Chemotherapy with or without selective internal radiation therapy for intrahepatic cholangiocarcinoma: Data from clinical trials.

BACKGOUND AND AIMS: In advanced, liver-only intrahepatic cholangiocarcinoma (iCCA), selective internal radiation therapy (SIRT) has been suggested as promising in nonrandomized studies. We aimed to compare data from patients with advanced, liver-only iCCA treated in the first line in clinical trials with either chemotherapy alone or the combination with SIRT. APPROACH AND RESULTS: We collected individual patients' data from the ABC-01, ABC-02, ABC-03, BINGO, AMEBICA, and MISPHEC prospective trials. Data from patients with liver-only iCCA treated in chemotherapy-only arms of the first 5 trials were compared with data from patients treated with SIRT and chemotherapy in MISPHEC. Emulated target trial paradigm and Inverse Probability of Treatment Weighting (IPTW methods) using the propensity score were used to minimize biases. We compared 41 patients treated with the combination with 73 patients treated with chemotherapy alone, the main analysis being in 43 patients treated with cisplatin-gemcitabine or gemcitabine-oxaliplatin. After weighting, overall survival was significantly higher in patients treated with SIRT: median 21.7 months (95% CI: 14.1; not reached) versus 15.9 months(95% CI: 9.8; 18.9), HR = 0.59 (95% CI: 0.34; 0.99), p = 0.049. Progression-free survival was significantly improved: median 14.3 months (95% CI: 7.8; not reached) versus 8.4 months (95% CI: 5.9; 12.1), HR = 0.52 (95% CI: 0.31; 0.89), p < 0.001. Results were confirmed in most sensitivity analyses. CONCLUSIONS: This analysis derived from prospective clinical trials suggests that SIRT combined with chemotherapy might improve outcomes over chemotherapy alone in patients with advanced, liver-only iCCA. Randomized controlled evidence is needed to confirm these findings.

Resection Postradioembolization in Patients With Single Large Hepatocellular Carcinoma.

OBJECTIVE: The aim of this study was to evaluate the efficacy of yttrium-90 transarterial radioembolization (TARE) to convert to resection initially unresectable, single, large (≥5 cm) hepatocellular carcinoma (HCC). BACKGROUND: TARE can downsize cholangiocarcinoma to resection but its role in HCC resectability remains debatable. METHODS: All consecutive patients with a single large HCC treated between 2015 and 2020 in a single tertiary center were reviewed. When indicated, patients were either readily resected (upfront surgery) or underwent TARE. TARE patients were converted to resection (TARE surgery) or not (TARE-only). To further assess the effect of TARE on the long-term and short-term outcomes, a propensity score matching analysis was performed. RESULTS: Among 216 patients, 144 (66.7%) underwent upfront surgery. Among 72 TARE patients, 20 (27.7%) were converted to resection. TARE-surgery patients received a higher mean yttrium-90 dose that the 52 remaining TARE-only patients (211.89±107.98 vs 128.7±36.52 Gy, P <0.001). Postoperative outcomes between upfront-surgery and TARE-surgery patients were similar. In the unmatched population, overall survival at 1, 3, and 5 years was similar between upfront-surgery and TARE-surgery patients (83.0%, 60.0%, 47% vs 94.0%, 86.0%, 55.0%, P =0.43) and compared favorably with TARE-only patients (61.0%, 16.0% and 9.0%, P <0.0001). After propensity score matching, TARE-surgery patients had significantly better overall survival than upfront-surgery patients ( P =0.021), while disease-free survival was similar ( P =0.29). CONCLUSION: TARE may be a useful downstaging treatment for unresectable localized single large HCC providing comparable short-term and long-term outcomes with readily resectable tumors.

A new software tool for planning interventional procedures in liver cancer.

INTRODUCTION: Intra-arterial therapy is an effective way of performing chemotherapy or radiation therapy in patients with primary liver cancer (i.e. hepatocellular carcinoma). Although this minimally invasive approach is now an established treatment option, support tools for pre-operative planning and intra-operative assistance might be helpful. MATERIAL AND METHODS: We developed an approach for semi-automatic segmentation of computed tomography angiography images of the main arterial branches (required for access path to the treatment site), automatic segmentation of the liver, arterial and venous tree, and interactive segmentation of the tumors (required for procedure-specific planning). This approach was then integrated into a liver-specific workflow within EndoSize® solution, a planning software for endovascular procedures. The main branches extraction approach was qualitatively evaluated inside the software, while the automatic segmentation methods were quantitatively assessed. RESULTS: Main branches extraction provides a success rate of 85% (i.e. all arteries correctly extracted) in a dataset of 172 patients. On public databases, a mean DICE of 0.91, 0.47 and 0.92 was obtained for liver, venous and arterial trees segmentation, respectively. CONCLUSIONS: This pipeline is suitable for directly accessing the treatment site, giving anatomic measurements, and visualizing the hepatic trees, liver, and surrounding arteries during the pre-operative planning. ABBREVIATIONS: HCC: hepatocellular carcinoma; TACE: transarterial chemoembolization; SIRT: selective internal radiation therapy; CT: computed tomography; CTA: computed tomography angiography; AMS: superior mesenteric artery; LGA: left gastric artery; RHA: right hepatic artery; LHA: left hepatic artery; rbHA: right branch of the hepatic artery; lbHA: left branch of the hepatic artery; GDA: gastroduodenal artery; VOI: volume of interest; SD: standard deviation; MICCAI: medical image computing and computer assisted interventions; MR: magnetic resonance.

Downstaging with Radioembolization or Chemotherapy for Initially Unresectable Intrahepatic Cholangiocarcinoma.

OBJECTIVE: The aim of this retrospective study was to compare the outcomes of patients resected for intrahepatic cholangiocarcinoma (ICC) with upfront surgery or after downstaging treatment. METHODS: All consecutive patients with ICC between January 1997 and November 2017 were included in a single-center database and retrospectively reviewed. Patients were divided into two groups: upfront resection or resection after downstaging using either chemotherapy alone or selective internal radiation therapy (SIRT) combined with chemotherapy. Survival rates of patients who underwent upfront surgery for ICC were compared with those of patients who underwent surgery after downstaging therapy. RESULTS: A total of 169 patients resected for ICC were included: 137 underwent upfront surgery and 32 received downstaging treatment because their tumor was initially unresectable (13 received chemotherapy, 19 received SIRT). Median OS was not different between the two groups: 32.3 months [95% confidence interval (CI) 23.9-40.7] with primary surgery versus 45.9 months (95% CI 32.3-59.4) with downstaging treatment (p = 0.54, log-rank test). In a multivariable Cox regression model, downstaging treatment was not associated with a better or worse prognosis; however, delivery of SIRT as a downstaging treatment was associated with a significant benefit in multivariable analysis (hazard ratio 0.34, 95% CI 0.14-0.84; p = 0.019). CONCLUSIONS: Overall survival of patients resected after downstaging treatment was not different compared with the OS of patients resected upfront. Patients should therefore again be discussed with the surgeon following medical treatment. SIRT may be an efficient neoadjuvant therapy in patients with resectable ICC, in order to improve surgical results.

Yttrium-90 glass microspheres radioembolization (RE) for biliary tract cancer: a large single-center experience.

PURPOSE: Radioembolization (RE) is a promising treatment option for biliary tract cancers (BTC). We report here the largest series to date using this treatment modality. METHODS: We retrospectively studied data from 64 patients treated outside prospective clinical trial at our institution. We studied baseline characteristics as potential prognostic factors. We studied dose delivered to the tumor as predictive factors of outcomes in patients not receiving concomitant chemotherapy. RESULTS: The Progression-Free Survival and Overall Survival (OS) were 7.6 months [95% Confidence Interval (CI): 4.6-10.6] and 16.4 months [95% CI: 7.8-25.0] in the whole cohort. The factors independently associated with OS in multivariable analysis were the primary localization of ICC (HR = 0.27, 95% CI: 0.11-0.68, p = 0.005) and a PS > 0 (HR = 2.21, 95% CI: 1.11-4.38, p = 0.024). During follow-up, 12 patients (19%) underwent surgery following downstaging, with a median OS of 51.9 months. In patients not treated with concomitant chemotherapy (n = 31), OS was significantly higher in patients with a dose delivered to the tumor 260Gy or higher than in patients with a dose delivered to the tumor lower than 260Gy (median 28.2 vs 11.4 months, log-rank p = 0.019). CONCLUSION: Our results confirm that RE is a promising treatment modality in BTC. A high proportion of patients could be downstaged to surgery, with promising long-term survival. Dose delivered to the tumor correlated with clinical outcomes when chemotherapy was not used concomitantly.

Preliminary results of the Phase 1 Lip-Re I clinical trial: biodistribution and dosimetry assessments in hepatocellular carcinoma patients treated with 188Re-SSS Lipiodol radioembolization.

PURPOSE: This study sought to provide preliminary results on the biodistribution and dosimetry following intra-arterial liver injection of 188Re-SSS Lipiodol on hepatocellular carcinoma patients included in the Phase I Lip-Re 1 study. METHODS: Results of the first six patients included are reported. Analysis of the 188Re-SSS Lipiodol biodistribution was based on planar scintigraphic and tomoscintigraphic (SPECT) studies performed at 1, 6, 24, 48, and 72 h post-administration. Quantification in blood, urine, and stool samples was performed. Determination of the tumour to non-tumour uptake ratio (T/NT) was calculated. Absorbed doses to target organs and tumours were evaluated using the MIRD formalism. RESULTS: The mean injected activity of 188Re-SSS Lipiodol was 1645 ± 361 MBq. Uptakes were seen in the liver (tumour and healthy liver) and the lungs only. All these uptakes were stable over time. A mean 1.4 ± 0.7% of 188Re-SSS Lipiodol administered was detected in serum samples at 6 h, declining rapidly thereafter. On average, 1.5 ± 1.6% of administered activity was eliminated in urine and feces over 72 h. Overall, 90.7 ± 1.6% of detected activity on SPECT studies was found in the liver (74.9 ± 1.8% in tumours and 19.1 ± 1.7% in the healthy liver) and 9.3 ± 1.6% in the lungs (5.7 ± 1.1% in right and 3.7 ± 0.5% in left lungs). Mean doses absorbed were 7.9 ± 3.7Gy to the whole liver, 42.7 ± 34.0Gy to the tumours, 10.2 ± 3.7Gy to the healthy liver, and 1.5 ± 1.2Gy to the lungs. Four patients had stable disease on CT scans at 2 months. The first patient with rapidly progressive disease died at 1 month, most probably of massive tumour progression. Due to this early death and using a conservative approach, the trial independent evaluation committee decided to consider this event as a treatment-related toxicity. CONCLUSION: 188Re-SSS Lipiodol has a favorable biodistribution profile concerning radioembolization, with the highest in-vivo stability among all radiolabeled Lipiodol compounds reported to date. These preliminary results must be further confirmed while completing this Phase I Lip Re1 study.

A MAA-based dosimetric study in patients with intrahepatic cholangiocarcinoma treated with a combination of chemotherapy and 90Y-loaded glass microsphere selective internal radiation therapy.

PURPOSE: Selective internal radiation therapy (SIRT) appears to be an interesting treatment possibility for locally-advanced intrahepatic cholangiocarcinoma (ICC), yet the appropriate dosimetry has never been evaluated in this context. METHODS: We retrospectively studied data from 40 patients treated at our institution with 90Y-loaded glass microsphere SIRT combined with chemotherapy for inoperable ICC as first-line treatment. Macroaggregated albumin (MAA)-based single-photon emission computed tomography (SPECT)/computed tomography (CT) quantitative analysis was used to calculate the tumor dose (TD), healthy-injected liver dose (HILD), and injected liver dose (ILD). Response was evaluated at 3 months using the European Association for the Study of the Liver criteria. Factors associated with response and toxicity were analyzed using univariate analysis. RESULTS: We assessed a total of 35 patients (five excluded) receiving 55 injections. Mean TD was 322 ± 165Gy and mean HILD was 74 ± 24Gy for a mean ILD of 128 ± 28Gy. All but two lesions responded, with a minimal TD for responding lesions of 158Gy. Six Grade 3-4 permanent liver toxicities were observed. Mean HILD was not associated with liver toxicity (73.2 ± 25.8Gy for patients with liver toxicity and 77.8 ± 16.9Gy for patients without, ns). Only underlying Child-Pugh status (p = 0.0014) and underlying cirrhosis (p = 0.0021) were associated with liver toxicity. Median progression-free survival was 12.7 months and median overall survival (OS) was 28.6 months. Median OS was 52.7 months for patients with Child-Pugh A5 status. CONCLUSIONS: When combined with chemotherapy, SIRT is highly effective, with a TD > 158Gy. Tolerance was good except for the few patients with cirrhosis or Child-Pugh status ≥A6, who exhibited some liver toxicity. Prospective studies are warranted to confirm.

Dosimetric parameters predicting contralateral liver hypertrophy after unilobar radioembolization of hepatocellular carcinoma.

PURPOSE: This study aimed at identifying prior therapy dosimetric parameters using 99mTc-labeled macro-aggregates of albumin (MAA) that are associated with contralateral hepatic hypertrophy occurring after unilobar radioembolization of hepatocellular carcinoma (HCC) performed with 90Y-loaded glass microspheres. METHODS: The dosimetry data of 73 HCC patients were collected prior to the treatment with 90Y-loaded microspheres for unilateral disease. The injected liver dose (ILD), the tumor dose (TD) and healthy injected liver dose (HILD) were calculated based on MAA quantification. Following treatment, the maximal hypertrophy (MHT) of an untreated lobe was calculated. RESULTS: Mean MHT was 35.4 ± 40.4%. When using continuous variables, the MHT was not correlated with any tested variable, i.e., injected activity, ILD, HILD or TD except with a percentage of future remnant liver (FRL) following the 90Y-microspheres injection  (r = -0.56). MHT ≥ 10% was significantly more frequent for patients with HILD ≥ 88 Gy, (52% of the cases), i.e., in 92.2% versus 65.7% for HILD < 88 Gy (p = 0.032). MHT ≥ 10% was also significantly more frequent for patients with a TD ≥ 205 Gy and a tumor volume (VT) ≥ 100 cm3 in patients with initial FRL < 50%. MHT ≥10% was seen in 83.9% for patients with either an HILD ≥ 88 Gy or a TD ≥ 205 Gy for tumors larger than 100cm3 (85% of the cases), versus only 54.5% (p = 0.0265) for patients with none of those parameters. MHT ≥10% was also associated with FRL and the Child-Pugh score. Using multivariate analysis, the Child-Pugh score (p < 0.0001), FRL (p = 0.0023) and HILD (p = 0.0029) were still significantly associated with MHT ≥10%. CONCLUSION: This study demonstrates for the first time that HILD is significantly associated with liver hypertrophy. There is also an impact of high tumor doses in large lesions in one subgroup of patients. Larger prospective studies evaluating the MAA dosimetric parameters have to be conducted to confirm these promising results.

Haralick textural features on T2 -weighted MRI are associated with biochemical recurrence following radiotherapy for peripheral zone prostate cancer.

PURPOSE: To explore the association between magnetic resonance imaging (MRI), including Haralick textural features, and biochemical recurrence following prostate cancer radiotherapy. MATERIALS AND METHODS: In all, 74 patients with peripheral zone localized prostate adenocarcinoma underwent pretreatment 3.0T MRI before external beam radiotherapy. Median follow-up of 47 months revealed 11 patients with biochemical recurrence. Prostate tumors were segmented on T2 -weighted sequences (T2 -w) and contours were propagated onto the coregistered apparent diffusion coefficient (ADC) images. We extracted 140 image features from normalized T2 -w and ADC images corresponding to first-order (n = 6), gradient-based (n = 4), and second-order Haralick textural features (n = 130). Four geometrical features (tumor diameter, perimeter, area, and volume) were also computed. Correlations between Gleason score and MRI features were assessed. Cox regression analysis and random survival forests (RSF) were performed to assess the association between MRI features and biochemical recurrence. RESULTS: Three T2 -w and one ADC Haralick textural features were significantly correlated with Gleason score (P < 0.05). Twenty-eight T2 -w Haralick features and all four geometrical features were significantly associated with biochemical recurrence (P < 0.05). The most relevant features were Haralick features T2 -w contrast, T2 -w difference variance, ADC median, along with tumor volume and tumor area (C-index from 0.76 to 0.82; P < 0.05). By combining these most powerful features in an RSF model, the obtained C-index was 0.90. CONCLUSION: T2 -w Haralick features appear to be strongly associated with biochemical recurrence following prostate cancer radiotherapy. LEVEL OF EVIDENCE: 3 J. Magn. Reson. Imaging 2017;45:103-117.