Study
Inclusion
Number of patients
Type of metastasis
Total dose per fraction
Toxicity
Median follow-up (months)
Local control rate
Survival
Herfarth et al. (2001) [38]
1–3 lesions
37
Not reported
14–26 Gy/1
No significant toxicity reported
14.9 (mean)
18 mo: 67 %
1 yr.: 76 %
2 yr.: 55 %
Hoyer et al. (2006) [39]
1–6 lesions, largest ≤6 cm
44
CRC (44)
45 Gy/3
1 liver failure2 severe late GI
52
2 yr.: 86 %
1 yr.: 67 %
2 yr.: 38 %
Mendez-Romero et al. (2006) [40]
1–3 lesions, largest <7 cm
25
CRC (14), Lung (1), Breast (1), Carcinoid (1)
37.5 Gy/3
Acute grade ≥ 3: 4 casesLate grade 3: 1 case
12.9
2 yr.: 86 %
1 yr.: 85 %
2 yr.: 62 %
Rusthoven et al. (2009) [41]
1–3 lesions, largest <6 cm
47
CRC (15), lung (10), breast (4), ovarian (3), Esophageal (3), HCC (2), Other (10)
60 Gy/3
Late grade 3/4: <2 %
16
2 yr.: 92 %
<3 cm: 100 %
Median: 17.6 mo
Lee et al. (2009) [42]
No maximum number or size
68
CRC (40), breast (12), gallbladder (4), lung (2), anal (2), melanoma (2)
28–60 Gy/6
median 42 Gy
Acute grade 3: 8 casesGrade 4: 1 case (thrombocytopenia)
10.8
1 yr.: 71 %
18 mo: 47 %
Ambrosino et al. (2009) [43]
1–3 lesions, largest <6 cm
27
CRC (11), other (16)
25–60 Gy/3
median 36 Gy
No significant toxicity reported
13
74 %
Not reported
Goodman et al. (2010) [44]
1–5 lesions, largest <5 cm
26
CRC (6), pancreatic (3), gastric (2), ovarian (2), other (6)
18–30 Gy/1
Late grade 2: 4 cases (2 GI, 2 soft tissue/rib)
17.3
1 yr.: 77 %
1 yr.: 62 %
2 yr.: 49 %
Rule et al. (2011) [45]
1–5 lesions
27
CRC (12), carcinoid (3), melanoma (2), other (10)
30 Gy/3, 50 Gy/5, 60 Gy/5
No grade 2 or higher reported
20
30 Gy: 56 %
50 Gy: 89 %
60 Gy: 100 %
30 Gy: 56 % (2 yr)
50 Gy: 67 % (2 yr)
60 Gy: 50 % (2 yr)
Scorsetti et al. (2013) [46]
1–3 lesions
largest <6 cm
61
CRC (29), breast (11), gynecologic (7), other (14)
52.5–75 Gy/3
No grade 3 or higher reported
24
91 %
1 yr.: 80 %
2 yr.: 70 %
17.4.1 Single-Fraction Stereotactic Body Radiation Therapy
There was early interest in single-fraction treatment for liver SBRT, similar to the single-fraction approach used in stereotactic radiosurgery for the brain.
Herfarth and colleagues [38] from the University of Heidelberg were the first to report prospective outcomes of SBRT for liver metastases.
The study enrolled 37 patients, with 55 liver metastases treated with single-fraction SBRT at a dose of 14–26 Gy.
Local control at 18 months was reported to be 67 %. No significant toxicity was reported.
There was a statistically significant difference in local tumor control between tumors treated with 14–20 Gy vs. 22–26 Gy, though this may have been due to a learning phase as investigators had noted local control also improved in patients who were enrolled later in the study, as more proper margin expansions were performed; patients enrolled in later years had an actuarial local control rate of 81 % at 18 months [38, 48].
Goodman and colleagues [44] at Stanford University performed a phase I single-fraction dose-escalation study for primary and metastatic liver tumors.
Of the 26 patients included, 19 patients had hepatic metastases.
Total radiation dose was escalated from 18 to 30 Gy at 4-Gy increments.
At a median follow-up of 17 months, there were no dose-limiting toxicities reported. There were nine acute grade 1, one acute grade 2, and two late grade 2 gastrointestinal toxicities observed.
Local control at 1 year was 77 %. For liver metastases patients, the 1-year and 2-year overall survival rates were 62 % and 49 %, respectively.
Investigators concluded that single-fraction SBRT is feasible with promising local control rates and tolerable side effects from treatment.
17.4.2 Hypofractionated Stereotactic Body Radiation Therapy
While the results of single-fraction liver SBRT appeared promising, the potential toxicity of the ultrahigh dose radiotherapy in the abdomen lead many groups to evaluate the use of hypofractionated SBRT [39, 40].
Hoyer and colleagues [39] reported outcomes of 44 hepatic lesions treated with SBRT 45 Gy in three fractions, with a 2-year actuarial local control of 79 %.
One and 2-year overall survival was 67 % and 38 %, respectively.
Treatment-related toxicity included one patient who died of hepatic failure, one patient with colonic perforation requiring surgical management, and two patients with duodenal ulceration treated conservatively.
Méndez-Romero and colleagues [40], evaluated 34 liver metastases treated to 37.5 Gy in three fractions.
Two-year local control rate of 86 %.
One and 2-year overall survival was 85 % and 62 %, respectively.
Three grade 3 toxicities were documented among the patients with liver metastases.
Schefter (phase I) and Rusthoven (phase II) and colleagues at the University of Colorado prospectively evaluated patients with three of fewer liver metastases, measuring less than 6 cm [41, 49].
In the phase I portion of the trial which included 18 patients, the dose of SBRT was escalated from 36 Gy to 60 Gy in three fractions, and no dose-limiting toxicity was observed.
In the subsequent combined phase I/II multi-institutional trial, 47 patients with 63 liver metastases were enrolled and treated at seven participating institutions to 60 Gy in three fractions, 13 patients received <60 Gy, and 36 patients received 60 Gy [41]. Of patients with at least 6 months of radiographic follow-up after SBRT, only three in-field local failures among 47 lesions occurred. At 2 years, the actuarial local control of all SBRT-treated lesions was 92 %; among lesions <3 cm, the 2-year actuarial local control was 100 %. Two-year overall survival was 30 %. One patient experienced late grade 3 soft tissue breakdown. There were no reported grade 4–5 toxicities or RILD.
Lee and colleagues [42] from Princess Margaret Hospital also published their phase I trial of SBRT delivered in six fractions (median prescription dose of 41.8 Gy) in 68 patients with metastatic liver disease.
Individualized radiation doses were chosen based on normal tissue complication probability (NTCP)-calculated risk of RILD at three risk levels (5 %, 10 %, and 20 %).
Observed 1-year local control was 71 % and no dose-limiting toxicity was observed.
Two patients experience acute grade 3 liver enzyme changes, and six patients had additional acute grade 3 toxicities including gastritis (2), nausea (2), lethargy (1), and thrombocytopenia (1). There was one grade 4 thrombocytopenia reported.
Ambrosino and colleagues [43] prospectively evaluated 27 patients with liver metastases treated with 25–60 Gy (median 36 Gy) delivered in three fractions.
Mean tumor volume was 81.6 ± 35.9 ml.
At a median follow-up of 13 months, crude local control was 74 %.
Mild to moderate transient hepatic dysfunction was observed in nine patients, pleural effusions in two, and partial portal vein thrombosis, pulmonary embolism, and upper gastrointestinal tract bleed in one patient each.
Rule and colleagues [45] from the University of Texas Southwestern reported results from their phase I SBRT dose-escalation trial, with three dose groups, 30 Gy/3 fractions, 50 Gy/5 fractions, and 60 Gy /5 fractions.
At 2 years, local control was 56 %, 89 %, and 100 %, respectively. Two-year overall survival was 56 %, 67 %, and 50 %, accordingly.
Further, there appeared to be a significant dose-response relationship between 30 Gy and 60 Gy (p = 0.009).
There were no grade 4–5 toxicities and one grade 3 asymptomatic transaminitis occurring in the 50 Gy cohort.
Scorsetti and colleagues [46] reported findings from a phase II trial including 61 patients with 76 liver metastases treated to 25 Gy in three fractions.
At a median follow-up of 12 months, the overall local control rate was 95 %.
One and 2-year overall survival was 80 % and 70 %, respectively.
No reported events of RILD; one patient experienced late grade 3 chest wall pain.
17.4.3 Additional Studies
Chang and colleagues [50] performed a multi-institutional analysis reporting on prognostic factors following SBRT for colorectal liver metastases.
The study included 65 patients treated at three institutions. All patients had one to four lesions and received one to six fractions of SBRT to a median total dose of 42 Gy (range 22–60 Gy).
The median follow-up was 1.2 years. On multivariate analysis, total dose of radiation, dose per fraction, and the BED were significantly associated with local control.
Local disease control also appeared to be a borderline significant factor associated with improved overall survival under multivariate analysis (p=0.06), demonstrating the impact local ablative therapy can have on overall survival.
The study further examined the correlation between total radiation dose and local control in a tumor control probability (TCP) model. Results from the TCP curves demonstrated that a 1-year local control rate exceeding 90 % could be achieved when doses of 46–52 Gy in three fractions were delivered and concluding doses of 48 Gy or higher in three fractions should be offered if feasible.
Several studies have also evaluated the role of hypofractionation using more than five fractions.
Sato and colleagues [51] evaluated 18 patients with 23 primary or metastatic liver lesions treated to a total dose of 50–60 Gy in five to ten fractions. At 10-month follow-up, the crude local control rate was reported at 100 %. Toxicity included 5 % with grade 1–2 and 5 % with grade 3–4.
Wurm and colleagues [52] included three patients. Patients were treated to a total dose of 74.8–79.2 Gy in 8–11 fractions to three patients with four liver metastases; they also noted a local control rate of 100 % (unspecified follow-up time).
Katz and colleagues [53] published results of 174 metastatic liver lesions treated to a median total dose of 48 Gy (range, 30–55 Gy), delivered in 2–6-Gy fractions. At a median follow-up of 14.5 months, actuarial local control rates were 76 % and 57 % at 10 and 20 months, accordingly. For liver metastases, the median overall survival was 14.5 months and progression-free survival at 6 and 12 months was 46 % and 24 %, respectively. There were no grade 3 or higher toxicity reported.
RTOG 0438 is a phase I trial evaluating dose-escalated hypofractionation for hepatic metastases and is currently presented in abstract form only [54].
Enrolled 26 patients and four dose levels were achieved: 35 to 50 Gy in 5-Gy increments delivered in ten fractions.
No dose-limiting toxicities reported. Four patients (two patients at 45 Gy, two patients at 50 Gy) developed grade 3 toxicity.
Concluded that a hypofractionated regimen of 50 Gy in ten fractions is a reasonable and safe approach to treat metastatic liver lesions.
Local control and survival outcomes have not been reported to date.
17.5 Long-Term Sequelae
Most published series of liver SBRT have relatively short follow-up due to the nature of treating metastatic disease.
Thus, the question remains as to what the long-term effects of SBRT may be on the biliary tree and overall liver function. The late effects of SBRT may become more significant as patients live longer with better systemic therapies.
Fortunately, several small retrospective studies have reported data on long-term follow-up and toxicity from SBRT to the liver.
Gunvén and colleagues [55] reported long-term radiation sequelae in 11 patients with up to 13-year follow-up.
Follow-up tests included regular blood chemistry panels in addition to clearance of indocyanine green and a segmental function study by single-photon emission-computed tomography (SPECT) using hepatic iminodiacetic acid (HIDA) derivatives including mebrofenin to evaluate uptake by normal functioning hepatocytes.Related posts:
Basics of Chemotherapy
Primary Liver Cancer: Background and Clinical Evidence
Stereotactic Body Radiation Therapy for Liver Metastases: Radiation Therapy Planning
Pancreatic Cancer: Background and Clinical Evidence
Rectal and Colon Cancer: Radiation Therapy Planning
Gastric Cancer: Radiation Therapy Planning
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