Chapter 10: Lung Cancer and Uncommon Lymphomas
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Dr. Cox describes the research he undertook when left the position of Vice President for Patient Care and returned to his full-time faculty position, beginning with his new role as “the lymphoma person.” He explains the lymphoma trials that combined radiation and chemotherapy and that resulted in a successful response as well as a genetic translocation that will give rise to a genetic marker. He notes studies of radiation and chemotherapy in uncommon lymphomas.
Dr. Cox next explains how he was involved in teasing out the natural history of unusual lymphomas to understand them as distinct cancers. He uses testicular lymphoma as an example, describing how this cancer is treated with both radiation and chemotherapy. Patients with this cancer were rarely cured before this approach was developed: with this treatment, the cancer is eliminated in 50% of cases. Dr. Cox conducted this work between 1992 and 2000.
Dr. Cox then explains that he always saw cancer as more than one disease: he explains what it means to understand this at the molecular and cytogenetic level, eventually resulting in diagnoses being rendered by biochemical, molecular or genetic findings. He notes that his work at MD Anderson was tightly linked to his work with the RTOG. He continues, explaining that he returned to work with lung cancer in the late nineties. He mentions that lung cancer still has the highest death rate among all cancers, though mortality from lymphoma is increasing and Dr. Cox explains this is largely attributed to environmental chemicals. He explains the “modest progress” that he and the lung group at MD Anderson have made combining drugs, radiation, and surgery. Dr. Cox explains his work using prophylactic cranial irradiation to decrease the risk of brain metastasis from small cell carcinoma and notes that studies were also done to determine if this irradiation increased the risk for neuropsychological complications.
Identifier
CoxJ_02_20130412_C10
Publication Date
4-12-2013
City
Houston, Texas
Interview Session
Topics Covered
The Interview Subject's Story - The Researcher; The Researcher; Discovery and Success; Patients; Patients, Treatment, Survivors; Healing, Hope, and the Promise of Research; The Scientist at Work; Overview; Devices, Drugs, Procedures; Understanding Cancer, the History of Science, Cancer Research
Transcript
Tacey Ann Rosolowski, PhD:
When were you able to return to design your own studies or collaborate very closely in more than a facilitative role in doing studies?
James D. Cox, MD:
When I returned to the full-time faculty in 1992. So after four years in the position of vice president for patient care and physician in chief, then I returned. And at that point, Dr. Peters—Lester Peters—who had the division at that time, needed somebody to succeed Dr. Fuller—Lillian Fuller in the lymphoma arena. I had a lot of interest and had done a lot of work in that area. So I became the lymphoma person for awhile.
Tacey Ann Rosolowski, PhD:
And what did you do in the studies?
James D. Cox, MD:
Well, I worked very closely with Fernando Cabanillas and other colleagues in the lymphoma department. We designed some trials—and pathologists, there were pathologists as well—designed some trials to look at trying to see if radiation therapy or chemotherapy—one or the other, and we did a randomized comparison—were able to achieve a molecular complete response. The study that we were looking at had a translocation at two different chromosomes. It gave rise to a market that we could follow over time in these studies. So we pursued that for quite awhile.
Tacey Ann Rosolowski, PhD:
So that sounds like—was the discovery of that marker really significant?
James D. Cox, MD:
Well the discovery of the marker was done by—I’m trying to remember who discovered that translocation and that marker. One of the people—and I don’t remember his name—was a guy who served as a consultant in the O.J. Simpson trial in California. He was a molecular biologist who—he was involved. But what we did, we had a colleague in pathology that had developed a way of expanding this marker—amplifying this marker—so that we could test patients to see whether they had it or not and to look at it following treatment. We’d look at it before treatment and then following treatment. So we did those studies for a while. And then—what else?
Tacey Ann Rosolowski, PhD:
Do we need to pause?
James D. Cox, MD:
No, let me see.
Tacey Ann Rosolowski, PhD:
Okay.
James D. Cox, MD:
Sorry.
Tacey Ann Rosolowski, PhD:
That’s all right. So the other areas of your work in lymphoma were—?
James D. Cox, MD:
Well we were looking at seeing about the role of radiation therapy and chemotherapy in uncommon lymphomas—lymphomas of the stomach, orbit, Waldeyer's ring—the ring around the pharynx. Small bowel—
Tacey Ann Rosolowski, PhD:
What’s the orbit?
James D. Cox, MD:
Eyes. Where the eyes—
Tacey Ann Rosolowski, PhD:
In the eyes. Okay. Uh-hunh (affirmative). And you said small bowel?
James D. Cox, MD:
Small bowel, thyroid—these are all tumors that are not common. So to know what happened when we saw those patients—they didn’t fit well in just calling them lymphomas because each one had a distinct natural history, and we were trying to tease out that natural history and also the response to treatment.
Tacey Ann Rosolowski, PhD:
One of the things that’s come up in a number of interviews is just the fact that given the critical mass of patients who come to MD Anderson, you actually have the opportunity to see unusual cancers.
James D. Cox, MD:
That’s right.
Tacey Ann Rosolowski, PhD:
I’m curious, in this case with this study of the very unusual cancers with unusual natural histories, what did that help you understand about the diseases (???)(inaudible, speaking at once) in general?
James D. Cox, MD:
Well, I think one of the things it did was help not only us, but everybody in the lymphoma group to realize that each one of these was a distinct entity, that to lump them together—let’s say as large-cell lymphoma, was not sufficient to understand the natural history and the way of solving the problem. An example that was—one of the more dramatic examples was testicular lymphoma, which occurs in men almost entirely over the age of sixty, whereas the other testicular tumors all occur very much earlier in life. It turned out that those tumors, although they spread to lymph nodes nearby, weren’t the main problem. The main problem was that it spread to the central nervous system. It spread to the brain and the spinal cord, and you had to treat the entire cerebrospinal axis. So it led to our giving chemotherapy intrathecally inside the thecal sac. Along with chemotherapy—and it also led to giving radiation therapy, not to the regional lymph nodes, but to the opposite testis because that was another sanctuary area where the drugs didn’t reach an adequate concentration, so we needed to treat the opposite testis to prevent the tumor from coming back.
Tacey Ann Rosolowski, PhD:
And what were the results that you were able to get from that?
James D. Cox, MD:
They were very much better. Those patients were rarely cured before adopting this approach. And afterwards—I don’t know what the numbers are because I haven’t stayed on top of it as it’s evolved—but I think well over half the patients or more—the tumor was eliminated. Now these are older men, so the survival was not an endpoint that was easy to draw any conclusions, but being able to eliminate all evidence of disease was the goal there.
Tacey Ann Rosolowski, PhD:
And obviously without surgery and preserving function— James Co,x MD Right—with no surgery. That was one example.
Tacey Ann Rosolowski, PhD:
And the dates around the time that you were doing these unusual lymphomas?
James D. Cox, MD:
I would say it was between about ’92 or ’93 up until about 2000.
Tacey Ann Rosolowski, PhD:
Of course this is important for historical record, but I’m also asking because one of the things that’s really struck me as a non-specialist coming in and talking to all of you, is that it’s starting to come clear to me how there was this huge shift in understanding cancer not as one monolithic entity, but actually as multiple diseases and then as a kind of moving target that can literally morph.
James D. Cox, MD:
Well, even in something like lymphoma, where saying a patient has lymphoma doesn’t tell me anything. It’s really what kind, how they present, it’s all of these subtypes. And there are many, many subtypes of lymphoma that are very different. Now more and more they’re characterizing them at the molecular level or at the cytogenetic level, and that is helping them find ways of at least categorizing them and then monitoring them. So increasingly to have the molecular or cytogenetic signature of these lymphomas helped a better understanding. Tacey Ann Rosolowski. PhD What was it like for you as a scientist who was trained pretty much in one way of seeing cancer, and then having the concept of the disease so radically altered?
James D. Cox, MD:
Well, for me it wasn’t a big deal because I—from the time of my pathology course in medical school, it was clear that cancer was not one disease—it was hundreds. And then when you got down to something more narrow like lymphoma, lymphomas were not one disease—they were maybe dozens. And cancer of the lung, more and more we’re understanding is not one disease—it’s different ones. The more we understand it at the molecular level, the more discrete entities we’re able to come up with—and discrete treatments. So I think as time goes on, increasingly, instead of having the diagnosis rendered by the microscope, by light microscopy— I don’t think we’ll do away with light microscopy, but I think it will be dependent upon the biochemical or molecular or cytogenetic findings that give the diagnosis.
Tacey Ann Rosolowski, PhD:
What I was hearing as you were describing the very different natural histories of those unusual or rare cancers, lymphomas was the contour—it’s starting to take shape of individualized therapy, personalized care and all of that.
James D. Cox, MD:
Uh-hunh (affirmative).
Tacey Ann Rosolowski, PhD:
So it’s just fascinating how that was evolving and being put together by all these different—
James D. Cox, MD:
—and more and more. Obviously you know that it’s moving in that direction towards individualized therapy and one of the areas that needs to be worked on much more, but there isn’t funding readily available for it is the platform of local treatment with radiation therapy and molecular agents given at the same time.
Tacey Ann Rosolowski, PhD:
What are some other significant studies that you were working on in the ‘90’s and—I’m just continuing your research story.
James D. Cox, MD:
Well it was interwoven between what I was doing here at MD Anderson and what I was doing at the RTOG because there was this big overlap. I was at Anderson—I would say all throughout the ‘90’s I was doing one thing, mostly with lymphoma patients, and then at the end of the ‘90’s, more with cancer of the lungs. And there it was designing trials, trying to look at altered fractionation plus chemotherapy for different types of cancer of the lung.
Tacey Ann Rosolowski, PhD:
Maybe I should just ask you, what are the figures for lymphoma and lung cancer nationwide? Is it increasing? Is it decreasing?
James D. Cox, MD:
Lung cancer is decreasing in frequency in men. I think it’s still going up or plateauing in women. But the death rate for lung cancer is the highest in both men and women. Cancer of the lung kills more women than cancer of the breast.
Tacey Ann Rosolowski, PhD:
And that’s the highest death rate among all the cancers?
James D. Cox, MD:
Uh-hunh (affirmative).
Tacey Ann Rosolowski, PhD:
Wow.
James D. Cox, MD:
Right. Lymphoma, which was much lower on the list early, has been increasing in frequency slowly over the last couple decades. I don’t know what the latest figures are, but it’s been increasing.
Tacey Ann Rosolowski, PhD:
Is there any sense about why that is?
James D. Cox, MD:
There’s a lot of speculations.
Tacey Ann Rosolowski, PhD:
Are you willing to share some of those? (laughs)
James D. Cox, MD:
Well, one, for example, is in the states where a lot of chemicals, primarily pesticides or similar kinds of chemicals, are used in the agricultural industry or in ranching and so on. Those states have had the highest increase in lymphomas, and one of the leading figures in lymphomas is from a bit of an unlikely place—Nebraska. Jim Armitage is recognized as one of the leading people in the country, but they see a lot of lymphoma patients in Nebraska, which doesn’t have a very high population. (laughs)
Tacey Ann Rosolowski, PhD:
Right. But those obviously have huge agricultural—
James D. Cox, MD:
And so that’s one connection. That’s the main one that comes to mind for me.
Tacey Ann Rosolowski, PhD:
So in the early ’90s you focused on lymphoma and then later lung.
James D. Cox, MD:
Uh-hunh (affirmative).
Tacey Ann Rosolowski, PhD:
And what were—did you go through the significant—did the lung studies that you spoke about earlier cover what you were doing in the late ’90s?
James D. Cox, MD:
No—I started out doing investigations in cancer of the lung, primarily these patterns of failure kinds of studies. But then I had very little to do with it except through the RTOG during the early ’90s. And then in the late ’90s I got very involved with the group here, and I’ve stayed involved with that group ever since with trying to put drugs together with radiation, some cases with surgery to try to achieve better results with cancer of the lung. I think we’ve made some modest progress, but not as much as I would like. As the chemotherapy gets better—we found this out with small-cell carcinoma of the lung—as the chemotherapy gets better, the local treatment becomes more important. That’s a bit counterintuitive because with small-cell carcinoma, it was so responsive to chemotherapy, they thought you didn’t need radiation therapy and did a series of studies and found out that you do.
Tacey Ann Rosolowski, PhD:
What are the drugs that are used?
James D. Cox, MD:
Primarily cisplatin—for small-cell carcinoma of the lung, primarily cisplatin and etoposide. For the non-small-cell—squamous and adenocarcinomas—well now they’re making a distinction, especially between those now—happily, something I’ve argued for, for a long time. Between adenocarcinoma and squamous, the main drugs are cisplatin and Paclitaxel for squamous and cisplatin and pemetrexed for adenocarcinomas. And then—it’s especially with the adenocarcinomas that you find these molecular abnormalities—EGFR, ALK, and drugs that can be used in patients with those abnormalities.
Tacey Ann Rosolowski, PhD:
Were there some studies during this period and also during the lymphoma period that you were particularly excited about or surprised by? James Cox. MD Surprised by—I don’t know that there were studies in cancer of the lung that were particularly surprising. The combination of radiation therapy and chemotherapy for small-cell lung cancer was very gratifying—it was not surprising.
Tacey Ann Rosolowski, PhD:
And the results there were—?
James D. Cox, MD:
—were a lot better than they had been with the previous studies, but still they have a long way to go. With small-cell carcinoma, you could probably cure somewhere between a quarter and a third of the patients, but that leaves an awful lot of patients where there was a long way to go. And then the other area that we focused on—from the patterns of case studies—was looking at brain metastases, and finding that with small-cell carcinoma of the lung, the frequency of brain metastases was extremely high. If we gave very modest doses of radiation therapy to the brain when there was no obvious evidence of brain metastases, then that would decrease—greatly decrease the risk of brain metastases. Ultimately, when the large trials were done—and they were done jointly between institutions in Europe and the Unites States—it turned out that that so-called prophylactic cranial irradiation actually improved survival, which again was a surprise—not to me—but to a lot of my colleagues in medical oncology. They were very surprised. They thought that the irradiation of the brain carried a grave risk of neuropsychological problems. We studied that prospectively. Dr. Komaki was the lead person on that. Who did that neuropsychological study? I’m blanking on her name. They did it before and after and found that there wasn’t very much effect from the brain irradiation. But the patients with small-cell carcinoma had abnormalities at the very beginning before any treatment, which was a new finding.
Recommended Citation
Cox, James D. MD and Rosolowski, Tacey A. PhD, "Chapter 10: Lung Cancer and Uncommon Lymphomas" (2013). Interview Chapters. 792.
https://openworks.mdanderson.org/mchv_interviewchapters/792
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