Selective internal radiation therapy for the treatment of liver cancer
1. HealthPACT
Health Policy and Advisory Committee
on Technology
Australia and New Zealand
Technology Brief
Selective internal radiation therapy for the
treatment of liver cancer
(v1.0)
August 2011
3. TECHNOLOGY BRIEF
REGISTER ID WP022 (V1.0)
NAME OF TECHNOLOGY SELECTIVE INTERNAL RADIATION THERAPY
PURPOSE AND TARGET GROUP TREATMENT OF PATIENTS WITH NON-RESECTABLE
HEPATOCELLULAR CARCINOMA OR LIVER METASTASES
STAGE OF DEVELOPMENT (IN AUSTRALIA)
Yet to emerge Established
Established but changed indication
or modification of technique
Experimental
Investigational Should be taken out of use
Nearly established
AUSTRALIAN THERAPEUTIC GOODS ADMINISTRATION APPROVAL
Yes ARTG number 149332
No
Not applicable
INTERNATIONAL UTILISATION
LEVEL OF USECOUNTRY
Trials underway or
completed
Limited use Widely diffused
Australia
Canada
Egypt
Europe
Hong Kong
India
Israel
Kuwait
Malaysia
New Zealand
Philippines
Saudi Arabia
Singapore
South Africa
South Korea
Switzerland
Taiwan
Thailand
Turkey
United States of America
Selective internal radiation therapy for the treatment of liver cancer: August 2011 1
4. IMPACT SUMMARY
Selective internal radiation therapy (SIRT) is a new modality for the treatment of primary
and metastatic liver cancer. Radioactive microspheres containing the beta radiation emitting
isotope yttrium-90 are delivered to the tumorous part of the liver via injection into the
hepatic artery.
BACKGROUND
Liver cancers can be primary or secondary/metastatic. Hepatocellular carcinoma (HCC) is
the most common form of primary liver cancer in adults. It is commonly caused by chronic
liver diseases such as hepatitis and cirrhosis (Russell et al 2004). Patient prognosis largely
depends on the TNM staging*
of the disease at the time of diagnosis, its histological pattern
and coexistent cirrhosis (Balis and Lauwers 2004). Secondary liver cancer or liver
metastases are often due to primary colorectal cancer. Metastases from colorectal cancer may
spread by local extension or through the blood stream or lymphatic system (most commonly
via the portal vein) (Russell et al 2004). According to the National Institute for Health and
Clinical Excellence (NICE) in the United Kingdom, the five-year survival rate after
diagnosis of colorectal cancer is approximately 45 per cent (NICE 2004). The National
Comprehensive Cancer Network in the United States of America (USA) affirms that the
remaining 50–60 per cent of colorectal cancer patients eventually develop metastases
(NCCN 2009). The liver is often the first site of metastases and may be the only site of
spread in 30–40 per cent of patients with advanced colorectal cancer (Simmonds et al 2006).
Surgical resection is the best curative option for liver cancer. In the case of isolated HCC,
liver transplantation is a treatment option. Ablation techniques such as cryotherapy,
radiofrequency thermal ablation, microwave coagulation and laser electrocoagulation are
treatment options in patients for whom resection presents a risk. However, the majority of
liver cancers are not eligible for surgery or ablation at the time of diagnosis (Gray et al
2001).
Chemotherapy plays an important role in the treatment of liver metastases. Patients may
benefit in terms of both survival and quality of life (QOL) by receiving a combination of
chemotherapy and best supportive care†
(Ahmed et al 2004). Patients with unresectable
metastatic disease have a median survival of < 10 months if treated by best supportive care
alone, while an improved median survival of 15 to 21.5 months may be achieved by
*
TNM staging is based on the number and size of the primary tumour (T), the extent of the spread to nearby lymph nodes
(N) and the presence of metastases (M) (American Cancer Society 2011).
†
According to the European Organization for Research and Treatment of Cancer (EORTC) Pain and Symptom Control Task
Force, best supportive care for cancer patients is defined as multi-professional attention to the patient’s overall physical,
psychosocial, spiritual and cultural needs, and should be available at all stages of the illness, for patients of all ages, and
regardless of the current intention of any anti-cancer treatment (Ahmedzai et al 2001).
5. administering a combination chemotherapy regimen (Delaunoit et al 2005; Grothey et al
2004; Tournigand et al 2004). A minority of initially unresectable patients (3.3–12.5%)
become resection candidates following chemotherapy (Delaunoit et al 2005). Chemotherapy
for liver metastases can be either systemic or regional (administered via the hepatic artery),
and use agents such as fluoropyrimidines (commonly 5-fluorouracil with irinotecan or
oxaliplatin).
SIRT, also known as radio-embolisation or transarterial radio-embolisation (TARE), is a new
and developing modality for managing liver cancers that are not amenable to surgery. High-
energy beta particles of yttrium-90 (with a half-life of 64 hours and maximum tissue
penetration of 11 mm) are delivered via the hepatic artery, through either a surgically
implanted permanent hepatic artery port or a percutaneous transfemoral hepatic artery
catheter. The latter technique has been the technique of choice since 2002. The increased
yttrium concentration within the microvasculature of the liver tumour produces a local radio-
therapeutic effect.
Two products were identified for use in SIRT at the time of writing: SIR-Spheres® (Sirtex
Medical Limited, Australia) and TheraSphere®
(Nordion, Canada).
CLINICAL NEED AND BURDEN OF DISEASE
The incidence of liver cancer has steadily increased in recent years (AIHW 2010). During
2001, 853 new cases of primary liver cancer were reported in Australia, excluding HCC
caused by hepatitis B and C (AIHW 2010). By 2007 this number had increased to 1,169 and
accounted for 1,109 deaths (AIHW 2010). The incidence and prevalence of hepatitis B and C
have also steadily increased over time, with a total of 242,000 Australians reported to have
been infected in 2004 (including 14,499 new cases in that year alone) (National Centre in
HIV Epidemiology and Clinical Research 2004).
Many patients with colorectal cancer will develop metastatic liver disease. Colorectal cancer
is the second most common cancer in Australia, making up 13.1 per cent of all reported
cancers in 2007 (males 12.6%, females 13.9%) (AIHW 2010). From 1982 to 2007 the
incidence of colorectal cancer in males increased from 67 to 75 cases per 100,000 and in
females from 50 to 55 cases per 100,000 (AIHW 2010). Interactive National Hospital
Morbidity Data reported that 1,731 patient days‡
were utilised during 1998–99 due to
malignant neoplasm of the liver and intrahepatic bile ducts, which increased to 3,371 patient
days by 2007–08 (AIHW 2011). These data may describe the burden for both primary and
secondary liver cancers.
‡
Patient days were defined as “the total number of days for patients who were admitted for an episode of care and who
separated during a specified reference period. A patient who is admitted and separated on the same day is allocated 1 patient
day”.
6. DIFFUSION
SIR-Spheres are microspheres labelled with yttrium-90 that are delivered direct to the
tumour via a catheter in the hepatic artery. This product is available in the USA, Europe,
Australia, New Zealand, Hong Kong, Switzerland, Turkey, Taiwan, South Korea, Singapore,
Malaysia, India, Philippines, Thailand and Egypt.
SIR-Spheres microspheres were first listed on the Australian Register of Therapeutic Goods
(ARTG) on February 27, 1998 as a medical device under AUSTL No 63369 and were
subsequently approved as an Active Implantable Medical Device on January 21, 2008 under
ARTG number 149332 (under the Therapeutic Goods Administration (TGA) revised
legislation). The TGA defines SIR-Spheres as radionuclide permanent implants for the
treatment of inoperable liver cancer (TGA 2008).
In the USA, SIR-Spheres are fully approved by the Food and Drug Administration (FDA) for
use in the treatment of inoperable liver metastases secondary to colorectal cancer. SIR-
Spheres microspheres were issued with a European CE Mark approval by British Standards
Institution, acting as an official Notified Body, on October 16, 2002 (No CE 60079) (Sirtex
Medical Limited 2011).
Currently, three Medicare Benefit Schedule (MBS) item numbers relate to SIR-Spheres. One
refers to the dosimetry, preparation and injection of SIR-Spheres by a nuclear medicine
specialist (35404) and the remaining two describe the interventional radiologist’s
catheterisation process for administering SIR-Spheres into the liver (35406, 35408) (MBS
2011a; MBS 2011b; MBS 2011c). Medicare does not appear to cover the cost of the SIR-
Spheres product itself. However, SIR-Spheres (including delivery apparatus) appear on the
Prosthesis List, as a temporary listing pending review, with a minimum benefit of $8,230.00.
The TheraSphere medical device delivers yttrium-90 loaded glass microspheres to the
tumorous part of the liver and is intended for use during SIRT in HCC. TheraSphere is
available in Canada, USA, Europe (Belgium, France, Germany, Italy and Spain), Turkey,
Egypt, Saudi Arabia, India, Kuwait and South Africa (Nordion 2011a). Nordion has not
sought TGA approval for ThereSphere in Australia. TheraSphere received humanitarian
device exemption for the treatment of HCC in the USA (Nordion 2011b).
COMPARATORS
Treatment for liver cancer depends on TNM stage. Surgical resection is the ideal option and
ablation techniques may also be useful. However, the majority of liver cancers are not
eligible for surgical resection or local ablation at the time of diagnosis (Gray et al 2001).
Patients with advanced liver cancer who receive best supportive care would benefit in both
survival and QOL by also receiving chemotherapy, which should be considered the primary
comparator to SIRT. Chemotherapy may be administered either systemically or regionally
7. via the hepatic artery, using agents such as the fluoropyrimidines (commonly 5-fluorouracil
together with irinotecan or oxaliplatin).
SAFETY AND EFFECTIVENESS ISSUES
Three randomised controlled trials (RCTs) reporting on the use of SIRT for the treatment of
liver metastases were identified (Gray et al 2001; Hendlisz et al 2010; Van Hazel et al 2004).
No RCTs were identified for the use of SIRT for HCC.
Study profiles
Hendlisz et al (2010) conducted a prospective, open label phase III RCT at three sites in
Belgium to assess the safety and efficacy of intra-arterial yttrium-90 resin microspheres
(SIR-Spheres). Patients were over 18 years of age with histologically-proven colorectal
adenocarcinoma that had metastasised only to the liver. None were candidates for curative
resection or ablation and all were resistant to, or intolerant of, standard chemotherapy.
Patients were also required to have adequate function of bone marrow, liver and kidneys.
Patients were randomised using the minimisation technique, with institution and type of
progression (while on chemotherapy or 6 months post-chemotherapy) as stratification
factors. Of 46 randomised patients, 44 were eligible, of whom 21 were assigned to the
interventional group and 23 to the control group.
The control group received intravenous (IV) fluorouracil 300 mg/m2
for 14 days every three
weeks until progression. The intervention group received isotope yttrium-90 bound to resin
microspheres (radio-embolisation) via a hepatic intra-arterial injection. The intervention
group also received IV fluorouracil 225 mg/m2
for 14 days followed by a one week break,
and then 300 mg/m2
for 14 days, every three weeks. All patients were followed up for a
median duration of 24.8 months (range 2–41 months).
Van Hazel et al (2004) conducted a phase II RCT that compared a single administration of
SIR-Spheres plus systemic chemotherapy with systemic chemotherapy alone in patients with
liver metastases due to advanced colorectal cancer (with or without extra-hepatic
metastases). This study was based at the Mount Hospital (Western Australia (WA)), Sir
Charles Gairdner Hospital (WA) and Greenslopes Hospital (Queensland) and was designed
to detect a 20 per cent difference in grade 4 toxicity event rate, with a required sample size of
18 patients. A total of 21 patients were recruited. Selection criteria included histologically-
proven large bowel adenocarcinoma with unequivocal computed tomography (CT) scan
evidence of liver metastases that could not be treated by resection or any locally ablative
method, plus adequate haematological, hepatic and renal function. Patients who previously
received chemotherapy or radiotherapy for liver metastases, and those who had cerebral
metastases and evidence of cirrhosis, ascites or portal hypertension, were excluded. Patients
were stratified before randomisation by hospital, according to the presence/absence of extra-
8. hepatic metastases and the extent of tumour involvement in the liver (> or < 25%
involvement). Randomisation occurred through an independent body using a computer-based
program. Blinding of patients and treatment providers was not logistically possible; however,
all serial CT scans were read by a blinded independent person.
Both treatment groups received systemic chemotherapy, which consisted of 5-fluoruracil 425
mg/m2
body surface area (BSA) per day plus leucovorin 20 mg/m2
per day for five
consecutive days, repeated at four-weekly intervals. This was continued until evidence of
unacceptable toxicity or disease progression were apparent, or until patients requested
cessation. Patients in the intervention group received SIR-Spheres into the hepatic artery via
a transfemoral catheter on the third or fourth day of the second cycle of chemotherapy. Five
patients in the intervention group received the standard dose of 2.5 gigabecquerel (GBq) of
yttrium-90, while the remaining six received a dose from 1.5 to 2.1 GBq of yttrium-90,
according to a formula based on BSA and percentage tumour involvement. Minimum
follow-up duration was not mentioned; however, at 42.5 months following randomisation
only one patient was still alive.
Finally, Gray et al (2001) conducted an early phase III RCT that compared SIRT and
chemotherapy with chemotherapy alone. This study enrolled 74 patients at the Royal Perth
Hospital (WA) and the Sir Charles Gairdner Hospital (WA) from 1991–97. Several authors
were common to the study by Van Hazel et al (2004) above. Patients were diagnosed with
bi-lobar, non-resectable and non-ablatable metastases in the liver and regional lymph nodes
arising from primary adenocarcinoma of the large bowel, without distant metastases. All
patients had undergone complete surgical resection of a primary adenocarcinoma of the large
bowel. Previous systemic chemotherapy for the metastases was acceptable but patients who
had received hepatic radiotherapy were excluded. Of the initial 74 patients, 70 were
ultimately eligible for trial inclusion. Patients were stratified into three groups based upon
tumour involvement of the liver prior to randomisation (< 25% involvement, 25–50%
involvement, > 50% involvement). Randomisation took place using the blinded envelope
batch method and was controlled by an independent person; however, the method used to
develop the randomisation sequence was not reported. Patients received either a regimen of
hepatic artery chemotherapy with floxuridine (control group) or the same chemotherapy with
a single injection of SIR-Spheres (intervention group). Chemotherapy was administered in
12-day cycles every four weeks. The dosage of the SIR-Spheres injection was determined by
tumour size and ranged from 2–3 GBq of yttrium-90. Follow-up tests consisted of monthly
physical examination, haematological screening, liver function tests, and serum carcino-
embryonic antigen (CEA) in addition to three-monthly CT scans of the abdomen. All
patients were followed up for a minimum of 3.5 years.
Additional study characteristics for the three identified RCTs are presented below in Table 1.
9. Table 1: Study characteristics of included studies
Pre-interventional patient and tumour characteristicsStudy na
/Nb
SIRT Comparator
Male
(%)
Mean age
(years)
Primary
cancer
Extra-
hepatic
metastases
(%)
> 25%
Liver
involved
(%)
Prior treatment
with
chemotherapy
(%)
Hendlisz et al
2010
44/46 SIR-Spheres
(n=21)
Systemic
chemotherapy
(n=23)
64 62
(SIRT 62;
comparator 62)
Colorectal 0 NR 100
Van Hazel et
al 2004
21/21 SIR-Spheres
(n=11)
Systemic
chemotherapy
(n=10)
86 65
(SIRT 64;
comparator 65)
Colorectal 24 29 0
Gray et al
2001
70/74 SIR-Spheres
(n=36)
HAC (n=34) 77 61
(SIRT 62;
comparator 59)
Colorectal 0 31 14
HAC: hepatic artery chemotherapy; NR: not reported; SIRT: selective internal radiation therapy
a
Number completing trial.
b
Number originally enrolled.
Selective internal radiation therapy for the treatment of liver cancer: August 2011 7
10. Safety
The safety outcomes measured included treatment-related toxicity, adverse events and
mortality. All three studies reported the frequency of grade 3 and 4 toxicity (Table 2).
Table 2: Reported adverse events and treatment-related deaths
Hendlisz et al
2010
Van Hazel et al
2004
Gray et al 2001Event
SIRT
(n=21)
Comp
(n=22)
SIRT
(n=11)
Comp.
(n=10)
SIRT
(n=36)
Comp
(n=34)
Grade 3 and 4 toxicity events
Low haemoglobin or
granulocytopenia NR NR 3 0 0 1
GI events (nausea, vomiting,
diarrhoea, stomatitis, anorexia) 0 2 8 5 1 3
Liver abscess NR NR 1 0 NR NR
Radiation-induced cirrhosis NR NR 1a
0 NR NR
Liver function test abnormality NR NR 0 0 22 19
Fatigue 0 6 NR NR NR NR
Pulmonary events 0 2 NR NR NR NR
Allergy 0 1 NR NR NR NR
Hand-foot syndrome 1 0 NR NR NR NR
Total number of grade 3 and 4
toxicity events 1 11 13 5 23 23
Treatment related deaths NR NR 1b
0 NR NR
GI: gastrointestinal; comp: comparator; NR: not reported.
a
Very small patient and SIRT dose considered excessive.
b
Death due to chemotherapy-induced neutropenia and associated sepsis after the fourth cycle of treatment.
Hendlisz et al (2010) showed an advantage of SIR-Spheres over systemic chemotherapy
in terms of toxicity, although the difference was not statistically significant (p = 0.10). In
contrast, Van Hazel et al (2004) showed 13 grade 3 and 4 toxicities and one treatment-
related death in the intervention group, compared with only five toxicities in the control
group (no statistical analysis provided). Gray et al (2001) reported that the risk of death
from progression of liver metastases was 3.1 times higher in the control group (95%
confidence interval (CI); [1.1, 8.8], p=0.03) compared with the interventional group. In
Selective internal radiation therapy for the treatment of liver cancer: August 2011 8
11. Selective internal radiation therapy for the treatment of liver cancer: August 2011 9
this study, the addition of SIR-Spheres did not create statistically significant, clinically
relevant, treatment-related toxicity, as both groups experienced the same number of grade
3 and 4 toxicities (n=23).
Effectiveness
The effectiveness outcomes measured included tumour response rate, time to disease
progression in the liver, survival rate and QOL.
Hendlisz et al (2010) reported hepatic response according to the Response Evaluation
Criteria in Solid Tumours (RECIST) criteria§
for target lesions. Most patients had a
minimum of two lesions at the time of randomisation. The median sum of diameters of
targeted lesions was 176.5 mm for the interventional group and 216 mm for the control
group. Two patients from the interventional group had tumour response (9.5%) compared
with none in the control group (p = 0.22). The disease control rate was calculated by
adding partial response and stable diseases rates. Significantly more intervention patients
than control patients recorded disease control (18/21, 86% versus 8/23, 35%, p = 0.001).
The primary endpoint was time to liver progression, and the median time was 5.5 months
in the intervention group and 2.1 months in the control group (Hazard ratio [HR] 0.38;
95% CI [0.20, 0.72], p = 0.003). The overall time for tumour progression was 4.5 months
for the intervention group versus 2.1 months for controls (HR 0.51; 95% CI [0.28, 0.94],
p = 0.03). Overall survival was measured as the time elapsed between randomisation and
death). Median overall survival was 10 months for the intervention group compared with
7.3 months for the control group (HR 0.92; 95% CI [0.47, 1.78], p = 0.80). Notably, for
ethical reasons, 25/44 patients received further treatment after disease progression
(including 10 control group patients who received radio-embolisation treatment).
Van Hazel et al (2004) also measured tumour response using the RECIST criteria. No
complete responses were recorded in either group, and the differences in tumour response
rates were not statistically significant. Several patients in the intervention group showed
partial response, with CT evidence of tumour replacement by small dense calcifications.
Time to progressive disease was significantly longer in the intervention group (18.6
months versus 3.6 months in the control group) (p < 0.0005). Median survival was
significantly longer in the intervention group (29.4 months versus 12.8 months in the
control group, HR 0.33; 95% CI [0.12, 0.91], p = 0.025). QOL and patient well-being
were measured at randomisation and at 3-month intervals using the validated 23-point
§
RECIST Criteria: Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30%
decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, Stable
Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as
reference the smallest sum LD since the treatment started, Progressive Disease (PD): At least a 20% increase in the sum
of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the
appearance of one or more new lesions (adapted from National Cancer Institute 2011).
12. Functional Living Index - Cancer questionnaire and the Spitzer index. Neither showed
statistically significant differences between the treatment groups (p = 0.96 and p = 0.98,
respectively).
Finally, in the study by Gray et al (2001) tumour response was measured by two
independent medical practitioners according to tumour volume, serum CEA changes and
tumour area. For tumour volume, a partial response was defined as ‘an objectively
measured decrease in tumour size by 50 per cent on two or more successive CT scans not
less than four weeks apart, after randomisation and before evidence of progressive
disease in the liver’ and a complete response was defined as ‘the disappearance of all
tumour on two successive CT scans not less than four weeks apart, after randomisation
and before evidence of progressive disease in the liver.’ Significantly more patients in the
intervention group achieved either a complete or partial response in tumour volume (50%
versus 24% of the control group, p = 0.03). Serum CEA changes were measured only for
patients in whom the serum CEA was elevated before the start of protocol treatment.
Patients in the intervention group experienced a significantly larger change in serum CEA
levels compared with the control group (72% versus 47%, p = 0.004), indicating a greater
proportion of these patients responded to treatment. To measure tumour area, cross-
sectional diameters of all measurable lesions seen on serial CT scans were summed.
Significantly more patients in the intervention group achieved either a complete or partial
response (44% versus 18% for control group patients, p = 0.01). Time to disease
progression was significantly longer in the intervention group than in the control group in
terms of tumour area (15.9 versus 9.7 months, p = 0.001) and tumour volumes (12.0
versus 7.6 months, p = 0.04). Survival time from randomisation to death or last follow up
was not different according to a Kaplan-Meier analysis, although a non-significant trend
favoured the intervention group. Cox regression analysis suggested that patients who
received the SIRT treatment and who survived more than 15 months experienced a
survival advantage compared with those who received chemotherapy alone. With respect
to QOL, differences between treatment groups were not statistically significant.
A summary of the statistically significant findings reported in the three included RCTs is
provided in Table 3. All of these results significantly favoured SIRT for treatment of liver
metastases.
Selective internal radiation therapy for the treatment of liver cancer: August 2011 10
13. Table 3: Statistically significant findings reported in the included RCTs
Outcome SIRT group Comparator
group
P value
Hendlisz et al 2010
Disease control rate 86% 35% 0.001
Median time to liver progression 5.5 months 2.1 months 0.003
Overall time to tumour progression 4.5 months 2.1 months 0.03
Van Hazel et al 2004
Time to disease progression 18.6 months 3.6 months <0.0005
Median survival time 29.4 months 12.8 months 0.025
Gray et al 2001
Tumour response: tumour volume 50% 24% 0.03
Tumour response: serum CEA changes 72% 47% 0.004
Tumour response: tumour area 44% 18% 0.01
Time to disease progression: tumour area 15.9 months 9.7 months 0.001
Time to disease progression: tumour volume 12 months 7.6 months 0.04
COST IMPACT
A 2002 Medical Services Advisory Committee (MSAC) report stated that, at that time, it
was not possible to give a reliable estimate of cost per life year saved or cost per quality
adjusted life year due to the lack of reliable evidence regarding the benefit of the
outcomes achieved using SIRT (Howard and Stockler 2002). MSAC concluded that a
comprehensive, Australian-based assessment of costs and effects associated with
systemic chemotherapy, hepatic arterial chemotherapy and SIRT was needed, to provide
a basis for a comparison between systemic therapy and hepatic chemotherapy with or
without SIRT (Howard and Stockler 2002).
Subsequently, in an abstract published in the Italian Journal of Public Health, Norris and
Coleman (2005) presented cost data pertaining to the use of SIRT for the treatment of
colorectal liver metastases. In what they considered a highly conservative cost
effectiveness analysis, an incremental cost effectiveness ratio (ICER) of $21,033 per life
Selective internal radiation therapy for the treatment of liver cancer: August 2011 11
14. year gained was reported, with one- and two-way sensitivity analyses ranging from
$12,002 - $86,172 per life year gained. The authors stated that, considering the average
survival gain of 12 months per patient and the ICER of $21,033 per life year gained, the
addition of SIRT to systemic chemotherapy represents good value for money for a
population of patients with otherwise poor prognosis.
According to the manufacturer of SIR-Spheres, the cost of one dose is $8,230 plus GST,
which is fully funded by health funds (i.e. there is no gap payment) (Sirtex Medical
Limited, pers. comm., 5 May 2011). The manufacturer also stated that the associated cost
of equipment for the work-up procedure in the angiography suite (including guide wires,
micro catheters and contrast media), CT/positron emission tomography (PET) scans and
the implantation procedure are covered by all health funds (with gap payments dependent
upon the health fund) (Sirtex Medical Limited, pers. comm., 5 May 2011).
ETHICAL, CULTURAL OR RELIGIOUS CONSIDERATIONS
There were no issues identified from the retrieved material.
OTHER ISSUES
All three included studies may be associated with a risk of bias. Hendlisz et al (2010)
permitted patients with documented progression to cross over from the control to the
interventional group at the investigator’s discretion and 10 patients did so. The SIR-
Spheres used in the study were supplied by Sirtex and one author received honoraria from
this manufacturer. Van Hazel et al (2004) reported that two patients in the control group
were removed from treatment due to rapid deterioration. It was also noted that the control
group received more chemotherapy cycles compared with the intervention group.
Gray et al (2001) reported the presence of extra hepatic disease that was not balanced
between the treatment groups at baseline. A majority (77%) of the intervention group
were reported to have had extra-hepatic malignancy, compared with only half of the
control group. Additionally, the study was originally designed to enrol 95 patients in
order to detect a 30 per cent increase in median survival, but was closed after entering 74
patients. Authors listed the reasons for insufficient enrolment as: ‘increasing patient and
physician reluctance to undergo randomisation, a decision by the FDA to accept
treatment-related response and time to disease progression as acceptable criteria for
premarket application approval, and lack of funding to complete the study.’
Sirtex is currently sponsoring a post-marketing RCT on SIR-Spheres microspheres across
sites in Australia, New Zealand, Europe, the Middle East and the USA (with sites in Asia
anticipated to open shortly), with the aim of recruiting 460 patients. There are also two
Selective internal radiation therapy for the treatment of liver cancer: August 2011 12
15. RCTs (funded by Sirtex) underway for the treatment of HCC with SIR-Spheres, one in
Singapore and another in Germany. A third in France is expected to commence shortly.
SUMMARY OF FINDINGS
All three RCTs reported safety issues relating to grade 3 and 4 toxicity. One study
showed the superiority of SIR-Spheres in terms of potential toxicity (Hendlisz et al
2010). Similarly, in one study the risk of death from disease progression was three times
higher in the control group compared with the interventional group (P = 0.03) (Gray et al
2001). In contrast, the study by Van Hazel et al (2004) reported more incidents of severe
toxicity in the intervention group compared with the control group (13 versus 5; no
statistical analysis provided).
In all three RCTs, SIRT patients demonstrated higher tumour response rates than patients
who received comparator treatments; however, these differences were not statistically
significant. SIRT patients also showed better outcomes in terms of hepatic progression,
with one study showing statistical significance. Progression-free survival and overall
survival were better in SIRT patients; however, again none of these differences were
statistically significant. Two of the included studies reported QOL outcomes, and these
were not significantly different between treatment groups.
Overall, this technology brief does not identify alarming safety issues related to the use of
SIRT instead of standard treatments. In the three included studies, the likelihood of
achieving better tumour response, and time to progression or progression-free survival,
appears to be higher using SIRT.
HEALTHPACT ASSESSMENT
Available evidence appears promising and highlights the potential benefits of SIRT for
the treatment of liver cancer; however, a company-based trial is currently underway, the
results of which are scheduled to be presented to MSAC in due course. As such,
HealthPACT have recommended that no further assessment of SIRT is required at this
time.
NUMBER OF STUDIES INCLUDED
Total number of studies 3
Total Level II studies 3
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SEARCH CRITERIA TO BE USED
Selective internal radiation therapy OR selective internal radiation
SIR-Spheres OR TheraSpheres
Liver cancer OR hepatocellular carcinoma OR liver metastases
