Frederic Deschamps

Liver/biliary injuries following chemoembolisation of endocrine tumours and hepatocellular carcinoma: Lipiodol vs. drug-eluting beads

BACKGROUND & AIMS Transarterial chemoembolisation (TACE) is usually performed by injecting an emulsion of a drug and iodised oil. Drug-eluting beads (DEBs) have undeniable pharmacological advantages by offering simultaneous embolisation and sustained release of the drug to the tumour. No data are currently available on liver/biliary injury following DEB-TACE. This study describes and compares liver/biliary injuries encountered with TACE in tumours developed in cirrhotic (hepatocellular carcinoma (HCC)) and non-cirrhotic (endocrine tumours (NETs)) livers. METHODS In consecutive patients treated for a well-differentiated metastatic NET (n=120) or a HCC (n=88), 684 CT- and MR-scans were analysed. Liver/biliary injuries were classified as follows: dilated bile duct, portal vein narrowing, portal venous thrombosis and biloma/liver infarct. A generalised estimating equation logistic regression model was used. RESULTS A liver/biliary injury followed 17.2% (82/476) of sessions in 30.8% (64/208) of patients. The occurrence of liver/biliary injury was associated with DEB-TACE (OR=6.63; p<0.001) irrespectively of the tumour type. Biloma/parenchymal infarct was strongly associated with both DEB-TACE (OR=9.78; p=0.002) and NETs (OR: 8.13; p=0.04). Biloma/liver infarcts were managed conservatively but were associated with an increase in serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatases, and gamma glutamyl transpeptidase (p=0.005, p=0.005, p=0.012, and p=0.006, respectively). CONCLUSIONS Liver/biliary injuries are independently associated with DEB-TACE. Biloma/liver infarct, the most serious injury, is independently associated with both DEB-TACE and NETs. The absence of such an association in TACE of HCC may be explained by the hypertrophied peribiliary plexus observed in cirrhosis, which protects against the ischemic/chemical insult of bile ducts. We suggest caution when using DEB-TACE in the non-cirrhotic liver.

High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial

High-throughput genomic analyses may improve outcomes in patients with advanced cancers. MOSCATO 01 is a prospective clinical trial evaluating the clinical benefit of this approach. Nucleic acids were extracted from fresh-frozen tumor biopsies and analyzed by array comparative genomic hybridization, next-generation sequencing, and RNA sequencing. The primary objective was to evaluate clinical benefit as measured by the percentage of patients presenting progression-free survival (PFS) on matched therapy (PFS2) 1.3-fold longer than the PFS on prior therapy (PFS1). A total of 1,035 adult patients were included, and a biopsy was performed in 948. An actionable molecular alteration was identified in 411 of 843 patients with a molecular portrait. A total of 199 patients were treated with a targeted therapy matched to a genomic alteration. The PFS2/PFS1 ratio was >1.3 in 33% of the patients (63/193). Objective responses were observed in 22 of 194 patients (11%; 95% CI, 7%-17%), and median overall survival was 11.9 months (95% CI, 9.5-14.3 months).Significance: This study suggests that high-throughput genomics could improve outcomes in a subset of patients with hard-to-treat cancers. Although these results are encouraging, only 7% of the successfully screened patients benefited from this approach. Randomized trials are needed to validate this hypothesis and to quantify the magnitude of benefit. Expanding drug access could increase the percentage of patients who benefit. Cancer Discov; 7(6); 586-95. ©2017 AACR.See related commentary by Schram and Hyman, p. 552This article is highlighted in the In This Issue feature, p. 539.

Role of FDG PET/CT and Chest CT in the Follow-up of Lung Lesions Treated with Radiofrequency Ablation

PURPOSE To compare fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with computed tomography (PET/CT) and chest CT in the evaluation of the effectiveness of lung radiofrequency (RF) ablation. MATERIALS AND METHODS Institutional review board approved the study, and all patients gave written informed consent. Thirty-four patients (22 men and 12 women; mean age, 64 years) planned to undergo lung RF ablation were prospectively included and underwent FDG PET/CT and chest CT before (pre-RF ablation PET) and 24 hours, 1 month, and 3 months after RF ablation. Persistent equivocal findings up to 3 months were followed up. RESULTS Pre-RF ablation PET led to changes in the treatment strategy in nine patients (26%) by depicting unexpected metastases. Two patients without FDG uptake in lesions to be treated were excluded. Overall, 28 patients (46 lesions: five primary cancer, 41 metastases) were treated and followed up. Within 3 months after RF ablation, incomplete treatment was diagnosed in four of 28 patients (14%, three at 1 month and one at 3 months). Findings of FDG PET/CT were true-positive in four, false-positive in one, and true-negative in 23 patients. Findings of chest CT were true-positive in one, false-positive in one, false-negative in three, and true-negative in 23 patients. Inflammatory FDG uptake in mediastinal lymph nodes and at the needle path puncture site used for RF ablation was observed in 15%, 21%, and 15% of patients and in 19%, 11%, and 15% of patients at 24 hours, 1 month, and 3 months, respectively. CONCLUSION FDG PET/CT can be used for the evaluation of the effectiveness of lung RF ablation. Inflammatory FDG uptake in mediastinal lymph nodes or at the needle path site used for RF ablation may occur.

SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma.

Cyclophosphamide–dacarbazine–vincristine regimen is recommended for the treatment of malignant pheochromocytoma and paraganglioma (MPP); however, dacarbazine is the only recognized active drug in neuroendocrine tumours. We investigated the therapeutic benefit of temozolomide (TMZ), an oral alternative to dacarbazine, in patients with MPP. This is a retrospective study of consecutive patients with documented progressive MPP. We examined the correlation between Succinate dehydrogenase B (SDHB) mutation and O(6)‐methylguanine‐DNA methyltransferase (MGMT) promoter methylation and MGMT expression in the French nation‐wide independent cohort of 190 pheochromocytomas or paragangliomas (PP). Progression‐free survival (PFS) according to RECIST 1.1 and PERCIST 1.0 criteria was the primary end point. Fifteen consecutive patients with MPP were enrolled; ten (67%) carried a mutation in SDHB. The mean dose intensity of TMZ was 172 mg/m2/d for 5 days every 28 days. Median PFS was 13.3 months after a median follow‐up of 35 months. There were five partial responses (33%), seven stable (47%) and three progressive diseases (20%). Grade 3 toxicities were lymphopenia in two patients and hypertension in one. Partial responses were observed only in patients with mutation in SDHB. MGMT immunohistochemistry was negative in tumour samples from four patients who responded to treatment. SDHB germline mutation was associated with hypermethylation of the MGMT promoter and low expression of MGMT in 190 samples of the French nation‐wide independent cohort. This study demonstrates that TMZ is an effective antitumour agent in patients with SDHB‐related MPP. The silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB‐mutated tumours may explain this finding.

Left‐liver hypertrophy after therapeutic right‐liver radioembolization is substantial but less than after portal vein embolization

In patients with liver malignancies potentially amenable to curative extended right hepatectomy but insufficient size of the future liver remnant (FLR), portal vein embolization (PVE) of the tumor‐bearing liver is used to induce contralateral liver hypertrophy but leaves the tumor untreated. Radioembolization (RE) treats the tumor in the embolized lobe along with contralateral hypertrophy induction. We performed a matched‐pair analysis to compare the capacity for hypertrophy induction of these two modalities. Patients with right‐hepatic secondary liver malignancies with no or negligible left‐hepatic tumor involvement who were treated by right‐lobar PVE (n = 141) or RE (n = 35) at two centers were matched for criteria known to influence liver regeneration following PVE: 1) baseline FLR/Total liver volume ratio (<25 versus ≥25%); 2) prior platinum‐containing systemic chemotherapy; 3) embolization of segments 5‐8 versus 4‐8; and 4) baseline platelet count (<200 versus ≥200 Gpt/L).The primary endpoint was relative change in FLR volume from baseline to follow‐up. Twenty‐six matched pairs were identified. FLR volume increase from baseline to follow‐up (median 33 [24‐56] days after PVE or 46 [27‐79] days after RE) was significant in both groups but PVE produced significantly more FLR hypertrophy than RE (61.5 versus 29%, P < 0.001). Time between treatment and follow‐up was not correlated with the degree of contralateral hypertrophy achieved in both groups. Although group differences in patient history and treatment setting were present and some bias cannot be excluded, this was minimized by the matched‐pair design, as remaining group differences after matching were found to have no significant influence on contralateral hypertrophy development. Conclusion: PVE induces significantly more contralateral hypertrophy than RE with therapeutic (nonlobectomy) doses. However, contralateral hypertrophy induced by RE is substantial and RE minimizes the risk of tumor progression in the treated lobe, possibly making it a suitable modality for selected patients. (Hepatology 2014;59:1864–1873)

Adjuvant chemotherapy after resection of colorectal liver metastases in patients at high risk of hepatic recurrence: a comparative study between hepatic arterial infusion of oxaliplatin and modern systemic chemotherapy.

Introduction:After curatively intended surgery for colorectal liver metastases, liver recurrences occur in more than 60% of patients, despite the administration of adjuvant systemic chemotherapy. The aim of this study was to assess the benefit of combined adjuvant hepatic arterial infusion (HAI) and intravenous (IV) 5-FU compared with standard modern adjuvant IV chemotherapy in patients at high risk of hepatic recurrence. Patients and Methods:From January 2000 to December 2009, 98 patients, who had undergone curative resection of at least 4 colorectal liver metastases, were selected from a prospective database. Among them, 44 (45%) had received postoperative HAI combined with systemic 5-FU (HAI group) and 54 (55%) had received “modern” systemic chemotherapy (IV group). Results:The 2 groups were similar in terms of age, sex, the stage of the primary, and the administration of preoperative chemotherapy. The median number of HAI cycles received per patient was 7 [range, 1–12]. Twenty-nine patients (66%) had received at least 6 cycles of HAI oxaliplatin, and 22 patients (50%) had received the full planned treatment. For the remaining 22 patients (50%), HAI chemotherapy had been discontinued because of toxicity (n = 8), HAI catheter dysfunction (n = 6), an early recurrence (n = 6), and patients refusal (n = 2). After a median follow-up of 60 months (51–81 months), 3-year overall survival was slightly higher in the HAI group (75% vs 62%, P = 0.17). Three-year disease-free survival was significantly longer in patients in the HAI group than those in the IV group (33% vs 5%, P < 0.0001). In the multivariate analysis, adjuvant HAI chemotherapy and an R0 resection margin status were the only independent predictive factors for prolonged disease-free survival. Conclusions:Postoperative HAI oxaliplatin combined with systemic chemotherapy after curatively intended surgery of colorectal liver metastases is feasible and may significantly improve disease-free survival of patients at high risk of hepatic recurrence compared with adjuvant modern systemic chemotherapy alone. These results should be confirmed in a randomized study.

Hepatic Malignancies: Percutaneous Radiofrequency Ablation during Percutaneous Portal or Hepatic Vein Occlusion

PURPOSE To prospectively evaluate the technical feasibility, effectiveness, and complications of percutaneous radiofrequency (RF) ablation for hepatic malignancies during temporary percutaneous balloon occlusion (PBO) of a large hepatic or portal vein. MATERIALS AND METHODS During a 4-year period, RF ablation was performed in 201 patients (106 men, 95 women; age range, 41-88 years) with 233 liver tumors. Institutional review board approval was obtained to attempt RF ablation during PBO for 18 tumors that were larger than 35 mm (mean, 43 mm +/- 7.6 [standard deviation]; range, 36-60 mm) and did not abut a portal or hepatic vein 4 mm in diameter or larger (group 1), 58 tumors 35 mm or smaller (mean, 23 mm +/- 7.3; range, 12-35 mm) that abutted a large vessel (group 2), and 20 tumors that were both larger than 35 mm (mean, 42 mm +/- 5.7; range, 38-50 mm) and abutted a large vessel (group 3). RF ablation without PBO was performed for 137 tumors 35 mm or smaller (mean, 22 mm +/- 6.8; range, 9-35 mm) and remote from large vessels (group 4). Rate of local tumor progression was estimated with the Kaplan-Meier method, and tumor progression-free rates were compared between the four groups with the log-rank test. Complications were compared by using the Fisher exact test between the four groups and between the two RF devices used. RESULTS PBO was achieved in 94 of 96 attempts (98%), including 64 of 64 hepatic veins and 30 of 32 portal branches. After a mean follow-up of 18 months +/- 9, 10 tumors in eight patients were lost to follow-up. Local tumor progression was observed in six (40%) of 15 tumors in group 1, in six (11%) of 56 tumors in group 2, in eight (40%) of 20 tumors in group 3, and in 12 (9%) of 130 tumors in group 4. Combined analysis of tumor size and the use of PBO showed that size was the only prognostic factor for tumor progression, with a hazard ratio of 4.9 (95% confidence interval: 2.4, 9.9) (P < .001). There were no differences between groups 2 and 4. Asymptomatic, transient postprocedure venous thrombosis was seen in nine of 94 RF ablations with PBO, while occlusion of one permanent portal branch induced segmental liver atrophy. There were no differences in rates of complications (5% and 6% for RF ablation with and that without PBO, respectively). CONCLUSION RF ablation with PBO provides tumor control for tumors smaller than 35 mm in diameter that abut vessels 4 mm or larger, equivalent to tumor control of the same-size tumors away from vessels. PBO does not seem to affect the results of RF ablation for tumors 35 mm or larger.

Cementoplasty of Metastases of the Proximal Femur: Is It a Safe Palliative Option?

PURPOSE Percutaneous cementoplasty has proved very effective for the palliation of pain from bone metastases. However, several studies argue that it should be contraindicated for metastases that are located in the proximal femur because of inadequate bone consolidation. The aim of this study was to evaluate the risk factors for fracture despite performing cementoplasty for metastases of the proximal femur. METHODS We retrospectively analyzed all consecutive patients who underwent cementoplasty for metastases of the proximal femur who had a high risk for fracture (N = 21) from June 2003 to October 2010. Cementoplasty was performed for preventive consolidation as well as for pain palliation in 16 patients. The risk factors studied were the patient characteristics, the Mirels score, the maximal size and cortical involvement of the lesion, and a history of a previous fracture of the lesser trochanter. RESULTS The 1-year pathologic fracture rate was 40.6% (seven fractures). The risk of fracture was significantly higher for cortical involvement greater than 30 mm (n = 7/11 vs n = 0/10; P = .0005) and a history of a previous fracture of the lesser trochanter (n = 3/3 vs 4/18; P = .0009). CONCLUSIONS Percutaneous cementoplasty can be considered for patients with metastases of the proximal femur under certain conditions: cortical involvement less than 30 mm and no history of a fracture of the lesser trochanter. Otherwise, the risk of fracture is too high, and cementoplasty is contraindicated.

THERAPY OF ENDOCRINE DISEASE: Treatment of malignant pheochromocytoma and paraganglioma

Metastatic pheochromocytomas and paragangliomas (MPPs) present clinicians with three major challenges: scarcity, complexity of characterization, and heterogeneous behavior and prognosis. As with the treatment for all neuroendocrine tumors, the control of hormonal symptoms and tumor growth is the main therapeutic objective in MPP patients. A significant number of MPP patients still die from uncontrolled hormone secretion. In addition, the management of MPPs remains palliative. Steps forward include proper characterization of MPP patients at large cancer referral centers with multidisciplinary teams; improved strategies to stratify patients prognostically; and implementation of trials within national and international networks. Progress in the molecular characterization and staging of MPPs constitutes the basis for significant treatment breakthroughs.

GEP-NETS UPDATE: Interventional radiology: role in the treatment of liver metastases from GEP-NETs

Neuroendocrine tumors from gastro-pancreatic origin (GEP-NET) can be responsible for liver metastases. Such metastases can be the dominant part of the disease as well due to the tumor burden itself or the symptoms related to such liver metastases. Intra-arterial therapies are commonly used in liver only or liver-dominant disease and encompass trans-arterial chemoembolization (TACE), trans-arterial embolization (TAE), and radioembolization (RE). TACE performed with drug emulsified in Lipiodol has been used for the past 20 years with reported overall survival in the range of 3-4 years, with objective response up to 75%. Response to TACE is higher when treatment is used as a first-line therapy and degree of liver involvement is lower. Benefit of TACE over TAE is unproven in randomized study, but reported in retrospective studies namely in pancreatic NETs. RE provides early interesting results that need to be further evaluated in terms of benefit and toxicity. Radiofrequency ablation allows control of small size and numbered liver metastases, with low invasiveness. Ideal metastases to target are one metastasis <5 cm, or three metastases <3 cm, or a sum of diameter of all metastases below 8 cm. Ablation therapies can be applied in the lung or in the bones when needed, and more invasive surgery should be probably saved for large-size metastases. Even if the indication of image-guided therapy in the treatment of GEP-NET liver metastases needs to be refined, such therapies allow for manageable invasive set of treatments able to address oligometastatic patients in liver, lung, and bones. These treatments applied locally will save the benefit and the toxicity of systemic therapy for more advanced stage of the disease.