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.