CyberKnife for Liver Lesions

Malignant tumors involving the liver take a variety of forms, including primary hepatocellular carcinoma (HCC) (a malignant tumor arising from the liver itself), primary bile duct or gallbladder cancer (a malignant tumor arising from the bile duct or gallbladder) and liver metastases (secondary cancer lesion(s) that have spread to the liver from a different primary malignant tumor, such as colorectal cancer).

The primary treatment for liver and bile duct/gallbladder cancers has been surgical removal, which represents potentially curative therapy for patients with localized disease, including those with limited liver metastases if their primary tumor is controlled (1-8). Unfortunately, many patients are not surgical candidates for a variety of reasons, including inoperability due to the extent of disease itself, patient inability to withstand the surgical procedure due to poor health, or additional malignant activity elsewhere in the body that renders aggressive surgical therapy inappropriate.

Many nonsurgical approaches have also been applied to unresectable liver and bile duct/gallbladder cancers, including radiofrequency ablation (inserting a probe that heats the tumor), cryoablation (inserting a probe that freezes the tumor), chemoembolization (inserting a tube into the blood vessel that feeds the tumor and infusing small foreign bodies coated with chemotherapy drugs), direct liver chemotherapy infusion (inserting a tube into the blood vessel that feeds the tumor and infusing a concentrated dose of chemotherapy drugs), and systemic chemotherapy (delivering chemotherapy to the whole body, including the liver) (9-14).

Radiotherapy has also been used to treat liver and bile duct/gallbladder cancers (15-20). Traditional forms of radiotherapy have had a limited role in the management of liver and bile duct/gallbladder cancers, largely due to the fact that the liver itself is very sensitive to radiation injury (20).

Contemporary high dose conformal radiotherapy (including 3DCRT; IMRT; Proton beam) has yielded more meaningful and durable clinical responses in patients with liver and bile duct/gallbladder cancers, due to its ability to better concentrate the radiation dose in the targeted area and spare uninvolved liver tissue, though cure remains uncommon (15-19).

Potential Therapeutic Gain

Stereotactic radiotherapy, describes a more localized form of radiation that is delivered over a very short course of 1-5 treatments, using large doses per treatment (hypofractionated treatment). With stereotactic radiation approaches, it is possible to deliver a more sharply marginated form of radiation that is more sparing of surrounding tissue, allowing an increased dose to be delivered. This form of applied radiation is biologically ablative of tissue within the high dose volume, and represents a potentially more effective method of eradicating liver and bile duct/gallbladder cancers, compared with prior radiotherapy techniques (21-23).

In an ongoing Multi-Institutional stereotactic radiotherapy dose escalation protocol, liver tolerance to radiation with stereotactic radiotherapy still has not been reached, as long as 30% of the liver tissue is spared from a significant radiation dose. The radiation dose delivered in this study has been estimated as the biological equivalent of two to three times the conventional dose, representing a far more biologically potent radiotherapy application compared with prior “conventional” or standard conformal radiotherapy approaches (22,23). Such a high dose radiotherapy course is only safely delivered by very sophisticated approaches, such as stereotactic radiotherapy or stereotactic radiosurgery.

A Higher Order of Precision

CyberKnife Treatment Margins

Because of its closeness to the diaphragm, the liver moves considerably with respiration. Even sophisticated stereotactic radiation approaches do not fully overcome the problem of respiration-induced target volume motion in liver lesions, causing the necessary application of a larger therapeutic margin to compensate, which also increases the dose to adjacent normal liver and in some cases, stomach, duodenum, small intestine and large intestine, potentially increasing the risk of radiation injury. Though adaptive methods such as shallow breathing or radiotherapy gating to the respiratory cycle have been used to reduce respiration-induced marginal dose degradation, they have not eliminated it.

Targeting Angles

Whereas traditional radiotherapy systems target the lesion from a relatively small number of fixed positions, the inherently noncoplanar geometry of the CyberKnife® device allows literally hundreds of targeting angles to be selected, increasing the ability to conform the ablative dose to the target lesion(s) within the liver, while better sparing the surrounding hepatic tissue.

Lesion Tracking

The CyberKnife® Synchrony® Respiratory Tracking System locks onto implanted gold fiducial markers and correlates their position with the respiratory cycle as determined by optical tracking, to track the targeted lesion with 1.5 mm accuracy, allowing a smaller applied margin compared with other stereotactic radiation delivery systems, giving CyberKnife® the distinction of being the only device that currently brings radiosurgical precision to respiration-induced moving targets.

Technical Summary:

The CyberKnife® device brings an unprecedented level of radiation dose shaping  and targeting precision, effectively bringing radiosurgical ablation capability to liver lesions, while minimizing the risk of serious injury to normal hepatic parynchema and adjacent tissues.

The CyberKnife® Radiosurgery Solution

Hepatocellular Carcinoma - Combined Modality

CyberKnife® radiosurgery represents a biologically potent intervention against HCC that may be employed as an aggressive “bridge treatment” to patients awaiting liver transplantation. It may be used alone, or in combination with other therapies, such as the infusion of chemotherapeutic agents (16 ,21-23).

Due to it’s very sharp therapeutic margin, CyberKnife® radiosurgery will typically have less effect on adjacent sensitive tissues compared with other radiotherapeutic approaches, causing less potential impairment of surgical tissue healing at the subsequent resection or transplantation procedure. CyberKnife® radiosurgery is also capable of covering large, irregular lesions well, potentially providing a more complete treatment of complex tumors compared with radiofrequency ablation or other non-surgical ablative therapies. These tumor coverage and margin control characteristics would appear to make CyberKnife® a very reasonable “bridge treatment” for HCC patients awaiting their definitive procedure.

Unfortunately, a majority of patients with HCC will be inoperable for a variety of reasons (2). Though cure is unlikely in these patients, prolonged disease-free survival has also been reported with various radiotherapeutic approaches, with longer disease-free survival periods and occasional apparently cured patients with larger radiation doses (15-17).

Hepatocellular carcinoma may be three dimensionally mapped with reasonable accuracy from radiology studies such CT or MRI (24). This level of radiologic mapping accuracy allows the application of a precise radiation dose sculpting tool such as CyberKnife® to be accomplished in a manner that spares the maximum possible amount of normal liver tissue and other adjacent sensitive tissues, enabling the application of a very high radiation dose that is potentially biologically ablative of the malignancy

In fact, the upper limit of partial liver tolerance to precisely conformal stereotactic radiotherapy has not yet been reached, in a large ongoing multi-institutional prospective dose escalation trial, which has already reached a biologic radiation dose equivalent to the targeted lesions greater than double that achievable with conventional radiotherapy (22,23)

CyberKnife® radiosurgery effectively addresses the technical limitations of other radiotherapy methods, producing precise ablative radiation coverage of the HCC lesion, and accurately tracking the lesion as it moves with respiration, in a manner whose precision is unequaled by other radiation delivery systems. It may be reasonably be applied as an aggressive “bridge therapy” in a HCC patient awaiting removal of their diseased liver and liver transplantation, either alone or in combination with other therapies, or it may be used as a radiosurgical ablative method with curative intent in selected patients for whom traditional surgery is not an option. Further study of this treatment method in HCC patients is warranted.

Liver Metastases

Stereotactic radiotherapy/radiosurgery allows a substantial radiation dose escalation to liver metastases, translating to a radiation biologic potency greater than double that of conventional radiation therapy approaches (22,23). This brings a new nonsurgical liver tumor ablation method that is more precise and powerful than traditional radiotherapy, and less invasive than surgical removal, radiofrequency ablation (heating) or cryosurgery (freezing).

The unique CyberKnife® dose sculpting and target tracking attributes (Synchrony™) make it a particularly attractive option for the treatment of liver metastatic lesions. As the only radiation delivery system that tracks respiratory tumor movement with 1.5 mm accuracy, the CyberKnife® is uniquely capable of delivering an ablative radiation dose to liver metastases, with the sharpest margin possible, allowing the maximum possible sparing of adjacent normal liver tissue and nearby upper gastrointestinal organs.

The efficacy of CyberKnife® radiosurgery relative to metastatic resection or other ablative approaches such as cryosurgery or radiofrequency ablation is appropriately studied in prospective comparative clinical trials. Meanwhile, it is reasonably applied to patients with liver metastases who are not surgical candidates, or to those who refuse surgery or other invasive treatment methods.

Cholangiocarcinoma

Due to the rarity of this tumor type, stereotactic radiotherapy literature is sparse, though prolonged local control of cholangiocarcinoma following stereotactic radiotherapy has been reported (25).

Anatomically, cholangiocarcinomas may be more difficult to treat with stereotactic radiotherapy/radiosurgery than other liver lesions, due to their frequent close proximity to the stomach and small intestine. Even with a very focal radiation approach such as CyberKnife® radiosurgery, immediate approximation of the intestinal wall against the tumor volume predicts an increased risk of ulceration following treatment, warranting extreme caution in managing these tumors with focal ablative radiation approaches.

A sensible approach to cholangiocarcinoma would be to perform exploratory surgery with the intent of surgically removing the tumor if possible. If the tumor proves inoperable, a reasonable response would then be to surgically move sensitive gastrointestinal tissues away form the tumor bearing area, simultaneously implanting CyberKnife® targeting markers into the tumor for radiosurgery beam guidance. It would then be safer to proceed with CyberKnife® radiosurgery to the cholangiocarcinoma tumor, with consideration of more traditional radiotherapy and chemotherapy before or afterward, to deal with cancer cells that may have spread beyond the visible tumor.

Conclusion

CyberKnife® radiosurgery represents an extremely precise ablative radiation technique that offers a potent new treatment alternative for patients with hepatocellular carcinoma, cholangiocarcinoma, or liver metastases. The large number of targeting angles and the target tracking capability of the CyberKnife® Synchrony® respiratory tracking feature, enables radiation conformality around the tumor volume approaching that of a surgeon’s scalpel.

CyberKnife® radiosurgical treatment is reasonable to administer as aggressive “bridge therapy” to  hepatocellular carcinoma (HCC) patients awaiting transplantation, or as potentially curative therapy to HCC patients that are not candidates for surgical removal of their HCC tumor. It is a radiobiologically ablative form of radiation against liver metastases, allowing extreme radiation dose escalation compared with standard radiation delivery systems. Used with caution and in conjunction with judicious surgical displacement of sensitive gastrointestinal tissues, it also appears appropriately directed against selected cholangiocarcinoma tumors.

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