"Expanding the Horizons of Proton Beam Therapy"

Minesh P Mehta, MD; Katja Langen, PhD; William F. Regine, MD

The Cancer Letter recently published information regarding proton therapy facilities in the US, highlighting a contention that 85% of patients treated with protons have prostate cancer, the logical implication of which would be that this important resource is utilized minimally for other cancers.  In this response, we wish to correct this erroneous impression and also wish to highlight the direction that this technology is moving in. 

Proton beam therapy, characterized by its significantly lower total body integral dose relative to photon therapy, is a natural and logical extension of the bioethics concept of “primum non nocere”, or “first, do no harm” (1).  There is no evidence in the literature, nor is there logical reason to believe that excess radiation to normal tissues (irrespective of whether it exceeds some arbitrarily defined threshold or not) is beneficial to any patient.  The logical, almost “tongue-in-cheek” extrapolation of this is that the vast majority of patients eligible for radiation therapy should be considering proton therapy because in almost all instances they will receive a lower radiation dose to their normal tissues; in reality, significantly less than 10% of all cancer patients undergoing radiotherapy are treated with proton therapy (2).

There are four critical reasons why proton therapy is not in widespread use at present:

  1. Availability: access to proton therapy centers is quite limited; currently, there are only 14 operational centers in the US (http://www.proton-therapy.org/map.htm), in comparison to over 2200 conventional photon therapy centers (3).

  2. Cost: A key reason for the limited availability of proton therapy is the higher initial construction and subsequent operational costs. Several recent developments are likely to alter this to some extent, explaining the anticipated relatively rapid growth of proton centers in the US in the next decade (4).

  3. Measurable clinical benefits: Since a significant proportion of cancer patients have relatively short life expectancy, the long-term benefits of reduced integral dose to normal tissue may not be realized by some or many of these patients. Further, the relative paucity of completed and published randomized clinical trials demonstrating benefit in terms of reduction in acute toxicity, long-term morbidity, improved tumor control, superior survivorship parameters, etc. has hampered more rapid and broad acceptance of this modality (5).

  4. Limited applicability: One often comes across statements such as “Yet about 85 percent of patients who receive proton therapy have prostate cancer”, suggesting that the modality has limited applicability and focus      (http://www.cancerletter.com/articles/20140620_4).

The landscape in the US, and increasingly at a global level, in terms of all four of these issues is likely to change rapidly in the next 5–10 years.  First, an evaluation of institutional and industry analysis suggests that at least 24 centers are operational or under construction, interested in, or already pursuing proton therapy, and this will potentially increase and improve access to this modality (http://www.proton-therapy.org/map.htm).    A market research firm, ASD Reports, in its latest research report, "US Proton Therapy Market Analysis to 2017", provides a thorough opportunity assessment and clearly states that although proton therapy is in its infancy, there is unprecedented demand for it. They estimate that by 2017, the number of sites providing proton therapy in the US is expected to cross 22 (www.asdreports.com/ASDR-43356). 

In part, this growth in proton therapy centers is being fueled by reduced initial capital costs as single or 2-3 room solutions, with more compact architecture, became feasible.  In 2013, the first single room facility in the US became operational and several medium sized hospitals are considering this as an option.  It is in fact anticipated that future developments in technology will likely further reduce capital costs (http://www.proton-therapy.org/documents/dotmed511.pdf). In addition, a number of studies which have taken the approach of calculating lifetime costs after a therapeutic intervention, and thereby incorporating the costs of follow-up and management of toxicities, demonstrate that in several situations, although the cost of delivering proton treatment might be higher, lifetime costs are actually lower with this modality, compared to photon therapy (6).

The provision of high-level evidence regarding the value of proton therapy requires the conduct and completion of large-scale multi-institutional clinical trials and to date this effort has been hampered by the very limited number of institutions capable of delivering proton therapy. This scenario is however rapidly changing.  The Particle Therapy Co-operative Group (PTCOG) lists in excess of 50 ongoing clinical trials with proton therapy, encompassing an array of malignancies ranging from cancers of the breast, prostate, lung, esophagus, head and neck, base of skull, pediatric, liver, sarcomas, etc. (http://www.ptcog.ch/index.php/clinical-protocols).  As a larger number of centers participate in these trials, extensive data will be generated, contributing to an explosion in knowledge and evidence in this field. Registry databases, both adult & pediatric, have already started collecting and collating data about patients receiving proton therapy. Accrual to one such multi-institutional registry and prospective clinical trial database, completely funded at present by member institutions, is approaching nearly 4000 patients (http://www.pcgresearch.org). Further, randomized photon verses proton trials previously considered “impossible” or “unethical” are now actually underway (or planned) in several diseases such as prostate cancer, lung cancer, breast cancer, head and neck cancer, glioblastoma, low grade glioma, etc. (7).  In fact, by the end of 2014, with support from the NCI, NRG-Oncology will have launched two such major randomized trials (http://www.rtog.org/ClinicalTrials/ProtocolTable.aspx), one for lung cancer and the other for brain tumors.

In large measure, this explosive growth in indications and substantial expansion of scope is made possible by a major technological breakthrough in the proton delivery technology, referred to as pencil beam scanning (PBS), which results in further reduction in integral dose (8). Unlike conventional proton therapy, PBS technology allows more complicated and larger targets to be treated. Not surprisingly, therefore, the focus of modern pencil beam scanning proton therapy is on a wide range of malignancies.

Although precise numbers regarding the utilization of particle beam therapy in the US for various cancer indications are not readily available, a review of the data from tumor registries allows some insight.  The Proton Collaborative Group (PCG), a multi-institutional collaborative effort by multiple proton centers has maintained a comprehensive prospective registry trial since 2009.  Figure 1 below demonstrates that through June 2014, 3497 patients were entered on this online Registry Study for Proton Therapy Outcomes (NCT01255748).  The cumulative percentage of prostate cancer patients has dropped dramatically from more than 90% initially, to 74% within 6 months, and has consistently declined at each semi-annual evaluation to under 50% at present; this is a far cry from the wildly speculative 85% contention, In fact, because this is a cumulative percentage, prostate cancer currently accounts for significantly lower actual proportions (personal communication, Megan Dunn, PCG Coordinator 7/14/14). 

The introduction of the newer PBS systems has opened up the indications that were difficult to treat with conventional proton therapy. For example, the treatment of complex head and neck targets is now possible at centers that have access to PBS and they represent a significant patient fraction at these centers.  At the University of Texas, MD Anderson Cancer Center, one of the busiest US proton facilities, over a 7-year timeframe from 2006-13, 4521 new patients were treated with proton therapy, of whom 43% had prostate cancer.  An evaluation of time trends shows a significant drop in the proportion of patients with prostate cancer from 2006 through 2013, especially after the introduction of PBS, with commensurate increase in the proportion of more complex cases; for example, the proportion of all proton treated cases accounted for by genitourinary tumors dropped from 35 to 32 to 25% from 2012-14. (NAPT Conference, Washington DC, 2014, Steven J Frank, MD, Proton Center Medical Director).  The National Proton Therapy Consortium, a member organization, is currently surveying its US membership and in the near future shall be able to provide insights regarding these numbers from an even larger cohort of centers.  Most current centers have added or will add PBS technology while some of the newer facilities will use PBS exclusively. The patient mix will likely broaden accordingly.

Therefore, it is very safe to headline “Proton Therapy: Not Just for Prostate Cancer” as today’s reality, rather that perpetuate an inaccurate myth regarding its utilization, and more importantly, an inaccurate reflection of its potential.

So where is proton therapy headed?  The recent recognition that there is no safe dose to the heart for women with breast cancer receiving radiotherapy will likely lead to large scale evaluation of the role of proton therapy to minimize cardiac dose (9).  A large multi-center randomized trial to evaluate this is already in the planning stages.  Malignancies where significant reduction in dose to mucosal tissues can be achieved, e.g. head and neck cancer, might be logical to consider for randomized evaluation of reduction in acute toxicity and improvement in patient-centered outcomes.  A number of these trials are also already underway or in the planning stages.  In diseases where dose-escalation and normal tissue sparing is a required strategy, such as lung cancer and brain tumors, randomized trials are also already underway.  Hypofractionation remains a major area of exploration and in particular, if combined with surgery in a pre-operative fashion, might lead to a number of paradigm-changing approaches. The sparing of large volumes of bone marrow, especially in combined chemo-radiotherapy approaches, such as is the case with pelvic neoplasm, craniospinal irradiation, etc., remains a major testable hypothesis for proton therapy.  Newer PBS centers are also being equipped with on-board volumetric imaging that will significantly enhance the process of patient set-up verification, and improve tumor visualization at the time of treatment. The improved precision made possible by “image guided” proton therapy (IGPT) will enhance the treatment capabilities of PBS, especially for tumors that are currently challenging, such as lung cancer and tumors in the upper abdominal region (e.g. within the liver/pancreas).  So acknowledging the well-known automobile commercial, it is fair and appropriate to headline that “today’s proton therapy is not your father’s proton therapy, and is not just for prostate cancer” (http://godsofadvertising.wordpress.com/2008/10/14/this-is-not-your-fathers-oldsmobile).  The horizons of proton beam therapy are indeed expanding rapidly.

References:

  1. Chang JY:  Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in Stage I or Stage III non–small-cell lung cancer.  Int J Radiat Oncol Biol Phys, 65(4): 1087, 2006.

  2. Glimelius B, Ask A, Bjelkengren G, Björk-Eriksson T, Blomquist E, Johansson B, Karlsson M, Zackrisson B: Number of patients potentially eligible for proton therapy.  Acta Oncol, 44(8):836-849, 2005.

  3. Ballas LK, Elkin EB, Schrag D, Minsky BD, Bach PB: Radiation Therapy Facilities in the United States.  Int J Radiat Oncol Biol Phys, 66(4):1204-11, 2006.

  4. Lievens Y: Proton beam therapy: Too expensive to become true?  Radiother and Oncol, 75(2)131–133, 2005.

  5. Olsen DR, Bruland OS, Frykholm G, Norderhaug IN: Proton therapy – A systematic review of clinical effectiveness.  Radiother and Oncol, 83(2)123–132, 2007.

  6. Lundkvist J, Ekman M, Ericsson SR, Jönsson B, Glimelius B:  Proton therapy of cancer: Potential clinical advantages and cost-effectiveness.  Acta Oncol. 2005;44(8):850-61.

  7. Suit H, Kooy H, Trofimov A, Farr J, Munzenrider J, DeLaney T, Loeffler J, Clasie B, Safai S, Paganetti H: Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No.  Radiother and Oncol, 86(2):148–153, 2008.

  8. Steneker M, Lomax A, Schneider U:  Intensity modulated photon and proton therapy for the treatment of head and neck tumors.  Radiother and Oncol, 80(2): 263–267, 2006.

  9. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, Correa C, Cutler D, Gagliardi G, Gigante B, Jensen MB, Nisbet A, Peto R, Rahimi K, Taylor C, Hall P: Risk of Ichemis Heart Disease in Women after Radiotherapy for Breast Cancer, New Engl J Med, 3689110:987-98, 2013.

Figure 1: Cumulative enrollment on PCG Registry Study for Proton Therapy Outcomes (NCT01255748) between 2009-2014.  The dual Y-axis represents total number of patients enrolled with all diagnosis on the left, and percent of these represented by prostate cancer on the right.  The percent of patients with prostate cancer is expressed as a cumulative figure, and this has dropped from over 90% at initiation to under 50% currently, reflecting maturity of the usage of proton therapy and rapidly broadening application to other disease sites. 
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Minesh P Mehta, M.B.Ch.B., F.A.S.T.R.O.
Professor of Radiation Oncology
University of Maryland School of Medicine
Medical Director, Maryland Proton Treatment Center (MPTC)

Katja M Langen, Ph.D.
Associate Professor of Radiation Oncology
University of Maryland School of Medicine
Associate Chief of Proton Physics, MPTC

William F. Regine, MD
Isadore and Fannie Schneider Foxman Chair and Professor of Radiation Oncology
University of Maryland School of Medicine
Executive Director, MPTC

 

 




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