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10.1245/ASO.2004.10.907
Annals of Surgical Oncology 11:130-138 (2004)
© 2004 Society of Surgical Oncology
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NEW APPROACHES TO THE TREATMENT OF HEPATIC MALIGNANCIES

Stereotactic Body Radiation Therapy: An Ablative Treatment Option for Primary and Secondary Liver Tumors

Martin Fuss, MD and Charles R. Thomas, Jr., MD

From the Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Correspondence: Address correspondence and reprint requests to: Martin Fuss, MD, Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229; Fax: 210-949-5085; E-mail: fuss{at}uthscsa.edu

ABSTRACT

Only a subset of patients with primary and secondary liver tumors are eligible for surgical resection because of either the presence of extrahepatic disease, increased number of hepatic lesions, the anatomical distribution of tumors within the liver, and/or general medical inoperability. Nonsurgical, ablative tumor treatment may benefit selected patients by preserving normal liver function. This review presents the concept and technology of stereotactic body radiation therapy and summarizes available clinical data describing applications in the treatment of malignant liver tumors. We present predominantly peer-reviewed data but also summarize recent clinical developments along with discussions of current ongoing and planned multicenter studies.

Key Words: Key Words: Stereotactic body radiation therapy • Review • Liver ablation • Liver metastasis • Hepatocellular carcinoma

Surgical resection of liver metastases and primary liver malignancies is currently the only established curative treatment option for either disease and results in 5-year survival rates of 40% to 50%, respectively.1,2 Despite advances in surgical techniques, only approximately 20% of patients with liver tumors are candidates for curative resection.3 Presence of nonresectable extrahepatic disease, extensive organ involvement, and general medical condition render the majority of patients nonsuitable for surgical curative treatment approaches. A variety of alternative treatment modalities have been explored in this significant patient population. Systemic chemotherapy, regional chemotherapy, or chemoembolization and percutaneous injection techniques (using ethanol, acetic acid, and hot saline) have become the most commonly employed therapeutic approaches. Local minor invasive lesion ablative techniques, such as radiofrequency ablation, microwave coagulation therapy, and cryotherapy, have been established in recent years and promising results with respect to local control have been reported.4–11 A consensus proposal to standardize the terminology associated with those local image-guided ablation techniques and related reporting criteria has been recently made available.12

Noninvasive stereotactic body radiation therapy (SBRT, also commonly referred to as extracranial stereotactic radiotherapy or extracranial radioablation) is a recent conceptual development defining prescription and delivery of large single radiation doses or a limited numbers of radiation fractions (hypofractionated radiotherapy) to small target volumes within major visceral organs such as the lung and liver.13 As of today, no definitive consensus exists in the definition of SBRT with respect to a maximum number of radiation fractions, the minimum radiation dose per fraction, or the maximum number and diameter of lesions to be treated under this paradigm. Typically, stereotactic localization and targeting techniques, similar to those developed and established in intracranial radiosurgery, are employed. Although the adaptation of a stereotactic treatment concept in which the center and extent of a lesion are defined in reference to a patient independent room coordinate system was facilitated by dedicated body immobilization systems, the main obstacle in enabling precise and reproducible radiation delivery outside the brain is the primary challenge to achieve a reliable, accurate, and reproducible target position. Since hepatic target lesions may move with the liver relative to the surface of the patient during normal respiration, advanced imaging techniques need to be employed to individually characterize and optimally minimize or offset such target motion. This is mandated by the need to reduce additional safety margins extending into normal tissues, which in conventional radiotherapy are assigned to secure a high probability of target volume coverage by the prescribed radiation dose on any day of a radiation treatment course.

This review will highlight the major radiobiological concepts and technology and treatment concepts associated with SBRT and summarize available clinical outcome data and ongoing clinical research including presently active or planned clinical multicenter trials. We will try to characterize the future potential of the method in the noninvasive treatment of focal liver malignancies.

RADIOBIOLOGY AND TREATMENT CONCEPT OF FOCUSED SINGLE-DOSE AND HYPOFRACTIONATED STEREOTACTIC RADIATION THERAPY OF LIVER LESIONS

The low tolerance of the liver to ionizing radiation has been recognized and limits the use of radiotherapy, an otherwise common antitumor therapy modality, for primary and secondary hepatic malignant disease. If the liver as a whole is exposed to therapeutic radiation, a dose of approximately 30 Gy in 10 to 15 fractions is considered to represent the maximum tolerated dose, based on a 5% to 10% probability to induce radiation-induced liver disease, with clinically relevant loss of liver function. Due to the liver’s amazing potential to regenerate, smaller portions of liver may be exposed to much higher radiation doses without the risk of damaging an excess portion of vital liver reserve. In fact, a striking liver volume/radiation dose tolerance relationship has been established indicating that radiation doses as high as 100 Gy may be tolerated with low normal tissue complication probability if no more than one third of the whole liver is exposed to high radiation doses.14,15

The radiobiologic principle of SBRT is in part founded upon the clinical observation of increased liver radiation tolerance if smaller, well-defined volumes of the liver are exposed to ionizing radiation. By using stereotactic patient immobilization, advanced lesion targeting techniques, high degrees of dose conformality, and steep radiation dose gradients (a significant difference between radiation dose delivered in a spatial shape that closely follows the outline of a target lesion as opposed to radiation dose exposure to the organ at risk, the liver) the overall amount of normal liver tissue exposed to potentially harmful radiation doses can be substantially reduced (Fig. 1). The prescribed high radiation doses delivered in a single or few radiation fractions (typically higher than 5 Gy and up to 28 Gy per fraction; for comparison, in conventional radiotherapy a typical daily dose ranges between 1.8 and 2 Gy) was conceptually chosen to overcome malignant cell radiation resistance. This treatment concept has been successfully applied in brain radiosurgery for more than three decades, with excellent local lesion control rates and maintained brain functionality.16,17 Differences in delivering the whole radiation dose in a single session (radiosurgery) or splitting a total dose between three to six treatment fractions (hypofractionated treatment) is predicated on the basis of classic radiation biology, suggesting benefits for splitting a total radiation dose into multiple smaller radiation fractions to allow for tumor re-oxygenation (oxygenated cells are more sensitive to radiation than hypoxic cells) and malignant cell redistribution (cells entering the cell cycle are more sensitive to radiation than dormant cells). However, since the radiobiology of multiple large radiation fractions differs from the conventional 2 Gy per fraction regimen in conventional radiotherapy, the rationale and benefit of using large single or multiple slightly smaller radiation fractions is currently the subject of a controversial scientific debate.



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  		FIG. 1. Dose distribution of intensity-modulated stereotactic body radiation therapy for two small colorectal cancer metastases. Depicted are the planning target volumes (PTV) in red and purple (the lesion and safety margins of 5 mm transversally and 15 mm craniocaudally). The PTVs are conformally encompassed by the blue 100% isodose line, which is the equivalent to the total delivered dose of 36 Gy in three fractions of 12 Gy. The achieved steep dose gradients toward normal liver tissue are documented by the 90% (red), 70% (yellow), and 50% (green) isodose lines.

 
With respect to stereotactic radiation therapy of liver lesions, the methodological approaches we discuss all involve an ablation of tissues within the high-dose radiation region (including a rim of normal liver tissue surrounding the lesion) and rely on the capability to confine this high-dose radiation region so that the functional reserve of the organ will not be compromised (Fig. 2). The potential advantage of these techniques is second to the functional redundancy of the liver, which represents the classical parallel organ. The organ’s capacity to replace lost functional organ subsets by regeneration makes such novel approaches possible.



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  		FIG. 2. Eight-month outcomes following stereotactic body radiation therapy for a solitary, right posterior-inferior liver lobe (segment VI) colorectal cancer metastasis. The upper images document the planned and delivered dose distribution (total dose 36 Gy in three fractions). The lower figure documents the ablative character of this treatment with residual scar tissue and obliteration of the lower, posterior high dose exposed aspect of the right liver lobe.

 
PATIENT IMMOBILIZATION AND LESION TARGETING

Delivery of high radiation doses safely to small target regions in the liver is highly reliant on the ability to describe the location of a lesion relative to the surface of the patient’s body. Necessitated by the potential for lesion motion to occur relative to the body surface, the capability to describe the location of a target as a function of time becomes an important aspect of confining radiation dose delivery to small volumes in the liver safely. Ideally, a patient immobilization system would provide for accurate assurance of the patient’s position for one or more treatment sessions and restriction of any target motion within the liver. The simultaneous demand for a comfortable, noninvasive, high compliance immobilization technique will unavoidably compromise such aims. All currently employed commercially available systems for which peer-reviewed performance data exist combine a baseboard and stereotactic localization and targeting systems with a vacuum base cushion to accommodate the patient. The vacuum cushions allow for individualized tailoring of a "cast" to provide for the highest probability of reliable patient repositioning (Fig. 3). Mechanical abdominal pressure devices may aid to restrict breathing related motion of the liver.18 Those stereotactic body immobilization systems carry repositioning accuracies with standard deviations along the principal room axes of up to 4 mm.19–21



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  		FIG. 3. Stereotactic body immobilization system. The upper image documents a patient setup for treatment on the linear accelerator table. The lower image depicts the negative "vacuum cast" providing for the required setup accuracy.

 
Thin slice computed tomography (CT) imaging is typically the imaging basis for conformal stereotactic radiotherapy planning (contiguous slice thickness of 3 to 5 mm). Intravenous contrast media aids to define the boundaries of intrahepatic lesions. Image coregistration of magnetic resonance imaging and/or positron emission tomography may aid in the definition of lesion boundaries. The target volume (gross tumor volume) is typically the anatomically appreciated liver lesion. Safety margins of 5 mm in the transversal plane and 10 mm craniocaudally are added for a planning target volume to account for microscopic tumor extension into normal liver tissue, patient setup uncertainties, and lesion motion with respiration. Individually, the craniocaudal motion is enlarged to reflect larger breathing motion amplitude.

Most recently "respiration gating" technologies yield the prospect of a time-coded positional description of a mobile target, which moves secondary to breathing as a function of time within the breathing cycle. To this end, imaging information acquired during a subset of the breathing cycle can be purged from a CT imaging data set and simultaneous avoidance to actual radiation dose delivery during the same subset of the breathing cycle will virtually "freeze" a target lesion in space, enabling smaller safety margins and potential reduction of treatment-related side effects. The trade off is prolongation of radiation treatment planning imaging data acquisition and potentially significantly prolonged radiation deliver time.

Conformal avoidance of normal liver tissue and excellent target coverage by the prescribed radiation dose are achieved by using multiple (typically 5 to 10) intersecting radiation beams or rotational radiation delivery techniques. The goal of confining the high-dose radiation region to the target volume can be facilitated by prescribing a so-called inhomogeneous dose distribution.18,22,23 Thus, the center of a target lesion may receive up to 150% of the prescribed dose to the margin of the target volume. Such dose prescription concepts enable steeper dose fall off toward the normal surrounding liver tissue and higher conformality of the computed dose distribution. More recent technological developments such as intensity-modulated radiotherapy yield benefits in conformal dose delivery while allowing one to selectively spare organs at risk with limited radiation tolerance.

CLINICAL EXPERIENCE (PEER-REVIEWED DATA)

Almost a decade ago, investigators from the Karolinska Hospital, Stockholm, Sweden, were the first to describe an immobilization and dose prescription technique to treat malignancies in the abdomen under stereotactic conditions.18 This article was the original report outlining much of the concepts and technology associated with SBRT. In a case report embedded in this publication, stereotactic radiation treatment of a colorectal cancer metastasis to the right lobe of the liver was presented. The lesion was treated using two large radiation fractions of 20 Gy each, separated by a 2-month interval. The same group of investigators published details of dose prescription and outcomes in two consecutive publications. The first report on clinical outcomes presented treatment specific parameters and outcomes of both primary hepatic tumors (primarily hepatocellular carcinoma) and hepatic metastases in 23 patients, while a later update analyzed outcomes in 11 patients with primary hepatic tumors and 16 patients with metastatic lesions.24,25 Since most patients from the first report are comprised in the later publication (the first five patients treated were excluded from the later analysis), only those most recently reported are summarized. While predominantly solitary lesions were treated, in seven patients two to four liver lesions were treated. Doses prescribed ranged from 15 Gy to 45 Gy, delivered in one to three fractions. The time interval between the deliveries of consecutive fractions in cases where a hypofractionated approach was chosen (39/40 lesions treated) ranged from 3 to 44 days. While the imaging response varied from disappearance (complete response) to increase in size, in the majority of lesions at least a temporary growth delay could be achieved. Local tumor control was achieved in all primary liver tumors at a mean follow-up of 12 months (range, 1.5–38 months). Despite this finding, at the time of publication all patients had expired with an average survival of 13.4 months (range, 1.5–39 months). The predominant cause of death was progressive liver cirrhosis and progression of extrahepatic malignant disease (9/11 cases). Treatment related acute toxicity was mild, with cases of observed nausea and fever in the hours following radiation. Two patients developed nontractable ascites within 6 weeks of radiation and subsequently expired. One case of subcapsular bleeding was associated with tumor necrosis. Typically, a zone of liver edema developed around the primary liver tumor, which persisted for months. In metastatic lesions, local tumor control was achieved in 18/19 tumors (mean follow-up of 9.6 months; range, 1.5–24 months). Partial and complete response was observed in four lesions each. Mean survival was 17.8 months (range, 8–36 months) in 9/17 patients reported expired at publication. Treatment related acute toxicity was similar to symptoms observed in primary liver tumors. Two patients developed hemorrhagic gastritis and a duodenal ulcer, both potentially related to focal radiation exposure of the gastric wall and duodenal loop. The positive conclusion of those reports of clinical feasibility, patient tolerance and outcomes stimulated a variety of investigators from centers in Europe and Japan to adapt and optimize the presented stereotactic treatment concept.

Herfarth and colleagues presented methodology and outcomes of patients treated for predominantly metastatic lesions to the liver in a prospective dose-escalation phase I/II trial at the University of Heidelberg, Germany.26 The treatment concept was single-dose radiation delivery (radiosurgery) in doses starting at 14 Gy (dose prescription to the reference point, with the minimum dose to the margin of the planning target volume being equal or higher than 80% of this dose). Despite an observed lack of major dose-limiting toxicity, the phase I dose escalation was stopped at 26 Gy. Actuarial local tumor control of lesions treated with doses of 20 Gy and higher was 81% at 18 and 24 months. Local failure of lesions treated with doses lower than 20 Gy was observed in 3/6 cases and interpreted as being an effect of low radiation dose and the potential for target underdosing due to narrower safety margins in those early patients. Typical tumor response to therapy at the time of first imaging follow-up was stable disease, or partial and complete response in 54 of 55 treated lesions (98%). At 6 and 12 months of imaging follow-up, tumor control was maintained in 34/43 and 19/21 lesions assessable. In follow-up CT imaging, a reactive edema surrounding the targeted lesion was observed, although the clinical relevance remained uncertain with functional laboratory findings showing only marginally elevated concentrations of serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, and alkaline phosphatase. These data have been augmented by two consecutive publications which provide added evidence of the potential of a single-dose stereotactic radiation delivery to locally control malignant liver disease.27,28 Most recently, the time course and relevance of the observed liver edematous reaction has been analyzed.28 In all 36 analyzed patients a focal liver reaction was observed during follow-up (Fig. 4). The edematous reaction occurred at a median of 1.8 months after stereotactic radiotherapy and the extent and time to occurrence was correlated with radiation dose. While this liver reaction needs to be discriminated from local tumor recurrence, the prognostic significance of this finding with respect to later manifestation of irreversible, chronic liver toxicity or long-term tumor control remains unclear.



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  		FIG. 4. Typically observed edematous reaction following stereotactic body radiotherapy for two colorectal cancer metastases (see Fig. 1 for planned and delivered dose distribution). The edema follows the 25 Gy isodose line, with peak appearance after approximately 4 to 6 weeks and slow disappearance during the following months. Note that the dose dependency of edema development is related to the schedule of dose delivery. Following single-dose, radiosurgical treatments, an edema zone develops within the liver tissue exposed to lower median threshold doses of 13.7 Gy.28

 
Wulf et al. from the University of Wuerzburg, Germany, reported treatment parameters and outcomes for 24 hepatic lesions.23 A solitary cholangiocarcinoma and 22 liver metastases were treated in three radiation fractions of 10 Gy to total doses of 30 Gy (representing the minimal dose to the target volume). One patient with a lesion close to the esophagus was treated in four fractions of 7 Gy to a total dose of 28 Gy. Treatment fractions were delivered in 2- to 4-day intervals. Local control was achieved in 20/24 (83%) lesions during follow-up (median 9 months; range, 2–28 months). Actuarial tumor control at 12 and 24 months was 76% and 61%, respectively. At the time of evaluation, an overall survival of 63% was observed (actuarial estimate 71% and 43% overall survival at 12 and 24 months, respectively). Treatment related toxicity was limited to World Health Organization grade 1/2 toxicity (acute: fever, nausea, chills) with one case of delayed hepatitis and one case of symptomatic pneumonitis.

ONGOING INVESTIGATIONS

The role of SBRT is currently explored in a number of single institutional phase I/II trials. Institution specific dosing, treatment technique, and preliminary outcomes have been made available in abstract form or are currently under peer-review for future publication.

Investigators at the University of Colorado treated 14 patients with malignant liver lesions.29 The predominance of lesions (15/16 lesions) was metastatic. Total treatment doses ranged from 21 Gy to 30 Gy to the perimeter of the target volume in three fractions. At a median and maximum follow-up of 10 and 25 months, respectively, 8/15 (53%) assessable lesions showed local tumor progression. The median progression free interval in those patients was 11.7 months.

Preliminary outcomes of 11 patients treated by three fractions of 5 Gy to 12.5 Gy at the Technical University of Munich, Munich, Germany,30 indicate that total doses lower than 30 Gy yield the risk for early treatment failure with documented failure of 3/4 (75%) lesions treated below this dose level. When doses higher than 30 Gy were prescribed, local control at a maximum follow-up of approximately 1 year was 100% (7/7 locally controlled).

At The University of Texas Health Science Center at San Antonio, 15 patients with 18 hepatic lesions were treated by intensity-modulated SBRT. The lesions were predominantly metastatic (17/18 lesions), with one small hepatocellular carcinoma treated. Prescribed total minimal radiation doses were 36 Gy, delivered in three fractions of 12 Gy (n = 14) for lesions with median volumes of 56 cm3 (range, 1.25–124 cm3) and in six fractions of 6 Gy for larger lesions (n = 4; median volume 490 cm3; range, 280–807 cm3). Local control at a median and maximum imaging follow-up of 6.5 and 12.5 months was 94%. Overall survival during the follow-up period was 80%. Cause of death was progression of extrahepatic disease (n = 2) and local progression of hepatic disease (n = 1). This group also investigates the value of ultrasound-based image-guided targeting for lesion localization on the linear accelerator treatment table. Using an approach developed for conventionally fractionated radiotherapy of upper abdominal malignancies,31,32 outlines of the target(s) and so-called guidance structures (hepatic outline, branches of portal vein and hepatic veins) are superimposed onto real-time acquired ultrasound images using a dedicated ultrasound targeting device. This system allows for virtual shifts of the superimposed organ structures until a best match between ultrasound anatomy and CT planning study-derived organ outlines is achieved (Fig. 5). Subsequently, the system indicates correctional translations along the principal room axes to correct for potential misalignments.



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  		FIG. 5. Ultrasound-based image-guided targeting of a solitary colorectal liver metastasis (see Fig. 2 for the corresponding organ outlines and computed dose distribution). The organ and target outlines derived from the treatment planning computed tomography study are superimposed onto real-time acquire ultrasound images of the region of interest in treatment position (here lower right liver lobe). Correctional measures allow for an adjustment of patient and target position relative to the radiation beam geometry. While the lesion may be difficult to appreciate in the present ultrasound images, liver and kidney outline provide for the necessary guidance to optimize target setup for treatment delivery.

 
At the University of Iowa, 20 hepatic tumors were treated by SBRT with 9 primary liver tumors (8 hepatocellular carcinoma, 1 neuroendocrine tumor) and 11 metastatic lesions. Fourteen hepatic lesions were treated radiosurgically with median doses of 20 Gy to the perimeter of the target volumes. Large hepatic lesions (n = 6) were treated in a hypofractionated regimen in two to four fractions of 6 Gy to 12.5 Gy. Acute toxicity was observed to be minimal with three cases of nausea. During the available preliminary imaging follow-up, the majority of lesions had documented stable disease or volume reduction (J. Buatti, personal communication September 2003).

The probably largest series of hepatocellular carcinomas treated in 3 to 12 fractions (median 5 fractions) of 4 Gy to 9 Gy (median 6 Gy), to median total doses of 30 Gy, included 52 patients with 62 hepatic lesions at Staten Island University Hospital.33 At a maximum follow-up of 31 months, the local control rate in 25 patients with 34 lesions for whom imaging follow-up was available was 94%. The median survival following stereotactic radiation therapy in all 52 patients was 6.4 months. Of note, this series differs from other reported series in this review by the relatively reduced single doses and higher number of fractions in a subset of patients. Applying a stricter request for doses and dose scheduling covered by the term SBRT, a number of patients treated in this series potentially would not be included under this treatment paradigm.

CLINICAL TRIALS

Currently, three prospective clinical trials are attempting to determine the optimal radiation dose and dose scheduling for SBRT of liver lesions.

An active multicenter phase III randomized trial, initiated by investigators from the Universities of Heidelberg and Wuerzburg, Germany, researches the question of dose scheduling in the treatment of liver metastases. Two one-to-one randomized arms compare a single dose of 28 Gy to the isocenter (22.4 Gy minimum dose to the lesion) with a hypofractionated approach delivering three fractions of 12.5 Gy as the minimum dose to the target volume for a total dose of 37.5 Gy. The primary end point is local tumor control, with recurrence-free survival, treatment related toxicity, and quality of life being secondary end points. The study aims to accrue 276 patients in 5 years. Eligibility criteria stipulate a maximum number of three liver metastases with a maximum diameter of 5 cm each. Patients must be declared inoperable by a multidisciplinary conference or refuse surgical resection to qualify for randomization.

In the United States, two phase I/II multicenter dose escalation trials aim to define the optimal dose and the maximally tolerated dose for hypofractionated treatment of hepatocellular carcinoma (PI H. Cardenes, Indiana University) and liver metastases (PI T. Schefter, University of Colorado). Both protocols have a similar study design and investigate the tumor entities separately, secondary to the perceived increased risk of treatment-related toxicity in patients with primary liver malignancies. Dosing started at three fractions of 12 Gy (total minimal target dose 36 Gy in 5 to 10 days) and dose escalation will be performed in steps of 2 Gy per fraction (6 Gy total dose) up to a total dose of 60 Gy. Objectives of both studies are identification of the maximally tolerated dose by determining the dose limiting toxicity. Secondary end points are the 6-month in-field tumor response and failure rate, as well as disease-free survival and overall survival. A maximum of 15 patients will be enrolled in the phase I portion of each trial (a minimum of three at each dose level), and an additional 13 to 35 patients will be enrolled in the phase II portion of the studies.

SUMMARY

During the last decade, SBRT has been investigated as a focal noninvasive radiation treatment modality for a limited number of localized malignant lesions in the lung and liver. While the clinical experience in the treatment of primary and secondary lung tumors by far exceeds the available clinical experience in use of this modality for liver lesions, growing evidence and positive preliminary outcomes suggest a role for this new treatment concept in the multidisciplinary management of localized malignant liver disease.

Until today, localized stereotactic radiation treatment of primary and secondary hepatic malignancies has been predominantly applied in patients considered unresectable for medical or surgical reasons. SBRT has been documented to provide a noninvasive treatment alternative in malignant liver lesions when established curative treatment modalities cannot be applied. Current experience supports the perceived curative potential of this new modality for ablative treatment of up to three lesions in the liver with diameters ideally not exceeding 5 to 6 cm. Preliminary clinically observed outcomes suggest that the efficacy of SBRT is radiation dose dependent, with minimum single doses of 20 Gy or hypofractionated total doses of 30 Gy and higher resulting in 12 months local control rates of at least 75%. Primary liver malignancies such as hepatocellular carcinoma and cholangiocarcinoma respond as favorably to these treatments as metastatic lesion within the liver. In the presence of local tumor control, overall survival depends predominantly on the prevalence of extrahepatic metastatic disease or progression of untreated intrahepatic lesions. However, it needs to be acknowledged that quite favorable overall survival rates reported in early trail experiences might be associated with selective patient inclusion criteria.

As of today the role of SBRT as a first line curative treatment modality remains unclear. Despite the favorable toxicity profile associated with these treatments and the excellent achieved local control rates in single center experiences, testing this new modality in curative intent against surgical resection or other forms of local ablative therapy may be preemptive at present. Even testing the role of the modality in combination with chemotherapy versus the standard treatment of chemotherapy alone for unresectable colorectal liver metastases in a controlled clinical trial, as is currently tested for the role of radiofrequency ablation in Europe, may still be premature. Before embarking on such advanced and important trials, it seems prudent to await the results of active prospective multicenter trials assessing the role of single-dose or hypofractionated treatment delivery and definitive assessment of the maximally tolerated dose in three-fraction hypofractionated regimens. Similarly, the feasibility to transfer this technically demanding radiation treatment modality into more community-oriented settings, as has successfully occurred with radiofrequency ablation and cryoablation, remains to be determined. While today this treatment modality is primarily implemented and refined in academic centers, several stand-alone or community hospital based radiation oncology practices have acquired the technology and expertise to substantively increase the number of centers capable to provide such advanced radiation therapies.

In the multidisciplinary management of primary and secondary malignant tumors of the liver, SBRT adds to the arsenal of available treatment modalities. Its unique noninvasive capabilities to achieve high local control rates may benefit a significant number of patients in the near future.

FOOTNOTES

Review of stereotactic body radiotherapy for the treatment of primary and secondary malignant liver tumors. Presentation of peer-reviewed data, recent clinical developments along with discussions of current ongoing and planned multicenter studies.

Received for publication October 8, 2003. Accepted for publication November 19, 2003.

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L. A. Dawson
Radiation Therapy for Liver Metastases
ASCO Educational Book, January 1, 2008; 2008(1): 161 - 164.
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