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Should Randomized Clinical Trials Be Required for Proton Radiotherapy? An Alternative View

Authors:
Should Randomized Clinical Trials Be Required for
Proton Radiotherapy? An Alternative View
Eli Glatstein, Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA
John Glick, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
Larry Kaiser, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA
Stephen M. Hahn, Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA
The great tragedy of Science—the slaying of a beautiful hypoth-
esis by an ugly fact.
—T.H. Huxley
Recently, an editorial in the Journal of Clinical Oncology (JCO)
1
offered reasons why there have been no randomized prospective clin-
ical trials that compare proton beam radiation therapy to conven-
tional photon x-ray therapy. Herein we offer an alternative view on the
need for randomized clinical trials.
The facts offered by Goitein and Cox are incontrovertible in that
the dose distribution of proton therapy is superior that of to x-rays.
The question really has to do with whether or not these facts translate
into measurable benefits for patients, and how significant those gains
may be. The editorial in question alluded to a prior article in JCO by
Brada et al,
2
in which data were reviewed for a number of treatment
sites and a conclusion was made that there was no evidence to dem-
onstrate an obvious superiority of protons over photons, despite the
confidence that Drs Goitein and Cox express for the superiority of
proton treatment. Although the analysis performed by Brada et al does
not lead one to make definitive conclusions regarding the clinical
benefit of proton therapy, it does raise important questions that our
field must answer. Most important is the necessity of performing
randomized clinical trials of proton therapy versus conventional
x-rays. Given the fact that the analysis by Brada et al does not show
clear evidence of a clinical superiority for protons, then it is difficult, in
our opinion, to see why it would be “unethical” to perform such
randomized trials.
Goitein and Cox believe that the superiority of protons rests
largely on an improvement of the dose distribution that will almost
certainly make for less morbidity. Exploiting that improvement in
treatment-related toxicity suggests that dose escalation is feasible and
that an improvement of local control should follow. Though local
control is important, it is not clear that this will affect overall survival at
all, which is, in our opinion, still the most important end point.
Nonetheless, there is a potential for clinical benefit to be derived from
proton therapy compared with conventional x-rays, either from dose
escalation and improved local control and/or survival, or from re-
duced treatment-related morbidity, especially in children. Another
important consideration is the potential for increased secondary can-
cers from proton therapy that has been postulated on a theoretical
basis by Hall
3
in a recent article. Of course, Hall makes such predic-
tions on the basis of a scattered proton beam, which is not the most
modern technology available. The scattered beam is almost certainly
going to have a higher rate of induced cancer than a scanning beam,
which is now in use in Switzerland and is considered state-of-the-art
treatment. All of these conflicting concerns highlight the importance
of determining the benefit from protons in well-designed, random-
ized clinical trials.
In our opinion, some of the largest gains for protons are likely to
be found in conjunction with other modalities, such as surgery and
chemotherapy. The fact that the dose is confined and that normal
tissue will see a considerably lower dose suggests strongly that
combined-modality treatments will be much easier to carry out with
protons than with photons. We think it is essential for the radiation
oncology community to think more in terms of combined-modality
treatment rather than radiation therapy alone. Indeed, at the moment,
significant improvements in survival have taken place over the last
several years in randomized controlled studies for breast,
4,5
lung,
6,7
head and neck,
8,9
cervix,
10
and rectum
11
; all of these studies exploited
combined-modality treatment rather than single-modality treatment.
We believe this trend toward multimodality treatment ultimately
yielding improvements in survival will continue, and we think that
proton treatments will facilitate that to a major degree. Enhanced
effects on the tumors but without overlapping toxicities should make
for such improved outcomes. The only conclusive way to demonstrate
this, however, is with carefully constructed randomized prospective
clinical trials.
Goitein and Cox argue that it is difficult to present this option to
the patient. The fact that it is difficult does not mean that it is impos-
sible; no one ever said it was supposed to be easy. There is no doubt
that conducting a randomized clinical trial is difficult, as many pa-
tients come with a preconceived idea about the treatment they are
seeking. This, in particular, has been the case in trials in which patients
are randomly assigned to a surgical procedure or nonsurgical treat-
ment in situations where the benefit of operation is unclear. Despite
the contention by Goitein and Cox that protons are superior to pho-
tons, it is fair to say that there remains enough uncertainty in the
medical community that randomized clinical trials can be justified. In
fact, such trials are on strong ethical ground based on the principle of
clinical equipoise, a situation that exists when there is collective pro-
fessional uncertainty about treatment.
JOURNAL OF CLINICAL ONCOLOGY
COMMENTS AND CONTROVERSIES
VOLUME 26 NUMBER 15 MAY 20 2008
2438 © 2008 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 26, No 15 (May 20), 2008: pp 2438-2439
DOI: 10.1200/JCO.2008.17.1843; published online ahead of print at www.jco.org on April 28, 2008
Copyright © 2008 by the American Society of Clinical Oncology. All rights reserved.
Downloaded from jco.ascopubs.org on May 20, 2008 . For personal use only. No other uses without permission.
The secret in doing a randomized clinical trial that is controver-
sial is that the investigators really have to want to do it. They have to
spend time explaining it to patients. They have to explain the other
options and go into details about the potential differences in morbid-
ities. Not every patient will agree, but we think it will be possible to
carry out perhaps two or maybe three randomized studies that look at
protons versus photons. These studies will have to be well designed,
and, where appropriate clinically, they will need to be multimodal.
Why is it important to do such studies? Most importantly, we
want to deliver treatments to our patients that have measurable ben-
efits. Patients depend on us to recommend therapies based on evi-
dence, typically derived from well-designed clinical trials. In addition,
the new treatments are expensive. We cannot and should not make
light of this fact. In some instances governments want to know
whether there really is an advantage to protons because, without
demonstrating such an advantage, they would be unwilling to invest in
the new technology. Third-party payers want to know if they really
need to support such a treatment or not. A randomized study is one
way to get the answer that they need. This not only has implications for
third-party payers, but also for their subscribers: the patients and those
who are ultimately going to be patients.
It can be argued that intensity-modulated radiation therapy did
not go through such a clinical trial. The reason for that is that the
proliferation of intensity-modulated radiation therapy technology
was so rapid that it was available to virtually every radiation oncologist
overnight (and thus every patient) before a randomized study could be
done. In our opinion, that was unfortunate. This inability to perform
the randomized trials has hurt our field within the broader medical
community, whether we admit it or not. The enormous expenditures
to build a proton center at the moment mean that during the next 5 to
10 years, there will be a relatively small number of facilities that have
proton beam therapy.
12
The rest of the radiotherapeutic community
will be interested in the outcomes to see if they really need to obtain
such technology. It is likely that well-designed clinical trials that ran-
domly assign proton beam therapy to patients would be supported by
the National Cancer Institute and possibly even third-party payers
themselves. To accrue the required numbers for such studies would
probably require a concerted effort from virtually all the major centers
where proton beam therapy is available. We believe this would be a
good thing.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
AUTHOR CONTRIBUTIONS
Collection and assembly of data: Eli Glatstein
Data analysis and interpretation: Eli Glatstein
Manuscript writing: Eli Glatstein, John H. Glick, Larry R. Kaiser,
Stephen M. Hahn
Final approval of manuscript: Eli Glatstein, John H. Glick, Larry R.
Kaiser, Stephen M. Hahn
REFERENCES
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radiotherapy? J Clin Oncol 26:175-176, 2008
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clinical practice: Current clinical evidence. J Clin Oncol 25:965-970, 2007
3. Hall EJ: Intensity-modulated radiation therapy, protons and the risk of
second cancers. Int J Radiat Oncol Biol Phys 65:1-7, 2006
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22:2246-2250, 2004
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Comments and Controversies
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Copyright © 2008 by the American Society of Clinical Oncology. All rights reserved.
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... In the medical literature animated debates have been held on the necessity or ethical justification of randomized controlled trials to test proton beam therapy [66][67][68][69] . Given the fact that systematic reviews fail to demonstrate clear evidence of a clinical superiority for protons, it is difficult to understand why it would be unethical to perform randomized trials 67,69 , except in those cases where there are manifest anatomical and physical reasons against the use of photons (e.g. low-grade glioma, craniopharyngioma, skull base chordoma and skull base osteosarcoma). ...
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... In de medische literatuur zijn geanimeerde debatten gehouden over de noodzaak of de ethische verantwoording van gerandomiseerde gecontroleerde studies om de klinische effectiviteit van protontherapie aan te tonen. [66][67][68][69] Gezien het feit dat systematische literatuuroverzichten geen duidelijk bewijs van een klinische superioriteit van protontherapie hebben kunnen aantonen, is het moeilijk te begrijpen waarom het onethisch zou zijn om gerandomiseerde studies uit te voeren, 67,69 behalve dan in die gevallen waar er manifeste anatomische en fysieke redenen zijn tegen het gebruik van fotonen (bijv. laaggradig glioom, craniofaryngeoom, chordoom van de schedelbasis en osteosarcoom van de schedelbasis). ...
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We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P=0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P=0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P=0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)
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For patients with locally or regionally advanced non-small-cell lung cancer radiation is the standard treatment, but survival remains poor. We therefore conducted a randomized trial to determine whether induction chemotherapy before irradiation improves survival. All the patients had documented non-small-cell cancer of the lung with Stage III disease established by clinical or surgical staging. Eligibility requirements included excellent performance status, minimal weight loss, and visible disease on radiography. Patients randomly assigned to group 1 received cisplatin (100 mg per square meter of body-surface area given intravenously on days 1 and 29) and vinblastine (5 mg per square meter given intravenously on days 1, 8, 15, 22, and 29) and then began radiation therapy on day 50 (60 Gy over a 6-week period). Patients assigned to group 2 received the same radiation therapy but began it immediately and received no chemotherapy. The eligible patients in group 1 (n = 78) and group 2 (n = 77) were comparable in terms of age (median, 60 years), sex, performance status, histologic features, stage of disease, and completeness of radiation therapy. The median survival was greater for those in group 1-13.8 versus 9.7 months (P = 0.0066 by log-rank test). Rates of survival in group 1 were 55 percent after one year, 26 percent after two years, and 23 percent after three years, as compared with 40, 13, and 11 percent, respectively, in group 2. Those in group 1 had a higher incidence of serious infections requiring hospitalization (7 percent, vs. 3 percent in group 2) and severe weight loss (14 percent vs. 6 percent), but there were no treatment-related deaths. In patients with Stage III non-small-cell lung cancer, induction chemotherapy with cisplatin and vinblastine before radiation significantly improves median survival (by about four months) and doubles the number of long-term survivors, as compared with radiation therapy alone. Since three quarters of the patients still die within three years, however, further improvements in systemic and local therapy are needed.
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