Stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma and oligometastatic liver disease

Stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma and... Background: To report our experience with SBRT in primary and secondary liver tumors. Methods: We retrospectively analysed 55 patients (70 lesions) with a median follow-up of 10 months (range 1–57) treated from 2011 to 2016. All patients had not been eligible for other local treatment options. Median age was 64 years and 64% were male. 27 patients (36 lesions) suffered from hepatocellular carcinoma (HCC, Child A:78%, Child B:18%, Child C:4%), 28 patients (34 lesions) had oligometastatic liver disease (MD). Treatment planning was based on 4D-CT usually after placement of fiducials. Dose and fractionation varied depending on localization and size, most commonly 3 × 12.5 Gy (prescribed to the surrounding 65%-isodose) in 56% and 5x8Gy (80% isodose) in 20% of the treated lesions. Results: Local recurrence was observed in 7 patients (13%) and 8 lesions (11%), resulting in estimated 1- and 2-year local control rates (LC) of 91 and 74%. Estimated 1- and 2-year rates of Freedom from hepatic failure (FFHF) were 42 and 28%. Number of lesions was predictive for LC and FFHF in the entire cohort. Estimated 1- and 2-year overall survival (OS) was 76 and 57%. OS was significantly affected by number of treated lesions and performance status. In the HCC subgroup, pretreatment liver function and gender were also predictive for OS. Maximum acute non-hepatic toxicity was grade 1 in 16%and grade2in10%of thepatients. ThreeHCC patients (11%) developed marked deterioration of liver function (grade 3/4). Conclusions: SBRT resulted in high local control and acceptable survival rates in patients with HCC or MD not amendable to other locally-ablative treatment options with limited toxicity. Care should be taken in HCC patients with Child B cirrhosis. Keywords: Liver, HCC, Oligometastatic, SBRT Background Treatment options range from liver transplantation (for Primary and metastatic liver tumors are among the most HCC) or extended surgical resections (for MD) to less inva- common malignancies and tumour-related causes of death sive techniques like radiofrequency ablation (RFA), transar- worldwide [1, 2]. Treatment paradigms have changed dra- terial chemoembolization (TACE) or selective internal matically in the last decades in favor of local treatments in radiotherapy (SIRT). However, the potential benefit of such primary liver cancers and oligometastatic (especially treatment options needs to be weighed against the possibil- liver-confined) disease because of the evolving evidence for ity that local treatment results in impairment of liver func- possible cure or at least long-term survival [3, 4]. tion or liver failure, especially in the presence of an underlying liver disease, which is the background upon * Correspondence: falk.roeder@med.uni-muenchen.de most primary malignancies arise [4]. Moreover, any of the Department of Radiation Oncology, University Hospital LMU Munich, mentioned treatments has its limitations. For example sur- Marchioninistr. 15, 81377 Munich, Germany gery is often limited by comorbidities or poor liver function CCU Molecular Radiation Oncology, German Cancer Research Center, Heidelberg, Germany [4] while lesions directly adjacent to major vessels or bile Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gerum et al. Radiation Oncology (2018) 13:100 Page 2 of 9 ducts are not well suited for RFA [5]and patients with por- then, an increasing number of patients have been treated tal vein thrombosis are not eligible for TACE [6]. each year (fig. 1). For the current analysis, we retrospect- Stereotactic body radiation therapy (SBRT) is a highly ively selected and analyzed all patients affected by HCC conformal technique of percutaneous radiation therapy or MD who underwent SBRT to 1–3 liver lesions. Indi- delivered in a small number of large fractions [7]. It suf- cation for SBRT was seen in patients not eligible for ficiently spares dose to adjacent organs at risk due to its other local treatment options according to multidiscip- sharp dose fall-off outside the target, while adequate linary evaluation. Pretreatment investigations included tumor control is maintained due to the enhanced bio- MRI and/or contrast-enhanced biphasic liver CT, liver logical effectivity of the large single doses. Stereotactic function tests for HCC patients and additional CT/ radiation approaches have been already successfully in- PET-CT staging for MD patients. troduced into the treatment of primary and secondary brain and lung tumors and have shown to result in low Patient characteristics toxicity and at least comparable outcome with regard to The entire cohort consisted of 55 patients with 70 surgery [7–10]. Several groups have shown that SBRT treated lesions. Median age was 64 years (31–83), 64% can also be effectively employed with acceptable toxicity were male and the median Karnofsky performance score for the treatment of liver malignancies [11]. However, no (KPS) was 90% (60–100%). 28 patients showed MD in randomized trials comparing SBRT to other local treat- whom 34 lesions were treated. Most of them suffered ment options have been conducted so far, and only from colorectal cancer (32%) followed by NSCLC (14%) scarce prospective data on the employment of SBRT in and soft-tissue sarcomas (14%). 27 patients showed HCC the treatment of liver lesions are available. Moreover, no in whom 36 lesions were treated. Underlying liver cir- generally accepted criteria for patient selection or a gen- rhosis was present in all HCC patients, caused by viral erally accepted dose and fractionation concept exists. hepatitis (B and C) in 10 patients (37%), alcohol con- Therefore we report our experience with SBRT for pri- sumption in 5 (19%), autoimmune hepatitis in 1 (4%) mary and secondary liver tumors. and by unknown reason in 11 patients (41%). Liver func- tion was moderately restricted in the majority of them Methods (Child A: 21[78%], Child B: 5[18%], Child C: 1[4%]), In our institution, SBRT has been used for the treatment Table 1. The patient with Child C cirrhosis presented of malignant liver lesions for the first time in 2011. Since with good performance score and was listed for liver Fig. 1 Number of treatments per year Gerum et al. Radiation Oncology (2018) 13:100 Page 3 of 9 Table 1 patient and treatment characteristics entire cohort HCC MD number of patients 55 27 28 number of lesions 70 36 34 single/multiple lesions 40/15 18/9 22/6 gender (male/female) 35/20 19/8 16/12 age (median/range in years) 64/31–83 63/46–83 67/31–80 KPS (median/range in %) 90/60–100 90/60–100 95/70–100 histology (CRC/LC/BC/S/O) –– 10/4/4/2/9 Child-Pugh stage (A/B/C) – 21/5/1 – fiducials (n/%) 42/76 18/67 24/86 abdominal compression (n/%) 26/47 14/52 12/43 GTV per patient (median/range in ccm) 14.6/0.4–204 15.5/1.2–204 13.25/0.4–98.2 GTV per lesion (median/range in ccm) 6.6/0.2–204 7.5/0.9–204 6.2/0.2–98.2 PTV per patient (median/range in ccm) 75.5/17.7–511.6 92.7/17.7–511.6 61.1/19.3–314 PTV per lesion (median/range in ccm) 59/15–512 61/15–512 51/15–314 dose concept (3 × 12.5/5 × 8/other) 28/11/16 16/6/5 12/5/9 BED max (median/range) 168.1/60.3–190 168.2/60.3–168.2 118/80.4–190 actual treatment (SBRT/TACE+SBRT) – 12/15 – HCC: hepatocellular carcinoma, MD: metastatic disease, KPS: Karnofsky performance score, CRC: colorectal cancer, LC: lung cancer, BC: breast cancer, S: sarcoma, o: other, GTV: gross tumor volume [cubic centimeters], PTV: planning target volume [cubic centimeters], BED: biologically equivalent dose, SBRT: stereotactic body radiotherapy, TACE: transarterial chemoembolization, all doses in [Gy] transplantation, therefore our interdisciplinary tumor- contrast-enhanced 4D-CT. Gross tumor volume (GTV) board opted for SBRT as bridging. was contoured as the visible tumor on the free-breathing CT and on all respiratory phases of the 4D-CT supple- Treatment characteristics mented by information from MRI if available. An in- Treatment in HCC patients consisted of SBRT alone in ternal target volume (ITV) was constructed and 12 patients while 15 patients received selective TACE to enlarged by an isotropic margin of 6 mm to obtain the the same lesions upfront to SBRT (within 6 weeks). Five planning target volume (PTV). Dose was prescribed to patients received additional RFA treatments to different the PTV surrounding isodose in all patients. Prescription lesions prior to SBRT (within 6 weeks). 23/27 patients isodose, single dose and number of fractions depended had a median of 2 (range 1–8) previous local treatments on size and location of the lesions. Number of lesions (surgery, RFA, TACE or SIRT). Treatment of metastatic did not influence prescription dose in general. The most patients consisted of SBRT alone in 25 patients or SBRT common schemes were 3 × 12.5 Gy (65%-isodose) in combined with surgery or RFA to different lesions 56% and 5x8Gy (80%-isodose) in 20% of the treated le- (within 6 weeks) in 3 patients. Primary tumor was con- sions delivered every other day. Implanted fiducials or trolled in all patients with MD at the time of SBRT. lipiodol enhancement were contoured accordingly to re- Additive systemic therapy within three months from ceive a fiducial or lipiodol ITV, which was used for daily SBRT was given to 1 patient with HCC and 8 patients patient set-up. Treatment was performed using daily with MD. CBCT image-guidance. SBRT Statistical and legal considerations Prior to SBRT, 42 patients received CT-guided implant- Regular follow-up examinations (including physical ation of 1–3 fiducials (Visicoil™, IBA dosimetry or examination, laboratory tests (liver function and tumor MPB™, MPB Scherer Medizinprodukte) per lesion unless marker tests), MRI/CT of the liver) took place at our de- enhancement of lipiodol in patients with prior TACE partment or the departments of gastroenterology/oncol- (n = 8) or the presence of surgical clips (n = 5) were ogy every three months for one year, every 6 months for deemed sufficient to guide the procedure. Patients were the second and annually thereafter. Toxicity was scored immobilized using a vacuum pillow in combination with retrospectively according to CTCAE v4.03. Because of an alpha-cradle. Abdominal compression was used since the retrospective nature not all patients had received 2014 (n = 26, 47%). Treatment planning was based on exactly the same laboratory tests. Therefore changes in Gerum et al. Radiation Oncology (2018) 13:100 Page 4 of 9 Table 2 univariate analysis for LC, FFHF and OS p-value of < 0.05 was defined as statistically significant. The analysis was in accordance to the declaration of LC FFHF OS Helsinki in its latest version and was approved by our in- 1-year p value 1-year p value 1-year p value rate rate rate dependent Ethics committee. gender Results male 88% 0.279 44% 0.679 83% 0.055 Median follow-up in all patients was 10 months (1–57) female 94% 41% 67% and 13 months in survivors. Since implementation of age the technique at our center in 2011 we have seen a con- ≤ median (64 yrs) 92% 0.265 40% 0.687 77% 0.76 tinuous increase in patient numbers per year resulting in > median 90% 43% 75% 56% of the included patients treated in 2015/16 (fig. 1). Median GTV (measured on free-breathing CT) per pa- histology tient was 14.6 ccm (0.4–204) and 6.6 ccm per lesion HCC 92% 0.492 41% 0.895 68% 0.701 (0.2–204) and median PTV was 75.5 ccm (17.7–511.6) MD 89% 40% 84% per patient and 59 ccm (15–512) per lesion. KPS ≤70 100% 0.425 42% 0.579 50% 0.028 LC > 70 90% 42% 79% Local recurrence was observed in 7/55 patients (13%) translating into estimated 1- and 2-year LC-rates of 91 GTV and 74% (fig. 2). Median time to local failure in these 7 ≤ median (14.6 ccm) 100% 0.535 46% 0.794 80% 0.416 patients was 8 months (2–39). In univariate analysis, > median 88% 44% 77% only the number of lesions was predictive for LC BED (1-year-LC single 97% vs. multiple 67%,p = 0.011, Fig. 2, ≤ 100 87% 0.651 38% 0.419 75% 0.806 Table 2). In the HCC group we observed estimated 1- > 100 94% 48% 77% and 2-year LC-rates of 92%. The number of lesions was the only factor with significant impact on LC (1-year-LC lesions single 100% vs. multiple 71%,p = 0.024). No significant single 97% 0.011 49% 0.047 80% < 0.001 difference was observed comparing patients with TACE multiple 67% 19% 40% +SBRT versus SBRT alone. In the MD group, we ob- LC: Local control, FFHF: Freedom from hepatic failure, OS: Overall survival, served estimated 1- and 2-year LC-rates of 89 and 64%. yrs.: years, HCC: hepatocellular carcinoma, MD: metastastic disease, KPS: Karnofsky performance score, GTV: Gross tumor volume (measured per Improved LC was significantly associated with treatment patient on free-breathing CT), ccm: cubic centimeters, BED: biological of a single lesion (1-year-LC 95% vs. 0%,p = 0.027), equivalent dose BED>150Gy (1-year-LC 100% vs. 82%,p = 0.036) and fe- hepatic laboratory tests without symptoms were not male gender (1-year-LC 100% vs. 78%,p = 0.039). We counted as toxicity. Marked deterioration of liver func- further analyzed possible associations between the num- tion was defined as change in CHILD-Pugh class from A ber of lesions and dose parameters (BED maximum, pre- to B or B to C in HCC patients or symptomatic changes scription dose) but did not find any significant in liver function in MD patients. Biological effective dose correlations (data not shown). (BED) of the maximum PTV dose was calculated ac- If LC was analysed per lesion, we observed local fail- cording to the LQ formalism: BED = n*d*(1 + d/{α/β}) ures in 8/70 lesions (11%), translating into 1- and 2-year with n being the number of fractions, d the daily single LC-rates of 91 and 74%. No factors with significant im- fraction dose and alpha-beta for tumor tissue of 10 Gy. pact on LC could be identified for the entire cohort or Local control (LC) was defined as absence of tumor pro- the HCC subgroup. However, regarding the MD sub- gression in the region of the treated lesion. Freedom group, we observed a significant association of LC with from hepatic failure (FFHF) was defined as absence of GTV volume (1-year LC GTV ≤6.25ccm 100% vs. 80% tumor progression in the liver. All time-to-event data with GTV > 6.25ccm;p = 0.041). was calculated from the first day of SBRT using the Kaplan-Meier method. All endpoints and subgroup ana- FFHF lyses are reported referring to patients (not lesions) if 29/55 patients (53%) showed hepatic failure of whom only not otherwise specified. Differences in subgroups were 1 had an isolated local failure, while 22 showed isolated fail- assessed by the logrank test for univariate analysis. Due ures outside the treated volume and 6 had combined fail- to the low number of events multivariate analysis was ures. Estimated 1- and 2-year FFHF-rates were 42 and 28% not performed. The pearsons test was used for evalu- (fig. 3). Again, only the number of lesions (1-yr-FFHF single ation of possible correlations between parameters. A 49% vs. 19% multiple,p = 0.047) was predictive for FFHF Gerum et al. Radiation Oncology (2018) 13:100 Page 5 of 9 Fig. 2 Local control left: entire cohort, right: according to number of treated lesions (Fig. 3,Table 2). In theHCC subgroup,weobservedesti- 1- and 2-year OS-rates of 68 and 57%. OS was signifi- mated 1- and 2-year FFHF-rates of 41%. FFHF was signifi- cantly associated with number of treated lesions cantly affected by the number of lesions (1-year-FFHF (1-year-OS single 84% vs 39% multiple,p < 0.001), pre- single 53% vs 15% in multiple,p =0.01). In the MD sub- treatment liver function (1-year-OS Child-Pugh A 76% group we found estimated 1- and 2-year FFHF-rates of 40 vs. Child-Pugh B 28%,p = 0.036) and gender (1-year-OS and 25%. FFHF was significantly associated with perform- male 83% vs. female 43%,p = 0.049). In the MD subgroup ance status (1-year-FFHF KPS ≤ 70 0% vs. 43% with KPS > we observed estimated 1- and 2-year OS-rates of 84 and 70,p =0.006). 67%. OS was significantly associated with performance status (1-year-OS KPS > 70 90% vs. 33% KPS ≤ 70,p < OS 0.001) and number of treated lesions (1-year-OS single 16 patients (29%) have died, translating into estimated 90% vs. 42% multiple,p = 0.036). 1- and 2-year OS-rates of 76 and 57% (Fig. 4). Prognos- tic factors regarding OS were number of treated lesions Toxicity (1-yr-OS single 88% vs 40% in multiple,p < 0.001, Fig. 4) CT-guided fiducial placement was feasible without any and performance status (1-yr-OS KPS > 70 79% vs 50% complications. SBRT treatment could be performed as KPS ≤ 70,p = 0.028, Fig. 4), see Table 2. A trend was also planned in all except one patient (2%) who prematurely observed for gender (1-yr-OS male 83% vs 67% female, finished radiation treatment due to humerus fracture. p = 0.055). In the HCC subgroup we observed estimated Maximum acute toxicity was grade 1 in 9 patients (16%), Fig. 3 Freedom from hepatic failure left: entire cohort, right: according to number of treated lesions Gerum et al. Radiation Oncology (2018) 13:100 Page 6 of 9 Fig. 4 Overall Survival left: entire cohort, middle: according to number of treated lesions, right: according to performance status grade 2 in 6 (10%), grade 3 in 2 (4%) and grade 4 in 1 Mendez-Romero et al. [12] described their results of a patient (2%), see Table 3. The most frequent side effects phase I-II trial including 25 patients with HCC or MD were fatigue and gastrointestinal symptoms like mild treated mainly with a 3 × 12.5Gy concept and found 1- nausea or diarrhea. Three patients with HCC (11%) de- and 2-year LC-rates of 91 and 82%. If HCC and MD are veloped marked deterioration of liver function without considered separately, our results are still in the pub- disease progression. Two had a decline in Child-Pugh lished range of 75–100% 1-year-LC in HCC [4]and 71– stage from A to B. One patient with Child-Pugh C cir- 94% 1-year-LC in MD patients [13] reported in recent rhosis developed hepatic failure (grade 4) shortly after major series (Table 4). SBRT which was successfully treated by liver With regard to OS, we observed 1- and 2-year-rates of transplantation. 76 and 57% for the entire cohort. OS seemed to be slightly better in the MD group with 1- and 2-year Discussion OS-rates of 84 and 67% compared to the HCC group Outcome with SBRT with 1- and 2-year OS-rates of 68 and 57%, although this Regarding LC, we observed 1- and 2-year-rates of 91 difference did not reach statistical significance. and 74% for the entire cohort. LC seemed slightly im- Mendez-Romero et al. [12] described similar outcomes proved in the HCC group with 1- and 2-year-rates of with 1- and 2-year OS-rates of 82 and 54% for the whole 92% compared to the MD group with 1- and group, 85 and 62% for patients with MD and 75 and 2-year-rates of 89 and 64%, although this difference did 40% for patients with HCC. Moreover, our results are in not reach statistical significance. These results are in line the range of published results focusing on primary or with other series including both primary and secondary secondary liver tumors with 1- and 2-year OS-rates of liver tumors treated with similar concepts. For example 62–85% and 38–70% in metastatic patients [3] and 55– 100 and 53%–69% in HCC patients [4]. In contrast to the encouraging rates for LC and OS, Table 3 Acute toxicity we observed rather poor 1- and 2-year FFHF-rates of 42 CTCAE CTCAE ° CTCAE ° CTCAE ° and 28% for the entire cohort, which were mainly driven °I II III IV by intrahepatic outfield failures indicating a high risk for n (%) the development of new lesions in these heavily pre- nausea (n/%) 4 (7) 4 (7) treated patients. This pattern was seen in patients with fatigue 3 (5) HCC (1- and 2-year FFHF 42%) as well as in patients pneumonitis 1 (2) with MD (1- and 2-year FFHF 40 and 25%) although tachyarrhythmia 1 (2) more pronounced in the latter group. Similar results have been reported by others for both entities. For ex- cholangitis 1 (2) ample Yoon et al. [14] found a crude rate of 63% intra- diarrhea 1 (2) hepatic outfield failures and 71% hepatic failures in total, severe deterioration of liver n.a. n.a. 2 (4) 1 (2) translating into a 1-year hepatic-failure-free-survival-rate function of 52% in their cohort of 92 patients with HCC treated n.a.: not applicable, CTCAE: common toxicity criteria for adverse events Version 4.03 with SBRT. Chang et al. [15] reported a crude rate of Gerum et al. Radiation Oncology (2018) 13:100 Page 7 of 9 Table 4 Selected SBRT series in patients with primary and secondary liver tumors Author, Year n (patients) n (primary LT) GTV volume 1 yr-LC (%) 1 yr-OS (%) Toxicity Study-Type n (lesions) n (metastases) (median/range) (HCC/MD) (HCC/MD) Gr3+ (%) Mendez-Romero et al. 2006 25 HCC: 11 3.5 (0.5–7.2) 94 82 12.5 Phase I/II 45 MD: 34 (75/100) (75/85) Goodman et al. 26 HCC/CCC: 7 32.6 (0.8–146.6) 77 62 0 2010 40 MD: 19 Phase I Own data 55 HCC: 27 6.6 (0.2–204) 91 76 5 70 MD: 28 (92/89) (68/84) Bujold et al. 102 HCC only 7.2 (1.4–23.1) 87 55 30 Phase I/II Lasley et al. 59 HCC only 33.6 (2.2–107.3) 91 (Child A) 94 (Child A) 11 (Child A) 2015 59 82 (Child B) 57 (Child B) 38 (Child B) Phase I/II Own data 27 HCC only 7.5 (0.9–204) 92 68 11 Scorsetti et al. 42 MD only 3.5 (1.1–5.4) 91 (2 yr) 65 (2 yr) 0 2015 52 Phase I/II Andratschke et al. 74 MD only n.r. 75 77 0 2015 91 Retro, pooled Own data 28 MD only 6.2 (0.2–98.2) 89 84 0 n: number, LT: liver tumors, GTV: gross tumor volume per lesion, yr.: year, LC: local control, OS: overall survival, HCC: hepatocellular carcinoma, MD: metastatic a b disease, Gr3+: grade 3+, in cubic centimeters, : deterioration of liver function, no other grade 3+ toxicity, n.r.: not reported 68% intrahepatic outfield failures in their study on 65 diameter [15, 23], GTV volume [16, 17] and dose [24] patients with colorectal liver metastases. for HCC and/or MD as well as Child-Pugh stage for HCC [17, 24] and histology for MD [16, 22]. However, Prognostic factors the prognostic value of those factors is far from being We analyzed our entire cohort and both subgroups consistently evident as negative or even opposing results (HCC and MD) with regard to possible prognostic fac- have been reported also for any of the mentioned factors tors for each endpoint. Regarding LC, lesion size [16– [15, 16, 20, 21, 23, 25]. In our study, we identified the 18] and dose of SBRT [5, 15, 16, 18–20] have been the number of lesions and performance status as factors as- most consistently reported prognostic factors for both sociated with OS for the entire cohort. In the HCC sub- groups. Although a variety of definitions and tresholds group Child-Pugh stage and gender were additional have been used and some studies did not found any as- factors with significant impact. Although conflicting data sociations at all [19–22]. We could not confirm a statis- exists, it seems reasonable to assume that patients with tically significant association of GTV volume or BED multiple lesions are at higher risk for the development with LC regarding the entire cohort and the subgroup of of consecutive lesions with consequently reduced sur- HCC patients. However, we observed a significantly re- vival, especially in a patient group like ours with limited duced LC-rate with lower BED and larger GTV volume salvage options. This is further supported by our data in the subgroup of patients with MD, thus emphasizing with regard to the clearly reduced FFHF in patients with the findings of others suggesting a relationship between multiple lesions. The same assumption seems true for LC and lesion size and/or dose at least in metastatic pa- performance status which has been shown in many tients. Interestingly, the number of lesions was the main other oncological situations to be a key factor in predict- factor in our study with a significant impact on LC, ing outcome [26, 27]. Regarding the HCC subgroup, it however this might be simply due to statistical reasons has been shown that OS is clearly associated with as patients with more lesions obviously have a high Child-Pugh stage [28]. It therefore seems no surprise probability to fail at least in one. that OS of patients with HCC lesions (which developed Regarding OS, an even larger variety of factors with on the basis of advanced liver cirrhosis) is affected by possible impact have been described in the literature, in- the severity of the underlying cirrhosis. In contrast, the cluding gender [23], number of lesions [22], lesion observed negative influence of female gender on OS of Gerum et al. Radiation Oncology (2018) 13:100 Page 8 of 9 HCC patients is difficult to explain. Huertas et al. [23] Limitations reported a similar result in their HCC series even ac- Clearly our analysis has some limitations, namely its cording to multivariate analysis, however Yamashita et retrospective nature, the small sample size, the mixed al. [25] found the opposite association leaving this ques- cohort and the rather short follow-up. However, in the tion unanswered. absence of prospective randomized trials and only a lim- ited number of prospective studies reported in the litera- Toxicity ture our experience may help clinicians and researchers Given the high rate of outfield failures with the need for to guide their further decisions. salvage treatments, toxicity and preservation of liver function are of important value in the decision process Conclusions for locally-ablative treatments. With our approach, we SBRT resulted in high LC and acceptable survival rates observed high treatment compliance with predominantly in patients with HCC or MD not amendable to other mild toxicities mainly including fatigue and nausea. locally-ablative treatments. However, especially patients Three patients with HCC (11%) developed marked de- with multiple lesions are at high risk for intrahepatic terioration of liver function. Similar results have been outfield failures indicating a possible need for additional published in most other series. For patients treated for therapies. OS was predicted by number of lesions and MD, acute and late grade3+ toxicities are reported in the performance status as well as pretreatment liver function range of 0–16% and 0–5% [3]. Similar to our results, in HCC patients. Toxicity was generally mild. High Andratschke et al. [16] reported mild side effects mainly grade toxicity was restricted to patients with HCC suf- consisting of fatigue and nausea but no grade3+ reac- fering from underlying cirrhosis Child-Pugh class B indi- tions in their series of 74 patients treated with compar- cating the need for special attention in those patients. able dose and fractionation concepts. In patients with HCC higher complications rates have been observed. Abbreviations 4D-CT: Four-dimensional computed tomography; BED: Biologically effective Acute grade3+ toxicities ranged from 5 to 37% including dose; CBCT: Cone beam computed tomography; ccm: Cubic centimeters; up to 7% deaths [4], mainly in Child-Pugh B patients. CT: Computed tomography; CTCAE: Common toxicity criteria for adverse Decline in Child-Pugh class has also been reported in events; FFHF: Freedom from hepatic failure; GTV: Gross tumor volume; Gy: Gray; HCC: Hepatocellular carcinoma; ITV: Internal target volume; 13–29% [12, 20, 24], although some authors described a KPS: Karnofsky performance score; LC: local control; MD: Oligometastatic marked recovery over time [20]. Our toxicity rate seem disease; MRI: Magnetic resonance imaging; OS: Overall survival; PET- to compare favorably with those rates, however some of CT: Positron-emission-tomography with computed tomography; PTV: Planning target volume; RFA: Radiofrequency ablation; RILD: Radiation these studies included larger lesions resulting in more induced liver disease; SBRT: Stereotactic body radiation therapy; dose to normal liver tissue and a higher percentage of SIRT: Selective internal radiotherapy; TACE: Transarterial chemoembolization Child-Pugh B patients. Both factors have been shown to be associated with toxicity [24, 29]. For example Ando- Funding The study did not receive any funding. lino et al. [24] described progressive liver dysfunction in 4/8 patients with Child-Pugh≥8 of whom 2 could be sal- Availability of data and materials vaged by transplant but 2 died. They concluded to fur- The datasets used and/or analysed during the current study are available ther treat Child-Pugh B patients only if listed for from the corresponding author on reasonable request. transplantation. Lasley et al. [29] observed grade 3/4 liver toxicity of 11% in patients with Child-Pugh A com- Authors contributions SG performed data acquisition and participated in patient treatment, pared to 38% in Child-Pugh B patients and further ex- statistical analysis and in drafting the manuscript. CH participated in cluded patients with Child-Pugh≥8 from treatment. treatment of the patients and statistical analysis. FW, PP, ED treated the Finally, Culleton et al. [30] analyzed specifically patients patients and participated in data acquisition. CB revised the manuscript critically. FR participated in data acquisition, statistical analysis, treatment of with Child-Pugh B/C and described a decline of ≥2 the patients, drafting the manuscript and critically reviewed the data and the points in 63% at 3 months. Therefore SBRT treatment manuscript. All authors read and approved the final manuscript should be used with caution or restricted in dose in pa- tients with already restricted pretreatment liver function Ethics approval and consent to participate The study was approved by the Ethics committee of the University of (Child Pugh B) while SBRT seems to be generally well Munich (LMU), reference number 617–16. tolerated in patients with Child Pugh A or in patients with MD. Moreover, a recent systematic review includ- Competing interests ing 5 studies with 392 patients suffering from primary The authors declare that they have no competing interests. and secondary liver tumors treated with SBRT demon- strated well-preserved post-treatment quality-of-life at Publisher’sNote least comparable or even favorable compared to other Springer Nature remains neutral with regard to jurisdictional claims in surgical or non-surgical approaches [1]. published maps and institutional affiliations. Gerum et al. Radiation Oncology (2018) 13:100 Page 9 of 9 Author details 21. Scorsetti M, Comito T, Tozzi A, et al. Final results of a phase II trial for Department of Radiation Oncology, University Hospital LMU Munich, stereotactic body radiation therapy for patients with inoperable liver Marchioninistr. 15, 81377 Munich, Germany. Department of Radiology, metastases from colorectal cancer. J Cancer Res Clin Oncol. 2015;141: University Hospital LMU Munich, Marchioninistr. 15, 81377 Munich, Germany. 543–53. Department of Internal Medicine, University Hospital LMU Munich, 22. Habermehl D, Herfarth KK, Bermejo JL, et al. Single-dose radiosurgical |Marchioninistr. 15, 81377 Munich, Germany. CCU Molecular Radiation treatment for hepatic metastases – therapeutic outcome of 138 treated Oncology, German Cancer Research Center, Heidelberg, Germany. lesions from a single institution. Radiat Oncol. 2013;8:175. 23. Huertas A, Baumann AS, Saunier-Kubs F, et al. Stereotactic body radiation Received: 28 February 2018 Accepted: 16 May 2018 therapy as an ablative treatment for inoperable hepatocellular carcinoma. Radiother Oncol. 2015;115:211–6. 24. Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2011;81: References e447–53. 1. Mutsaers A, Greenspoon J, Walker-Dilks C, Swaminath A. Systematic 25. Yamashita H, Onishi H, Murakami N, et al. Survival outcomes after review of patients reported quality of life following stereotactic ablative stereotactic body radiotherapy for 79 japanese patients with hepatocellular radiotherapy for primary and metastatic liver cancer. Radiat Oncol. carcinoma. J Radiat Res. 2015;56:561–7. 2017;12:110. 26. Lancia A, Ingross G, Carosi A, et al. Oligometastatic cancer: stereotactic 2. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide ablative radiotherapy for patients affected by isolated body metastases. Acta incidence and trends. Gastroenterology. 2004;127:5–16. Oncol. 2017;56:1621–5. 3. Goodman KA, Kavanagh BD. Stereotactic body radiotherapy for liver 27. Fode MM, Hoyer M. Survival and prognostic factors in 321 patients treated metastases. Sem Radiat Oncol. 2017;27:240–6. with stereotactic body radiotherapy for olio-metastases. Radiother Oncol. 4. Murray LJ, Dawson LA. Advances in stereotactic body radiation therapy for 2015;114:155–60. hepatocellular carcinoma. Sem Radiat Oncol. 2017;27:247–55. 28. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic 5. Kalogeridi MA, Zygogianni A, Kyrgias G, Kouvaris J, Chatziioannou S, Kelekis indicators of survival in cirrhosis: a systematic review of 118 studies. J N, Kouloulias V. Role of radiotherapy in the management of hepatocellular Hepatol. 2006;44:217–31. carcinoma: a systematic review. World J Hepatol. 2015;7:101–12. 29. Lasley FD, Maninna EM, Johnson CS, et al. Treatment variables related to 6. Waller LP, Deshpande V, Pyrsopoulos N. Hepatocellular carcinoma: a liver toxicity in patients with hepatocellular carcinoma, Child-Pugh class a comprehensive review. World J Hepatol. 2015;7:2648–63. and B enrolled in a phase 1-2 trial of stereotactic body radiation therapy. 7. Guckenberger M, Andratschke N, Alheit H, Holy R, Moustakis C, Nestle U, Pract Radiat Oncol. 2015;5:e443–9. Sauer O. Definition of stereotactic body radiotherapy: principles and 30. Culleton S, Jiang H, Haddad CR, et al. Outcomes following definitive practice for the treatment of stage I non-small cell lung cancer. Strahlenther stereotactic body radiotherapy for patients with Child-Pugh B or C Onkol. 2014;190:26–33. hepatocellular carcinoma. Radiother Oncol. 2014;111:412–7. 8. El-Khatib M, El Majdoub F, Hunsche S, Hoevels M, Kocher M, Sturm V, Maarouf M. Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and safety after a follow-up of over 12 years. Strahlenther Onkol. 2015;191:921–7. 9. Kocher M, Wittig A, Piroth MD, Treuer H, Seegenschmiedt H, Ruge M, Grosu AL, Guckenberger M. Stereotactic radiosurgery for treatment of brain metastases. A report of the DEGRO working group on stereotactic radiotherapy. Strahlenther Onkol. 2014;190:521–32. 10. Tanadini-Lang S, Rieber J, Filippi AR, et al. Nomogram based overall survival prediction in stereotactic body radiotherapy for oligo-metastatic lung disease. Radiother Oncol. 2017;123:182–8. 11. Herfarth KK, Debus J, Lohr F, Bahner ML, Rhein B, Fritz P, Höss A, Schlegel W, Wannenmacher MF. Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol. 2001;19:164–70. 12. Mendez Romero A, Wunderink W. Hussain et al. stereotactic body radiation therapy for primary and metastatic liver tumors: a single institution phase I- II study. Acta Oncol. 2006;45:831–7. 13. Comito T, Clerici E, Tozzi A, D’Agostino G. Liver metastases and SBRT: a new paradigm ? Rep Pract Oncol Radiother. 2015;20:464–71. 14. Yoon SM, Lim YS, Park MJ, et al. Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma. PLoS One. 2013;8:e79854. 15. Chang DT, Swaminath A, Kozak M, et al. Stereotactic body radiotherapy for colorectal liver metastases – a pooled analysis. Cancer. 2011;117:4060–9. 16. Andratschke NH, Nieder C, Heppt F, Molls M, Zimmermann F. Stereotactic radiation therapy for liver metastases: factors affecting local control and survival. Radiat Oncol. 2015;10:69. 17. Kwon JH, Bae SH, Kim JY, et al. Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection. BMC Cancer. 2010;10:475. 18. Scorsetti M, Comito T, Cozzi L, et al. The challenge of inoperable hepatocellular carcinoma (HCC): results of a single-institutional experience on stereotactic body radiation therapy (SBRT). J Cancer Res Clin Oncol. 2015; 141:1301–9. 19. Wahl DR, Stenmark MH, Tao Y, et al. Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol. 2016;34:452–9. 20. Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol. 2013;31:1631–9. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma and oligometastatic liver disease

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Biomedicine; Cancer Research; Oncology; Radiotherapy; Imaging / Radiology
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Abstract

Background: To report our experience with SBRT in primary and secondary liver tumors. Methods: We retrospectively analysed 55 patients (70 lesions) with a median follow-up of 10 months (range 1–57) treated from 2011 to 2016. All patients had not been eligible for other local treatment options. Median age was 64 years and 64% were male. 27 patients (36 lesions) suffered from hepatocellular carcinoma (HCC, Child A:78%, Child B:18%, Child C:4%), 28 patients (34 lesions) had oligometastatic liver disease (MD). Treatment planning was based on 4D-CT usually after placement of fiducials. Dose and fractionation varied depending on localization and size, most commonly 3 × 12.5 Gy (prescribed to the surrounding 65%-isodose) in 56% and 5x8Gy (80% isodose) in 20% of the treated lesions. Results: Local recurrence was observed in 7 patients (13%) and 8 lesions (11%), resulting in estimated 1- and 2-year local control rates (LC) of 91 and 74%. Estimated 1- and 2-year rates of Freedom from hepatic failure (FFHF) were 42 and 28%. Number of lesions was predictive for LC and FFHF in the entire cohort. Estimated 1- and 2-year overall survival (OS) was 76 and 57%. OS was significantly affected by number of treated lesions and performance status. In the HCC subgroup, pretreatment liver function and gender were also predictive for OS. Maximum acute non-hepatic toxicity was grade 1 in 16%and grade2in10%of thepatients. ThreeHCC patients (11%) developed marked deterioration of liver function (grade 3/4). Conclusions: SBRT resulted in high local control and acceptable survival rates in patients with HCC or MD not amendable to other locally-ablative treatment options with limited toxicity. Care should be taken in HCC patients with Child B cirrhosis. Keywords: Liver, HCC, Oligometastatic, SBRT Background Treatment options range from liver transplantation (for Primary and metastatic liver tumors are among the most HCC) or extended surgical resections (for MD) to less inva- common malignancies and tumour-related causes of death sive techniques like radiofrequency ablation (RFA), transar- worldwide [1, 2]. Treatment paradigms have changed dra- terial chemoembolization (TACE) or selective internal matically in the last decades in favor of local treatments in radiotherapy (SIRT). However, the potential benefit of such primary liver cancers and oligometastatic (especially treatment options needs to be weighed against the possibil- liver-confined) disease because of the evolving evidence for ity that local treatment results in impairment of liver func- possible cure or at least long-term survival [3, 4]. tion or liver failure, especially in the presence of an underlying liver disease, which is the background upon * Correspondence: falk.roeder@med.uni-muenchen.de most primary malignancies arise [4]. Moreover, any of the Department of Radiation Oncology, University Hospital LMU Munich, mentioned treatments has its limitations. For example sur- Marchioninistr. 15, 81377 Munich, Germany gery is often limited by comorbidities or poor liver function CCU Molecular Radiation Oncology, German Cancer Research Center, Heidelberg, Germany [4] while lesions directly adjacent to major vessels or bile Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gerum et al. Radiation Oncology (2018) 13:100 Page 2 of 9 ducts are not well suited for RFA [5]and patients with por- then, an increasing number of patients have been treated tal vein thrombosis are not eligible for TACE [6]. each year (fig. 1). For the current analysis, we retrospect- Stereotactic body radiation therapy (SBRT) is a highly ively selected and analyzed all patients affected by HCC conformal technique of percutaneous radiation therapy or MD who underwent SBRT to 1–3 liver lesions. Indi- delivered in a small number of large fractions [7]. It suf- cation for SBRT was seen in patients not eligible for ficiently spares dose to adjacent organs at risk due to its other local treatment options according to multidiscip- sharp dose fall-off outside the target, while adequate linary evaluation. Pretreatment investigations included tumor control is maintained due to the enhanced bio- MRI and/or contrast-enhanced biphasic liver CT, liver logical effectivity of the large single doses. Stereotactic function tests for HCC patients and additional CT/ radiation approaches have been already successfully in- PET-CT staging for MD patients. troduced into the treatment of primary and secondary brain and lung tumors and have shown to result in low Patient characteristics toxicity and at least comparable outcome with regard to The entire cohort consisted of 55 patients with 70 surgery [7–10]. Several groups have shown that SBRT treated lesions. Median age was 64 years (31–83), 64% can also be effectively employed with acceptable toxicity were male and the median Karnofsky performance score for the treatment of liver malignancies [11]. However, no (KPS) was 90% (60–100%). 28 patients showed MD in randomized trials comparing SBRT to other local treat- whom 34 lesions were treated. Most of them suffered ment options have been conducted so far, and only from colorectal cancer (32%) followed by NSCLC (14%) scarce prospective data on the employment of SBRT in and soft-tissue sarcomas (14%). 27 patients showed HCC the treatment of liver lesions are available. Moreover, no in whom 36 lesions were treated. Underlying liver cir- generally accepted criteria for patient selection or a gen- rhosis was present in all HCC patients, caused by viral erally accepted dose and fractionation concept exists. hepatitis (B and C) in 10 patients (37%), alcohol con- Therefore we report our experience with SBRT for pri- sumption in 5 (19%), autoimmune hepatitis in 1 (4%) mary and secondary liver tumors. and by unknown reason in 11 patients (41%). Liver func- tion was moderately restricted in the majority of them Methods (Child A: 21[78%], Child B: 5[18%], Child C: 1[4%]), In our institution, SBRT has been used for the treatment Table 1. The patient with Child C cirrhosis presented of malignant liver lesions for the first time in 2011. Since with good performance score and was listed for liver Fig. 1 Number of treatments per year Gerum et al. Radiation Oncology (2018) 13:100 Page 3 of 9 Table 1 patient and treatment characteristics entire cohort HCC MD number of patients 55 27 28 number of lesions 70 36 34 single/multiple lesions 40/15 18/9 22/6 gender (male/female) 35/20 19/8 16/12 age (median/range in years) 64/31–83 63/46–83 67/31–80 KPS (median/range in %) 90/60–100 90/60–100 95/70–100 histology (CRC/LC/BC/S/O) –– 10/4/4/2/9 Child-Pugh stage (A/B/C) – 21/5/1 – fiducials (n/%) 42/76 18/67 24/86 abdominal compression (n/%) 26/47 14/52 12/43 GTV per patient (median/range in ccm) 14.6/0.4–204 15.5/1.2–204 13.25/0.4–98.2 GTV per lesion (median/range in ccm) 6.6/0.2–204 7.5/0.9–204 6.2/0.2–98.2 PTV per patient (median/range in ccm) 75.5/17.7–511.6 92.7/17.7–511.6 61.1/19.3–314 PTV per lesion (median/range in ccm) 59/15–512 61/15–512 51/15–314 dose concept (3 × 12.5/5 × 8/other) 28/11/16 16/6/5 12/5/9 BED max (median/range) 168.1/60.3–190 168.2/60.3–168.2 118/80.4–190 actual treatment (SBRT/TACE+SBRT) – 12/15 – HCC: hepatocellular carcinoma, MD: metastatic disease, KPS: Karnofsky performance score, CRC: colorectal cancer, LC: lung cancer, BC: breast cancer, S: sarcoma, o: other, GTV: gross tumor volume [cubic centimeters], PTV: planning target volume [cubic centimeters], BED: biologically equivalent dose, SBRT: stereotactic body radiotherapy, TACE: transarterial chemoembolization, all doses in [Gy] transplantation, therefore our interdisciplinary tumor- contrast-enhanced 4D-CT. Gross tumor volume (GTV) board opted for SBRT as bridging. was contoured as the visible tumor on the free-breathing CT and on all respiratory phases of the 4D-CT supple- Treatment characteristics mented by information from MRI if available. An in- Treatment in HCC patients consisted of SBRT alone in ternal target volume (ITV) was constructed and 12 patients while 15 patients received selective TACE to enlarged by an isotropic margin of 6 mm to obtain the the same lesions upfront to SBRT (within 6 weeks). Five planning target volume (PTV). Dose was prescribed to patients received additional RFA treatments to different the PTV surrounding isodose in all patients. Prescription lesions prior to SBRT (within 6 weeks). 23/27 patients isodose, single dose and number of fractions depended had a median of 2 (range 1–8) previous local treatments on size and location of the lesions. Number of lesions (surgery, RFA, TACE or SIRT). Treatment of metastatic did not influence prescription dose in general. The most patients consisted of SBRT alone in 25 patients or SBRT common schemes were 3 × 12.5 Gy (65%-isodose) in combined with surgery or RFA to different lesions 56% and 5x8Gy (80%-isodose) in 20% of the treated le- (within 6 weeks) in 3 patients. Primary tumor was con- sions delivered every other day. Implanted fiducials or trolled in all patients with MD at the time of SBRT. lipiodol enhancement were contoured accordingly to re- Additive systemic therapy within three months from ceive a fiducial or lipiodol ITV, which was used for daily SBRT was given to 1 patient with HCC and 8 patients patient set-up. Treatment was performed using daily with MD. CBCT image-guidance. SBRT Statistical and legal considerations Prior to SBRT, 42 patients received CT-guided implant- Regular follow-up examinations (including physical ation of 1–3 fiducials (Visicoil™, IBA dosimetry or examination, laboratory tests (liver function and tumor MPB™, MPB Scherer Medizinprodukte) per lesion unless marker tests), MRI/CT of the liver) took place at our de- enhancement of lipiodol in patients with prior TACE partment or the departments of gastroenterology/oncol- (n = 8) or the presence of surgical clips (n = 5) were ogy every three months for one year, every 6 months for deemed sufficient to guide the procedure. Patients were the second and annually thereafter. Toxicity was scored immobilized using a vacuum pillow in combination with retrospectively according to CTCAE v4.03. Because of an alpha-cradle. Abdominal compression was used since the retrospective nature not all patients had received 2014 (n = 26, 47%). Treatment planning was based on exactly the same laboratory tests. Therefore changes in Gerum et al. Radiation Oncology (2018) 13:100 Page 4 of 9 Table 2 univariate analysis for LC, FFHF and OS p-value of < 0.05 was defined as statistically significant. The analysis was in accordance to the declaration of LC FFHF OS Helsinki in its latest version and was approved by our in- 1-year p value 1-year p value 1-year p value rate rate rate dependent Ethics committee. gender Results male 88% 0.279 44% 0.679 83% 0.055 Median follow-up in all patients was 10 months (1–57) female 94% 41% 67% and 13 months in survivors. Since implementation of age the technique at our center in 2011 we have seen a con- ≤ median (64 yrs) 92% 0.265 40% 0.687 77% 0.76 tinuous increase in patient numbers per year resulting in > median 90% 43% 75% 56% of the included patients treated in 2015/16 (fig. 1). Median GTV (measured on free-breathing CT) per pa- histology tient was 14.6 ccm (0.4–204) and 6.6 ccm per lesion HCC 92% 0.492 41% 0.895 68% 0.701 (0.2–204) and median PTV was 75.5 ccm (17.7–511.6) MD 89% 40% 84% per patient and 59 ccm (15–512) per lesion. KPS ≤70 100% 0.425 42% 0.579 50% 0.028 LC > 70 90% 42% 79% Local recurrence was observed in 7/55 patients (13%) translating into estimated 1- and 2-year LC-rates of 91 GTV and 74% (fig. 2). Median time to local failure in these 7 ≤ median (14.6 ccm) 100% 0.535 46% 0.794 80% 0.416 patients was 8 months (2–39). In univariate analysis, > median 88% 44% 77% only the number of lesions was predictive for LC BED (1-year-LC single 97% vs. multiple 67%,p = 0.011, Fig. 2, ≤ 100 87% 0.651 38% 0.419 75% 0.806 Table 2). In the HCC group we observed estimated 1- > 100 94% 48% 77% and 2-year LC-rates of 92%. The number of lesions was the only factor with significant impact on LC (1-year-LC lesions single 100% vs. multiple 71%,p = 0.024). No significant single 97% 0.011 49% 0.047 80% < 0.001 difference was observed comparing patients with TACE multiple 67% 19% 40% +SBRT versus SBRT alone. In the MD group, we ob- LC: Local control, FFHF: Freedom from hepatic failure, OS: Overall survival, served estimated 1- and 2-year LC-rates of 89 and 64%. yrs.: years, HCC: hepatocellular carcinoma, MD: metastastic disease, KPS: Karnofsky performance score, GTV: Gross tumor volume (measured per Improved LC was significantly associated with treatment patient on free-breathing CT), ccm: cubic centimeters, BED: biological of a single lesion (1-year-LC 95% vs. 0%,p = 0.027), equivalent dose BED>150Gy (1-year-LC 100% vs. 82%,p = 0.036) and fe- hepatic laboratory tests without symptoms were not male gender (1-year-LC 100% vs. 78%,p = 0.039). We counted as toxicity. Marked deterioration of liver func- further analyzed possible associations between the num- tion was defined as change in CHILD-Pugh class from A ber of lesions and dose parameters (BED maximum, pre- to B or B to C in HCC patients or symptomatic changes scription dose) but did not find any significant in liver function in MD patients. Biological effective dose correlations (data not shown). (BED) of the maximum PTV dose was calculated ac- If LC was analysed per lesion, we observed local fail- cording to the LQ formalism: BED = n*d*(1 + d/{α/β}) ures in 8/70 lesions (11%), translating into 1- and 2-year with n being the number of fractions, d the daily single LC-rates of 91 and 74%. No factors with significant im- fraction dose and alpha-beta for tumor tissue of 10 Gy. pact on LC could be identified for the entire cohort or Local control (LC) was defined as absence of tumor pro- the HCC subgroup. However, regarding the MD sub- gression in the region of the treated lesion. Freedom group, we observed a significant association of LC with from hepatic failure (FFHF) was defined as absence of GTV volume (1-year LC GTV ≤6.25ccm 100% vs. 80% tumor progression in the liver. All time-to-event data with GTV > 6.25ccm;p = 0.041). was calculated from the first day of SBRT using the Kaplan-Meier method. All endpoints and subgroup ana- FFHF lyses are reported referring to patients (not lesions) if 29/55 patients (53%) showed hepatic failure of whom only not otherwise specified. Differences in subgroups were 1 had an isolated local failure, while 22 showed isolated fail- assessed by the logrank test for univariate analysis. Due ures outside the treated volume and 6 had combined fail- to the low number of events multivariate analysis was ures. Estimated 1- and 2-year FFHF-rates were 42 and 28% not performed. The pearsons test was used for evalu- (fig. 3). Again, only the number of lesions (1-yr-FFHF single ation of possible correlations between parameters. A 49% vs. 19% multiple,p = 0.047) was predictive for FFHF Gerum et al. Radiation Oncology (2018) 13:100 Page 5 of 9 Fig. 2 Local control left: entire cohort, right: according to number of treated lesions (Fig. 3,Table 2). In theHCC subgroup,weobservedesti- 1- and 2-year OS-rates of 68 and 57%. OS was signifi- mated 1- and 2-year FFHF-rates of 41%. FFHF was signifi- cantly associated with number of treated lesions cantly affected by the number of lesions (1-year-FFHF (1-year-OS single 84% vs 39% multiple,p < 0.001), pre- single 53% vs 15% in multiple,p =0.01). In the MD sub- treatment liver function (1-year-OS Child-Pugh A 76% group we found estimated 1- and 2-year FFHF-rates of 40 vs. Child-Pugh B 28%,p = 0.036) and gender (1-year-OS and 25%. FFHF was significantly associated with perform- male 83% vs. female 43%,p = 0.049). In the MD subgroup ance status (1-year-FFHF KPS ≤ 70 0% vs. 43% with KPS > we observed estimated 1- and 2-year OS-rates of 84 and 70,p =0.006). 67%. OS was significantly associated with performance status (1-year-OS KPS > 70 90% vs. 33% KPS ≤ 70,p < OS 0.001) and number of treated lesions (1-year-OS single 16 patients (29%) have died, translating into estimated 90% vs. 42% multiple,p = 0.036). 1- and 2-year OS-rates of 76 and 57% (Fig. 4). Prognos- tic factors regarding OS were number of treated lesions Toxicity (1-yr-OS single 88% vs 40% in multiple,p < 0.001, Fig. 4) CT-guided fiducial placement was feasible without any and performance status (1-yr-OS KPS > 70 79% vs 50% complications. SBRT treatment could be performed as KPS ≤ 70,p = 0.028, Fig. 4), see Table 2. A trend was also planned in all except one patient (2%) who prematurely observed for gender (1-yr-OS male 83% vs 67% female, finished radiation treatment due to humerus fracture. p = 0.055). In the HCC subgroup we observed estimated Maximum acute toxicity was grade 1 in 9 patients (16%), Fig. 3 Freedom from hepatic failure left: entire cohort, right: according to number of treated lesions Gerum et al. Radiation Oncology (2018) 13:100 Page 6 of 9 Fig. 4 Overall Survival left: entire cohort, middle: according to number of treated lesions, right: according to performance status grade 2 in 6 (10%), grade 3 in 2 (4%) and grade 4 in 1 Mendez-Romero et al. [12] described their results of a patient (2%), see Table 3. The most frequent side effects phase I-II trial including 25 patients with HCC or MD were fatigue and gastrointestinal symptoms like mild treated mainly with a 3 × 12.5Gy concept and found 1- nausea or diarrhea. Three patients with HCC (11%) de- and 2-year LC-rates of 91 and 82%. If HCC and MD are veloped marked deterioration of liver function without considered separately, our results are still in the pub- disease progression. Two had a decline in Child-Pugh lished range of 75–100% 1-year-LC in HCC [4]and 71– stage from A to B. One patient with Child-Pugh C cir- 94% 1-year-LC in MD patients [13] reported in recent rhosis developed hepatic failure (grade 4) shortly after major series (Table 4). SBRT which was successfully treated by liver With regard to OS, we observed 1- and 2-year-rates of transplantation. 76 and 57% for the entire cohort. OS seemed to be slightly better in the MD group with 1- and 2-year Discussion OS-rates of 84 and 67% compared to the HCC group Outcome with SBRT with 1- and 2-year OS-rates of 68 and 57%, although this Regarding LC, we observed 1- and 2-year-rates of 91 difference did not reach statistical significance. and 74% for the entire cohort. LC seemed slightly im- Mendez-Romero et al. [12] described similar outcomes proved in the HCC group with 1- and 2-year-rates of with 1- and 2-year OS-rates of 82 and 54% for the whole 92% compared to the MD group with 1- and group, 85 and 62% for patients with MD and 75 and 2-year-rates of 89 and 64%, although this difference did 40% for patients with HCC. Moreover, our results are in not reach statistical significance. These results are in line the range of published results focusing on primary or with other series including both primary and secondary secondary liver tumors with 1- and 2-year OS-rates of liver tumors treated with similar concepts. For example 62–85% and 38–70% in metastatic patients [3] and 55– 100 and 53%–69% in HCC patients [4]. In contrast to the encouraging rates for LC and OS, Table 3 Acute toxicity we observed rather poor 1- and 2-year FFHF-rates of 42 CTCAE CTCAE ° CTCAE ° CTCAE ° and 28% for the entire cohort, which were mainly driven °I II III IV by intrahepatic outfield failures indicating a high risk for n (%) the development of new lesions in these heavily pre- nausea (n/%) 4 (7) 4 (7) treated patients. This pattern was seen in patients with fatigue 3 (5) HCC (1- and 2-year FFHF 42%) as well as in patients pneumonitis 1 (2) with MD (1- and 2-year FFHF 40 and 25%) although tachyarrhythmia 1 (2) more pronounced in the latter group. Similar results have been reported by others for both entities. For ex- cholangitis 1 (2) ample Yoon et al. [14] found a crude rate of 63% intra- diarrhea 1 (2) hepatic outfield failures and 71% hepatic failures in total, severe deterioration of liver n.a. n.a. 2 (4) 1 (2) translating into a 1-year hepatic-failure-free-survival-rate function of 52% in their cohort of 92 patients with HCC treated n.a.: not applicable, CTCAE: common toxicity criteria for adverse events Version 4.03 with SBRT. Chang et al. [15] reported a crude rate of Gerum et al. Radiation Oncology (2018) 13:100 Page 7 of 9 Table 4 Selected SBRT series in patients with primary and secondary liver tumors Author, Year n (patients) n (primary LT) GTV volume 1 yr-LC (%) 1 yr-OS (%) Toxicity Study-Type n (lesions) n (metastases) (median/range) (HCC/MD) (HCC/MD) Gr3+ (%) Mendez-Romero et al. 2006 25 HCC: 11 3.5 (0.5–7.2) 94 82 12.5 Phase I/II 45 MD: 34 (75/100) (75/85) Goodman et al. 26 HCC/CCC: 7 32.6 (0.8–146.6) 77 62 0 2010 40 MD: 19 Phase I Own data 55 HCC: 27 6.6 (0.2–204) 91 76 5 70 MD: 28 (92/89) (68/84) Bujold et al. 102 HCC only 7.2 (1.4–23.1) 87 55 30 Phase I/II Lasley et al. 59 HCC only 33.6 (2.2–107.3) 91 (Child A) 94 (Child A) 11 (Child A) 2015 59 82 (Child B) 57 (Child B) 38 (Child B) Phase I/II Own data 27 HCC only 7.5 (0.9–204) 92 68 11 Scorsetti et al. 42 MD only 3.5 (1.1–5.4) 91 (2 yr) 65 (2 yr) 0 2015 52 Phase I/II Andratschke et al. 74 MD only n.r. 75 77 0 2015 91 Retro, pooled Own data 28 MD only 6.2 (0.2–98.2) 89 84 0 n: number, LT: liver tumors, GTV: gross tumor volume per lesion, yr.: year, LC: local control, OS: overall survival, HCC: hepatocellular carcinoma, MD: metastatic a b disease, Gr3+: grade 3+, in cubic centimeters, : deterioration of liver function, no other grade 3+ toxicity, n.r.: not reported 68% intrahepatic outfield failures in their study on 65 diameter [15, 23], GTV volume [16, 17] and dose [24] patients with colorectal liver metastases. for HCC and/or MD as well as Child-Pugh stage for HCC [17, 24] and histology for MD [16, 22]. However, Prognostic factors the prognostic value of those factors is far from being We analyzed our entire cohort and both subgroups consistently evident as negative or even opposing results (HCC and MD) with regard to possible prognostic fac- have been reported also for any of the mentioned factors tors for each endpoint. Regarding LC, lesion size [16– [15, 16, 20, 21, 23, 25]. In our study, we identified the 18] and dose of SBRT [5, 15, 16, 18–20] have been the number of lesions and performance status as factors as- most consistently reported prognostic factors for both sociated with OS for the entire cohort. In the HCC sub- groups. Although a variety of definitions and tresholds group Child-Pugh stage and gender were additional have been used and some studies did not found any as- factors with significant impact. Although conflicting data sociations at all [19–22]. We could not confirm a statis- exists, it seems reasonable to assume that patients with tically significant association of GTV volume or BED multiple lesions are at higher risk for the development with LC regarding the entire cohort and the subgroup of of consecutive lesions with consequently reduced sur- HCC patients. However, we observed a significantly re- vival, especially in a patient group like ours with limited duced LC-rate with lower BED and larger GTV volume salvage options. This is further supported by our data in the subgroup of patients with MD, thus emphasizing with regard to the clearly reduced FFHF in patients with the findings of others suggesting a relationship between multiple lesions. The same assumption seems true for LC and lesion size and/or dose at least in metastatic pa- performance status which has been shown in many tients. Interestingly, the number of lesions was the main other oncological situations to be a key factor in predict- factor in our study with a significant impact on LC, ing outcome [26, 27]. Regarding the HCC subgroup, it however this might be simply due to statistical reasons has been shown that OS is clearly associated with as patients with more lesions obviously have a high Child-Pugh stage [28]. It therefore seems no surprise probability to fail at least in one. that OS of patients with HCC lesions (which developed Regarding OS, an even larger variety of factors with on the basis of advanced liver cirrhosis) is affected by possible impact have been described in the literature, in- the severity of the underlying cirrhosis. In contrast, the cluding gender [23], number of lesions [22], lesion observed negative influence of female gender on OS of Gerum et al. Radiation Oncology (2018) 13:100 Page 8 of 9 HCC patients is difficult to explain. Huertas et al. [23] Limitations reported a similar result in their HCC series even ac- Clearly our analysis has some limitations, namely its cording to multivariate analysis, however Yamashita et retrospective nature, the small sample size, the mixed al. [25] found the opposite association leaving this ques- cohort and the rather short follow-up. However, in the tion unanswered. absence of prospective randomized trials and only a lim- ited number of prospective studies reported in the litera- Toxicity ture our experience may help clinicians and researchers Given the high rate of outfield failures with the need for to guide their further decisions. salvage treatments, toxicity and preservation of liver function are of important value in the decision process Conclusions for locally-ablative treatments. With our approach, we SBRT resulted in high LC and acceptable survival rates observed high treatment compliance with predominantly in patients with HCC or MD not amendable to other mild toxicities mainly including fatigue and nausea. locally-ablative treatments. However, especially patients Three patients with HCC (11%) developed marked de- with multiple lesions are at high risk for intrahepatic terioration of liver function. Similar results have been outfield failures indicating a possible need for additional published in most other series. For patients treated for therapies. OS was predicted by number of lesions and MD, acute and late grade3+ toxicities are reported in the performance status as well as pretreatment liver function range of 0–16% and 0–5% [3]. Similar to our results, in HCC patients. Toxicity was generally mild. High Andratschke et al. [16] reported mild side effects mainly grade toxicity was restricted to patients with HCC suf- consisting of fatigue and nausea but no grade3+ reac- fering from underlying cirrhosis Child-Pugh class B indi- tions in their series of 74 patients treated with compar- cating the need for special attention in those patients. able dose and fractionation concepts. In patients with HCC higher complications rates have been observed. Abbreviations 4D-CT: Four-dimensional computed tomography; BED: Biologically effective Acute grade3+ toxicities ranged from 5 to 37% including dose; CBCT: Cone beam computed tomography; ccm: Cubic centimeters; up to 7% deaths [4], mainly in Child-Pugh B patients. CT: Computed tomography; CTCAE: Common toxicity criteria for adverse Decline in Child-Pugh class has also been reported in events; FFHF: Freedom from hepatic failure; GTV: Gross tumor volume; Gy: Gray; HCC: Hepatocellular carcinoma; ITV: Internal target volume; 13–29% [12, 20, 24], although some authors described a KPS: Karnofsky performance score; LC: local control; MD: Oligometastatic marked recovery over time [20]. Our toxicity rate seem disease; MRI: Magnetic resonance imaging; OS: Overall survival; PET- to compare favorably with those rates, however some of CT: Positron-emission-tomography with computed tomography; PTV: Planning target volume; RFA: Radiofrequency ablation; RILD: Radiation these studies included larger lesions resulting in more induced liver disease; SBRT: Stereotactic body radiation therapy; dose to normal liver tissue and a higher percentage of SIRT: Selective internal radiotherapy; TACE: Transarterial chemoembolization Child-Pugh B patients. Both factors have been shown to be associated with toxicity [24, 29]. For example Ando- Funding The study did not receive any funding. lino et al. [24] described progressive liver dysfunction in 4/8 patients with Child-Pugh≥8 of whom 2 could be sal- Availability of data and materials vaged by transplant but 2 died. They concluded to fur- The datasets used and/or analysed during the current study are available ther treat Child-Pugh B patients only if listed for from the corresponding author on reasonable request. transplantation. Lasley et al. [29] observed grade 3/4 liver toxicity of 11% in patients with Child-Pugh A com- Authors contributions SG performed data acquisition and participated in patient treatment, pared to 38% in Child-Pugh B patients and further ex- statistical analysis and in drafting the manuscript. CH participated in cluded patients with Child-Pugh≥8 from treatment. treatment of the patients and statistical analysis. FW, PP, ED treated the Finally, Culleton et al. [30] analyzed specifically patients patients and participated in data acquisition. CB revised the manuscript critically. FR participated in data acquisition, statistical analysis, treatment of with Child-Pugh B/C and described a decline of ≥2 the patients, drafting the manuscript and critically reviewed the data and the points in 63% at 3 months. Therefore SBRT treatment manuscript. All authors read and approved the final manuscript should be used with caution or restricted in dose in pa- tients with already restricted pretreatment liver function Ethics approval and consent to participate The study was approved by the Ethics committee of the University of (Child Pugh B) while SBRT seems to be generally well Munich (LMU), reference number 617–16. tolerated in patients with Child Pugh A or in patients with MD. Moreover, a recent systematic review includ- Competing interests ing 5 studies with 392 patients suffering from primary The authors declare that they have no competing interests. and secondary liver tumors treated with SBRT demon- strated well-preserved post-treatment quality-of-life at Publisher’sNote least comparable or even favorable compared to other Springer Nature remains neutral with regard to jurisdictional claims in surgical or non-surgical approaches [1]. published maps and institutional affiliations. Gerum et al. Radiation Oncology (2018) 13:100 Page 9 of 9 Author details 21. Scorsetti M, Comito T, Tozzi A, et al. Final results of a phase II trial for Department of Radiation Oncology, University Hospital LMU Munich, stereotactic body radiation therapy for patients with inoperable liver Marchioninistr. 15, 81377 Munich, Germany. Department of Radiology, metastases from colorectal cancer. J Cancer Res Clin Oncol. 2015;141: University Hospital LMU Munich, Marchioninistr. 15, 81377 Munich, Germany. 543–53. Department of Internal Medicine, University Hospital LMU Munich, 22. Habermehl D, Herfarth KK, Bermejo JL, et al. Single-dose radiosurgical |Marchioninistr. 15, 81377 Munich, Germany. CCU Molecular Radiation treatment for hepatic metastases – therapeutic outcome of 138 treated Oncology, German Cancer Research Center, Heidelberg, Germany. lesions from a single institution. Radiat Oncol. 2013;8:175. 23. Huertas A, Baumann AS, Saunier-Kubs F, et al. Stereotactic body radiation Received: 28 February 2018 Accepted: 16 May 2018 therapy as an ablative treatment for inoperable hepatocellular carcinoma. Radiother Oncol. 2015;115:211–6. 24. Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2011;81: References e447–53. 1. Mutsaers A, Greenspoon J, Walker-Dilks C, Swaminath A. Systematic 25. Yamashita H, Onishi H, Murakami N, et al. Survival outcomes after review of patients reported quality of life following stereotactic ablative stereotactic body radiotherapy for 79 japanese patients with hepatocellular radiotherapy for primary and metastatic liver cancer. Radiat Oncol. carcinoma. J Radiat Res. 2015;56:561–7. 2017;12:110. 26. Lancia A, Ingross G, Carosi A, et al. Oligometastatic cancer: stereotactic 2. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide ablative radiotherapy for patients affected by isolated body metastases. Acta incidence and trends. Gastroenterology. 2004;127:5–16. Oncol. 2017;56:1621–5. 3. Goodman KA, Kavanagh BD. Stereotactic body radiotherapy for liver 27. Fode MM, Hoyer M. Survival and prognostic factors in 321 patients treated metastases. Sem Radiat Oncol. 2017;27:240–6. with stereotactic body radiotherapy for olio-metastases. Radiother Oncol. 4. Murray LJ, Dawson LA. Advances in stereotactic body radiation therapy for 2015;114:155–60. hepatocellular carcinoma. Sem Radiat Oncol. 2017;27:247–55. 28. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic 5. Kalogeridi MA, Zygogianni A, Kyrgias G, Kouvaris J, Chatziioannou S, Kelekis indicators of survival in cirrhosis: a systematic review of 118 studies. J N, Kouloulias V. Role of radiotherapy in the management of hepatocellular Hepatol. 2006;44:217–31. carcinoma: a systematic review. World J Hepatol. 2015;7:101–12. 29. Lasley FD, Maninna EM, Johnson CS, et al. Treatment variables related to 6. Waller LP, Deshpande V, Pyrsopoulos N. Hepatocellular carcinoma: a liver toxicity in patients with hepatocellular carcinoma, Child-Pugh class a comprehensive review. World J Hepatol. 2015;7:2648–63. and B enrolled in a phase 1-2 trial of stereotactic body radiation therapy. 7. Guckenberger M, Andratschke N, Alheit H, Holy R, Moustakis C, Nestle U, Pract Radiat Oncol. 2015;5:e443–9. Sauer O. Definition of stereotactic body radiotherapy: principles and 30. Culleton S, Jiang H, Haddad CR, et al. Outcomes following definitive practice for the treatment of stage I non-small cell lung cancer. Strahlenther stereotactic body radiotherapy for patients with Child-Pugh B or C Onkol. 2014;190:26–33. hepatocellular carcinoma. Radiother Oncol. 2014;111:412–7. 8. El-Khatib M, El Majdoub F, Hunsche S, Hoevels M, Kocher M, Sturm V, Maarouf M. Stereotactic LINAC radiosurgery for the treatment of typical intracranial meningiomas. Efficacy and safety after a follow-up of over 12 years. Strahlenther Onkol. 2015;191:921–7. 9. Kocher M, Wittig A, Piroth MD, Treuer H, Seegenschmiedt H, Ruge M, Grosu AL, Guckenberger M. Stereotactic radiosurgery for treatment of brain metastases. A report of the DEGRO working group on stereotactic radiotherapy. Strahlenther Onkol. 2014;190:521–32. 10. Tanadini-Lang S, Rieber J, Filippi AR, et al. Nomogram based overall survival prediction in stereotactic body radiotherapy for oligo-metastatic lung disease. Radiother Oncol. 2017;123:182–8. 11. Herfarth KK, Debus J, Lohr F, Bahner ML, Rhein B, Fritz P, Höss A, Schlegel W, Wannenmacher MF. Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol. 2001;19:164–70. 12. Mendez Romero A, Wunderink W. Hussain et al. stereotactic body radiation therapy for primary and metastatic liver tumors: a single institution phase I- II study. Acta Oncol. 2006;45:831–7. 13. Comito T, Clerici E, Tozzi A, D’Agostino G. Liver metastases and SBRT: a new paradigm ? Rep Pract Oncol Radiother. 2015;20:464–71. 14. Yoon SM, Lim YS, Park MJ, et al. Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma. PLoS One. 2013;8:e79854. 15. Chang DT, Swaminath A, Kozak M, et al. Stereotactic body radiotherapy for colorectal liver metastases – a pooled analysis. Cancer. 2011;117:4060–9. 16. Andratschke NH, Nieder C, Heppt F, Molls M, Zimmermann F. Stereotactic radiation therapy for liver metastases: factors affecting local control and survival. Radiat Oncol. 2015;10:69. 17. Kwon JH, Bae SH, Kim JY, et al. Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection. BMC Cancer. 2010;10:475. 18. Scorsetti M, Comito T, Cozzi L, et al. The challenge of inoperable hepatocellular carcinoma (HCC): results of a single-institutional experience on stereotactic body radiation therapy (SBRT). J Cancer Res Clin Oncol. 2015; 141:1301–9. 19. Wahl DR, Stenmark MH, Tao Y, et al. Outcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol. 2016;34:452–9. 20. Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol. 2013;31:1631–9.

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Radiation OncologySpringer Journals

Published: May 29, 2018

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