We recently incorporated Hepatic Artery Infusion (HAI) therapy into our oncology practice at Ochsner MD Anderson Cancer Center. Although HAI has been utilized since the early 90s, treatment protocols and patient selection have improved markedly since the therapy’s introduction. Those refinements, along with consistent data demonstrating a positive impact on patient outcomes, have spurred renewed enthusiasm for the therapy and increasing adoption by leading cancer centers around the country. Yet, despite compelling data and more widespread availability, many eligible patients are still not presented with the option.

A review of the clinical literature convinced me that HAI was well worth incorporating into our practice. I have since seen the impact of this therapy on my own patients. My hope is that by sharing my experience setting up an HAI program I can help encourage other oncologists to consider this therapy for appropriate patients who otherwise have limited options.

Until recently, as I trained at a program that did not offer HAI, I was only vaguely familiar with HAI therapy and lacked a detailed understanding of the specifics. When one of our surgical oncologists who had long been interested in HAI therapy broached the idea of establishing our own HAI practice, my colleagues and I reviewed the literature to determine whether this would be a valuable offering at our cancer center.

HAI therapy uses an implantable pump that is activated by body heat to administer a continuous flow of floxuridine directly to tumors in the liver through the hepatic artery. As a result, this liver-directed therapy can achieve intratumor drug concentration up to 400 times higher than systemic chemotherapy. In addition, the 97% first-pass metabolism of floxuridine by the liver translates into negligible systemic exposure and side effects.

A review of the clinical literature for HAI revealed an impressive and consistently positive impact on patient outcomes in the treatment of colorectal cancer liver metastases (CRLM). Studies have shown that the application of HAI in combination with systemic chemotherapy significantly downsized initially unresectable tumors compared with systemic chemotherapy alone, enabling many previously unresectable CRLM to be resected. Notably, patients who converted to surgical resection with HAI therapy had long-term survival rates on par with patients who presented with initially resectable disease. This was very appealing since many of our patients remain unresectable even after maximal response to systemic chemotherapy. Furthermore, studies showed that median overall survival was doubled in patients with unresectable CRLM who were treated with HAI, regardless if they were able to achieve conversion to resection.

Data also strongly support use of HAI in the adjuvant setting – to delay or reduce the rate of recurrence after successful CRLM resection. Because HAI treats the entire liver, it addresses remaining microscopic disease before it can develop into macroscopic tumors that impact survival. Studies have documented that median overall survival among patients treated with HAI plus systemic chemotherapy following CRLM resection averages around two years longer than comparable surgical patients who received adjuvant systemic chemotherapy alone.

While Ochsner had already established a strong program for treating metastatic colorectal cancer, we wanted to offer every option that could improve patients’ chances of survival all at one center, especially for those patients whose options were limited. The clinical data on HAI convinced us, and we were ready to move forward with implementing HAI to fill this gap.

We built a core HAI therapy team consisting of medical oncologists and advanced practice providers to oversee treatment, surgical oncologists to implant the pump, pharmacists to build out the dosing plan and verify dose adjustments, infusion nurses to manage the refill process, and a nurse navigator to assist with external referrals and education. To learn more about implementing the therapy, we consulted experts at established HAI centers for advice, clinical shadowing, and hands-on training. In addition, 

, the manufacturer of the HAI pump, provided training and educational resources that were an integral part of the onboarding process. Once our core team was fully trained, we worked to educate our center staff and ensure all were aware of our program through informal lectures and department presentations.

The first patient we selected to treat with HAI had high-burden unresectable disease confined to the liver that achieved the best response of stable disease on first-line multi-agent systemic chemotherapy. Treatment options for this patient were limited beyond lifelong chemotherapy given her lack of actionable mutations. When presented the option of HAI pump therapy, the patient understood the need to come in every two weeks for pump refills during active treatment and the importance of adhering to treatment guidelines. We implanted our first HAI pump in February 2024 and the patient began floxuridine through her pump 2 weeks thereafter. The patient tolerated the HAI therapy well and achieved radiographic shrinkage of her intrahepatic tumor burden and a precipitous and sustained decline in her CEA level. While receiving treatment via her HAI pump, we were able to lower the dose of her systemic chemotherapy, thereby reducing her overall side effect burden.This successful experience confirmed that we were on the right path and our eyes were open to other patients who might be a good fit for HAI therapy. We have observed similar biochemical and radiographic responses with HAI in many of our other patients with CRLM who had otherwise maximized their responses to systemic chemotherapy.

Nine months after starting our HAI program, we now have 12 patients receiving HAI under our care and receive patient referrals from community oncologists. In these cases, we work closely with the referring physicians to keep them updated while we temporarily manage the patients during active HAI treatment. After the treatment concludes, patients return to their referring physicians for ongoing care.

All the patients we treated were very amenable and eager to receive HAI, with many finding its liver-directed approach intuitive. In some cases, we discussed HAI around the time of diagnosis; in others, we kept it in mind as a potential option for later in their treatment journey.

For those reading this article and considering including HAI among their treatment options, my recommendation would be to:

Start with getting buy-in from the multidisciplinary team that will be involved in the therapy – partnership between surgical and medical oncologists in identifying patients and managing them through their HAI therapy is key.

Establish comfort with your team of infusion nurses in management of HAI pump refills. Intera Oncology offers invaluable support in this training. Clinical pharmacists are also a vital component of the treatment team.

Get required training and additional guidance from HAI experts from experienced centers. Maintaining communication with experts for guidance on individual patient scenarios that arise will improve your comfort with HAI therapy.

Identify patients who have liver confined CRLM who are failing to respond adequately to systemic treatment. This includes patients who are progressing on systemic treatment and those with stable disease where addition of HAI offers the possibility of downstaging for resection. Patients must also be healthy enough to undergo surgery and willing to commit to the treatment protocol.

Ensure these patients meet with the surgeon to evaluate whether they could be candidates for this therapy - the earlier this consultation occurs, the better.

Educate medical oncology colleagues at your center and community about your positive experience to make therapy accessible to patients who may benefit.

It took a concerted effort, but our multidisciplinary team really came together to make this important treatment option available, which was critical to the program’s success. I see our experience at Ochsner MD Anderson Cancer Center as a good example of how a new therapy can be integrated seamlessly, and I hope to continue seeing more patients benefit as adoption of HAI grows. When I think about the patients that we were able to help, who otherwise had limited treatment options, I am compelled to encourage others to take advantage of this therapy as a viable addition to the treatment armamentarium.

Articles

Embracing Hepatic Artery Infusion Therapy for My Patients with Colorectal Cancer Liver Metastases   

Jonathan Mizrahi, MD, fellow at The University of Texas MD Anderson Cancer Center, discusses the addition of veliparib to chemotherapy in 

In a recent randomized phase 2 trial, investigators examined the combination of gemcitabine and cisplatin with or without the PARP inhibitor in the frontline treatment of patients with pancreatic ductal adenocarcinomas and a germline 

 mutation, says Mizrahi.Investigators wanted to evaluate whether the addition of a PARP inhibitor to chemotherapy would improve the effectiveness of chemotherapy in this patient population.

Unfortunately, the study showed no benefit with the addition of the PARP inhibitor to the chemotherapy doublet, but patients did have a good overall survival (OS). The median OS for those randomized to the doublet arm was 15.5 months and 16.4 months for those randomized to the triplet arm, which are favorable data for the frontline metastatic setting, says Mizrahi.

 mutations do not inherently have a better prognosis than patients without those mutations. Instead, they do better when they are treated with platinum agents, concludes Mizrahi.

Videos

Jonathan Mizrahi, MD, discusses the addition of veliparib to chemotherapy in BRCA1/2 or PALB2-mutated pancreatic cancer.

Dr. Mizrahi on Addition of PARP Inhibitors to Chemotherapy in Mutated Pancreatic Cancer

Jonathan Mizrahi, MD, fellow at The University of Texas MD Anderson Cancer Center, discusses efforts being made to target treatment for patients with metastatic colorectal cancer (mCRC).

In terms of looking at targeted agents, it's important to incorporate broad-based molecular profiling to all patients upon diagnosis of mCRC, says Mizrahi. One target that is gaining in popularity in terms of treatment options is HER2. In early-phase studies, patients with HER2 amplifications have been shown to benefit greatly from HER2-targeted therapies, including drugs such as trastuzumab (Herceptin), pertuzumab (Perjeta), or antibody-drug conjugates such as ado-trastuzumab emtansine (T-DM1).

There is a lot of area for exploration in patients whose tumors have HER2 amplification. Additionally, for patients with microsatellite instability—high CRC, immunotherapy is moving to the frontline setting. Failing to use this approach in the frontline treatment of this patient population would be a great disservice, concludes Mizrahi.

Jonathan Mizrahi, MD, discusses efforts being made to target treatment for patients with metastatic colorectal cancer.

Dr. Mizrahi on Targeting Treatment in Metastatic Colorectal Cancer

Jonathan Mizrahi, MD, fellow at The University of Texas MD Anderson Cancer Center, discusses optimal sequencing in patients with 

 V600E-mutant metastatic colorectal cancer (mCRC).

 V600E-mutant mCRC can receive a chemotherapy doublet, such as FOLFOX or FOLFIRI, in the frontline setting, says Mizrahi. Upon progression, the alternate regimen can be used. However, data from the phase III TRIBE2 trial showed that the combination of FOLFOXIRI and bevacizumab (Avastin) led to an improvement in progression-free survival 2 versus sequential use of FOLFOX/bevacizumab and FOLFIRI/bevacizumab in patients with mCRC. In the context of patients with 

-mutant mCRC, who have worse prognosis, Mizrahi recommends using FOLFOXIRI/bevacizumab in the frontline setting.

If the patient progresses on that regimen, the combination of encorafenib (Braftovi) and cetuximab (Erbitux) with or without binimetinib (Mektovi) can be used, adds Mizrahi. The recommendation is based on data from the phase III BEACON CRC trial, which showed an improvement in overall survival (OS) with the doublet and triplet versus irinotecan-based chemotherapy in patients with 

 V600E-mutant mCRC. Because the trial showed equivalent OS data in both of the investigational arms, Mizrahi recommends using the doublet to reduce the toxicity of adding a third drug.

Jonathan Mizrahi, MD, discusses optimal sequencing in patients with BRAF V600E-mutant metastatic colorectal cancer.

Dr. Mizrahi on Optimal Sequencing in BRAF V600E-Mutant mCRC

Jonathan Mizrahi, MD, fellow at The University of Texas MD Anderson Cancer Center, discusses the goal of the phase III COMMIT trial (NCT02997228) in mismatch repair deficient (dMMR) colorectal cancer (CRC).

The ongoing COMMIT trial is evaluating the effectiveness of combination chemotherapy, bevacizumab (Avastin) and/or atezolizumab (Tecentriq) in the treatment of patients with dMMR metastatic CRC. Patients with be randomized 1:1:1 to 3 arms: mFOLFOX6 plus bevacizumab, atezolizumab monotherapy, or mFOLFOX6 plus atezolizumab and bevacizumab, explains Mizrahi.

The goal of the COMMIT trial is to see whether chemotherapy can be omitted altogether for this patient population or whether the addition of immunotherapy to chemotherapy will improve outcomes. Results from this study should provide clarity for how best to treat this patient population, concludes Mizrahi.

Jonathan Mizrahi, MD, discusses the goal of the phase III COMMIT trial in mismatch repair deficient colorectal cancer.

Dr. Mizrahi on the Goal of the COMMIT Trial in dMMR Metastatic CRC

Jonathan Mizrahi, MD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, discusses encouraging trial findings in metastatic colorectal cancer (mCRC).

A phase II trial presented at the 2019 Gastrointestinal Cancers Symposium evaluated the combination of durvalumab (Imfinzi) and tremelimumab. The study examined PD-L1 inhibition and CTLA-4 inhibition in a refractory patient population. Investigators looked at all-comers and observed an overall survival (OS) benefit, irrespective of PD-L1 status and microsatellite instability-high (MSI-H) status. The OS difference was small but enough to meet the primary endpoint.

Additionally, data were presented on the phase III BEACON CRC study, which is looking at the combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) in patients with 

-mutant metastatic disease. The preliminary results were encouraging, says Mizrahi. In July 2019, the triplet regimen was confirmed to have an OS advantage and to have resulted in a 48% reduction in the risk of progression or death. Due to these findings having exceeded historic data, the combination will likely become the standard of care for these patients, concludes Mizrahi.

Dr. Mizrahi on Encouraging Trial Findings in mCRC

Jonathan Mizrahi, MD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, discusses the importance of early genomic testing in patients with metastatic colorectal cancer (mCRC).

It is crucial to implement genomic testing early in the disease course because doing it later on could cause the patient to miss out on a potentially effective treatment, says Mizrahi. Testing early is always appropriate and is starting to become widely adopted. Unlike dealing with a patient who has oligometastatic disease where cure is still feasible, a patient with mCRC is being treated palliatively.

These are patients who will run through every line of therapy assuming they are fit enough, and as such, they will get to a point where they should be enrolled in a clinical trial. Testing them early, when they are still fit and have a good performance status, is important to inform subsequent therapy decisions, Mizrahi reiterates, adding that it should be done right at diagnosis.

Jonathan Mizrahi, MD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, discusses the importance of early genomic testing in patients with colorectal cancer.

Dr. Mizrahi on the Importance of Early Genomic Testing in CRC

Jonathan Mizrahi, MD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, discusses the importance of personalized care in patients with metastatic colorectal cancer (mCRC).

There is a limited number of cytotoxic chemotherapies that are efficacious for every patient with mCRC. 5-fluorouracil—based regimens with oxaliplatin and irinotecan are effective. Regorafenib (Stivarga) and TAS-102 (trifluridine/tipiracil; Lonsurf) have also shown promise in the refractory setting. Beyond that, personalized therapy is key, Mizrahi says.

Adding biologic agents like anti—EGFR therapy with cetuximab (Erbitux) is a prime example of individualized care. A number of patient factors like tumor sidedness, 

 status, microsatellite instability—high and mismatch repair deficiency can help practitioners make effective treatment decisions.

 also have to be taken into consideration. Once a patient’s mutational status is determined, the optimal combination regimen can be chosen. HER2-targeted therapy is also emerging for the 3% to 4% of patients who have 

 amplification in their tumors. A greater adoption of molecular profiling will help researchers develop more therapies, Mizrahi concludes.

Jonathan Mizrahi, MD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, discusses the importance of personalized care in patients with metastatic colorectal cancer.

Dr. Mizrahi on the Importance of Personalized Care in mCRC

Jonathan Mizrahi, MD, hematology/oncology fellow, The University of Texas MD Anderson Cancer Center, discusses bevacizumab (Avastin) as a chemoprotectant in colorectal cancer (CRC).

In October 2018, Mizrahi and Michael Overman, MD, of The University of Texas MD Anderson Cancer, published a study in 

 on bevacizumab’s ability to reduce oxaliplatin-induced hepatic sinusoidal injury in patients with CRC. The study was done to see if there are certain therapies that, when added to oxaliplatin, could reduce the liver injury caused by oxaliplatin. Hepatic sinusoidal injury is often seen following hepatic resections of metastasectomies, a procedure that is often performed in patients with limited liver metastases, says Mizrahi.

Notably, in patients treated with preoperative bevacizumab and oxaliplatin, the rates of hepatic sinusoidal injury went down. These findings have led physicians to believe that bevacizumab can serve as a protectant against hepatic sinusoidal injury by way of VEGF inhibition and its interaction with reactive oxygen species. Patients who have hepatic sinusoidal injury have increased morbidity after they have liver resection with metastasectomy. If patients can receive bevacizumab preoperatively, the rate of morbidity associated with hepatic sinusoidal injury may decrease.

Jonathan Mizrahi, MD