selective internal radiation therapy for the treatment of liver cancer

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

© State of Queensland (Queensland Health) 2011

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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 USE COUNTRY 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

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).

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”.

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

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-

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.

Table 1: Study characteristics of included studies

Pre-interventional patient and tumour characteristics Study 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


Systemic chemotherapy

(n=10)

86 65 (SIRT 64;

comparator 65)

Colorectal 24 29 0

Gray et al 2001


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.


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 2001 Event

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



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).

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.


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


Van Hazel et al 2004 Time to disease progression

18.6 months 3.6 months <0.0005

Median survival time


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


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


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


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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SOURCES OF FURTHER INFORMATION

Andrews JC, Walker SC, et al. Hepatic radioembolization with yttrium-90 containing glass microspheres: preliminary results and clinical follow-up. Journal of Nuclear Medicine 1994; 35(10): 1637-1644.

Gray BN, Anderson JE, et al. Regression of liver metastases following treatment with yttrium-90 microspheres. Australian and New Zealand Journal of Surgery 1992; 62(2): 105-110.



Gray BN, van Hazel G, et al. Treatment of colorectal liver metastases with SIR-Spheres plus chemotherapy. GI Cancer 2000; 3(4): 249-257.

Ho S, Lau WY, Leung TW, et al. Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer. European Journal of Nuclear Medicine 1997; 24(3): 293-298.

Lau WY, Ho S, et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90 yttrium microspheres. International Journal of Radiation Oncology, Biology, Physics 1998; 40(3): 583-592.

Stubbs RS, Cannan RJ, Mitchell AW. Selective internal radiation therapy with 90 yttrium microspheres for extensive colorectal liver metastases. Journal of Gastrointestinal Surgery 2001; 5(3): 294-302.

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

selective internal radiation therapy for the treatment of liver cancer

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