Chapter 13: Studies of Concurrent Radiation and Chemotherapy in Lung Cancer
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Description
In this chapter, Dr. Komaki talks about a series of studies she conducted with James Cox, MD between 1988 and 1999 to compare the effects of sequential versus (the more effective) concurrent treatment of small cell lung cancer with radiation at various frequencies and chemotherapy. She explains the various treatments studied and the significance of the results. She explains that the most effective concurrent treatment plan created side effects and these discouraged clinicians in private practice from accepting and prescribing this course of treatment, despite its improved outcomes for treating the cancer. She goes into detail describing the different dosages studied.
Identifier
KomakiR_03_20181219_C13
Publication Date
12-19-2018
Publisher
The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center
City
Houston, Texas
Interview Session
Topics Covered
The Interview Subject's Story - The Researcher; The Researcher; Definitions, Explanations, Translations; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Discovery and Success
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Disciplines
History of Science, Technology, and Medicine | Oncology | Oral History
Transcript
T.A. Rosolowski, PhD:
What were some other studies that you started in those early years when you were transitioning from the gynecologic work into lung cancer?
R. Komaki, MD:
I have done studies of how to combine radiation treatment with chemotherapy. Since medical oncologists were so interested to see the response of lung cancer to chemotherapy, [the chemotherapy was given upfront for several months or one year till the tumor started to grow]. When it did not shrink or metastasized to lymph nodes or some other place, we gave radiation treatment. My emphasis was to give chemotherapy and radiation treatment at the same time. It’s more beneficial, because cisplatin has radiation sensitization effects because break through of a double strand of DNA by radiation treatment, is not always predictable. It does not break through the double strand, maybe just one strand, which we call it sublethal damage. Cisplatin has the same effect of DNA strand breaking through, so if we add cisplatin with radiation, then we can break the double strand better, so cancer doesn’t come back. Which is better? To go induction chemo followed by radiation for a stage II, unresectable lung cancer patients? Or to give concurrent chemo and radiation treatment? That’s the randomized study we have done. When I came here in 1988, there was already an ongoing study: that was Jim Cox, he was the PI, giving radiation treatment twice a day with concurrent chemotherapy, to spare normal tissue but to kill cancer cells by giving adequate dose to the cancer, and comparing one steady fractionation with concurrent chemo. That’s the study, it was ongoing.
T.A. Rosolowski, PhD:
And this was also a lung cancer study.
R. Komaki, MD:
Yeah, that’s correct. Then, we started to do sequential versus concurrent, and then we put the twice daily fractionation with concurrent chemo as a third arm. So a three-arm study. This was open at the MD Anderson. Also, around the same time, I started to do small-cell limited stage, small stage lung cancer study here. That was eighty-eight fifteen, ECOG and RTOG, and some SWOG, with all those collaborative study groups to get together. Limited small cell lung cancer, it’s not so common compared to non-small cell lung cancer. It’s only 15 percent of entire lung cancer. Limited stage is more rare because small cell lung cancer, it grows so fast, dividing --we call it doubling time, in only a few weeks, the number of cancer cells will be double. So they spread very quickly, and 85 percent of the small cell lung cancers, they already have metastasis. But the 15 percent of small cell lung cancer patients, they do have limited stage: that means in the thorax and the lymph nodes it metastasizes, but does not spread in the brain or other distant site metastasis. Small cell lung cancer, very frequently metastasizes to the brain. Small cell lung cancer has this attraction to the brain. So I started to do prophylactic cranial irradiation (PCI) for small cell lung cancer patients. That was one of the trials we have done, with and without PCI, and that PCI group was the winner since PCI improved outcome of the patients. The other one, going limited small cell lung cancer patient, like twice daily radiation treatment, versus once daily fractionation, with etoposide cisplatin. This was published in New England Journal of Medicine, on August 1, 1999. The first author, Dr. Andrew Turrisi, and I was collaborator, because I put so many patients from MD Anderson Cancer Center. So this trial, giving radiation treatment within a short time, within three weeks, giving twice daily radiation treatment, 1.5 Gray twice a day, with five hours inter-fractional intervals, giving total dose 45 Gray within three weeks, no treatment Saturday and Sunday, with etoposide cisplatin versus 45 Gray daily fraction 1.8 Gray daily fraction, five days a week and going 45 Gray five weeks with etoposide cisplatin. That’s the comparison we did. There were four hundred patients analyzed. As I said, limited small cell lung cancer is not common, so it took a long time to finish up this trial. The patients who received twice daily fractionation, within three weeks they were the winner in regards to their survival in five years. That was 26 percent overall survival in five years. And the other group who received 45 Gray over five weeks showed 16 percent of 5 year overall survival . The difference in the 5 year over all survivals were significantly different (p<0.05). So, the winner was twice daily. But this trial could not convince private practitioners at non-academic institutions to give twice daily treatment. Nobody wanted to do twice daily fractionation, so I had to give talks all over United States. I showed you the results, randomized trial supported by NCI. Why are you not doing twice daily fractionation? They said that acute esophagitis, grade three or four, was significantly higher by twice daily radiation therapy compared to once daily treatment because small cell lung cancer metastasizes to the mediastinal lymph nodes, and it’s almost impossible to avoid to radiate the esophagus. The epithelium of the esophagus is very sensitive to radiation, so if you combine radiation with cisplatin, which is a radio sensitizer, they usually develop terrible esophagitis when the cancer involves multiple levels of mediastinal nodes . The grade three, that means they had to get the feeding tube to support their nutrition because they could not swallow the food, with more than 10 percent weight loss. So, grade three or four, four means they have to be hospitalized and with terrible esophagitis and sometimes they have to put in a feeding tube. So, they were so scared. Private practioners do not want to cause toxicity. They can die from cancer --because as I mentioned, cancer of the lung equal to death-- so dying from cancer is okay, but causing severe esophagitis and to be hospitalized with pain medication or a narcotic, morphine through the IV, that’s a no, no. So, private practice, they didn’t want to do twice daily fractionation. We can do it at MD Anderson, not to cause that kind of toxicity, because we have sophisticated planning and we have dosimetrists and a great physics group, and I check every tiny detail, predicting the volume or predicting grade three or four esophagitis, and if that will be too long a segment we have to do. Sometimes we have to give induction chemotherapy to shrink it down, and then give twice daily radiation treatment. So I know how to separate, select out those patients just because we have so many patients. We can select them out, but some of the institutions, small places, they cannot select out.
T.A. Rosolowski, PhD:
It’s an amazing example of what academic medical centers could bring.
R. Komaki, MD:
Correct, that is correct. So even now, we have so many randomized studies, but certain things they cannot do at the private practice. I feel sorry for them, but I learned from Dr. Juan Del Regato, wherever you are, whatever you can get, that’s what you have to do: the best for the patients. Sometimes they cannot participate in a trial because they don’t have enough patients to select out, but from this trial, shorter time with concurrent chemo is better than prolonging radiation treatment. Although 45 Gray given over five weeks, we call it biological equivalent dose (BED) was much lower compared to within three weeks, 45 Gray. That was a much higher dose, equivalent dose. That was 110 BED, compared to like a hundred BED given over five weeks. What we have learned from our prospective randomized trail, was that radiation treatment should be given within a certain time, especially for a fast growing type of cancer, without causing too much toxicity, that’s the best way to treat cancer. Now, we have evidence. If the cancer is small enough, we can do stereotactic body radiation treatment, (SBRT) or Stereotactic Abrasive Body Radiotherapy (SABR). Of course, you have to do all the diagnostic validation variations. They can’t have any lymph node metastasis or brain metastasi. If that’s the one spot, we can zap it with radiation treatment without causing normal tissue toxicity. That’s very effective to get rid of that cancer, so that’s the way we are moving possibly with immunotherapy.
T.A. Rosolowski, PhD:
Interesting, yeah.
R. Komaki, MD:
Non-smoking, that will make better outcome, and early detection. Early stage lung cancer we can cure. And the important thing, the local control with SBRT, or sometimes they call it stereotactic abrasive body radiation treatment (SABR). That’s the same thing: zapping the tumor instead of using knife by the surgery. We can use radiation, killing cancer cells, but some of the patients, they do develop distant metastasis later on, because we cannot cure a hundred percent of those patients. The majority of our patients who were treated by SBRT are not candidates for surgery because of their chronic obstructive disease (COPD). Terrible diabetes not controlled by medication, cardiac problems, or very elderly patients. If you get a 95 year old patient with lung cancer in a tiny spot, what do you do? We can treat this elderly patient by radiation treatment rather than opening the chest, but their outcome regarding over all survival after SBRT, it is not so great compared to surgery, because surgical patients, physically fitted without medical problems. Very young patients without COPD or other medical problems of course, they can have better over all survival. More and more, we are combining in those patients, SBRT with immunotherapy, which might be very successful. Eventually, we can do SBRT plus immunotherapy, compared to maybe surgery plus immunotherapy, randomized study. Yeah.
T.A. Rosolowski, PhD:
Very interesting, yeah, I mean it’s amazing.
R. Komaki, MD:
Yeah. Small cell lung cancer, right now an ongoing study …I was PI until I retired at the end of—well actually, my retirement was August of this year, tenure position. But what we are doing was 45 Gray --I’m talking about limited stage small cell lung cancer, giving etoposide cisplatin for three weeks. Forty five Gray over three weeks was the winner from previous study, compared tp 45 Gray for five weeks, with etoposide cisplatin. However, ECOG, the Easterm Clinical Oncology Group, insists that 70 Gray over 7 weeks is better than 45 Gray over three weeks, from their phase II trial. I said that small cell lung cancer, most of them, 90 percent that’s rapidly growing. Once you go beyond six weeks, whatever we could not kill --we call it clonogens-- that will start to regrow and we cannot control the regrowth of the cancer, proliferation of the chromatin. It’s a very, very bad prognosis. It will metastasize and even if we go eight thousand, seven, nine thousand centigrade, we cannot control the growth. So we have to finish this radiation treatment within a certain time. That was already done for the head and neck. If you prolong treatment, those bad clonogens start to grow, so you have to give over a certain duration to kill cancer cells. If we ould not kill certain bad genes, clonogens, you have to do something else to remove it or immunotherapy, or maybe chemotherapy if that works. But we have to realize why we cannot kill cancer a hundred percent. Those cancer cells, when we see even one centimeter cubic, it is so inhomogeneous, they are not exactly the same. Some of them have really, really bad behavior, so you really have to select out which ones we can kill. And if we cannot kill them, use radiation treatment or combined some sensitizer. We really have to do something else. More and more we are trying to do molecular targeted. You know, if [a patient has] adenocarcinoma of the lung and never smoked, the women usually, those EGFR-mutated patients, like 19 (inaudible) or 21 mutation, those patients, they do respond to ERISA or TASIVA. Those are pills, and it just disappears. But that’s a whole genetic mutation, and they have a tendency to go to the brain or bone. This mets, because they have incredible susceptibility, some carcinogen, we don’t know what, but usually those are women from China or a genetic mutation they have. So we have to select them out.
T.A. Rosolowski, PhD:
Absolutely. I’m looking at the time because we’re almost at noon and I’m going to need to close off for today.
R. Komaki, MD:
Okay, okay.
T.A. Rosolowski, PhD:
I didn’t mean to shut you down.
R. Komaki, MD:
No, no, no, you have to go.
T.A. Rosolowski, PhD:
Yeah. We can set up another time to talk more, that will be great, because I know you’ve gotten involved with so much and we haven’t even talked about the Proton Therapy Center.
R. Komaki, MD:
I know, I know.
T.A. Rosolowski, PhD:
We need to do that, and we will need to do that.
R. Komaki, MD:
After January third, we’re going to be refreshed, I hope your cough goes away by that time.
T.A. Rosolowski, PhD:
Absolutely. Well get something on the calendar. That sounds good.
R. Komaki, MD:
Yeah, we’ll set it up, January.
T.A. Rosolowski, PhD:
That sounds great. So, I wanted to thank you.
R. Komaki, MD:
Thank you.
T.A. Rosolowski, PhD:
And say for the record—and thank you for the cookies and the tea.
R. Komaki, MD:
Thank you for telling me about your background.
T.A. Rosolowski, PhD:
Oh, sure.
R. Komaki, MD:
And somebody who is interested in foie gras, I am so happy to talk about cooking.
T.A. Rosolowski, PhD:
Oh, and I’ll get you that website, there we go. So I’m saying for the record, I’m turning off the recorder at about eleven fifty-eight.
Recommended Citation
Komaki, Ritsuko MD and Rosolowski, Tacey A. PhD, "Chapter 13: Studies of Concurrent Radiation and Chemotherapy in Lung Cancer" (2018). Interview Chapters. 1294.
https://openworks.mdanderson.org/mchv_interviewchapters/1294
Conditions Governing Access
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