Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No

Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Radiotherapy and Oncology (Impact Factor: 4.36). 03/2008; 86(2):148-53. DOI: 10.1016/j.radonc.2007.12.024
Source: PubMed


Evaluate the rationale for the proposals that prior to a wider use of proton radiation therapy there must be supporting data from phase III clinical trials. That is, would less dose to normal tissues be an advantage to the patient?
Assess the basis for the assertion that proton dose distributions are superior to those of photons for most situations. Consider the requirements for determining the risks of normal tissue injury, acute and remote, in the examination of the data from a trial. Analyze the probable cost differential between high technology photon and proton therapy. Evaluate the rationale for phase III clinical trials of proton vs photon radiation therapy when the only difference in dose delivered is a difference in distribution of low LET radiation.
The distributions of biological effective dose by protons are superior to those by X-rays for most clinical situations, viz. for a defined dose and dose distribution to the target by protons there is a lower dose to non-target tissues. This superiority is due to these physical properties of protons: (1) protons have a finite range and that range is exclusively dependent on the initial energy and the density distribution along the beam path; (2) the Bragg peak; (3) the proton energy distribution may be designed to provide a spread out Bragg peak that yields a uniform dose across the target volume and virtually zero dose deep to the target. Importantly, proton and photon treatment plans can employ beams in the same number and directions (coplanar, non-co-planar), utilize intensity modulation and employ 4D image guided techniques. Thus, the only difference between protons and photons is the distribution of biologically effective dose and this difference can be readily evaluated and quantified. Additionally, this dose distribution advantage should increase the tolerance of certain chemotherapeutic agents and thus permit higher drug doses. The cost of service (not developmental) proton therapy performed in 3-5 gantry centers operating 14-16 h/day and 6 days/week is likely to be equal to or less than twice that of high technology X-ray therapy.
Proton therapy provides superior distributions of low LET radiation dose relative to that by photon therapy for treatment of a large proportion of tumor/normal tissue situations. Our assessment is that there is no medical rationale for clinical trials of protons as they deliver lower biologically effective doses to non-target tissue than do photons for a specified dose and dose distribution to the target. Based on present knowledge, there will be some gain for patients treated by proton beam techniques. This is so even though quantitation of the clinical gain is less secure than the quantitation of reduction in physical dose. Were proton therapy less expensive than X-ray therapy, there would be no interest in conducting phase III trails. The talent, effort and funds required to conduct phase III clinical trials of protons vs photons would surely be more productive in the advancement of radiation oncology if employed to investigate real problems, e.g. the most effective total dose, dose fractionation, definition of CTV and GTV, means for reduction of PTV and the gains and risks of combined modality therapy.

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    • "These arguments depend on the accuracy of the predicted dose distribution and sound estimates of the relative biological effectiveness (RBE) values for the cancer and for each normal tissue [17]. The debate between the advocates in favour of randomised studies for all circumstances, and those who consider this to be unethical when reduced radiation dose can be delivered to OAR, continues [18] [19] [20] [21] [22] [23]. X-ray (photon) treatment and imaging techniques have significantly improved over recent decades with increased implementation of IMRT, arc and helical treatment and SABR in routine clinical practice [24] [25] [26] [27]. "
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    ABSTRACT: Although proton therapy has been used for many decades because of their superior dose distribution over photons and reduced integral dose, their clinical implementation is still controversial. We updated a systematic review of charged particle therapy. Although still no randomised trials were identified, the field is moving quickly and we therefore also formulated ways to move forward. In our view, the aim should be to build enough proton therapy facilities with interest in research to further improve the treatment and to run the needed clinical trials.
    Radiotherapy and Oncology 02/2012; 103(1):5-7. DOI:10.1016/j.radonc.2012.01.003 · 4.36 Impact Factor
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    • "A number of pre-clinical and clinical studies have shown that the effect of proton radiotherapy on normal tissue as well as on tumors is comparable to photon radiotherapy. The RBE values for clinical proton beams have been determined for a wide spectrum of in vitro as well as in vivo systems, as well as in clinical trials [11,12]. Therefore, it has been concluded that proton therapy can replace photon therapy without any further clinical trials when the same dose is applied [13]. "
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    ABSTRACT: Treatment standard for patients with primary glioblastoma (GBM) is combined radiochemotherapy with temozolomide (TMZ). Radiation is delivered up to a total dose of 60 Gy using photons. Using this treatment regimen, overall survival could be extended significantly however, median overall survival is still only about 15 months. Carbon ions offer physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increase relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons. First Japanese Data on the evaluation of carbon ion radiation therapy showed promising results in a small and heterogeneous patient collective. In the current Phase II-CLEOPATRA-Study a carbon ion boost will be compared to a proton boost applied to the macroscopic tumor after surgery at primary diagnosis in patients with GBM applied after standard radiochemotherapy with TMZ up to 50 Gy. In the experimental arm, a carbon ion boost will be applied to the macroscopic tumor up to a total dose of 18 Gy E in 6 fractions at a single dose of 3 Gy E. In the standard arm, a proton boost will be applied up to a total dose 10 Gy E in 5 single fractions of 2 Gy E. Primary endpoint is overall survival, secondary objectives are progression-free survival, toxicity and safety. The Cleopatra Trial is the first study to evaluate the effect of carbon ion radiotherapy within multimodality treatment of primary glioblastoma in a randomized trial comparing this innovative treatment of the treatment standard, consisitng of photon radiotherapy in combination with temozolomide. ISRCTN37428883 and NCT01165671.
    BMC Cancer 09/2010; 10(1):478. DOI:10.1186/1471-2407-10-478 · 3.36 Impact Factor
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    • "5. New beams (protons, ions) will become increasingly available for radiotherapy in the coming years. The potential of such beams can only be scientifically tested in clinical outcome studies if combined with state of the art treatment planning, monitoring and adapting techniques [31] [32]. 6. Radiotherapy is currently prescribed based on broad clinical parameters such as TNM stage, histology, tumour location and volume-dosetolerence parameters for normal tissues. "

    Acta oncologica (Stockholm, Sweden) 02/2008; 47(7):1188-92. DOI:10.1080/02841860802304556 · 3.00 Impact Factor
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