A prospective, multicentre, randomised, controlled study evaluating SIR-Spheres® Y-90 resin microspheres preceding standard cisplatin-gemcitabine (CIS-GEM) chemotherapy versus CIS-GEM chemotherapy alone as first-line treatment of patients with unresectable intrahepatic CholangioCArcinoma.

Despite the advances in different modalities for cholangiocarcinoma the 3 and 5
year survival in non-surgically resected selected patients remains below 50%
and 10% respectively.
This approach to integrating potentially curative tumoricidal therapies
(ablation, locoregional SIRT and external beam radiotherapy) in patients with
unresectable intrahepatic cholangiocarcinoma has to be compared to the current
standard of care therapy * cisplatin and gemcitabine (CIS-GEM) systemic
chemotherapy (Valle 2009 (65), Valle 2010 (66)) * in order to judge potential
benefits.
SIR-Spheres Y-90 resin microspheres have been studied for the treatment of
patients with inoperable intrahepatic cholangiocarcinoma. Although no
randomised controlled study has been performed to date, the results of SIRT in
patients with ICC, in either prospective or retrospective cohort studies, look
very promising and provide preliminary evidence that SIRT is a safe and
effective treatment option for unresectable ICC.

This study will assess the benefit of adding SIRT to a standard regimen of
cisplatin and gemcitabine (CIS-GEM) systemic chemotherapy in unresectable
liver-only or liver predominant intrahepatic cholangiocarcinoma.
Patients will be offered the accepted treatment in conventional practice and
the active arm of the trial will combine the standard of care with
radioembolization. Such a trial design guarantees that patients do not lose the
benefits of conventional therapy and allows the determination of survival
benefits of the combined approach.

This clinical study is a prospective, multicentre, randomised, controlled study
evaluating SIR-Spheres Y-90 resin microspheres preceding standard
cisplatin-gemcitabine (CIS-GEM) chemotherapy vs. CIS-GEM chemotherapy alone as
first-line treatment of patients with unresectable intrahepatic
cholangiocarcinoma.
The target recruitment is about 180 randomised patients who started treatment.
However, it is expected that about 160 of the patients in both arms will
satisfy the compliance criteria i.e. (Arm A: completed at least one cycle; Arm
B completed SIRT treatment and complete at least one cycle).
Patients will be randomised 1:1 (about 90 patients in each arm) to receive
either:
1. Treatment Arm A: Standard of care systemic chemotherapy with an intention to
treat with 8 cycles of cisplatin + gemcitabine, or until progression, toxicity
or patient choice. Treatment may be continued beyond 8 cycles in the absence of
significant disease progression, at the treating clinicians* discretion.
2. Treatment Arm B: A single treatment of hepatic arterial injection of
SIR-Spheres Y-90 resin microspheres followed 14-16 days later by standard of
care systemic chemotherapy (ABC-02 CIS-GEM protocol) with an intention to treat
with 8 cycles of cisplatin + gemcitabine, or until progression, toxicity or
patient choice. Treatment may be continued beyond 8 cycles in the absence of
significant disease progression, at the treating clinicians* discretion.
Patients will be stratified by: presence of extra-hepatic disease, presence of
cirrhosis, intention for whole liver versus non-whole liver Y-90 treatment,
baseline albumin levels (< 35g/L vs * 35g/L) and ECOG status (0 versus 1).

Patients will be randomised 1:1 (about 90 patients in each arm) to receive
either:
1. Treatment Arm A: Standard of care systemic chemotherapy with an intention to
treat with 8 cycles of cisplatin + gemcitabine, or until progression, toxicity
or patient choice. Treatment may be continued beyond 8 cycles in the absence of
significant disease progression, at the treating clinicians* discretion.
2. Treatment Arm B: A single treatment of hepatic arterial injection of
SIR-Spheres Y-90 resin microspheres followed 14-16 days later by standard of
care systemic chemotherapy (ABC-02 CIS-GEM protocol) with an intention to treat
with 8 cycles of cisplatin + gemcitabine, or until progression, toxicity or
patient choice. Treatment may be continued beyond 8 cycles in the absence of
significant disease progression, at the treating clinicians* discretion.

With more than 50,000 doses (as of June 2015) supplied, SIRT has been shown to
be generally well tolerated.

Minor side effects of SIRT include the following
1. Most frequently, patients develop a fever that begins within 24 hours of
treatment. This will usually go away without treatment. This fever is a
result of the action of the SIRT in the liver.
2. Up to half of patients develop pain in the upper abdomen after SIRT. This
may start during the procedure and usually lasts only for a few hours. .
3. Nausea is common in approximately half of patients but this subsides with
time and medication.
4. Some patients complain of feeling *off colour* or tired with loss of
appetite for several days after treatment. This goes away with time, and it is
due to the fact that, although the SIRT is only administered once, the effects
of treatment last for several weeks.

More serious side effects include:
1. It is possible that the SIR-Spheres Y-90 resin microspheres can be
incorrectly delivered and they do not all remain in the liver. This can be due
to technical problems while inserting the catheter into the artery in the
liver. If this happens, the spheres may be inadvertently supplied to other
organs in the body, including the stomach, intestine, pancreas and lungs. If
this were to happen then it may cause pancreatitis or gastritis. If too many
SIR-Spheres Y-90 resin microspheres go to the lung, then this may cause
pneumonitis.
2. There is a very small risk that the treatment with SIRT could result in a
fatal complication, however from past experience the chance of this is less
than 1%.
3. The dose of radiation that you receive is individually calculated. However,
if the normal liver receives too high a dose, some patients may develop
long-term damage to the liver. In a recent study using SIR-Spheres Y-90 resin
microspheres, in a very small number of cases, there was evidence of damage to
the normal healthy part of the liver, but this will be minimised by carefully
assessing the individual dose.

The use of chemotherapy and radiation using SIR-Spheres Y-90 resin microspheres
together may increase the effect of the treatment, but may also increase the
possibility of side effects. It is presumed that any side effects would be the
same sort as are known to occur with each treatment alone, but they may be more
common or more severe.

Risks associated with the insertion of SIR-Spheres Y-90 resin microspheres, the
hepatic angiogram and the MAA breakthrough scan:
There is a risk of pain, bruising, infection and minor blood loss from the
groin artery where the catheter is inserted. Allergic reactions to the contrast
dye used may occur. Rarely, the arteries may be damaged from the insertion of
the catheter but this risk is minimised because only experienced doctors will
perform these procedures.

Advice radiation committee:
In this multi-center study a maximum of 180 patients with Cholangiocarcinoma
(20 patients in AMC) will be treated with SIR-spheres. We estimate the target
dose due to the treatment around 120 Gy. For the study also some extra
diagnostic tests will be done. The organ doses due to these diagnostic tests
are expected to be more than 100 times lower than the therapeutic doses and
therefore are considered negligible compared to the target dose. A calculation
of the extra risk due to the diagnostic scans is therefore not meaningful. On
top of this comes the fact that the targeted patients are not considered
*normal average adults*, due to their limited life expectancy of on average ca.
1 year. This makes the risk much less than in other cases.