Breaking down histotripsy

Inside a new ablation modality with cancer applications

With ever-evolving technologies, cancer treatments will almost certainly become more effective and less invasive in the future. A new procedure that will likely play an important role in the future of interventional oncology is histotripsy. Histotripsy (Greek for “tissue” and “breakdown”) is a noninvasive focused ultrasound method that mechanically breaks down soft tissue.1 Since first being used to create atrial septal defects in a canine model, the technology has been applied to a variety of tissues in animal models, including liver, kidney, thyroid, prostate, vessels, brain, fat and the heart.2,3 In addition, histotripsy has been used to treat the prostate and liver in humans.3,4

Though the initial applications for histotripsy were focused on the mechanical destruction of normal or benign tissues, promising early local and systemic effects after treatment indicate that the greatest application will likely be in the treatment of cancer. What ties histotripsy to interventional oncology is the critical role that imaging plays at every step of the process, from planning to treatment monitoring and posttreatment assessment. While the procedure could be adopted by a variety of specialties, we believe that interventional oncologists are well-positioned and best equipped to lead the introduction and clinical translation of this new technology.

What is histotripsy?

Histotripsy was invented at the University of Michigan department of biomedical engineering more than a decade ago by Charles Cain, PhD, Timothy Hall, PhD, J. Brian Fowlkes, PhD, William Roberts, MD, and Zhen Xu, PhD. Histotripsy is the first nonthermal, nonionizing, and noninvasive ablation modality guided by real-time imaging of the treatment effect. Histotripsy works by focusing ultrasound energy from an external treatment transducer to a point in the body to create cavitation. A robot then translates the ultrasound beam throughout the selected treatment volume to create an ablation zone of any size and shape. While bearing superficial similarities to high-intensity focused ultrasound (HIFU), histotripsy uses different pulse sequences (high amplitude, much shorter pulses, low ultrasound on-time) to produce cavitation rather than heat to destroy tissue.

Cavitation is produced at the focal point by applying microsecond ultrasound bursts. Heating is avoided by using a low duty cycle less than 1%. Off-target cavitation damage is avoided due to the binary treatment effect which only occurs when a tissue-specific pressure cavitation threshold is exceeded. Cavitation in tissue creates a sonographically visible “bubble cloud” by generating and then collapsing microbubbles which are formed from high negative pressures that pull out endogenous dissolved gas present in all tissues. At the cellular level, the mechanical strain imparted by the rapid expansion and collapse of the microbubbles fractures cells and creates a liquid-appearing acellular slurry that is rapidly absorbed by the body. The treatment effect is highly precise, causes minimal surrounding inflammation and is semiautomated due to advanced planning software and a robotic interface controlled by the treating physician. 

Getting involved in histotripsy

The Abdominal Image-guided Interventions Laboratory at the University of Wisconsin has a long history of translational research. From percutaneous cryoablation in the early 1990s to multiprobe radiofrequency ablation in the early 2000s, to microwave ablation in the 2010s, we have helped push emerging tumor ablation technologies from concepts and prototypes into routine human clinical use. We had been aware of the pioneering work of Drs. Cain and Xu for several years and thought that our laboratory, in partnership with the University of Michigan and HistoSonics, Inc. (the University of Michigan spin-off company developing histotripsy for human use), may be able to assist in the translation of histotripsy from concept to clinical practice. We began working with histotripsy in 2016, initially performing proof-of-concept liver treatments in human-size pigs with a prototype system to be sure that the concept was translatable. During these initial treatments, multiple lab members remarked that the treatment “looked like the future.”

Our lab then worked with HistoSonics to develop pre-clinical data supporting regulatory submission for the initial human trial of hepatic histotripsy. We proved that we could safely make precise ablations of a clinically relevant size (3 cm sphere) with minimal effect on overlying tissues.5,6 During these initial studies, we noted five critically important findings5-7:

  1. The achieved ablation zones were within millimeters of what was prescribed.
  2. Densely collagenous structures, such as bile ducts and vessels, were patent within treatment zones while there was uniform cellular necrosis.
  3. While portal venous clots developed in the vicinity of the ablation zone, they typically resolved within 30 days without specific treatment.
  4. There was rapid involution of the ablation zone with a 64% volume reduction at 4 weeks.
  5. The transition zone between completely ablated and normal tissue was 4 mm, half that of the best achieved with thermal ablation.

While the translation of an animal model to the clinic is never assured, the first four critical findings were all recapitulated in the initial human trial of hepatic histotripsy. The fifth couldn’t be evaluated, as treatment zones were not resected.

A current limitation of the technology that we are working to overcome is an inability to target tumors that are either isoechoic to liver tissue on ultrasound imaging or where there is an inadequate acoustic window. Advanced multimodal imaging strategies for targeting and guiding histotripsy are in development and will complement the current ultrasound-based approach. A C-arm is an ideal imaging modality for targeting during histotripsy given the dual fluoroscopic and cone-beam CT (CBCT) imaging capabilities. Leveraging the robotic nature of histotripsy, a C-arm can be used to target invisible tumors throughout the body with millimeter-level accuracy.

Additional organs and cancer models

It is theoretically possible to use histotripsy in any organ in which enough ultrasound energy can be applied safely. In addition to liver treatments, our lab has demonstrated the safety and efficacy of treatments in the kidney, spleen, thyroid and subcutaneous fat as potential future treatment targets.8,9 There is ongoing research at the University of Michigan and Virginia Tech University into treating the heart, prostate, pancreas, brain and musculoskeletal tissue, among others.3 All of the previously mentioned targetable organs have achieved successful treatments in cancer model studies. Perhaps the most interesting findings noted in these studies are that local tumor control can be achieved with partial treatment of tumors and that the off-target (abscopal) effects of histotripsy equal or exceed that of other local therapies. A study in a rat hepatocellular carcinoma (HCC) model where nine animals underwent complete tumor treatment and six animals had 50–75% of the tumor treated resulted in complete pathologic response in 14/15 animals (5/6 partially treated tumors).10

Another study in a mouse model using both melanoma and HCC cell lines showed that histotripsy caused an intense CD8+ cell infiltration into both the treatment site as well as a second, nontreated tumor. This was compared with both radiofrequency ablation and radiation therapy, with histotripsy being the only modality to demonstrate a significant intratumoral CD8+ cell infiltration at both sites. Histotripsy was also noted to potentiate checkpoint inhibition in these models. Additionally, a melanoma metastasis model was utilized in this study, where histotripsy of a flank tumor resulted in significantly fewer pulmonary metastases following a tail vein injection of a melanoma cell line.11

Human studies

Two studies have been completed in humans and two more trials are currently in progress. The first trial treated 25 patients with benign prostatic hyperplasia (NCT01896973) and the second treated eight patients with liver tumors (THERESA: NCT03741088). In the benign prostatic hyperplasia study, the procedure was deemed safe with only a single device-related adverse event (8 days of urinary retention). There was an improvement in prostate-related symptoms and quality of life. Interestingly there was no visible reduction in prostate size or improvement of postvoid residuals, which was attributed to the transperineal approach blocking energy delivery.4 In the THERESA study, the successful creation of an ablation zone encompassing the tumor was achieved in all patients at a median time of 25 minutes with no device-related adverse events. Two of the eight patients (one with HCC and one with colorectal metastases) in this study had off-target (abscopal) effects on nontreated tumors with continued decrease in tumor markers and stable or decreasing non-treated tumors over the 2-month study follow-up period.3 Currently, there are two actively recruiting multicenter trials for the treatment of liver tumors in both the United States and Europe.

The future of histotripsy

At baseline, histotripsy will be an alternative to current thermal ablation modalities in ultrasound-accessible locations given the non-invasive nature and precision of the treatment. Histotripsy may also open the possibility for noninvasive and safe ablation in critical locations that are difficult or not possible to treat with current technologies, such as adjacent to bile ducts and vessels in the central liver given the collagen-sparing properties. A more aspirational role would be for histotripsy to be an adjunct to conventional systemic cancer treatments. For example, when considering the possibility of combining histotripsy tumor treatments with immunotherapy to treat metastasis, we can imagine a future where a patient has a routine outpatient histotripsy procedure as an immune-stimulating treatment either once or at routine intervals similar to current chemotherapy schedules. Histotripsy is an entirely new paradigm of treatment that will become widely available to interventional oncologists in the coming years and has the potential to revolutionize how we deliver cancer care.

References

  1. Xu Z, Ludomirsky A, Eun LY, Hall TL, Tran BC, Fowlkes JB, et al. Controlled ultrasound tissue erosion. IEEE Trans Ultrason Ferroelectr Freq Control. 2004;51(6):726–36.
  2. Xu Z, Owens G, Gordon D, Cain C, Ludomirsky A. Noninvasive creation of an atrial septal defect by histotripsy in a canine model. Circulation. 2010;121(6):742–9.
  3. Xu Z, Hall TL, Vlaisavljevich E, Lee FT, Jr. Histotripsy: The first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound. Int J Hyperthermia. 2021;38(1):561–75.
  4. Schuster TG, Wei JT, Hendlin K, Jahnke R, Roberts WW. Histotripsy Treatment of benign prostatic enlargement using the Vortx Rx system: Initial Human safety and efficacy outcomes. Urology. 2018;114:184–7.
  5. Smolock AR, Cristescu MM, Vlaisavljevich E, Gendron-Fitzpatrick A, Green C, Cannata J, et al. Robotically assisted sonic therapy as a noninvasive nonthermal ablation modality: Proof of concept in a porcine liver model. Radiology. 2018:171544.
  6. Longo KC, Knott EA, Watson RF, Swietlik JF, Vlaisavljevich E, Smolock AR, et al. Robotically assisted sonic therapy (RAST) for noninvasive hepatic ablation in a porcine model: Mitigation of Body wall damage with a modified pulse sequence. Cardiovasc Intervent Radiol. 2019;42(7):1016–23.
  7. Longo KC, Zlevor AM, Laeseke PF, Swietlik JF, Knott EA, Rodgers AC, et al. Histotripsy ablations in a porcine liver model: Feasibility of respiratory motion compensation by alteration of the ablation zone prescription shape. Cardiovasc Intervent Radiol. 2020;43(11):1695–701.
  8. Knott EA, Swietlik JF, Longo KC, Watson RF, Green CM, Abel EJ, et al. Robotically-assisted sonic therapy for renal ablation in a live porcine model: Initial preclinical results. J Vasc Interv Radiol. 2019;30(8):1293–302.
  9. Swietlik JF, Mauch SC, Knott EA, Zlevor A, Longo KC, Zhang X, et al. Noninvasive thyroid histotripsy treatment: Proof of concept study in a porcine model. Int J Hyperthermia. 2021;38(1):798–804.
  10. Worlikar T, Mendiratta-Lala M, Vlaisavljevich E, Hubbard R, Shi J, Hall TL, et al. Effects of histotripsy on local tumor progression in an in vivo orthotopic rodent liver tumor model. BME Frontiers. 2020.
  11. Qu S, Worlikar T, Felsted AE, Ganguly A, Beems MV, Hubbard R, et al. Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy. J Immunother Cancer. 2020;8(1).