Treatment of Inoperable Liver Cancers with Radioactive

a report by

D r A nd r ew S K e n n e d y

Co-medical Director of a Private, Freestanding Radiation Oncology Practice

Treatment o f Inoperab le L iver Cancer s wi th Rad ioac t i ve Mic rospheres

B U S I N E S S B R I E F I N G : E U R O P E A N O N C O L O G Y R E V I E W 2 0 0 5

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Diagnostics & Imaging RADIATION ONCOLOGY

Dr Andrew S Kennedy is co-medicaldirector of a private, free-standingradiation oncology practice in Cary,North Carolina, US. He is an activemember of several committees ofthe American Society forTherapeutic Radiology and Oncology(ASTRO) and American College ofRadiation Oncology (ACRO) andrecently served as course directorof the First Radioactive MicrosphereSymposium held in Boston,Massachusetts, June 2005, attendedby physicians from Europe and theUS. He is the youngest physician tobe inducted as a Fellow in ACRO.Previously he was AssociateProfessor of Radiation Oncology, Co-director of the GI Oncology Group,and Head of GI Radiation Oncologyat the Department of RadiationOncology, University of MarylandSchool of Medicine, in Baltimore,Maryland. He completed residencyand fellowship in radiation oncologyat the University of North CarolinaChapel Hill School of Medicine afterattending medical school andinternship at Loma Linda UniversitySchool of Medicine in Loma Linda, California.

Un 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 andfrustrating occurrence of patients dying of liver-dominant disease. Exciting new advances inbiologic, genetic and cytotoxic agents haveproduced important and significant prolongation oftime to progression and survival for many solidtumours, particularly colorectal adenocarcinoma.However, nearly all patients with metastatic liverdisease will die of that condition. In the US that isover 80,000 patients per year, and a similar numberin Europe. Radiation therapy is a cornerstone ofcurative and palliative therapy in nearly allmalignancies, but has not been applied with muchsuccess to hepatic disease due to the low toleranceof the organ to radiation compared with tumour.Although technology advances in radiationdelivery have improved to some degree, use ofhepatic radiation, the best opportunity to irradiatethe tens of thousands of potential patients withhepatic tumours, may be via implantationinternally with radioactive particles, i.e. 90Y-microspheres.

New App 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 tumourswith radiation – has a long and established historyof successful anti-tumour activity in many organs,with the most common use in prostate, uterinecervix and head and neck malignancies. The keyprinciples of brachytherapy involve delivery oftumourcidal doses of radiation to the malignanttumour, but, due to rapid radiation dose fall-off,minimal adjacent normal tissues are damaged.Currently, a few specialised centres can placeradiation sources manually into the liverpercutaneously or via open laparotomy. A moreeasily and broadly applied technique is 90Y-microspheres, which use the unique vascularanatomy of the liver to preferentially implanthepatic tumours. It is established that the hepaticarterial system supplies 80% to 100% of the bloodto liver tumours (primary and metastatic);however, the normal liver derives nearly all of itsblood flow from the parallel portal system. In

addition, metastatic tumours in particular form upto 200 times more vessels in plexus around tumourscompared with the normal liver immediatelynearby. This combination has led to the discoverythat 90Y-microsphere release in the hepatic arteryproduces preferential accumulation of spheres inthe tumours of at least 3:1 and up to 20:1 ratiocompared with normal liver. Thus, the therapeuticindex is favourable just like in other brachytherapyapproaches, i.e. prostate. The diameter of themicrospheres enables them to become implanted inthe tumour, but they cannot pass through the endarterioles in the capillary bed, which have arestrictive diameter of only 8–10µ. Only if arterial-venous fistulas in the tumour are present withdiameters of >30µ would microspheres pass intothe next capillary bed, which is the lung. Theactive radiation source – yttrium – is a pure betaemitter, with energy deposition and dose rate closeto that of external beam therapy, yet the effectiverange is only 3mm from the sphere.

90Y -M i c r o s p h e r e T r e a tmen 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 carriedout in appropriately staffed, multidisciplinaryoncology teams that have proven expertise intreating patients with liver-related illnesses,complications and special therapeuticinterventions. The liver brachytherapyprogrammes do not require capital expenditures asthey utilise the personnel, skills, equipment andphysical infrastructure already in place. Theradioactive source (90Y-microspheres) is containedin a small acrylic holder that provides radiationprotection, and is typically handled in the hotlaboratory of the nuclear medicine or radiationoncology sections. Therefore, new containmentfacilities are not needed for acceptance, storage ordisposal of the radiation therapy system. Mostpatients will be referred from a medical oncologistfor evaluation by the team. Diagnostic imaging,typically computed tomography (CT) and (asappropriate by tumour type) fluorodeoxyglucosepositron emitted tomography (FDG-PET)scanning,, are standard, but magnetic resonance

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imaging (MRI) or OctreoScan may also be used ascomplementary information. The liver vasculatureis meticulously mapped with angiogram byinterventional radiology, with special attention toany vessels that could carry microspheres awayfrom the liver and into the stomach, duodenum orgall bladder. At the conclusion of the hepaticangiogram, a simulation of the actual treatment isperformed, with albumin particles thatapproximate the size of microspheres, tagged withtechnicium-99m, a gamma source that is easilyimaged. The test is called macro aggregatedalbumin (MAA). It will also reveal the amount ofabnormal shunting of particles that allowsmicrospheres to bypass the hepatic capillary bed tocollect in the pulmonary vasculature. The nuclearmedicine team will calculate the percentage ofshunt from acquired axial single photon emissioncomputed tomography (SPECT) and planar AP-PA gamma scans obtained from the MAAinjection. The amount of activity injected into theliver is known, and the ratio of uptake in the lungscompared with the total (lungs and liver) representsthe shunt fraction of particles. If this exceeds 15%,then a significant dose reduction is used or the 90Y-microsphere treatment aborted to avoidpulmonary fibrosis from radiation. The treatmentdelivery itself occurs on a separate day and uses allthe data acquired from the angiogram, MAA andradiation treatment planning to safely deliver 90Y-microspheres to the affected lobes of the liver,or whole liver as needed.

Immediately after treatment, an additional gammascan is obtained in planar and SPECT to confirmthe location of the majority of microspheres.Characteristic X-rays are emitted during beta decayof 90Y, which can be captured and imaged. Patientsare seen in follow-up every few weeks and liverfunction tests obtained to monitor for radiation ortumour-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 eT r e a tmen t

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 chemotherapyoptions, and recurred after cryotherapy,radiofrequency ablation and/or transarterialchemoembolisation. In Australia (1990 to 2002), aresin-based microsphere was developed and usedpredominately in colorectal liver metastases, but also

in hepatocellular – primary – liver cancer. In NorthAmerica a glass microsphere, also using 90Y as thetherapeutic moiety, was used in Canada forhepatocellular cancer until 2000, when it wasreintroduced into the US medical system and usedto treat all types of solid tumours in the liver.1

However, it was not US Food and DrugAdministration (FDA)-approved, and could only beused under protocol and Institutional Review Boardoversight due to its FDA humanitarian deviceexemption, which is still in place. Encouragingresults as salvage therapy were reported for bothmicrospheres in a variety of metastatic and primaryliver tumours, and resin microspheres were grantedfull FDA approval in 2002 for treatment ofcolorectal cancer metastases given concurrently withhepatic artery chemotherapy.

In 2002, Sirtex Medical obtained CE mark, andinitial treatments began in late 2003 in several EUcountries. The glass microsphere is not availableoutside of North America. The key early clinicalresults in the largest patient cohort colorectal cancermetastases have come from Australia and the US.Clinical trials of selective internal radiation therapy(SIRT) for colorectal cancer have been conductedin Australia in chemotherapy-naïve patients, and inthe US in salvage patients. The pivotal SIRT trialaccepted by the FDA was interesting but notapplicable to most patients today. Gray2 randomised74 patients with liver-only colon cancer metastasesto hepatic artery infusion of floxuridine (FUDR)versus FUDR plus one treatment of resinmicrospheres, termed SIRT. The partial andcomplete response rate by CT andcarcinoembryonic antigen (CEA) was improved forpatients receiving SIRT. The median time to diseaseprogression in the liver was significantly longer forpatients receiving SIRT in comparison with patientsreceiving hepatic artery chemoembolisation (HAC)alone. The one-, two, three- and five-year survivalfor patients receiving SIRT was 72%, 39%, 17% and3.5%, compared with 68%, 29%, 6.5% and 0% forHAC alone, respectively. Cox regression analysissuggested an improvement in survival for patientstreated with SIR-Spheres® who survive more than15 months (p=0.06). There was no increase in grade3 to 4 treatment-related toxicity for patientsreceiving SIRT in comparison with patientsreceiving HAC alone.

Resin microspheres in the US are used in patientswith chemorefractory liver metastases but minimalextrahepatic 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 livermetastases from primary large bowel cancer”, Ann. Oncol. (2001);12 (12): pp. 1,711–1,720.


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sometimes three courses of SIRT withoutconcurrent chemotherapy. The largest experiencewith either glass microspheres or resin was presentedrecently with 329 patients in the US treated withmicrospheres alone.3 The abstract was updated from243 patients to 329 patients at presentation (201resin, 128 glass), with the median survival of bothresin and glass microsphere patients (actuarial) of 11months versus a similar cohort of patients withoutmicrosphere treatment of 5.0 months (p=0.001).

All patients were followed until alternate therapywas given at which point they were censured in theanalysis or, if no other therapy, until death. Acuteand late toxicities were reported based on CTC 2.0,

with all gastrointestinal (GI)-related side effectsadded together for a total of 30% grade 3 (nausea,emesis, anorexia and abdominal pain, gastric orduodenal ulceration). No cases of veno-occlusivedisease or procedure-related mortality occurred.Three cases of radiation-induced liver dysfunctionwere found, with chronic ascites and low albuminand CT scan evidence of hepatic fibrosis. Objectiveresponse rates were encouraging with CT scan(35%), PET (90%) and CEA (70%) achieving amaximal response at three months post-treatment.3

90Y -M i c r o s p h e r e T r e a tmen t C ome s o f A g e

Nearly all solid tumours that are treated with radiationalso benefit from concurrent chemotherapy or abiologic agent to sensitise and produce at leastadditive, but usually synergistic, cell killing. Cancers ofthe colon and rectum are the prototypicalchemoradiotherapy tumour type and the mostcommon metastatic lesion in the liver in Europe andNorth America. Combining the newest and mosteffective chemotherapy agents for colorectal cancerwith microspheres is the logical next step now that the

effectiveness and safety have been established inmicrosphere-alone-treated patients. Two importantphase I studies have been reported this year in patientswith liver metastases from colon cancer. Van Hazel4

treated newly diagnosed patients with FOLFOX4 andone application of microspheres during the first weekof chemotherapy. The dose escalation involvedoxaliplatin, which was found to be well tolerated atfull dose (85mg/m2) for that regimen withmicrospheres. Response (RECEIST) by CT scan wassignificant in 10 of 11 evaluable patients. Van Hazel5

also tested chemotherapy and microspheres in 23patients that had failed fluorouracil (5-FU), but wereirinotecan-naïve. Dose escalation of irinotecan wasnot yet complete at the time of the report, but the

desired dose of 100mg/m2 concurrent withmicrospheres was well tolerated in all patients treatedthus far. Interestingly, the median time to liverprogression was 6.3 months, and median survival 12.0months (2–25+ months).

Additional phase I/II clinical trials combiningchemotherapy, biologics and resin microspheres areon-going in Europe and the US for colorectalcancer liver disease. Additional experience withresin spheres is also being gained for metastaticbreast, neuroendocrine and hepatocellular cancersin Europe, the US and Asia.

By the end of this year, additional advances will bepublished regarding radiation dosimetry andfractionation. These will include more than oneapplication of microspheres, imaging and follow-upguidelines, and long-term results in colon, breast,neuroendocrine, hepatocellular and many other solidtumours. It is a therapeutic approach that has shownpromise, safety and flexibility in the application tomany tumour types, in patients with both early andadvanced hepatic disease, even with heavy pre-treatment profiles. ■

3. Kennedy A S, et al., “Liver brachytherapy for unresectable colorectal metastases: US results 2000-2004”, Proceedings ofthe 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 Idose 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 Idose escalation study”, Proceedings of the 2005 Gastrointestinal Cancers Symposium, 2005: p. 137.

Nearly all solid tumours that are treated with radiation also

benefit from concurrent chemotherapy or a biologic agent.



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Treatment of Inoperable Liver Cancers with Radioactive