While we are familiar with the use of MIBG and Octreotide PET imaging and therapy has now entered the nuclear arena to evaluate and treat neuroendocrine tumors (NET). We will first explore the imaging of, with PET and then continue with therapy and treatment.

1. A new ⁶⁸Ga imaging agent can be labeled to DOTATATE, DOTATOC, or DOTANOC. Currently only DOTATATE has been approved by the FDG (June 2016)
   
   http://radiopharma.com/product-category/product-portfolio/
   1. The ⁶⁸Ge/⁶⁸Ga generator
      1. Via a cyclotron ⁶⁸Ge is made: ⁶⁸Zn(p,n)⁶⁸Ga
      2. T1/2 of ⁶⁸Ge is 271 days and the T1/2 of ⁶⁸Ga is 68 minutes
      3. The elution used is 0.1NHCl
      4. Following an elution of ⁶⁸Ga of 60 mCi, how long would you have to wait to get an additional 45 mCi?
      
      5. Here is an example of three generators linked to an accessory cartridge
         
   2. Compounding

      Drug Preparation (link to entire package insert)
      The NETSPOT kit is supplied as 2 vials and an accessory cartridge [see Dosage Forms and Strengths
      (3) ] which allows for direct preparation of Ga 68 DOTATATE injection with the eluate from an Eckert &
      Ziegler GalliaPharm Germanium 68/Gallium 68 (Ge 68/Ga 68) generator. The Eckert & Ziegler
      GalliaPharm Ge 68/Ga 68 generator (“GalliaPharm generator”) is not supplied with the NETSPOT kit.
      The safety and efficacy of the Ga 68 DOTATATE injection drug product prepared from the NETSPOT kit
      has been established only when using a Ga 68 chloride solution eluted from the GalliaPharm generator.
      

      Components of the kit:
      Vial 1 (reaction vial with lyophilized powder) contains: 40 mcg dotatate, 5 mcg 1,10-phenanthroline;
      6 mcg gentisic acid; 20 mg mannitol.
      Vial 2 (buffer vial) contains: 60 mg formic acid; 56.5 mg sodium hydroxide and water for injection.
      Accessory cartridge contains: 660 mg porous silica. The accessory cartridge reduces the amount
      of Ge 68 potentially present in generator eluate.
      

      Prepare Ga 68 dotatate for intravenous injection according to the following aseptic procedure (see above diagram):
      a. Use suitable shielding to reduce radiation exposure.
      b. Wear waterproof gloves.
      c. Set the temperature of the shielded dry bath to 203 °F (95 °C), and wait for the temperature to reach the set point and stabilize.
      d. Prepare a syringe containing 5 mL of 0.1 N sterile HCl, to be used for elution of the GalliaPharm generator. Use 0.1N sterile HCl supplied by the generator manufacturer. Test periodically (weekly) the Ga 68 chloride eluate for Ge 68 breakthrough by suitable method. Ge 68 breakthrough and
      other gamma emitting radionuclides should be ≤ 0.001%. The Ga 68 chloride is sterile as eluted from the GalliaPharm generator.
      e. Remove the cap from Vial 1 (reaction vial), swab the top of the vial with alcohol to disinfect the surface, and allow the stopper to dry.
      f. Pierce the Vial 1 septum with a sterile needle connected to a 0.22 micron sterile vented filter (not supplied) to maintain atmospheric pressure within the vial during the reconstitution process.
      g. Remove the cap from the Vial 2 (buffer vial), swab the top of the vial with alcohol to disinfect the surface, and allow the stopper to dry.
      h. Using a 1 mL sterile syringe, withdraw the required volume of the reaction buffer from Vial 2.
      Calculate the volume (in mL) by multiplying the volume of HCl used for the elution of the generator in mL by its molarity:
      Reaction buffer volume in mL = HCl volume in mL x HCl molarity (for the GalliaPharm generator eluate, 5 mL x 0.1 N = 0.5 mL of reaction buffer).
      i. Connect the top of the cartridge to the male luer of the outlet line of the GalliaPharm generator. Connect the bottom of the cartridge with a sterile needle.
      j. Connect Vial 1 to the outlet line of the GalliaPharm generator by pushing the needle through the rubber septum and place the vial in a lead shield container.
      k. Elute the generator directly into the Vial 1 through the cartridge and the needle according to the instructions for use of the GalliaPharm generator that are supplied by Eckert & Ziegler, in order to reconstitute the lyophilized powder with 5 mL of eluate. Perform the elution manually or by means of a pump.
      l. At the end of the elution, disconnect the generator from Vial 1 by removing the needle from the rubber septum, and immediately (do not delay buffer addition more than 10 min) add the kit reaction buffer in the 1 mL sterile syringe (the amount of reaction buffer was determined from Step h). Withdraw the syringe and the 0.22 micron sterile air venting filter, and then using a tong, move Vial 1 to the heating hole of the dry bath, and leave the vial at 203 °F (95 °C, not to exceed 98 °C) for at least 7 minutes (do not exceed 10 minutes heating) without agitation or stirring. Do not invert or shake the reaction vial because contact between the solution and the rubber septum can lead to zinc leaching and can interfere with binding of Ga 68 to the peptide.
      m. After 7 minutes, remove the vial from the dry bath, place it in an appropriate lead shield and let it cool down to room temperature for approximately 10 minutes.
      n. Assay the whole vial containing the Ga 68 dotatate injection for total radioactivity concentration using a dose calibrator and record the result.
      o. Perform the quality controls according to the recommended methods in order to check the compliance with the specifications [see Dosage and Administration (2.5)].
      p. Prior to use, visually inspect the solution behind a shielded screen for radioprotection purposes. Only use solutions that are clear without visible particles.
      q. Keep the vial containing the Ga 68 dotatate injection upright in a radio-protective shield container at a temperature below 77 °F (25 °C) until use.
      r. After addition of Ga 68 chloride to the reaction vial, use Ga 68 dotatate injection within 4 hours.
      s. Drug name ⁶⁸Ga-DOTA-OCTREOTATE

   3. Neuroendocrine tumors²
      1. There is a direct correlation between DOTATATE and Octreoscan
      2. Tumors that contain a high expression of receptors:
         1. Sympathoadrenal system tumors (pheochromocytoma, paraganglioma, neuroblastoma, ganglioneuroma)
         2. Gastroenteropancreatic tumors (e.g. carcinoids, gastrinoma, insulinoma, glucagonoma, VIPoma, etc.), functioning and non functioning
         3. Medullary thyroid carcinoma
         4. Pituitary adenoma
         5. Medulloblastoma
         6. Merkel cell carcinoma
         7. Meningioma
         8. Small-cell lung cancer (mainly primary tumors)
      3. Tumors that contain low expression of receptors:
      1. Breast carcinoma
      2. Melanoma
      3. Lymphomas
      4. Prostate carcinoma
      5. Non-small-cell lung cancer
      6. Sarcomas
      7. Renal cell carcinoma
      8. Differentiated thyroid carcinoma
      9. Astrocytoma
      10. Ependymoma
   4. Pathophysiology²
      1. All radiopharmaceuticals bind to somatostatin (SST) receptors that have the DOTA peptide. Hence any tumor that has SST receptors may receive the DOTA peptide. It should also be noted that DOTA peptides are classified octreotide peptides
      2. General statement - all DOTAs' bind to SST 2 receptors, however, some have greater affinity for other receptor sites
      3. ⁶⁸Ga-DOTA-TOC also binds to SST 5 receptor
      4. ⁶⁸Ga-DOTA-NOC binds more to SST 3 and 5 receptors
      5. ⁶⁸Ga-DOTA-TATE binds mostly to SST receptor 2
   5. Applications of DOTA in PET have an advantage over Octreoscan with
      1. Improved resolution
      2. Better pharmacokinetics
      3. Defines primary tumor and metastatic disease
      4. Can be used to stage the disease
      5. Evaluate recurrences and/or residual disease
      6. Apply SUV to determine the role of therapy
      7. If SST receptor is present therapy with ¹⁷⁷Lu or ⁹⁰Y-DOTA can be applied
      8. When compared with ¹¹¹In-Octreotide, the PET agent gives a lower radiation dose
   6. Imaging Procedure
      1. Patient Prep
         1. Normal diet is allowed
         2. Some physicians recommend that that somatostatin therapy be discontinued
      2. Not patient history
         1. Note lab test related to the identification of tumor markers
         2. Attain other imaging exam results
         3. Identify all prior therapeutically applications
      3. Administering the radiopharmaceuticals
         1. IV with indwelling cath should be established
         2. Administers 100 to 200 MBq. How many mCi is this?
      4. Images
         1. Acquire data in 3D and at 45 to 90 minutes post dose
         2. Scan Head to mid-thigh
         3. Suggested imaging time 60 minutes, but variations should be considered based on crystal type
         4. Maximum tumor concentration occurs in 70 minus (±20 minutes)
         5. Clears from the blood stream within 4 hours
         6. SST receptors will image in any cell type that has that expression and include: liver, spleen, thyroid, kidney, salivary, stomach, pituitary, adrenal, stomach and bowel walls, pancreas (mostly SST 2), minimal uptake in breast and prostate
2. Cases
   
   1. Case I - There two anterior views display the difference between using the gamma emitting radiopharmaceuticals and the 511 keV radiopharmaceutical. Which agent shows better resolution? Which image shows tumors in the liver?
   
   2. Case II - Carcinoid resected 1 year ago with negative octreotide image results. However, it shows positive with the PET procedure
   3. The discussion and application of diagnostic and therapeutic medicine which is specifically designed to treat and evaluate disease at the molecular level can be referred to as "personal management of disease." The more scientific definition is theranostic,, where we can image and target specific ligands/receptors. This can be done with SPECT, MRI, or PET. In today's review, DOTATATE, DOTATOC, and DOTANOC are applied in a theranostic manner
3. Peptide receptor radionuclide therapy (PRRT)⁴
   1. The are at least two types of radiopharmaceuticals we will consider: ¹⁷⁷Lu-DOTATATE and ⁹⁰Y-DOTATOC
   2. Protocol
      1. A patient is a candidate for therapy if
         1. Shows tumor uptake
         2. Healthy bone marrow production
         3. Adequate renal function
      2. Amino acid solution is administered
         1. Reduce the renal reabsorption of the radio-trace causing reduced dosimetry
         2. May contain 1% lysine and 2.5% L-arginine in 1000 ml solution
      3. Average dose based on literature review
         1. 3,600 to 7,400 MBq of ⁹⁰Y-DOTANOC (3 patients) and then dosed again with ¹⁷⁷Lu-DOTATATE
         2. 2,500 to 7,400 MBq of ¹⁷⁷Lu-DOTATATE (61 patients) with 1 to 4 cycles
         3. Side effects included: nausea, vomiting, abdominal discomfort, hematological toxicity, hair loss
      4. Physical characteristics
         1. ¹⁷⁷Lu - β-emission with a max of 0.5 MeV and a tissue penetration of 2mm with a T_1/2 of 6.7 days and a 208 (10%) and 113 (6%) keV gammas
         2. ⁹⁰Y - is a pure β-emission with a max of 2.27 MeV and a T_1/2 of 64 hours and a tissue penetration of 12mm
         3. Given the radioisotopes - which one would be better for smaller tumors vs larger tumors?
         4. Which one would display less radiotoxicity?
      5. Response
         
         1. Seven difference studies generated the above results
         2. Defining the terms: CR - Complete response, PR - partial response, MR - minimal response, SD - stable disease, and PD - progressive disease
   3. Case review
      
      1. Compare DOTATOC to DOTATATE in a patient that has gastroenteropancreatic NET.
         1. Which agent has better tumor uptake? Can you give a reason why one is better than the other?
         2. SST receptors in gastroenteropancreatic NET
      
      2. Patient has VIPoma Patient was treated with ⁹⁰Y-DATATATE. No additional therapy was given. One year post dose liver and kidney functions are normal and only 1 metastatic tumor remains in the liver

Suggested reading, Theranostics in nuclear medicine practice, Yordanova A, et. al., OncoTarget and Therapy. 2017

References

1. Cyclotron production of 68Ga via the 68Zn(p,n)68Ga reaction in aqueous solution by Pandey MK, Byrne JF, et al. Am J Nucl Mol Imaging . v.4(4); 2014
2. Procedure guidelines for PET/CT tumour imaging with 68Ga-DOTA-conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE by Virgonlini I, Ambrosini V, et al. Euro Journ of NM and Mol Imaging Vol. 37.10 Oct 2010