This document discusses radioembolization with Yttrium-90 as a treatment for hepatic metastases caused by colorectal cancer. It provides background on the disease, current treatment options, and rationale for using radioembolization. Radioembolization involves administering Yttrium-90 microspheres via the hepatic artery to target tumor cells. The document reviews patient selection criteria, outcomes from clinical trials showing median survival of 15.5 months, and potential adverse effects including nausea, abdominal pain and fatigue.

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Radioembolization of Hepatic
Metastases Caused by
Colorectal Cancer with
Yttrium-90
Brandon Wright
Directed study
Dr. Kiel
05/02/2015

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Hepatic metastases caused by colorectal cancer can lead to a significant increase in
morbidity and mortality. This disease state has very few treatment options and can lead to death
in 4-6 months if left untreated. In the article “Yttrium-90 Radioembolization of Hepatic
Metastases from Colorectal Cancer”, the author states,
“The liver is the most common site of metastases from colorectal cancer (CRC).
Approximately 20% of patients are found to have distant metastases at the time of CRC
diagnosis with approximately 40% to the liver (1, 2). An additional 35–60% of patients develop
liver metastases in the course of the disease. Presence of liver metastases portends a poor
prognosis” (Raval et al.).
Current treatment options for this detrimental disease include systemic chemotherapy
and in a select amount of patients surgical resection may be required. For patients that fail both
systemic chemotherapy and surgical resection, there is one last treatment option; the
radioembolization of hepatic metastases with Yttrium-90, also known as selective internal
radiation therapy (SIRT). This treatment has been proven to be effective by providing a survival
benefit and extending time to progression of the disease. This paper will discuss the rational for
the use of radioembolization, the methods behind the treatment, the criteria for selecting and
appropriately dosing patients, any methods that are utilized for monitoring the progression of the
disease, primary and secondary outcomes from various clinical trials, and the toxicities
associated with the radiopharmaceutical.
Radioembolization with Yttrium-90 is an effective treatment for slowing the progression
of hepatic metastases. It is not a cure for the disease but it has shown promise. This therapy is

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administered by hepatic artery infusion. The rationale behind this method is that tumors growing
in the liver receive over 80% of their blood flow from the hepatic artery versus the normal liver
cells receiving the bulk of their blood flow from the hepatic vein. This means that any
medication administered via the hepatic artery will have an increased rate of passage through the
metastatic cells. Raval states, “In addition, the microvascular density of the hepatic tumors is 3–
200 times higher than the surrounding normal liver parenchyma leading to a higher localized
entrapment of microparticles in the tumor when the microparticles are infused through the
hepatic artery” (Raval et al.). Another reason this therapy is utilized is because the metastatic
cells in the liver show high susceptibility to radioactive isotopes such as Yttrium-90, and
demonstrate no cross resistance to radiation therapy, even though they have shown resistance to
some chemotherapeutic agents.
Yttrium-90 is a beta-emitting radioisotope; it releases long destructive waves of radiation
versus gamma emitters, which release short pulsating waves. This explains why beta emitters are
utilized for therapy and gamma emitters are used for imaging studies. The therapy is available in
two forms; TheraSpheres and SIR-spheres, both measure 20-60 μm across. TheraSpheres are
glass microspheres that have the radioactive isotope incorporated in the actual sphere while the
SIR-spheres are made of a resin, which are then coated with the Yttrium -90. The glass spheres
have a higher density of radioactivity, because they are incorporated into the microsphere versus
just having a coating on the outside. These microspheres are then infused through the hepatic
artery, which increases the uptake into hepatic metastases. Once the microspheres are
internalized, the radiation starts to destroy the cancer from the inside out explaining why the
treatment is termed selective internal radiation therapy (SIRT). This therapy minimizes the risk
of radiation exposure to normal liver cells, which would normally lead to liver disease.

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Patient selection criteria can vary among institutions. The best way to properly assess
the criteria used for multiple institutions is to use a systematic review and pooled analysis of
multiple studies. The article is titled “Treatment of unresectable intrahepatic
cholangiocarcinoma with yttrium-90 radioembolization: A systematic review and pooled
analysis”. The inclusion criteria for this review are: “studies with greater than one patient were
included in order to ensure the comprehensive capture of the available clinical experience. This
included human case-series (>1 case), randomized controlled trials, non-randomized controlled
trials, prospective cohort series” (Al-Adra, D.P. et al). The main selection criteria for patients to
undergo radioembolization for hepatic metastases includes patients that have previously received
some type of treatment for their cancer, whether it be chemotherapy or surgical resection once
patients were known to be refractory to chemotherapy, or have unresectable cancer after the first
surgical resection.
According to the article, “Safety and efficacy of Y-90 microsphere treatment in patients with
primary and metastatic liver cancer: The tumor selectivity of the treatment as a function of tumor
to liver flow ratio”, there are two methods to calculate the required dose for Yttrium-90. The
first way is the empiric method; when using this method 2GBq of Y-90 is given when the tumor
is <25% of the liver, 3GBq of Y-90 when the tumor is 25-50% of the liver, and 5GBq when the
tumor is more than 50% if the liver. The second method is called the BSA method. This method
takes into account the patients BSA, tumor volume in the liver, and total liver volume. The
equation is as follows: Dose (GBq) = [BSA- 0.2 + {Volume of tumor/ (Volume of tumor/
Volume of liver)}]. The BSA method is known to be much safer for the patient as compared to
the empiric method. In the article “Yttrium-90 Radioembolization of Hepatic Metastases from

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Colorectal Cancer”, the author states that use of the empiric method can lead to an overestimated
dose, which in turn can lead to harmful and sometimes fatal effects on the liver.
Based on the systematic review that was used to assess the patient selection criteria, we
can now review the primary and secondary outcomes for radioembolization with Yttrium-90 in
hepatic metastases. The primary outcome for this review was survival; this was assessed with
median survival. The result of this analysis was a median survival of 15.5 months, which was
based on the 11 studies included in the systematic review. The authors of this review stated,
“Most commonly, the response evaluation criteria in solid tumors (RECIST) was
reported. RECIST is defined as complete response (disappearance of all target lesions), partial
response (decrease ≥30% in the sum in the greatest dimension of target lesions), stable disease
(decease <30% or increase <20% in sum in greatest dimension of target lesions) and progressive
disease (increase ≥20% in sum in greatest dimension of target lesions and/or progression of non-
target lesion)” (Al-Adra, D.P. et al).
Using this evidence, the investigators were able to assess the efficacy of the radiation
therapy in decreasing tumor size along with predicting an overall survival outcome. The
secondary outcomes reported by this systematic review were as follows: ability to convert the
tumor from unresectable to resectable, mortality, morbidity, and type of morbidity. 3 out of the
11 studies reported unresectable to resectable as a secondary outcome, including 75 patients.
Out of those 75 patients 7 were able to undergo surgery post-radioembolization. Mortality was
reported as a secondary outcome in 3 out of 11 studies, and out of those studies there was one
treatment related death. The last two secondary outcomes were morbidity and type of morbidity.
The author states, “The most common types of morbidity following radioembolization therapy

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with yttrium-90 microspheres were fatigue (33%), abdominal pain (28%) and nausea (25%)”
(Al-Adra, D.P. et al). Based on this information one can conclude that this therapy can cause
significant morbidity to the patient.
Continuing on topic of morbidity, one can assume there will be some observed adverse
effects associated with this therapy. Adverse effects can range anywhere from nausea/ vomiting
to radiation pneumonitis. Some of the more common adverse effects are included in the post
radioembolization syndrome (PRS). This syndrome includes nausea/ vomiting, right upper
quadrant pain/ discomfort, and cachexia. The article titled “Side Effects of Yttrium-90
Radioembolization” states that for PRS “Hospitalization is rarely required (44–47). Incidence of
PRS ranges from 20% to 70% (17, 44–46). In a two-institution, 112-patient analysis, the
incidence of PRS was 70% (48). Patients should be made aware of these potential side effects
before therapy” (Riaz, Awais, Salem). Some other complications that can arise are hepatic
dysfunction, biliary sequelae, radiation cholecystitis, radiation pneumonitis, gastrointestinal
complications, acute pancreatitis, lymphopenia, thrombocytopenia, and contrast induced
nephrotoxicity. Hepatic dysfunction is directed correlated to the patients Child-Pugh score prior
to treatment. If a patient has a higher Child-Pugh score prior to receiving radioembolization they
are at an increased risk of developing Radiation-Induced Liver Disease (RILD). In addition to
having a high Child-Pugh score, if a patient has received external beam radiation therapy
(EBRT) prior to radioembolization they are at an even high risk of developing RILD. Biliary
sequelae are another set of adverse events that one must keep in mind. In the article “Side
Effects of Yttrium-90 Radioembolization”, the author states “Post-radioembolization biliary
complications are potential side effects of radioembolization. The incidence of these
complications is less than 10% (33). These may be due to the microembolic effect or radiation-

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induced injury to the biliary system.” (Riaz, Awais, Salem). Radioembolization can lead to
radiation induce cholecystitis, radiation induced cholangitis, and abscess/bilomas. One of the
more rare adverse effects of radioembolization with Yttrium-90 is radiation pneumonitis. This is
a condition where the microspheres used to deliver the radiation somehow make it to the lungs
and embed themselves. This leads to restricted ventilation following radioembolization. Like
radiation pneumonitis, gastrointestinal problems can occur from the microspheres traveling to the
stomach or intestinal tract and imbedding themselves there as well. This can lead to ulcers and
frequent diarrhea. Other rare adverse effects are acute pancreatitis, thrombocytopenia,
lymphopenia, and radiation induced nephrotoxicity.
Although radiation has a bad stigma associated with it, sometimes it can be very helpful.
There are many ways that radiation helps humans on a daily basis. Radiation therapy is one of
these ways and is truly making its presence known in the medical field, whether it is for
diagnostic purposes or for it therapeutic modalities. Radioembolization of hepatic metastases is
a great way for selective radiation therapy to make a wave in the medical field. It has been
proven effective at delaying disease progression and improving quality of life for the patients
that it treats. Hopefully in the near future SIRT can be used for other disease states different than
hepatic metastases, and expand its spectrum of therapy.

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References:
1. Raval, Mihir et al. “Yttrium-90 Radioembolization of Hepatic Metastases from
Colorectal Cancer.” Frontiers in Oncology 4 (2014): 120. PMC. Web.
2. Al-Adra, D.P. et al. “Treatment of Unresectable Intrahepatic Cholangiocarcinoma with
Yttrium-90 Radioembolization: A Systematic Review and Pooled Analysis.” European
Journal of Surgical Oncology 41.1 (2015): 120–127. PMC. Web.
3. Murthy, Ravi et al. “Radioembolization of Yttrium-90 Microspheres for Hepatic
Malignancy.” Seminars in Interventional Radiology 25.1 (2008): 48–57. PMC.
4. Gulec, Seza A et al. “Safety and Efficacy of Y-90 Microsphere Treatment in Patients
with Primary and Metastatic Liver Cancer: The Tumor Selectivity of the Treatment as a
Function of Tumor to Liver Flow Ratio.” Journal of Translational Medicine 5 (2007):
15. PMC. Web.
5. Riaz, Ahsun, Rafia Awais, and Riad Salem. “Side Effects of Yttrium-90
Radioembolization.” Frontiers in Oncology 4 (2014): 198. PMC. Web.