Interventional Oncology Year in Review

This past year has been marked by the completion of some long-awaited studies that led to a number of surprises. In February 2016, Dr Brown’s prospective, randomized study comparing doxorubicin-loaded beads vs bland beads for hepatocellular carcinoma (HCC) was published. Both groups had similar patient characteristics and tumor burden. The embolization technique was uniform in both groups, except that upsizing to the larger-size beads occurred sooner in the bland-bead group compared with the doxorubicin-loaded group. The study found no difference in response, progression-free survival, or overall survival. The trial utilized an “intent to treat” design and 9 patients (6 in the Bead Block group and 3 in the LC Bead group; both products by BTG) were neither treated nor imaged, which contributed to poor median progression-free survival.¹ One criticism leveled at the study was that it was underpowered; however, 101 patients were included without a difference detected. This adds a high-quality, prospective, randomized trial to the previous studies that failed to detect any difference between bland embolization and chemoembolization. One thing is certain: doxorubicin is not a great option for HCC.

In April 2016, a study presented at the European Association for the Study of the Livermeeting was fast-tracked for publication, causing an upset in the community.² Indeed, direct-acting antivirals (DAA) have been a major breakthrough against hepatitis C, with a high cure rate (greater than 90%) and few side effects. The impressive results of DAA were expected to lead to a reduction in progression of cirrhosis and HCC. However, DAA resulted in an unexpectedly high rate of HCC recurrence in patients treated with DAA for hepatitis C (HVC).² This was an observational publication.² Of the 103 HCC patients treated with DAA, 58 patients had confirmed complete response and no uncharacterized nodules. Of those, 16 patients had recurrence (27.5%) and the median time to recurrence was only 3.5 months.² To be clear, these are patients with recurrences, not HCC-naïve patients. However, this study raised concerns about the need to gather more information about DAA, especially in populations not included in the pivotal trials. Further larger trials are needed to validate these findings and develop ways of mitigating recurrence. 

In June 2016, the data of the RESORCE trial was presented. This was a placebo-controlled, phase III study evaluating the efficacy and safety of regorafenib (Stivarga; Bayer) in HCC patients who had documented disease progression after sorafenib (Nexavar; Bayer).³ The oral multikinase inhibitor regorafenib was shown to significantly improve survival in patients with previously treated HCC.³ The RESORCE trial enrolled 573 patients with BCLC B or C HCC, Child-Pugh A, and ECOG 0-1. They had to have tolerated a minimum of 20 days of sorafenib at 400 mg twice a day and the reason for cessation had to be disease progression. Within 10 weeks of sorafenib cessation, they were randomized to a regorafenib vs placebo 2:1 design.³ The overall survival with regorafenib was 10.6 months vs 7.8 months with placebo (hazard ratio, 0.62; 95% confidence interval [CI], 0.50–0.78; P<.001). The median progression-free survival almost doubled between regorafenib and placebo (3.5 months vs 1.5 months).³ Response rates per mRECIST were also significantly higher.⁴ These results are prompting recommendations that regorafenib become the gold-standard second-line therapy after sorafenib.⁴ FDA approval is expected in 2017.

In September 2016, a prospective, randomized trial of 58 patients comparing cone-beam computed tomography (CBCT) navigation (29 patients) and conventional CT (29 patients) for routine image-guided biopsies was published.⁵ The study examined the number of “needle repositionings,” defined as needle pullback and readvancement, radiation dose, accuracy of final needle position, and histopathological diagnosis. Patient characteristics and lesion location, size, and depth were similar in both groups. The operators were allowed to reposition the needle as many times as necessary, until they were satisfied with the position for sampling, reproducing routine clinical practice.⁵ Therefore, the histopathological diagnosis was similar between the two groups; however, the number of needle repositionings was significantly lower with CBCT navigation (0.3 ± 0.5) vs CT (1.9 ± 2.3) (P<.001). Accounting for body mass index, the average skin entry dose measured by dosimeters placed on the patients was reduced by 29% with CBCT vs CT (P=.04). The average estimated effective dose for planning scan from phantom data was reduced by 49% with CBCT vs CT (P=.01). Accuracy of the needle position was also significantly better with CBCT compared with CT.⁵ These results need to be reproduced in a multicenter setting, but if validated, the use of navigation may become standard. 

In October 2016, Salem et al published a phase II, investigator-initiated, prospective, single-center, open-label, randomized study comparing radioembolization and chemoembolization for HCC.⁶ Of the 179 BCLC A/B HCC patients eligible for the study, 45 were enrolled over 6 years. Twenty-one patients were randomized to cTACE and 24 were randomized to Y-90. Time to progression was significantly longer with Y90 compared with cTACE: 26 months vs 6.8 months, respectively (P=.0012).⁶ However, the proportion of patients who had response was similar in both groups, and median survival time censored to transplant was also similar in both groups. As bridge to transplant, Y-90 may be a better option.⁶

In November 2016, Duffy et al published a study combining anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) human monoclonal antibody tremelimumab and ablation in patients with advanced HCC.⁷ The patients enrolled were BCLC B/C, Child-Pugh A/B7, and ECOG 0-1, and had demonstrated progression prior to enrollment. Tremelimumab was infused every 4 weeks for 6 doses, then every 3 months until off study. Patients underwent two biopsies: one at baseline and one at time of ablation (6 weeks after the initial infusion). Ablations were subtotal, meaning that one lesion was ablated completely in the setting of multifocal disease.7 Of the 32 patients enrolled, 4 progressed rapidly and did not undergo an interventional radiology procedure. Of the patients with evaluable disease outside of the ablated area, 26% had confirmed partial response. Median overall survival for this advanced refractory HCC population was 12.3 months (95% CI, 9.3 to 15.4 months) and probabilities of tumor progression-free survival at 6 months and 12 months were 55.7% and 33.1%, respectively. Patients who showed clinical benefit with therapy also demonstrated evident increase in CD8+ T cells on 6-week biopsy.⁷ This pilot study demonstrates synergy between checkpoint inhibitors and ablative therapies encouraging further studies.
I hope that this non-exhaustive tour of IO papers in 2016 will inspire you to find out more!

References

1. Brown KT, Do RK, Gonen M, et al. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol. 2016;34:2046-2053.
2. Reig M, Marino Z, Perello C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol. 2016;65:719-726.
3. Bruix J MP, Merle P, Granito A, et al. Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: results of the international, randomized phase 3 RESORCE trial. Ann Oncol. 2016;27(Suppl 2):LBA–03.
4. Trojan J, Waidmann O. Role of regorafenib as second-line therapy and landscape of investigational treatment options in advanced hepatocellular carcinoma. J Hepatocell Carcinoma. 2016;3:31-36.
5. Abi-Jaoudeh N, Fisher T, Jacobus J, et al. Prospective randomized trial for image-guided biopsy using cone-beam CT navigation compared with conventional CT. J Vasc Interv Radiol. 2016;27:1342-1349.
6. Salem R, Gordon AC, Mouli S, et al. Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2016;151:1155-1163.e2.
7. Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol. 2016 Nov 2 (Epub ahead of print).