Stereotactic Radiosurgery for Liver Lesions

Abstract

Oligometastases of solid tumors to the liver might lead to severe functional affections and, in some cases, to fatal organ failure in patients (f/m) with liver lesions.

Invasive surgical procedures like partial hepatectomy performed seem to be the historic “standard.” Any “standard” has to prove its superiority in terms of safety and effectiveness for patients (f/m), and it is true in the frame of cost efficiency too.

Image-guided stereotactic radiosurgery with its multiple labels like stereotactic ablative radiotherapy (SABR) or stereotactic body radiotherapy (SBRT) could affect liver lesions by deactivating tumor cells. They are responsive to high-dose radiotherapy. Metastases, limited by volume, number, and occurrence site, react to radiation by stopping their growth. The aim would be the deactivation of lesions or, at least, to prolong the time free of hepatic symptoms and, therefore, to have a better quality of life.

Consecutively, it demonstrates a noninvasive high-precision and safe technique in treating patients (f/m).

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Background

The liver is frequently the first site for metastasizing cancers because of its function as a filter in the portal blood circulation system. This statement is particularly true for gastrointestinal neoplasms. In addition, metastases of several cancer types with primary sites in other organs (i.e., beyond gastrointestinal neoplasms) exhibit a natural trajectory that includes development in the hepatic parenchyma.

Primary cancers of the liver, gallbladder, and bile duct are rare; although for decades, the “standard” approach was surgery and despite the hegemony of invasive mechanistic medicine, emerging valid, high-quality data demonstrate the use of stereotactic radiosurgery (SRS) for these cancers.

In this chapter, we will focus on different SRS methods used to treat cancers with oligometastases to the liver.

Historical Context

Since the 1980s, many research groups have obtained results indicative of improved clinical outcomes in patients (f/m).

As historically presupposed, the initial valuable efforts, which were undertaken between 1980 and 2000, were branded as pragmatic methods of execution by more experimental investigations. In a typically very slow manner, investigators’ thoughts became engrossed with the notion of a systematic approach to the issue of the treatment of hepatic metastases. This transformation in scientific thinking was accompanied by fundamental changes in the features and widespread availability of imaging technologies. Computed tomography (CT) scanning became available outside of large university medical centers in the mid-1990s, followed by the availability of magnetic resonance imaging (MRI) for broad clinical usage in midsize medical centers. This progression was also true for ultrasound technology, although it occurred for different market-driven reasons. The rapid dynamics of imaging technologies had profoundly practical technological and conceptual implications on conventional surgery, minimally invasive surgery, and radiosurgery. In addition, array of so-called interventional radiology procedures was made available specifically for liver metastases.

Historically, the conventional “standard” of care for patients (f/m) with cancer and liver oligometastases has involved surgical resection techniques such as hemihepatectomy (right, left) and extended hemihepatectomy (right, left). Subsequent sophisticated techniques, such as segmentectomy or wedge resection, completed the invasive surgical arsenal. In the early 1980s, Wagner and colleagues reflected on the options and likelihood of treating colorectal cancers with a limited number and volume of metastases to the liver, which is a very frequently encountered clinical scenario [1]. These authors stated that the 5-year overall survival rate after the resection of hepatic metastases from colorectal cancer “is 25 %. Although resection palliates some patients who do not live that long, 50 % of patients so treated are not helped at all. Until ignorance of a cancer’s real stage is resolved by improved techniques, the evaluation and choice of therapy can be based only upon knowledge of the natural history of untreated metastases and determinants of prognosis derived from treated patients. Analysis of the survival rates of 252 patients who had biopsy proven, unresected hepatic metastases that were the only evidence of residual disease shows the extent to which natural history, rather than resection, may determine length of survival– and indicates the need for critical analysis of 2- and 3-year survival rates reported after any therapy. Study of 141 patients who had hepatic metastases resected shows that the stage of the primary lesion, being female, and the absence of extra-hepatic metastases are significant determinants of favorable prognosis after resection of hepatic metastases” [1]. At that time, the efforts of Dr. Wagner and colleagues comprised an avant-garde investigation [2]. The source outcome data for their analysis included archived information recorded from 1948 to 1982. The authors commented, “the overall 5-year survival rate was 25 %, significantly higher than that of a group of historical controls who had resectable metastases that were not removed. The size and nature of our extended sample allowed identification of some determinants of favorable prognosis: Dukes’ stage of the primary lesion, absence of extra-hepatic metastases, and being female. Contrary to our earlier observations, this study justified removal of some multiple hepatic metastases” [2]. Interestingly, the term “multiple,” which refers to the tumor burden, was not the focus of the attention in that paper.

At that time, the natural history of untreated metastatic colorectal cancer was considered the natural state against which the effectiveness of any new treatment method should be measured. Accordingly, surgery was found to yield better results [1, 2].

As we observed in the 1990s and beyond, the invasive surgical arsenal comprised the first therapeutic “standard” for hepatic metastases from colorectal cancer [3]. At the end of the 1990s, Fong and colleagues published one of the largest research series to date, in which they addressed the question of prognosis in 1001 such cases [4].

Clearly defined and widely applicable clinical criteria for the selection of patients who may benefit from hepatic resection for metastatic colorectal cancer are needed. Such criteria would also be useful for the stratification of patients in clinical trials for this disease. Fong and colleagues evaluated clinical, pathologic, and outcome data in consecutive patients undergoing liver resection for metastatic colorectal cancer between July 1985 and October 1998. In that study, the resections included 237 tri-segmentectomies, 394 lobectomies, and 370 resections encompassing less than one lobe. The surgical mortality rate was 2.8 %. The 5- and 10-year survival rates were 37 % and 22 %, respectively. In that study, seven factors were found to be significant and independent predictors of poor long-term outcomes in a multivariate analysis: positive margin (p = 0.004), extrahepatic disease (p = 0.003), node-positive primary disease (p = 0.02), disease-free interval from primary to metastases <12 months (p = 0.03), >1 hepatic tumor (p = 0.0004), largest hepatic tumor >5 cm (p = 0.01), and carcinoembryonic antigen level >200 ng/ml (p = 0.01). When the last five of these criteria were used in a preoperative scoring system (each criterion = 1 point), the total score was highly predictive of the outcome (p < 0.0001). No patient with a score of 5 was a long-term survivor. The resection of hepatic metastases of colorectal cancer might yield long-term survival and could thus be considered curative. The long-term outcomes of all patients considered for resection can thus be predicted using five readily available criteria [4].

For the past two decades, surgery has been considered the “standard” treatment. Although the prognostic factors mentioned above have since been frequently confirmed, these criteria have not comprised a constitutive factor in the decision-making processes of surgical departments worldwide.

The extent of the invasive surgical arsenal widened further in response to pragmatism, positivism, and progressivism, despite the lack of a solid foundational epistemic concept.

Sixteen years later, in a very recent “meta-analysis” of retrospective reports, Petrelli and colleagues examined the role of prognostic factors after the complete resection of liver metastases in patients (f/m) with colorectal cancer [5]. The aim of that study was to identify risk factors related to overall survival (OS) after the complete resection of liver metastases. Twenty-four publications, with a total of 4855 patients, were eligible. Through multivariate analyses, a disease-free interval <12 months (hazard ratio [HR] = 1.47, p = 0.0002), size of the largest metastasis (HR = 1.56, p < 0.0001), total number of metastases (HR = 1.73, p < 0.00001), primary tumor with a node-positive status (HR = 1.56, p = 0.002), rectal primary tumor (HR = 1.48, p < 0.00001), high carcinoembryonic antigen level (HR = 1.49, p = 0.02), high tumor grade (HR = 2.42, p < 0.00001), and extrahepatic disease (HR = 2.03, p < 0.00001) were associated with an increased risk of death after complete resection of liver metastases from colorectal cancer. The most interesting comment in that review was that “in particular burden of liver and extra-hepatic metastases and grade are those associated with a higher risk of death” [5].

Current Concepts of Noninvasive Image-Guided Stereotactic Radiosurgery for Metastatic Liver Lesion

For more than two decades, maximally invasive and minimally invasive surgeries have been the new “standards” against which the safety and effectiveness of any new treatment method should be measured.

We focus here on the role of image-guided SRS for the treatment of cancers with oligometastases to the liver.

The first report on the use of radiation for liver lesions was published in 1954 by Phillips and colleagues [6]. This was considered an archaic period of radiotherapy.

The first contemporary and clinically relevant paper was published in 2000 by Herfarth and colleagues of the Heidelberg group [7]. That well-designed clinical protocol represented the starting point for a new field of liver lesion treatment in terms of the use of noninvasive, highly precise image-guided SRS.

A high accuracy of repositioning and reduction in target movement were constructed for this technique. The accuracy of setup was evaluated in patients with liver metastases who were treated with single-dose radiation. A total of 24 patients (f/m) were treated using a self-developed stereotactic frame. Liver movement was reduced using abdominal pressure. The effectiveness was evaluated via fluoroscopy. CT scans were performed on the planning day and directly before treatment. Representative reference marks were selected, and the coordinates were calculated. In addition, target displacement was quantitatively evaluated after treatment. Diaphragmatic movement was reduced to a median of 7 mm (range, 3–13 mm). The final body setup accuracy limited a median of 1.8 mm in the latero-lateral direction (range, 0.3–5.0 mm) and 2.0 mm in the anteroposterior direction (range, 0.8–3.8 mm). Deviations of the body in the cranio-caudal direction were always less than the thickness of one CT slice (<5 mm). However, repositioning was necessary in 16 cases. The final target shift was a median of 1.6 mm (range, 0.2–7.0 mm) in the latero-lateral and 2.3 mm (range, 0.0–6.3 mm) in the anteroposterior direction. The median shift in the cranio-caudal direction was 4.4 mm (range, 0.0–10.0 mm). The authors concluded that in patients (f/m) “with liver metastases, a high set-up accuracy of the body and the target can be achieved. This allows a high-dose focal radiotherapy of these lesions. However, a control CT scan should be performed directly before therapy to confirm set-up accuracy and possibly prompt necessary corrections” [7]. An outcome update was reported 4 years later [8].

Availability and Quality of the Scientific Evidence

A sufficient number of available publications describe the use of image-guided SRS for patients with liver oligometastases. These publications could be used to ensure a fair, patient-centered, and objectively differential approach to the recommendation and discussion of innovative treatment options that are safe, noninvasive, and effective and that lie beyond the traditional “standard” surgical method. This does not mean that the patient’s preferences should be influenced, but rather that the patient should be encouraged to provide informed consent based on the best available data from recent years.

The following text describes the degrees of validity and quality of the available data for the initial, postoperative, or hybrid usage of SRS in question and answer format.

Are plausible and valid data available at the “level of evidence 1a” with particular regard to the use of SRS for liver oligometastases?

No, there are no data in the context of a proper and fully published meta-analysis of prospectively designed controlled randomized trials (CRTs).

Are plausible and valid data available at the “level of evidence 1b” with particular regard to the use of SRS for liver oligometastases?

No, there are no data not in the context of proper and fully published controlled randomized trials with prospective designs.

Are plausible and valid data available at the “level of evidence 2a” with particular regard to the use of SRS for liver oligometastases?

Yes, there are data available that demonstrate the feasibility, safety, and effectiveness of noninvasive image-guided stereotactic radiosurgery for metastatic liver lesions.

In 2011, Chang and colleagues published the first systematic review of mostly prospective cohort studies. Patients (f/m) with liver oligometastases of colorectal cancer at three institutions were included if they had 1–4 lesions, had received 1–6 fractions of image-guided SRS (designated stereotactic body radiation therapy [SBRT]), and had undergone radiologic imaging ≥3 months posttreatment. Sixty-five patients with 102 lesions were treated. A tumor control probability model was used to estimate the 3-fraction dose required for >90 % local control after converting the schedule into biologically equivalent doses, single-fraction equivalent doses, or linear quadratic model-based single-fraction doses. Forty-seven (72 %) patients had been treated with ≥1 chemotherapy regimen before SBRT, and 27 (42 %) had been treated with ≥2 regimens. The median follow-up duration was 1.2 years (range, 0.3–5.2 years). The median radiation dose was 42 Gy (range, 22–60 Gy). When evaluated separately in a multivariate analysis, the total dose (p = 0.0015), dose/fraction (p = 0.003), and biologically equivalent dose (p = 0.004) all correlated with local lesion control. In the multivariate analysis, non-active extrahepatic disease was associated with overall survival (OS; p = 0.046) and closely correlated with sustained local control (p = 0.06). By using a single-fraction equivalent dose, biologically equivalent dose, or linear quadratic model-based single-fraction dose in the tumor control probability model, the estimated dose range needed to achieve a 1-year local control rate >90 % was 46–52 Gy in 3 fractions. This regimen appeared well tolerated and effective for liver metastases of colorectal cancer [9].

Scorsetti and colleagues summarized the evidence available in 2014 [10] after assuming that “approximately 70–90 % of liver metastases, however, are unresectable and an effective and safe alternative therapeutic option is necessary” for these patients (f/m). These authors reviewed image-guided SRS data of oligometastatic patients (f/m) and found promising results that were attributed to the ability of this procedure to deliver a conformal high radiation dose to the target lesion and a minimal dose to surrounding critical tissues [10]. Subsequent reviews confirmed those statements [11].

In 2014, the German Society for Radiation Oncology (German acronym, DEGRO) summarized data in order to develop a guideline for clinical practice [12]. Recommendations were developed for patient selection, imaging, planning, treatment delivery, motion management, dose reporting, and follow-up. Radiation dose constraints to the critical organs at risk were provided. The authors concluded that image-guided SRS “is a well-established treatment option for primary and secondary liver tumors associated with low morbidity” [12].

Are plausible and valid data available at the “level of evidence 2b” with particular regard to the use of SRS for liver oligometastases?

Yes, there are data available that demonstrate the feasibility, safety, and effectiveness of noninvasive image-guided stereotactic radiosurgery for metastatic liver lesions.

In 2005, Schefter and colleagues reported a phase I study [13]. Phase I studies attempt to determine the maximum tolerated dose of the given interventional method, in this case image-guided SRS (SBRT). Patients (f/m) with 1–3 liver metastases, a tumor diameter <6 cm, and adequate liver function were included. The first cohort received 36 Gy to the planning target volume (PTV) in 3 fractions. Subsequent cohorts received higher doses up to a set maximum of 60 Gy/3 fractions. At least 700 mL of the normal liver volume was required to receive a total dose <15 Gy. Dose-limiting toxicities included acute grade 3 liver or intestinal toxicities and any acute grade 4 toxicity. The maximum tolerated dose was considered to have been exceeded if two of six patients in a cohort experienced a dose-limiting toxicity. Eighteen patients were enrolled (ten men, eight women) with a median age of 55 years (range, 26–83 years). The most common primary tumor site was colorectal (6 patients), and the median aggregate gross tumor volume was 18 ml (range, 3–98 ml). Four patients had multiple tumors. No patient experienced a dose-limiting toxicity, and the dose was escalated to 60 Gy/3 fractions without reaching the maximum tolerated dose. The conclusion was that a biologically effective dose was well tolerated in patients with oligometastases to the liver [13].

In 2006, Wulf and colleagues reported on their experiences [14]. A total of 51 hepatic metastases were treated using image-guided SRS. Twenty-eight targets in a “low-dose” group were treated with three 10-Gy fractions (n = 27) or four 7-Gy fractions (n = 1) prescribed to the planned target volume enclosed within the 65 % isodose line. Patients in a “high-dose” group were treated with three 12–12.5-Gy fractions (n = 19; same dose prescription) or one 26-Gy fraction to the planned target volume enclosed within the 80 % isodose line (n = 9). The median follow-up duration was 15 months. Among 51 metastases, nine local failures (range to incidence, 3–19 months) were observed, resulting in actuarial local control rates of 92 % at 12 months and 66 % at ≥24 months. A borderline significant correlation between dose and local control was observed (p = 0.077); the actuarial local control rates at 12 and 24 months was 86 % and 58 % in the low-dose group versus 100 % and 82 % in the high-dose group. In a multivariate analysis, a high versus low dose was the only significant factor predictive of local control (p = 0.0089). The conclusion was that “patient selection is important, because those with low risk for systemic progression are more likely to benefit from this approach” [14]. The records of 69 patients who were treated for 174 metastatic liver lesions were reviewed. The most common primary tumors were colorectal (n = 20), breast (n = 16), pancreas (n = 9), and lung (n = 5). The mean number of lesions treated per patient was 2.5 (range, 1–6). The longest lesion diameters ranged from 0.6 to 12.2 cm (median, 2.7 cm). The dose per fraction ranged from 2 to 6 Gy, with a median total dose of 48 Gy (range, 30–55 Gy). The median follow-up duration was 14.5 months. Sixty patients were evaluable for response, based on abdominal CT scans obtained at a minimum of 3 months after treatment completion. The actuarial overall in-field local control rates of the irradiated lesions were 76 % and 57 % at 10 and 20 months, respectively. The median overall survival duration was 14.5 months. The progression-free survival rates were 46 % and 24 % at 6 and 12 months, respectively. None of the patients developed grade 3 or higher toxicities [15].

Image-guided SRS via CyberKnife was introduced in some publications. In 2009, Ambrosino and colleagues reported the local control of unresectable liver metastases from colorectal and non-colorectal cancer [16]. A total of 27 patients (median age, 62 years; range, 47–80 years) were enrolled in the study. The diagnoses were liver metastasis of colorectal cancer in 11 patients (41 %), and other secondary malignancies in 16 (59 %) patients. The patients were treated with 25–60 Gy (median, 36 Gy) delivered in 3 consecutive fractions, and the isodose value covering the planning target volume was 80 % of the prescribed dose. Overall, the mean tumor volume was 81.6 ± 35.9 ml. Growth inhibition or size reduction was achieved in 20 (74.1 %) patients: seven with a complete response and 13 with a partial response. Three patients (11.1 %) achieved local complete responses in other single lesions, whereas four (14.8 %) exhibited disease progression. The median posttreatment tumor volume was 24 ml (range, 0–54 ml) among the responders. Mild or moderate transient hepatic dysfunction was detected in nine patients, and five patients developed minor complications. Two patients with progressive disease died of liver failure. In conclusion, “in patients with liver metastases, stereotactic radiosurgery achieves high rates of local disease control, representing an acceptable alternative therapy, but should be further studied in larger series” [16].

In 2009, Lee and colleagues published another phase I study [17]. Individualized radiation doses were selected to maintain the same nominal risk of radiation-induced liver disease at three estimated risk levels (5, 10, and 20 %). Additional patients in an expanded cohort were treated at the maximal study dose. The median dose was 41.8 Gy (range, 27.7–60 Gy) in 6 fractions over 2 weeks. Sixty-eight patients with inoperable metastases of colorectal (n = 40), breast (n = 12), or other cancers (n = 16) were treated. The median tumor volume was 75.2 mL (range, 1.19–3,090 mL). The highest investigated radiation-induced liver disease risk level was safe, with no dose-limiting toxicities. Two grade 3 liver enzyme changes occurred, but no radiation-induced liver disease or other grade 3–5 liver toxicities was seen among patients with a low estimated risk of serious liver toxicity (95 % confidence interval [CI], 0–5.3 %). Six (9 %) patients developed acute grade 3 toxicities (gastritis, two; nausea, two; lethargy and thrombocytopenia, one each), and one patient (1 %) developed a grade 4 toxicity (thrombocytopenia). The 1-year local control rate was 71 % (95 CI, 58–85 %). The median overall survival duration was 17.6 months (95 % CI, 10.4–38.1 months). Image-guided SRS appeared to be safe and was accompanied by sustained local control in the majority of patients (f/m) [17].

Experiences with a Dutch study were published by Rusthoven and colleagues in 2009 [18]. In that multi-institutional phase I/II study, patients (f/m) with 1–3 hepatic lesions and maximum individual tumor diameters <6 cm were enrolled and treated with 3 fractions of image-guided SRS (SBRT). During phase I, the total dose was safely escalated from 36 to 60 Gy. The phase II dose was 60 Gy. The primary endpoint was local control. Lesions with >6 months of radiographic follow-up were considered assessable for local control. The secondary endpoints were toxicity and survival. A total of 47 patients (f/m) with 63 lesions were included. Among them, 69 % had received at least one prior systemic therapy regimen for metastatic disease (range, 0–5 regimens), and 45 % had extrahepatic disease at the time of study entry. Only one patient experienced a grade 3 or higher toxicity (2 %). Forty-nine discrete lesions were assessable for local control. The median follow-up duration of assessable lesions was 16 months (range, 6–54 months). The median maximal tumor diameter was 2.7 cm (range, 0.4–5.8 cm). Local progression occurred in only three lesions at a median of 7.5 months (range, 7–13 months). The actuarial in-field local control rates at 1 and 2 years after SBRT were 95 % and 92 %, respectively. Among lesions with maximal diameter of ≤3 cm, the 2-year local control rate was 100 %. The median survival duration was 20.5 months. According to the authors, this multi-institutional phase I/II trial demonstrated “that high-dose liver SBRT is safe and effective for the treatment of patients with one to three hepatic metastases” [18].

In 2011, Rule and colleagues reported findings from a phase I dose escalation study [19]

Patients (f/m) with 1–5 hepatic metastases, a Karnofsky Performance Scale score of ≥60, the ability to spare a critical hepatic volume (volume receiving <21 Gy) of 700 mL, and adequate baseline hepatic function were enrolled into three dose escalation cohorts: 30 Gy in 3 fractions, 50 Gy in 5 fractions, and 60 Gy in 5 fractions. Dose-limiting toxicities included treatment-related grade 3 gastrointestinal, hepatobiliary/pancreatic, and metabolic/laboratory toxicities. Any grade 4 or 5 event attributable to therapy was defined as a dose-limiting toxicity. The local control and complete plus partial response rates were assessed. Twenty-seven patients with 37 lesions were enrolled (9 per cohort) and treated; the patients included 17 men and 11 women with a median age of 62 years (range, 48–86 years). The most common site of primary disease was colorectal (44.4 %). The median follow-up duration was 20 months (range, 4–53 months). There were no grade 4 or 5 toxicity or treatment-related grade 3 toxicity events. The actuarial 24-month local control rates for the 30-, 50-, and 60-Gy cohorts were 56 %, 89 %, and 100 %, respectively. There was a statistically significant difference in local control between the 60- and 30-Gy cohorts (p = 0.009), but not between the 60- and 50-Gy cohorts (p = 0.56) or the 50- and 30-Gy cohorts (p = 0.091). The maximum tolerated dose was not reached. The authors concluded that a “dose of 60 Gy in 5 fractions can be safely delivered to selected patients with hepatic metastases as long as the critical liver volume is respected. A dose of 60 Gy in 5 fractions yields an excellent level of local control” [19].

A prospective phase II clinical trial was published by Scorsetti and colleagues [20]. In this trial, patients (f/m) with 1–3 liver metastases, a maximum individual tumor diameter <6 cm, and Karnofsky Performance Scale Score of ≥70 were enrolled and treated with SBRT. The dose prescription was 75 Gy on consecutive days. SBRT was delivered as volumetric modulated arc therapy via the RapidArc (Varian, Palo Alto, CA, USA) technique. The primary endpoint was in-field local control. The secondary endpoints were toxicity and survival. A total of 61 patients with 76 lesions were treated. Among these patients, 21 (34.3 %) had stable extrahepatic disease upon study entry. The most frequent primary sites were colorectal (45.9 %) and breast (18 %). Of the patients, 78.7 % had one lesion, 18.0 % had two lesions, and 3.3 % had three lesions. After a median of 12 months (range, 2–26 months), the in-field local response rate was 94 %. The median overall survival duration was 19 months, and the actuarial survival rate at 12 months was 83.5 %. None of the patients experienced grade 3 or higher acute toxicity events. No radiation-induced liver disease was detected. One patient experienced a late grade 3 toxicity event at 6 months due to chest wall pain. Image-guided SRS is “a therapeutic option, with excellent rates of local control and a low treatment-related toxicity” [20].

The research group later updated these data [21]. The updated median follow-up duration was 24 months (range, 4–47 months). In-field progression was observed in five lesions. The 24-month actuarial local control rate was 91 %. The median overall survival duration was 29.2 ± 3.7 months. The actuarial overall survival rate at 24 months was 65 %. The median progression-free survival duration was 12.0 ± 4.2 months, with a 24-month actuarial progression-free survival rate of 35 %. No patients experienced radiation-induced liver disease or grade 3 or higher toxicity. The authors concluded that image-guided SRS “represents a feasible alternative for the treatment of colorectal liver metastases not amenable to surgery or other ablative treatments in selected patients, showing optimal local control and promising survival rate” [21].

Another well-designed study was communicated in 2015 by Goodman and colleagues, who reported the long-term safety and efficacy of image-guided SRS for hepatic oligometastases [22]. Eligible patients had 1–3 liver metastases, a maximum summed diameter of 6 cm, and no extrahepatic progression. We treated 106 lesions in 81 patients, of whom 67 % had colorectal primaries. The median dose was 54 Gy in 3–5 fractions. At a median follow-up of 33 months (range, 2.5–70 months), the overall local control rate was 94 % (95 % CI, indeterminate); Kaplan–Meier survival estimates were 96 % at 1 year and 91 % at 2, 3, and 4 years. Partial or complete response was observed in 69 % of the lesions and less than 3 % exhibited progression. The median survival time was 33.6 months (95 % CI, 29.1–38.4), and the Kaplan–Meier survival estimates at 1, 2, 3, and 4 years were 89.9 %, 68.6 %, 44.0 %, and 28.0 %, respectively. The incidence of grade 3 or higher liver toxicity was 4.9 %. The authors stated that image-guided SRS is “effective for selected patients with hepatic oligometastases with limited toxicities” [22].

Summary

The past decade has seen a real increase in the understanding of image-guided SRS, as well as related publications and conference contributions.

For more than two decades, maximally invasive or minimally invasive surgery was the “standard” against which the safety and effectiveness of any new treatment method were measured.

If the above evidence is taken seriously, image-guided SRS appears to be a good, safe, and effective new method that is essentially noninvasive and cost-effective.

As it is embedded in a coherent, rational, and empirically reproducible oncologic concept, namely, the oligometastatic state concept initially proposed by Dr. Samuel Hellmann in 1995, followed by extensive discussion, proof, and dispute, image-guided SRS will introduce a new pathway in the complex dialectics of cure and palliation and may lead toward a chance of long-term control (and even cure) of cancers with limited metastases.

Radiosurgery for Hepatocellular Carcinoma

Background

Invasive surgical procedures or palliative chemotherapy has been the standard treatment for hepatocellular carcinoma [23]. The potential effects of image-guided stereotactic radiosurgery for these lesions have been investigated, and the implementation in the real-world scenarios remains controversial and difficult. The status of a noninvasive procedure seems to be complicated; even a significant number of patients (f/m) have declared as palliative without the attempt to execute image-guided stereotactic radiosurgery.

We, therefore, provide an overview on available data in this field, without an in-depth analysis.

Current Concepts of Noninvasive Image-Guided Stereotactic Radiosurgery for Hepatocellular Carcinoma

Availability and Quality of the Scientific Evidence

A certain number of available publications describe the use of image-guided SRS for patients with hepatocellular carcinoma. These publications could be used to ensure a fair, patient-centered, and objectively differential approach to the recommendation and discussion of innovative treatment options that are safe, noninvasive, and effective and that lie beyond the traditional “standard” surgical method. This does not mean that the patient’s preferences should be influenced, but rather that the patient should be encouraged to provide informed consent based on the best available data from recent years.

The following text describes the degrees of validity and quality of the available data for the initial, postoperative, or hybrid usage of SRS in question and answer format.

Do we have plausible and valid data on the “level of evidence 1a” in special regard to the usage of SRS for hepatocellular carcinoma?

No, when we think of a proper and fully published meta-analysis of controlled randomized trials (CRT) with prospective design.

Do we have plausible and valid data on the “level of evidence 1b” in special regard to the usage of SRS for hepatocellular carcinoma?

No, when we think of proper and fully published controlled randomized trials (CRT) with prospective design.

Do we have plausible and valid data on the “level of evidence 2a” in special regard to the usage of SRS for hepatocellular carcinoma?

No. There is no systematic review available to date.

There has been one review that included most relevant papers published in recent years; it was published in 2015 by Meng and colleagues [24].

Herein, they discuss the emerging role of image-guided stereotactic radiosurgery (here named SBRT) as well as current indications, implementation, efficacy, and toxicities after the treatment. It was noted that image-guided stereotactic was a safe and effective therapeutic option for hepatocellular carcinoma lesions unsuitable for standard locoregional therapies, with acceptable local control rates and low treatment-related toxicity. The significant correlation between local control and higher doses and between LC and overall survival supports the clinical value of SBRT in these patients (f/m) [24].

Do we have plausible and valid data on the “level of evidence 2b” in special regard to the usage of SRS for hepatocellular carcinoma?

Yes, there are data describing in a prospective setting the effectiveness and safety of image-guided stereotactic radiosurgery for this indication. In the following paragraphs, we merely review the last two years, in terms of demonstration of feasibility, safety, and effectiveness of image-guided stereotactic radiosurgery in this specific scenario, even to date, besides Japan, few centers perform high-volume radiosurgery for hepatocellular carcinoma.

Lasley and colleagues reported on 38 patients (f/m) in 2015 [23]. Median follow-up was 33.3 months (2.8–61.1 months) for Child A group and 46.3 months (3.7–70.4 months) for Child B patients. Local control at 6 months was 92 % for Child A group and 93 % for Child B group. Kaplan–Meier estimated 2- and 3-year local control was 91 % for Child A group and 82 % for Child B group (p = .61). Median overall survival was 44.8 months and 17.0 months for Child A group and Child B group. Estimated overall survival after 2- and 3-years was 72 % and 61 % for Child A group and 33 % and 26 % for Child B group (p = .03). Overall, Child A patients with ≥grade III liver toxicity had 4.59 (95 % confidence interval, 1.19–17.66) times greater risk of death than those without toxicity (p = .0268). No such correlation was seen for Child B patients; however, three of these Child B patients (f/m) underwent orthotopic liver transplant. Child B patients (f/m) experiencing grade III/IV liver toxicity had significantly higher mean liver dose, higher dose to one-third normal liver, and larger volumes of liver receiving doses <2.5 to 15 Gy in 2.5-Gy increments. For Child A patients, there was no critical liver dose or volume constraint correlated with toxicity [23].

Yamashita and colleagues published in 2015 their experiences [25]. A total of 79 patients (f/m) were treated. The median age was 73 years, 76 % were males, and their Child–Pugh scores were grades A (85 %) and B (11 %) before SBRT. The median biologically effective dose (alpha/beta = 10 Gy) was 96.3 Gy. The median follow-up time was 21.0 months for surviving patients. The 2-year overall survival, progression-free survival, and distant metastasis-free survival were 53 %, 40 %, and 76 %, respectively. Sex and serum PIVKA-II values were significant predictive factors for overall survival. Hypo- or hypervascular types, sex, and clinical stage were significant predictive factors for progression-free survival. The 2-year progression-free survival was 66 % in stage I versus 18 % in stages II–III. Multivariate analysis indicated that clinical stage was the only significant predictive factor for progression-free survival. No grade 3 toxicities in the acute, subacute, and chronic phases were observed. Progression-free survival after image-guided stereotactic radiosurgery for liver lesions was, here too, satisfactory, especially for stage I, even though these patients were unsuitable for resection and ablation. The authors concluded that image-guided stereotactic radiosurgery is safe and might be an alternative to resection and ablation [25].

The Florence team of Dr. Scorsetti and colleagues who had published an image-guided stereotactic radiosurgery for liver metastases did this hepatocellular carcinoma too [26]. Patients (f/m) with 1–3 inoperable lesions with diameter ≤6 cm were treated. According to lesions’ size and liver function, two prescription regimens were adopted: 48–75 Gy in three fractions and 36–60 Gy in six fractions. Image-guided stereotactic radiosurgery was delivered using the volumetric modulated arc therapy technique with flattening filter-free photon beams. The primary endpoints of this study were in-field local control and toxicity. Secondary endpoints were overall survival (OS) and progression-free survival. A total of 43 patients (f/m) with 63 lesions were treated. All patients had Child–Pugh class A or B disease. Thirty lesions (48 %) were treated with 48–75 Gy in three consecutive fractions, and 33 (52 %) received 36–60 Gy in six fractions. Median follow-up was 8 months (range, 3–43 months). Actuarial local control at 6, 12, and 24 months was 94.2 ± 3.3, 85.8 ± 5.5, and 64.4 ± 11.5 %, respectively. A biological equivalent dose (BED) >100 Gy and GTV size were significant prognostic factors for local control in univariate analysis (p < 0.001 and p < 0.02). Median overall survival was 18.0 ± 5.8 months. Actuarial overall survival at 6, 12, and 24 months was 91.1 ± 4.9, 77.9 ± 8.2, and 45.3 ± 14.0 %, respectively. Univariate analysis showed that OS is correlated with local control (p < 0.04), BED >100 (p < 0.05), and cumulative gross tumor volume GTV <5 cm (p < 0.04). Median progression-free survival was 8 months, with a 1-year progression-free survival rate of 41 %. A significant (≥ grade 3) toxicity was observed in seven patients (16 %) 2–6 months after the completion of the treatment. No classic radiation-induced liver disease was observed. The authors concluded that the noninvasive therapy is a safe and effective therapeutic option for lesions unsuitable to standard locoregional therapies, with acceptable local control rates and low treatment-related toxicity. The significant correlation between local control and higher doses and between local control and overall survival supports the clinical value of this treatment method [26].

Sanuki and colleagues reported with the special regard to toxicity of image-guided stereotactic radiosurgery in patients (f/m) with hepatocellular carcinoma in 2015 [27].

The study included 194 cases that were treated with image-guided stereotactic radiosurgery. Among them, patients followed up for more than 6 months were eligible. Laboratory results and Child–Pugh scores were obtained before treatment and at monthly follow-up visits. A total of 108 cases were evaluated with a median follow-up of 28.2 months. Fatal hepatic failure within 12 months occurred in eight patients (4 %). On univariate analysis, grade 3 or more elevated transaminases, Child–Pugh scores of 8 or more, and/or grade 3 or more decreased platelet count significantly predicted fatal hepatic failure within 12 months. Combinations of these factors (i.e., having at least one criterion) also predicted fatal hepatic failure within 12 months (16 % with criteria versus 1 % without criteria). Two-year overall survival rates for patients with and without radiation-induced liver disease was 64.9 % and 83.8 % (p < 0.001), respectively. The authors concluded that the identified three criteria that affected overall survival in patients (f/m) may help to promote a better selection in future prospective trials [27].

Kimura and colleagues communicated their experiences in 2015 [28]. Overall, 65 patients with 74 lesions (median tumor size, 16 mm) were enrolled. They were treated at the prescribed dose of 48 Gy in four fractions at the isocenter. Child–Turcotte–Pugh (CTP) scoring was used to classify 56 and nine patients into classes A and B, respectively. Local progression was defined as irradiated tumor growth on a dynamic computed tomography follow-up. The median follow-up period was 26 months. Tumor responses were assessed according to the modified Response Evaluation Criteria in Solid Tumors. Treatment-related toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. The 2-year overall survival, progression-free survival, and local control rates were 76.0 % (95 % confidence interval [CI], 65.4–86.7 %), 40.0 % (95 % CI, 27.6–52.3 %), and 100 % (95 % CI, 100 %), respectively. At 6–12 months after SBRT, grade 3 or higher toxicities were observed in 15 (23.1 %) patients. The incidence of grade 3 or higher toxicities was higher in CTP class B than in class A (p = 0.0127). The conclusion of the authors was that the method is “effective and relatively safe for patients with small hepatocellular carcinoma who were ineligible for resection or ablation therapies” [28].

Another team reported on image-guided stereotactic radiosurgery as an ablative treatment for inoperable hepatocellular carcinoma [29]. A total of 77 consecutive patients were treated for 97 liver-confined lesions. A total dose of 45 Gy in 3 fractions was prescribed to the 80 % isodose line. The median follow-up was 12 months. The median tumor diameter was 2.4 cm. The local control rate was 99 % at 1 and 2 years. The 1- and 2-year overall survival was 81.8 % and 56.6 %, respectively. The median time to progression was 9 months (0–38). The rate of hepatic toxicity was 7.7 % [1.6–13.7], 14.9 % [5.7–23.2], and 23.1 % [9.9–34.3] at 6 months, 1 year, and 2 years, respectively. In multivariate analysis, female gender (HR, 7.87 [3.14–19.69]), a Child B–C stage (HR, 3.71 [1.41–9.76]), a sum of all lesion diameters 2 cm (HR, 7.48 [2.09–26.83]), and a previous treatment (HR, 0.10 [0.01–0.79]) were independent prognostic factors of overall survival. The conclusion of the authors was that image-guided stereotactic radiosurgery (here named SBRT) leads to high local control rates for inoperable hepatocellular carcinomas and that “it should be considered when an ablative treatment is indicated in Child A patients” [29].

In a study in which patients (f/m) received image-guided stereotactic radiosurgery after incomplete transarterial chemoembolization, Zhong and colleagues reported on outcome data in 2014 [30]. A total of 72 patients with large hepatocellular carcinomas lesions were treated. The median total dose of 35.6 Gy was delivered over 12–14 days with a fractional dose of 2.6–3.0 Gy and 6 fractions per week. The patients were classified into those with tumor encapsulation (group A, n = 33) and those without tumor encapsulation (group B, n = 39). The clinical outcomes of tumor response, overall cumulative survival, and toxicities/complications were retrospectively analyzed. Among the 72 patients, complete remission was achieved in 6 (8.3 %) and partial remission in 51 (70.8 %), respectively, within a median follow-up of 18 months. The objective response rate was 79.1 %. The overall cumulative 1-, 3-, and 5-year survival rates and the median survival time were 38, 12, and 3 % and 12.2 months, respectively. In group A, the overall cumulative 1-, 3-, and 5-year survival rates were 56, 21, and 6 %, respectively, with a median survival of 19 months; in group B, the overall cumulative 1-, 3-, and 5-year survival rates were 23, 4, and 0 %, respectively, with a median survival of 10.8 months (p = 0.023). The treatment was well tolerated, with no severe radiation-induced liver disease and no reported > grade 3 toxicity. In conclusion, it “was shown to be a safe and effective treatment option for patients with unresectable huge hepatocellular carcinomas” [30].

A large study was recently published by Takeda and colleagues [31]. A total of 221 cases underwent image-guided stereotactic radiosurgery. Among them, patients (f/m) with untreated solitary lesions, treated only with this method preceded by transarterial chemoembolization, were eligible. Based on baseline liver function and liver volume receiving ≥20 Gy, 35–40 Gy in five fractions was prescribed to the planning target volume surface. Sixty-three patients were eligible, with a median follow-up duration of 31.1 (range, 12.0–88.1) months. No patients were lost to follow-up. Twenty patients were treated with only SABR. In 43 patients treated with SABR preceded by transarterial chemoembolization, accumulation of lipiodol in the lesion remained complete in five, a partial defect in 38 on pretreatment computed tomography. The 1-, 2-, and 3-year local control rates were 100 %, 95 %, and 92 %, respectively; the intrahepatic recurrence-free rates were 76 %, 55 %, and 36 %, respectively; and the overall survival rates were 100 %, 87 %, and 73 %, respectively. Grade 3 laboratory toxicities in the acute, subacute, and chronic phases were observed in 10, 9, and 13 patients, respectively, and ascites occurred in one patient. The author team concluded that “local control and overall survival… were excellent despite the candidates being unfit for resection and ablation [31]. The method “is safe and might be an alternative to resection and ablation” [31].

With focus on re-radiation, Lo and colleagues published a paper in 2014 [32].

A total of 14 patients (f/m) with local recurrence (18 lesions) after liver radiosurgery received repeated radiotherapy CyberKnife SRS. No patients experienced radiation-induced liver disease after the first treatment course. The median first dose was 41 Gy (range, 34–60 Gy); the median second dose, 40 Gy (range, 25–50 Gy); and the median interval, 12.9 months. Local recurrence was divided into in-field recurrence and outfield recurrence. Objective responses were observed in 11 tumors (61.1 %), including five tumors (27.8 %) with complete responses. Intrahepatic outfield failure was the main cause of treatment failure (7 of 14 patients). In-field failure had developed in 1 of 18 tumors (5.6 %), resulting in a 2-year in-field failure-free rate of 88.2 %. The median time to progression was 14.0 months, with 1- and 2-year progression-free survival rates of 68.6 % and 42.9 %, respectively. One- and 2-year overall survival rates were 76 % and 59.1 %, respectively. Of the 14 patients, one developed radiation-induced liver disease and three showed progression of the Child–Turcotte–Pugh class after the second SABR course. Other toxicities were generally mild and tolerable. Obviously, retreatment by using image-guided stereotactic radiosurgery again “is feasible with acceptable toxicity” [32].

Culleton and colleagues reported in 2014 on a prospective trial in patients (f/m) with Child–Pugh B or C hepatocellular carcinoma [33]. All patients (f/m) with Child–Pugh B7 or B8 unresectable lesions <10 cm were selected. A total of 29 patients with Child–Pugh B/C lesions were treated with a median dose 30 Gy in 6 fractions. The majority had Child–Pugh B7 liver function (69 %) and portal vein tumor thrombosis (76 %). The median survival was 7.9 months (95 % CI, 2.8–15.1). Survival was significantly better in patients with Child–Pugh = B7 and AFP less that 4491 ng/mL. Of 16 evaluable patients, 63 % had a decline in Child–Pugh score by ≥2 points at 3 months. They concluded that this method is a treatment option for patients (f/m) “with small hepatocellular carcinomas and modestly impaired liver function” [33].

Summary

In the past decade, there has been a real increase of publications, conference contributions, and understanding of image-guided stereotactic radiosurgery for liver lesions. Cancer with oligometastases to the liver could be controlled by radiosurgery in a safe and effective way. Increasing number of patients (f/m) in this condition will undergo stereotactic techniques because they are not operable. Data outcome will convince even skepticism.

This is not true for hepatocellular carcinoma; in spite of data showed above, the clinical routine in large- and middle-sized medical centers is not reflecting the available evidence of grade 2b and less.

Image-guided stereotactic radiosurgery, in case we take evidence showed above seriously, is demonstrating the safety and effectiveness of a good and new method that is essentially noninvasive and cost-effective.