Editor’s note: As part of the celebration of U.S. Medicine’s 60th anniversary, we will be profiling some of the remarkable achievements in federal medicine over the last six decades. In the first of that series, U.S. Medicine spoke with Michael J. Kelley, MD, executive director of the VA’s National Oncology Program, chief of Hematology and Oncology at the Durham VAMC, and professor of medicine at Duke University, about the VA’s leadership in cancer research.
Interview with Michael J. Kelley, MD, Executive Director, National Oncology Program, VA by Chief Medical Writer Annette M. Boyle
DURHAM, NC — For the 60 years that this publication has been around – and even decades before that — the VA has been at the forefront of cancer research in the United States. Starting with the establishment of its first tumor research laboratory in 1932 and groundbreaking work in the 1950s on the association between smoking and respiratory tract cancers, the agency has repeatedly changed the course of oncology.
Michael J. Kelley, MD, Executive Director of the VA’s National Oncology Program, Chief of Hematology and Oncology at the Durham VAMC, and Professor of Medicine at Duke University
In 1962, Donald Gleason, MD, of the Minneapolis VAMC, developed the eponymous Gleason score widely used today to predict the aggressiveness of prostate cancer. Building on that work, Timothy Wilt, also of the Minneapolis VAMC, led the groundbreaking Prostate Cancer Intervention Versus Observation Trial (PIVOT), which showed surgery did not significantly reduce mortality risk in most men with prostate cancer, but did increase adverse events.2,3
USM: How did PIVOT change care in the VA and prompt discussion about prostate cancer treatment more broadly?
Kelley: I think the fact that that study was completed is worth noting; huge kudos to my colleagues who did it. That, in fact, you can randomize patients to surgery versus observation, after you tell them that they have cancer, is pretty amazing. It was an extremely important study to complete because they were really looking to establish whether there was a difference in how long people lived whether they got surgery or not.
One thing that they learned is that not too many people died of prostate cancer, right? It’s only about 10%, regardless of surgery. That led us to understand that there was a lot of prostate cancer that doesn’t need to be treated and to refine how we think about which patients need to be treated. [The study also] improved shared decision making, as clinicians can provide information from a very large study that allows us to answer questions we couldn’t before such as the chances of dying from prostate cancer for different populations and what the impact of surgery was on the different endpoints.
It also led to some other improvements in terms of how we assess how much cancer patients have. [Now we use a type] of MRI scan called a multi-parametric magnetic resonance imaging, which is done to try to target the biopsy in early-stage prostate cancer. And then there’s another scan, the PSMA [prostate-specific membrane antigen) PET scan that helps be able to assess different sites in the body that might have cancer, so that you’re not going to be treating patients [with surgery] who might already have metastatic disease, for example.
USM: The VA established the National Precision Oncology Program in 2016, one of the first to provide comprehensive genomics-driven oncology services to patients. How has that grown and what has the impact been on care?
Kelley: The National Oncology Program demonstrated the ability to systematically provide comprehensive precision oncology service to patients across the country through the VA. We started with non-small cell lung carcinoma and quickly expanded out from there to prostate, colon and breast cancer.
It’s not just sequencing, we make associated clinical expertise available because the testing results are quite complicated, and provide informatics to be able to identify who should be tested and systematically identify patients who have been missed. It’s best-in-class program; I talk to colleagues at major academic centers and they say, “Wow, I wish I had that.”
We’ve also looked at the impact on targeted agents that have more recently been approved. Are they safe in VA populations? How does the dose impact outcomes? Other studies have looked at response rates, targeted agents, off-label use of drugs, and which types of mutations are more likely to be associated with a response. We have a tumor board as well and case-based educational activities where experts discuss the intricacies of testing and interpret the results for clinicians who are learning how to implement this.
USM: A study in 2019 showed that 70% of VA patients with tumors evaluated through NOP had actionable mutations for which a clinical trial was available, but just 9% had an approved drug available for treatment. How has that changed in the last five years and how has the VA contributed to that change?
Kelley: For lung cancer, for example, 27% of our population now has a drug available for treatment. That’s because there have been new drugs approved for different genetic variants that were not previously able to be treated. That’s for adenocarcinomas. Squamous cell carcinoma does not have a very high rate of gene operations that can be targeted with a drug.
When a new drug is approved for patients who didn’t have access to that drug previously, we are able to go into our database and identify those patients and their providers [for whom it is appropriate] and letting them know there is a new drug available.
USM: How has the increased participation of veterans changed the structure of clinical trials for these drugs or made it possible to bring some of them more quickly to market?
Kelley: There are a number of efforts to increase access to clinical trials for veterans with cancer. There’s a partnership called Navigate the Algorithm that brings in National Cancer Institute-sponsored trials and sets them up in the VA. [That gets back to NOP,] if you don’t do the testing, you can’t know that there are trials available. So, when we do the testing, a report goes back to the provider that includes information on the clinical trials.
The clinicians can also ask the expert consultation service for help: Can you look at the results and tell if there’s a drug I can use? Of course, we will also try to see if there’s a clinical trial. Then there’s a concierge clinical trial navigation service to help find clinical trials for patients, those are oftentimes outside the VA. Our partnership with the NCI also helps facilitate evaluation of veterans for trials and streamlines their access to the veteran’s medical records and images from radiographic studies.
We are also starting to do clinical trials by telehealth, where we bring the trial to the veteran rather than have the veteran come to the clinical trial, which is often very impractical. We hope to launch a treatment study specifically for patients with lung cancer and a genetic alteration that is IRB approved and the FDA is supportive. We’re hoping to get the first site activated in the next month or two. Everything done where the patient is, is standard of care. For instance, drawing blood is not a research activity, so if we need blood drawn, the local hospital can do it. What they can’t do is do experiments on that blood. They send it to use and we do the experiment, so the remote research team does all the research.
USM: The VA launched the CONFIRM trial in 2017 for colorectal cancer. What should we looking for coming out of that study?
Kelley: CONFIRM is a randomized controlled trial comparing colonoscopy versus fecal immunochemical testing (FIT), a stool test, in patients at risk for colon cancer, which we all are. While the rate of colon cancer is declining overall, it is increasing in the population under age 50, which has led to some changes in the recommended age to start screening.4
Another study published in 2022 from Europe, the NordicICC trial, [which compared FIT to colonoscopy in 84,585 patients,] showed that that FIT missed about 26% of cancers that were found by colonoscopy. That led to being able to use the test on an annual basis as opposed to less frequently.5
Enrollment in CONFIRM ended in 2017 with 50,000 participants, who will be followed until 2027. We won’t know the final results until the next year, but there have been a few things published so far. First, the rate at which colonoscopy was done was pretty high, about 71%, which doesn’t sound that good, but in the NordicICC, it was only 42%. The rate of completing the FIT test was 83%, higher than colonoscopy, but there is a fall off right after that first year.
The problem is, if colonoscopy is better, how do we provide that because there’s not capacity to provide colonoscopy to everyone in the country.
With the VA’s long history at the forefront of lung cancer prevention, diagnosis and treatment, what are the patient characteristics and disease considerations now for selecting first-line treatments and and subsequent lines of treatment for small cell lung cancer patients in the VA.
Clinical pathways are published on a public facing website and they show what the treatments are for all cancers that we have gone through, which is most of them now, and for small cell lung cancer treatment, it is primarily chemotherapy. So there’s our platinum agent and usually entopisides, the two chemotherapy drugs. Many of the patients also get immune therapy. Some patients will get radiation and then a very small fraction might have surgery.
And then there’s that first line treatment is usually chemotherapy, with radiation if they’re what’s called limited stage, so the disease in the chest, and without radiation, if it’s outside the chest. Those patients with tumors outside the chest, they get immune therapy and now there’s a recent study that suggests that there might be some benefit to using that and using square the disease is still in the chest.
And for second line, there are several different options, a couple of chemotherapy agents, and there’s a recent FDA approval, I don’t know if it’s going to be on that pathway, but for an immune therapy, which is called a BiTE (bispecific T-cell engager therapy). [tarlatamab-Dlle] It’s not quite car-T, but it’s not like just an immune checkpoint inhibitor, it’s in between in terms of its aggressiveness and turning down the immune system, so that that drug has recently been approved. It’s not on the pathway yet. It takes us a little while to get the data and look at the data and consider whether we’re going to change the treatment or not.
- Wilt TJ, Brawer MK, Jones KM, et al. Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012 Jul 19;367(3):203-13. doi: 10.1056/NEJMoa1113162. Erratum in: N Engl J Med. 2012 Aug 9;367(6):582. PMID: 22808955; PMCID: PMC3429335.
- Wilt TJ, Vo TN, Langsetmo L, et al. Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Eur Urol. 2020 Jun;77(6):713-724. doi: 10.1016/j.eururo.2020.02.009. Epub 2020 Feb 21. Erratum in: Eur Urol. 2022 Feb;81(2):e52. doi: 10.1016/j.eururo.2021.11.009. PMID: 32089359.
- Schrek R, Baker LA, et al. Tobacco smoking as an etiologic factor in disease; cancer. Cancer Res. 1950 Jan;10(1):49-58. PMID: 15398042.
- Dominitz JA, Robertson DJ, Ahnen DJ, et al. Colonoscopy vs. Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM): Rationale for Study Design. Am J Gastroenterol. 2017 Nov;112(11):1736-1746. doi: 10.1038/ajg.2017.286. Epub 2017 Oct 10. PMID: 29016565.
- Bretthauer M, Løberg M, Wieszczy P, et al. NordICC Study Group. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death. N Engl J Med. 2022 Oct 27;387(17):1547-1556. doi: 10.1056/NEJMoa2208375. Epub 2022 Oct 9. PMID: 36214590.