# Summary of Safety and Effectiveness Data

## General Information

> **[Device Generic Name]{.underline}:** Radioactive Implant (Yttrium-90
> microspheres)
>
> **[Device Trade Name]{.underline}:** SIR-Spheres^^
>
> **[Applicant's Name and Address]{.underline}:** Sirtex Medical Inc.
>
> c/o Matrix Medical Consulting Corp.
>
> 16835 West Bernardo Drive
>
> Suite 120
>
> San Diego, CA 92127
>
> **[Date of Panel Recommendation:]{.underline}** November 6, 2000
>
> **[Premarket Approval Application Number:]{.underline}** P990065
>
> **[Date of Good Manufacturing Practice Inspection:]{.underline}**
> October 10 and 14, 2001
>
> **[Date of Notice of Approval to Applicant:]{.underline}** March 5,
> 2002

## Indications for Use

# 

SIR-Spheres^^ is indicated for the treatment of unresectable metastatic
liver tumors from primary colorectal cancer with adjuvant intra-hepatic
artery chemotherapy (IHAC) of FUDR (Floxuridine).

## Device Description

SIR-Spheres^^ is a device consisting of radioactive microspheres. It
has two components, the microspheres and yttrium. The device is provided
in water for injection to allow measurement of desired activity as a
volume in a syringe.

#### **How the device works**

The active moiety of the device is the beta radiation emitted from the
microspheres. Yttrium-90 is a beta emitter, to which hepatic tumors, as
well as healthy liver tissue, are sensitive. The small penetration depth
of these beta emissions into tissue limits the collateral damage that
can occur with radiation sources implanted into tumors. The short
half-life of 64 hours limits the radiation hazards to patients, staff
and other caregivers, while providing a clinically appropriate dose of
radiotherapy.

The properties of the beta radiation emitted from the microspheres are
listed below.

#### **Physical Properties of Yttrium-90**

-   Pure beta emitter with no associated primary gamma emission

-   Energy of beta particles

    -   Maximum 2.27MeV

    -   Mean 0.93MeV

-   Range

    -   Maximum in air 9621mm

    -   Maximum in tissue 11mm

    -   Mean in air 3724mm

    -   Mean in tissue 2.5mm

-   Effective treatment time when isotope applied to infinity = 92.4
    hours

-   In a therapeutic application of decay to infinity, 94% of radiation
    is delivered in 11 days

-   Fractional Bremsstrahlung yield

    -   At maximal energy (2.27MeV)

        -   In air 0.0089

        -   In water 0.0081

        -   In bone 0.0110

    -   At mean energy (0.93MeV)

        -   In air 0.0037

        -   In water 0.0034

        -   In bone 0.0043

-   The fractional Bremsstrahlung yield may be roughly estimated from
    the following formula:

> f = [E~T~.Z]{.underline}
>
> 3000

where f = fractional Bremsstrahlung

Z = atomic number

E~T~= transitional energy of the beta particles

#### **Principles of the operation of SIR-Spheres^^**

The device exploits the dominance of hepatic artery flow to tumor
tissue. Normal hepatic tissue receives the majority of blood flow from
the portal vein, with very little from the hepatic artery. Conversely,
flow to tumor tissue is almost exclusively from the hepatic artery. By
placing the microspheres via the hepatic artery, they are preferentially
delivered to tumor tissue while sparing healthy tissue.

When yttrium-90 is implanted simultaneously or in close time
relationship to either systemic or regional chemotherapy with suitable
drugs, a synergy in tumor cell response occurs. This same synergy occurs
in healthy tissue, thus it is important that microspheres be as
contained as possible. The synergy continues until the emissions from
the source have diminished. Placement of yttrium-90 into tumors,
including those not readily detected before chemotherapy, can maximize
response to treatment.

The total radioactivity required by a patient will be dependent on the
extent and presentation of the tumor tissue, and is at the discretion of
the treating physician. The time elapsed since calibration time and date
will influence the volume or number of microspheres delivered to the
patient. Currently, calibration is at 0900 hours Sydney, Australia time
on day of calibration. Calculation of the remaining radioactivity at the
time of patient treatment is via the decay curve for yttrium-90. The
amount of radiation required is removed as a volume (in milliliters) for
implantation into the patient. The calibration time also serves as a
lockout time, before which the microspheres cannot be implanted. The
time from shipping to calibration provides a window for product recall.

The device is presented as 2 vials, each containing 3 or 3.6 GBq±10% in
5mL at the time and date of calibration (as labeled). It carries a
24-hour expiration from time and date of calibration. This limit is
imposed because, although the device is sterilized, it contains no
preservative.

***Patient Selection***

Patient selection is critical in achieving a benefit from the use of
SIR-Spheres^^. Patients should be assessed before considering
SIR-Spheres^^ to determine

-   that they have metastatic colorectal cancer;

-   if the tumor(s) are amenable to resection with curative intent; and

-   if there are significant other sites of metastatic disease.

Liver cancer is considered 'resectable' if, in the opinion of an
experienced hepato-biliary surgeon, all macroscopic evidence of tumor
can be removed while maintaining sufficient normal hepatic parenchyma to
sustain life. Determination of resectability should be via imaging with
a triple-phase contrast angio-portal CAT scan or MRI.

In any of the following circumstances, patients would generally be
considered non-resectable:

1.  multiple liver metastases together with involvement of both lobes;

2.  tumor invasion of the hepatic confluence where the three hepatic
    veins enter the IVC;

3.  such that none of the hepatic veins could be preserved if the
    metastases were resected;

4.  tumor invasion of the porta hepatis such that neither origin of the
    right or left portal veins could be preserved if resection were
    undertaken; and

5.  widespread metastases, such that resection would leave less liver
    than is necessary to maintain life.

Patients who are considered candidates for treatment with SIR-Spheres^^
should be evaluated to determine the presence or absence of metastatic
disease at extra-hepatic sites. As SIR-Spheres^^ is a form of
loco-regional treatment only, the device has no beneficial effect on
cancer at extra-hepatic sites. Therefore, when assessing patients for
treatment with SIR-Spheres^^, clinicians should determine if control of
disease within the liver is likely to translate into patient benefit. If
the liver cancer is the immediate life-threatening event, then treatment
with SIR-Spheres^^ may still be indicated.

Renal and hepatic function should be assessed to determine the
patient\'s ability to handle any concurrent chemotherapy and establish
baseline liver function test (LFT) values. Seriously ill patients may
not tolerate radiation therapy. SIR-Spheres^^ should not be implanted
into patients with seriously compromised liver function or who have
liver failure.

***Patient Tests Before Treatment with SIR-Spheres^^***

Patients need both a hepatic angiogram and a nuclear medicine
break-through scan. The former establishes the arterial anatomy of the
liver while the later determines the percent lung shunting. Evaluation
of patients for treatment should include appropriate tests to determine
the extent of the disease. Appropriate tests might include chest X-ray,
CT scan of chest and abdomen, abdominal ultrasound and bone scan.
Serologic tests of liver function should be performed to determine the
extent of compromise of liver function. Measurement of serologic tumor
markers is useful as a baseline for subsequent monitoring of patients to
determine response to treatment.

***Restrictions on Use***

SIR-Spheres^^ is a radioactive device and as such is subject to the
provisions of Title 10 CFR Part 35. This restricts usage to facilities
(medical institutions) and physicians duly qualified to handle
therapeutic radiation. Only doctors qualified and licensed under Title
10 CFR Part 35 may implant SIR-Spheres^^. The sponsor has designed and
will provide a training program to physicians for handling and
implanting SIR-Spheres^^. The company will restrict the sale of
SIR-Spheres^^ to physicians who have undergone this training.

SIR-Spheres^^ is available only from Sirtex Medical Inc. (or its
appointed representative) on receipt of a request from a licensed
physician. Patients are not able to purchase SIR-Spheres^^. A medical
institution may place an order on behalf of a doctor.

SIR-Spheres^^ may only be dispatched to a duly licensed or accredited
facility capable of handling therapeutic medical isotopes. Such a
facility may be a hospital with a medical physics department or a
radioisotope dispensing facility.

######## Contraindications

SIR-Spheres^^ is contraindicated in patients who have

-   had previous external beam radiation therapy to the liver,

-   ascites or are in clinical liver failure,

-   markedly abnormal synthetic and excretory liver function tests,

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-   greater than 20% lung shunting of the hepatic artery blood flow
    determined by Technetium MAA scan,

-   pre-assessment angiogram that demonstrates abnormal vascular anatomy
    that would result in significant reflux of hepatic arterial blood to
    the stomach, pancreas or bowel,

-   disseminated extra-hepatic malignant disease,

-   been treated with capecitabine within the two previous months, or
    who will be treated with capecitabine at any time following
    treatment with SIR-Spheres^^,

-   portal vein thrombosis.

**V. Warnings**

-   Inadvertent delivery of SIR-Spheres^^ to the gastrointestinal tract
    or pancreas will cause acute abdominal pain, acute pancreatitis or
    peptic ulceration.

• High levels of implanted radiation and/or excessive shunting to the
lung may lead to radiation pneumonitis.

-   Excessive radiation to the normal liver parenchyma may result in
    radiation hepatitis.

#### 

#### **VI. Precautions**

-   No studies have been done on the safety and effectiveness of this
    device in pregnant women, nursing mothers or children.

-   Due to the radioactivity of this device and the significant
    consequences of misplacing the microspheres in situ, this product
    must be implanted by doctors with adequate training in the handling
    and implantation technique for this device.

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-   Sirtex Medical Inc recommends a SPECT scan of the upper abdomen be
    performed immediately after implantation of SIR-Spheres^®^. The
    SPECT scan will detect the Bremsstrahlung radiation from the
    yttrium-90 to confirm placement of the microspheres in the liver.

-   This product is radioactive. The use of this device is regulated
    under Title10 of the Code of Federal Regulations Part 35. These
    regulations must be followed when handling this device.

-   All persons handling, dispensing and implanting this device must be
    familiar with and abide by all Local, State and Federal regulatory
    requirements governing therapeutic radioactive materials. Accepted
    radiation protection techniques should be used to protect staff when
    handling both the isotope and the patient.

-   Some patients may experience gastric problems following treatment
    but H-2 blocking agents may be used the day before implantation of
    SIR-Spheres^^ and continued as needed to reduce gastric
    complications.

-   Many patients may experience abdominal pain immediately after
    administration of SIR-Spheres^®^ and pain relief may be required.

-   SIR-Spheres^^ demonstrated a mild sensitization potential when
    tested dermally in an animal model.

######## Alternative Practices and Procedures

## *Hepatic Perfusion Chemotherapy without Sir-Spheres^^* {#hepatic-perfusion-chemotherapy-without-sir-spheres .unnumbered}

This modality restricts chemotherapy to the liver. The drugs most
commonly used are either floxuridine or 5-fluorouracil. This therapy
requires the placement of an internal pump, or alternatively, a port to
accommodate an external pump to deliver the chemotherapy. The pump is
loaded at regular intervals and delivers the drug over an extended
period in monthly cycles.

Hepatic artery chemotherapy is generally only indicated for patients
with liver metastases from the gastrointestinal tract and when the liver
is the only site of disease. Response rates are higher than for systemic
chemotherapy and there is probably a small advantage for those patients
with disease limited to the liver.

########  {#section-2 .unnumbered}

######## VIII. Marketing History {#viii.-marketing-history .unnumbered}

##### 

This device was approved for marketing by the Therapeutic Goods
Administration in Australia in February 1998. This device is approved
for unrestricted sale in Australia (within radiation safety guidelines)
and for export to nine other countries, these being Hong Kong, New
Zealand, Philippines, Thailand, South Korea, Taiwan, Japan, Singapore
and Canada. There are no further regulatory restrictions on the sale of
the product in Hong Kong, Philippines, Thailand or New Zealand, other
than radiation safety practices. SIR-Spheres^^ has not been withdrawn
from marketing for any reason relating to the safety or effectiveness of
the device.

**IX. Adverse Effects of the Device on Health**

The following toxicity events were observed during the randomized
clinical trial with 34 patients on intra-hepatic chemotherapy alone and
36 patients on intra-hepatic chemotherapy plus SIR-Spheres^^.

## [Adverse Events]{.underline}  {#adverse-events .unnumbered}

+---------------+--------------------------+---------------------------+
| ##            | ##  Grade 1 and 2 {#gr   | ##  Grade 3 and 4 {#g     |
|   {#section-4 | ade-1-and-2 .unnumbered} | rade-3-and-4 .unnumbered} |
|  .unnumbered} |                          |                           |
+---------------+--------------------------+---------------------------+

+---------------+-----------+-------------+-------------+-------------+
| ## Ev         | **FUDR**  | **FUDR +    | **FUDR**    | **FUDR+     |
| ents {#events |           | SIR-S       |             | SIR-S       |
|  .unnumbered} |           | pheres^^** |             | pheres^^** |
+---------------+-----------+-------------+-------------+-------------+
| ## Hemoglobin | 4         | 5           | 1           | 0           |
|  {#hemoglobin |           |             |             |             |
|  .unnumbered} |           |             |             |             |
+---------------+-----------+-------------+-------------+-------------+
| **Bilirubin** | 7         | 2           | 0           | 1           |
+---------------+-----------+-------------+-------------+-------------+
| **AST         | 110       | 109         | 14          | 7           |
| (SGOT)**      |           |             |             |             |
+---------------+-----------+-------------+-------------+-------------+
| **Alk.        | 90        | 188         | 5           | 14          |
| Phos.**       |           |             |             |             |
+---------------+-----------+-------------+-------------+-------------+
| **Naus        | 5         | 13          | 2           | 1           |
| ea/vomiting** |           |             |             |             |
+---------------+-----------+-------------+-------------+-------------+
| **Diarrhea**  | 6         | 3           | 1           | 0           |
+---------------+-----------+-------------+-------------+-------------+
|               |           |             |             |             |
+---------------+-----------+-------------+-------------+-------------+
| **Total**     | 222       | 320         | 23          | 23          |
+---------------+-----------+-------------+-------------+-------------+

Adverse events experienced in the first two months of treatment were
analyzed separately and are presented above. This window was selected
because the acute effects of yttrium-90 will have occurred and any
longer term events (such as, for example, radiation pneumonitis) should
be evident by this time.

Eleven patients who received SIR-Spheres^^ and chemotherapy experienced
Grade 3 or 4 adverse events in the first two months post-treatment
compared with five patients receiving chemotherapy alone. However, the
type of events and grades (severity) of events experienced by patients
on both arms were similar. The majority of events were grade 1 or 2
toxicity, which are not clinically significant in this patient group.
These toxicity data are captured in the above table.

In the three cases where SIR-Spheres^^ and chemotherapy together were
considered the cause, two were grade 1 nausea and one was pancreatitis.
This was one of two grade three events on the SIR-Spheres^^ plus
chemotherapy arm, the other being nausea and vomiting attributed to
chemotherapy. The patient who experience acute pancreatitis had
uncontrolled mild diabetes before treatment which was exacerbated by the
pancreatitis. The pancreatitis was brought under control with
medication. The pancreatitis settled rapidly with conservative
management.

Virtually all patients develop a post-operative fever that starts
immediately after implantation of SIR-Spheres^^ and can last from a few
days to a week. The fever does not necessarily indicate sepsis but may
be related to the embolic effect of the microspheres and the acute toxic
effects on the tumor.

Many patients experience abdominal pain immediately after administration
of SIR-Spheres^®^ and may need pain relief with narcotic analgesia. The
pain generally subsides within an hour or so, but patients may require
oral analgesia for up to several days.

Many patients will experience nausea that may last up to several weeks
and this may occasionally be severe enough to require anti-emetic
medication, which should be continued until the symptoms subside.

######### Potential Adverse Events

Immediate severe unremitting pain post procedure could suggest that the
microspheres have lodged in a site such as the pancreas and should
prompt investigations to determine whether microspheres have lodged in
an organ other than the liver. An yttrium-90 nuclear scan will determine
if the microspheres have lodged in the pancreas or other organs.
Diagnosis of the pain must include other tests such as serum amylase.
Treatment of the affected organ requires standard medical practice.

The development of acute peptic ulceration is suggested by the
recognized symptoms of ulcer disease and diagnosed by endoscopy.
Treatment is the same as for any cause of acute peptic ulceration.

High levels of implanted radiation and/or excessive shunting to the lung
may lead to radiation pneumonitis. This may be suspected if patients
develop a non-productive cough several days or weeks after the
implantation of SIR-Spheres^®^ and is diagnosed by chest X-ray. Patients
may be treated with systemic corticosteroids and supportive care until
the disease has subsided.

Excessive radiation to the normal liver parenchyma may result in
radiation hepatitis. This can be difficult to diagnose, and may appear
many weeks after the implantation of SIR-Spheres^®^. It is suspected if
there is unexplained progressive deterioration in liver function. The
diagnosis can be confirmed by histologic examination of core liver
biopsy. If the diagnosis is suspected or proven then patients should be
treated with appropriate therapy and supportive care.

This device is permanently implanted and cannot be retrieved. There is
no evidence to date that the decayed microspheres remaining in the tumor
or liver cause adverse reactions.

######## X. Summary of Pre-clinical Studies {#x.-summary-of-pre-clinical-studies .unnumbered}

The safety of the microspheres for tissue implantation (using
non-radioactive yttrium microspheres) was investigated using seven
studies (three animal studies and four in vitro studies). All studies
were conducted using Good Laboratory Practice in compliance with United
Kingdom Regulations 1997 (SI 1997 N0 654) that are in turn in compliance
with the OECD principles of GLP.

#### Study 1 Mutation capacity (bacterial reverse mutation test)

The objective of this study was to test the ability of SIR-Spheres^^ in
vivo to induce mutations in four histidine-dependent auxotrophic mutants
of S. typhimurium, strains TA1535, TA1537, TA98 and TA100 and one
tryptophan-dependent auxotrophic mutant of E. coli, strain WP2 uvrA. No
statistically significant increase in revertant numbers was observed for
any strain at any dose with or without S-9, in either experiment.
Yttrium microspheres were not mutagenic under the conditions of this
test.

#### Study 2 Cytogenetic activity (in vitro mammalian cell cytogenetic test in Chinese hamster ovary cells)

This study was to assess the mutagenic activity of SIR-Spheres^^ by its
ability to cause structural damage to chromosomes. There were some small
but statistically significant increases in the aberrations after
exposure to the microspheres. These were not consistent between cultures
or experiments and were within the background range for this cell line.
Yttrium microspheres do not show clastogenic activity under the
conditions of this test.

*Study 3 Haemocompatibility (tested to ISO 10993)*

This study was intended to determine if endogenous or extraneous
substances present in or on SIR-Spheres^^, as tested in vitro, have
hemolytic activity against human erythrocytes. Under the experimental
conditions employed, the yttrium microspheres demonstrated no hemolytic
activity against human erythrocytes. The suspending water, as expected,
caused hemolysis in preclinical testing.

#### Study 4 Cytotoxicity (in vitro cytotoxicity to ISO 10993 Part 5)

This study was to evaluate the toxicity, in vitro, of leachable
endogenous or extraneous substances present on or in SIR-Spheres^^. The
yttrium microspheres did not cause any changes in cell morphology and
did not have any cytotoxic capacity.

#### Study 5 Sensitization (maximum sensitization test in the guinea pig ISO 10993-10)

This study evaluated the potential of SIR-Spheres^^ to cause a delayed
dermal hypersensitivity/Type IV immune response in guinea pigs. The
procedures used were based on the methods described in the document ISO
10993-10 Biological Evaluation of Medical Devices: Test for Irritation
and Sensitization of March 1995. Weak positive responses in the test
group were observed. These are indicative of a delayed dermal
hypersensitivity immune response according to the criteria described in
ISO 10993. Therefore, yttrium microspheres can be considered a mild
sensitizer under the conditions of this test.

#### Study 6 Tissue toxicity (intracutaneous injection test in the rabbit ISO 10993-10)

This study was to assess the potential of Sir-Spheres^^ to produce
irritation following intracutaneous injection. The methods used were
based on those described in ISO 10993-10 Biological Evaluation of
Medical Devices: Tests for Irritation and Sensitization, March 1995.
Yttrium microspheres gave a mild irritant dermal reaction under the
conditions of this test due to the alkaline nature of the yttrium test
material.

*Study 7 Systemic toxicity (systemic injection test in the mouse ISO
10993-11 (modified*)

This study evaluated systemic responses to extracts of SIR-Spheres^^
following intravenous or intraperitoneal injection into mice. The
procedures used were based on the methods described in ISO 10993-11
Biological Evaluation of Medical Devices -- Part 11: tests for systemic
toxicity and the United States Pharmacopoeia 23, 1995 for the assessment
of biological reactivity, in vivo, section 88 page 1699. Under the
conditions of this study, yttrium microspheres did not produce any
systemic toxicity.

# XI. Summary of Clinical Studies

### 

######### Trial Design

A randomized prospective trial was designed to compare the benefit of
adding a single implantation of SIR-Spheres^^ to a regimen of
intra-hepatic artery chemotherapy with FUDR for patients with advanced
non-resectable liver metastases from primary adenocarcinoma of the
colorectum.

######### Subject Selection Inclusion and Exclusion Criteria

All patients had advanced non-resectable liver metastases from
adenocarcinoma of the large bowel that had been completely resected and
an acceptable performance status. Patients with distant extra-hepatic
metastases or previous radiation treatment to the liver were excluded,
but previous chemotherapy was allowed. Patients underwent surgical
implantation of a hepatic artery port for delivery of the treatment
specified by the protocol.

#### **Treatment**

Patients eligible for trial entry were stratified according to the size
of tumor within the liver and then randomized to a control or
investigational treatment arm. Treatment for patients randomized into
the Control Arm consisted of ongoing cycles of continuous infusion
hepatic artery chemotherapy with Floxuridine (0.3mg/kg/day) in 12-day
cycles and repeated at 4 weekly intervals for 18 months. The
Investigational Arm consisted of the same chemotherapy with the addition
of a single implantation of SIR-Spheres^^.

######### Study Population

Patients were treated at two major teaching hospitals in Western
Australia. Seventy-four patients entered the trial of which 70 were
eligible for analysis. The population was 77% male with an average age
of approximately 60 years. The majority of patients had primary cancer
arising from the colon (91% on the Control Arm and 78% on the
Investigational Arm) with remainder having primary rectal cancer. The
two arms were matched for patient and tumor characteristics.

Seventy-one percent of patients on the Control Arm and 67% of patients
on the Investigational Arm had involvement of regional draining bowel
nodes. Just over 70% of patients on both arms had moderately
differentiated primary bowel cancer. About 70% of patients on each arm
had less than 25% of liver replacement by tumor, and a further 25% had
between 25 and 50%. The remainder had greater than 50% liver replacement
with tumor. Fifteen percent of patients on each arm had had previous
chemotherapy for their liver metastases.

The lead-time from diagnosis of liver metastases until randomization was
an average of 51 days for the Control Arm and 56 days for the
Investigational Arm. For the duration of protocol treatment, patients on
the Control Arm averaged 1822mg per day of FUDR compared with 1863mg per
day for patients on the Investigational Arm.

######### Study Period

The study period was from trial entry until death. This period included
a Protocol Treatment period (the time from start of treatment conforming
to the trial protocol until there was evidence of disease progression in
the liver, development of cancer at non-hepatic sites, or failure of the
port). This was followed by a non-protocol period that continued until
date of death or last known to be alive.

######### Safety and Effectiveness Data

1.  Effectiveness Data

> Patients were evaluated for Response and Progression by blinded serial
> measurement of changes in:

i)  Tumor Volume - using two independent medical reviewers (JA, PM) and
    an average of all operators

ii) Cross Sectional Tumor Areas - using a medical reviewer (BG)

iii) Serum Carcinoembryonic Antigen (CEA).

The following tables summarize the primary and secondary findings from
this trial. Data is provided for each criterion that measured an outcome
for the trial as recorded by each independent operator. It should be
noted that the study failed to achieve the primary objectives of the
study. No difference was seen in the overall survival nor in the quality
of life for these patients.

All p-values in the following Tables are derived from 2-tailed tests of
significance. Response in the following table includes both complete
response (disappearance of all tumor on two successive CAT scans not
less than 4 weeks apart) and partial response (a 50% or more objectively
measured decrease in tumor size on two successive CAT scans not less
than 4 weeks apart).

**Primary Findings**

+-------------------+-------------+---+---------------+---+-----------------+
| **Parameter**     | **Control   | * |               | * |                 |
|                   | Arm**       | * |               | * |                 |
|                   |             | I |               | p |                 |
|                   | ###### C    | n |               | - |                 |
|                   | hemotherapy | v |               | v |                 |
|                   |             | e |               | a |                 |
|                   |             | s |               | l |                 |
|                   |             | t |               | u |                 |
|                   |             | i |               | e |                 |
|                   |             | g |               | * |                 |
|                   |             | a |               | * |                 |
|                   |             | t |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | o |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | l |               |   |                 |
|                   |             | A |               |   |                 |
|                   |             | r |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | * |               |   |                 |
|                   |             | * |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | * |               |   |                 |
|                   |             | * |               |   |                 |
|                   |             | S |               |   |                 |
|                   |             | I |               |   |                 |
|                   |             | R |               |   |                 |
|                   |             | T |               |   |                 |
|                   |             | + |               |   |                 |
|                   |             | C |               |   |                 |
|                   |             | h |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | o |               |   |                 |
|                   |             | t |               |   |                 |
|                   |             | h |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | r |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | p |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | * |               |   |                 |
|                   |             | * |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| ## Respo          |             |   |               |   |                 |
| nse (Complete + P |             |   |               |   |                 |
| artial Responses) |             |   |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Volume (JA) | 9 patients  | 1 |               | p |                 |
|                   |             | 9 |               | = |                 |
|                   |             | p |               | 0 |                 |
|                   |             | a |               | . |                 |
|                   |             | t |               | 0 |                 |
|                   |             | i |               | 5 |                 |
|                   |             | e |               | 3 |                 |
|                   |             | n |               | ( |                 |
|                   |             | t |               | e |                 |
|                   |             | s |               | ) |                 |
|                   |             |   |               | p |                 |
|                   |             |   |               | = |                 |
|                   |             |   |               | 0 |                 |
|                   |             |   |               | . |                 |
|                   |             |   |               | 1 |                 |
|                   |             |   |               | 0 |                 |
|                   |             |   |               | 2 |                 |
|                   |             |   |               | ( |                 |
|                   |             |   |               | a |                 |
|                   |             |   |               | ) |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Volume (PM) | 9 patients  | 1 |               | p |                 |
|                   |             | 9 |               | = |                 |
|                   |             | p |               | 0 |                 |
|                   |             | a |               | . |                 |
|                   |             | t |               | 0 |                 |
|                   |             | i |               | 2 |                 |
|                   |             | e |               | 0 |                 |
|                   |             | n |               | ( |                 |
|                   |             | t |               | e |                 |
|                   |             | s |               | ) |                 |
|                   |             |   |               | p |                 |
|                   |             |   |               | = |                 |
|                   |             |   |               | 0 |                 |
|                   |             |   |               | . |                 |
|                   |             |   |               | 0 |                 |
|                   |             |   |               | 3 |                 |
|                   |             |   |               | 9 |                 |
|                   |             |   |               | ( |                 |
|                   |             |   |               | a |                 |
|                   |             |   |               | ) |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Volume      | 8 patients  | 1 |               | p |                 |
| (Averaged)        |             | 8 |               | = |                 |
|                   |             | p |               | 0 |                 |
|                   |             | a |               | . |                 |
|                   |             | t |               | 0 |                 |
|                   |             | i |               | 3 |                 |
|                   |             | e |               | 3 |                 |
|                   |             | n |               | ( |                 |
|                   |             | t |               | e |                 |
|                   |             | s |               | ) |                 |
|                   |             |   |               | p |                 |
|                   |             |   |               | = |                 |
|                   |             |   |               | 0 |                 |
|                   |             |   |               | . |                 |
|                   |             |   |               | 0 |                 |
|                   |             |   |               | 6 |                 |
|                   |             |   |               | 4 |                 |
|                   |             |   |               | ( |                 |
|                   |             |   |               | a |                 |
|                   |             |   |               | ) |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Area        | 6 patients  | 1 |               | p |                 |
|                   |             | 6 |               | = |                 |
|                   |             | p |               | 0 |                 |
|                   |             | a |               | . |                 |
|                   |             | t |               | 0 |                 |
|                   |             | i |               | 1 |                 |
|                   |             | e |               | 1 |                 |
|                   |             | n |               | ( |                 |
|                   |             | t |               | e |                 |
|                   |             | s |               | ) |                 |
|                   |             |   |               | p |                 |
|                   |             |   |               | = |                 |
|                   |             |   |               | 0 |                 |
|                   |             |   |               | . |                 |
|                   |             |   |               | 0 |                 |
|                   |             |   |               | 2 |                 |
|                   |             |   |               | 3 |                 |
|                   |             |   |               | ( |                 |
|                   |             |   |               | a |                 |
|                   |             |   |               | ) |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| CEA               | 16 patients | 2 |               | p |                 |
|                   |             | 6 |               | = |                 |
|                   |             | p |               | 0 |                 |
|                   |             | a |               | . |                 |
|                   |             | t |               | 0 |                 |
|                   |             | i |               | 0 |                 |
|                   |             | e |               | 4 |                 |
|                   |             | n |               | ( |                 |
|                   |             | t |               | e |                 |
|                   |             | s |               | ) |                 |
|                   |             | ( |               | p |                 |
|                   |             | e |               | = |                 |
|                   |             | ) |               | 0 |                 |
|                   |             |   |               | . |                 |
|                   |             | 2 |               | 0 |                 |
|                   |             | 9 |               | 0 |                 |
|                   |             | p |               | 2 |                 |
|                   |             | a |               | ( |                 |
|                   |             | t |               | a |                 |
|                   |             | i |               | ) |                 |
|                   |             | e |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | t |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| **Duration of     |             |   |               |   |                 |
| Response (only    |             |   |               |   |                 |
| patients with a   |             |   |               |   |                 |
| \'Response\' are  |             |   |               |   |                 |
| included in this  |             |   |               |   |                 |
| Table)**          |             |   |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Volume (JA) | 314 days    | 5 |               | p |                 |
|                   | (mean)      | 9 |               | = |                 |
|                   |             | 3 |               | 0 |                 |
|                   | 315 days    | d |               | . |                 |
|                   | (median)    | a |               | 1 |                 |
|                   |             | y |               | 6 |                 |
|                   |             | s |               | ( |                 |
|                   |             | ( |               | a |                 |
|                   |             | m |               | ) |                 |
|                   |             | e |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 4 |               |   |                 |
|                   |             | 0 |               |   |                 |
|                   |             | 6 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Volume (PM) | 454 days    | 5 |               | p |                 |
|                   | (mean)      | 0 |               | = |                 |
|                   |             | 5 |               | 0 |                 |
|                   | 315 days    | d |               | . |                 |
|                   | (median)    | a |               | 4 |                 |
|                   |             | y |               | 4 |                 |
|                   |             | s |               | ( |                 |
|                   |             | ( |               | a |                 |
|                   |             | m |               | ) |                 |
|                   |             | e |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 4 |               |   |                 |
|                   |             | 0 |               |   |                 |
|                   |             | 6 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Volume      | 511 days    | 5 |               | p |                 |
| (Averaged)        | (mean)      | 1 |               | = |                 |
|                   |             | 3 |               | 0 |                 |
|                   | 365 days    | d |               | . |                 |
|                   | (median)    | a |               | 8 |                 |
|                   |             | y |               | 9 |                 |
|                   |             | s |               | ( |                 |
|                   |             | ( |               | a |                 |
|                   |             | m |               | ) |                 |
|                   |             | e |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 3 |               |   |                 |
|                   |             | 5 |               |   |                 |
|                   |             | 7 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Area        | 386 days    | 6 |               | p |                 |
|                   | (mean)      | 1 |               | = |                 |
|                   |             | 0 |               | 0 |                 |
|                   | 388 days    | d |               | . |                 |
|                   | (median)    | a |               | 3 |                 |
|                   |             | y |               | 1 |                 |
|                   |             | s |               | ( |                 |
|                   |             | ( |               | a |                 |
|                   |             | m |               | ) |                 |
|                   |             | e |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 5 |               |   |                 |
|                   |             | 5 |               |   |                 |
|                   |             | 7 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| ### CEA           | 207 days    | 3 |               | p |                 |
|                   | (mean)      | 0 |               | = |                 |
|                   |             | 7 |               | 0 |                 |
|                   | 169         | d |               | . |                 |
|                   | d           | a |               | 9 |                 |
|                   | ays(median) | y |               | 6 |                 |
|                   |             | s |               | ( |                 |
|                   |             | ( |               | a |                 |
|                   |             | m |               | ) |                 |
|                   |             | e |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 1 |               |   |                 |
|                   |             | 8 |               |   |                 |
|                   |             | 2 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| **Time to First   |             |   |               |   |                 |
| Progression in    |             |   |               |   |                 |
| the Liver (all    |             |   |               |   |                 |
| patients)**       |             |   |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Volume (JA) | 244 days    | 4 |               | p |                 |
|                   | (mean)      | 5 |               | = |                 |
|                   |             | 9 |               | 0 |                 |
|                   | 222 days    | d |               | . |                 |
|                   | (median)    | a |               | 0 |                 |
|                   |             | y |               | 0 |                 |
|                   |             | s |               | 3 |                 |
|                   |             | ( |               | ( |                 |
|                   |             | m |               | a |                 |
|                   |             | e |               | ) |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 3 |               |   |                 |
|                   |             | 2 |               |   |                 |
|                   |             | 1 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Volume (PM) | 291 days    | 5 |               | p |                 |
|                   | (mean)      | 0 |               | = |                 |
|                   |             | 6 |               | 0 |                 |
|                   | 203 days    | d |               | . |                 |
|                   | (median)    | a |               | 0 |                 |
|                   |             | y |               | 1 |                 |
|                   |             | s |               | 7 |                 |
|                   |             | ( |               | ( |                 |
|                   |             | m |               | a |                 |
|                   |             | e |               | ) |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 3 |               |   |                 |
|                   |             | 6 |               |   |                 |
|                   |             | 1 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Tumor Volume      | 306 days    | 4 |               | p |                 |
| (Averaged)        | (mean)      | 8 |               | = |                 |
|                   |             | 2 |               | 0 |                 |
|                   | 230 days    | d |               | . |                 |
|                   | (median)    | a |               | 0 |                 |
|                   |             | y |               | 8 |                 |
|                   |             | s |               | ( |                 |
|                   |             | ( |               | a |                 |
|                   |             | m |               | ) |                 |
|                   |             | e |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 3 |               |   |                 |
|                   |             | 2 |               |   |                 |
|                   |             | 4 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
|                   | 312 days    | 5 |               | P |                 |
|                   | (mean)      | 1 |               | = |                 |
|                   |             | 0 |               | 0 |                 |
|                   | 233 days    | d |               | . |                 |
|                   | (median)    | a |               | 0 |                 |
|                   |             | y |               | 4 |                 |
|                   |             | s |               | 3 |                 |
|                   |             | ( |               | ( |                 |
|                   |             | m |               | e |                 |
|                   |             | e |               | ) |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 3 |               |   |                 |
|                   |             | 6 |               |   |                 |
|                   |             | 6 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Cross Sectional   | 300 days    | 5 |               | p |                 |
| Tumor Area        | (mean)      | 6 |               | = |                 |
|                   |             | 3 |               | 0 |                 |
|                   | 287 days    | d |               | . |                 |
|                   | (median)    | a |               | 0 |                 |
|                   |             | y |               | 0 |                 |
|                   |             | s |               | 1 |                 |
|                   |             | ( |               | ( |                 |
|                   |             | m |               | a |                 |
|                   |             | e |               | ) |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 4 |               |   |                 |
|                   |             | 6 |               |   |                 |
|                   |             | 9 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| CEA (may not be   | 195 days    | 3 |               | p |                 |
| Progression in    | (mean)      | 2 |               | = |                 |
| the liver)        |             | 8 |               | 0 |                 |
|                   | 174 days    | d |               | . |                 |
|                   | (median)    | a |               | 0 |                 |
|                   |             | y |               | 6 |                 |
|                   |             | s |               | 4 |                 |
|                   |             | ( |               | ( |                 |
|                   |             | m |               | a |                 |
|                   |             | e |               | ) |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
|                   |             |   |               |   |                 |
|                   |             | 2 |               |   |                 |
|                   |             | 0 |               |   |                 |
|                   |             | 1 |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | y |               |   |                 |
|                   |             | s |               |   |                 |
|                   |             | ( |               |   |                 |
|                   |             | m |               |   |                 |
|                   |             | e |               |   |                 |
|                   |             | d |               |   |                 |
|                   |             | i |               |   |                 |
|                   |             | a |               |   |                 |
|                   |             | n |               |   |                 |
|                   |             | ) |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| #### **Survival** |             |   |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Kaplan-Meier      | 550 days    |   | 684 days      |   | p = 0.20        |
| Analysis          | (mean) (a)  |   | (mean) (a)    |   |                 |
|                   |             |   |               |   |                 |
|                   | 477days     |   | 501 days      |   |                 |
|                   | (median)    |   | (median) (a)  |   |                 |
|                   | (a)         |   |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
|                   | 563 days    |   | 716 days      |   | p = 0.18        |
|                   | (mean) (e)  |   | (mean) (e)    |   |                 |
|                   |             |   |               |   |                 |
|                   | 487 days    |   | 519 days      |   |                 |
|                   | (median)(e) |   | (median) (e)  |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Time Dependent    | \< 15       |   |               |   | p = 0.97        |
| Cox Regression    | months (e)  |   |               |   |                 |
| Analysis          |             |   |               |   | p = 0.075       |
|                   | \> 15       |   |               |   |                 |
|                   | months (e)  |   |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
| Hazard Ratios     | 1.29 (all   |   |               |   | p = 0.3         |
|                   | patients)   |   |               |   |                 |
|                   | unadjusted  |   |               |   |                 |
|                   | for strata  |   |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
|                   | 1.38 (all   |   |               |   | p = 0.2         |
|                   | patients)   |   |               |   |                 |
|                   | adjusted    |   |               |   |                 |
|                   | for strata  |   |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
|                   | 1.33        |   |               |   | P = 0.25        |
|                   | (eligible   |   |               |   |                 |
|                   | patients)   |   |               |   |                 |
|                   | unadjusted  |   |               |   |                 |
|                   | for strata  |   |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+
|                   | 1.41        |   |               |   | p = 0.18        |
|                   | (eligible   |   |               |   |                 |
|                   | patients)   |   |               |   |                 |
|                   | adjusted    |   |               |   |                 |
|                   | for strata  |   |               |   |                 |
+-------------------+-------------+---+---------------+---+-----------------+

-   \(e\) = eligible patients, (a) = all patients SIRT = Selective
    Internal Radiation Therapy

####### **Secondary Findings**

+--------------------------+--------------+-----------------+---------+
| **Parameter**            | **Control    | **              | **p-    |
|                          | Arm**        | Investigational | value** |
|                          |              | Arm**           |         |
|                          | **Ch         |                 |         |
|                          | emotherapy** | *               |         |
|                          |              | *Chemotherapy + |         |
|                          |              | SIRT**          |         |
+--------------------------+--------------+-----------------+---------+
|                          |              |                 |         |
+--------------------------+--------------+-----------------+---------+
| **Duration of Protocol   | 206 days     | 230 days (mean) | p =     |
| Chemotherapy**           | (mean)       |                 | 0.52    |
|                          |              | 208 days        | (a)     |
|                          | 151 days     | (median)        |         |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| **Survival After         | 328 days     | 439 days (mean) | p =     |
| Protocol Treatment**     | (mean)       |                 | 0.38    |
|                          |              | 289 days        | (a)     |
|                          | 283 days     | (median)        |         |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| **Time to Treatment      | 235 days     | 372 days (mean) | p =     |
| Failure**                | (mean)       |                 | 0.297   |
|                          |              | 216 days        | (a)     |
|                          | 183 days     | (median)        |         |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
|                          | 240 days     | 393 days (mean) | p =     |
|                          | (mean)       |                 | 0.25    |
|                          |              | 240 days        | (e)     |
|                          | 187 days     | (median)        |         |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| **Size of Regression     |              |                 |         |
| (all patients)**         |              |                 |         |
+--------------------------+--------------+-----------------+---------+
| Tumor Volume (JA)        | 68.1% (mean) | 78.4% (mean)    | p =     |
|                          |              |                 | 0.38    |
|                          | 73.7%        | 83.4% (median)  | (e)     |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
|                          | 68.1% (mean) | 76.1% (mean)    | p =     |
|                          |              |                 | 0.53    |
|                          | 73.7         | 82.7% (median)  | (a)     |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| Tumor Volume (PM)        | 70.9% (mean) | 67.7% (mean)    | p =     |
|                          |              |                 | 0.88    |
|                          | 75.3%        | 70% (median)    | (e)     |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
|                          | 70.9% (mean) | 66.8% (mean)    | p =     |
|                          |              |                 | 0.77    |
|                          | 75.3%        | 70% (median)    | (a)     |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| Tumor Volume (averaged)  | 65.8% (mean) | 71% (mean)      | p =     |
|                          |              |                 | 0.54    |
|                          | 64% (median) | 74.2% (median)  | (e)     |
+--------------------------+--------------+-----------------+---------+
|                          | 65.8% (mean) | 69.6% (mean)    | p =     |
|                          |              |                 | 0.65    |
|                          | 64% (median) | 73.6% (median)  | (a)     |
+--------------------------+--------------+-----------------+---------+
| Tumor Area               | 53% (mean)   | 67% (mean)      | p =     |
|                          |              |                 | 0.11    |
|                          | 46% (median) | 72% (median     | (e)     |
+--------------------------+--------------+-----------------+---------+
|                          | 53% (mean)   | 66% (mean)      | p =     |
|                          |              |                 | 0.11    |
|                          | 46% (median) | 71% (median)    | (a)     |
+--------------------------+--------------+-----------------+---------+
| CEA                      | 61% (mean)   | 82% (mean)      | p =     |
|                          |              |                 | 0.008   |
|                          | 68.5%        | 85.7% (median)  | (e)     |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
|                          | 61% (mean)   | 82.7% (mean)    | p =     |
|                          |              |                 | 0.005   |
|                          | 68.5%        | 87.8% (median)  | (a)     |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| **Time to First Response |              |                 |         |
| (for patients with       |              |                 |         |
| \'Response\')**          |              |                 |         |
+--------------------------+--------------+-----------------+---------+
| Volume (JA)              | 128 days     | 135 days (mean) | p =     |
|                          | (mean)       |                 | 0.71    |
|                          |              | 120 days        | (a)     |
|                          | 124 days     | (median)        |         |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| Volume (PM)              | 134 days     | 127 days (mean) | p =     |
|                          | (mean)       |                 | 0.88    |
|                          |              | 124 days        | (a)     |
|                          | 124 days     | (median)        |         |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| Volume (averaged)        | 142 days     | 126 days (mean) | p =     |
|                          | (mean)       |                 | 0.54    |
|                          |              | 121 days        | (a)     |
|                          | 131 days     | (median)        |         |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| Area                     | 151 days     | 116 days (mean) | p =     |
|                          | (mean)       |                 | 0.28    |
|                          |              | 121 days        | (a)     |
|                          | 132 days     | (median)        |         |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| ### CEA                  | 60 days      | 60 days (mean)  | p =     |
|                          | (mean)       |                 | 0.66    |
|                          |              | 50 days         | (e)     |
|                          | 56 days      | (median)        |         |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
|                          | 60 days      | 58 days (mean)  | p =     |
|                          | (mean)       |                 | 0.51    |
|                          |              | 49 days         | (a)     |
|                          | 56 days      | (median)        |         |
|                          | (median)     |                 |         |
+--------------------------+--------------+-----------------+---------+
| **Toxicity and Adverse   |              |                 |         |
| Events**                 |              |                 |         |
+--------------------------+--------------+-----------------+---------+
| Grade 3 & 4 Events       | 23 (e) 26    | 22 (a)          |         |
|                          | (a)          |                 |         |
+--------------------------+--------------+-----------------+---------+
| Events/Cycle (all        | 0.9          | 1.1             |         |
| grades)                  |              |                 |         |
+--------------------------+--------------+-----------------+---------+
| Serious Adverse Events   | 14           | 13              |         |
+--------------------------+--------------+-----------------+---------+

2.  Safety Data

######### Adverse Reactions and Complications

There were two groups of adverse reactions: toxicity from the
chemotherapy, with or without the addition of the device; and serious
events requiring hospitalization. The toxicity profile for both arms of
the study was similar in profile and the number of events. Serious
toxicity (grade 3 or 4 on the Union Internationale Contre le Cancer
scale) occurred infrequently, in the order of about 20 events on each
arm over the duration of protocol chemotherapy. This represents about
0.08 high-grade toxicity events per treatment cycles for the control arm
and 0.07 for the Investigational Arm. There was approximately one toxic
event per cycle of treatment administered on both arms of the study when
all grades of toxicity were considered.

The serious adverse event rate was also similar on both arms of the
treatment, and consisted primarily of complications related to the
implanted port required for the administration of the intra-hepatic
artery chemotherapy. This same port was utilized to implant the device.
Fourteen serious events occurred in the Control Arm and 13 in the
Investigational Arm. Of these, 9 and 10 respectively were related to
port management. For the remainder, it was difficult to discern if they
were disease or treatment related.

**Serious Adverse Events Occurring during Protocol Chemotherapy**

  ----------------------- ----------------------- -----------------------
  **Event**               **Chemotherapy only     **Chemotherapy + SIRT
                          Arm**                   Arm**

  Removal of port for any 1                       2
  reason                                          

  Resiting of port for    1                       6
  any reason                                      

  Infection or blockage   4                       2
  of port not leading to                          
  removal or resiting                             

  Other port related      3                       0
  events                                          

  Fever of uncertain      2                       1
  origin                                          

  GI symptoms of          2                       1
  uncertain origin                                

  Surgical complications  1                       1

  Total                   14                      13
  ----------------------- ----------------------- -----------------------

######### Patient Discontinuation

The device is permanently implanted and cannot be retrieved unless the
tumors become suitable for resection at some later stage, which occurs
for very few patients in this target population. It was implanted only
once at the start of protocol treatment for patients on the
Investigational Arm. The radiation emitted from the device has a
half-life of 64.1 hours, thus over a period of two weeks over 97% of the
effective ionizing radiation has been delivered. Thereafter, protocol
treatment was the same on both arms, consisting of regional
intra-hepatic artery chemotherapy for 12 days per month for a maximum of
18 cycles. As such, patients could not discontinue use of the device,
only use of the ensuing chemotherapy.

Patients on both arms discontinued protocol chemotherapy when they
completed the 18 cycles, or required a change of therapy for a variety
of reasons. More patients on the Investigational Arm completed the full
18-cycle protocol (7 vs. 1), while more patients on the Control Arm
discontinued treatment due to progressive disease in the liver (13 vs.
6). A similar number of patients discontinued protocol therapy due to
the development of extra-hepatic metastases (35% on the Control Arm and
36% on the Investigational Arm). Patients were followed after
introduction of non-protocol chemotherapy until death or last known to
be alive.

######### Device Failures and Replacements

Device failure occurs if the isotope leaches from the microsphere and
deposits in bone. SIR-Spheres^^ has leaching of less than 0.1% as
determined by Sirtex Medical, Inc. This represents the only potential
failure point for this device. In addition, monthly blood tests
indicated that no myelosuppression occurred, corroborating the lack of
leaching.

#### **Statement on Gender Bias**

Patients treated with SIR-Spheres^^ were selected for treatment on the
basis of selection criteria as previously outlined. Patients were
sequentially enrolled into the trial on the basis of inclusion criteria,
and gender was not a randomization stratum nor deliberately balanced. No
significant differences were found between males and females when tested
by hazard ratios for time to treatment failure, time to disease
progression and survival, however, the majority of patients were male.

######## XII. Conclusions Drawn from Nonclinical and Clinical Studies {#xii.-conclusions-drawn-from-nonclinical-and-clinical-studies .unnumbered}

> For patients with advanced colorectal liver metastases, the addition
> of a single treatment of SIR-Spheres^^ to intra-hepatic artery
> chemotherapy with FUDR significantly increases both the Tumor Response
> Rate and Time to Disease Progression.
>
> SIR-Spheres^^ is safe when correctly implanted into tissues, and does
> not leach toxic substances into the systemic circulation.
>
> The microspheres are a mild dermal sensitizer.
>
> The most significant potential adverse events are radiation hepatitis
> and pneumonitis. While uncommon, these are potentially life
> threatening.

**XIII. Panel Recommendation**

The Radiological Devices Panel met on November 6, 2000 to discuss this
PMA for SIR-Spheres^^. Following a thorough discussion of the issues,
the Panel unanimously recommended approval of the PMA with conditions.

The specific conditions recommended were the following:

1.  Revise the labeling to include dosimetry information, radiation
    protection information for the users and improved patient
    information.

2.  Require appropriate training for users.

3.  Revise the Indications for Use to specify that the device is for
    metastatic colorectal cancer.

4.  Require post-approval observational studies of safety and
    effectiveness to be designed with the FDA.

**XIV. CRDH Decision**

On the basis of the pivotal clinical study, CDRH concluded that the
Indication for Use of this device should be limited to use with FUDR,
the chemotherapy agent used in the study. CDRH considered the need for
the panel-recommended post-approval study and concluded that a
post-approval study is not required. The company has provided adequate
data to substantiate the safety and effectiveness of its device for the
approved indications for use. The bases for this conclusion are as
follows:

1\. The primary study end-points established by the applicant were 1)
increased survival and 2) improved quality of life. Neither end-point
was demonstrated in a statistically valid manner, although the data
suggested a trend toward longer survival and also showed that quality of
life did not worsen.

2\. CDRH concluded that increased survival and improved quality of life
(QOL) measures are not necessary end-points for this PMA. Survival is
determined not only by metastases in the liver (the treated organ), but
also by metastases in other, non-treated organs. Therefore, treating the
liver may have little effect on the survival of the patient. QOL would
not reasonably be expected to improve because patients in both arms of
the study were treated with chemotherapy and suffered its side effects.

3\. The secondary end-points established by the applicant were 1) tumor
regression and 2) increased time to tumor progression. Given that
SIR-Spheres^^ targets only the liver, these end-points are more
appropriate as [primary]{.underline} end-points. The study showed
statistically significant improvement in both end-points.

4\. The panel concluded that the PMA is approvable, based on the
effectiveness data presented above. However, because the proposed
indications for use included use with any chemotherapy agent and because
FUDR was the only agent used during clinical trials, the panel
recommended a post-approval study, which was to have collected data on
results with other chemotherapy agents and may have contributed to a
better understanding of survival. The panel stated that an observational
study would suffice. CDRH considered the need for a post-approval study
and concluded that a study to bolster the survival data would have to be
a randomized, controlled trial similar to the pre-market study, but
larger. However, given that the indications for use have been limited to
use with FUDR only and given that survival is not a necessary end-point
and that tumor regression and increased time to progression are more
appropriate end-points, CDRH concluded that there is no need for a
mandatory post-approval study.

Therefore, CDRH concluded that SIR-Spheres^^ is effective in tumor
regression and increased time to tumor progression and that there is no
need for a post-approval study.

The Panel also recommended a modification to the sponsor\'s proposed
patient labeling. CDRH does not believe that patient labeling is
mandatory for this device. Our reasons for this determination are: 1)
Sir-Spheres^^ is for professional use only; 2) Prior to use, the
patient will receive counseling on the use, potential benefits, and
potential complications of the device from the attending physician; and
3) There are numerous sources (American Brachytherapy Society, American
College of Radiology, etc.) of patient information and counseling on
these types of radiation therapy products that can provide information
to the patient.

CDRH recommended approval of the device for marketing. The applicant's
manufacturing facility was inspected on October 10 and 14, 2001 and was
found to be in compliance with the Quality Systems regulations. FDA
issued an approval order on March 5, 2002.

########  {#section-6 .unnumbered}

######## Approval Specifications

Directions for use: See the attached labeling.

Hazards to Health from Use of the Device: See Indications,
Contraindications, Warnings, and Precautions in the attached labeling.

Postapproval Requirements and Restrictions: See approval order.