Radionuclide therapy of bone metastases and non-Hodgkin’s lymphoma (radioimmunotherapy)

Radionuclide therapy of bone
metastases and non-Hodgkin’s
lymphoma
(radioimmunotherapy)
 Herbert A. Klein
 Acknowledgements:
Michael Sheetz for help with physics
Oliver Sartor (Tulane) for multiple slides on Ra-223
Misc. references

2 key kinds of radiation
 Penetrating rays, good for imaging, including
dosimetry: γ-rays.
 Particles, not good for imaging, but good for
depositing energy in a localized manner as
desired in therapy: β– rays (electrons) and α-
rays (2 protons + 2 neutrons = helium nucleus,
2+ charge)
 Among β particles, higher energy is associated
with longer range. However, α particles have
both higher energy and shorter range than beta
particles.

Critical Differences in Alpha- and Beta-Particles
α β
Relative particle mass 7300 1
Initial energy (MeV) per particle 3-8 0.01-2.5
Range in tissue (μm) 40-100 50-5000
LET (KeV/μm) 60-230 0.015-0.4
DNA hits to kill cells 1-10 100-1000
LET = linear energy transfer.
Henriksen et al. J Nucl Med. 2003;44:252-259.
Alpha Beta

Radiophar-
maceutical
→
Properties↓
Sm-153
lexidronam
(Quadra-
met)
Sr-89
chloride
(Metastron)
Ra-223
chloride
(Alphara-
din)
Y-90 ibri-
tumomab
tiuxetan
(Zevalin)
I-131
tositumo-
mab
(Bexxar)
Nature of
radiation
β - β - α β - β -
Half-life (d) 1.9 50.5 11.4 2.67 8.04
LET (keV/µm) ~0.2 ~0.2 ~80-100 ~0.2 ~0.2
γ, imaging
(imageable
gamma)
Y N N In-111 analog Y
Bone metastases
________________________
NHL
___________________

Radiophar-
maceutical
→
Properties↓
Sm-153
lexidronam
(Quadra-
met)
Sr-89
chloride
(Meta-
stron)
Ra-223
chloride
(Alpha-
radin)
Y-90 ibritumo-
mab tiuxetan
(Zevalin)
I-131 tositumo-
mab (Bexxar)
Mechanism
of binding
Chelation to
bone
surface
Calcium
analog
Calcium
analog
Mab to surface
antigen
Mab to surface
antigen
Administered
dose formula
(maximum)
1 mCi/kg 4 mCi 0.008 mCi/kg 0.4 mCi/kg Dosimetry
(75cGy WB
max)
Typical
administered
dose
70 mCi 4 mCi 0.57 mCi 28 mCi 75 mCi
FDA approval Y Y Pending Y Y
Bone metastases
_______________________
_
NHL
___________________

Thought question
Everything else being equal, in designing a
radionuclide therapy for bulky tumor masses,
which would you choose?
1. An alpha-emitter
2. A beta (minus)
emitter
3. A positron-emitter
4. A gamma-emitter.
5. 2 or 3.
0% 0% 0% 0% 0%
0%
20%
40%
60%
80%
100%

Sr-89 Cl and Ra-223 Cl are alkali metals like
calcium
McDevitt et al. Eur J Nucl Med. 1998;25:1341-1351.
Calcium
Strontium
Radium
Barium

Bone pain
• Most frequent pain in cancer.
• Breast and prostate >80% of symptomatic bone
metastases.
• Chemotherapy and EBRT may be insufficient.
• EBRT limited in multifocal osseous metastases.
• Pain treatments have been considered only palliative.

Two FDA-approved Radiopharmaceuticals for bone
pain
• Quadramet and Metastron, the former more popular.
• Incorporated into sites of osteoblastic bone
metastases>normal metabolically active bone (~5x).
• Quadramet’s shorter range in tissue and shorter half-
life may be advantages, but neither has been
definitively shown to be better.

• Therapeutic Agent
– Sm-153 + tetraphosphonate
chelator (EDTMP)
– Colorless to light amber isotonic
solution
– Sterile non-pyrogenic
– Does not contain a preservative
O
O
O O
153Sm
C
C
C
C
N N
C
C
Quadramet (samarium Sm-153 lexidronam injection) prescribing information.
September 2003.
The structural formula of
Sm-153 lexidronam
Description

Tc-99m methylene diphosponate
Like the other two, Quadramet accumulates in bone in association with
hydroxyapatite. Response rates ~75%.
zoledronic acid
(Zometa)
Sm-153 lexidronam

Check list before Quadramet therapy
• Clinical and imaging information: positive bone scan
within 8 weeks.
• Correlation between osteoblastic lesions and painful
sites.
• Analgesics inadequate.
• Not a candidate for EBRT (e.g. too many sites).
• No large-field EBRT in past 3 months.
• No long-acting myelosuppressive chemotherapy for
6-8 weeks.
• Signed informed consent (as for all therapies).

Laboratory data (stable for ~2 months)
• PlateletsPlatelets >100,000/µL WBC > 3,500/ µL
• Neutrophil count >1,500/ µL
• Hemoglobin 9 g/dL
• Glomerular filtration rate >50 mL/min

Additional problem areas
• There is concern for spinal cord compression, which
may be addressed by EBRT.
• With C-spine involvement, corticosteroids may be
used as a precaution against compression.
• Extensive bone involvement like “superscan.”
• Possible risk of disseminated intravascular
coagulation.
• Some problems are relative contraindications, may
call for reduced or fractionated dose (cytopenia,
extensive bone involvement, moderate renal failure).

Absolute contraindications
• Pregnancy
• Breast-feeding
• Dialysis (logistic issues)

Other practical points
• Onset of pain relief occurs within days or weeks;
duration varies.
• Not recommended if life expectancy is less than 4
weeks.
• Temporary worsening of pain may occur soon after
administration.
• The toxicity of greatest concern is to bone marrow, as
is the case, in general, with radiopharmaceutical
therapy.
• Blood count drops are generally tolerable and
reversible, but one should follow with blood counts 2
weeks after and then every week for 8 weeks or until
recovery.

Points (cont.)
• Unlike Sr-89, it has gamma emission at 103.2 keV,
which enables imaging, but they are like bone scans
and not essential.
• Retreatment may be done as needed 12 or more
weeks later if bone marrow recovery has occurred.
• Patients advised to avoid pregnancy for at least 6
months,
• Precautions essentially based on beta emission:
avoid body fluid contamination for ~1 week. (Gamma
is minimal).
• Bladder catheterization if incontinent.
• IV injection of 1 mCi/kg over 1-2 minutes (typical 70
mCi).

68-
68-y.o. F, metastatic breast carcinoma.

68-y.o. female with metastatic breast
ca
What do you need to check prior to her therapy?
1. Correlation of pain
sites with bone scan
2. Renal function test.
3. Risk of spinal cord
compression.
4. CBC.
5. All of the above.
0% 0% 0% 0% 0%
0%
20%
40%
60%
80%
100%

What do you need to check prior to
her therapy?
1. Correlation of pain sites with bone scan
2. Renal function test.
3. Risk of spinal cord compression.
4. CBC.
5. All of the above.

• Hot spots correlated with pain.
• Taking bisphosphonate.
• Had tamoxifen (anti-estrogen, not marrow toxic).
• Absolute neutrophils had dropped from 5,200/µL to
2,730/ µL—adequate, but needing proof of stability.
• With further following, they rose to 5,000/µL. Platelets
were 216,000/ µL.
• PET/CT: encroachment on spinal canal at T5, but MRI
did not support risk of cord compression.
• Finally met all criteria and received 64.2 kg x 1mCi/ kg
=64.2 mCi.

Weeks WBC (3,800-
10,000/µL)
Abs. neutrophils
(1,600-6,700/µL)
Platelets (130,000-
400,000/µL)
-1.3 5,000 2,820 216,000
0 (treatment)
1.3 4,000 2,400 160,000
2.3 3,300 1,750 135,000
3.3 4,800 2,976 107,000
4.3 4,300 2,540 107,000
5.3 3,000 1,360 131,000
6.3 3,600 2,010 154,000

Strontium-89 chloride (Metastron)
• Sr-89 is a divalent cation, an alkaline earth metal like
calcium.
• Minimal radiation precautions.
• No imageable gamma.
• Dose is 4 mCi to everyone.

Side effects from radiopharmaceutical therapy for
bone pain include all except:
1. Decrease in
neutrophil count
2. Transient increase
in pain
3. Drop in the platelet
count
4. Hypercalcemia
0% 0% 0% 0%
0%
20%
40%
60%
80%
100%

Side effects from radiopharmaceutical therapy
for bone pain include all except:
1. Decrease in neutrophil count
2. Transient increase in pain
3. Drop in the platelet count
4. Hypercalcemia

Bisphosphonates
• Often used in patients with bone mets to palliate pain,
prevent skeletal related events.
• Might they compete for binding sites with
radiopharmaceuticals like Sm-153 lexidronam for sites
on hydroxyapatite?
• No disadvantage found.
• Storto et al (Bone 2006:35-41) showed that patients
receiving Sr-89 chloride along with continued
bisphosphonate therapy had better bone pain
palliation than either used separately.

Killing cancer?
• If we are successfully irradiating sites that are
implicated in pain causation, are we killing cancer
cells in a fashion that will achieve improved outcomes
like longer survival. This has not been shown for Sm-
153 lexidroman or Sr-89 chloride when given alone. At
most, there are only hints.
• New contender: Radium-223 chloride (Alpharadin), an
alkaline earth metal like Sr-89 and calcium, but an
alpha-emitter with short range and high LET.
• It has been shown not only to relieve pain, but also to
prolong life, with tolerable bone marrow effects in
prostate cancer with bone metastases.

ALSYMPCA Overall Survival at First Look
0
10
20
30
40
50
60
70
80
90
100
%
Radium-223, n = 541
Median OS: 14.0 months
Placebo, n = 268
Median OS: 11.2 months
HR 0.695; 95% CI, 0.552-0.875
P = 0.00185

Ra-223 chloride
• It is theorized that the deposition of much energy in a
short path length allows for the benefits while sparing
more distant bone marrow.
• There is no reason to think Ra-223 chloride targets
any but bone metastases, not e.g. liver or lymph
nodes.
• The dose is 0.008 mCi/kg in 6 divided doses at 4-week
intervals; i.e. typical total of 0.6 mCi.
• Not surprisingly, there is a trial underway giving it
along with docetaxel as chemotherapy. This has been
done with other such agents. Some chemotherapy
agents enhance the effect of radiation.
• There are plans to test it with breast cancer, etc.

• Alpha particles are a significant development in
devising new radiopharmaceuticals to exploit special
properties for treatment.
• Potentially uses include radioimmunotherapy.
• My questions:
1. Will it enable patients to have such therapy when
their hematological parameters are too low for Sr-89
chloride or Sm-153 lexidronam?
2. Might the prolongation of life be due to another
factor like fractionated doses?
 The theory is important, but empirical results are what
count.

• One should not conclude that alpha-particles are
always better in treating cancer. Short-range particles
like alpha-particles might be more effective in treating
microscopic tumor foci, but long-range beta particles
in irradiating larger tumor clusters, though possibly
associated with higher toxicity.

Figure 3 Track length of alpha-particles, beta-particles, and Auger
electrons relative to the cell diameter
Pouget J.-P. et al. (2011) Clinical radioimmunotherapy—the role of radiobiology
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2011.160

Figure 1 Radiobiology of radioimmunotherapy
Pouget J.-P. et al. (2011) Clinical radioimmunotherapy—the role of radiobiology
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2011.160

Radioimmunotherapy of NHL.
 There are many types of NHL.
 We are concerned with B-cell lymphomas
bearing a surface protein antigen, CD20.
 B-cells arise from reticuloendothelial elements
in the prenatal liver and spleen.
 Mainstays of treatment include chemotherapy
and rituximab (Rituxan), an anti-CD20
monoclonal antibody. We will be concerned
with several anti-CD20 monoclonal antibodies,
as follows:

Monoclonal antibodies for NHL
Antibody Type Radioactive
label
Commercial
name
rituximab chimeric none Rituxan®
ibritumomab murine yttrium-90 Zevalin®
tositumomab murine iodine-131 Bexxar®
 Monoclonal antibody “mab” : an antibody produced by a single clone of cells grown in
culture that is both pure and specific and capable of producing unlimited quantities of
identical antibodies.
 Note “code” in yellow. “tu” tumor, “mo” murine, “xi” chimeric (mouse plus human).
 Y-90 clivatuzumab tetraxetan (Y-90-hPAM4) is an investigational therapy for pancreatic
cancer, a humanized (zu) antibody, which we may be testing here..

Monoclonal antibodies for therapy
Which of the following statements about
(a) ibritumomab and (b) tositumomab is true
1. (a) and (b) are both murine
antibodies and target the
same antigen on the B-cell
antibodies, but they target
different antigens on the B-
cell
3. (a) is a chimeric antibody,
whereas (b) is a murine
antibody. They both target
the same antigen on the B-
cell
4. (a) is a chimeric antibody,
whereas tositumomab is a
murine antibody. They
target different antibodies
on the B-cell
0% 0% 0% 0% 0%
0%
20%
40%
60%
80%
100%

Monoclonal antibodies for therapy
Which of the following statements about
(a) ibritumomab and (b) tositumomab is true
antibodies and target the same
antigen on the B-cell
antibodies, but they target different
antigens on the B-cell
3. (a) is a chimeric antibody, whereas
(b) is a murine antibody. They both
target the same antigen on the B-cell
4. (a) is a chimeric antibody, whereas
tositumomab is a murine antibody.
They target different antibodies on
the B-cell

 Rituximab, by binding to tumor cells, brings
about cell death with significant clinical
benefits.
 The radioactivity of the 2 agents we will
discuss, adds another dimension.
 The CD20 antigen occurs not only on B-cell
tumors, but also on normal B-cells, including
circulating B-lymphocytes, though not the
plasma cells that result from further
differentiation.
 Radioimmunotherapy requires the additional
use of unlabeled antibody to saturate the
nontumor antibody binding sites.

Yttrium-90 ibritumomab tiuxetan (Zevalin)
 While I-13 is directly bound to antibody
(Bexxar), binding of Y-90 (or In-111) to
antibody requires the linker-chelator tiuxetan;
hence the generic name of Zevalin.
 Zevalin seems to be more commonly used.
 It is indicated for patients with relapsed or
refractory low-grade or follicular B-cell non-
Hodgkin’s lymphoma (e.g. after rituximab
therapy). (E.g. not large cell.)
 In general, broader use may be warranted.
 New: indicated (unlike Bexxar) for previously
untreated follicular NHL after a partial or
complete response to first-line chemotherapy.

Check list before therapy
 Histopathologic confirmation of NHL with
expression of CD-20.
 Bone marrow within 2 months showing <25%
tumor involvement.
 Marrow cellularity >15%.
 Platelets >150,000 (allowing full dose), or
 Platelets ≤150,000 but >100,000 (calling for
reduced dose).
 Absolute neutrophils ≥ 1,500.

Absolute contraindications
 Pregnancy
 Breast feeding.

Other practical points
 Infusions of rituximab are performed one week
before therapeutic Zevalin and again up to 4 hours
before the Zevalin.
 Cold antibody like rituximab may be associated
with infusion reactions, like hives, dyspnea,
hypotension, even death.
 Before rituximab, premedicate orally:
acetaminophen 650 mg, diphenhydramine 50 mg.
 Close monitoring should be performed during
cold and labeled antibody infusions.
 Transient fatigue and a flu-like syndrome may
occur after several days.

 Toxicity of greatest concern is to bone marrow.
Check CBC, platelets weekly for ≥6 weeks. Misc.
other risks (e.g. allergic reaction).
 Concern about the risk of myelodysplastic
syndrome and acute myelogenous leukemia.
 Precautions essentially based on beta emission:
avoid body fluid contamination for ~1 week.
 Patients no longer need In-111 Zevalin WB
scanning after first rituximab infusion, to check
biodistribution (e.g. not too much kidney, lung
or other organ activity, blood clearance not too
rapid, liver usually “hottest”).
 Known hypersensitivity to murine proteins is a
contraindication.

 When antibodies with a mouse component are
injected in humans, there is the potential to
produce human antimurine antibody (HAMA)
or human anti-chimeric antibody (HACA)
which may alter the response to subsequent
antibody infusions, but this occurs infrequently
in NHL patients.

Clinical routine
 Infuse rituximab 250 mg/m2 rituximab IV
slowly one week in advance.
 Repeat rituximab routine followed by Y-90
Zevalin IV over 10 minutes.
 0.4 mCi/kg for platelets >150,000, 0.3 mCi/kg
for Platelets ≤150,000 but >100,000, typical dose
28 mCi, maximum allowed 32 mCi.

Case
 The patient is a 70-y o male weighing 69 kg,
with diffuse large-cell B-cell lymphoma, with
progressive disease after chemotherapy. He has
severe pulmonary emphysema.
 CD20 antigen: +
 Bone marrow cellularity 30% (≥15%).
 Lymphoma cells in bone marrow: 0% (≤25%).
 Absolute neutrophils 4,940 ( ≥ 1,500).
 Platelets 193,000 (≥150,000 for full dose).

With regard to eligibility for Zevalin, which of the
following is true:
1. His platelet count is
too high.
2. His platelet count is
too low.
3. He has an FDA-
approved indication.
4. He doesn’t floss his
teeth frequently
enough.
5. None of the above.
0% 0% 0% 0% 0%
0%
20%
40%
60%
80%
100%

With regard to eligibility for Zevalin, which of the
following is true:
1. His platelet count is too high.
2. His platelet count is too low.
3. He has an FDA-approved indication.
4. He doesn’t floss his teeth frequently
enough.
5. None of the above.

 Rx 69 kg x 0.4 mCi/kg = 27.6 mCi.
 Post therapy blood counts.
Weeks WBC (3,800-
10,000/µL)
Abs. neutrophils
(1,600-6,700/µL)
Platelets (130,000-
400,000/µL)
0 5,200 3,700 193,000
3 3,300 2,300 18,000
16.1 6,900 5,500 84,000
21.6 4,300 2,900 98,000
26.9 6,200 4,500 108,000

I-131-tositumomab (Bexxar)
 I is bound to protein with no need for
linker/chelator.
 Substantial gamma emission, 8-day half-life:
more stringent precautions required, involving
not only body fluids but also distance from
others for a certain period of time, as
determined by RSO.
 Hospitalization would rarely if ever be
required for radiation safety reasons (unlike
thyroid cancer).

 Analogously to Zevalin, on each of 2 days,
separated by about 1 week, the patient gets a
slow infusion of unlabeled antibody (in this
case, tositumomab) followed by radioactive
tositumomab, 5-6 mCi on the first day, a
calculated amount on the later day.
 The gamma irradiation is made good use of for
purposes of 3 consecutive whole body scans
from which whole body residence time is
measured and used to calculate the number of
mCi required to achieve 75 cG whole body dose
(65 if platelets are between 100,000 and 150,000).
Thus, administered dose is more highly
individualized than any of the other therapies
that we have discussed.

 The scans can also give information about
biological distribution.
 The time-period the radiation precautions is
guided by the whole body residence time also.
 Its indications are similar to Zevalin: CD20
antigen-expressing relapsed or refractory, low
grade, follicular, or transformed (indolent to
more aggressive) NHL, but have not been
extended to first-line consolidation therapy.

Which radiopharmaceutical carries a risk of
hypothyroidism?
1. Sm-153 lexidronam
(Quadramet)
2. Sr-89 chloride
(Metastron)
3. Ra-223 chloride
(Alpharadin)
4. Y-90 ibritumomab
tiuxetan (Zevalin)
5. I-131 tositumomab
(Bexxar)
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
20%
40%
60%
80%
100%

I-131 tositumomab (Bexxar)
 I-131 that breaks free goes to the thyroid.
Hypothyroidism occurs in up to 19 % of
patients. To minimize the risk, patients are
required to take non-radioactive iodine
(Lugol’s or SSKI) for approximately 3 weeks
starting 1 day before the first dose.


 Neither of the radioimmunotherapy agents has
been definitively proved to be better than the
other.
 Based on the principle of giving the largest safe
dose, clinical trials have been reported
involving myeloablative doses with stem cell
transplantation.
 "There are no studies that support repeat
[radioimmunotherapy] administration,
although this is feasible.”

Radionuclide therapy of bone metastases and non-Hodgkin’s lymphoma (radioimmunotherapy)

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