Chapter 15: Research to Compare Proton Therapy with Standard Radiation Treatment
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In this chapter, Dr. Komaki discusses the clinical trials designed to study the value of proton therapy in comparison to standard radiation treatments. She notes that it was the goal that every patient treated at the Proton Therapy Center be involved in a clinical trial. She explains her reasoning: that there was no other way to establish standard of treatment with this relatively new therapy. She also explains that the lack of insurance reimbursement for treatment (with the bill to the patient being between 200 and 700 thousand dollars) was an obstacle to running trials.
Dr. Komaki also recalls that both surgeons and medical oncologists had objections to proton therapy, and she explains her responses to them. She then explains that the results of clinical trials over the last thirteen years has helped convince clinicians to accept proton therapy.
Dr. Komaki then talks about the results of a randomized phase 2 trial comparing proton therapy with IMRT. She notes that patients treated after 11 September 2011 did significantly better and explains that this date marks the period when MD Anderson became compliant with National Cancer Center Network [NCCN] guidelines for dosage and volume for normal tissue. She comments briefly on the reorganization of regional radiation oncology groups and sketches a comparative study they are not collaborating on to determine overall survival rates. Dr. Komaki then notes that patients are requesting proton therapy as their tolerance of chemotherapy is better than with standard radiation therapy. She explains that she sees the difference in patients.
Dr. Komaki then talks more about the increasing acceptance of proton therapy among medical oncologists, attributable to the fact that the treatment planning teams now include a radiation oncologist who can interpret and explain the proposed radiation treatment plans.
Next, she talks about attempts to promote proton therapy, including an initiative to allow pediatric patients to be treated for free. She also explains that MD Anderson purchased the fifty percent share of the Center controlled by private investors and has plans to build a second center behind the first. This center will be equipped with special imaging to address problems of tumor motion during therapy. Finally, she explains some her concerns about carbon ion radiotherapy (and all special particle treatment), a treatment that is gaining in acceptance internationally, and which will also be studied at the new center.
Identifier
KomakiR_04_20190123_C15
Publication Date
1-23-2019
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; Discovery and Success; Definitions, Explanations, Translations; Overview; Research; The History of Health Care, Patient Care; The Business of MD Anderson; The Institution and Finances; Technology and R&D
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:
Did you initiate some studies, because as I understood, weren’t pretty much all the patients who were receiving proton therapy also on some kind of clinical trial?
R. Komaki, MD:
Yeah, yeah.
T.A. Rosolowski, PhD:
So what were your studies, what were you looking at?
R. Komaki, MD:
You know, before we started to use proton for our patients in 2006, I did chemo first, followed by radiation, or concurrent chemo/radiation treatment since I came to MDACC in 1988. Or if we gave combined chemo/radiation treatment twice a day it’s better in regards to the radiation treatment. That’s the kind of trials I have initiated though RTOG or MDACC for the Lung Cancer. I was always trying to make the radiation work better than just regular radiation. I started to do a radiation sensitizer study, and also I did an amifostine study to reduce normal tissue toxicity. Amifostine is a radiation protector.
T.A. Rosolowski, PhD:
What’s the name again?
R. Komaki, MD:
Amifostine.
T.A. Rosolowski, PhD:
Amifostine.
R. Komaki, MD:
Yes. A-m-i … Amifostine. So that’s the studies I have done. Then on the trial of the proton, I helped to initiative IMRT versus proton treatment, a randomized study.
T.A. Rosolowski, PhD:
Were these pediatric patients?
R. Komaki, MD:
No, no, no, those are adults. I don’t treat pediatric patients. [Also randomized trials were not required or not necessary for the pediatric patients since proton was approved by insurance company for pediatric patients. This means there is obvious less normal tissue toxicity by proton treatment especially late normal tissue toxicity. However insurance companies did not cover proton treatment for adult patients with the Head/ Neck, Lung, Esophageal, Pancreatic, other GI, GYN and GU malignancies.] I was the section chief of Thoracic Radiation Oncology. The outcome of the lung cancer patients are so bad, so my goal was that every patient with lung cancer treated at MDACC should be treated on one of the trials, so we’ll learn from the results. If we don’t treat the patient on a trial, it’s very difficult to figure out what worked for the patients or what will be the standard treatment. Without any trials, there are all different kind of prognostic factors and we have to stratify, depending on cell type, stage,age and performance status. That’s the way we can figure out what worked and what should be the standard treatment. Therefore you have to go step by step to establish standard treatment. When I said, “You know this proton treatment should work in theory, to spare skin and the other surrounding normal tissue,” everybody said, ”How do we know?” I said, ”Okay, we have to do a randomized study.” But the randomized study was very difficult because insurance companies denied proton treatment for lung cancer and other adult cancer except for recurrent cancer and prostate cancer. If the patient was 65 or older, who had Medicare, we could treat them. Medicare approved. They paid for proton treatment for elderly patients. But the young patients who really needed proton treatment to spare normal tissue because their life expectancy is much longer, they did not have any approval for proton unless they paid by cash. We couldn’t get those patients younger than age 65 to be on the trial.
T.A. Rosolowski, PhD:
What was the cost of the treatment at that time?
R. Komaki, MD:
Approximately $150,000-$200,000. Yeah, yeah it was not cheap. [ ] The surgeons and the medical oncologists were totally against proton treatment. Also, the surgeons said, “surgery is much cheaper than the proton treatment.” They did not have any concept about proton how it works. Some of medical oncologists were scared to death to get proton for their patients. They thought that proton might explode, like it’s a nuclear weapon or something, because nobody really had experience with proton treatment. This is clinical proton treatment, the first one done in North America. They had a proton center at Loma Linda and also at the MGH. At MGH, they were treating benign adenoma of the brain or aneurysm in the brain, really more experimental. But our institution is the first institution to use proton for clinical applications for lung cancer, esophageal cancer and head/neck cancer in 2006. Nobody really had done anything on prospective clinical trials or treat a lot of patients without any previous radiation therapy. Proton treatment was used for terminal recurrent cases or experimental application.
T.A. Rosolowski, PhD:
So it’s been about 13 years since the center opened.
R. Komaki, MD:
Yeah.
T.A. Rosolowski, PhD:
And in that time, what kinds of results have you seen, and has the acceptance within MD Anderson and elsewhere changed?
R. Komaki, MD:
It changed a lot. The first prospective proton trial was published in JCO, Journal of Clinical Oncology, January this year. It took a long time to complete this trial, because of the slow accrual. It’s a randomized phase II trial. The primary endpoints were local control and severe pneumonitis. Then, secondary endpoint was overall survival. [ ] There were about 400 patients entered, but the variable patients, there were 250 patients (inaudible), and there was no difference in the overall survival. The local control and severe pneumonitis rates, they are very similar between IMRT and the proton, with concurrent chemotherapy. The most important findings from that study was that the patients who were after September 11, 2011 did significantly better in regards to the local central and severe pneumonitis rates. The time point was very important in both the IMRT group and the proton group. So what made the difference at that point in September 2011? I think that we started to be very compliant to the NCCN guidelines: I was a member of NCCN Guidelines Committee.
T.A. Rosolowski, PhD:
What does NCCN stand for?
R. Komaki, MD:
National Cancer Center Network. Dr. David Ettinger, is the chair of NSCLC NCCN guidelines. We have NCCN guidelines of every site, and I have been involved with non-small cell lung cancer NCCN Guidelines Committee over the past ten years. So what we have to do? Every year we have to update the guidelines based on pertinent published references. The NCCN NSCLC Guideline Committee is consist of pathology groups, surgical groups, radiation oncologists, medical oncologists --they were all experts in North America. Patients advocacy has been included. We put the most important standard treatment based on the prospective randomized study as category IA. That’s from a randomized trial showing significant difference in survival without any argument among the guideline committee members. Category II A and B means that Category IIA is good based on the phase II trial, but it’s not a randomized trial. Category II B is controversial, a lot of discussion. Category III is not a prospective study, but it’s based on review articles or something strongly recommended. And if we put the NCCN guideline Category IV, then it’s not a standard treatment at all. So we categorize our recommendation as the NCCN Guidelines and we have to update every year.
T.A. Rosolowski, PhD:
So how was that having—because I’m not seeing how that had an impact on patient outcomes.
R. Komaki, MD:
You know why?
T.A. Rosolowski, PhD:
No.
R. Komaki, MD:
To create NCCN Guidelines requires so much strict review of the published papers based on improvement of survival, local control and normal tissue toxicities. And if we follow lung cancer --non-small cell lung cancer (NSCLC)-- NCCN Guidelines, it said that volume (V) of 20 Gray more than 40 percent showed a very high risk developing severe pneumonitis. When we combine with radiation and the concurrent chemotherapy, therefore we have to limit V-20, less than 40 percent [to avoid severe pneumonitis. Once patients will develop severe pneumonitis, there is not much effective treatment other than steroid. The prevention is the most important to reduce severe pneumonitis.] NCCN guidelines show that dose volume limit for the organ at risk when we treat lung cancer such as V40 less than 40 percent for the heart, maximal point dose 45 Gray for the spinal cord. So each normal tissue has dose volume constraints. That’s what we started to follow these guidelines very strictly. Every patient, we discussed at the new patient conference at Thoracic Radiation Oncology. That was starting 2011, September, and we went very strictly, we have to follow this guideline and that made a difference.
T.A. Rosolowski, PhD:
So you started getting—how did the outcomes for proton and the standard therapy change as a result of that?
R. Komaki, MD:
It made a significant difference for the severe pneumonitis rate, local control rate, in both IMRT and the proton. But when you compare the results of patients treated by IMRT vs. Proton both time periods before and after September 2011, there was no significant difference. So right now, at the NRG –RTOG since they have changed RTOG to NRG, since NSABP, RTOG and GOG, merged to call it NRG rather than RTOG. The NCI, they couldn’t handle 11 corporate groups doing separate trials , so we merged from 11 corporate groups, down to six. Pediatric [Oncology Group, South Western Oncology Group (SWOG)], and ECOG-ACRIN Group. There are a couple others. At NRG now, we have prospective randomized study going on: IMRT with concurrent chemo and proton treatment, with concurrent chemotherapy for patients with inoperable or unresectable NSCLC. This is truly a randomized phase III trial to look at overall survival difference. The previous prospective Bayesian Method phase II study had 99 percent of the patients from MDACC, so that was our trial. And MGH, they put just three patients treated by IMRT. Since we started the proton center, there have been 20 proton centers created in North America. We asked them to put their patients on this trial, so that’s an ongoing study now. $$
T.A. Rosolowski, PhD:
What do you think about the proliferation of the proton therapy centers? Do you think that all cancer centers need to have one? I mean, it’s an enormously expensive enterprise. What’s your view of that?
R. Komaki, MD:
Okay. The price is coming down because now, the equipment has become smaller. Also, the cost is less and the insurance approval became a little bit more reasonable. Some of the patients had recurrence of lung cancer after surgery where they did not approve proton treatment. So the denial by the insurance company became less and less, so we can get more patients for proton treatment. Also, those patients who received proton treatment, they started to advocate proton treatment. Not only because of better local control, but also the tolerance to chemotherapy was is much better when the patients were treated by proton. We checked all those patients’ blood counts after the proton and chemotherapy, and their blood count did not go down, because there was not much low dose scattering to the bone marrow. So their tolerance to the chemotherapy afterwards was much better. We are all human beings and the immune system is very important to keep up T-cells function, and [theoretically their immune system should be that’s much better among those patients who are treated by proton since their lymphocyte count did not go down compared to those who were treated by IMRT although this was based on the retrospective study in our institution]. The patients, they get all this information and it is obvious, those patients who … I have had it both ways: the IMRT patient and the proton patient, and the proton patients, they never get tired toward the end of six weeks of radiation treatment or seven weeks of radiation treatment by proton. They don’t have much difficulty in swallowing or a terrible cough or shortness of breath and their blood count did not go down. Every day, we see those patients who are treated both ways, and we have to review those patients once a week, and you can see the difference. Is that just a difference of the performance status, to start with? We stratify, so they should be the same way to start with: performance data and weight loss it’s the same. But when they are getting treatment, the proton patients, they are so active and they don’t feel so tired. How we can convince the people that patients treated by proton will do better? The bottom line, we have to show that overall survival is better, so that’s the ongoing study.
T.A. Rosolowski, PhD:
So what’s been the acceptance rate within MD Anderson, I mean are the surgeons responding the same way?
R. Komaki, MD:
Yes, it is much better. Some of our medical oncologists, at the beginning, didn’t want their patients to get proton treatment, just because at the beginning, they had to wait till their insurance companies approve the cost coverage. At the beginning , we had to wait for the insurance approval almost two months --and lung cancer grows. We cannot wait, and so they said “Okay, forget about this proton treatment, we’ll go just IMRT.” This was true among some of our radiation oncologists. Now approval times are getting shorter and shorter. Since directors of insurance companies, general internists or surgeons, they don’t know anything about the differences of the radiation treatment modalities --between proton and IMRT. So now, they refer the case to a radiation oncologist, and that made it much faster for the approval or denial of proton treatment. And more expert people, they look at the plan. We send both plans, IMRT versus proton, and they show the difference between proton and IMRT overlapped, and it is obvious. The dose to the heart and the lung and the spinal cord, that’s significantly lower compared to IMRT. Internists or surgeons do not understand the meaning of these lines which we call dove volume histogram. But the radiation oncologists know the difference. So it became shorter for the approval of the insurance company. And some of the patients heard about the good results or less toxicities treated by proton from friends or family members. They advocated proton treatment, so they want proton treatment. Yeah. In that case, we could not randomize them since they want proton treatment.
T.A. Rosolowski, PhD:
Right.
R. Komaki, MD:
Yeah, and that’s another problem we are facing. They believe in proton treatment and they want to be treated by proton, and we cannot randomize. Sometimes it happened that when I had a patient, and when he was randomized to IMRT, he said, “Take my name off of the randomized study, I would like to get the proton treatment.” We talked to them about the randomization and some of them, they agreed, but some of them, they said, “Don’t put me in randomization, I believe in proton, so put me proton treatment.” We have a lot of patients like that.
T.A. Rosolowski, PhD:
Yeah, interesting, interesting. Is there a plan to kind of aggressively promote proton therapy?
R. Komaki, MD:
Yes.
T.A. Rosolowski, PhD:
Tell me about that.
R. Komaki, MD:
Okay. Especially young patients. We are trying to get all the pediatric patients treated by proton free, free no charge, like Saint Jude’s Hospital. That’s one thing. The other one is that MD Anderson bought this proton center from the private investment business people, so now the proton center belongs to MD Anderson a hundred percent. Now they are planning --and they just had the ground-breaking ceremony for proton center two. They are going to create the proton center two, number two, just behind the current proton center.
T.A. Rosolowski, PhD:
And let me just say for the record, for whoever is using this interview, the narrative, the business narrative of the Proton Center is in Leon Leach’s interview and also Amy Hay’s and Jim Cox’s as well talks about it. Yeah, that discussion of how the finances were arranged has been recorded.
R. Komaki, MD:
Right, right, right.
T.A. Rosolowski, PhD:
So that’s interesting. So the second center is going to be right behind the first, the original
R. Komaki, MD:
Right, right.
T.A. Rosolowski, PhD:
And what’s the expansion in to that area going to be like?
R. Komaki, MD:
We are going to get more image oriented, because when we treat, say a lung cancer patient, we have to make sure the tumor motion will be controlled. Proton is very focused, so if the patient is breathing, the tumor will move. We cannot miss the tumor because of the motion due to patients’ breathing. The capability of imaging during the proton treatment and immediately after proton treatment to verify the site of treatment is very important. This imaging capability is not there at the Proton Center right now.
T.A. Rosolowski, PhD:
Are you working at all with the Center for Advanced Biomedical Imaging, the CABI?
R. Komaki, MD:
Yes, we are, we are.
T.A. Rosolowski, PhD:
I mean, I was just thinking about the conversations I had with Donald Podoloff [oral history interview] about this.
R. Komaki, MD:
Cancer of the esophagus, we send the patient for the MRI and yes, we do.
T.A. Rosolowski, PhD:
Are they helping with this new technology that’s going to put into the second proton therapy center?
R. Komaki, MD:
Yes, they are. Then, so the second facility, proton center, we’re going to put imaging capability, immediate imaging capability, by looking at the image, and that’s the place we’re going to treat. They are also thinking about putting proton treatment and possibly the carbon ion equipment.
T.A. Rosolowski, PhD:
And what’s the advantage of that?
R. Komaki, MD:
Well, carbon ion would be more effective compared to proton if the tumor is big or an osteosarcoma, or a soft tissue sarcoma, since there is hypoxia right in the middle of the tumor.
T.A. Rosolowski, PhD:
Right.
R. Komaki, MD:
The proton, the RBE, the radiobiological equivalent dose, is same as x-ray, or photon treatment, and if there is hypoxia, the proton does not overcome it. If the tumor is small enough that’s okay to use this x-ray or proton since we have to use oxygen, and free radicals to kill cancer cells. The best thing of heavy particle treatment is to overcome hypoxia, that’s --we call it high LET, linear emission transfer, like a neutron or carbon ion.
T.A. Rosolowski, PhD:
Are you saying carbon ion?
R. Komaki, MD:
Carbon or heavy particle. CO-2, carbon ion. That overcomes hypoxia. In Japan, they do have this carbon ion facility in Chiba, and they really are pushing us to use carbon ion. Osteosarcoma and soft tissue sarcoma, there is evidence it works, but we don’t know if it works for lung cancer or pediatric patients. Our concern about the carbon ion is the late normal tissue toxicity. They have never really published on the late effects of carbon ion, because they have high LET. It scares me, because we have had neutron, which had high LET. We used to treat the patients --prostate cancer, cancer of the cervix, and some head and neck, parotid gland tumor-- and they developed incredible late normal tissue toxicity, especially subcutaneous fibrosis. Their pelvic wall was like this, [knocks on the table] hard, hard wood, and they discontinued [neutron]. This went way back to 1980. Dr. Lester Peters and Dr. David Hussey, they were doing a NCI supported grant, a randomized study, neutron versus x-ray treatment, and they had to discontinue because of the late effects on normal tissue toxicity without evidence of effectiveness to improve patients’ survival. When I came here as a fellow in 1980, they were doing a randomized study. When I came back as an attending, 1988, they still had the neutron facility but they were not using it anymore. [Dr. Ito from Japan as a post doctoral fellow under Dr. Podoloff at the Nuclear Medicine Department of MDACC produced PET scan from that equipment which I used to identify lung fibrosis to separate out tumor recurrence for the lung cancer pateints treated by radiotherapy. But the maintenance was too expensive] costing $2 million a year, so they just totally discontinued the Neutron. They were treating originally, patients by the neutron at College Station.
T.A. Rosolowski, PhD:
Right. I think I remember you telling about that, yeah.
R. Komaki, MD:
Right. It’s a big concern we have regarding [late effects on the normal tissue by Carbon Iron treatment.] Maybe it doesn’t make any difference if we are treating a tiny, tiny spot in the lung, because very small legion, less than 1.5 centimeter cubic centimeter, you can do anything: surgery or SBRT stereotactic body radiation, carbon ion, or proton, because the rest of the lung will compensate, so you don’t see any dysfunction. But once it gets big enough, what’s the best way to treat? Carbon ion, we have to watch out for toxicity and maybe they’re going to start GBM or head and neck, the tumors not significantly surrounded by critical organs. Maybe they can use some carbon ion treatment for osteosarcoma of soft tissue sarcoma. We have to do something better treatment about GBM, cancer of the pancreas or hepatoma. But whether special particle treatment resolves this problem or not, that’s a big question. Of course, Sumitomo and all the equipment companies, they would like to sell this equipment. At Stanford, they are getting carbon ion, that’s what they are thinking.
T.A. Rosolowski, PhD:
Interesting.
R. Komaki, MD:
Second proton center is on the way.
T.A. Rosolowski, PhD:
Yeah, interesting. What’s the ground breaking for that do you think, have they set a date for it?
R. Komaki, MD:
I think they already did it.
T.A. Rosolowski, PhD:
Oh okay, so it’s open?
R. Komaki, MD:
No, no, no, ground breaking, that’s starting like a building.
T.A. Rosolowski, PhD:
Right. So I don’t know.
R. Komaki, MD:
It will take two years from now to build.
Recommended Citation
Komaki, Ritsuko MD and Rosolowski, Tacey A. PhD, "Chapter 15: Research to Compare Proton Therapy with Standard Radiation Treatment" (2019). Interview Chapters. 1296.
https://openworks.mdanderson.org/mchv_interviewchapters/1296
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