dr kennedy bringing srx to 1billion chinese

Dr Kennedy is bringing sir spheres to one billion chinese people also in addition to the European UNION;a report by
Dr Andrew S Kennedy
Co-medical Director of a Private, Freestanding Radiation Oncology Practice
Treatment of Inoperable Liver Cancers with Radioactive Microspheres
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Diagnostics & Imaging RADIATION ONCOLOGY
Dr Andrew S Kennedy is co-medical
director of a private, free-standing
radiation oncology practice in Cary,
North Carolina, US. He is an active
member of several committees of
the American Society for
Therapeutic Radiology and Oncology
(ASTRO) and American College of
Radiation Oncology (ACRO) and
recently served as course director
of the First Radioactive Microsphere
Symposium held in Boston,
Massachusetts, June 2005, attended
by physicians from Europe and the
US. He is the youngest physician to
be inducted as a Fellow in ACRO.
Previously he was Associate
Professor of Radiation Oncology, Codirector
of the GI Oncology Group,
and Head of GI Radiation Oncology
at the Department of Radiation
Oncology, University of Maryland
School of Medicine, in Baltimore,
Maryland. He completed residency
and fellowship in radiation oncology
at the University of North Carolina
Chapel Hill School of Medicine after
attending medical school and
internship at Loma Linda University
School of Medicine in Loma
Linda, California.
U n i v e r s a l C h a l l e n g e i n O n c o l o g y
All oncologists must deal with the frequent and
frustrating occurrence of patients dying of liverdominant
disease. Exciting new advances in
biologic, genetic and cytotoxic agents have
produced important and significant prolongation of
time to progression and survival for many solid
tumours, particularly colorectal adenocarcinoma.
However, nearly all patients with metastatic liver
disease will die of that condition. In the US that is
over 80,000 patients per year, and a similar number
in Europe. Radiation therapy is a cornerstone of
curative and palliative therapy in nearly all
malignancies, but has not been applied with much
success to hepatic disease due to the low tolerance
of the organ to radiation compared with tumour.
Although technology advances in radiation
delivery have improved to some degree, use of
hepatic radiation, the best opportunity to irradiate
the tens of thousands of potential patients with
hepatic tumours, may be via implantation
internally with radioactive particles, i.e. 90Ymicrospheres.
N e w A p p r o a c h t o a n E s t a b l i s h e d I d e a
Brachytherapy – physically implanting tumours
with radiation – has a long and established history
of successful anti-tumour activity in many organs,
with the most common use in prostate, uterine
cervix and head and neck malignancies. The key
principles of brachytherapy involve delivery of
tumourcidal doses of radiation to the malignant
tumour, but, due to rapid radiation dose fall-off,
minimal adjacent normal tissues are damaged.
Currently, a few specialised centres can place
radiation sources manually into the liver
percutaneously or via open laparotomy. A more
easily and broadly applied technique is 90Ymicrospheres,
which use the unique vascular
anatomy of the liver to preferentially implant
hepatic tumours. It is established that the hepatic
arterial system supplies 80% to 100% of the blood
to liver tumours (primary and metastatic);
however, the normal liver derives nearly all of its
blood flow from the parallel portal system. In
addition, metastatic tumours in particular form up
to 200 times more vessels in plexus around tumours
compared with the normal liver immediately
nearby. This combination has led to the discovery
that 90Y-microsphere release in the hepatic artery
produces preferential accumulation of spheres in
the tumours of at least 3:1 and up to 20:1 ratio
compared with normal liver. Thus, the therapeutic
index is favourable just like in other brachytherapy
approaches, i.e. prostate. The diameter of the
microspheres enables them to become implanted in
the tumour, but they cannot pass through the end
arterioles in the capillary bed, which have a
restrictive diameter of only 8–10µ. Only if arterialvenous
fistulas in the tumour are present with
diameters of >30µ would microspheres pass into
the next capillary bed, which is the lung. The
active radiation source – yttrium – is a pure beta
emitter, with energy deposition and dose rate close
to that of external beam therapy, yet the effective
range is only 3mm from the sphere.
90Y - M i c r o s p h e r e T r e a t m e n t
E v a l u a t i o n a n d P r o c e d u r e
The treatment of liver tumours should be carried
out in appropriately staffed, multidisciplinary
oncology teams that have proven expertise in
treating patients with liver-related illnesses,
complications and special therapeutic
interventions. The liver brachytherapy
programmes do not require capital expenditures as
they utilise the personnel, skills, equipment and
physical infrastructure already in place. The
radioactive source (90Y-microspheres) is contained
in a small acrylic holder that provides radiation
protection, and is typically handled in the hot
laboratory of the nuclear medicine or radiation
oncology sections. Therefore, new containment
facilities are not needed for acceptance, storage or
disposal of the radiation therapy system. Most
patients will be referred from a medical oncologist
for evaluation by the team. Diagnostic imaging,
typically computed tomography (CT) and (as
appropriate by tumour type) fluorodeoxyglucose
positron emitted tomography (FDG-PET)
scanning,, are standard, but magnetic resonance
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Diagnostics & Imaging RADIATION ONCOLOGY
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imaging (MRI) or OctreoScan may also be used as
complementary information. The liver vasculature
is meticulously mapped with angiogram by
interventional radiology, with special attention to
any vessels that could carry microspheres away
from the liver and into the stomach, duodenum or
gall bladder. At the conclusion of the hepatic
angiogram, a simulation of the actual treatment is
performed, with albumin particles that
approximate the size of microspheres, tagged with
technicium-99m, a gamma source that is easily
imaged. The test is called macro aggregated
albumin (MAA). It will also reveal the amount of
abnormal shunting of particles that allows
microspheres to bypass the hepatic capillary bed to
collect in the pulmonary vasculature. The nuclear
medicine team will calculate the percentage of
shunt from acquired axial single photon emission
computed tomography (SPECT) and planar APPA
gamma scans obtained from the MAA
injection. The amount of activity injected into the
liver is known, and the ratio of uptake in the lungs
compared with the total (lungs and liver) represents
the shunt fraction of particles. If this exceeds 15%,
then a significant dose reduction is used or the
90Y-microsphere treatment aborted to avoid
pulmonary fibrosis from radiation. The treatment
delivery itself occurs on a separate day and uses all
the data acquired from the angiogram, MAA and
radiation treatment planning to safely deliver
90Y-microspheres to the affected lobes of the liver,
or whole liver as needed.
Immediately after treatment, an additional gamma
scan is obtained in planar and SPECT to confirm
the location of the majority of microspheres.
Characteristic X-rays are emitted during beta decay
of 90Y, which can be captured and imaged. Patients
are seen in follow-up every few weeks and liver
function tests obtained to monitor for radiation or
tumour-related complications and/or dysfunction.
H i s t o r i c a l R e s u l t s o f 90Y - M i c r o s p h e r e
Treatment
Prior to 2002, the majority of patients had
received microspheres as a stand-alone therapy,
usually as salvage after the hepatic tumours
had become refractory to best chemotherapy
options, and recurred after cryotherapy,
radiofrequency ablation and/or transarterial
chemoembolisation. In Australia (1990 to 2002), a
resin-based microsphere was developed and used
predominately in colorectal liver metastases, but also
in hepatocellular – primary – liver cancer. In North
America a glass microsphere, also using 90Y as the
therapeutic moiety, was used in Canada for
hepatocellular cancer until 2000, when it was
reintroduced into the US medical system and used
to treat all types of solid tumours in the liver.1
However, it was not US Food and Drug
Administration (FDA)-approved, and could only be
used under protocol and Institutional Review Board
oversight due to its FDA humanitarian device
exemption, which is still in place. Encouraging
results as salvage therapy were reported for both
microspheres in a variety of metastatic and primary
liver tumours, and resin microspheres were granted
full FDA approval in 2002 for treatment of
colorectal cancer metastases given concurrently with
hepatic artery chemotherapy.
In 2002, Sirtex Medical obtained CE mark, and
initial treatments began in late 2003 in several EU
countries. The glass microsphere is not available
outside of North America. The key early clinical
results in the largest patient cohort colorectal cancer
metastases have come from Australia and the US.
Clinical trials of selective internal radiation therapy
(SIRT) for colorectal cancer have been conducted
in Australia in chemotherapy-naïve patients, and in
the US in salvage patients. The pivotal SIRT trial
accepted by the FDA was interesting but not
applicable to most patients today. Gray2 randomised
74 patients with liver-only colon cancer metastases
to hepatic artery infusion of floxuridine (FUDR)
versus FUDR plus one treatment of resin
microspheres, termed SIRT. The partial and
complete response rate by CT and
carcinoembryonic antigen (CEA) was improved for
patients receiving SIRT. The median time to disease
progression in the liver was significantly longer for
patients receiving SIRT in comparison with patients
receiving hepatic artery chemoembolisation (HAC)
alone. The one-, two, three- and five-year survival
for patients receiving SIRT was 72%, 39%, 17% and
3.5%, compared with 68%, 29%, 6.5% and 0% for
HAC alone, respectively. Cox regression analysis
suggested an improvement in survival for patients
treated with SIR-Spheres® who survive more than
15 months (p=0.06). There was no increase in grade
3 to 4 treatment-related toxicity for patients
receiving SIRT in comparison with patients
receiving HAC alone.
Resin microspheres in the US are used in patients
with chemorefractory liver metastases but minimal
extrahepatic disease, treated with one, two and
1. Kennedy A S, et al., “Outpatient Hepatic Artery Brachytherapy for Primary and Secondary Hepatic Malignancies”,
Radiology (2001);221P (Suppl): p. 468.
2. Gray B, et al., “Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver
metastases from primary large bowel cancer”, Ann. Oncol. (2001);12 (12): pp. 1,711–1,720.

sometimes three courses of SIRT without
concurrent chemotherapy. The largest experience
with either glass microspheres or resin was presented
recently with 329 patients in the US treated with
microspheres alone.3 The abstract was updated from
243 patients to 329 patients at presentation (201
resin, 128 glass), with the median survival of both
resin and glass microsphere patients (actuarial) of 11
months versus a similar cohort of patients without
microsphere treatment of 5.0 months (p=0.001).
All patients were followed until alternate therapy
was given at which point they were censured in the
analysis or, if no other therapy, until death. Acute
and late toxicities were reported based on CTC 2.0,
with all gastrointestinal (GI)-related side effects
added together for a total of 30% grade 3 (nausea,
emesis, anorexia and abdominal pain, gastric or
duodenal ulceration). No cases of veno-occlusive
disease or procedure-related mortality occurred.
Three cases of radiation-induced liver dysfunction
were found, with chronic ascites and low albumin
and CT scan evidence of hepatic fibrosis. Objective
response rates were encouraging with CT scan
(35%), PET (90%) and CEA (70%) achieving a
maximal response at three months post-treatment.3
90Y - M i c r o s p h e r e T r e a t m e n t
Comes of Age
Nearly all solid tumours that are treated with radiation
also benefit from concurrent chemotherapy or a
biologic agent to sensitise and produce at least
additive, but usually synergistic, cell killing. Cancers of
the colon and rectum are the prototypical
chemoradiotherapy tumour type and the most
common metastatic lesion in the liver in Europe and
North America. Combining the newest and most
effective chemotherapy agents for colorectal cancer
with microspheres is the logical next step now that the
effectiveness and safety have been established in
microsphere-alone-treated patients. Two important
phase I studies have been reported this year in patients
with liver metastases from colon cancer. Van Hazel4
treated newly diagnosed patients with FOLFOX4 and
one application of microspheres during the first week
of chemotherapy. The dose escalation involved
oxaliplatin, which was found to be well tolerated at
full dose (85mg/m2) for that regimen with
microspheres. Response (RECEIST) by CT scan was
significant in 10 of 11 evaluable patients. Van Hazel5
also tested chemotherapy and microspheres in 23
patients that had failed fluorouracil (5-FU), but were
irinotecan-naïve. Dose escalation of irinotecan was
not yet complete at the time of the report, but the
desired dose of 100mg/m2 concurrent with
microspheres was well tolerated in all patients treated
thus far. Interestingly, the median time to liver
progression was 6.3 months, and median survival 12.0
months (2–25+ months).
Additional phase I/II clinical trials combining
chemotherapy, biologics and resin microspheres are
on-going in Europe and the US for colorectal
cancer liver disease. Additional experience with
resin spheres is also being gained for metastatic
breast, neuroendocrine and hepatocellular cancers
in Europe, the US and Asia.
By the end of this year, additional advances will be
published regarding radiation dosimetry and
fractionation. These will include more than one
application of microspheres, imaging and follow-up
guidelines, and long-term results in colon, breast,
neuroendocrine, hepatocellular and many other solid
tumours. It is a therapeutic approach that has shown
promise, safety and flexibility in the application to
many tumour types, in patients with both early and
advanced hepatic disease, even with heavy pretreatment
profiles. ■
3. Kennedy A S, et al., “Liver brachytherapy for unresectable colorectal metastases: US results 2000-2004”, Proceedings of
the 2005 Gastrointestinal Cancers Symposium, 2005: p. 155.
4. Van Hazel G, et al., “Selective internal radiation therapy (SIRT) plus systemic chemotherapy with FOLFOX A phase I
dose escalation study”, Proceedings of the 2005 Gastrointestinal Cancers Symposium, 2005: p. 216.
5. Van Hazel G, et al., “Selective internal radiation therapy (SIRT) plus systemic chemotherapy with irinotecan. A phase I
dose escalation study”, Proceedings of the 2007 Gastrointestinal Cancers Symposium, 2007: p. 137.
Nearly all solid tumours that are treated with radiation also
benefit from concurrent chemotherapy or a biologic agent.
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