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0:00 - Segment 00B: Interview Identifier

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Partial Transcript: "This is Tacey Ann Rosolowski, and today I’m at the Proton Therapy Center in the office of Dr. James Cox, and we’re in our second session. The time is about 11:25, and the date is April 12, 2013. So thank you Dr. Cox for agreeing to do this session. We were strategizing before I turned on the recorder and decided that today would be a good day to devote to the discussion of the research that you have done. I’m hoping that we can go back to fairly early—the research that you first conducted when you first came to MD Anderson and even if there’s a relevance in tracing the roots of that in your previous positions and tracing the evolution of that research career and story."

Segment Synopsis:

Keywords:

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1:01 - Segment 08: Clinical versus Basic Research; Focusing Research on Patterns of Failure Studies

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Partial Transcript: "We were strategizing before I turned on the recorder and decided that today would be a good day to devote to the discussion of the research that you have done. I’m hoping that we can go back to fairly early—the research that you first conducted when you first came to MD Anderson and even if there’s a relevance in tracing the roots of that in your previous positions and tracing the evolution of that research."

Segment Synopsis: Dr. Cox begins the discussion of his research career with his residency. He explains that hypotheses in clinical research derive from the care of patients. Survival is the “immutable endpoint” that determines whether a treatment is successful, but survival does not tell you why a treatment is successful. Early in his career, Dr. Cox developed an approach to determine why treatments succeed, though he observes that many of the questions he asks about patterns of failure are irrelevant from other perspectives (e.g. medical oncology).

Next Dr. Cox describes studies done in the 70s with lung cancer to determine why treatments failed. When he became involved in the Radiation Therapy Oncology Group (RTOG) his style of designing studies influenced the group. All of the ROTG studies during his ten years with the group used survival as the endpoint. Returning to his residency years, Dr. Cox talks about his studies of cancer of the breast and cervix.

Keywords:

Subjects: 1. Segment Code - A: The Researcher 2. Story Codes - A: Overview A: Definitions, Explanations, Translations B: MD Anderson Culture C: Healing, Hope, and the Promise of Research C: Patients, Treatment, Survivors C: Professional Practice D: On Research and Researchers D: The History of Health Care, Patient Care D: Understanding Cancer, the History of Science, Cancer Research

13:29 - Segment 09: Research Focused on a Range of Body Areas

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Partial Transcript: "Uh-hunh (affirmative). How did that focus [on patterns of failure in radiation treatments] evolve as you began to undertake your own studies that you can see from the beginning?"

Segment Synopsis: Dr. Cox summarizes the range of research he administered on fractionation while involved with the RTOG: lung cancer, head and neck cancers, cervix and brain. He also discusses the key importance of adding chemotherapy to patients’ treatment regimens to get the best results.

Dr. Cox next explains that while he was Chair of the RTOG he was able to move combined treatments forward in the NCI and other organizations. He explains why the NCI is biased toward chemotherapy. He also comments on NCI politics is influencing how gynecologic cancers will be investigated.

Dr. Cox next comments on other cancer studies he oversaw during the period when he was Vice President for Patient Care under Dr. Charles LeMaistre [Oral History Interview].

Keywords:

Subjects: 1. Segment Code - A: The Researcher 2. Story Codes - A: The Administrator A: Definitions, Explanations, Translations A: Overview C: Professional Practice C: The Professional at Work D: On Research and Researchers D: The History of Health Care, Patient Care

33:29 - Segment 10: Lung Cancer, Uncommon Lymphomas, and Other Cancers

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Partial Transcript: "When were you able to return to design your own studies or collaborate very closely in more than a facilitative role in doing studies?"

Segment Synopsis: 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.

Keywords:

Subjects: 1. Segment Code - A: The Researcher 2. Story Codes - C: Discovery and Success A: Definitions, Explanations, Translations A: Overview B: Devices, Drugs, Procedures C: Healing, Hope, and the Promise of Research C: Patients C: Patients, Treatment, Survivors C: The Scientist at Work D: Understanding Cancer, the History of Science, Cancer Research

58:31 - Segment 11: Documenting the Benefits of Proton Therapy

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Partial Transcript: "Uh-hunh (affirmative). Now when you said surprised or that you weren’t surprised, it sounds to me that you weren’t surprised because you really believe in the ability of radiation to do this. Am I interpreting that correctly?"

Segment Synopsis: Dr. Cox explains a difficulty with proton therapy: the advantages can be seen on paper and modeled by computer, but “we don’t yet have the evidence that people want.” He describes the kinds of treatment advantages that proton therapy provides, particularly the reduction of toxicity.

Dr. Cox explains a study showing that proton therapy avoided toxicity in treatment of 15 patients with cancer of the tongue, then describes the next step of this research: to demonstrate the differences between two dimensional and three dimensional, conformational therapy. He explains that proton therapy offers these advantages because the beam can be targeted to hit very isolated structures.

Keywords:

Subjects: 1. Segment Code - A: The Researcher 2. Story Codes - A: Overview A: Definitions, Explanations, Translations B: Devices, Drugs, Procedures C: Discovery and Success C: Healing, Hope, and the Promise of Research D: On Research and Researchers

67:47 - Segment 12: Multidisciplinary Conferences at MD Anderson Lead to More Effective Treatment Plans

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Partial Transcript: "What were the discussions like with your collaborators in figuring out how to do this?"

Segment Synopsis: Dr. Cox notes that proton therapy treatment focuses heavily on lung cancer and lists other cancers being studied, explaining that the study of esophageal cancer puts all the modalities together. This leads Dr. Cox to talk about the Tumor Board and Thoracic Conference –weekly multi-disciplinary meetings where specialists from different disciplines discuss cases and treatment options for patients. He explains that surgical techniques have improved so much that surgery is now also being integrated into the treatment modalities. He then describes the history of the conferences, which go back to the earliest years of MD Anderson and have proliferated through the entire institution. Dr. Cox describes how these meetings educated everyone, e.g. by having specialists from a wide range of fields talk to a radiologist, a pathologist, or someone conducting research on molecular markers. (He acknowledges that attendees are self-selected).

Keywords:

Subjects: 1. Segment Code - A: The Researcher 2. Story Codes - B: Building/Transforming the Institution A: The Clinician B: Institutional Mission and Values B: Institutional Processes B: MD Anderson Culture B: Multi-disciplinary Approaches C: Patients D: On Care

0:00

ROSOLOWSKI:

This is Tacey Ann Rosolowski, and today I'm at the Proton Therapy Center in the office of Dr. James Cox, and we're in our second session. The time is about 11:25, and the date is April 12, 2013. So thank you Dr. Cox for agreeing to do this session. We were strategizing before I turned on the recorder and decided that today would be a good day to devote to the discussion of the research that you have done. I'm hoping that we can go back to fairly early—the research that you first conducted when you first came to MD Anderson and even if there's a relevance in tracing the roots of that in your previous positions and tracing the evolution of that research career and story.

ROSOLOWSKI:

We were strategizing before I turned on the recorder and decided that today would be a good day to devote to the discussion of the research that you have done. I'm hoping that we can go back to fairly early—the research that you first conducted when you first came to MD Anderson and even if there's a relevance in tracing the roots of that in your previous positions and tracing the evolution of that research

COX:

Well it starts back as early as my residency, and it is all clinical research. Now a side comment about clinical research is that it is not very highly respected academically.

ROSOLOWSKI:

Yeah, you were talking about the last time we spoke.

COX:

So for somebody to spend a career doing that, you could say, "Well, that's a lot of wasted time." And it is if you look at it from the point of view of a basic scientist, where to design a discrete experiment in the laboratory, carry it out over a period of weeks or months or maybe a couple years, and then have a paper to write or more papers to write because the research has been based on a specific hypothesis. Now in clinical research, I think the hypothesis derives, at least to a considerable degree, from the care of patients. And I think in caring for patients, one comes up against questions that are not adequately answered. One can develop a hypothesis about what that might be.

ROSOLOWSKI:

Can you give me an example?

COX:

Well an example that goes back far but also comes to the present time is when people do clinical trials, the ultimate endpoint is survival. And that is an immutable endpoint. Nobody can argue with being alive or dead. Any of the other endpoints are less crisp, I guess—they're not as definitive. Well that tells you whether you have been successful in a certain kind of treatment, but it doesn't tell you anything about why. And so early on I developed an approach that said, "Okay. If we're failing in treatment, why are we failing? Is it because we have not eradicated the local tumor? Is it because if we were treating with radiation therapy, we have not had a large enough field so the tumor's recurred at the margin of the field that we treated? Or the tumor has spread." Now in some quarters—and I think this is true in much of medical oncology—those questions are immaterial because their paradigm for the treatment of cancer is leukemia, which is disseminated from the very beginning. And so they don't find it very useful to ask about patterns of failure. But I've been doing that all of my career, and I can continue to be doing that with the proton effort now. We've uncovered some interesting things. If you fail to eradicate the local tumor, is it because the dose—I'm talking now entirely about radiation therapy—is it because the dose was not enough? Or was there uncertainty in the dose distribution? And of course disseminated disease speaks for itself. Well I started to this with cancer of the lung in the 1970s.

ROSOLOWSKI:

What prompted you to begin asking questions in that way?

COX:

It was, in part, my training. It was, in part, the discussions with Dr. del Regado, my mentor. He didn't frame it in the way that I just did, but he did ask, "Why did we fail?" And that's an important question. It's an important question for anybody that's dealing with local treatment. It would be a similarly important question for a surgeon who's trying to remove a tumor and ideally remove it all. Or the sidelight of it is the consequences of treatment, the toxicity, the functional deficits. So that's another side of the treatment equation. And so having an approach to that—as far as research strategies are concerned—when I became involved with the Radiation Therapy Oncology Group in the very late 1970s, I brought those questions to the group, and over time that helped color some of the research that went on with the group. Although all of the phase three studies that were designed at the time when I led the group during that ten-year period, all of them had survival as the endpoint. Now that is not true at the present time. It's not true in studies that are being done here, but still I contend that it's the ultimate endpoint. Still it doesn't give you the answer of why you succeed or fail. And you're happy to succeed so you pass that off, but if you fail, there's a reason. And as time went on, I guess that carried some weight as far as being selected to become chair of the RTOG.

ROSOLOWSKI:

Uh-hunh (affirmative). When you were a resident, what were the studies that you were doing that helped you frame this approach?

COX:

One of the studies I was doing had to do with cancer of the breast. Another one had to do with cancer of the cervix, actually very early cancer of the cervix—what's now called—well we call it carcinoma in situ. It now goes primarily by the title intraepithelial neoplasia—what's this?

ROSOLOWSKI:

Shall I pause the recorder? Do you need to—

COX:

No. Okay, I know what they need. I have to do something.

ROSOLOWSKI:

Okay, I'll just pause the recording.

COX:

Yeah.

[The recorder is paused.]

Tacey Ann Rosolowski Ph,D Let me just get this back on. Okay, we're recording again. So you were talking about the breast and cervical cancer that you were working on as a resident.

COX:

Uh-hunh (affirmative).

ROSOLOWSKI:

And what were the studies that you were running? What exactly were you doing?

COX:

Well they had treated a series of patients with intraepithelial neoplasia with radiation therapy at that time which was not—this is in the very, very early days of treatment of intraepithelial cancer of the cervix. The standard treatment was hysterectomy . We were trying to spare patients a hysterectomy and give them an opportunity, actually, to still bear children. And so it was not my hypothesis, but that of my mentor, that you could do this with very localized radiations delivered only to the cervix. So I pulled all those patients together, wrote them up. It was a retrospective study. It was prospective on his part, but for me it was just gathering the data. Now interestingly, the study that we were doing on cancer of the breasts was to go back and review all of the patients that had been treated at the Penrose Cancer Hospital and have the path reviewed and try in a very primitive way at that time to understand better the findings in pathology that would predict recurrence or no recurrence. Unfortunately, that never got completed because my mentor was interested in something else, and we just never got it completed.

ROSOLOWSKI:

What was the—

COX:

But it was the discussions with him about that, whether it was with lymphomas or whether it was cancer of the prostate. All of those were situations where we asked that question. In about 1983, actually, I had a symposium at the Medical College of Wisconsin that was published in a NCI—it wasn't called an NCI monograph—I think it was called Cancer Treatment Symposium. We had some funds to invite some people from around the country, and many of the people working in cancer came and addressed this issue—patterns of failure. It was published. Many people have told me over the years that it was a really remarkable body of data because we asked them to come not just with opinions; we asked them to bring data. They did, and it was a rich resource. But that was a carryover of this effort on patterns of failure.

ROSOLOWSKI:

Uh-hunh (affirmative). How did that focus [on patterns of failure in radiation treatments] evolve as you began to undertake your own studies that you can see from the beginning?

COX:

Well the other area of interest—and they kind of went together—was the area that's called fractionation. That is—you split up the dose of radiations that you give a patient to exploit the differences between the cancer cells ability to—the inability of the cancer cells to recover between doses of radiation and the ability of normal tissues to recover. And if you don't give too big a dose at one time, you can exploit that difference. So I was working in that area.

ROSOLOWSKI:

And what kind of cancer?

James Cox MD That was primarily cancer of the lung, head and neck, cervix. It seems to me there was another—brain. This was in the context of the RTOG by that time, and we mounted a series of trials looking at fractionation and found that some fractionation experiments just didn't seem to help. Others, and cancer of the lung, did seem to help.

ROSOLOWSKI:

When I was looking at the array of body areas that you focused on, they're so different. I'm wondering what—I'm sure this is a terribly naive question—but what are the unique challenges that each of these areas of the body presents to the radiation oncologist?

COX:

Well the challenges are similar for each of the areas, and that is basically to improve the control of the tumor locally because radiation therapy is a local treatment means. And so that went together with the patterns of failure analyses. For many, there are disease sites where you're trying to improve the tumor locally. As it turned out, a much more important approach, which did not come from our work—that came from the work of people in the Netherlands adding chemotherapy simultaneously with radiation therapy and then comparing that with radiation therapy alone. It turned out that that was a much more powerful way to approach controlling the disease than the altered fractionation. That's proven to be true in many disease sites. One of the first ones was cancer of the esophagus and then cancer of the lung, head and neck, cervix, and all these areas where we did the chemotherapy and radiation therapy at the same time. The chemotherapy plus concurrent radiation therapy was better than radiation therapy alone, and that was measured by survival in every case.

ROSOLOWSKI:

What were some of the figures that you came up with—the survivorship rates?

COX:

Well for example, one of the biggest ones—and this didn't come from the group in the Netherlands as a starter—was cancer of the esophagus, where the results with radiation therapy alone, with relatively high doses, were poor—very poor. Well, when we did the randomized trial, at three years no patient was alive that was treated with radiation therapy alone, and a lesser dose of radiation combined with chemotherapy led to a survival of about twenty-five percent, which is a long way from what you would like it to be, but it's very different than zero. And so that was one of the ones. Later on we did head and neck, initially looking at preserving the larynx—preserving function and later on looking at survival.

ROSOLOWSKI:

Now were these all accommodations with chemo, or did you also work with people in surgery on this?

COX:

The one for head and neck was with the surgeons because if there wasn't a very favorable response by a certain point in time, then they would go on to a laryngectomy.

ROSOLOWSKI:

Uh-hunh (affirmative). I think I remember talking to Dr. [Kent] Gifford about this.

James Cox MD Right. He was very much involved. Dr. [Kie Kian] Ang was very much involved.

Tacey Ann Rosolowski PhD Tell me about that collaboration. When did that take place, and what exactly did you do for that study?

COX:

Well, in the RTOG they had done a study in the Veterans Administration system where they compared chemoradiation—where they did chemoradiation for cancer of the larynx that otherwise would be completely removed—the larynx would be removed. So if they did chemoradiation and there was a favorable response, then they would go on to pursue chemoradiation and avoid surgery. If there was not a favorable response, they would proceed to surgery. So that was the study that was done largely by Dr. Ang and the Veterans Administration system. We took one step back from that and said, "Well, if we did chemotherapy and radiation therapy together, would it be better than radiation therapy alone?" And it did prove to be better. The chemoradiation was better primarily in larynx preservation because if that failed, they went on to laryngectomy, and the survival was pretty much the same in both groups. One of the interesting things that we did that involved very much the investigators at MD Anderson—and I will give you the expurgated view of that—was to look at concurrent chemoradiation for cancer of the cervix, and a disease that is pretty curable with radiation therapy of the lung. And it turned out that the chemoradiation was clearly superior. That has now become the standard throughout the world.

ROSOLOWSKI:

When were those findings made?

COX:

Oh I think that was published in—those findings were published in the early 1990s. And that's become a standard ever since.

ROSOLOWSKI:

Who were your collaborators on that project?

COX:

Well actually I was chairing the RTOG, so officially I wasn't a collaborator. Although Dr. Eifel would acknowledge that I did a huge amount of work in moving that forward, both within the RTOG and within the National Cancer Institute because all of those studies had to be approved by part of the NCI called the Cancer Therapy Evaluation Program and within that a branch called the Clinical Investigations Branch. They were not as sympathetic to what we were doing as we wanted them to be.

ROSOLOWSKI:

Why was that?

COX:

But eventually they came around.

ROSOLOWSKI:

And was that—I think you mentioned last time that there was a bias in the NCI and maybe other organizations towards surgery and chemo. Am I remembering that correctly?

COX:

Well, at the NCI it's a bias primarily toward chemo because the cooperative groups were started to investigate leukemia.

Tacey Ann Rosolowski PhD Oh, I see. Okay.

COX:

Since the vast majority of the physicians at NCI are medical oncologists and a handful—a small handful are surgeons, and an even smaller group are radiation oncologists, the view of the chemotherapy lobby, if you will, is vastly stronger.

ROSOLOWSKI:

Were the sources of resistance to the treatment you were proposing in this study different, or did that come from the same bias?

COX:

They were different in one way. The RTOG didn't have an NCI approved actual committee on gynecologic cancer. There was a separate cooperative group—the gynecology, oncology group—that was doing those studies. And from the NCI perspective, all of those studies ought to be done by that group and not by the RTOG. I had to lobby very hard to get it started by the RTOG and even to get it continued because in the middle of all this, we had a once-every-five-year review. There was a chance that they would make us close down the study. But they didn't, fortunately. But it did require a lot of effort, both within the group and within NCI. It was highly successful. Another one that was done, which again, in this case, didn't involve a big survival advantage because, like the larynx study, you could do surgery afterwards, and it would help correct the failure. That was for cancer of the anal canal, and there the goal was to avoid colostomy. There was a separate trial in cancer of the nasopharynx where surgery doesn't come into the picture at all, but radiation therapy is quite effective. Perusing chemotherapy and radiation therapy at the same time led to a much better result with cancer of the nasopharynx. So we had all of these series of trials that were carried out—either started or came to fruition during the period that I chaired the group. A lot of them were published afterwards.

ROSOLOWSKI:

So this sounds like a really, really fruitful time for MD Anderson work, certainly.

COX:

It was. And the interesting part of that is going back to when I first came here, and the position I was in—vice president for patient care—I think I related to you that it turned out to be, from my view, not a very satisfactory position. The thing that kept me sane was the research efforts with the RTOG.

ROSOLOWSKI:

Now tell me about setting up the connections with these different researchers during that unsatisfying period when you were VP, but nonetheless obviously helping to forward these collaborations and careers of other MD Anderson faculty.

COX:

Well it was generated from the radiation oncologists and the surgeons. The medical oncologists were not the primary players during that time in these studies.

ROSOLOWSKI:

Why do you think that was? Why do you think medical oncology was—

COX:

Well, they were involved, but they were not testing new drugs, so it was not of paramount interest to them. Their goal, by and large, is to test new drugs and try to see if they get better results. Sometimes the results are only measured in the shrinkage of a tumor, then to have it return rather quickly. Or, in patients that have widespread disease, to improve survival by a matter of weeks or a few months. So the endpoints for drug studies are very different than the endpoints for radiation studies. We do not consider response an important endpoint. Local control of the tumor within the field of irradiation becomes the primary endpoint for radiation studies.

ROSOLOWSKI:

So you were saying it was the radiation oncologists and the surgeons who were really the prime movers behind this. So who are some significant people that you (???)(inaudible, speaking at once) connections with.

COX:

Well in the head and neck arena, it was Dr. Ang—Kian Ang—and Helmuth Geopfert [Oral History Interview]. The collaboration has always been—well almost always—it depends on far back you want to go. But in recent years, there's always been a strong collaboration between the head and neck surgeons and the radiation oncologist. And so Geopfert was a champion with us along with Kian Ang, Moshe Maor. And then in the lung studies, it was Dr. [Wuan Ki] Hong [Oral History Interview] and as far as feeding into them, Dr. [Jack] Roth in surgery, and then Dr. [Ritsuko] Komaki. The three of them served as a resource for the implementation of these trials. There were a few other medical oncologists involved—Jin Soo Lee, who is now in a leadership position in a cancer center in South Korea. Then in the cervix area it was Patricia Eifel in radiation oncology and Mitch Morris who left the institution years ago to pursue a career. He was the gynecologic oncologist who was most involved with the cervix studies. In fact, the publication that came out, he was the first author. Then he went off in the field of information technology. That interested him. I don't think he ever practiced after that, but I don't know for sure. But he was very actively involved. And then—what else? Those were the main ones where positions from MD Anderson were very actively involved in these studies.

ROSOLOWSKI:

When were you able to return to design your own studies or collaborate very closely in more than a facilitative role in doing studies?

COX:

When I returned to the full-time faculty in 1992. So after four years in the position of vice president for patient care and position 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.

ROSOLOWSKI:

And what did you do in the studies?

COX:

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.

ROSOLOWSKI:

So that sounds like—was the discovery of that marker really significant?

COX:

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?

ROSOLOWSKI:

Do we need to pause?

COX:

No, let me see.

ROSOLOWSKI:

Okay.

COX:

Sorry.

ROSOLOWSKI:

That's all right. So the other areas of your work in lymphoma were—?

COX:

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—

ROSOLOWSKI:

What's the orbit?

COX:

Eyes. Where the eyes—

ROSOLOWSKI:

In the eyes. Okay. Uh-hunh (affirmative). And you said small bowel?

ROSOLOWSKI:

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.

ROSOLOWSKI:

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.

COX:

That's right.

ROSOLOWSKI:

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?

COX:

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.

ROSOLOWSKI:

And what were the results that you were able to get from that?

COX:

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.

ROSOLOWSKI:

And obviously without surgery and preserving function—

James Co,x MD Right—with no surgery. That was one example.

ROSOLOWSKI:

And the dates around the time that you were doing these unusual lymphomas?

COX:

I would say it was between about '92 or '93 up until about 2000.

ROSOLOWSKI:

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.

COX:

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?

COX:

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.

ROSOLOWSKI:

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.

COX:

Uh-hunh (affirmative).

ROSOLOWSKI:

So it's just fascinating how that was evolving and being put together by all these different—

COX:

—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.

ROSOLOWSKI:

What are some other significant studies that you were working on in the '90's and—I'm just continuing your research story.

COX:

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.

ROSOLOWSKI:

Maybe I should just ask you, what are the figures for lymphoma and lung cancer nationwide? Is it increasing? Is it decreasing?

COX:

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.

ROSOLOWSKI:

And that's the highest death rate among all the cancers?

COX:

Uh-hunh (affirmative).

ROSOLOWSKI:

Wow.

COX:

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.

ROSOLOWSKI:

Is there any sense about why that is?

COX:

There's a lot of speculations.

ROSOLOWSKI:

Are you willing to share some of those? (laughs)

COX:

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)

ROSOLOWSKI:

Right. But those obviously have huge agricultural—

COX:

And so that's one connection. That's the main one that comes to mind for me.

ROSOLOWSKI:

So in the early '90s you focused on lymphoma and then later lung.

COX:

Uh-hunh (affirmative).

ROSOLOWSKI:

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?

COX:

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.

ROSOLOWSKI:

What are the drugs that are used?

COX:

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.

ROSOLOWSKI:

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.

ROSOLOWSKI:

And the results there were—?

COX:

—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.

ROSOLOWSKI:

Uh-hunh (affirmative). Now when you said surprised or that you weren't surprised, it sounds to me that you weren't surprised because you really believe in the ability of radiation to do this. Am I interpreting that correctly?

James Cox MD Well, I don't know if I believe it. I take it back, you're probably quite right. (laughter) I'm in a situation now—and you're going to want to come to that eventually—where proton therapy, because we can see the advantages on paper or in the computer, we can see that the dose distributions that avoid normal tissues have to decrease the risk of complications because it avoids the tissues where complications occur. But we don't have the evidence that people want and they're in a great hurry for—comparing protons versus x-rays.

Tacey Ann Rosolowski PhD Uh-hunh (affirmative). Talk to me about what you are seeing on paper and on computer that creates these advantages.

COX:

Well, you're seeing that you're able to spare normal structures. For lung we're able to spare the lung, the normal lung—and the heart and the esophagus better than we can with even the most sophisticated x-rays, which would be IMRT or intensity-modulated radiation therapy. Is that going to play out in the advantage of either reducing toxicity or improving tumor control? I think the main difference there is going to be a difference in survival because I think it's going to be a combination of controlling the tumor and avoiding toxic effects on the lung. But in head and neck, Steven Frank, one of my colleagues, is taking the lead in treating patients with cancer of the oropharynx—that's tonsil and base of tongue, mostly tonsil and base of tongue—tonsillar fossa and base of tongue, showing that by using protons with the scanning beam, he's able to avoid toxicity in the tongue. When they treat such patients with IMRT, they have to spread the dose out, so a lot of the dose goes into the oral cavity. That is incredibly adverse in terms of altering people's lives—interfering with the quality of life. He has shown with just a handful of patients—15 patients—that there's an ability to avoid that toxicity in the oral cavity that is very striking.

ROSOLOWSKI:

And his name again?

COX:

Steven Frank.

ROSOLOWSKI:

Thank you. What was the research that you did after the lung studies in the '90s or continuing with them into the 2000s that brought you to the interest in the proton center or in proton therapy?

COX:

Well, I'm not sure that the lung studies brought me into the interest in the proton center. Actually the study—that I didn't do, it was done by other people at MD Anderson—that shed the greatest light on showing the difference between the older kind of 2D treatment versus a 3-dimensional conformal therapy to a higher total dose showed that the patients who were treated to the higher total dose did better in terms of biochemical freedom from progression, and that was one of the earliest studies that showed that difference. Then it seemed obvious that by avoiding the normal structures that caused toxicity when treating cancer to the prostate and giving a higher dose, you can improve survival. Then on paper or in the computer, proton therapy is the ultimate way to do it—maybe not the ultimate way, but a way very different than anything that can be done with x-rays because protons stop and can be made to stop wherever you want them to stop in the body. And so that was the genesis in my interest in proton therapy because I knew that in the future so much more could be done. And then, when we started developing the portfolio of clinical investigations for proton therapy, cancer of the lung was at the top of my list because I thought we could make a lot of progress there, and we have, but we don't have enough patients treated in comparison with IMRT that have been followed long enough to say anything.

ROSOLOWSKI:

How would you like to proceed next? Because obviously there's lots going on with the Proton Therapy Center and the research in the different studies, but I want to make sure that we fill in the blanks so that we know how you moved up to working with that. Do you feel we've covered the research that you've done prior to the Proton Center adequately? Or are there some other studies you'd like to mention?

COX:

Well, we could talk for a long time about all of those studies. I think we've covered it generally. It was a mix. If you look at the overlap if you were to try a Venn diagram, you would see the studies that were being done in the RTOG overlapping that were being done at MD Anderson. In lymphoma there was no overlap, but with lung there was a great deal of overlap. Then I got directed into studies also of cancer of the esophagus, which really is a story of putting all modalities together of the surgery and the radiation therapy and the chemotherapy—chemotherapy and radiation therapy being given at the beginning, and then following that was surgery.

ROSOLOWSKI:

What were the discussions like with your collaborators in figuring out how to do this?

COX:

Well, we have a tumor board that's—we can call it a tumor board. We have a thoracic conference every Tuesday afternoon, and then they have a separate conference on cancer of the esophagus at noon on Tuesday, and discussions in those groups with the interested parties and the people who are actually treating the patients. Those kind of interchanges led to the efforts in that direction—and some efforts that were done really didn't make it very much effect. For example, induction chemotherapy turned out not to be very valuable. Chemoradiation is very valuable prior to surgery. But it's so effective, some have argued, "Well, do you need the surgery at all?" And in the past I would have argued, "Probably not." But the surgeons have become so good, and they can do that surgery, which is really, really big surgery, in a very sophisticated way and avoid most major complications—that having surgery, to me, as part of the equation is very compelling.

ROSOLOWSKI:

When did these weekly conferences start? Maybe I should ask, how did they start?

COX:

Well no, the very earliest ones started in the early years of MD Anderson treatment. There were two groups—the gynecologic oncologist and the radiation oncologist. That was one. And the head and neck surgeons and the radiation oncologist, that was another. In both cases, the medical oncologist didn't play very much of a role. The thoracic conference started right around the time that we arrived, and it started—it was a joint effort between Dr. Hong, Dr. Roth, and Dr. Komaki.

ROSOLOWSKI:

And what was the logic for them?

COX:

There were two pieces that—many patients required at least two, if not all three disciplines involved. And secondly, and this was Dr. Roth's and Hong's strong push, that every patient ought to be on protocol; every possible patient should be on a study.

ROSOLOWSKI:

Did some people disagree with that?

COX:

There were some people who didn't care. They wouldn't object, but they weren't going to go out of their way to do it, but they were influenced by that conference. And whether it was Dr. Roth in surgery who—very, very highly respected person. The other surgeons in the department then, they couldn't really object to it very easily. The same thing is true with Dr. Hong. And the same thing is true with Dr. Komaki. Now, since that time, those kind of conferences have proliferated throughout the whole institution. There are ones dealing with brain and spine and sarcoma. The various GI sites—colon.

ROSOLOWSKI:

And what do they add to patient care and then also to the intellectual drivers of research?

COX:

They add a lot. To patient care, sometimes they help make a determination of the best way to treat the patient. And it evolves in a discussion. It's not obvious. We were, I guess, trying to figure out where to go next. Is that right?

ROSOLOWSKI:

Well, I actually was hoping you would say a bit more about these conferences and what they added.

COX:

Oh the conferences, yeah.

ROSOLOWSKI:

Because you said that first of all it helped make a determination about the best way to treat patients.

COX:

And plus it helped support the clinical research activities of enrolling the patients on treatment. Plus, it was educational for everyone when we had some of the people who are expert—including the pathologist—who are expert in these molecular markers, in the biomarkers. That's something that is not discussed very much in the radiation oncology community here or nationally. But it was an ongoing education, and pretty much all—the medical oncologist, some more than others—Dr. Tsao, Anne Tsao, Vassiliki Papadimitrakopoulou, Merrill Kies—all of these people in the discussions about molecular abnormalities, and are there drugs that can be used that are directed toward them. All of that was a great education for the rest of us that attended the conference. So it had an educational, a patient care advantage, and then it had a clinical research advantage. So all of the conferences go in those directions.

ROSOLOWSKI:

Now is it self-selecting who attends those?

COX:

Yes.

ROSOLOWSKI:

Because I'm just—

COX:

It is.

ROSOLOWSKI:

Yeah, as you were describing it, I'm thinking you really have to have an openness to be there. And would you say that those conferences attract a certain type?

COX:

Yes.

ROSOLOWSKI:

And how would you characterize that person?

COX:

Well they attract a certain type, and if you have an hour in the middle of the day or at the end of the day, somebody has to ask themselves, "Is it valuable to go to the conference or should I stay at my desk and get caught up on all the things that I have to do?" So there are a lot of people who never come, and there are some people who come most of the time, and there are a handful of people who are there all the time unless they're out of town. And the other advantage is that there's usually a pathologist and somebody from diagnostic imaging at each one of those conferences. So it's not just the treatment side, but it's also the path and the diagnostic imaging side. And all of that's educational too. I think I get a great deal out of going to those conferences. And I really encourage our residents to go to them, but they are now pretty much all over the institution and all of the major disease-site areas.

ROSOLOWSKI:

Do you think they've affected the culture of MD Anderson at all?

COX:

Yes.

ROSOLOWSKI:

How so?

COX:

Well I think multidisciplinary care of the cancer patient is a hallmark of MD Anderson. It's not that it's not done other places, but it's not done as readily and willingly—it's not embraced with the same degree of commitment at other places than it is here. Now part of that is also the financial structure of MD Anderson, where all of the positions are salaried. So at these conferences, there's no economic incentive for somebody to recommend something other than that which is best for the patient. So doing something which is best for the patient, that has not only benefits for the patient, but it has benefits for the institution because then—I don't know how many thousands of times I've heard people want to go to MD Anderson because it's the best and they know that they're going to get the best care. And in many cases, they know they're going to have input from anybody that can help. I very frequently tell patients when I see them first, "We function as a team. We're a multidisciplinary team and we're going to call upon anybody at the institution to consult that would be an advantage for you as a patient." And they've come to—so that has become the culture. And that's a big change over the time when I first came here. Now the thing that's missing is that there's some groups—and we probably ought to talk about some of this off the record—(laughs)

ROSOLOWSKI:

Let me know when you want me to—

COX:

—but there are some groups that talk to themselves and have convinced themselves of something, but they're ignored nationally because they're just not considered—the work that they're doing is not considered cutting edge or broadly relevant or suitable for export into the community. And I can give you examples of that—but later. (laughs)

ROSOLOWSKI:

Understood. So I'm trying to get a sense of the balance or the evolution. When you arrived, how was the culture different from what you see now?

COX:

More frequently than today, the people in a discipline or in a disease-site area were talking just to each other. They were not even talking to the people outside the institution. Now with my coming, I brought the institution into the RTOG. That included the surgeons and the medical oncologist and, of course, colleagues in radiation oncology. I think that had a favorable effect on the institution. It really got the discussion of what they were doing much more broadly throughout the cancer world outside of MD Anderson.

ROSOLOWSKI:

I can see why you see the RTOG and the work at MD Anderson as being part—

COX:

They're linked.

ROSOLOWSKI:

Yeah, they're very linked.

COX:

—very strongly linked. Now there are groups—there are a handful of positions that are involved with the Southwest Oncology Group. I think that's the only—oh, of course, the Gynecologic Oncology Group, the GOG. But now they're restructuring the cooperative groups at the National Cancer Institute level, and there are certain groups that are going to be forced to fit together. They don't necessarily include all of the groups that might be of greatest interest to the RTOG or MD Anderson. We'll have to see how that goes. It's in its early phase of development and it's very much a work in progress that it's hard to know if it's going to be at all successful.

ROSOLOWSKI:

Uh-hunh (affirmative). We're almost at noon and earlier you said you need—

COX:

Yeah, I'm going to have to go.

ROSOLOWSKI:

Okay. All right. Well thank you for your time today.

COX:

We're at a pretty good stopping point I think.

ROSOLOWSKI:

Okay. And I'm turning off the recorder at 12:00 noon.

COX:

Okay, great.

(End of Audio 2)