Research Roundup in Interventional Oncology

Interventional oncology is a rapidly advancing field for interventional radiologists. These image-guided and minimally invasive procedures are increasing patient quality of life through easier recoveries with less burdensome procedures, including chemoembolization, Y90 therapies, radioembolization, CT, CBCT, and microwave ablation, among others. This research roundup showcases some of the advances in interventional therapies over the last year.

Chemoembolization

During this exciting year of interventional therapies, chemoembolization played a key role. One study aimed to compare the outcome of embolization using microspheres alone with chemoembolization using doxorubicin-eluting microspheres for patients with liver tumors.¹ The study found no difference between drug-eluting versus bland microspheres for liver tumors, bringing into question the usefulness of doxorubicin-eluting beads for chemoembolization of hepatocellular carcinoma.¹ 

Yttrium-90 Therapies

Another main area of study this year involved the use of selective internal radiation therapy (SIRT) and adding this treatment to standard chemotherapy. The SIRFLOX trial is one of particular interest in this area.² In the setting of liver metastases from colorectal cancer (CRC), radioembolization with Y90 has been used to treat chemotherapy refractory disease with a growing interest in establishing its efficacy in prospective trials combined with first- and second-line chemotherapy. Preliminary results from SIRFLOX demonstrate that radioembolization combined with first-line chemotherapy is safe and feasible. There was no significant difference in median overall progression-free survival (PFS) between the combined radioembolization-chemotherapy and chemotherapy-only arms (10.7 vs 10.2 months). Combining radioembolization with chemotherapy in the first-line setting may be most effective for liver-limited metastatic CRC. Since radioembolization targets liver disease, it is plausible that the trial failed to achieve an improvement in PFS given that 40% of the SIRFLOX population had extra-hepatic disease.^2,3 

Another study compared Choi criteria with Response Evaluation Criteria in Solid Tumors (RECIST) for the prediction of overall survival (OS) in patients treated with glass-microsphere, Y90 selective internal radiation therapy (SIRT) for intrahepatic cholangiocarcinoma (ICC). Computed tomography scans performed before and after treatment were analyzed using both RECIST 1.1 and Choi criteria. The response was correlated with survival. The authors concluded that Choi criteria appear more appropriate than RECIST to identify responders with long survival among patients who received SIRT for ICC.⁴ Shady et al⁵ also evaluated RECIST version 1.1 tumor-attenuation criteria, Choi criteria, and European Organization for Research and Treatment of Cancer (EORTC) PET criteria as measures of response and subsequent predictors of liver progression-free survival (PFS) after radioembolization of colorectal liver metastases (CLM). In this study, researchers concluded that RECIST 1.1 has poor sensitivity for detecting metabolic responses classified by EORTC-PET criteria. EORTC-PET criteria, Choi criteria, and tumor attenuation criteria appear to be equally reliable surrogate imaging biomarkers of liver PFS after radioembolization in patients with CLM.⁵

In a retrospective study to determine the safety and efficacy of Y90 transarterial radioembolization in patients who had undergone chemoembolization for hepatocellular carcinoma, Johnson et al found that transarterial radioembolization is safe and effective salvage therapy in patients after chemoembolization. In patients who have undergone >4 chemoembolizations to the Y90 target, feasibility of transarterial radioembolization tends to be decreased.⁶ Biederman et al compared outcomes of Y90 radioembolization performed with resin-based and glass-based microspheres in the treatment of hepatocellular carcinoma (HCC) with associated portal vein invasion, and found that imaging response of Y90 treatment in patients with HCC and portal vein thrombosis was not significantly different between Y90 glass and Y90 resin groups.⁷ However, lower toxicity and improved OS were observed in the glass microsphere group.⁷ Further evaluation of Y90 resin microspheres took place in the RESiN Registry.

The Radiation-Emitting SIR-Spheres in Non-resectable Liver Tumor (RESiN) registry is a national, multicenter database that enrolled patients with primary or secondary liver cancer who are scheduled for treatment with Y90 resin microspheres as part of their care plan.⁸ The RESiN registry is a resource that provides the oncology community with a more comprehensive understanding of the benefits and risks of Y90 resin microspheres as a localized treatment for a range of hepatic tumors and patients, including patients who would likely not be included in clinical trials. The registry serves as a guide for future research into Y90 resin microsphere therapy, especially for conditions for which limited data currently exist.⁸

The RESiN Registry will assist future research into Y90 therapies, but despite less well-defined indications for Y90 SIRT in non-conventional hepatic metastasis, a few small studies have produced favorable initial results.⁹ The study limitations are heterogeneity of patient cohort, lack of standardized treatment response criteria, and difference in treatment dosage. Many factors may contribute to discrepancy in median OS among tumor types, including small patient cohort size and variable tumor burden, difference in disease progressiveness, and time to first follow-up, among others. According to the studies, a justifiable benefit (or lack thereof) from Y90 SIRT on any given patient depends largely upon both tumor type and patient status.⁹ For example, one analysis showed the effect of Y90 radioembolization in a porcine model at different absorbed dose endpoints, where six pigs underwent transfemoral angiography and infusion of Y90 resin microspheres into arteries supplying part of the gastric wall.¹⁰ Upon treatment completion, their upper gastrointestinal (GI) tracts were excised for analysis, and researchers concluded that the upper GI tract may be less sensitive to Y90 radioembolization than previously thought.¹⁰ Lack of charged-particle equilibrium at the luminal mucosa may contribute to decreased toxicity of Y90 radioembolization compared with external-beam radiation therapy in gastrointestinal tissue.¹⁰ 

Y90 Imaging

It is important to consider not only the effects of Y90 therapies on tumors but also how the effects are evaluated through imaging and various other methods. Partition-model predictive dosimetry relies on differential tumoral and non-tumoral perfusion evaluated on pretreatment 99mTc macroaggregate albumin (MAA) single-photon emission tomography (SPECT) computed tomography (CT).¹¹ This study evaluated the agreement between predictive dosimetry of 99mTc-MAA SPECT/CT and post-treatment dosimetry based on Y90 time-of-flight (TOF) positron emission tomography (PET)/CT.¹¹ Results showed that in Y90 radioembolization of HCC, predictive dosimetry based on 99mTc-MAA SPECT/CT provided good estimates of absorbed doses calculated from post-treatment Y90-TOF PET/CT, for tumor and non-tumor tissues. The authors also note that low variability of dose ratio indicates that pretreatment dosimetry could reduce radiation-induced hepatotoxicity.¹¹

Other Imaging Therapies

Imaging modalities play a large role in cancer treatment, whether that includes Y90 therapies or not, and several studies this year looked at this subject area. Van den Hoven et al compared right gastric (RGA) and segment 4 artery (A4) origin detection rates during radioembolization work-up between early and late arterial phase liver CT protocols in their study.¹² This study was conducted in 100 patients who underwent liver CT with early or late arterial phase protocol (50 in each arm; 10 second vs 20 second post-threshold delay).¹² The authors concluded that a 10 second delay arterial phase CT protocol does not significantly improve detection of small intra- and extrahepatic branches, and RGA origin detection needs improvement. Original detection for A4/MHA is adequate and has good inter-rater reproducibility. Computed tomography is still an important tool for preprocedural planning, because it may reveal arterial anatomy not identified via digital subtraction angiography.¹²

Another review focused on cone-beam computed tomography (CBCT), which provides additional information to conventional 2D imaging. Researchers explored the use of CBCT to improve the performance of interventional liver oncology procedures (intra-arterial treatments such as chemoembolization or selective internal radiation therapy, and percutaneous tumor ablation).¹³ CBCT provides accurate tumor detection and targeting, periprocedural guidance, and postprocedural evaluation of treatment success.¹³

Intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) is another imaging modality studied by Pieper et al for early arterial blood flow stasis during transarterial radioembolization of liver-dominant breast metastases (LdBM).¹⁴ The authors found that perfusion-sensitive IVIM parameters may predict early blood flow stasis in patients undergoing transarterial radioembolization for LdBM. Determining this parameter before intervention may provide important information to the interventionalist and increase safety of microsphere administration.¹⁴

Pan et al assessed the effectiveness of percutaneous CT-guided radiofrequency ablation (RFA) for lymph node (LN) oligometastases from HCC in 119 consecutive patients with HCC and LN oligometastases, and found that percutaneous CT-guided RFA may be a safe and effective treatment for these patients.¹⁵ 

Angiogenic Response After Radioembolization

In order to treat patients well, clinicians should also be aware of angiogenic responses to therapies. Lewandowski et al studied 23 patients with unresectable HCC awaiting orthotopic liver transplantation who were prospectively randomized to receive radioembolization alone or radioembolization with sorafenib.¹⁶ In the Y90-alone group, all growth factors were elevated above baseline levels at 2 and 4 weeks. In the Y90/sorafenib arm, angiopoietin-2 and platelet-derived growth factor decreased at 2 weeks and the remainder increased. By 4 weeks, only platelet-derived growth factor remained below baseline levels. The authors concluded that radioembolization is associated with a mild increase in angiogenic markers. The addition of sorafenib blunts platelet-derived growth factor response; other factors such as vascular endothelial growth factor remain unaffected.¹⁶  

Microwave Ablation

Velez et al sought to determine whether variable hepatic microwave ablation (MWA) can induce local inflammation and distant pro-oncogenic effects compared with hepatic radiofrequency ablation (RFA) in an animal model using rats with subcutaneous breast adenocarcinoma tumors.¹⁷ These rats had normal non-tumor-bearing liver treated with RFA, rapid higher-power MWA, slower lower-power MWA, or a sham procedure (needle placement without energy). The authors concluded that although hepatic MWA can incite periablational inflammation and increased distant tumor growth similar to RFA in an animal tumor model, use of higher power, faster heating protocols may mitigate such undesired effects.¹⁷

Another retrospective study on MWA included 221 patients with 356 malignant hepatic lesions.¹⁸ Ninety-four patients with 133 lesions underwent low-frequency microwave ablation (LF-MWA) between September 2008 and February 2011, while 127 patients with 223 lesions were treated with high-frequency microwave ablation (HF-MWA). While some differences were more significant, the difference in survival rates was not significant (P>.05). The authors concluded that LF- and HF-MWA systems are effective treatment options for oligonodular liver malignant lesions, but significantly higher ablation volumes, longer time to progression, and lower progression rates were observed in HF-MWA.¹⁸ 

Cryoablation 

Breast cancer was also a popular research subject this year, particularly the application of cryoablation, which is an appealing alternative to surgery for several reasons – it is minimally invasive, requires no surgical resection or general anesthesia, is office-based, with intrinsic analgesia, is inexpensive, and has excellent cosmetic outcomes, because patients do not undergo mastectomy.¹⁹ An additional advantage of cryoablation is its potential to enhance immunological response following the procedure.¹⁹ 

Conclusion

With excellent, ongoing research opportunities and continued growth in interventional therapies, patients will benefit from more advanced technologies as research continues to thrive. Further improvements in interventional therapies will not only benefit patients but clinicians and institutions due to the cost-effectiveness of these therapies, requiring fewer hospital stays and offering more outpatient options. Providers can also experience the satisfaction that patients are receiving the best care through a comprehensive approach. 

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. Sangha BS, Nimeiri H, Hickey R, et al. Radioembolization as a treatment strategy for metastatic colorectal cancer to the liver: what can we learn from the SIRFLOX trial? Curr Treat Options Oncol. 2016;17:26.
3. van Hazel GA, Heinemann V, Sharma NK, et al. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016;34:1723-1731.
4. Beuzit L, Edeline J, Brun V, et al. Comparison of Choi criteria and response evaluation criteria in solid tumors (RECIST) for intrahepatic cholangiocarcinoma treated with glass-microspheres Yttrium-90 selective internal radiation therapy (SIRT). Eur J Radiol. 2016;85:1445-1452.
5. Shady W, Sotirchos VS, Do RK, et al. Surrogate imaging biomarkers of response of colorectal liver metastases after salvage radioembolization using 90Y-loaded resin microspheres. AJR Am J Roentgenol. 2016 Jul 6 (Epub ahead of print).
6. Johnson GE, Monsky WL, Valji K, et al. Yttrium-90 radioembolization as a salvage treatment following chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol. 2016;27:1123-1129.
7. Biederman DM, Titano JJ, Tabori NE, et al. Outcomes of radioembolization in the treatment of hepatocellular carcinoma with portal vein invasion: resin versus glass microspheres. J Vasc Interv Radiol. 2016;27:812-821.e2. 
8. Banovac F, Brown DB. US RESiN registry for the study and evaluation of patients treated with SIR-Spheres. Intervent Oncol 360. 2016;4:E101-E111. 
9. Park JK, Phyu W, Zaw T, Walsworth M, Lee HY, Lee EW. Yttrium-90 radioembolization of nonconventional liver tumors. Intervent Oncol 360. 2016;4:E115-E129. 
10. Pasciak AS, Nodit L, Bourgeois AC, et al. How sensitive is the upper gastrointestinal tract to Yttrium 90 radioembolization? A histologic and dosimetric analysis in a porcine model. J Nucl Med. 2016 (Epub ahead of print).
11. Gnesin S, Canetti L, Adib S, et al. Partition model based 99mTc-MAA SPECT/CT predictive dosimetry compared to 90Y TOF PET/CT post-treatment dosimetry in radioembolisation of hepatocellular carcinoma: a quantitative agreement comparison. J Nucl Med. 2016 Jun 15 (Epub ahead of print).
12. van den Hoven AF, Braat MN, Prince JF, et al. Liver CT for vascular mapping during radioembolisation workup: comparison of an early and late arterial phase protocol. Eur Radiol. 2016 Apr 23 (Epub ahead of print).
13. Bapst B, Lagadec M, Breguet R, et al. Cone beam computed tomography (CBCT) in the field of interventional oncology of the liver. Cardiovasc Intervent Radiol. 2016;39:8-20.
14. Pieper CC, Willinek WA, Meyer C, et al. Intravoxel incoherent motion diffusion-weighted MR imaging for prediction of early arterial blood flow stasis in radioembolization of breast cancer liver metastases. J Vasc Interv Radiol. 2016 Jul 8 (Epub ahead of print).
15. Pan T, Xie QK, Lv N, et al. Percutaneous CT-guided radiofrequency ablation for lymph node oligometastases from hepatocellular carcinoma: a propensity score-matching analysis. Radiology. 2016 Jul 11:151807 (Epub ahead of print).
16. Lewandowski RJ, Andreoli JM, Hickey R, et al. Angiogenic response following radioembolization: results from a randomized pilot study of yttrium-90 with or without sorafenib. J Vasc Interv Radiol. 2016 Jun 4 (Epub ahead of print).
17. Velez E, Goldberg SN, Kumar G, et al. Hepatic thermal ablation: effect of device and heating parameters on local tissue reactions and distant tumor growth. Radiology. 2016 Jul 13:152241 (Epub ahead of print).
18. Vogl TJ, Hagar A, Nour-Eldin NA, et al. High frequency versus low frequency microwave ablation in malignant liver tumors: evaluation of local tumor control and survival. Int J Hyperthermia. 2016:1-34 (Epub ahead of print).
19. Klevos G, Collado-Mesa F, Net JM, Yepes MM. Cryoablation of benign and malignant breast tumors. Intervent Oncol 360. 2016;4:E95-E100.