“Building Bridges” Between Integrative and Conventional Oncology

Integrative oncology strategies, including pulsed electric fields (PEF) and other flagship intratumoral approaches, may help engage the immune system to help facilitate an immune response, bolstering quality of life (QOL) outcomes for patients.

In an interview with CancerNetwork®, Nathan Goodyear, MD, integrative medicine physician at the Williams Cancer Institute, discussed clinical thresholds his teams use to recommend dose modification with integrative therapies, methods for standardizing the reporting of patient-reported outcomes (PROs), and emergent immunotherapy options featured in key clinical trials oncologists should be following.

Regarding clinical thresholds, Goodyear touched upon his team’s use of the Common Terminology Criteria for Adverse Events (CTCAE) criteria to follow adverse effects (AEs) in clinical practice to contribute to the same scientific literature as conventional oncology and help improve QOL outcomes. Furthermore, his team also uses Response Evaluation Criteria in Solid Tumors (RECIST) criteria to gage tumor response to avoid arbitrary responses and align data with conventional oncology. Finally, Goodyear touched upon key clinical trials, both preclinical and in-human, evaluating intratumoral immunotherapy or with PEF to help facilitate immune responses perioperatively, including a review trial discussing perioperative immune system engagement.

CancerNetwork: What are the key criteria or clinical thresholds that lead you to recommend discontinuation or dose reduction of an integrative therapy due to potential AEs, particularly in patients who are frail, comorbid or heavily pretreated?

Goodyear: First, being in the integrative oncology space, we must always lead with the science, and we follow it. With that, in the conventional oncology space, they have set a lot of the parameters that help guide us in AEs, outcomes, [and other things]. It's not enough to know the science, but we must contribute to the science. In that, everything we do must be scientific.

It must be evidence based––clinical assessment, laboratory, but then we follow the criteria, both before and during treatment related to performance status scale. We follow that intimately through this process, because that's something that… will lead to partial response [or] complete response, but then QOL goes up [as well]. Now you have something where patients are healing and their QOL is improving. What we have had over the past is not a lot of looking at QOL. What’s interesting is now patients are saying, “I won’t sacrifice QOL for treatment.” We have to meet both. Patients as a consumer are driving that.

At the same time, the CTCAE we use to follow [AEs] through treatment. For example, in a phase 1 prostate cancer [study], 95% of patients for metastatic, castration-resistant prostate cancer, only had grade 1 or grade 2 [AEs], which means, [they did not] require any hospitalization, hospital visits, etc. It was easily managed, maybe by phone [or] a short course of medication, maybe not. It’s something that we follow [using] those same parameters, because we are not just knowing the science, we are following [and] contributing to the science. We’re going to follow those same parameters before, during and even after [treatment].

When you look at the scientific process, you have to say, “We have great advancement there. We don’t have to recreate the wheel. Let’s work with our colleagues in the conventional space, and speak that common language, and build bridges to help patients.” In that 5% [grade 3 AE incidence]––it was only grade 3, there [was no] 4 or 5 events––but in that 95%, 53% of the patients in the prostate cancer study [were] at remission and have [experienced] that for a year. This is in an arena of prostate cancer where conventional medicine does not have anything to offer. Not only are we seeing little to no AEs, but we are also seeing these patients [improve] where there are no treatment options available, and their QOL is not being negatively impacted, which is going to meet what consumers are demanding, which is precision-targeting, personalized treatment, yet QOL is not compromised.

Given the personalized nature of integrative care, what steps does Williams Cancer Institute take to standardize the reporting of patient outcomes and adverse effects in a way that is comparable with data generated in conventional oncology clinical trials?

We are wrapping up retrospective data mining of our patients [undergoing] fecal transplantation. We have a phase 2 study now open in the US for prostate cancer that the US FDA [gave a] fast track [designation to] from a phase 1 study done in Mexico. We have other phase 1 studies ongoing in Mexico, which is COFEPRIS, the Mexican arm that is comparable with the FDA. In essence, we are not just knowing the science and applying it for patients, we are engaged in elevating the science as well.

The Williams Cancer Institute [has] 3 arms: treat, innovate, elevate, and empower. We treat patients with the future of cancer care today. The innovation is on the research side. Building out a research arm to what we do at the Williams Cancer Institute, allowing us to take that innovation that goes through the scientific process––open for debate and discourse in the public arena––to then engage to help more doctors help more patients. Then we [have] to teach. There’s the clinical aspect of treatment, there’s a research aspect, and then there is the teaching aspect, all of that geared to innovate, elevate and empower, not just what we do for patients, and not just what patient’s immune system do, but what other doctors can do to help their patients.

We will use those same quantification measurements in those studies. That’s what we do. Of course, we follow labs, we follow imaging. For example, on the imaging, the way we follow that is with the RECIST. That’s where we’re gaging the response of the tumors to the treatment. It’s not something that’s arbitrary. It has strict criteria that has been recognized internationally about how to gage the response of these solid tumors to treatment.

How do you see localized and combinatory immunotherapy options emerging in the clinical landscape, and what clinical trials should oncologists be looking out for?

We are at the cusp of massive changes in how cancer is approached in an exciting way. It benefits those in the integrative oncology space, but it benefits those in the conventional oncology space. That’s why I am so excited, because we are going to build bridges. One area to look at is the combination of PEF plus intratumoral immunotherapy. That combination is critical because there are people advocating for systemic immunotherapy, but what we know about systemic immunotherapy as it relates to systemic chemotherapy, the estimates based on published studies, is only about 0.5% to 2%––approximately 1%––reaches the tumor. What if there’s a large tumor burden? What if there’s multiple tumors? There are multiple mechanisms by which dilution, degradation barriers, and even the liver uptake––the toxicity with systemic therapy is built in because the liver and the healthy tissue preferentially uptakes all this systemically delivered therapy, and most of it never reaches the tumor. The [flawed] assumption we make is that, once it reaches the tumor, that 1%, it penetrates, it goes to work, and it does the job.

We now know within that arena of the tumor microenvironment, there are at least currently recognized 3 tumor immune microenvironments. There is the inflamed environment. That means the immune cells are there. They are active. They are targeting the tumor, and they’re creating an immune response. However, within that context, there is the issue of inhibition, immune cell exhaustion, particularly T-cell exhaustion, natural killer cell as well, and suppression, all of that can happen. It’s a restraining issue, but the immune system is there. If we can activate the immune system more, get away from the suppression, get away from the inhibition, and reverse the exhaustion, we can engage that immune system to do better.

The majority are what’s called immune-excluded. That means the immune cells are on the periphery, the boundary, of the tumor, but they never get in. They cannot engage with the tumor. They are present, but they are outside. In that aspect, giving systemic delivery, it does not get in, and so the immune system does not engage at all. It’s not the issue of the agents employed. The issue is the delivery method employed that is flawed. By going into the tumor with PEF and intratumoral immunotherapy, we completely bypass that, recruit the immune system in there and activate it. We take an immune-excluded [tumor] and now make it inflamed and steer it.

Then the other category, though, a smaller one, about 25% is called an immune desert, meaning the immune system does not know the tumors there. There are no immune cells that have been primed to even see it. What we must do is recognize we do not want to just treat the inflamed tumor environment. We want to treat all 3 environments. The PEF and the intratumoral combination allow us to do that.

Two examples of therapeutics that are going to be exciting that we have been using for many years intratumorally is the combination of CD40 and CpG. These are intratumor Immunotherapeutics that are now starting to show early human data. The problem with most of that is particularly with the CD40 when given systemically. Again, the problem there is not the drug, [it’s] the delivery method. It’s toxic systemically, but when you give it intratumorally, you completely bypass that. It was listed in a 2025 study showing that it creates tertiary lymphoid structures and is generating an intratumoral immune response. In a study of 12 patients, 2 were lost. [Of] 10 patients, 2 patients experienced a complete remission with CD40 intratumoral alone, so we can give the proper method with the proper drug at a microdose, and create an immune response. CpG is a Toll-like receptor type 9 activists, and these are 2 combinations that we have been using for quite some time that you are going to start to see take off in the intratumoral approach.

We want to build bridges with our conventional colleagues. The way we do that is helping what they are doing work better. The way we do that research suggests we combine the intratumor approach with the conventional approach––doing intratumoral immunotherapy prior to surgery. There was a recent study for 4 different cell culture models where they were able to significantly reduce the metastatic and local recurrence, but overall response in terms of destruction of these cells’ cultures based on this intratumor approach, by doing it before surgery in mice. Looking at the pheochromocytoma cell arm, they were able to 100% eradicate with no recurrence. When they try to reintroduce the tumor by engaging the immune system before surgery, they prevented the opportunity for recurrence.

A beautiful review article was published in 2025 in January, talking about the need to engage the immune system before surgery, not saying we do not need surgery. It said, “Surgery does not allow for antigen exposure. It does not allow for antigen and immune system training. Let's do that first.” Then if you need to do surgical resection, you do that. Now what you have done is brought the immune system to “the party” [or] “the fight,” and after this bulk of the tumor is removed, now you have engaged the immune system to go out there and look for the smaller areas to target, and you have that tumor burden removed, and you are going to get better results.

The point here is, by combining these neoadjuvantly, intraarterially, we can engage the immune system… to get a better response. It's the integration of the hallmarks of cancer and the integration of the hallmarks of aging. By looking at what combination of therapies are we going and where we're seeing, you can see here just a few examples of where we are and where we're going.

Reference

Skalickova M, Vanova KH, Uher O, et al. Injecting hope: the potential of intratumoral immunotherapy for locally advanced and metastatic cancer. Front Immunol. 2025;15: 1479483. doi:10.3389/fimmu.2024.1479483