Nuclear Oncology Applications Michael G. Stabin Vanderbilt University Nashville, TN XX Congresso Brasileiro de Física Médica e Simpósio Internacional de Proteção Radiológica em Medicina 12 a 15/Ago/2015 Rio de Janeiro/RJ
Introduction Nuclear medicine therapy is being used increasingly in the treatment of cancer: Thyroid cancer Leukemia and lymphoma with radioimmunotherapy (RIT) Primary and secondary (breast and prostate cancer) bone malignancies Neuroendocrine tumors (NET)
Introduction The use of internal emitters, specifically targeted to diseased tissues, is resulting in significant benefits in the treatment of many of these neoplasms. Both electron and alpha emitters are being used in a variety of new approaches to the fight against cancer. Positive responses have been recorded in many patient populations, resulting in the commercial development of new approved agents and techniques.
Introduction The highest rates of success are with traditional I- 131 NaI therapy against hyperthroidism and thyroid cancer. Significant gains are being seen in the treatment of bone and marrow cancers. Some novel targeting strategies and radionuclides are being proposed for other cancers. The use of high LET emitters, including alpha and Auger electron emitters, is also on the increase in newly proposed regimens.
Radionuclide Therapy Strategies The effectiveness of an agent will depend on two key quantities, The range of the principal emission and The physical half-life of the radionuclide.
Nuclide Half-life Emissions Range 125 I 60.0 d Auger, gamma 10 nm 211 At 7.2 h Alpha 65 µm 212 Bi 1.0 h Alpha, gamma 70 µm 169 Er 9.5 d Beta 1.0 mm 177 Lu 6.7 d Beta, gamma 1.5 mm 131 I 8.04 d Beta, gamma 2.0 mm 153 Sm 1.95 d Beta, gamma 3.0 mm 186 Re 3.77 d Beta, gamma 5.0 mm 89 Sr 50.5 d Beta 8.0 mm 32 P 14.3 d Beta 8.7 mm 188 Re 16.95 h Beta, gamma 11.0 mm 90 Y 2.67 d Beta 12.0 mm
Radionuclide Therapy Strategies I-131 sodium iodide (NaI) curative against thyroid cancer and metastases and corrective of Graves hyperthyroidism. P-32 phosphate lower red blood cell count in patients with polycythemia vera. Y-90, Re-186, Er-169 colloids treatment of malignant pleural/peritoneal effusions in synovial joints.
Cancer Diagnosis with Radiopharmaceuticals 18 F fluoroestradiol (FES) targets estrogen receptors on breast tumors. 18 F FDG is generally useful in tumor imaging.
Use of 18 F-FDG in cancer diagnosis FDG PET images of patient with recurrent breast cancer involving left axillary and supraclavicular lymph nodes (arrows). MRI has been interpreted as consistent with fibrosis after radiation. PET findings were verified by biopsy. Left and right panels depict more anterior and more posterior coronal views, respectively. Vranjesevic et al. J Nucl Med Vol. 43 No. 3 325-329, March 2002
Tumor Response with Zevalin Slide courtesy of Dr. Greg Wiseman, Mayo Clinic, Rochester, MN
Radionuclide Therapy Strategies Monoclonal antibodies Köhler and Milstein first described the production of monoclonal antibodies through hybridoma technology in 1975, and were awarded a Nobel Prize. A mouse is repeatedly immunized with an antigen of choice, causing B cells to produce antibodies specific for that antigen. A hybridoma is created by fusing two cells, a secreting cell from the immune system and a longlived cancerous immune cell, within a single membrane.
The resulting hybrid cell can be cloned, producing many identical offspring. Each of these daughter clones will secrete, over a long period of time, the immune cell product. B-cell hybridomas secrete a single specific antibody.
Monoclonal Antibodies against Non Hodgkin s Lymphoma Individual B and T cells of the immune system express a broad variety of surface antigens, which are cell surface markers. As with other cell types in the body, B cells and T cells may become malignant and develop into immune system tumors, such as B-cell NHLs. B-cell NHLs are cancers of the immune system which currently afflict approximately 300,000 patients in the United States. Treatment alternatives for B-cell NHL patients include chemotherapy, radiation therapy and, more recently, Rituxan.
Monoclonal Antibodies Y-90 Zevalin For treatment of B-cell NHLs, a cell surface marker known as CD20 may be targeted which is present only on B cells but not on B-cell precursors. Zevalin is IDEC Pharmaceutical Corp s radioimmunotherapy for treatment of B-cell NHL. Y-90 is chelated to the antibody prior to therapeutic infusion. The antibodies themselves also may cause tumor cell lysis, in addition to the radiation effects.
Monoclonal Antibodies against Non Hodgkin s Lymphoma I-131 tositumomab (Bexxar) Y-90 ibritumomab tiuxetan (Zevalin) Treatment with either agent appears well tolerated. Reversible hematologic toxicity is dose-limiting. Approach to radiation dosimetry differs: I-131 is directly imaged. Dose to total body in patient-specific ellipsoid correlated with marrow toxicity, used to guide administration. In-111 labeled Zevalin used to infer distribution and dosimetry of Y-90 Zevalin, using MIRDOSE/OLINDA dose calculations and some patient-specific modifications.
Monoclonal Antibodies Y-90 Zevalin On February 19, 2002, IDEC received marketing approval for for Zevalin (ibritumomab tiuxetan) from the U.S. Food and Drug Administration (FDA) This is the first radioimmunotherapy agent approved by the FDA. Efficacy study - 54 patients with relapsed follicular lymphoma who no longer adequately responded to Rituxan, 74% ORR, 15% complete remission (CR).
Monoclonal Antibodies Y-90 Zevalin Phase III randomized, controlled trial -143 patients with relapsed or refractory, low grade or follicular NHL or transformed B- cell NHL: ORR of 80% for the Zevalin therapeutic regimen, (n=73) compared to 56% of patients (n=70) who received Rituxan alone. Thirty percent (30%) of Zevalin patients achieved a CR, compared to sixteen percent (16%) of Rituxan patients.
Monoclonal Antibodies Y-90 Zevalin Serious adverse reactions of the Zevalin therapeutic regimen included: severe infusion reactions, severe and prolonged cytopenias including thrombocytopenia and neutropenia in patients with < 150,000 platelets/mm 3 prior to treatment. Approval patients who have failed Rituxan therapy, <25% marrow involvement of disease, no evidence of altered biodistribution with In-111 scan.
Monoclonal Antibodies Y-90 Zevalin Baseline platelet counts >150,000/mm 3 : 0.4 mci/kg Do not exceed 32 mci Baseline platelet counts 100,000-150,000/mm 3 : 0.3 mci/kg Do not exceed 32 mci
Monoclonal Antibodies I-131 Bexxar Monoclonal antibody (Tositumomab) labeled with iodine-131. Also binds to CD20 found on B-cells, including normal cells and those that become cancerous in non- Hodgkin s lymphoma, thereby delivering the dose of radiation. Given in four visits over one to two weeks, is specifically administered based on an individual s drug clearance rate, allowing the delivery of a predetermined amount of radiation to each patient.
Monoclonal Antibodies I-131 Bexxar June 30, 2003: approved for use in patients with non-hodgkins lymphoma. In September, the drug also was approved for Medicare reimbursement. Zevalin was approved for reimbursement in October 2002.
Monoclonal Antibodies I-131 Bexxar Their use, however, was far less than expected, Bexxar recently has been removed from the market. Reluctance of physicians to employ radioimmunotherapy due to concerns about bone marrow suppression market driven forces
Radionuclide Therapy Strategies: Y-90 Microsphere Therapy of Liver Cancer Y-90 SirSpheres and Theraspheres Patients with primary and metastatic liver cancer Technique involves injecting radioactive microspheres into the hepatic artery accessed via transfemoral route or through a hepatic arterial infusion port/pump.
Products: Y-90 Microsphere Therapy of Liver Cancer SIR-Spheres -resin microspheres with a specific activity of 40-70 Bq/sphere (Sirtex Medical Inc, Lake Forest, IL) Theraspheres TM glass microspheres with a specific activity of 2400-2700 Bq/sphere (MDS Nordion) Both products are between 35-40 (microns) in diameter. Microspheres injected intrahepatic arterially are distributed preferentially in the tumor compartment and are trapped within the microvasculature of the tumors. Microspheres are biocompatible but not biodegradable, and therefore there is no biologic elimination.
Y-90 Microsphere Therapy of Liver Cancer Although in reality, the Y-90 microsphere distribution is never uniform, and in fact, is invariably patchy with a wide range of variation, dose estimations are based on the assumption of a uniform distribution. Obviously this assumption of uniform distribution of the microspheres is acceptable only as a first order of approximation. Despite this recognized limitation, the dose methodology provides a consistent and reproducible dose estimates. 3D dosimetry is also possible.
Commercial Microsphere Products MDS Nordion Theraspheres Sirtex SirSpheres
Murthy et al. RadioGraphics 2005; 25:S41 S55
Dosimetry Whole organ Voxel level Mean dose BED, EUBED
Imaging Considerations A serious concern in microsphere brachytherapy for hepatic cancers is the possibility of arteriovenous shunting from the arterial deliver point directly to the lungs or other body sites. Once the delivery point has been identified, 70 150 MBq of 99m Tc macroaggregated albumin (MAA) are infused into the liver as a surrogate for the 90 Y microspheres.
Imaging Considerations Whole-body planar imaging is done with a moving, large field-of-view gamma system with low energy, high resolution, parallel-hole collimators capable of obtaining conjugate anterior and posterior images of the patient. A whole-body scan from the top of the neck to the bottom of the hips is sufficient.
Murthy et al. RadioGraphics 2005; 25:S41 S55
Lung Shunting Whole-body gamma camera imaging of 99m Tc MAA provides data about the shunting of labeled particles to the lungs. The lung shunt ratio is the quotient of the total lung counts (C Lung ) to the sum of lung and liver counts (C Liver ).
Lung Shunting Patients who have considerable shunting of the activity to the lungs, typically greater than 20% shunt value or 16.2 mci (600 MBq) delivered lung activity, should be disqualified from the use of microsphere brachytherapy due to the possibility of radiation pneumonitis. This activity is determined by assuming a maximum dose of 30 Gy to 1 kg lung mass. However, activity reduction methods have been suggested to maintain the lung dose below 30 Gy.
Welsh et al. Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 2, Supplement, pp. S62 S73, 2006
Organ Level Dosimetry
TheraSphere Specifics The prescribed activity for TheraSphere is calculated by solving the equation above for activity, determining the mass of perfused volume to be treated from a CT image set and choosing a dose to be delivered. A typical dose between 100 and 120 Gy is selected for TheraSphereVR treatments involving patients with HCC. The target dose for a particular solid tumor is not known but it is currently believed that this dose range balances the response rate with the risk of hepatic fibrosis.
Dosimetry The general dose formula was given above. The radiation absorbed doses to tumor, lung, and normal liver tissue can be further calculated based on a partition model which is described in the following. Assume that all of the administered activity is deposited in the normal liver, tumor, or lungs giving
Dosimetry The tumor/liver activity uptake can be determined from ROIs drawn on the 99m Tc-MAA images:
Dosimetry Dose to normal liver: Dose to tumor: The lung and normal liver limiting activities can be determined by setting a dose limit and solving the above equations for activity.
Small Scale Dosimetry A substantial increase in computing speed has made it possible to implement dosimetry calculations based on volumetric integration. The basic approach to kernel convolution dosimetry is to convolve a 3D in vivo activity distribution with a Monte Carlo derived 3D dose kernel.
Ebert and Zavgorodni, Med. Phys. 27 2, February 2000
Sarafaz et al. Med Phys 31:9, 2004
Kennedy et al. Int. J. Radiation Oncology Biol. Phys., Vol. 60, No. 5, pp. 1552 1563, 2004
Radiobiology Strigari et al. 2010 dose/response curve Chiesa et al. 2011 glass microspheres, specific patient set - = 0.0026.Gy, almost negligible (0.000008)! Spatial distribution of dose explains lack of hepatic toxicity at levels suggested by organ level dosimetry.
Guimaraes et al., Med. Phys. 37(2), February 2010
Radionuclide Therapy Strategies: Radiolabeled Peptides Radiolabeled peptides (amino acid sequences, often small pieces of antibodies that have receptor binding properties) have several advantages over antibodies mainly related to immunogenicity and size. Tumor localization and total body clearance of peptides are more rapid compared to antibodies.
Radionuclide Therapy Strategies: Radiolabeled Peptides An example is octreotide, which is a piece of the hormone somatostatin. Octreotide can be labeled directly with 99m Tc or to 111 In by the linker DTPA or to 90 Y by the linker DOTA. 90 Y-DOTATOC (yttrium-90 DOTA-D-Phe1-Tyr3- octreotide) is used for treatment of patients with neuroendocrine tumours, gliomas, and even thyroid carcinomas that express somatostatin receptors. The use of 213 Bi-DOTATOC has been proposed and tested in animals.
Radionuclide Therapy Strategies: Radiolabeled Peptides Bodei et al. Peptide receptor radionuclide therapy with 177 Lu-DOTATATE 51 patients, multiple cycles. 3.7 5.18 GBq/cycle, group 1; 5.18 7.4 GBq/cycle, group 2) Cumulative activities ranged from 3.7 to 29.2 GBq.
Radionuclide Therapy Strategies: Radiolabeled Peptides No major acute or delayed renal or haematological toxicity occurred (one grade 3 leukopenia and thrombocytopenia). Cumulative renal absorbed doses were 8 37 Gy (9 41 Gy bioeffective doses). Median decrease of creatinine clearance of 21.7% 6 months after PRRT, 23.9% after 1 year and 27.6% after 2 years was observed.
Radionuclide Therapy Strategies: Skeletal Targeted Therapy (STR) Palliate pain of osseous metastases - Early utilization of radionuclides is cost effective and efficacious for diminishing bone pain from osseous metastases with or without concomitant use of local external radiotherapy. Sr-89 Chloride Sm-153 EDTMP (ethylenediamine tetramethylene phosphoric acid) Re-188 HEDP (hydroxyethylene diphosphonate) Ra-223 Chloride Ablate marrow (multiple myeloma patients) Ho-166 DOTMP (tetraphosphonate, 1,4,7,10-tetraaza cyclodo-decane-1,4,7,10-tetramethylenephosphonic acid)
Introduction 223 Ra-Chloride targets bone metastases with high LET, short range (<100 μm) alpha particles. Physical half-life 11.4 days. Clinical trials have showed safety and efficacy of palliation of painful bone metastases in patients with prostate cancer using 223 Rachloride (also called Alpharadin, now Xofigo). Extension of life from ~11 to ~15 months.
223 Ra decay series
Table 1. Properties of the 223 Ra progeny. Ra-223 progeny Half life Decay mode Rn-219 3.96 s Alpha Po-215 1.78 ms Alpha Pb-211 36.1 m Beta Bi-211 2.17 m Alpha/Beta Tl-207 4.77 m Beta Po-211 0.516 s Alpha
Clinical Data Imaging: 223 Ra itself has X-rays at 81 and 84 kev and gamma peaks at 269 and 154 kev and the 219 Rn daughter (short half-life) has a significant peak at 271 kev. Manageable (max grade 3) toxicity, more likely with neutrophils. Seven serious adverse events. One supraventricular arrhythmia and a nausea/vomiting episode were assumed to be treatment related, but were treatable. Episodes of transient diarrhea were reported at all dose levels.
Dosimetry Lassmann and Nosske 2012: Radium is excreted mainly via the gastrointestinal (GI) tract. While radium in the liver is retained with a biological half-time of 50 d before it is re-transferred to the blood, most of the radium in other tissues is quickly retransferred to the blood with biological half-times of 0.1 d and 1 d, respectively.
Radiation Dose and Hazard Assessment for Use of 223 Ra Dichloride in Radionuclide Therapy Stabin MG. Dept of Radiology/Radiological Sciences, Vanderbilt University, Nashville, TN, USA. Siegel JA. Nuclear Physics Enterprises, Marlton, NJ
Conclusions Many very effective agents are available for performing therapy with radiopharmaceuticals. Some are well accepted and effectively used (I-131 NaI, Y-90 microspheres, radiolabeled peptides), others (Bexxar, Zevalin, Ho-166 DOTMP) are underused or not used at all. Patient-individualized dosimetry is rarely used, but should become routine practice.