- Mishal Mendiratta-Lala, MD, is an abdominal and cross-sectional interventional radiologist at the University of Michigan who led the US liver tumor histotripsy clinical trial (#HOPE4LIVER).
- She describes her preclinical and clinical research and plans to continue using histotripsy to treat patients with liver cancer.
Mishal Mendiratta-Lala, MD, is an abdominal and cross-sectional interventional radiologist at the University of Michigan (UM) who led the United States clinical trial investigating histotripsy for the treatment of liver tumors (#HOPE4LIVER). In this investigator profile, Dr. Mendiratta-Lala describes her preclinical and clinical histotripsy research along with her plans to continue to treat patients with liver cancer. She is one of the few women clinicians in the United States who performs focused ultrasound in her clinical practice.
What is your background in medicine?
I am board certified in diagnostic radiology and fellowship trained in abdominal imaging and cross-sectional interventional radiology. I focus mostly on hepatobiliary imaging, hepatobiliary intervention, and treatment response after therapy for primary or metastatic liver cancer (or any sort of liver-directed therapy). I am the current director of abdominal MRI at UM.
How did you first learn about focused ultrasound and histotripsy?
I joined the UM in 2015, and I have always had an interest in liver imaging and liver interventions. Someone in my department told me that there was a woman in biomedical engineering (Zhen Xu, PhD) who was looking for someone who would be willing to read preclinical MRIs. I said that I would be willing to help because I had done similar work in my previous research. A few days later, Zhen came to my office in the basement of the hospital with a couple of CDs in her hand and we loaded them onto my computer to look at the images. A few weeks later, I went to her laboratory to learn more about her work and started helping with the research. This was fairly early in the transition of histotripsy to liver cancer research and therapy. The liver cancer preclinical to clinical translation occurred within seven years from start to finish, which is an incredible speed, almost unheard of in medical technology clinical adoption.
How were you involved in the #HOPE4LIVER clinical trial?
Multiple centers enrolled participants in the trial. At UM, we had an excellent team in place to screen patients. When we saw patients in the clinic, we were diligent about documenting the location of each of their liver tumors. We used ultrasound imaging to determine eligibility, because the histotripsy device can reach some lesions but not others. I personally consented every participant, no matter where I was clinically – I made sure that I was readily available for every consent and consult. We did a phenomenal job and discussed the clinical trial with more than 100 patients. Of those, we enrolled 10 patients and treated 12 lesions. All of the other sites combined enrolled the other 11 patients. Our team enrolled and treated the most patients around the world, which is very exciting since the technology was discovered at UM.
Who are your internal collaborators?
It is really nice to have a collaborative multidisciplinary team at UM. They provide balance for me, because I am so excited about the technology that I want to treat every patient. We have a highly talented and dedicated team that works well together.
The Histotripsy Ablation Team is directed by:
- Mishal Mendiratta-Lala, MD, clinical professor of radiology and director of the Abdominal Magnetic Resonance Imaging Division of Abdominal Radiology
- Neehar Parikh, MD, MS, medical director of the Multidisciplinary Liver Tumor Clinic and medical director of the Living Donor Liver Transplantation Program
- Vaibhav Sahai, MBBS, MS, associate professor of medical oncology, hematology (internal medicine), and internal medicine
Key members of the team include:
- Kim Vanderwall RN, clinical research and nurse coordinator, Multidisciplinary Liver Tumor Clinic, Division of Gastroenterology and Hepatology, Department of Internal Medicine
- Valerie Khyakin, clinical research coordinator, Division of Gastroenterology and Hepatology, Department of Internal Medicine
- Elaine Caoili, MD, Saroja Adusumilli Collegiate Professor of Radiology, Division of Abdominal Radiology
- Maggie (Man) Zhang, MD, PhD, clinical associate professor of radiology, director of ultrasound in the Division of Abdominal Radiology
- Clifford Suhyun Cho, MD, C. Gardner Child Professor of Surgery in the Division of Hepatopancreatobiliary and Advanced Gastrointestinal Surgery
- Ellen Higgins, PA-C, radiology physician assistant and radiology cross-sectional interventional advanced practice provider manager
- Giovanna Fox, PA-C, radiology physician assistant
- Silvana Davis, PA-C, cross-sectional interventional radiology physician assistant
- John Christopher Krauss, MD, clinical associate professor of medical oncology, hematology (internal medicine), and internal medicine
Those involved in the #HOPE4LIVER clinical trial also included:
- Nathan Loudon, MD, interventional radiology resident
- Matt O’Grady, patient care tech associate
- Zhen Xu, PhD, biomedical engineer and an inventor of Histotripsy
- Vikas Gulani, MD, PhD, chair of the Department of Radiology and co-director of the Michigan Institute of Imaging Technology and Translation
For the clinical trial, how did you explain histotripsy treatment to your patients?
My consent process was told as a story, where I started from the beginning of liver histotripsy, explaining to the patients about the preclinical studies and how we developed the treatment for humans. I explained that the treatment is completely noninvasive, and there would be no needles. I described how liver cells contain air pockets and how histotripsy vibrates the cells; eventually the air bubbles expand to the point that they pop. I also explained to patients that histotripsy does not cure cancer – it only treats some of the lesions, and that hopefully the treatment would work. It might buy you more time or reduce disease burden, but it is not a cure. I always clearly told the patients, “If you are coming to me for a cure, it is not going to happen, because I am only treating a few lesions at the most.” It was incredible that I still had a 100% of them sign the consent to undergo treatment.
After receiving histotripsy for liver cancer, did the patients stay in the hospital overnight?
No, they were discharged. Our workflow after a thermal ablation is for patients to stay in recovery for five hours; however, after histotripsy ablation, most patients stayed only for a couple of hours or less – until they met criteria for Phase 2 recovery. The discharge to home is made by the anesthesiologist based on recovery from the general anesthesia. Even though the procedure is noninvasive, we used general anesthesia to prevent erratic breathing, because our target in the liver is a moving target. As we continue to develop the treatment, in the future we hope to not need general anesthesia for every treatment.
What questions or misconceptions do patients have about the technology?
The hardest thing for patients to understand is that the treatment is not curative for diffuse disease. If a patient has one lesion, histotripsy will cure only the lesion that is being targeted. In fact, I feel relatively confident about that, although I do hope that one day the ‘abscopal’ effect will work, which is that non-targeted tumors will also shrink. It is an excellent technology, just like many types of thermal ablation (e.g., microwave or radiofrequency ablation).
What was it like pressing the histotripsy button for the first time in a human?
It was actually on my birthday, and it was the best birthday present ever. It was so exciting; I let my resident help. I was there, but I let him actually press the pedal while I was controlling it. It was a thrill for both of us. When we took the CT scan afterward and saw that the whole tumor was gone, it was so exciting. The procedure was successful, and the entire journey has been incredible.
Do you have a clinical story that you would like to share?
All of the participants I treated in the liver histotripsy clinical trial were amazing patients, many with diffuse metastatic disease. They were all so special. Some of them said, “I only have a few months to live, but I want to help science.” We had patients from all over the country.
The very first patient I treated had metastatic colon cancer. She was an elderly woman who, it seemed, had never really made a decision in her life and who probably did not have more than 45 days to live. Her husband made all of her decisions. He decided that she was not going to get chemotherapy because it was unnatural. So, she came to me very end stage, and I met her in the cancer center for a consult. She just wanted another opportunity, and I was able to convince her and her husband to try histotripsy because it was more natural than chemotherapy. But I was also able to convince them to meet with the oncology team to consider chemotherapy after the end of the histotripsy trial period. Because she trusted me, I was able to curate her whole medical team at UM. She ended up agreeing to see all of the specialists and get more treatment. She lived over 2 years. She was the first patient treated with histotripsy, and we just had our two-year anniversary of that treatment on October 20. She and her family continued to call me and consult with me. I really felt like I made a difference.
What has happened since histotripsy was approved by the US Food and Drug Administration (FDA)?
Since the FDA approval in October 2023, our clinic has been inundated with emails, phone calls, and image CDs in Fedex boxes. Referring physicians somehow found my address. I have received unsolicited boxes of medical records from people requesting treatment with histotripsy, even to my personal address. There is such a sense of urgency because these are incredibly sick people with advanced cancers. It will take time to work through the backlog of requests.
Which patients are best suited for liver histotripsy?
We are in the process of developing the criteria that specifies which patients with liver tumors are eligible to be treated with histotripsy. A few, but not all of the general criteria include:
1. Only primary or metastatic tumors in the liver can be treated at this time.
2. The liver tumors must be smaller than 5 cm in size and there must be fewer than six tumors in the liver.
3. Tumors outside of the liver must be smaller than 1.5 cm each, with a maximum of three tumors outside of the liver.
Is histotripsy liver cancer treatment covered by insurance?
The American Medical Association issued a Current Procedural Terminology (CPT®) code for liver histotripsy in July 2021. The Centers for Medicare & Medicaid Services (CMS) then approved reimbursement of histotripsy for liver tumors in November 2021. In November 2023, CMS announced an increase in the Medicare reimbursement rate. We still need more insurance companies to approve it, but all procedures are submitted for pre-authorization.
What is needed for histotripsy to become available at more medical centers?
The histotripsy devices that were used for the clinical trial were first generation. During the trial, HistoSonics continued to develop the Edison device, adding technical improvements. Health systems or hospitals will need to obtain funding to purchase the Edison commercial treatment system, and we purchased the device at UM, which was deliver late December 2023. We have begun doing patient consults in the multidisciplinary liver clinic in the UM Rogel Cancer Center. We have two cases scheduled for January already.
How will patients be referred to UM for liver histotripsy?
We have developed a webpage for histotripsy at the University of Michigan Rogel Cancer Center.
Patients who are interested in being considered for histotripsy treatment should contact the Rogel Cancer Center’s Cancer AnswerLine by emailing CancerAnswerLine@med.umich.edu or calling 800-865-1125.
What do you tell patients who want to believe that histotripsy will cure their cancer?
Histotripsy can only cure the treated lesions, not all of the lesions.
Will there be a registry to keep track of all of the patients who receive liver histotripsy?
We have been discussing creating a prospective registry, and we are trying to find funding to do that. Here are UM, we have extensive experience maintaining a registry and have the full support of the institution and the clinicians.
In a setting with other ablation technologies, where does histotripsy fit?
Right now, patients with early-stage liver cancer may receive thermal ablation or radiation to one to three lesions. Histotripsy is a competing technology that is noninvasive, giving it many benefits. If further research shows that histotripsy can be combined with immunotherapy to improve overall survival, it will likely undergo even more rapid clinical adoption as a treatment option for cancer therapy, particularly in patients with liver tumors.
What is your vision for future liver histotripsy clinical trials?
We are planning to divide our patients into two or three cohorts. The first cohort will include patients who meet the eligibility requirements for the FDA-approved clinical treatment of oligometastatic disease (1 to 6 lesions in the liver only). The protocol for the second cohort will have a staged approach that allows us to treat liver lesions over different treatment sessions. A third cohort will be a prospective study that will require Institutional Review Board approval; the intent will be to combine immunotherapy and histotripsy to investigate whether the combination of the two treatments can boost the immune system. We will need to apply for grant funding for that cohort, so it will take time.
Will you be conducting clinical trials for other type of histotripsy treatment?
Because we are leading the way with liver treatment, we are not planning to participate in HistoSonics’ renal study, which is called #HOPE4KIDNEY. That trial has begun in the United States and Europe, however.
Will other specialists at UM, such as surgical oncologists, be providing histotripsy treatments? How are physicians trained to provide histotripsy?
At UM, other cross-sectional interventional radiologists (like me) will be doing the histotripsy procedures. It is an image-guided procedure, so physicians need to know how to use an ultrasound machine, how to change its technical parameters in order to find the lesion, and how to find and approach each specific lesion. Personally, I have years of image-guided experience, including many years spent in training and doing fellowships and use image guidance to perform clinical procedures every day.
When it comes to treating patients, anyone who can help revolutionize cancer therapy is needed. We need a lot of champions for this technology. Any healthcare systems that can purchase the Edison system and safely and correctly perform the procedures should do so. Performing histotripsy is best done with a collaborative team, including medical oncologists, surgical oncologists, hepatologists and radiologists. The best model includes several specialists who work together to help patients. Interventional radiology is now known as the fifth pillar of oncology treatment.
Could histotripsy be performed remotely, from a central command center, to reach remote countries or underserved areas?
One of the physicians at HistoSonics did communicate online with clinical trial PIs who treated fewer patients. I worked virtually with Eli Vlaisavljevich, PhD, at Virginia Tech when he was conducting preclinical histotripsy experiments on the pancreas, but the pancreas is a challenge. Having remote technology for histotripsy might work with the right team.
What comes next?
At this time, UM has purchased the Edison device, which is physically present at the hospital. The next steps are to primarily devise an effective workflow to review clinical histories and imaging on all the patients who are being referred for treatment. Furthermore, we need to continue to refine our inclusion criteria for patients who can be treated by the technology. Thankfully, we have a supportive team and department.