Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma

Background

Occasionally, patients with hepatocellular carcinoma (HCC) who receive radioembolization with palliative intent are downstaged for radical treatments. The aim of this study was to describe and analyze the overall survival (OS) in these patients compared with patients of the same baseline stage (UNOS T3), who were not eligible for radical treatment after radioembolization.

Methods

Between September 2003 and August 2010, 118 patients with HCC received radioembolization with yttrium-90 (⁹⁰Y) resin microspheres. Of these, 21 patients with UNOS T3 stage were retrospectively identified and included in this analysis.

Results

In total, 6 of 21 patients were downstaged and treated radically between 2 and 35 months post-radioembolization. Three patients were resected, 2 received liver transplantation and 1 was ablated and then resected. Patients treated radically were significantly younger (62 vs. 73 years, p = 0.006) and had higher tumor volume (583 mL vs. 137 mL, p = 0.001) than patients who did not achieve radical treatment. There were no differences between the groups in number of lesions, BCLC stage, previous cirrhosis, activity administered per tumor volume, or median levels of alpha-fetoprotein or total bilirubin. Across the whole series, the median OS was 27.0 months (95% CI 5.0–48.9), varying significantly between those treated radically (OS not reached after a median follow-up of 41.5 months since radical therapy) and those who received palliative treatment only (22.0 months; 95% CI 15.0–30.9).

Conclusions

Radical therapy following tumor downstaging with radioembolization provides the possibility of long-term survival in a select subgroup (UNOS T3 stage) with otherwise limited options.     

A comparison of right and extended right hepatectomy with all other hepatic resections for colorectal liver metastases: A ten-year study

Aims

Colorectal liver metastases are treated by a combination of adjuvant chemotherapy followed by liver resection. In this study we compared all major right-sided resections with left or parenchymal sparing resections.

Methods

Consecutive patients (n = 283) who had successful hepatic resections for colorectal metastases from September 1996 to November 2006 were prospectively studied. Early and late outcomes of those who had right and extended right hepatectomies (RH) were compared with those who had all other types of liver resection (AOLR). Adjuvant therapy and pre-operative assessment were standardised for all.

Results

The 1-, 3- and 5-year overall survival rates in the RH group were 84.1%, 54.3% and 38.9%, respectively. The 1-, 3- and 5-year overall survival rates in the AOLR group were 95.4%, 65.9% and 53.3%, respectively. The difference was statistically significant (p = 0.03). The 1-, 3- and 5-year disease-free survival rates in the RH group were 69.5%, 34.4% and 25.5%, respectively and 68.4%, 34.91% and 34.91%, respectively in the AOLR group (p = 0.46). Operative mortality was 3.9% in the RH group and 0.7% in the AOLR group (p = 0.04). Morbidity was 31.3% in the RH group and 18% in the AOLR group.

Conclusion

Patients undergoing right and extended right hepatectomies for colorectal metastases have a greater operative morbidity and mortality and have a significantly worse overall survival compared to all other liver resections for the same disease.     

Decrease of survivin,p53 and Bcl-2 expression in chemorefractory colorectal liver metastases may be predictive of radiosensivity after radioembolization with yttrium-90 resin microspheres

In a prospective multicenter phase II trial of radioembolization with yttrium-90 (⁹⁰Y-RE) in chemorefractory liver-dominant metastatic colorectal cancer (mCRC), we showed that median survival was 12.6 months (95% CI 7.0–18.3) with 48% of 50 patients achieving disease control. In this extension retrospective study, we analyzed whether a panel of biomarkers, known to be associated to an adverse clinical outcome, underwent variations in CRC liver metastases pre and post ⁹⁰Y-RE.Of the 50 patients included in the study, 29 pre-⁹⁰Y-RE therapy and 15 post-⁹⁰Y-RE had liver biopsy specimens available. In these series we investigated survivin, p53, Bcl-2 and Ki-67 expression pre- and post-⁹⁰Y-RE by immuhistochemistry (IHC). Our findings evidenced a decrease of survivin (77% vs 33%), p53 (93% vs 73%), Bcl-2 (37% vs 26%) expression as well as of Ki-67 proliferation index (62.5% vs 40%) on liver biopsies collected post-⁹⁰Y-RE as compared to pre-⁹⁰Y-RE. In the subset of 13 matched liver metastases we further confirmed the reduction of survivin (92.3% vs 53.8%; p = 0.06), p53 (100% vs 69.2%; p = 0.05) and Bcl-2 (69.2% vs 53.8%; p = 0.05) expression post-⁹⁰Y-RE. This biomarker modulation was accompanied by morphological changes as steatohepatitis, hepatocyte necrosis, collagen deposition, proliferating and/or bile duct ectasia, focal sinusoidal dilatation and fibrosis.Although our analysis was conducted in a very limited number cases, these changes appear strictly related to the response to ⁹⁰Y-RE therapy and may deserve further investigation on a larger series of patients.     

The use of neoadjuvant lobar radioembolization prior to major hepatic resection for malignancy results in a low rate of post hepatectomy liver failure

BackgroundNeoadjuvant yttrium-90 transarterial radioembolization (TARE) is increasingly being used as a strategy to facilitate resection of otherwise unresectable tumors due to its ability to generate both tumor response and remnant liver hypertrophy. Perioperative outcomes after the use of neoadjuvant lobar TARE remain underinvestigated.MethodsA single center retrospective review of patients who underwent lobar TARE prior to major hepatectomy for primary or metastatic liver cancer between 2007 and 2018 was conducted. Baseline demographics, radioembolization parameters, pre- and post-radioembolization volumetrics, intra-operative surgical data, adverse events, and post-operative outcomes were analyzed.ResultsTwenty-six patients underwent major hepatectomy after neoadjuvant lobar TARE. The mean age was 58.3 years (17–88 years). 62% of patients (n=16) had primary liver malignancies while the remainder had metastatic disease. Liver resection included right hepatectomy or trisegmentectomy, left or extended left hepatectomy, and sectorectomy/segmentectomy in 77% (n=20), 8% (n=2), and 15% (n=4) of patients, respectively. The mean length of stay was 8.3 days (range, 3–33 days) and there were no grade IV morbidities or 90-day mortalities. The incidence of post hepatectomy liver failure (PHLF) was 3.8% (n=1). The median time to progression after resection was 4.5 months (range, 3.3–10 months). Twenty-three percent (n=6) of patients had no recurrence. The median survival was 28.9 months (range, 16.9–46.8 months) from major hepatectomy and 37.6 months (range, 25.2–53.1 months) from TARE.ConclusionsMajor hepatectomy after neoadjuvant lobar radioembolization is safe with a low incidence of PHLF.     

Hepatic imaging response to radioembolization with yttrium-90-labeled resin microspheres for tumor progression during systemic chemotherapy in patients with colorectal liver metastases

Background

To assess response and the impact of imaging artifacts following radioembolization with yttrium-90-labeled resin microspheres (⁹⁰Y-RE) based on the findings from a central independent review of patients with liver-dominant metastatic colorectal cancer (mCRC).

Methods

Patients with mCRC who received ⁹⁰Y-RE (SIR-Spheres^®; Sirtex Medical, Sydney, Australia) at nine US institutions between July 2002 and December 2011 were included in the analysis. Tumor response was assessed at baseline and 3 months using either the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or 1.1. For each lesion, known artifacts affecting the interpretation of response (peri-tumoral edema and necrosis) were documented. Survivals (Kaplan-Meier analyses) were compared in responders [partial response (PR)] and non-responders [stable (SD) or progressive disease (PD)].

Results

Overall, 195 patients (mean age 62 years) received ⁹⁰Y-RE after a median of 2 (range, 1-6) lines of prior chemotherapy. Using RECIST 1.0 and RECIST 1.1, 7.6% and 6.9% of patients were partial responders, 47.3% and 48.1% had SD, and 55.0% and 55.0% PD, respectively. RECIST 1.0 and RECIST 1.1 showed excellent agreement {Kappa =0.915 [95% confidence interval (CI): 0.856-0.975]}. Peri-tumoral edema was documented in 32.8%, necrosis in 48.1% and both in 57.3% of cases (using RECIST 1.0). Although baseline characteristics were similar in responders and non-responders (P>0.05), responders survived significantly longer in an analysis according to RECIST 1.0: PR median (95% CI) 25.2 (range, 9.2-49.4) months vs. SD 15.8 (range, 9.3-21.1) months vs. PD 7.1 (range, 6.0-9.5) months (P<0.0001).

Conclusions

RECIST 1.0 and RECIST 1.1 imaging responses provide equivalent interpretations in the assessment of hepatic tumors following ⁹⁰Y-RE. Radiologic lesion responses at 3 months must be interpreted with caution due to the significant proportion of patients with peri-tumoral edema and necrosis, which may lead to an under-estimation of PR/SD. Nevertheless, 3-month radiologic responses were predictive of prolonged survival.     

Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium

PURPOSE: To standardize the indications, techniques, multimodality treatment approaches, and dosimetry to be used for yttrium-90 (Y90) microsphere hepatic brachytherapy. METHODS AND MATERIALS: Members of the Radioembolization Brachytherapy Oncology Consortium met as an independent group of experts in interventional radiology, radiation oncology, nuclear medicine, medical oncology, and surgical oncology to identify areas of consensus and controversy and to issue clinical guidelines for Y90 microsphere brachytherapy. RESULTS: A total of 14 recommendations are made with category 2A consensus. Key findings include the following. Sufficient evidence exists to support the safety and effectiveness of Y90 microsphere therapy. A meticulous angiographic technique is required to prevent complications. Resin microsphere prescribed activity is best estimated by the body surface area method. By virtue of their training, certification, and contribution to Y90 microsphere treatment programs, the disciplines of radiation oncology, nuclear medicine, and interventional radiology are all qualified to use Y90 microspheres. The panel strongly advocates the creation of a treatment registry with uniform reporting criteria. Initiation of clinical trials is essential to further define the safety and role of Y90 microspheres in the context of currently available therapies. CONCLUSIONS: Yttrium-90 microsphere therapy is a complex procedure that requires multidisciplinary management for safety and success. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies.     

Phase I study of capecitabine combined with radioembolization using yttrium-90 resin microspheres (SIR-Spheres) in patients with advanced cancer

Background:

This was a prospective single-centre, phase I study to document the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended phase II dose for future study of capecitabine in combination with radioembolization.

Methods:

Patients with advanced unresectable liver-dominant cancer were enrolled in a 3+3 design with escalating doses of capecitabine (375–1000 mg/m² b.i.d.) for 14 days every 21 days. Radioembolization with ⁹⁰Y-resin microspheres was administered using a sequential lobar approach with two cycles of capecitabine.

Results:

Twenty-four patients (17 colorectal) were enrolled. The MTD was not reached. Haematologic events were generally mild. Common grade 1/2 non-haematologic toxicities included transient transaminitis/alkaline phosphatase elevation (9 (37.5%) patients), nausea (9 (37.5%)), abdominal pain (7 (29.0%)), fatigue (7 (29.0%)), and hand-foot syndrome or rash/desquamation (7 (29.0%)). One patient experienced a partial gastric antral perforation with a capecitabine dose of 750 mg/m². The best response was partial response in four (16.7%) patients, stable disease in 17 (70.8%) and progression in three (12.5%). Median time to progression and overall survival of the metastatic colorectal cancer cohort was 6.4 and 8.1 months, respectively.

Conclusions:

This combined modality treatment was generally well tolerated with encouraging clinical activity. Capecitabine 1000 mg/m² b.i.d. is recommended for phase II study with sequential lobar radioembolization.     

Remnant liver regeneration after two-stage hepatectomy for multiple bilobar colorectal metastases.

AIMS: Two-stage hepatectomy for multiple, bilobar liver metastases from colorectal cancer aimed to minimize liver failure risk by performing the second resection after regeneration, but impact of this strategy on volume of the future liver remnant (FLR) remained to be demonstrated. We compared two-stage hepatectomy with one stage following portal vein embolization (PVE) for multiple, bilobar liver metastases from colorectal cancer as to effects on volume of the FLR. METHODS: Forty-three patients undergoing major hepatectomy for multiple colorectal cancer metastases were divided retrospectively into patients undergoing hepatectomy following PVE (n=21) and those undergoing two-stage hepatectomy (n=22). Increases in FLR volume were compared. RESULTS: While the increase in the volume FLR averaged approximately 70 mL (302.6 mL before PVE vs. 370.9 mL after PVE) and the increase in the ratio of FLR to total liver volume averaged approximately 7.5% (30.2% to 37.5%) following PVE, first-stage hepatectomy increased FLR volume by approximately 100mL (from 259.4 to 361.4), and the ratio, by 15% (26.9% to 41.6%). The FLR hypertrophy ratio relative to pre-procedure volume estimates in the two-stage group (50.2%) was twice that in the PVE group (25.3%). CONCLUSIONS: Superiority of two-stage hepatectomy in hypertrophy of the FLR was confirmed.     

Laparoscopic anatomic liver resection of segment 7 using a caudo-dorsal approach to the right hepatic vein

BackgroundLaparoscopic anatomic liver resection of segment 7 (S7) is technically challenging because of the posterosuperior location and the lack of clear anatomical landmarks [[1], [2], [3], [4]]. Here, we introduce a caudo-dorsal approach, which may offer a benefit for the difficult procedure.MethodsThe patient was a 53-year-old man with hepatocellular carcinoma located in S7 of the liver. After the transection of caudate process, the Glissonean pedicle of S7 (G7) extending from the right posterior Glissonean pedicle was identified on the liver dorsal side. The demarcation line was noted by isolating and clamping G7. The intraoperative ultrasound was then used to assess the extent of the tumor. The right hepatic vein was approached from the dorsal side and continuously exposed in a caudal-cranial direction along the anterior surface of inferior vena cava after isolating and cutting the venous branches draining S7. Following the dissection of G7, the liver parenchymal transection was proceeded along the ischemic line between segment 6 and 7 with the ventral cutting plane extended to join the dorsal one. The liver parenchyma of the ventral side of the exposed right hepatic vein (RHV) was further transected from the dorsal side toward the root side of RHV. The resection of S7 was completed with perihepatic ligaments dissection.ResultsThe intermittent Pringle maneuver (15 min occlusion and 5 min reperfusion) was applied when necessary with a total time of 45 min. The operation time was 200 min, the estimated blood loss was 300 ml, and no transfusion was required. Pathology confirmed moderately differentiated HCC with negative surgical margin. The patient was discharged on postoperative day 8 with no complications and has been followed up for 8 months without recurrence.ConclusionThis caudo-dorsal approach for laparoscopic anatomical S7 segmentectomy is easy and feasible when performed by experienced surgeons at experienced centers in well-selected patients     

Comparative study of right portal vein ligation versus embolisation for induction of hypertrophy in two-stage hepatectomy for multiple bilateral colorectal liver metastases

Aim

In patients with two-stage hepatectomy (TSH) for multiple bilobar liver metastases from colorectal cancer, few clinical series compare functional remnant hypertrophy of the liver volume between right portal vein ligation (PVL) and embolisation (PVE). Our objective is to analyse the effectiveness of portal vein ligation to achieve hypertrophy of the functional remnant volume (FRV) of the liver and to compare the results with portal vein embolisation in a series of patients with multiple bilobar liver metastases from colorectal carcinoma.

Patients and methods

Between September 2001 and September 2011 we performed a TSH in 41 patients with multiple bilobar colorectal liver metastases. A right PVL was performed in 23 patients with an insufficient FRV (three patients did not complete the second stage due to tumour progression and were excluded). We prospectively compare these results with the increased remnant volume obtained in 18 patients with right PVE.

Results

The median FRV was higher in the patients with PVE, rising from 501 ml (range 309–703) to 636 ml (range 387–649), than those with PVL, rising from 510 ml (range 203–824) to 595 ml (range 313–1213) (p < 0.05). The median %FRVI was higher in the patients with PVE (median 40%; range 21–65%) than those with PVL (median 30%; range 21–60%) (p < 0.05).

Conclusions

PVL and PVE were effective in all cases for obtaining hypertrophy of the FRV before major liver resection. Right PVE obtains better results and should be used where necessary to achieve a further increase in volume.