Trial Information

International, Phase II Study of CyberKnife® for Hepatic Metastases From Colorectal Cancer

Colorectal cancer is the fourth most commonly diagnosed malignant disease worldwide, with an
estimated 1,023,000 new cases and 529,000 deaths each year. The liver is the most frequent
site of metastatic spread from colorectal cancer, 25% of colorectal cancer patients will
have liver metastases at the time of initial colorectal resection and more than 50% of
colorectal cancer patients will develop liver metastases during the course of the disease.

The current standard of care and only potential curative therapy for colorectal liver
metastases is liver resection of the metastatic lesions. Surgical resection provides long
term survival in patients with colorectal carcinoma (CRC) liver metastases. In a report of
1001 patients with metastatic colorectal cancer from Memorial Sloan-Kettering Cancer Center
in NY, USA, surgical resection of liver metastases resulted in 3- and 5-year survival rates
of 37% and 22%, respectively. Advances in pre- and intra-operative imaging and chemotherapy
during recent years have increased overall survival up to 60% at 5 years after liver
resection. However, 80-90% of liver metastases are unresectable at the time of diagnosis
usually due to tumor location, multifocality, inadequate functional hepatic reserve or the
patient's overall condition. For those patients, harboring unresectable liver metastases,
alternative treatment approaches include neoadjuvant chemotherapy, local ablation therapy
and stereotactic radiation therapy.

The recent availability of neoadjuvant chemotherapeutic agents has increased the response
rates and doubled the median overall survival time for metastatic colorectal cancer from 10
to 20 months. Recent studies have demonstrated that neoadjuvant therapy allows 12.5% of
patients with unresectable CRC liver metastases to be significantly downstaged and eligible
for hepatic resection.

For unresectable CRC liver metastases, local ablative therapies are widely applied. Local
ablative treatment refers to a variety of intervention techniques that specifically target
tumors to directly destroy them. Numerous methods of ablation have been developed including
cryoablation, percutaneous ethanol injection, radiofrequency ablation (RFA) and stereotactic
radiation therapy. The most widely employed non-radiation based local ablative treatment is
RFA which induces thermal ablation by passing high-frequency alternating current through the
tumor utilizing electrodes that are placed within the tumor and surrounding tissue. RFA can
be applied percutaneously under ultrasonic guidance or directly during laparoscopy or open
laparotomy. Local recurrence rates of 44.4% at 18 months were reported by Solbiati et al.
for CRC liver metastases with a median diameter of 2.6 cm. For tumors greater than 4 cm the
local recurrence rate was 68%. RFA has an overall 3-year survival rate of 28-46% and a
5-year survival rate of 25%. However, patients with advanced hepatic decompensation, large
tumors (3 to 5 cm), or multifocal tumors are generally considered poor candidates for RFA.

Conventional radiation therapy has been shown useful for palliation of hepatic capsular
pain, but historically it has played a minor role in the treatment of patients with
unresectable liver metastases. This can be attributed chiefly to the low tolerance of the
whole liver to radiation. The liver was thought to be a relatively radiosensitive organ and
with whole liver irradiation, it was difficult to achieve the radiation doses necessary to
eradicate gross tumors without causing radiation induced liver disease. Partial liver
irradiation has shown some promise. Limiting irradiation to only one-third of the liver
through three-dimensional (3D) conformal radiotherapy techniques, including intensity
modulated radiotherapy (IMRT), several studies have shown that partial liver irradiation is
safe with doses up to 50-72.6 Gy. However, further dose escalation with conventional
radiation therapy techniques risks injury to adjacent abdominal organs.

Stereotactic Body Radiation Therapy (SBRT) has emerged as a novel approach for the local
ablation of liver metastases. SBRT provides a conformal isodose distribution with a steep
radiation dose gradient allowing much higher doses of radiation than conventional radiation
therapy and conformal radiotherapy techniques to be delivered safely with high precision to
focal liver metastases while minimizing the radiation dose to normal liver and adjacent
organs. To achieve this, precise localization of the target during treatment is required
which necessitates accounting for tumor motion. SBRT technology utilizes a number of
techniques to accommodate for tumor and respiratory motion including motion-restrictive
techniques such as frames and abdominal compression, as well as motion-compensating
techniques such as active breathing control and tumor tracking. The motion-restrictive
techniques can be difficult for some patients to withstand, limiting those patients from
being able to receive treatment. The motion-restrictive techniques can also necessitate the
use of wide margins. Rusthoven et al. found a gross tumor volume (GTV) to planning target
volume (PTV) expansion of up to 15 mm necessary in the craniocaudal direction. Wide margins
can result in irradiation of a substantial volume of normal liver, potentially increasing
the risk of radiation-induced injury. Some studies suggest the motion-compensating approach
of active breathing control can aid in reducing the margins required by motion-restrictive
approaches, however, Korreman et al. suggest those reductions may only be applicable with
the use of image-guidance between and within sessions.

The CyberKnife robotic radiosurgery system (Accuray Incorporated, Sunnyvale, CA) an advanced
platform to deliver SBRT, provides a therapeutic solution to this problem by continuously
tracking the tumor during treatment while it accounts for organ motion due to respiratory
movement, using the Synchrony respiratory tracking system (Accuray Incorporated, Sunnyvale,
CA). Utilizing continuous tumor tracking, margin expansion to account for motion uncertainty
can be reduced, having the potential to make this a safe and effective treatment. The
frameless nature of the CyberKnife and its continuous image guidance system eliminates the
need of motion-restriction techniques increasing the comfort and availability of the
treatment to patients.