Case Study TH
Radioimmunotherapy (RIT) and radionuclide therapy
RIT- Radioimmunotherapy
Objective of RIT is to deliver a lethal radiation dose to tumor cells
Effective due to Antigen-Antibody reaction
Maximize dose to tumor while minimizing dose to normal tissue
Primary limiting factor = bone marrow depression
Decrease in blood cells
Noticeable in 2-3 weeks
Lowest at 4-8 weeks
Recovery at 12 weeks
RIT
Informed consent is important for therapy and includes:
Pregnancy/lactation
Radiation safety post dose/written instructions
Risk of cytopenia
Risk of hypothyroidism (Bexxar™)
Development of secondary tumor/leukemia
HAMA response
RIT
Human Anti-Mouse Antibody (HAMA) Response
Antibody treatment is a type of therapy that is used to treat certain types of cancer and immune disorders
Antibodies are proteins naturally formed by the body in response to a foreign substance - known as an antigen
Antibodies can also be grown outside the patient’s body and then injected to help aid the immune system to fight disease - called monoclonal antibodies because they are created to target one specific antigen
HAMA
For decades mice were used extensively in the production of monoclonal antibodies
But the treatments were not as effective as doctors had hoped
Patients reacted to the mouse antibodies as if they were a foreign substance, and created a new set of antibodies to the mouse antibodies
Doctors have termed this the “HAMA response,” referring to the development of Human Anti-Mouse Antibodies (HAMA)
HAMA
The HAMA response is essentially an allergic reaction to the mouse antibodies that can range from mild (rash) to extreme and life-threatening (renal failure)
HAMA can also decrease the effectiveness of the treatment or create a future reaction if the patient is given a subsequent treatment containing mouse antibodies
Approximately one-third to half of patients receiving mouse-derived antibodies will develop some form of HAMA response
At least ten percent of the general population has been observed to carry some form of animal-derived antibodies, most often from mice due to the preponderance of medical agents made from the serum of animals
Zevalin™
1st Murine Antibody approved to treat CA
Extends life by inducing remission
Improves quality of life by reducing symptoms of disease
Zevalin™
Ibritumomab Tiuxetan
Ibritumomab = murine antibody parent of rituximab (Rituxan®)
Protein which interferes with growth and reproduction of lymphomas and leukemia cells
Tiuxetan = chelator that binds to RN
111In (imaging)
HL = 67.2 hr
Gamma = 245 & 172 keV
90Y (therapy)
HL = 64 hrs
β- = 2.28 MeV (Shackett)
940 kev + neutrino
Zevalin™
Initially approved for relapsed or refractory:
Low grade/Follicular or transformed B-cell Non-Hodgkins Lymphoma (NHL)
2002- FDA approved for 1st RIT drug for cancer
2009- FDA approved for untreated NHL
≈95% B-cell lymphomas have CD20 antigen on surface of cell
Zevalin™ targets CD20 antigen
Zevalin™
Contraindications
Pregnancy/nursing
Platelets < 100,000
Neutrophils < 1500
≥ 25% lymphoma marrow involvement (impaired bone marrow reserve)
Bone marrow transplant
Known hypersensitivity to murine proteins
Altered biodistribution as determined by 111In-Zevalin images
Zevalin™
No patient prep
Outpatient
Check for blood thinners:
Increased risk of bleeding due to an increased risk of thrombocytopenia (low platelet count)
Warfarin (coumadin)
Aspirin
NSAIDs (Non-steroidal anti-inflammatory drugs)
Ibuprofen, naproxen
Motrin, Advil, Aleve
Zevalin™
Day 1
250mg/m2 of Rituxan® via slow IV infusion
Begin infusion rate at 50mg/hr
If no reaction, increase rate in 50mg increments every 30 min up to 400mg/hr
Bolus may result in death w/in 24 hrs (MI, hypoxia, anaphylaxis)
If reaction occurs, decrease infusion rate by 50%
If severe reaction; stop- treat- restart at 50%
Onset may begin ≈ 30-120min
Zevalin™
Rituxan® saturates normal CD20 sites (spleen, circulating B cells)
Increases amount of RA Zevalin™ targeting tumor cells
Without Rituxan® ≈ 18% RP uptake
With Rituxan® ≈ 56-92% RP uptake (varies upon infusion rate)
Zevalin™
Day 1(Not currently required)
Within 4 hrs of Rituxan®, infuse 5mCi 111In Zevalin™ over 10 min IV push
Flush IV to ensure full dose
Whole body images taken at 2-24 hours and again at 48-72 hours
May need 90-120 hr imaging
Depending on biodistribution
Zevalin™
| Organ | Scan 2-24 hours | Scan 48-72 hours | Scan 90-120 hours (optional) |
| Blood pool | Present | Decreases | Decreases |
| Liver and Spleen | Moderate high-high | Moderate high-high | Moderate high-high |
| Kindeys, Bladder, Bowel | Moderate low-very low | Moderate low-very low | Moderate low-very low |
| Tumor | Variable | Variable | Variable |
Expected Bio-distribution
Zevalin™
| Organ | Scan 2-24 hours | Scan 48-72 hours | Scan 90-120 hours (optional) |
| Blood Pool | Not Visualized | Not Visualized | Not Visualized |
| Lungs | > Cardiac Blood Pool | Difuse uptake > Liver | Diffuse uptake > Liver |
| Kidneys | > Liver in posterier view | > Liver in posterier view | > Liver in posterior view |
| Bowel | > Liver | > Liver | > Liver |
Altered Bio-distribution
Zevalin™
Imaging evaluates biodistribution of RP
Tumors may be less evident in abnormal biodistribution
Concerns about radiation to non-target organs if altered
Normal distribution via In-111 Zevalin imaging was previously required before starting therapy
Was only a requirement in US, Switzerland, and Japan
42 other countries approved the therapy without In-111
NO LONGER REQUIRED IN THE UNITED STATES- Nov 2011
Zevalin™
Expected Biodistribution Observed
Blood pool visible on early images less on delayed
Moderately high-high liver on early and delayed
Moderately low-low in kidney, bladder and bowel in early and delayed
Tumor uptake in left axilla, mesenteric lymph nodes, bilateral pelvis, testicular regions
Zevalin™
Day 7-9
Therapy regimen
2nd Rituxan® infusion (same rate)
Within 4 hrs, 90Y Zevalin™ infused over 10 min
Dosage = 0.4 mCi/kg if platelets ≥ 150,000
Dosage = 0.3 mCi/kg if platelets 100,000-149,000
Zevalin™
Typical dosage = 21-30 mCi
Can not exceed 32 mCi
Assures:
No normal organ receives > 2000 rads
No red bone marrow receives > 300 rads
Zevalin™
Approximately 73-83% patients responded to therapy
Approximately15-51% remained in remission lasting ≈ 23 months
Side effects:
GI symptoms, cough, dizziness, anxiety
Delayed myelosuppression
Zevalin™
Blood/platelet counts monitored ≈ 12 weeks
≈ 29% develop infections (low WBC)
≈ 7% need hospitalization (infections)
Bleeding/bruising (low platelets)
Fatigue (low RBC)
HAMA ≈ 2%
Zevalin™
No isolation from family required
No patient specific calculations needed (pure β-)
Dose to others < 1 mrem (due to brems)
Return to work immediately in most cases
Avoid body fluid contact for about 1 week following therapy
Bexxar™- Discontinued Feb 2014
RIT
Tositumomab
131I
NHL
Procedure includes both Dosimetric and Therapeutic steps
Bexxar™
Patient requirements:
> 50,000/mm3 platelet counts
Absolute Neutrophil Count > 800/mm3
Bexxar™
Patient Prep:
Pre-dose with 650 mg Acetaminophen and 50 mg Antihistamine
30 min prior to dosing with non-radioactive tositumomab
Reduces side effects
Bexxar™
Daily Iodine supplement to block thyroid uptake of 131I
SSKI (4 drops orally 3x per day)
Lugol’s (20 drops orally 3x per day)
KI (130 mg daily)
≈ 9% become hypo
Start 24 hours pre-dose
Continue 2 weeks post dose
Bexxar™
Dosimetric step
450 mg “cold” tositumomab in 50 ml normal saline
Distributes RP
IV infusion over 60 min
5 mCi 131I Bexxar™ in 30 ml normal saline
IV infusion over 20 min
Bexxar™
WB image post infusion
Determines localization in body
Day 2-6:
WB image (check for residual activity)
Used to calculate therapy dosage
Bexxar™
Day 7-10:
Infuse cold tositumomab over 60 min
Infuse 131I Bexxar™ therapy dosage over 20 min
Dosages = 30-200 mCi
Bexxar™
Side effects:
Flu-like symptoms
1-2 days post dose
Bruising/bleeding
3-4 weeks (decreased platelet ct.)
Allergic reaction (rash, swelling, cough)
Antihistamine helps in limiting symptoms)
≈ 10% HAMA
Bexxar™
Hospitalization due to radiation exposure
Sent home if dose specific calculation done
Give instructions on Rad Safety – similar to thyroid ablation restrictions
Public safety issue due to high energy gamma
Normal Hct
Polycythemia Radionuclide Treatment
Many types of polycythemia disorders
Polycythemia Vera (primary, true)
Impacts 5-26 people/1million/year
Chronic neoplastic disease of bone marrow
High RBC ( Hematocrit [Hct] > normal)
May have high WBC ( >12,000/ μL)
May have high platelets (>400,000/μL)
Average age of onset ≈ 60
Survival rate:
1.5 years without therapy
10 years with therapy
Not effective on other forms of polycythemia
Secondary Polycythemia
Over stimulation of bone marrow
Increase of RBC production due to increase of erythropoietin
Relative Polycythemia
Normal RBC, but decreased plasma volume
Can be treated by bleeding
Polycythemia Radionuclide Treatment
Treatment:
Phlebotomy (nearly always performed)
Chemotherapy (preferred treatment along with phlebotomy)
Radiation therapy (secondary treatment)
Untreated:
Slow circulation (thick blood)
Local hypoxia
Decreased blood flow to vital organs
Thrombosis
Polycythemia Radionuclide Treatment
Polycythemia
32P sodium phosphate
Same as used for bone mets
Was first used to treat leukemia
Not as common
Dose = 2.3 mCi/m2
3-5 mCi with 10 ml normal saline
IV butterfly
30-60 sec injection
Polycythemia
≈ 85% RP selectively concentrates in mitotically active cells of bone/bone marrow
Incorporated into DNA in cells
Direct damage due to β-
Polycythemia
Results:
Blood chemistry normal within 4-6 weeks
Remission ≥ 2 years
10-20% develop acute leukemia
No remission:
Increase dose by 25%
Check blood levels at 3 months
Increase dose by 25% again, check at 3 months
Do not exceed 7 mCi within 6 months!!!
Malignant Effusions Therapy
Effusion:
Abnormal collection of fluid in a cavity
Due to:
Increased fluid production (serosal irritation)
Decreased fluid reabsorption (lymphatic obstruction)
Malignant Effusions
Pleural
Primaries: Breast, lung, ovarian, lymphomas
Nonmalignant: infections, cirrhosis, cardiac, TB
Peritoneal – Ascites
Primaries: ovarian, renal, GI
Nonmalignant: cirrhosis, peritonitis, CHF
Pericardial
Primaries: Lung, breast, lymphomas, melanomas
Nonmalignant: infection, radiation induced pericarditis
Malignant Effusion
Therapy
Palliative treatment of symptoms
Prevention of recurring disease
Other therapies
Centesis (puncture fluid removal)
Chemotherapy
Malignant Effusion
32P chromic phosphate (colloid)
Dose depends on cavity
Peritoneal = 10-25 mCi in 30-500 ml normal saline
Pleural = 6-15 mCi in 30-50 ml normal saline
Pericardial = 5-10 mCi in 30-50 ml normal saline
Malignant Effusion
Insert catheter and remove fluid
Administer RP into organ
1-3 mCi 99mTc SC may be added for imaging
Remove catheter, add dressing for leakage
Change positions every 10-15 min for 2 hrs
Distributes RP
Malignant Effusion
RP taken up by macrophages in cavity
RP adsorbs to serosal lining
β- energy deposited in tissue
Fibrosis of mesothelium and small blood vessels
Decrease fluid production results
Malignant Effusions
Cavity leakage ≤ 10%
Regional lymph node uptake ≈ 2%
< 5% remains free @ 24 hrs
Image using Brems (160-450 keV) or added 99mTc SC
Malignant Effusions
Results take about 3 months
Decrease pain
May repeat dosing
Contraindications:
Loculated fluid
Pocket of fluid walled off from other fluid
Expected live span < 6 months
32P Radiation Safety
Patient may be hospitalized due to medical reasons, not radiation hazard
External exposure levels low
Why??
Minimal exposure due to Brems
Leakage, contaminated gauze
Synovitis Radionuclide Therapy
Inflammation of synovial membrane
Causes:
Rheumatoid Arthritis – autoimmune disease
Bleeding into joint: hemophilia
Nodules projecting into cavity
Synovitis
Results:
Increased secretion of synovial fluid
Release of enzymes/cell factors that cause destruction of cartilage/joints
Local irradiation:
Decrease fluid production/pain
Destroys cells that release enzymes that cause joint destruction
Synovitis
RP used depends on joint size and synovial thickness
Large, stable particles (phagocytized by synovial macrophages)
32P chromic phosphate- Phosphocol (Colloid)
Knees and elbows
90Y
Large joints, knees with thick synovia
186Re (Rhenium)
Intermediate joint sizes
169Er (Erbium)
Small joints
Synovitis
Typical dose range for 32P:
Knees = 0.5-1mCi
Elbows/wrists = 150-500 µCi
Depends on size of joint involved
Synovitis
Possible Patient Prep:
Factor VIII – hemophiliacs given anti-hemophilic factor (AHF) pre-therapy, as well as 24 and 72 hrs post therapy
Betadine – prep for spinal tap
1% lidocaine – topical anesthetic
Synovitis
Place needle in synovial space (fluoro, U/S)
Connect tubing/stopcock
Attach syringe/aspirate fluid
Inject 1mCi 99mTc SC for image (or use Brems)
Inject RP
Attach syringe with 1% lidocaine
Synovitis
Inject lidocaine along needle tract while needle is withdrawn
Helps prevent inflammation/leakage of dose
Flex joint to distribute RP
Immobilize joint for 48 hrs (minimizes leakage)
GM meter to assess nodal uptake (≈ 2%) at 24 hrs, 72 hrs, and 7 days
Synovitis
Results:
Decreased pain/inflammation in joint
Decreased degradation of cartilage/bone in joint
Increased joint function
78-84% improvement in 3-6 months
Radiation dermatitis @ injection site
Prostate CA Bone METS Treatment
Xofigo ®
Used for treatment of prostate CA that is resistant to medical or surgical treatments that lower testosterone, or bone metastases of prostate CA
Termed Castration-Resistant Prostate Cancer (CRPC) or Metastatic Castration-Resistant Prostate Cancer (mCRPC)
223Radium
11.43 day half-life
4.78 MeV alpha emitter
Debate over therapeutic or palliative value
Xofigo ®
Dosage
1.35 mCi per kg
One dose every 4 weeks for 6 cycles
Slow IV injection for 1 minute
Flush IV line with 10 ml saline before and after
Pharmacology
Mimics calcium and forms complexes with bone mineral hydroxyapatite at areas of increased bone turnover
Excretion:
48 hours post dose, fecal excretion at 13%
7 days post dose, 63% excreted via feces
Xofigo ®
Precautions:
Advise male patients who are sexually active to use condoms and female partners to use highly effective contraceptive method for 6 months after treatment
Myelosuppression may occur
Hydration is important
Bathroom hygiene - Flush toilet several times, wash hands thoroughly
Xofigo ®
Contraindications
Pregnant?
Other important details:
No outpatient restrictions (alpha emitter)
Common side effects include:
Nausea
Diarrhea
Vomiting
Peripheral edema
Low blood counts
Just the beginning…
Research still continuing in radionuclide therapies
Possible avenues of therapy:
More Alpha-emitting particles
Peptide Receptor Radionuclide Therapy (PRRT)
Hormone-Delivered Radiotherapy
Alzheimer’s treatments
QUESTIONS?