Chapter 05: Melanoma Research and Comments on Research Disappointments

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Chapter 05: Melanoma Research and Comments on Research Disappointments

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In this chapter, Dr. Balch talks about his research. He begins with comments about the balance he had to find between his surgical interests and research and administrative commitments. He notes that general surgery training enabled him to take on a project of being one of the first to insert chemo infusion pumps via abdominal surgery, and that his later research led him to focus on melanoma and breast cancer. Dr. Balch talks about his work on melanoma staging. He describes how the project came about through a desire to create a database and then evolved into new criteria for staging melanoma because of the involvement of statistician Sing Jaw Son, PhD. He talks about his sabbatical year in Australia (1983) at the Sydney Melanoma Institute, a collaborator in the melanoma project and where he wrote a book on melanoma. Next Dr. Balch talks about lessons learned from two studies that did not yield real results.

Identifier

BalchC_01_20181022_C05

Publication Date

10-22-2018

Publisher

The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Definitions, Explanations, Translations; Overview

Transcript

T.A. Rosolowski, PhD:

What was happening at this time to your own surgical skills, and perspective on working with surgical methods in the operating room?

Charles Balch, MD:

Well, in the 1970s, we were trained to operate in all body cavities. So early on in my surgical career I did a lot of liver surgery, sarcomas, head and neck surgery,and pelvic surgery, because we were trained to operate in all of those areas. I was one of the first to put in chemotherapy infusion pumps [for liver metastases], and, again, with two other people, led a national clinical trial to pioneer the work in regional therapy with an implantable drug infusion pumps. [ ] My research was leading me into melanoma and breast cancer. [ ] So a lot of my interest as my career advanced gravitated towards melanoma and breast cancer, because of the multidisciplinary nature, and because of the randomized clinical trials I did on surgical treatment of melanoma, which is still used today, and because of the database management that we created with a biostatistician named Seng-Jaw Soong. We developed the largest melanoma databases in the world [at that time]. That allowed us to reform the staging system for melanoma that is still used today.

T.A. Rosolowski, PhD:

So tell me about that a bit. It's a big, big project with enormous impact, as I understand.

Charles Balch, MD:

It is. It's an interesting story about how you have to look for opportunities. [The story began when Dr.] John Durant, the Cancer Center Director, called me into his office, [where I met Dr. Seng-Jaw Soong], who'd just gotten his PhD on the clinical application of the Cox regression analysis, which we know today as the multifactorial analysis, and which is the standard statistical tool that everybody uses in the world. [This methodology] had never been used in a clinical study. And Dr. Soong, who was a brilliant Taiwanese mathematician, wanted to have a raw database so he could test the Cox regression analysis on real data, not on theoretical math. [Melanoma turned out to be the best candidate because] my senior partner, Bill Maddox, had followed his [melanoma] patients for their lifetime, and had careful records, including maps of exactly where the melanoma was located on the body. Dr. John Durant gave me a database management person and a research nurse, and we assembled a database with a survival outcome on 294 patients. Seng-Jaw Soong did a multifactorial analysis, and everything he found was different than [the criterial that others were using as] the staging criteria for melanoma. That was my first paper in melanoma, and it was a "grand slam homerun" because everything that we published turned out to be validated by others later on. So we were the first to describe that tumor thickness is better [predictor of survival compared to] level of invasion, the first to describe ulceration [as a predictor of survival], the first to demonstrate that there was a potential survival benefit of patients if they had their lymph nodes removed [electively]. [ ] But it leads to one other part of my story, which has been an essential element of my professional success. At a surgical meeting in the United States, I met an Australian surgeon named Gerry Milton, who had a large practice in melanoma. It turned out it was the largest in the world, and he told me he had a large prospective database but no statistician. And I remember telling Gerry that I have a small database but a very good statistician, and perhaps we should collaborate together. So that led to a collaboration with the Australians that, when we combined our data, [comprised] the largest series in the world. Everything we published after that drove the whole staging system, because we had more data than anyone else. And it was so successful that I actually had a sabbatical leave in Australia [in 1983], and that's where I wrote my first book, the first edition of our Cutaneous Melanoma book, which is now in its fifth edition. But what I learned from that was the importance of collaborating with people outside of your own institution, and even outside of your own nation. And it's made me into what I am today, of looking for international collaborations that are beneficial from a research perspective, because you can add unique features or volume of patient material that you may not get within the United States, or in our own practice.

T.A. Rosolowski, PhD:

Did you find that Gerry Milton had a slightly different perspective because of a difference in training, or? I mean, that's part of the value of collaboration.

Charles Balch, MD:

What was amazing is we were identical.

T.A. Rosolowski, PhD:

Really? Wow! [laughs]

Charles Balch, MD:

And the philosophy of their care was very similar. So [he was the founding director of] the Sydney Melanoma Institute, which later became the Melanoma Institute of Australia, which is the largest such program in the world. [ ] He had the vision for creating the database, but he didn't have the statistical wherewithal to analyze the data, other than reporting a large patient series [ ]. But Seng-Jaw Soong brought that unique dimension of understanding how to sort out all of these variables with this new statistical method called the multifactorial analysis, for which we published a series of papers that set the stage for other people to use that same statistical methodology and come up with the same results. Because of that, I was invited to come onto the AJCC Melanoma Staging Committee, where we used a new database to radically reform the entire staging system for melanoma. That has now been consistently validated and approved, even now in the eighth edition, which was just published, and led by Jeff Gershenwald here [at MD Anderson].

T.A. Rosolowski, PhD:

So I have kind of a funny question for you. You've talked about all of these studies that were incredibly successful, and hit on a hot button that just went through to success

Charles Balch, MD:

Yeah, I was hitting homeruns right and left.

T.A. Rosolowski, PhD:

You were. But was there something you took on that just didn't pan out? Because it's always interesting, with those things, what do you learn from it, whatever it might be? Because those are learning moments.

Charles Balch, MD:

Yes, I think one project was some of the pioneering work on regional chemotherapy for liver metastasis in colorectal cancer, in partnership with a company called Infusaid in Boston, which was subsequently bought by Medtronics. [My collage, Dr.] John Niederhuber, who was at Michigan at the time, Dr. Robert Barone in San Diego, and I did the first studies on that. I wrote up in the Annals of Surgery a phase II study. We organized a phase III randomized trial, comparing conventional intravenous 5-FU chemotherapy versus our regional pump therapy. It took the NIH a while to fund it. The Infusaid company decided they don't have time to do this randomized study, [which was only possible] because at the time they restricted the distribution of the pumps to a few academic centers. The company decided they couldn't wait, and so they released the pump to anyone who would buy it. [ ] It dried up the ability of us to do the randomized study, which was never completed. [However,] twenty years later, Memorial Sloan Kettering did the randomized study and demonstrated there was a survival benefit. So part of my frustration was a company who decided they'd make a quick profit by releasing an investigational device early, and so did not allow us to prove it in a randomized clinical trial. [ ] In the absence of a randomized trial it really never got any traction [in standard practice]. The company made a big profit for about two years, and then finally lost money because it fell out of favor because of insufficient evidence. And I think that the key point here is if you have something that's new and innovative, you do have to demonstrate the value in prospective clinical trials compared to the current standard of care, if it's going to be embedded into our standard practice and be reimbursed by insurance companies and by patients.

T.A. Rosolowski, PhD:

And I'm sure

Charles Balch, MD:

So it's always made me a champion of doing clinical trials and organizing your data in a prospective database and doing clinical trials as the way to advance the field.

T.A. Rosolowski, PhD:

ParticularlyI mean, again, you're in this field that's becoming more and more complicated with multidisciplinary care, all these different approaches to manage cancer, so all of the elements have to be working together, and the only way to do that is to do these close investigations.

Charles Balch, MD:

So there's one more story about a major professional disappointment. [We were] doing [some of] the first studies on immunotherapy with nonspecific immune stimulants, and later with a variety of melanoma vaccines. However, we did not understand the concept of immune tolerance. So for 25 years, all of our approaches in immunotherapy [were based on] an assumption that the immune system was crippled and deficient, and all we had to do was stimulate it in various ways [in order to stimulate] an immune rejection response. [All our trials failed to show a survival benefit of using various immune stimulation molecules.] It wasn't until people like Dr. Jim Allison discovered the concept of immune tolerance as the mechanism that tumors sneak through and grow that the field of immunotherapy has advanced, now with the checkpoint inhibitors and an understanding of immune tolerance. So I had 25 years of failed clinical trial efforts because we had the wrong strategy. We did not understand the concept of breaking immune tolerance and then coming back with all of these different immune stimulants, which are being tested again today.

T.A. Rosolowski, PhD:

That's amazing.

Charles Balch, MD:

So it gets back to you have to have the right strategy, and it has to have a scientific foundation.

T.A. Rosolowski, PhD:

Very cool. So you ready to tell me how you got to MD Anderson? [laughs]

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Chapter 05: Melanoma Research and Comments on Research Disappointments

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