Adding Dietary Supplements to Treatment Impacts Outcomes in Unresectable Pancreatic Cancer

The addition of dietary supplements to treatment with gemcitabine and nab-paclitaxel (Abraxane) plus metformin in patients with unresectable pancreatic cancer led to changes in gene expression, according to a study presented at the 2020 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium.

Seventeen supplements, designed by a trained nutritional oncologist, were given as 12 pills and 2 smoothies packets daily in conjunction with metformin 6 days prior to the start of chemotherapy. Standard doses of gemcitabine and nab-paclitaxel were given on day 1. Patients had samples collected on day 6, cycle 1 day 1, cycle 3 day 1, and at the end of treatment. Forty-eight samples were collected from 19 patients and analyzed. Samples were also evaluated for changes in gene expression.

The combination of supplements with chemotherapy led to small changes in gene expression. Following 2 months of treatment, investigators found that 17 genes were upregulated, and 4 genes were down regulated. Thirty-three genes were upregulated at the time of tumor resistance with an upregulation in growth factor pathways. Specifically, SPRY2 mRNA expression was upregulated, which can be used to determine effectiveness of multiple receptor tyrosine kinases.

Cell cycle and apoptosis pathways were the most impacted by the addition of supplements to the chemotherapy. IL-8 mRNA expression, which is involved in the immune response and associated with a pro-inflammatory state in pancreatic cancer, was upregulated the most during the initial run-in period prior to the start of chemotherapy. Chemotherapy decreased expression of IL-8.

In addition to the changes in gene expression, the study also found that the addition of supplements to standard chemotherapy was generally well tolerated among patients.

“Anecdotally, many of the patients said they had improvement of their symptoms,” Vincent Chung, MD, lead investigator and a medical oncologist at the City of Hope, said in an interview. “Some of them had a little more energy, and some of them felt better when they were taking the supplements in combination with the chemotherapy. There may have been an effect of the supplements improving their tolerance to the chemotherapy.”

In an interview withTargeted Oncology,Chung discussed the findings from the pilot trial evaluating the addition of dietary supplements to combination chemotherapy in patients with unresectable pancreatic cancer. He also highlighted the importance of these findings and the next steps necessary to evaluate the role of supplements in pancreatic cancer further.

TARGETED ONCOLOGY: What was the rationale for adding supplements to treatment in pancreatic cancer for this study?

Chung:This is an interesting study because if you think about it, supplements are being utilized every day. About 67% of the adult population in the United States are taking some sort of supplements, and in pancreatic cancer, a lot of patients have weight loss, GI issues, and they are always looking for new ways to supplement their nutrition. There are a lot of data online on how supplements may have potential anti-cancer properties. Many patients who come in to see me are already taking supplements, so I thought it would be a good idea to try and study this in patients with pancreatic cancer.

TARGETED ONCOLOGY: How was the study designed?

Chung:This was a pilot trial with gemcitabine and nab-paclitaxel plus metformin, as well as standardized dietary supplements. This is for patients with advanced pancreatic cancer. One of the things I want to start with is thanking the sponsors. None of this would have been possible without the support of the Biomedical Research and Longevity Institute, as well as Life Extension, who actually formulated the supplements because we needed to bring the supplements down to a smaller volume. There were 17 different supplements utilized within this clinical trial, and we needed to bring that down to a manageable number. The number of pills that patients were taking was 12 pills with 2 smoothie packets each day.

We could not have complete this research without the support of the City of Hope who, with their core facilities, were able to do a lot of the gene-expression analysis. In this particular clinical trial, we are accruing patients with advanced pancreatic cancer. We accrued 21 patients over the course of about 2 years. They started with these supplements initially to see how they tolerated it. Basically, the patients started with metformin because we know metformin has a lot of GI toxicities. If they were able to tolerate the metformin, they would start with the 12 supplement pills and 2 smoothie packets [about 4 days prior to their chemotherapy].

Once they completed their supplements, they then received combination chemotherapy with the supplements and metformin. Patients could continue on with daily dosing of their supplements, as well as chemotherapy on the regular standard FDA-approved schedule. We evaluated them for their overall response rate (ORR), as well as their overall survival (OS).

We also took blood samples to explore the gene expression pattern after they received the supplement and chemotherapy. They had blood samples collected prior to the initiation of the supplements, on cycle 1 day 1, on cycle 3 day 1, and at the end of treatment. Once treatment was completed, we could go back and see, retrospectively, what kind of gene expression profiling they had.

TARGETED ONCOLOGY:What were the findings?

Chung:In terms of the clinical aspects of the trial, we looked at the course of OS and ORR. The average OS was about 8.9 months, and about 29% of patients responded to the therapy. This is comparable with what you find in the MPACT trial, which is the large phase III randomized clinical trial [NCT00844649]. This is a small study, so we have to take everything with a grain of salt. However, these are fairly comparable results.

This was a study [to evaluate whether or not] patients aer able to tolerate taking these supplements on a regular basis in combination with chemotherapy. Since patients with pancreatic cancer commonly have GI problems, the question is if they can take the 12 pills per day as well as the 2 smoothie packets. We found that was feasible.

There was 1 patient who did not want to take that many supplements per day and decided to stop due to the physical volume of pills on a daily basis, not because of GI toxicity. The majority of patients tolerated it well. Anecdotally, many of the patients said they had improvement of their symptoms. Some of them had a little more energy, and some of them felt better when they were taking the supplements in combination with the chemotherapy. There may have been an effect of the supplements improving their tolerance to the chemotherapy.

TARGETED ONCOLOGY:What implications arise from these findings?

Chung:This is a trial trying to evaluate the feasibility of taking supplements regularly while on chemotherapy, and we showed that it was feasible. In terms of the molecular changes that occur, that has to be explored further. This is a small study with only 19 patients with samples that we were able to evaluate for gene expression patterns. In order to explore how the supplements are affecting [gene expression, you need to examine patients for] a longer time frame where they are on the supplements alone without the chemotherapy to evaluate if these changes will be prolonged.

One of the changes we did see with the supplements was the increase of IL-8 mRNA expression. That is interesting because IL-8 is a chemokine factor that is involved with inflammation. It is called a chemotactic factor, so it recruits in neutrophils. There may be some immune modulation with the supplements, so we gave the supplements on day 6 and took the blood sample after that week’s [administration of] the metformin and supplements. We saw a 3-fold increase in the IL-8 mRNA expression, so this is something interesting that could be studied further to see if there is some immunomodulation going on with the supplements.

TARGETED ONCOLOGY:In your opinion, what is the importance of genomic testing prior to treatment in pancreatic cancer?

Chung:For pancreatic cancer, genomic testing is important for patients with advanced cancer because we are seeing molecular subtypes that you can treat and target with therapies. They are rare, but we do find them. If you do find something like anNTRKgene fusion, which is rare, larotrectinib [Vitrakvi] is approved for [treating tumors with] these fusions. With microsatellite instability[-high] pancreatic cancer, which accounts for about 1% to 2% of pancreatic cancers, there are immunotherapies that work well. It is now in the NCCN [National Comprehensive Cancer Network] guidelines that patients with advanced pancreatic cancer should undergo genomic analysis, and all patients with pancreatic cancer should get germline testing done.

TARGETED ONCOLOGY: Are any next steps planned for this research?

Chung:This is the first step. Supplements are interesting. This was designed by Stephen Shibata, MD, at the City of Hope. He was a trained nutritional oncologist who was interested in evaluating how supplements affect the metabolism, as well as potentially cancer growth. There is definitely a lot more research that can be done. The challenge is going to be how to decide which supplements to use because in our trial, we had a combination of 17 different supplements. Part of the reason for that was because we wanted to give a combination of agents that had different effects, not only on the quality of life but some metabolic and anti-cancer effects. To study that, you need to single out each individual agent and understand the mechanisms behind it. That is going to be a much larger project, but I think that is the way to go if you want to study supplements and how they affects cancer metabolism.

TARGETED ONCOLOGY: Are there any other data you are most looking forward to at this year’s meeting?

Chung:I’m looking forward to hearing more about the clinical trial with gemcitabine and cisplatin plus or minus veliparib [ABT-888] because the POLO trial, which was presented at the ASCO Annual Meeting last year, showed that olaparib [Lynparza] doubled the survival for patients withBRCA-mutated pancreatic cancer. In December 2019,olaparib was approved[for this indication], so it will be interesting to see how a PARP inhibitor in combination with chemotherapy will have more impact.

Reference:

Chung V, Frankel H, Shibata S, et al. Gene expression profiling of unresectable pancreatic cancer patients treated with gemcitabine, nab-paclitaxel, metformin, and dietary supplements (DS). Presented at: 2020 ASCO GI Cancers Symposium; January 23-25, 2020; San Francisco, CA. bit.ly/2RpU8SL.

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