- Email: [email protected]
Stereotactic body radiotherapy (SBRT) with or without surgery for primary and metastatic liver tumors
HPB
http://dx.doi.org/10.1016/j.hpb.2015.07.007
ORIGINAL ARTICLE
Stereotactic body radiotherapy (SBRT) with or without surgery for primary and metastatic liver tumors Alexander Kirichenko1, Olivier Gayou1, David Parda1, Vijay Kudithipudi1, Kusum Tom2, Akhtar Khan2, Peter Abrams2, Molly Szramowski2, Jose Oliva3, Dulabh Monga4, Moses Raj4 & Ngoc Thai2 1
Department of Oncology, Division of Radiation Oncology, 2Department of General Surgery, Division of Abdominal Transplant, 3Division of Gastroenterology, Allegheny General Hospital, and 4Division of Medical Oncology, Allegheny General Hospital, Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA
Abstract Objectives: We report single center experience on the outcome and toxicity of SBRT alone or in combination with surgery for inoperable primary and metastatic liver tumors between 2007 and 2014. Patients and methods: Patients with 1–4 hepatic lesions and tumor diameter 9 cm received SBRT at 46.8Gy ± 3.7 in 4–6 fractions. The primary end point was local control with at least 6 months of radiographic followup, and secondary end points were toxicity and survival. Results: Eighty-seven assessable patients (114 lesions) completed liver SBRT for hepatoma (39) or isolated metastases (48) with a median followup of 20.3 months (range 1.9–64.1). Fourteen patients underwent liver transplant with SBRT as a bridging treatment or for tumor downsizing. Eight patients completed hepatic resections in combination with planned SBRT for unresectable tumors. Two-year local control was 96% for hepatoma and 93.8% for metastases; it was 100% for lesions 4 cm. Two-year overall survival was 82.3% (hepatoma) and 64.3% (metastases). No incidence of grade >2 treatment toxicity was observed. Conclusion: In this retrospective analysis we demonstrate that liver SBRT alone or in combination with surgery is safe and effective for the treatment of isolated inoperable hepatic malignancies and provides excellent local control rates. Received 25 March 2015; accepted 28 July 2015
Correspondence Alexander V. Kirichenko, Division of Radiation Oncology, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212-4772, USA. Tel: +1 412 359 3408. Fax: +1 412 359 3171. E-mail: akiriche@ wpahs.org
Introduction Resection of early primary and isolated metastatic liver tumors in combination with systemic therapy in selected patients is associated with improved survival; however only 10–25% are resectable.1–6 Management of unresectable hepatic tumors with curative intent represents a major challenge in the absence of effective local treatment, including radiofrequency ablation (RFA), which matches surgery for local control and survival.6–8 Over the recent decade SBRT has emerged as a non-invasive, safe and effective radiation therapy technique delivering ablative This study was presented at the Annual Meeting of the Americas Hepato-
doses of radiation to liver tumors with 5 or fewer fractions.9–14 With modern 3D-computer tomography (3D-CT) treatment planning, recent advances in tumor localization, management of respiratory motion and application of multiple conformal radiation beams under high quality image-guidance, SBRT allows delivery of very high doses of radiation to the tumor with dramatic reduction of mean dose to the hepatic parenchyma thus overcoming low liver tolerance to irradiation. We previously reported on the technique of liver SBRT with functional treatment planning utilizing hepatic single-photon emission computed tomography (SPECT) co-registered with 3D-CT.15 Application of 3D-CT/SPECT radiotherapy planning in cirrhotic patients allowed identification of functionally active
Pancreato-Biliary Association, 11–15 March 2015, Miami, Florida.
HPB 2016, 18, 88–97
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
89
hepatic parenchyma and its subsequent conformal avoidance during SBRT which resulted in low hepatic toxicity and absence of radiation-induced liver disease despite the inclusion of 40% patients with Child–Pugh B cirrhosis.16 Herein, we report our experience on the efficacy and tolerability of state of the art SBRT alone or in combination with surgery in patients with inoperable primary and metastatic liver tumors.
Materials and methods Patient eligibility Patients enrolled in this study according to an Institutional Review Board-approved outcome protocol. Only those patients who received high-dose SBRT with BED 100 Gy3 were included, where Gy3 is the unit of biological equivalent dose assuming an a/b ratio of 3 Gy. Patients with up to four isolated hepatic metastases (sum of tumor diameters 8 cm) and individual tumor diameter 9 cm were eligible as long as at least 35% of uninvolved liver parenchyma defined on 3D-CT (noncirrhotic patients) or 3D-CT/SPECT (patients with cirrhosis) was spared from threshold irradiation (specified in “SBRT Planning and Delivery”). Patients with tumors <2 cm from the duodenum or stomach were excluded from SBRT. Instead, they received fractionated stereotactic radiotherapy in combination with capecitabine and/or trans-arterial chemoembolization (TACE) for radiosensitization, or hepatic resections if eligible. Patients who underwent hepatectomies in combination with planned SBRT to unresectable hepatic tumors were included. Hepatocellular carcinoma (HCC) patients with Child–Pugh class A, B & C (low score) hepatic cirrhosis were eligible. We included patients who received SBRT to HCC for downsizing or as a bridging therapy prior to orthotopic liver transplant (OLT). Patients were not allowed to have chemotherapy within one week prior to initiation of SBRT; however, chemotherapy was permitted without delay after completion of SBRT. Concurrent chemotherapy or sorafenib was not allowed. Patients with synchronous isolated extra-hepatic metastases or primary tumors were included as long as all sites were eligible for radical surgery or definitive radiation therapy. SBRT planning and delivery Patients were immobilized in a custom-molded VacLoc® vacuum bag (Bionix, Toledo, OH). Treatment planning 3D-CT with intravenous contrast was acquired to delineate the gross tumor volume (GTV), immediately followed by a four-dimensional (4D) CT to quantify the internal tumor volume (ITV) from respiration-induced tumor motion. The planned target volume (PTV) included the ITV plus a 0.3–0.5 cm margin. SBRT dose was prescribed to the isodoseline encompassing the PTV (generally 90%) allowing up to 20% spot dose to the target volume (10% on average). The technique of functional treatment planning with 3D-CT/SPECT used in this study for all our
HPB 2016, 18, 88–97
patients with hepatic cirrhosis has been previously described.14 Briefly, the tomographic SPECT liver images with 99mTc sulfur colloid were acquired with a dual head gamma camera (GE Medical Systems, Milwaukee, WI) and rigidly fused to treatment planning 3D-CT utilizing a point-based registration algorithm. The residual functional hepatic parenchyma in cirrhotic patients was identified as the photogenic area on 3D-CT/SPECT, contoured as the functional liver volume and used for conformal avoidance during radiation beam placement process using the XiO® treatment planning system (Computerized Medical Systems, St. Louis, MO). In patients with hepatic cirrhosis, liver dose constraints were imposed exclusively on residual functional liver volume defined on 3D-CT/SPECT. For this reason, we calculated predicted functional liver volume (pFLV) from an equation used in transplant surgery17 and for 90Y radioembolization dosimetry:18 pFLV ¼ 794:41+1268:28×BSA where BSA is the body surface area. Next, we specified that at least 35% of pFLV from treatment-planning 3D-CT/SPECT should receive no more than 16 Gy, 18 Gy or 19 Gy delivered in 4, 5 or 6 fractions, respectively. Similarly, hepatic dose-volume constraints for non-cirrhotic patients with unaffected liver function specified that a minimum of 35% of the normal liver volume defined on treatment-planning 3D-CT should receive no more than 16 Gy, 18 Gy or 19 Gy from SBRT delivered in 4, 5 or 6 fractions, respectively. These dose constrains are biologically equivalent to the dose limits (threshold dose) the entire liver can safely tolerate19,20 and which were also used in other liver SBRT trials.11,12 Thirty five percent of residual functional liver to be avoided from threshold irradiation corresponds to a conservative estimate of normal liver volume to be spared from hepatic resections.21 Other constraints included stomach V25 <10 cc (max < 30 Gy); and small bowel V20 <20 cc (max < 30 Gy) where V20 and V25 are the corresponding organ volumes receiving at least 20 or 25 Gy, respectively. Eight patients with mean HCC diameter 5.4 cm (range 3–7.5 cm) completed 1–3 cycles of TACE at various intervals prior to SBRT. Two patients with tumor diameters 6.2 cm and 7 cm were treated with one cycle of TACE in combination with planned SBRT at a 1 month interval. The remaining patients received SBRT as salvage treatment with evidence of residual disease or tumor progression after completion of 2–3 cycles of TACE. All patients were analyzed for toxicity monthly at first, then every 3 months for the first year and semiannually thereafter with clinical examinations and laboratory tests including tumor markers, complete metabolic panel, coagulation profile (HCC patients) and complete blood count. Hepatic function in cirrhotic patients was evaluated with Child–Pugh classification and MELD score. Local response with either contrast-enhanced multiphase CT or MRI was documented at a minimum 6 months from completion of SBRT and then every 4–6 months
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
90
thereafter. However shorter follow up time was allowed for patients who completed orthotopic liver transplant (OLT) with tumor response assessed pathologically. Local control (LC) was defined as the absence of tumor radiographic progression within or at the PTV margin. New liver lesions arising outside the PTV were identified as intrahepatic progression. Acute and long-term toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Actuarial LC and overall survival (OS) curves were generated using the Kaplan–Meier method.
Results Patients Between November 2007 and December 2014, 120 lesions in 91 patients with either unresectable primary (n = 43) or metastatic liver cancer (n = 48) completed liver SBRT to 36–60 Gy delivered in 4–6 treatment fractions, with a mean BED of 197 Gy3 (range 108–300 Gy3). Eight patients with hepatic metastases completed hepatectomy for resectable lesions in combination with planned ablative SBRT for unresectable lesions from colorectal (4), neuroendocrine (1), carcinoid (1), sarcoma (1) primaries or intrahepatic cholangiocarcinoma (1). Patients in this group
completed 3D-CT/SPECT after hepatectomy in order to define hepatic functional reserve for SBRT planning. With this combination therapy seventeen operable metastases were resected and gold fiducials were placed into the unresectable lesions to facilitate precise targeting with ablative SBRT. The patient with solitary unresectable intrahepatic cholangiocarcinoma received preoperative SBRT followed by R0 resection. Twenty-nine out of 91 patients (32%) had a maximal tumor diameter larger than 4 cm; 24 patients (26%) had 2 or more tumors targeted with SBRT and 25 out of 43 patients (58%) in the HCC group had a MELD score greater than 10. There was 43% reduction (p < 0.001) in the amount of FLVSPECT as percentage of predicted liver volume in Child–Pugh B patients, but no such difference was observed for patients with Child–Pugh A cirrhosis or non-cirrhotic patients. Despite functional volume loss, optimal radiation beam placement with 3D-CT/SPECT planning permitted effective avoidance of functional hepatic parenchyma in patients with advanced cirrhosis. This resulted in lowering the mean dose to residual functional hepatic parenchyma to 11.7 ± 4.5 Gy and decreasing the percentage of predicted functional liver volume receiving threshold irradiation to 17.7 ± 10.8%. Functional treatment planning for patient with Child–Pugh B cirrhosis illustrated in Fig. 1.
Figure 1 Representative 3D-CT/SPECT treatment planning images with isodose distribution for a patient with Child–Pugh B cirrhosis. Func-
tional liver volume contoured on
Tc-sulfur colloid SPECT (FLV-SPECT – blue color wash) and anatomic liver volume contoured on 4D-CT
99m
(yellow color wash). There is 52% FLV-SPECT loss compared to CT-defined liver volume. 40 Gy in 4 fractions prescribed to the periphery of internal target volume (white color wash) with selective avoidance of FLV-SPECT pursuing the goal to keep 650 cc of FLV-SPECT (35% predicted) at 16 Gy. Dose-volume histogram curves reflect sparing effect on functional liver parenchyma with residual FLV-SPECT receiving 16 Gy equal to 18% predicted (blue line) and 28% for liver volume contoured on CT (yellow line)
HPB 2016, 18, 88–97
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
91
Patient and tumor characteristics are presented in Tables 1 and 2, respectively. Local control Of the 91 patients in this study, 4 patients were excluded from local control and survival analysis because they died within 6 months of completion of SBRT (no radiographic evidence of infield progression prior to death), and therefore did not meet the criterion of 6 months minimum follow-up. However, one patient who developed in-field local progression and deceased at 5.3 months after completion of SBRT remained in the analysis. Fourteen patients who received orthotopic liver transplant were excluded from radiographic analysis for local control. These patients were analyzed separately with explant pathology. For the remaining 73 patients evaluated radiographically, the median
Characteristics
66.8 years (42–89)
Metastases (n [ 48) 4
RFA
–
4
TACE
8
–
Combination of surgery with planned SBRT
–
8
Number of treated lesions (total)
(55)
(65)
1
32
33
2
10
8
3
1
4
4
0
1
48
45
30
12
Median
Patients with metastases (n = 48)
HCC (n [ 43)
Previous local treatment Hepatectomy –
Tumor volume (cc) Mean
Table 1 Patient characteristics
Median age
Table 2 Tumor and treatment characteristics
Tumor diameter (cm) 1–2
Timing of metastases - Synchronous (at diagnosis)
3
15
14 (29%)
2–3
12
13
- Metachronous
34 (71%)
3–4
13
6
Origin - Colorectal
4–5
4
7
24 (50%)
5–6
4
4
- Breast
10 (20%)
6–7
4
2
7–8
3
0
8
0
1
44.1 ± 4.9/ 5.0 ± 0.4
49.5 ± 3.4/ 4.9 ± 0.5
- Lung
3 (6.5%)
- Neuroendocrine
3 (6.5%)
- Soft tissue sarcoma
3 (6.5%)
- Head and Neck
2 (4%)
- Other
3 (6.5%)
Extrahepatic metastatic sites - No
30 (62%)
- Yes
18 (38%)
Etiology of cirrhosis Hepatitis C
59.3 years (44–76) 30 (70%)
Alcohol
8 (19%)
NASH
3 (7%)
Child–Pugh class A
27 (62%)
B
12 (28%)
C
3 (7%)
Non-Cirrhotic
1 (2%)
MELD score 9 10–12
18 (44%) 13 (32%)
13–15
6 (14%)
>15
4 (10%)
Abbreviations: NASH, non-alcoholic steatotic hepatitis; MELD, model end-stage liver disease.
HPB 2016, 18, 88–97
p < 0.001
Child–Pugh A
44.6 ± 4.4/ 5.0 ± 0.3
p < 0.001b
Child–Pugh B & C
43.2 ± 5.6/ 5.2 ± 0.6
p < 0.001b
BED (Gy3)
Patients with hepatoma (n = 43) Median age
Dose (Gy)/ Number of fractionsa
p-Value
174.8 ± 38.4
216.5 ± 25.2
p < 0.001
Child–Pugh A
178.9 ± 33.7
p < 0.001b
Child–Pugh B & C
167.8 ± 45.6
p < 0.001b
Abbreviations: TACE, trans-arterial chemoembolization; RFA, radiofrequency ablation; BED, biologically equivalent dose, expressed in Gy3 assuming a a/b=3 Gy. a SBRT delivered in 4–6 fractions. b Child–Pugh class vs non-HCC (unpaired two-tailed t-test).
follow up was 20.3 months (range 6.5–64.1 months). Local control was 96% (1/25 failure) for HCC group and 93.8% (3/48 failures, 2 from colorectal and 1 from breast metastases) for the metastatic group of patients (p = 0.397). Actuarial local control curves for each group and according to the tumor size are shown in Fig. 2(a), (b). The detailed characteristics of the lesions that progressed locally are presented in Table 3. Local control was 100% for lesions with maximal tumor diameter of 4 cm or less, compared to 82.6% (4/23 failures) for lesions more than 4 cm (p = 0.008).
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
92
Figure 2 Top: Actuarial local control (a) by tumor type (HCC vs metastases) and (b) tumor size. Bottom: Actuarial overall survival (c) by tumor
type (HCC vs metastases) and (d) for HCC patients, by liver transplant status. The curves were truncated when the number at risk fell under 5. The number at risk for each curve at 0, 20, 40 and 60 months followup are given in the table inside each plot. FU, followup; HCC, hepato-cellular carcinoma; OLT, orthotopic liver transplant; TS, tumor size
Table 3 Tumor and treatment characteristics in patients with
recurrent hepatic lesions Tumor origin
HCC Colorectal Colorectal Breast
Number of tumors treated
1
Dose (Gy)/Number of fractions
45/5 50/5
1
2
1
40/5
60/6
Sum of tumor diameters (cm) 4.3
4.2
6.6
5.0
Time to recurrence (months) 10.1
18.6
4.5
20.1
Distal metastatic progression at recurrence
Yes
No
Yes
Yes
Intrahepatic progression at recurrence
Yes
Yes
Yes
Yes
Salvage therapy
None Chemo
None
Chemo
Months from SBRT until death
11.3
5.3
32
HPB 2016, 18, 88–97
23.5
There were no in-field failures in 8 patients who received a combination of surgery with planned SBRT to the unresectable lesions. Two patients failured else-where in the liver. Four patients died in this group, 2 of whom were from liver failure and 2 from progressive systemic disease. One patient with multiple hepatic metastases from adenocarcinoma of sigmoid colon completed induction chemotherapy followed by resection of seven persistent peripheral metastatic lesions (including 2 lesions adjacent to the gastric wall) with a gold fiducial marker placed into the unresectable tumor located within the confluence of middle hepatic vein under intraoperative ultrasound guidance. One month after recovery from uncomplicated surgery, the patient received a planned five-day SBRT course to 50 Gy to the remaining unresectable metastasis guided by the intratumor gold fiducial marker, as shown in Fig. 3. This patient remains alive and
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
93
Figure 3 Combination of hepatic resections with planned SBRT to unresectable lesion for patient with multiple hepatic metastases from colo-
rectal cancer. Seven peripheral hepatic metastases, including two lesions next to the gastric wall (2A – red circles) were resected with limited hepatectomies. Gold fiducial marker was placed into the unresectable lesion (2B – blue circle) intraoperatively under ultrasound guidance (2C – yellow interrupted circle) for planned SBRT (2D – colored with isodose lines encompassing target volume)
Table 4 Outcome of patients who underwent orthotopic liver
transplant Characteristics
Complete pathological response
Partial pathological response (downsizing)
Stable
Number of patients
10
3
1
Median (range) tumor diameter (cm)
3.25 (2.0–6.2)
2.8 (2.3–4.6)
3.2
Number of lesions treated 1 7
4
1
3
0
0
Median (range) time to transplant (months)
6.3 (2.5–23.3)
3.6 (2.3–6.8)
1.6
Mean dose ± SD (Gy)/ Number of fractions
42.3 ± 5.0/ 5.1 ± 0.6
42.0 ± 7.2/ 5.3 ± 0.6
40/5
2
Child–Pugh class A B&C
HPB 2016, 18, 88–97
4
1
1
6
2
0
free of disease more than 5 years after completion of combined hepatectomy, SBRT and adjuvant chemotherapy. Though local control rate for primary and metastatic liver tumors was similar, there was a significant difference in actual and biologically equivalent doses of radiation delivered to the groups (Table 2). Tumor response in patients with hepatomas, who completed OLT as a result of SBRT for tumor downsizing or as bridging therapy, was assessed by explant pathology. The details on the 14 HCC patients who received SBRT prior to OLT are present in Table 4. Ten of 14 transplanted patients developed complete pathological response with median time to transplant of 5.7 months (range 1.7–23.3). Three patients had tumor downsizing with median time to transplant 3.6 months (2.3–6.8), and one patient had stable tumor within his explant liver at 1.5 months post SBRT. Toxicity No incidence of radiation-induced liver disease (RILD)22 or Grade >1 gastrointestinal, skin or hematologic toxicity was observed among all patients, including the eight patients who received a combination of surgery and SBRT. Grade 2 fatigue (40% Grade-1, 15% Grade-2) was the most prevalent toxicity, with a significant difference in rate between cirrhotic HCC
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
94
patients and non-cirrhotic non-HCC patients (53.5% vs 34.5%, p = 0.038). No other specific predictors of radiation-induced fatigue were found, including total radiation dose and dose per fraction, tumor volume or treatment with chemotherapy. The degree of fatigue did not correlate with the severity of hepatic cirrhosis. There was no accelerated Child–Pugh class migration from A to B or from B to C based on our calculations and with independent assessment by hepatology and transplant surgery teams. At 4–6 months after completion of SBRT, 8 of 27 patients with Child–Pugh A cirrhosis and 13 of 15 patients with Child–Pugh B&C cirrhosis developed clinically insignificant elevation of MELD score (mean 1.9, range 1–3). Three patients with Child–Pugh class C (2) and B (1) cirrhosis developed interval increase in MELD score by 4, 5 and 6 prior to successful liver transplant with waiting time of 2 months, 6.7 months and 7 months, respectively. There were no operative or perioperative complications in patients who received SBRT prior to OLT. Combination of hepatectomy with planned SBRT for unresectable lesions (8 patients) resulted in Grade 2 radiation toxicity with postoperative morbidity Grade 1. Intrahepatic progression Of the 73 patients who were radiographically evaluated (transplant patients excluded), 30 patients (41.1%) developed intrahepatic disease progression outside the PTV, including 22/48 patients (45.8%) in the non-HCC and 9/25 patients (36%) in the HCC groups. Salvage chemotherapy was considered for all patients who developed disease progression after completion of SBRT. Seven patients with intrahepatic recurrence outside the PTV from colorectal (4) or breast (1) metastases and HCC (2) received salvage stereotactic radiotherapy re-irradiation and remain alive at the time of last follow up. Two patients with Child–Pugh A cirrhosis completed liver SBRT re-treatment for HCC recurrence outside the PTV during the waiting period prior to successful OLT. Median time to salvage SBRT for patients with metastases was 17 months (range 2–63 months) and 12.6 months (range 2–60 months) for the HCC group. We applied the same dose constraints in the re-treatment setting as reported in the “Materials and methods” section utilizing 3D-CT/SPECT treatment planning for patients with cirrhosis. Full dose overlap liver volume of up to 5 cc (cumulative dose 90–100 Gy) was observed in two patients with hepatic metastases and one patient with HCC. There was no incidence of hepatic or GI toxicity in the entire re-treatment group. Survival Excluding the 4 patients who were not evaluated for control either radiographically or pathologically because of short follow up, the median survival was not reached for patients with HCC, including for both subgroups with and without liver transplant. The median survival was 26.9 months (range 5.3–64.1 months)
HPB 2016, 18, 88–97
for patients with isolated hepatic metastases. The actuarial OS for HCC (metastases) was 82.3% (71.2%) at the median followup of 20.3 months, and 82.3% (64.2%) at 2 years following SBRT (Fig. 2(d)). The actuarial OS at median follow up for HCC patients who did not receive liver transplant was 71.3%. All 14 patients who completed OLT were alive throughout the entire length of followup (Fig. 2(c)). Two patients from each group died from non-liver-cancer related causes including peritoneal carcinomatosis from pancreatic cancer (five months from SBRT), diffuse bilateral pulmonary metastases from non-small cell lung cancer (six months), AIDS-related complications (8.5 months) and combination of septic condition with coagulopathy (3.8 months).
Discussion In this single center retrospective study we report on the efficacy and toxicity of SBRT in 87 assessable patients with primary and metastatic liver tumors delivered as a single modality (65), in combination with hepatic resections (8) or as a bridge to transplant (14). The SBRT technique included current advances in tumor localization, assessment and control of respiratory motion, multi-beam conformal targeting and daily image guidance. In addition, all patients with hepatic cirrhosis completed 99m Tc labeled sulfur colloid liver SPECT co-registered with treatment planning 3D-CT for delineation and subsequent selective avoidance of residual functionally active hepatic parenchyma during SBRT. Local control was as high as 96% (1/25 failure) for the HCC group not receiving OLT and 93.8% (3/48 failures) for the metastatic group of patients (p = 0.397), with tumor size as a strong predictor. Local control was 100% for lesions with maximal tumor diameter 4 cm or less, compared to 82.6% (4/23 failures) for lesions more than 4 cm (p = 0.008). Overall survival at 2 years was 70.2% (64.2% for patients with hepatic metastases and 82.3% for HCC patients), exceeding 2year survival rates in other published SBRT series.10,11,23,24 Toxicity profile for this non-invasive treatment was favorable, with Grade 2 fatigue as the most prevalent toxicity observed. Local therapies directed to the primary or solitary metastases may be curative or result in long term tumor control with prolongation of hepatic failure-free survival. Surgery remains the gold standard curative option with 5-year survival rates around 70% for patients with small HCC and early stage cirrhosis, and with 1 and 5-year survival for selected isolated hepatic metastases (colorectal and non-colorectal primaries) of about 95% and 40%, respectively.1,2,6 Unfortunately, greater than 80% of patients with hepatic metastases are not candidates for hepatectomy at the time of initial presentation.1,5 Likewise most hepatomas are not resectable due to size, location or liver function impairment. Radiofrequency ablation (RFA) can be an alternative to surgery however, analysis of a prospective database at a tertiary care center demonstrates that RFA for solitary colorectal cancer metastasis not amendable for safe resection is associated with a
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
95
higher local recurrence rates and shorter recurrence-free and overall survival compared with hepatic resections even when small lesions (3 cm) are considered.6 Less invasive transarterial chemoembolization (TACE) has only modest impact on survival compared with best symptomatic care alone in patients with hepatomas.26,27 Although the dose range in our study was moderate in terms of biological equivalent dose compared to 60 Gy in 3 fractions used in the prospective Phase I/II multi-institutional study,11 local control as observed in our study was equivalent or superior to other SBRT trials regarding hepatic malignancies.10,23,24 It should be noted that with excellent local control rates, SBRT in our study and other SBRT trials was used for tumors larger than 3 cm, in the proximity of major blood or biliary vessels, or next to the diaphragm or chest wall – all representing challenging or prohibitive locations for RFA or surgery. It has to be admitted, that tumor size was a strong predictor of local control in our study. Four patients with tumor maximal diameter >4 cm developed in-field local recurrence which can be influenced by the growing proportion of radioresistant hypoxic cells in larger tumors. To address this issue, Jacob et al.34 in a retrospective study of liver SBRT with TACE as a radiosensitizing modality, demonstrated better local control and survival for HCC of 3 cm over treatment with TACE only. Oral capecitabine is another promising radiosensitizing agent for concurrent combination with liver radiotherapy for larger unresectable HCC.35 Median survival for patients with liver metastases in our study was 26.9 months compared to 20.5 months in the Intergroup trial. Better treatment outcome observed in our study can be explained in part by patient selection: only 12% of patients had metastases from unfavorable primary sites (lung, ovary, head & neck), 71% of patients were treated for metachronous metastases, and 62% patients did not have extrahepatic metastases at the time of SBRT. Most of our patients were treated for de novo oligometastatic disease (opposed to chemotherapy induced), described by Weichselbaum and Hellman25 as favorable for local treatment. Other factors that may contribute to better outcome in our study compared to early SBRT trials are consistently high SBRT dose range, use of personalized 4D-CT treatment planning to account for tumor respiratory motion margin and daily SBRT image guidance – all contributing to a reduction of systematic errors in daily tumor targeting. It has to be acknowledged, that outcome of any radical local therapies directed to isolated metastases is strongly influenced by the presence of chemotherapy and/or targeted biologic agents in the background. It was not possible in our study to assess contribution of systemic therapy on SBRT outcome due to limited number of patients, heterogeneous primary sites, variety of chemotherapy regimens and timing of administration. There was a significant difference in actual and biologically equivalent doses of radiation between groups of patients with hepatic metastases and liver HCC. Yet, local control rates were similar for the two groups. This can be explained by the intrinsic
HPB 2016, 18, 88–97
radiosensitivity of HCC compared to metastatic disease observed and discussed by others.28 Patients who completed planned SBRT for HCC prior to liver transplantation had 100% survival over the entire length of followup compared to 71.3% survival at two years in patients who could not have liver transplant. All 14 transplanted patients benefited from SBRT given as a bridge to transplant or for tumor downsizing. Despite similar SBRT dose and fractionation schedule, 10 patients (70%) achieved complete pathological response with no viable tumor in a specimen at a median time to transplant 6.3 months (2.5–23.3). Partial response was observed in 3 patients (20%) with median time to transplant 3.6 months (2.3–6.8). It is possible that shorter time to transplant may result in incomplete realization of radiation treatment effect. Only one patient with the shortest time to transplant of 52 days had stable disease after receiving SBRT as a bridging therapy to a solitary 3.2-cm HCC. Our outcome for the HCC group of patients is similar to a few published studies.23,24,29,30,34 Jacob et al.34 reported marked improvement in survival of 37 cirrhotic patients who received TACE in combination with adjuvant SBRT for HCC of 3 cm with two-fold reduction of local recurrence rate. Andolino et al.29 reported 2-year local control and overall survival of 90% and 67% respectively among 60 patients treated with SBRT for HCC. Subsequently, 23 patients received liver transplant at a median time of 7 months following radiation and remained alive at the entire length of followup. Of 12 HCC patients who completed hypofractionated stereotactic radiotherapy as bridge to transplant or prior to hepatectomy, Katz et al.30 observed 100% pathological response to treatment in 2 patients, >50% response in 3 patients and <50% pathologic response in 7 patients. Complete pathologic response rate in our study is higher (81%) likely due to the more dose intense SBRT schedule used (BED = 175 Gy3 vs 133 Gy3). No patient in either group developed classic RILD. The absence of accelerated MELD score progression in cirrhotic patients despite the inclusion of 25/43 patients with initial MELD score 10 and 15/41 (36.5%) patients with recurrent ascites and encephalopathy is encouraging. It is well recognized that HCC patients with advanced hepatic cirrhosis are at much higher risk of developing RILD for the same radiation dose than metastatic patients in the absence of cirrhosis, and the severity of hepatic cirrhosis correlates with the incidence of lethal RILD.31–33 Increased sensitivity of cirrhotic liver to irradiation could be explained by proliferation of fibrotic tissue with loss of hepatic functional reserve representing combined function of hepatocytes and non-parenchymal cells residing within sinusoids (Kupffer cells, endothelial cells, stellate and pit cells). All of our patients with HCC completed functional treatment planning with 99mTc sulfur colloid 3D-CT/SPECT for identification of residual, wellperfused functionally active hepatic parenchyma. Liver dose constraints were imposed exclusively on residual functional liver volume. Patients with hepatic cirrhosis in the HCC group developed retraction of functionally active hepatic parenchyma
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
96
compared to the non-HCC, non-cirrhotic group, as we previously reported.16 This resulted in statistically significant reduction of actual and biologically equivalent dose of radiation during SBRT planning by 17% for patients with Child–Pugh A cirrhosis and by 22% for the Child–Pugh B&C patients (Table 2). We postulate that tailoring hepatic dose-volume constraints to residual functionally active liver parenchyma defined on 99mTc sulfur colloid SPECT, with its subsequent conformal avoidance from high-dose irradiation during 3D-CT/SPECT treatment planning may contribute to reduction of hepatic toxicity in cirrhotic patients. However, a prospective randomized trial is required to estimate the true value of this method. In conclusion, our retrospective study indicates that SBRT is a safe, non-invasive treatment for unresectable primary and metastatic liver tumors providing excellent local control. It is an effective and reliable bridging therapy for patients awaiting liver transplantation with excellent pathological response. It can be used to target unresectable metastases in combination with limited hepatectomies for resectable peripheral lesions thereby expanding indications for resection of multiple hepatic metastases. This particular combination exploits the strengths of liver SBRT and hepatic resection while compensating for each treatment’s limitations.
7. Ueno, S., Sakoda, M., Kubo, F., Hiwatashi, K., Tateno, T., Baba, Y., et al. (2009). Surgical resection versus radiofrequency ablation for small hepatocellular carcinomas within the Milan criteria. J Hepatobiliary Pancreat Surg, 16, 359–366. 8. Zhou, Y., Zhao, Y., Li, B., Xu, D., Yin, Z., Xie, F., Yang, J., et al. (2010). Meta-analysis of radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma. BMC Gastroenterol, 10, 78–85. 9. Herfarth, K. K., & Debus, J. (2005). Stereotactic radiation therapy for liver metastases. Chirurg, 76, 564–569. 10. Hoyer, M., Roed, H., Traberg, H. A., Ohluis, L., Petersen, J., Nellemann, H., et al. (2006). Phase II study on stereotactic body radiotherapy of colorectal metastases. Acta Oncol, 45, 823–830. 11. Rusthoven, K. E., Kavanagh, B. D., Cardenes, H., Stieber, V. W., Burri, S. H., Feigenberg, S. J., et al. (2009). Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol, 27, 1572–1578. 12. Goodman, K. A., Wiegner, E. A., Maturen, K. E., Zhang, Z., Mo, Q., Yang, G., et al. (2010). Dose-escalation study of single-fraction stereotactic body radiotherapy for liver malignancies. Int J Radiat Oncol Biol Phys, 78, 486–493. 13. Chang, D. T., Swaminath, A., Kozak, M., Weintraub, J., Koong, A. C., Kim, J., et al. (2011). Stereotactic body radiotherapy for colorectal liver metastases: a pooled analysis. Cancer, 117, 4060–4069. 14. Scorsetti, M., Arcangeli, S., Tozzi, A., Comito, T., Alongi, F., Navarria, P., et al. (2013). Is stereotactic body radiation therapy an attractive option for unresectable liver metastasis? A preliminary report from a phase 2
Sources of funding for research and/or publication
trial. Int J Radiat Oncol Biol Phys, 86, 336–342. 15. Gayou, O., Day, E., Mohammadi, S., & Kirichenko, A. (2012). A method
None.
for registration of single photon emission computed tomography (SPECT) and computed tomography (CT) images for liver stereotactic
Conflicts of interest
radiotherapy (SRT). Med Phys, 39, 7398–7401.
None declared.
16. Kirichenko, A., Thai, N., Lappinen, E., Gayou, O., Kotinsley, K., Day, E., et al. (2013). Outcomes of Stereotactic radiotherapy (SRT) for primary
References 1. Groeschl, R. T., Nachmany, I., Steel, J. L., Reddy, S. K., Glazer, E. S., de
and metastatic liver tumors with 3-D CT and single photon emission
Jong, M. C., et al. (2012). Hepatectomy for noncolorectal non-
computed tomography (3D-CT/SPECT) treatment planning. Presented
neuroendocrine metastatic cancer: a multi-institutional analysis. J Am
at ASTRO 2013. Int J Radiat Oncol Biol Phys, 84, 11. 17. Urata, K., Kawasaki, S., Matsunami, H., Hashikura, Y., Ikegami, T.,
Coll Surg, 214, 769–777. 2. Fong, Y., Sun, R., Jamagin, W., & Blumgart, L. H. (1999). An analysis of 412 cases of hepatocellular carcinoma at a Western Center. Ann Surg,
Ishizone, S., et al. (1995). Calculation of child and adult standard liver volume for liver transplantation. Hepatology, 21, 1317–1321. 18. Kennedy, A., Nag, S., Salem, R., Murthy, R., McEwan, A. J., Nutting, C.,
229, 790–800. 3. Yao, F., Ferrell, L., Bass, N., Watson, J. J., Bacchetti, P., Venook, A.,
et al. (2007). Recommendations for radioembolization of hepatic ma-
et al. (2001). Liver transplantation for hepatocellular carcinoma:
lignancies using yttrium-90 microsphere brachytherapy: a consensus
expansion of the tumor size limits does not adversely impact survival.
panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys, 68, 13–23.
Hepatology, 33, 1394–1403. 4. Gold, J. S., Are, C., Kornprat, P., Jarnagin, W. R., Gönen, M., Fong, Y.,
19. Leibel, S. A., Pajak, T. F., Massullo, V., Order, S. E., Komaki, R. U.,
et al. (2008). Increased use of parenchymal-sparing surgery for bilateral
Chang, C. H., et al. (1987). A comparison of misonidazole sensitized
liver metastases from colorectal cancer is associated with improved
radiation therapy to radiation therapy alone for the palliation of hepatic
mortality without change in oncologic outcome: trends in treatment over
metastases: results of a Radiation Therapy Oncology Group random-
time in 440 patients. Ann Surg, 247, 109–117.
ized prospective trial. Int J Radiat Oncol Biol Phys, 13, 1057–1064.
5. Nordlinger, B., Van Cutsem, E., Rougier, P., Köhne, C. H., Ychou, M.,
20. Russell, A. H., Clyde, C., Wasserman, T. H., Turner, S. S., & Rotman, M.
Sobrero, A., et al. (2007). Does chemotherapy prior to liver resection
(1993). Accelerated hyperfractionated hepatic irradiation in the man-
increase the potential for cure in patients with metastatic colorectal
agement of patients with liver metastases: results of the RTOG dose
cancer? A report from the European Colorectal Metastases Treatment Group. Eur J Cancer, 43, 2037–2045. 6. Aloia, T. A., Vauthey, J. N., Loyer, E. M., Ribero, D., Pawlik, T. M., Wei, S. H., et al. (2006). Solitary colorectal liver metastasis: resection determines outcome. Arch Surg, 141, 460–466.
HPB 2016, 18, 88–97
escalating protocol. Int J Radiat Oncol Biol Phys, 27, 117–123. 21. Penna, C., & Nordlinger, B. (2002). Colorectal metastasis (liver and lung). Surg Clin North Am, 82, 1075–1090. 22. Reed, G. B., Jr., & Cok, A. J., Jr. (1966). The human liver after radiation injury. A form of veno-occlusive disease. Am J Pathol, 48, 597–611.
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
97
23. Dawson, L. A., Eccles, C., & Craig, T. (2006). Individualized image guided iso-NTCP based liver cancer SBRT. Acta Oncol, 45, 856–864.
carcinoma: clinical outcome and pathological correlation. Int J Radiat Oncol Biol Phys, 83, 895–900.
24. Mendez-Romero, A., Wunderink, W., Hussain, S. M., De Pooter, J. A.,
31. Lawrence, T. S., Ten Haken, R. K., Kessler, M. L., Robertson, J. M.,
Heijman, B. J., Nowak, P. C., et al. (2006). Stereotactic body radiation
Lyman, J. T., Lavigne, N. L., et al. (1992). The use of 3-D dose volume
therapy for primary and metastatic liver tumors: a single institution
analysis to predict radiation hepatitis. Int J Radiat Oncol Biol Phys, 23,
phase i-ii study. Acta Oncol, 45, 831–837.
781–788.
25. Weichselbaum, R. R., & Hellman, S. (2011). Oligometastases revisited. Nat Rev Clin Oncol, 8, 378–382.
32. Cheng, J. C., Wu, J.-K., Lee, P. C., Liu, H. S., Jian, J. J., Lin, Y. M., et al. (2004). Biologic susceptibility of hepatocellular carcinoma in patients
26. Lo, C. M., Ngan, H., Tso, W. K., Liu, C. L., Lam, C. M., Poon, R. T., et al. (2002). Randomized controlled trial of transarteriallipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology, 35, 1164–1171.
treated with radiotherapy to radiation induced liver disease. Int J Radiat Oncol Biol Phys, 60, 1502–1509. 33. Liang, S. X., Zhu, X. D., Xu, Z. Y., Zhu, J., Zho, J. D., Lu, H. J., et al. (2006).
27. Llovet, J. M., Real, M. I., Montana, X., Planas, R., Coll, S., Aponte, J.,
Radiation-induced
liver
disease
in
three-dimensional
conformal radiation therapy for primary liver carcinoma: the risk fac-
et al. (2002). Arterial embolisation or chemoembolisation versus
tors and hepatic radiation tolerance. Int J Radiat Oncol Biol Phys, 65,
symptomatic treatment in patients with unresectable hepatocellular
426 –434.
carcinoma: a randomised controlled trial. Lancet, 359, 1734–1739.
34. Jacob, R., Turley, F., Redden, D. T., Saddekni, S., Aal, A. K., Keene, K.,
28. Klein, J., & Dawson, L. A. (2013). Hepatocellular carcinoma radiation
et al. (2015). Adjuvant stereotactic body radiotherapy following trans-
therapy: review of evidence and future opportunities. Int J Radiat Oncol
arterial chemoembolization in patients with non-resectable hepatocellular carcinoma tumours of 3cm. HPB, 17, 140–149.
Biol Phys, 87, 22–32. 29. Andolino, D. L., Johnson, C. S., Maluccio, M., Kwo, P., Tector, A. J.,
35. McIntosh, A., Hagspiel, K. D., Al-Osaimi, A. M., Northup, P.,
Zook, J., et al. (2011). Stereotactic body radiotherapy for primary he-
Caldwell, S., Berg, C., et al. (2009). Accelerated treatment using
patocellular carcinoma. Int J Radiat Oncol Biol Phys, 81, 447–453.
intensity modulated radiotherapy plus concurrent capecitabine
30. Katz, A., Chawla, S., & Qu, Z. (2012). Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular
HPB 2016, 18, 88–97
for
unresectable
hepatocellular
carcinoma.
Cancer,
115,
5117 – 5125.
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.hpb.2015.07.007
ORIGINAL ARTICLE
Stereotactic body radiotherapy (SBRT) with or without surgery for primary and metastatic liver tumors Alexander Kirichenko1, Olivier Gayou1, David Parda1, Vijay Kudithipudi1, Kusum Tom2, Akhtar Khan2, Peter Abrams2, Molly Szramowski2, Jose Oliva3, Dulabh Monga4, Moses Raj4 & Ngoc Thai2 1
Department of Oncology, Division of Radiation Oncology, 2Department of General Surgery, Division of Abdominal Transplant, 3Division of Gastroenterology, Allegheny General Hospital, and 4Division of Medical Oncology, Allegheny General Hospital, Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA
Abstract Objectives: We report single center experience on the outcome and toxicity of SBRT alone or in combination with surgery for inoperable primary and metastatic liver tumors between 2007 and 2014. Patients and methods: Patients with 1–4 hepatic lesions and tumor diameter 9 cm received SBRT at 46.8Gy ± 3.7 in 4–6 fractions. The primary end point was local control with at least 6 months of radiographic followup, and secondary end points were toxicity and survival. Results: Eighty-seven assessable patients (114 lesions) completed liver SBRT for hepatoma (39) or isolated metastases (48) with a median followup of 20.3 months (range 1.9–64.1). Fourteen patients underwent liver transplant with SBRT as a bridging treatment or for tumor downsizing. Eight patients completed hepatic resections in combination with planned SBRT for unresectable tumors. Two-year local control was 96% for hepatoma and 93.8% for metastases; it was 100% for lesions 4 cm. Two-year overall survival was 82.3% (hepatoma) and 64.3% (metastases). No incidence of grade >2 treatment toxicity was observed. Conclusion: In this retrospective analysis we demonstrate that liver SBRT alone or in combination with surgery is safe and effective for the treatment of isolated inoperable hepatic malignancies and provides excellent local control rates. Received 25 March 2015; accepted 28 July 2015
Correspondence Alexander V. Kirichenko, Division of Radiation Oncology, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212-4772, USA. Tel: +1 412 359 3408. Fax: +1 412 359 3171. E-mail: akiriche@ wpahs.org
Introduction Resection of early primary and isolated metastatic liver tumors in combination with systemic therapy in selected patients is associated with improved survival; however only 10–25% are resectable.1–6 Management of unresectable hepatic tumors with curative intent represents a major challenge in the absence of effective local treatment, including radiofrequency ablation (RFA), which matches surgery for local control and survival.6–8 Over the recent decade SBRT has emerged as a non-invasive, safe and effective radiation therapy technique delivering ablative This study was presented at the Annual Meeting of the Americas Hepato-
doses of radiation to liver tumors with 5 or fewer fractions.9–14 With modern 3D-computer tomography (3D-CT) treatment planning, recent advances in tumor localization, management of respiratory motion and application of multiple conformal radiation beams under high quality image-guidance, SBRT allows delivery of very high doses of radiation to the tumor with dramatic reduction of mean dose to the hepatic parenchyma thus overcoming low liver tolerance to irradiation. We previously reported on the technique of liver SBRT with functional treatment planning utilizing hepatic single-photon emission computed tomography (SPECT) co-registered with 3D-CT.15 Application of 3D-CT/SPECT radiotherapy planning in cirrhotic patients allowed identification of functionally active
Pancreato-Biliary Association, 11–15 March 2015, Miami, Florida.
HPB 2016, 18, 88–97
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
89
hepatic parenchyma and its subsequent conformal avoidance during SBRT which resulted in low hepatic toxicity and absence of radiation-induced liver disease despite the inclusion of 40% patients with Child–Pugh B cirrhosis.16 Herein, we report our experience on the efficacy and tolerability of state of the art SBRT alone or in combination with surgery in patients with inoperable primary and metastatic liver tumors.
Materials and methods Patient eligibility Patients enrolled in this study according to an Institutional Review Board-approved outcome protocol. Only those patients who received high-dose SBRT with BED 100 Gy3 were included, where Gy3 is the unit of biological equivalent dose assuming an a/b ratio of 3 Gy. Patients with up to four isolated hepatic metastases (sum of tumor diameters 8 cm) and individual tumor diameter 9 cm were eligible as long as at least 35% of uninvolved liver parenchyma defined on 3D-CT (noncirrhotic patients) or 3D-CT/SPECT (patients with cirrhosis) was spared from threshold irradiation (specified in “SBRT Planning and Delivery”). Patients with tumors <2 cm from the duodenum or stomach were excluded from SBRT. Instead, they received fractionated stereotactic radiotherapy in combination with capecitabine and/or trans-arterial chemoembolization (TACE) for radiosensitization, or hepatic resections if eligible. Patients who underwent hepatectomies in combination with planned SBRT to unresectable hepatic tumors were included. Hepatocellular carcinoma (HCC) patients with Child–Pugh class A, B & C (low score) hepatic cirrhosis were eligible. We included patients who received SBRT to HCC for downsizing or as a bridging therapy prior to orthotopic liver transplant (OLT). Patients were not allowed to have chemotherapy within one week prior to initiation of SBRT; however, chemotherapy was permitted without delay after completion of SBRT. Concurrent chemotherapy or sorafenib was not allowed. Patients with synchronous isolated extra-hepatic metastases or primary tumors were included as long as all sites were eligible for radical surgery or definitive radiation therapy. SBRT planning and delivery Patients were immobilized in a custom-molded VacLoc® vacuum bag (Bionix, Toledo, OH). Treatment planning 3D-CT with intravenous contrast was acquired to delineate the gross tumor volume (GTV), immediately followed by a four-dimensional (4D) CT to quantify the internal tumor volume (ITV) from respiration-induced tumor motion. The planned target volume (PTV) included the ITV plus a 0.3–0.5 cm margin. SBRT dose was prescribed to the isodoseline encompassing the PTV (generally 90%) allowing up to 20% spot dose to the target volume (10% on average). The technique of functional treatment planning with 3D-CT/SPECT used in this study for all our
HPB 2016, 18, 88–97
patients with hepatic cirrhosis has been previously described.14 Briefly, the tomographic SPECT liver images with 99mTc sulfur colloid were acquired with a dual head gamma camera (GE Medical Systems, Milwaukee, WI) and rigidly fused to treatment planning 3D-CT utilizing a point-based registration algorithm. The residual functional hepatic parenchyma in cirrhotic patients was identified as the photogenic area on 3D-CT/SPECT, contoured as the functional liver volume and used for conformal avoidance during radiation beam placement process using the XiO® treatment planning system (Computerized Medical Systems, St. Louis, MO). In patients with hepatic cirrhosis, liver dose constraints were imposed exclusively on residual functional liver volume defined on 3D-CT/SPECT. For this reason, we calculated predicted functional liver volume (pFLV) from an equation used in transplant surgery17 and for 90Y radioembolization dosimetry:18 pFLV ¼ 794:41+1268:28×BSA where BSA is the body surface area. Next, we specified that at least 35% of pFLV from treatment-planning 3D-CT/SPECT should receive no more than 16 Gy, 18 Gy or 19 Gy delivered in 4, 5 or 6 fractions, respectively. Similarly, hepatic dose-volume constraints for non-cirrhotic patients with unaffected liver function specified that a minimum of 35% of the normal liver volume defined on treatment-planning 3D-CT should receive no more than 16 Gy, 18 Gy or 19 Gy from SBRT delivered in 4, 5 or 6 fractions, respectively. These dose constrains are biologically equivalent to the dose limits (threshold dose) the entire liver can safely tolerate19,20 and which were also used in other liver SBRT trials.11,12 Thirty five percent of residual functional liver to be avoided from threshold irradiation corresponds to a conservative estimate of normal liver volume to be spared from hepatic resections.21 Other constraints included stomach V25 <10 cc (max < 30 Gy); and small bowel V20 <20 cc (max < 30 Gy) where V20 and V25 are the corresponding organ volumes receiving at least 20 or 25 Gy, respectively. Eight patients with mean HCC diameter 5.4 cm (range 3–7.5 cm) completed 1–3 cycles of TACE at various intervals prior to SBRT. Two patients with tumor diameters 6.2 cm and 7 cm were treated with one cycle of TACE in combination with planned SBRT at a 1 month interval. The remaining patients received SBRT as salvage treatment with evidence of residual disease or tumor progression after completion of 2–3 cycles of TACE. All patients were analyzed for toxicity monthly at first, then every 3 months for the first year and semiannually thereafter with clinical examinations and laboratory tests including tumor markers, complete metabolic panel, coagulation profile (HCC patients) and complete blood count. Hepatic function in cirrhotic patients was evaluated with Child–Pugh classification and MELD score. Local response with either contrast-enhanced multiphase CT or MRI was documented at a minimum 6 months from completion of SBRT and then every 4–6 months
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
90
thereafter. However shorter follow up time was allowed for patients who completed orthotopic liver transplant (OLT) with tumor response assessed pathologically. Local control (LC) was defined as the absence of tumor radiographic progression within or at the PTV margin. New liver lesions arising outside the PTV were identified as intrahepatic progression. Acute and long-term toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Actuarial LC and overall survival (OS) curves were generated using the Kaplan–Meier method.
Results Patients Between November 2007 and December 2014, 120 lesions in 91 patients with either unresectable primary (n = 43) or metastatic liver cancer (n = 48) completed liver SBRT to 36–60 Gy delivered in 4–6 treatment fractions, with a mean BED of 197 Gy3 (range 108–300 Gy3). Eight patients with hepatic metastases completed hepatectomy for resectable lesions in combination with planned ablative SBRT for unresectable lesions from colorectal (4), neuroendocrine (1), carcinoid (1), sarcoma (1) primaries or intrahepatic cholangiocarcinoma (1). Patients in this group
completed 3D-CT/SPECT after hepatectomy in order to define hepatic functional reserve for SBRT planning. With this combination therapy seventeen operable metastases were resected and gold fiducials were placed into the unresectable lesions to facilitate precise targeting with ablative SBRT. The patient with solitary unresectable intrahepatic cholangiocarcinoma received preoperative SBRT followed by R0 resection. Twenty-nine out of 91 patients (32%) had a maximal tumor diameter larger than 4 cm; 24 patients (26%) had 2 or more tumors targeted with SBRT and 25 out of 43 patients (58%) in the HCC group had a MELD score greater than 10. There was 43% reduction (p < 0.001) in the amount of FLVSPECT as percentage of predicted liver volume in Child–Pugh B patients, but no such difference was observed for patients with Child–Pugh A cirrhosis or non-cirrhotic patients. Despite functional volume loss, optimal radiation beam placement with 3D-CT/SPECT planning permitted effective avoidance of functional hepatic parenchyma in patients with advanced cirrhosis. This resulted in lowering the mean dose to residual functional hepatic parenchyma to 11.7 ± 4.5 Gy and decreasing the percentage of predicted functional liver volume receiving threshold irradiation to 17.7 ± 10.8%. Functional treatment planning for patient with Child–Pugh B cirrhosis illustrated in Fig. 1.
Figure 1 Representative 3D-CT/SPECT treatment planning images with isodose distribution for a patient with Child–Pugh B cirrhosis. Func-
tional liver volume contoured on
Tc-sulfur colloid SPECT (FLV-SPECT – blue color wash) and anatomic liver volume contoured on 4D-CT
99m
(yellow color wash). There is 52% FLV-SPECT loss compared to CT-defined liver volume. 40 Gy in 4 fractions prescribed to the periphery of internal target volume (white color wash) with selective avoidance of FLV-SPECT pursuing the goal to keep 650 cc of FLV-SPECT (35% predicted) at 16 Gy. Dose-volume histogram curves reflect sparing effect on functional liver parenchyma with residual FLV-SPECT receiving 16 Gy equal to 18% predicted (blue line) and 28% for liver volume contoured on CT (yellow line)
HPB 2016, 18, 88–97
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
91
Patient and tumor characteristics are presented in Tables 1 and 2, respectively. Local control Of the 91 patients in this study, 4 patients were excluded from local control and survival analysis because they died within 6 months of completion of SBRT (no radiographic evidence of infield progression prior to death), and therefore did not meet the criterion of 6 months minimum follow-up. However, one patient who developed in-field local progression and deceased at 5.3 months after completion of SBRT remained in the analysis. Fourteen patients who received orthotopic liver transplant were excluded from radiographic analysis for local control. These patients were analyzed separately with explant pathology. For the remaining 73 patients evaluated radiographically, the median
Characteristics
66.8 years (42–89)
Metastases (n [ 48) 4
RFA
–
4
TACE
8
–
Combination of surgery with planned SBRT
–
8
Number of treated lesions (total)
(55)
(65)
1
32
33
2
10
8
3
1
4
4
0
1
48
45
30
12
Median
Patients with metastases (n = 48)
HCC (n [ 43)
Previous local treatment Hepatectomy –
Tumor volume (cc) Mean
Table 1 Patient characteristics
Median age
Table 2 Tumor and treatment characteristics
Tumor diameter (cm) 1–2
Timing of metastases - Synchronous (at diagnosis)
3
15
14 (29%)
2–3
12
13
- Metachronous
34 (71%)
3–4
13
6
Origin - Colorectal
4–5
4
7
24 (50%)
5–6
4
4
- Breast
10 (20%)
6–7
4
2
7–8
3
0
8
0
1
44.1 ± 4.9/ 5.0 ± 0.4
49.5 ± 3.4/ 4.9 ± 0.5
- Lung
3 (6.5%)
- Neuroendocrine
3 (6.5%)
- Soft tissue sarcoma
3 (6.5%)
- Head and Neck
2 (4%)
- Other
3 (6.5%)
Extrahepatic metastatic sites - No
30 (62%)
- Yes
18 (38%)
Etiology of cirrhosis Hepatitis C
59.3 years (44–76) 30 (70%)
Alcohol
8 (19%)
NASH
3 (7%)
Child–Pugh class A
27 (62%)
B
12 (28%)
C
3 (7%)
Non-Cirrhotic
1 (2%)
MELD score 9 10–12
18 (44%) 13 (32%)
13–15
6 (14%)
>15
4 (10%)
Abbreviations: NASH, non-alcoholic steatotic hepatitis; MELD, model end-stage liver disease.
HPB 2016, 18, 88–97
p < 0.001
Child–Pugh A
44.6 ± 4.4/ 5.0 ± 0.3
p < 0.001b
Child–Pugh B & C
43.2 ± 5.6/ 5.2 ± 0.6
p < 0.001b
BED (Gy3)
Patients with hepatoma (n = 43) Median age
Dose (Gy)/ Number of fractionsa
p-Value
174.8 ± 38.4
216.5 ± 25.2
p < 0.001
Child–Pugh A
178.9 ± 33.7
p < 0.001b
Child–Pugh B & C
167.8 ± 45.6
p < 0.001b
Abbreviations: TACE, trans-arterial chemoembolization; RFA, radiofrequency ablation; BED, biologically equivalent dose, expressed in Gy3 assuming a a/b=3 Gy. a SBRT delivered in 4–6 fractions. b Child–Pugh class vs non-HCC (unpaired two-tailed t-test).
follow up was 20.3 months (range 6.5–64.1 months). Local control was 96% (1/25 failure) for HCC group and 93.8% (3/48 failures, 2 from colorectal and 1 from breast metastases) for the metastatic group of patients (p = 0.397). Actuarial local control curves for each group and according to the tumor size are shown in Fig. 2(a), (b). The detailed characteristics of the lesions that progressed locally are presented in Table 3. Local control was 100% for lesions with maximal tumor diameter of 4 cm or less, compared to 82.6% (4/23 failures) for lesions more than 4 cm (p = 0.008).
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
92
Figure 2 Top: Actuarial local control (a) by tumor type (HCC vs metastases) and (b) tumor size. Bottom: Actuarial overall survival (c) by tumor
type (HCC vs metastases) and (d) for HCC patients, by liver transplant status. The curves were truncated when the number at risk fell under 5. The number at risk for each curve at 0, 20, 40 and 60 months followup are given in the table inside each plot. FU, followup; HCC, hepato-cellular carcinoma; OLT, orthotopic liver transplant; TS, tumor size
Table 3 Tumor and treatment characteristics in patients with
recurrent hepatic lesions Tumor origin
HCC Colorectal Colorectal Breast
Number of tumors treated
1
Dose (Gy)/Number of fractions
45/5 50/5
1
2
1
40/5
60/6
Sum of tumor diameters (cm) 4.3
4.2
6.6
5.0
Time to recurrence (months) 10.1
18.6
4.5
20.1
Distal metastatic progression at recurrence
Yes
No
Yes
Yes
Intrahepatic progression at recurrence
Yes
Yes
Yes
Yes
Salvage therapy
None Chemo
None
Chemo
Months from SBRT until death
11.3
5.3
32
HPB 2016, 18, 88–97
23.5
There were no in-field failures in 8 patients who received a combination of surgery with planned SBRT to the unresectable lesions. Two patients failured else-where in the liver. Four patients died in this group, 2 of whom were from liver failure and 2 from progressive systemic disease. One patient with multiple hepatic metastases from adenocarcinoma of sigmoid colon completed induction chemotherapy followed by resection of seven persistent peripheral metastatic lesions (including 2 lesions adjacent to the gastric wall) with a gold fiducial marker placed into the unresectable tumor located within the confluence of middle hepatic vein under intraoperative ultrasound guidance. One month after recovery from uncomplicated surgery, the patient received a planned five-day SBRT course to 50 Gy to the remaining unresectable metastasis guided by the intratumor gold fiducial marker, as shown in Fig. 3. This patient remains alive and
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
93
Figure 3 Combination of hepatic resections with planned SBRT to unresectable lesion for patient with multiple hepatic metastases from colo-
rectal cancer. Seven peripheral hepatic metastases, including two lesions next to the gastric wall (2A – red circles) were resected with limited hepatectomies. Gold fiducial marker was placed into the unresectable lesion (2B – blue circle) intraoperatively under ultrasound guidance (2C – yellow interrupted circle) for planned SBRT (2D – colored with isodose lines encompassing target volume)
Table 4 Outcome of patients who underwent orthotopic liver
transplant Characteristics
Complete pathological response
Partial pathological response (downsizing)
Stable
Number of patients
10
3
1
Median (range) tumor diameter (cm)
3.25 (2.0–6.2)
2.8 (2.3–4.6)
3.2
Number of lesions treated 1 7
4
1
3
0
0
Median (range) time to transplant (months)
6.3 (2.5–23.3)
3.6 (2.3–6.8)
1.6
Mean dose ± SD (Gy)/ Number of fractions
42.3 ± 5.0/ 5.1 ± 0.6
42.0 ± 7.2/ 5.3 ± 0.6
40/5
2
Child–Pugh class A B&C
HPB 2016, 18, 88–97
4
1
1
6
2
0
free of disease more than 5 years after completion of combined hepatectomy, SBRT and adjuvant chemotherapy. Though local control rate for primary and metastatic liver tumors was similar, there was a significant difference in actual and biologically equivalent doses of radiation delivered to the groups (Table 2). Tumor response in patients with hepatomas, who completed OLT as a result of SBRT for tumor downsizing or as bridging therapy, was assessed by explant pathology. The details on the 14 HCC patients who received SBRT prior to OLT are present in Table 4. Ten of 14 transplanted patients developed complete pathological response with median time to transplant of 5.7 months (range 1.7–23.3). Three patients had tumor downsizing with median time to transplant 3.6 months (2.3–6.8), and one patient had stable tumor within his explant liver at 1.5 months post SBRT. Toxicity No incidence of radiation-induced liver disease (RILD)22 or Grade >1 gastrointestinal, skin or hematologic toxicity was observed among all patients, including the eight patients who received a combination of surgery and SBRT. Grade 2 fatigue (40% Grade-1, 15% Grade-2) was the most prevalent toxicity, with a significant difference in rate between cirrhotic HCC
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
94
patients and non-cirrhotic non-HCC patients (53.5% vs 34.5%, p = 0.038). No other specific predictors of radiation-induced fatigue were found, including total radiation dose and dose per fraction, tumor volume or treatment with chemotherapy. The degree of fatigue did not correlate with the severity of hepatic cirrhosis. There was no accelerated Child–Pugh class migration from A to B or from B to C based on our calculations and with independent assessment by hepatology and transplant surgery teams. At 4–6 months after completion of SBRT, 8 of 27 patients with Child–Pugh A cirrhosis and 13 of 15 patients with Child–Pugh B&C cirrhosis developed clinically insignificant elevation of MELD score (mean 1.9, range 1–3). Three patients with Child–Pugh class C (2) and B (1) cirrhosis developed interval increase in MELD score by 4, 5 and 6 prior to successful liver transplant with waiting time of 2 months, 6.7 months and 7 months, respectively. There were no operative or perioperative complications in patients who received SBRT prior to OLT. Combination of hepatectomy with planned SBRT for unresectable lesions (8 patients) resulted in Grade 2 radiation toxicity with postoperative morbidity Grade 1. Intrahepatic progression Of the 73 patients who were radiographically evaluated (transplant patients excluded), 30 patients (41.1%) developed intrahepatic disease progression outside the PTV, including 22/48 patients (45.8%) in the non-HCC and 9/25 patients (36%) in the HCC groups. Salvage chemotherapy was considered for all patients who developed disease progression after completion of SBRT. Seven patients with intrahepatic recurrence outside the PTV from colorectal (4) or breast (1) metastases and HCC (2) received salvage stereotactic radiotherapy re-irradiation and remain alive at the time of last follow up. Two patients with Child–Pugh A cirrhosis completed liver SBRT re-treatment for HCC recurrence outside the PTV during the waiting period prior to successful OLT. Median time to salvage SBRT for patients with metastases was 17 months (range 2–63 months) and 12.6 months (range 2–60 months) for the HCC group. We applied the same dose constraints in the re-treatment setting as reported in the “Materials and methods” section utilizing 3D-CT/SPECT treatment planning for patients with cirrhosis. Full dose overlap liver volume of up to 5 cc (cumulative dose 90–100 Gy) was observed in two patients with hepatic metastases and one patient with HCC. There was no incidence of hepatic or GI toxicity in the entire re-treatment group. Survival Excluding the 4 patients who were not evaluated for control either radiographically or pathologically because of short follow up, the median survival was not reached for patients with HCC, including for both subgroups with and without liver transplant. The median survival was 26.9 months (range 5.3–64.1 months)
HPB 2016, 18, 88–97
for patients with isolated hepatic metastases. The actuarial OS for HCC (metastases) was 82.3% (71.2%) at the median followup of 20.3 months, and 82.3% (64.2%) at 2 years following SBRT (Fig. 2(d)). The actuarial OS at median follow up for HCC patients who did not receive liver transplant was 71.3%. All 14 patients who completed OLT were alive throughout the entire length of followup (Fig. 2(c)). Two patients from each group died from non-liver-cancer related causes including peritoneal carcinomatosis from pancreatic cancer (five months from SBRT), diffuse bilateral pulmonary metastases from non-small cell lung cancer (six months), AIDS-related complications (8.5 months) and combination of septic condition with coagulopathy (3.8 months).
Discussion In this single center retrospective study we report on the efficacy and toxicity of SBRT in 87 assessable patients with primary and metastatic liver tumors delivered as a single modality (65), in combination with hepatic resections (8) or as a bridge to transplant (14). The SBRT technique included current advances in tumor localization, assessment and control of respiratory motion, multi-beam conformal targeting and daily image guidance. In addition, all patients with hepatic cirrhosis completed 99m Tc labeled sulfur colloid liver SPECT co-registered with treatment planning 3D-CT for delineation and subsequent selective avoidance of residual functionally active hepatic parenchyma during SBRT. Local control was as high as 96% (1/25 failure) for the HCC group not receiving OLT and 93.8% (3/48 failures) for the metastatic group of patients (p = 0.397), with tumor size as a strong predictor. Local control was 100% for lesions with maximal tumor diameter 4 cm or less, compared to 82.6% (4/23 failures) for lesions more than 4 cm (p = 0.008). Overall survival at 2 years was 70.2% (64.2% for patients with hepatic metastases and 82.3% for HCC patients), exceeding 2year survival rates in other published SBRT series.10,11,23,24 Toxicity profile for this non-invasive treatment was favorable, with Grade 2 fatigue as the most prevalent toxicity observed. Local therapies directed to the primary or solitary metastases may be curative or result in long term tumor control with prolongation of hepatic failure-free survival. Surgery remains the gold standard curative option with 5-year survival rates around 70% for patients with small HCC and early stage cirrhosis, and with 1 and 5-year survival for selected isolated hepatic metastases (colorectal and non-colorectal primaries) of about 95% and 40%, respectively.1,2,6 Unfortunately, greater than 80% of patients with hepatic metastases are not candidates for hepatectomy at the time of initial presentation.1,5 Likewise most hepatomas are not resectable due to size, location or liver function impairment. Radiofrequency ablation (RFA) can be an alternative to surgery however, analysis of a prospective database at a tertiary care center demonstrates that RFA for solitary colorectal cancer metastasis not amendable for safe resection is associated with a
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
95
higher local recurrence rates and shorter recurrence-free and overall survival compared with hepatic resections even when small lesions (3 cm) are considered.6 Less invasive transarterial chemoembolization (TACE) has only modest impact on survival compared with best symptomatic care alone in patients with hepatomas.26,27 Although the dose range in our study was moderate in terms of biological equivalent dose compared to 60 Gy in 3 fractions used in the prospective Phase I/II multi-institutional study,11 local control as observed in our study was equivalent or superior to other SBRT trials regarding hepatic malignancies.10,23,24 It should be noted that with excellent local control rates, SBRT in our study and other SBRT trials was used for tumors larger than 3 cm, in the proximity of major blood or biliary vessels, or next to the diaphragm or chest wall – all representing challenging or prohibitive locations for RFA or surgery. It has to be admitted, that tumor size was a strong predictor of local control in our study. Four patients with tumor maximal diameter >4 cm developed in-field local recurrence which can be influenced by the growing proportion of radioresistant hypoxic cells in larger tumors. To address this issue, Jacob et al.34 in a retrospective study of liver SBRT with TACE as a radiosensitizing modality, demonstrated better local control and survival for HCC of 3 cm over treatment with TACE only. Oral capecitabine is another promising radiosensitizing agent for concurrent combination with liver radiotherapy for larger unresectable HCC.35 Median survival for patients with liver metastases in our study was 26.9 months compared to 20.5 months in the Intergroup trial. Better treatment outcome observed in our study can be explained in part by patient selection: only 12% of patients had metastases from unfavorable primary sites (lung, ovary, head & neck), 71% of patients were treated for metachronous metastases, and 62% patients did not have extrahepatic metastases at the time of SBRT. Most of our patients were treated for de novo oligometastatic disease (opposed to chemotherapy induced), described by Weichselbaum and Hellman25 as favorable for local treatment. Other factors that may contribute to better outcome in our study compared to early SBRT trials are consistently high SBRT dose range, use of personalized 4D-CT treatment planning to account for tumor respiratory motion margin and daily SBRT image guidance – all contributing to a reduction of systematic errors in daily tumor targeting. It has to be acknowledged, that outcome of any radical local therapies directed to isolated metastases is strongly influenced by the presence of chemotherapy and/or targeted biologic agents in the background. It was not possible in our study to assess contribution of systemic therapy on SBRT outcome due to limited number of patients, heterogeneous primary sites, variety of chemotherapy regimens and timing of administration. There was a significant difference in actual and biologically equivalent doses of radiation between groups of patients with hepatic metastases and liver HCC. Yet, local control rates were similar for the two groups. This can be explained by the intrinsic
HPB 2016, 18, 88–97
radiosensitivity of HCC compared to metastatic disease observed and discussed by others.28 Patients who completed planned SBRT for HCC prior to liver transplantation had 100% survival over the entire length of followup compared to 71.3% survival at two years in patients who could not have liver transplant. All 14 transplanted patients benefited from SBRT given as a bridge to transplant or for tumor downsizing. Despite similar SBRT dose and fractionation schedule, 10 patients (70%) achieved complete pathological response with no viable tumor in a specimen at a median time to transplant 6.3 months (2.5–23.3). Partial response was observed in 3 patients (20%) with median time to transplant 3.6 months (2.3–6.8). It is possible that shorter time to transplant may result in incomplete realization of radiation treatment effect. Only one patient with the shortest time to transplant of 52 days had stable disease after receiving SBRT as a bridging therapy to a solitary 3.2-cm HCC. Our outcome for the HCC group of patients is similar to a few published studies.23,24,29,30,34 Jacob et al.34 reported marked improvement in survival of 37 cirrhotic patients who received TACE in combination with adjuvant SBRT for HCC of 3 cm with two-fold reduction of local recurrence rate. Andolino et al.29 reported 2-year local control and overall survival of 90% and 67% respectively among 60 patients treated with SBRT for HCC. Subsequently, 23 patients received liver transplant at a median time of 7 months following radiation and remained alive at the entire length of followup. Of 12 HCC patients who completed hypofractionated stereotactic radiotherapy as bridge to transplant or prior to hepatectomy, Katz et al.30 observed 100% pathological response to treatment in 2 patients, >50% response in 3 patients and <50% pathologic response in 7 patients. Complete pathologic response rate in our study is higher (81%) likely due to the more dose intense SBRT schedule used (BED = 175 Gy3 vs 133 Gy3). No patient in either group developed classic RILD. The absence of accelerated MELD score progression in cirrhotic patients despite the inclusion of 25/43 patients with initial MELD score 10 and 15/41 (36.5%) patients with recurrent ascites and encephalopathy is encouraging. It is well recognized that HCC patients with advanced hepatic cirrhosis are at much higher risk of developing RILD for the same radiation dose than metastatic patients in the absence of cirrhosis, and the severity of hepatic cirrhosis correlates with the incidence of lethal RILD.31–33 Increased sensitivity of cirrhotic liver to irradiation could be explained by proliferation of fibrotic tissue with loss of hepatic functional reserve representing combined function of hepatocytes and non-parenchymal cells residing within sinusoids (Kupffer cells, endothelial cells, stellate and pit cells). All of our patients with HCC completed functional treatment planning with 99mTc sulfur colloid 3D-CT/SPECT for identification of residual, wellperfused functionally active hepatic parenchyma. Liver dose constraints were imposed exclusively on residual functional liver volume. Patients with hepatic cirrhosis in the HCC group developed retraction of functionally active hepatic parenchyma
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
96
compared to the non-HCC, non-cirrhotic group, as we previously reported.16 This resulted in statistically significant reduction of actual and biologically equivalent dose of radiation during SBRT planning by 17% for patients with Child–Pugh A cirrhosis and by 22% for the Child–Pugh B&C patients (Table 2). We postulate that tailoring hepatic dose-volume constraints to residual functionally active liver parenchyma defined on 99mTc sulfur colloid SPECT, with its subsequent conformal avoidance from high-dose irradiation during 3D-CT/SPECT treatment planning may contribute to reduction of hepatic toxicity in cirrhotic patients. However, a prospective randomized trial is required to estimate the true value of this method. In conclusion, our retrospective study indicates that SBRT is a safe, non-invasive treatment for unresectable primary and metastatic liver tumors providing excellent local control. It is an effective and reliable bridging therapy for patients awaiting liver transplantation with excellent pathological response. It can be used to target unresectable metastases in combination with limited hepatectomies for resectable peripheral lesions thereby expanding indications for resection of multiple hepatic metastases. This particular combination exploits the strengths of liver SBRT and hepatic resection while compensating for each treatment’s limitations.
7. Ueno, S., Sakoda, M., Kubo, F., Hiwatashi, K., Tateno, T., Baba, Y., et al. (2009). Surgical resection versus radiofrequency ablation for small hepatocellular carcinomas within the Milan criteria. J Hepatobiliary Pancreat Surg, 16, 359–366. 8. Zhou, Y., Zhao, Y., Li, B., Xu, D., Yin, Z., Xie, F., Yang, J., et al. (2010). Meta-analysis of radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma. BMC Gastroenterol, 10, 78–85. 9. Herfarth, K. K., & Debus, J. (2005). Stereotactic radiation therapy for liver metastases. Chirurg, 76, 564–569. 10. Hoyer, M., Roed, H., Traberg, H. A., Ohluis, L., Petersen, J., Nellemann, H., et al. (2006). Phase II study on stereotactic body radiotherapy of colorectal metastases. Acta Oncol, 45, 823–830. 11. Rusthoven, K. E., Kavanagh, B. D., Cardenes, H., Stieber, V. W., Burri, S. H., Feigenberg, S. J., et al. (2009). Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol, 27, 1572–1578. 12. Goodman, K. A., Wiegner, E. A., Maturen, K. E., Zhang, Z., Mo, Q., Yang, G., et al. (2010). Dose-escalation study of single-fraction stereotactic body radiotherapy for liver malignancies. Int J Radiat Oncol Biol Phys, 78, 486–493. 13. Chang, D. T., Swaminath, A., Kozak, M., Weintraub, J., Koong, A. C., Kim, J., et al. (2011). Stereotactic body radiotherapy for colorectal liver metastases: a pooled analysis. Cancer, 117, 4060–4069. 14. Scorsetti, M., Arcangeli, S., Tozzi, A., Comito, T., Alongi, F., Navarria, P., et al. (2013). Is stereotactic body radiation therapy an attractive option for unresectable liver metastasis? A preliminary report from a phase 2
Sources of funding for research and/or publication
trial. Int J Radiat Oncol Biol Phys, 86, 336–342. 15. Gayou, O., Day, E., Mohammadi, S., & Kirichenko, A. (2012). A method
None.
for registration of single photon emission computed tomography (SPECT) and computed tomography (CT) images for liver stereotactic
Conflicts of interest
radiotherapy (SRT). Med Phys, 39, 7398–7401.
None declared.
16. Kirichenko, A., Thai, N., Lappinen, E., Gayou, O., Kotinsley, K., Day, E., et al. (2013). Outcomes of Stereotactic radiotherapy (SRT) for primary
References 1. Groeschl, R. T., Nachmany, I., Steel, J. L., Reddy, S. K., Glazer, E. S., de
and metastatic liver tumors with 3-D CT and single photon emission
Jong, M. C., et al. (2012). Hepatectomy for noncolorectal non-
computed tomography (3D-CT/SPECT) treatment planning. Presented
neuroendocrine metastatic cancer: a multi-institutional analysis. J Am
at ASTRO 2013. Int J Radiat Oncol Biol Phys, 84, 11. 17. Urata, K., Kawasaki, S., Matsunami, H., Hashikura, Y., Ikegami, T.,
Coll Surg, 214, 769–777. 2. Fong, Y., Sun, R., Jamagin, W., & Blumgart, L. H. (1999). An analysis of 412 cases of hepatocellular carcinoma at a Western Center. Ann Surg,
Ishizone, S., et al. (1995). Calculation of child and adult standard liver volume for liver transplantation. Hepatology, 21, 1317–1321. 18. Kennedy, A., Nag, S., Salem, R., Murthy, R., McEwan, A. J., Nutting, C.,
229, 790–800. 3. Yao, F., Ferrell, L., Bass, N., Watson, J. J., Bacchetti, P., Venook, A.,
et al. (2007). Recommendations for radioembolization of hepatic ma-
et al. (2001). Liver transplantation for hepatocellular carcinoma:
lignancies using yttrium-90 microsphere brachytherapy: a consensus
expansion of the tumor size limits does not adversely impact survival.
panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys, 68, 13–23.
Hepatology, 33, 1394–1403. 4. Gold, J. S., Are, C., Kornprat, P., Jarnagin, W. R., Gönen, M., Fong, Y.,
19. Leibel, S. A., Pajak, T. F., Massullo, V., Order, S. E., Komaki, R. U.,
et al. (2008). Increased use of parenchymal-sparing surgery for bilateral
Chang, C. H., et al. (1987). A comparison of misonidazole sensitized
liver metastases from colorectal cancer is associated with improved
radiation therapy to radiation therapy alone for the palliation of hepatic
mortality without change in oncologic outcome: trends in treatment over
metastases: results of a Radiation Therapy Oncology Group random-
time in 440 patients. Ann Surg, 247, 109–117.
ized prospective trial. Int J Radiat Oncol Biol Phys, 13, 1057–1064.
5. Nordlinger, B., Van Cutsem, E., Rougier, P., Köhne, C. H., Ychou, M.,
20. Russell, A. H., Clyde, C., Wasserman, T. H., Turner, S. S., & Rotman, M.
Sobrero, A., et al. (2007). Does chemotherapy prior to liver resection
(1993). Accelerated hyperfractionated hepatic irradiation in the man-
increase the potential for cure in patients with metastatic colorectal
agement of patients with liver metastases: results of the RTOG dose
cancer? A report from the European Colorectal Metastases Treatment Group. Eur J Cancer, 43, 2037–2045. 6. Aloia, T. A., Vauthey, J. N., Loyer, E. M., Ribero, D., Pawlik, T. M., Wei, S. H., et al. (2006). Solitary colorectal liver metastasis: resection determines outcome. Arch Surg, 141, 460–466.
HPB 2016, 18, 88–97
escalating protocol. Int J Radiat Oncol Biol Phys, 27, 117–123. 21. Penna, C., & Nordlinger, B. (2002). Colorectal metastasis (liver and lung). Surg Clin North Am, 82, 1075–1090. 22. Reed, G. B., Jr., & Cok, A. J., Jr. (1966). The human liver after radiation injury. A form of veno-occlusive disease. Am J Pathol, 48, 597–611.
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
HPB
97
23. Dawson, L. A., Eccles, C., & Craig, T. (2006). Individualized image guided iso-NTCP based liver cancer SBRT. Acta Oncol, 45, 856–864.
carcinoma: clinical outcome and pathological correlation. Int J Radiat Oncol Biol Phys, 83, 895–900.
24. Mendez-Romero, A., Wunderink, W., Hussain, S. M., De Pooter, J. A.,
31. Lawrence, T. S., Ten Haken, R. K., Kessler, M. L., Robertson, J. M.,
Heijman, B. J., Nowak, P. C., et al. (2006). Stereotactic body radiation
Lyman, J. T., Lavigne, N. L., et al. (1992). The use of 3-D dose volume
therapy for primary and metastatic liver tumors: a single institution
analysis to predict radiation hepatitis. Int J Radiat Oncol Biol Phys, 23,
phase i-ii study. Acta Oncol, 45, 831–837.
781–788.
25. Weichselbaum, R. R., & Hellman, S. (2011). Oligometastases revisited. Nat Rev Clin Oncol, 8, 378–382.
32. Cheng, J. C., Wu, J.-K., Lee, P. C., Liu, H. S., Jian, J. J., Lin, Y. M., et al. (2004). Biologic susceptibility of hepatocellular carcinoma in patients
26. Lo, C. M., Ngan, H., Tso, W. K., Liu, C. L., Lam, C. M., Poon, R. T., et al. (2002). Randomized controlled trial of transarteriallipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology, 35, 1164–1171.
treated with radiotherapy to radiation induced liver disease. Int J Radiat Oncol Biol Phys, 60, 1502–1509. 33. Liang, S. X., Zhu, X. D., Xu, Z. Y., Zhu, J., Zho, J. D., Lu, H. J., et al. (2006).
27. Llovet, J. M., Real, M. I., Montana, X., Planas, R., Coll, S., Aponte, J.,
Radiation-induced
liver
disease
in
three-dimensional
conformal radiation therapy for primary liver carcinoma: the risk fac-
et al. (2002). Arterial embolisation or chemoembolisation versus
tors and hepatic radiation tolerance. Int J Radiat Oncol Biol Phys, 65,
symptomatic treatment in patients with unresectable hepatocellular
426 –434.
carcinoma: a randomised controlled trial. Lancet, 359, 1734–1739.
34. Jacob, R., Turley, F., Redden, D. T., Saddekni, S., Aal, A. K., Keene, K.,
28. Klein, J., & Dawson, L. A. (2013). Hepatocellular carcinoma radiation
et al. (2015). Adjuvant stereotactic body radiotherapy following trans-
therapy: review of evidence and future opportunities. Int J Radiat Oncol
arterial chemoembolization in patients with non-resectable hepatocellular carcinoma tumours of 3cm. HPB, 17, 140–149.
Biol Phys, 87, 22–32. 29. Andolino, D. L., Johnson, C. S., Maluccio, M., Kwo, P., Tector, A. J.,
35. McIntosh, A., Hagspiel, K. D., Al-Osaimi, A. M., Northup, P.,
Zook, J., et al. (2011). Stereotactic body radiotherapy for primary he-
Caldwell, S., Berg, C., et al. (2009). Accelerated treatment using
patocellular carcinoma. Int J Radiat Oncol Biol Phys, 81, 447–453.
intensity modulated radiotherapy plus concurrent capecitabine
30. Katz, A., Chawla, S., & Qu, Z. (2012). Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular
HPB 2016, 18, 88–97
for
unresectable
hepatocellular
carcinoma.
Cancer,
115,
5117 – 5125.
© 2015 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.