Although surgery is the standard of care for resectable pancreatic cancer (PC), standard-dose chemoradiation therapy and chemotherapy alone are suitable for patients with unresectable disease. ...Stereotactic body radiation therapy (SBRT) is an alternative, focused local therapy that delivers high radiation doses within a few fractions to the cancer, sparing the surrounding critical tissue. We performed a systematic review and pooled analysis of published trials to evaluate the efficacy and safety of this emerging treatment modality.
We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, SCOPUS, the Web of Science, and CINAHL for publications regarding SBRT for locally advanced PC. The 1-year overall survival (OS) rate was the primary endpoint, and the median OS, 2-year OS rate, 1-year locoregional control (LRC) rate, and grade 3 to 4 toxicities were the secondary endpoints. A multivariate random-effects meta-analysis was performed to calculate the aggregated OS rates at 1 and 2 years and the 1-year LRC rate.
A total of 19 studies, encompassing 1009 patients, were included in the present analysis. The pooled 1-year OS was 51.6% in 13 trials with data available. The median OS ranged from 5.7 to 47 months (median 17). The LRC rate at 1 year was 72.3%. Overall, the occurrence of severe adverse events did not exceed 10%. LRC appeared to correlate with the total SBRT dose and the number of fractions.
The advantages of SBRT in terms of treatment time, satisfactory OS, and LRC indicate that it is an effective option for inoperable PC. However, a definitive validation of this treatment modality in large randomized studies is required, owing to the nonrandomized nature of the included studies and the limitations of small single-center series that include mixed populations.
While surgery is the preferred option for isolated, operable liver metastases from colorectal cancer (CRC), ablative techniques are endorsed for medically or technically inoperable lesions. ...Stereotactic body radiotherapy (SBRT) is an alternative ablative local therapy that delivers high RT doses in a few fractions to the cancer, sparing surrounding critical tissue. We have performed a systematic review of published trials to evaluate the efficacy of SBRT as a primary modality therapy for CRC liver oligometastases.
We searched the Cochrane Central Register of Controlled Trials, Pubmed, and EMBASE for publications regarding SBRT for CRC liver metastases. Overall survival (OS: median, 1- and 2-year OS %) was the primary endpoint, and median PFS and one- and two-year local control (LC) were the secondary endpoints. A random-effect model pooled-analysis was performed to calculate the aggregated OS rates at 1 and 2 years as well as the one- and two-year LC.
A total of 18 studies, encompassing 656 patients, were included in the analysis. The pooled one- and two-year OS were 67.18% (95% CI, 42.1–92.2) and 56.5% (95% CI, 36.7–76.2), respectively. Median PFS and OS were 11.5 and 31.5 months. The pooled one-year LC was 67% (95% CI, 43.8–90.2), while the pooled two-year LC was 59.3% (95% CI, 37.2–81.5). Correlation analysis revealed a moderate/poor linear relationship between the SBRT (BED10) dose and LC (p = 0.001, R = 0.47)/OS (p = 0.001, R = 0.29) at 2 years. Mild-moderate and severe liver toxicity were 30.7% and 8.7%.
SBRT for liver oligometastases is an effective option for patients with advanced CRC, with encouraging local control and survival. However, a definitive validation in large randomised studies is required, due to the retrospective or non-randomised nature of the included studies and the limitations of series with different doses/schedules of treatment.
To evaluate the feasibility of high-dose stereotactic body radiation therapy (SBRT) in the treatment of unresectable liver metastases.
Patients with 1 to 3 liver metastases, with maximum individual ...tumor diameters less than 6 cm and a Karnofsky Performance Status of at least 70, were enrolled and treated by SBRT on a phase 2 clinical trial. Dose prescription was 75 Gy on 3 consecutive days. SBRT was delivered using the volumetric modulated arc therapy by RapidArc (Varian, Palo Alto, CA) technique. The primary end-point was in-field local control. Secondary end-points were toxicity and survival.
Between February 2010 and September 2011, a total of 61 patients with 76 lesions were treated. Among the patients, 21 (34.3%) had stable extrahepatic disease at study entry. The most frequent primary sites were colorectal (45.9%) and breast (18%). Of the patients, 78.7% had 1 lesion, 18.0% had 2 lesions, and 3.3% had 3 lesions. After a median of 12 months (range, 2-26 months), the in-field local response rate was 94%. The median overall survival rate was 19 months, and actuarial survival at 12 months was 83.5%. None of the patients experienced grade 3 or higher acute toxicity. No radiation-induced liver disease was detected. One patient experienced G3 late toxicity at 6 months, resulting from chest wall pain.
SBRT for unresectable liver metastases can be considered an effective, safe, and noninvasive therapeutic option, with excellent rates of local control and a low treatment-related toxicity.
Objectives
To evaluate the feasibility and efficacy of stereotactic body radiation therapy (SBRT) in the treatment of hepatocellular carcinoma (HCC) unsuitable for standard loco-regional therapies.
...Materials and methods
Patients with 1–3 inoperable HCC lesions with diameter ≤6 cm were treated by SBRT. According to lesions size and liver function, two prescription regimens were adopted: 48–75 Gy in three fractions or 36–60 Gy in six fractions. SBRT was delivered using the volumetric modulated arc therapy technique with flattening filter-free photon beams. The primary end points of this study were in-field local control (LC) and toxicity. Secondary end points were overall survival (OS) and progression-free survival (PFS).
Results
Forty-three patients with 63 HCC lesions were irradiated. All patients had Child–Turcotte–Pugh class A or B disease. Thirty lesions (48 %) were treated with 48–75 Gy in three consecutive fractions, and 33 (52 %) received 36–60 Gy in six fractions. Median follow-up was 8 months (range 3–43 months). Actuarial LC at 6, 12 and 24 months was 94.2 ± 3.3, 85.8 ± 5.5 and 64.4 ± 11.5 %, respectively. A biological equivalent dose (BED) >100 Gy and GTV size were significant prognostic factors for LC in univariate analysis (
p
< 0.001 and
p
< 0.02). Median OS was 18.0 ± 5.8 months. Actuarial OS at 6, 12 and 24 months was 91.1 ± 4.9, 77.9 ± 8.2 and 45.3 ± 14.0 %, respectively. Univariate analysis showed that OS is correlated with LC (
p
< 0.04), BED >100 (
p
< 0.05) and cumulative gross tumor volume GTV <5 cm (
p
< 0.04). Median PFS was 8 months, with a 1-year PFS rate of 41 %. A significant (≥grade 3) toxicity was observed in seven patients (16 %) 2–6 months after the completion of the treatment. No classic radiation-induced liver disease was observed.
Conclusion
Stereotactic body radiation therapy is a safe and effective therapeutic option for HCC lesions unsuitable to standard loco-regional therapies, with acceptable local control rates and low treatment-related toxicity. The significant correlation between LC and higher doses and between LC and OS supports the clinical value of SBRT in these patients.
To appraise the ability of a radiomics based analysis to predict local response and overall survival for patients with hepatocellular carcinoma.
A set of 138 consecutive patients (112 males and 26 ...females, median age 66 years) presented with Barcelona Clinic Liver Cancer (BCLC) stage A to C were retrospectively studied. For a subset of these patients (106) complete information about treatment outcome, namely local control, was available. Radiomic features were computed for the clinical target volume. A total of 35 features were extracted and analyzed. Univariate analysis was used to identify clinical and radiomics significant features. Multivariate models by Cox-regression hazards model were built for local control and survival outcome. Models were evaluated by area under the curve (AUC) of receiver operating characteristic (ROC) curve. For the LC analysis, two models selecting two groups of uncorrelated features were analyzes while one single model was built for the OS analysis.
The univariate analysis lead to the identification of 15 significant radiomics features but the analysis of cross correlation showed several cross related covariates. The un-correlated variables were used to build two separate models; both resulted into a single significant radiomic covariate: model-1: energy p < 0.05, AUC of ROC 0.6659, C.I.: 0.5585-0.7732; model-2: GLNU p < 0.05, AUC 0.6396, C.I.:0.5266-0.7526. The univariate analysis for covariates significant with respect to local control resulted in 9 clinical and 13 radiomics features with multiple and complex cross-correlations. After elastic net regularization, the most significant covariates were compacity and BCLC stage, with only compacity significant to Cox model fitting (Cox model likelihood ratio test p < 0.0001, compacity p < 0.00001; AUC of the model is 0.8014 (C.I. = 0.7232-0.8797)).
A robust radiomic signature, made by one single feature was finally identified. A validation phases, based on independent set of patients is scheduled to be performed to confirm the results.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To appraise the ability of a radiomics signature to predict clinical outcome after stereotactic body radiation therapy (SBRT) for pancreas carcinoma.
A cohort of 100 patients was included in this ...retrospective, single institution analysis. Radiomics texture features were extracted from computed tomography (CT) images obtained for the clinical target volume. The cohort of patients was randomly divided into two separate groups for the training (60 patients) and validation (40 patients). Cox regression models were built to predict overall survival and local control. The significant predictors at univariate analysis were included in a multivariate model. The quality of the models was appraised by means of area under the curve and concordance index.
A clinical-radiomic signature associated with Overall Survival (OS) was found significant in both training and validation sets (p = 0.01 and 0.05 and concordance index 0.73 and 0.75 respectively). Similarly, a signature was found for Local Control (LC) with p = 0.007 and 0.004 and concordance index 0.69 and 0.75. In the low risk group, the median OS and LC in the validation group were 14.4 and 28.6 months while in the high-risk group were 9.0 and 17.5 months respectively.
A CT based radiomic signature was identified which correlate with OS and LC after SBRT and allowed to identify low and high-risk groups of patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of this study was to evaluate long-term efficacy and survival prognostic factors of stereotactic body radiation therapy (SBRT) for un-resectable liver metastases in patients enrolled in a ...prospective phase II trial.
5-year local control (LC), overall survival (OS), progression free survival (PFS) and toxicity rates were analyzed in patients with un-resectable liver metastases enrolled in a Phase II Trial on liver SBRT, with a prescription dose of 75Gy in 3 consecutive fractions.
A total of 61 patients with 76 lesions were enrolled, with a median follow-up time of 6.1 years. One, three and 5 year LC rates were 94 ± 3.1%, 78.0 ± 5.9% and 78.0 ± 5.9%, without reaching the median LC time. Median OS was 27.6 months and the survival rates were 85.2 ± 4.5%, 31.1 ± 5.9% and 18.0 ± 4.9% at 1, 3 and 5-year after SBRT, respectively. Univariate analysis showed that favorable primary site (colorectal, breast and gynecological) of metastases (p = 0.001) improved survival. Toxicity was moderate. One patient experienced G3 late chest wall pain, which resolved within 1 year from SBRT. No cases of Radiation Induced Liver Disease (RILD) were detected.
Long-term results of this Phase II study suggest the efficacy and safety of SBRT for un-resectable liver metastases after 5-year of follow up. Selection of cases with positive prognostic factors may improve long-term survival of these oligo-metastastic patients and may confirm the role of SBRT as an effective alternative local therapy for liver metastases.
Introduction
Biliary tract cancers (BTC) are rare malignancies arising from biliary system. Systemic therapy is the cornerstone for stage IV disease, with poor overall survival (OS). Evidence is ...lacking about safety and efficacy of local ablative treatments, such as surgery and stereotactic body radiotherapy (SBRT) in the context of metastatic BTC (mBTC).
Materials and methods
We retrospectively analyzed clinical outcomes for a cohort of mBTC patients treated with SBRT for oligometastatic disease. Inclusion criteria were 1–5 distant metastases; SBRT with a dose/fraction of a least 5 Gy to a biological effective dose (BED) of at least 40 Gy considering an
α
/
β
of 10 Gy. Analyzed outcomes included local control (LC), distant progression-free survival (DPFS), PFS, and OS.
Results
51 patients meeting the inclusion criteria. Primary tumor sites were intrahepatic cholangiocarcinoma (35%), extrahepatic cholangiocarcinoma (31%), ampullary adenocarcinoma (20%), gallbladder adenocarcinoma (14%). 21 patients were treated on liver lesions, 17 on nodal metastasis, 5 patients on lung lesions, 4 patients on recurrence along the extrahepatic bile duct. After a median follow-up of 14 months median OS was 13.7 months, 1- and 2-year OS were 58% and 41%, respectively. Node and lung as metastatic sites were associated with a longer OS (
p
< 0.001). Median LC was 26.8 months, and intrahepatic cholangiocarcinoma was associated with longer LC (
p
= 0.036). Median DPFS was 11 months, with 1- and 2-year DPFS of 48% and 27.8%, respectively. Ten patients reported grade 1–2 toxicity and 2 cases of acute G3 biliary obstruction.
Conclusions
Stereotactic body radiotherapy (SBRT) is feasible in the context of mBTC. OS and PFS results are promising, considering that our patients were heavily pre-treated with systemic therapy. Patients with nodal or lung relapse have better prognosis. Distant relapses remain the main pattern of failure, but treatment of all metastatic sites seems to improve DMFS.
To investigate the role of intensity modulated proton therapy (IMPT) for advanced hepatocellular carcinoma in comparison with volumetric modulated arc therapy (VMAT).
An in-silico planning study was ...performed on 20 patients. The prescription dose was 60Gy in 6 fractions. Patients were planned with abdominal compression. IMPT plans were optimized with or without the inclusion of CT calibration (3%) and isocenter positioning (2,4,6mm) uncertainties. Plan robustness was appraised comparing rubust optimized plans vs standard plans and also in terms of the worst-case scenario. VMAT plans were optimized for 10FFF photon beams using 2 partial arcs.
Target coverage was fully achieved by both VMAT and IMPT plans with a significant improvement in homogeneity (~25%) with IMPT. Integral dose was reduced of ~60% with IMPT while the conformality of the dose distributions was similar among techniques. The sparing of the organs at risk was strongly improved with IMPT although all clinical objectives were met for both techniques. The inclusion of the uncertainties in the optimization lead to some deterioration in the target dose homogeneity (from 40 to 80% worse with 4 or 6mm position uncertainty) while none of the coverage parameters or OAR objective was violated. The worst-case scenario analysis demonstrated the risk of a major target underdosage only in the case of the most extreme errors (6mm) with D98% in average ~12% lower than the threshold.
IMPT with the support of abdominal compression, can be considered a viable solution also for advanced hepatocellular carcinoma patients. Great care shall be put in the minimization of the residual respiration and positioning uncertainties but the dosimetric advantage for organs at risk and the relative robustness on target coverage are promising factors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Liver resection (LR) of colorectal metastases is associated with high recurrence risk. Aggressive local retreatment is advocated, but further recurrences may occur. Poor is known about ...presentation, treatment, and outcome of iterative recurrences.
Methods
A series of 323 consecutive patients undergoing first LR in the period 2004–2013 was reviewed. Patients with recurrence were included. Any local treatment (surgery, radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT)) was analyzed. If first recurrence (1st Rec) was treated, further recurrences and treatments were considered.
Results
Overall, 206 (63.8%) patients had 1st Rec; 105 (51.0%) were treated (72 surgery, 19 RFA, 14 SBRT). Among treated patients, 78.1% had 2nd Rec, 74.4% 3rd Rec, 72.2% 4th Rec. Liver involvement progressively decreased (from 81.6 to 30.8%), and pulmonary one increased (from 23.3 to 53.8%). The proportion of treated patients remained stable (1st Rec = 51%, 2nd Rec = 55%, 3rd Rec = 56.3%, 4th Rec = 69.2%): surgery and RFA decreased (from 35.4 to 23.1%; from 9.2 to 0%) and SBRT increased (from 6.8 to 46.2%). Overall, 105 patients received 205 treatments (133 operations in 80 patients). Surgery had the best local disease control: at 2 years 93.4% versus RFA 56.4% (
p
= 0.0008) and SBRT 74.0% (
p
= 0.051). In comparison with chemotherapy, recurrence treatment improved survival after 1st Rec (3-year survival 62.9 vs. 13.4%,
p
< 0.0001), 2nd Rec (61.3 vs. 22.5%,
p
< 0.0001), and 3rd Rec (2-year survival 88.9 vs. 30.8%,
p
= 0.005).
Conclusions
Aggressive local treatment of recurrent metastases may improve survival, even in the case of iterative recurrences and extrahepatic lesions. Surgery is the standard, but a multidisciplinary approach should be adopted to enlarge the pool of treatable patients.
PDF
