduction of 68Ga-DOTA-NOC uptake in SSTR rich normal organs/tumors in patients treated with

somatostatin analogues (43).

Indications for PRRT

Based upon the clinical results gathered over the last decade, it is suggested that PRRT should be

reserved for patients with metastasized NET with documented evidence of disease progression after surgery or in some patients with inoperable tumors (e.g., inoperable primary tumors of the pancreas)


The definitive role of PRRT as first-line treatment modality has not yet been defined by centres
specialized in NET patient care. However, most patients who have been referred to our nuclear

medicine centre for PRRT were already in an advanced stage of disease.

In view of the authors, it would very likely be promising to apply PRRT to high risk patients immediately after surgery, rather than waiting for the tumor to metastasize on therapy with cold octreotide, chemotherapy, or interferon therapy.

Prior to PRRT, all lab values, morphologic and functional imaging results must be available.



Dosing schedule and quantity of radioactivity administered
After more than a decade of practicing PRRT, the issue of optimal dosing schedules still remains highly controversial. The most important criteria to decide upon when and how frequently PRRT can be and should be administered, are clinical stage of the disease, response to first PRRT, hematologic toxicity and renal function parameters.

As mentioned earlier, currently PRRT is indicated only after documented evidence of disease progression in patients with metastasized NET.


The amount of radioactivity chosen to be administered is primarily dependent upon renal function parameters, SSTR expression (quantitative and visual) on SR-PET/CT (if SR-PET/CT not available then SRS) and the extent of the disease (single vs. multiple metastases, tumor burden).
Many centres apply repeat PRRT (90Y-DOTATOC, 90Y-DOTA-TATE, 177Lu-DOTA-TATE) at

various and alternating time intervals.

Our experience in more than 1,000 PRRT cycles,administered in over 350 patients (with a maximum of 8 PRRT cycles in some patients) suggests that it is advisable to administer lower amounts of radioactivity at more frequent and prolonged intervals (3-6 months in between therapies), rather than giving high activities at short intervals. We dubbed this strategy the “Bad Berka PRRT concept” based on the rationale that slowly growing tumors are probably more susceptible to frequent low dose hits rather than to 2 or 3 “big bangs”.

Clinical results

The results of PRRT have varied widely depending upon which kind of radionuclide and somatostatin

analogue was utilized.

> In111: At first, the emission of auger electrons from 111In was utilized to treat somatostatin receptor positive tumor with up to 160 GBq of 111In-DTPA-octreotide. Partial remissions have been described in 8 % of patients as well as stabilization of disease in a higher proportion of patients (44-46) by some authors, whereas others did not see any objective response. Auger electron emission* is a major drawback for the treatment of larger tumor.  *(I think it has less than .3 to .5mm kill area or less)

>Y90: In contrast, using 90Y-DOTA-TOC in phase I and II clinical trials, complete or partial remissions were observed in nearly 27 % of patients (47,48). In these studies patients received 3 or more equal amounts of radioactivity. Waldherr et al. (49,50), using a different treatment regime (patients received  or more single injections of 90Y-DOTA-TOC with increasing amounts of radioactivity administered at 4-weekintervals), showed a partial response in 24 % of the patients. A comparison of two different treatment protocols used in 400 patients at the University Hospital Basel (one group of patients received 4 equal injections of 1,850 MBq/m2 at 6 weeks intervals, whereas the other group received two equal injections of 3,700 MBq/m2 at an interval of 8 weeks) has demonstrated that patients receiving higher doses at an 8 week-interval had a slightly better response rate (34% vs. 24% PR). (11mm kill zone)


> Lu177: Kwekkeboom et al. (51) reported complete remissions in 2 %, and PR in 26 % of 139 patients (28% cr/pr) with GEP NET treated with 177Lu-DOTA-TATE with a very low toxicity profile.

>Lu177 & Y90: In our center,using 90Y-DOTA-TATE and 177Lu-DOTA-TATE either alone or in combination (mostly sequentially), partial remissions were achieved in 39 % of the patients and in 9/302 (3%) patients a complete remission was observed (unpublished data).

A measurable clinical benefit (improvement of symptoms) was seen in over 90 % of the patients (Figure 6).- (usually patient stops needing MONTHLY SA injections!) A study conducted by Kwekkeboom et al. to assess the quality of life (QoL) in patients with GEP treated with 177Lu-DOTA-TATE demonstrated that global health/QoL improved significantly in patients post treatment.

Toxicity profile: PRRT vs. other treatment options

The primary concern of many non-nuclear medicine physicians prior to referring a patient for PRRT is radiation-induced toxicity. In fact, radiolabeled somatostatin analogues are primarily excreted through the kidneys and, with regards to toxicity, the kidney is the primary organ of interest.
Therefore, PRRT is administered under nephroprotective agents such as amino acids (lysine, arginine) to reduce renal radiation damage.
 A novel approach is the use of gelatine (gelofusine) prior to PRRT for reducing renal toxicity; initial results are promising (52-54).

With 111In-DTPAoctreotide, high cumulative radioactivity doses can be administered without any significant
deterioration in renal function (45).

Few studies have reported significant renal toxicity after 90YDOTA- TOC therapy, for the most part even in the absence of renal protection (55-60). With the advent of improved protective agents renal
toxicity can be reduced even further. In our centre, in patients with normal kidney function before
PRRT, no terminal kidney insufficiency has been observed so far at a mean follow up time of several years (Figure 7). Other adverse effects which are experienced, like hematological and liver toxicity, are usually mild and mostly reversible.

In a phase I study conducted in 47 patients in Rotterdam, Brussels and Tampa with 90Y-DOTATOC,
one patient with secondary myelodysplastic syndrome was observed, one showed liver toxicity,

and three patients developed grade 4 thrombocytopenia (39,61).

Studies using 177Lu-DOTA-TATE have documented less and mostly transient toxicity with only minimal bone marrow suppression (51,62,63).

In comparison to chemotherapy, PRRT using 177Lu DOTA-TATE have been shown to be less toxic

Kwekkeboom et al. (51) observed hematological toxicity in less than 2 % of the patients as compared to 5-61 % toxicity observed in patients treated with chemotherapy (20-22,64-67).


Similarly, renal toxicity was found to be much less as compared to that with chemotherapy (51).

Figure 7. Serial follow-up of hematological data by measuring hemoglobin, red blood cells (RBC), white

blood cells (WBC) and platelets (PLT) as well as serum creatinine. There is no significant hematological

toxicity after 3 cycles of 90Y- and 2 additional cycles of 177Lu DOTA-TATE therapy.

Multimodality Approach

In recent years, the value of combining different treatment modalities in order to achieve better

disease control in metastatic or inoperable NET has been increasingly investigated. Randomized clinical trials are underway to compare the efficacy of PRRT alone, and in combination with
chemotherapy. The concept of COMBIERT (Combined Internal External Radiotherapy),

developed by R.P. Baum, aims at combining internal and external radiation therapy for better
efficacy. Initial results in patients with neuroendocrine tumors (e.g. inoperable primary pancreatic NET as well as in recurrent glomus tumors (Figure 8) and paragangliomas) are promising.

Similarly, the use of PRRT for tumor debulking prior to surgery (neoadjuvant therapy)
should also be considered.

CONCLUSION

The significant and undeniable effects exerted by PRRT, even to the extent of being curative in
individual cases (Figure 9), has had a major impact on how patients with NET are treated in some
European countries. However, in spite of being an effective treatment option, PRRT is practiced in
Europe only at a few specialized centers (and even less in the U.S. and Canada), mainly due to the lack

of commercially available 90Y- and 177Lu- labeled somatostatin-derived peptides (radiopharmaceuticals). (NOTE: THIS IS A 2007 STUDY. THIS IS CHANGING AS NOW THIS IS IN AUSTRALIA, SINGAPORE, INDIA, AND I BELIEVE CHILE, PLUS MANY HOSITALS IN EUROPE)


Studies that directly compare the clinical results of standard octreotide therapy with PRRT are unfortunately missing. These and other yet unresolved questions regarding the optimal therapy of patients with localized and metastatic NET should be addressed by newly designed, cooperative multicentre trials.