Proton Therapy: Presumed initial positive benefit in 15 pediatric cancers, long-term proof needed

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 Proton therapy has become the recommended radiation treatment for cancerous tumors in children because of its ability to precisely target a tumor, reduce dose delivered, and spare surrounding healthy tissue and organs at risk. The types of cancers and numbers of pediatric patients treated are steadily increasing.

However, clinical data on the long-term effectiveness and potential harm of the treatment are lacking, according to a team of Belgian researchers whose findings were published in the May issue of the International Journal of Radiation Oncology Biology Physics. (1) The multi-institutional team reached this conclusion after conducting a comprehensive literature search of published data from 2007 through June 2015. They identified only 23 primary studies that fulfilled the inclusion criteria, the majority of which lacked long-term clinical outcomes.

Lead author Roos Leroy, PhD, of the Belgian Healthcare Knowledge Centre in Brussels, and co-authors at the Belgian Cancer Registry and the University of Leuven, are worried. While the benefits of proton therapy compared to conventional and other advanced types of radiation therapy are substantial, long-term outcomes (eg, local control), late toxicities (eg, secondary cancer), impact on quality of life, and overall survival are unknown. For this reason, they initiated a critical literature review to identify and assess the quality of clinical data published in peer-review journals.

Selection criteria included: ∙ clinical trials or studies with at least 5 patients who had been diagnosed with one of the 15 types of cancer under study*; ∙ studies that included only children; and ∙ outcomes reported by pathological conditions in cases where proton therapy was evaluated in several pathological conditions simultaneously.

For cases in which no children-only studies were retrieved for a certain pathology, mixed samples of children and adults were allowed. The authors excluded narrative reviews and studies evaluating treatment planning or dosimetry but not reporting clinical outcomes of the patients who received the therapy.

Between 1 and 5 studies were identified for 12 of the 15 types of cancer. Rhabdomyosarcoma had the largest number, with 5 studies, followed by craniopharyngloma and medulloblastoma, each with 3 studies. None of the studies were randomized, and only 2 were comparative. The majority were retrospective analyses. When the researchers applied GRADE criteria to classify the quality of evidence, all studies were rated low.(2)

“This review illustrates that for the indications investigated, there is either insufficient or no clinical evidence to support or refute the use of proton therapy in children,” the authors wrote. “When the low quality of the studies is taken into account, the published clinical evidence is far from convincing.”

The research team hypothesized that the lack of clinical studies of pediatric proton therapy is due to many clinicians not believing it is necessary to scientifically confirm the clinical outcomes of a radiation delivery technology that delivers superior dose distribution and lower integrated dose. Additionally, the logistics of long-term follow-up of 5to 10 years are daunting and, even if contact is made, patients may not wish to participate. The increase in dedicated clinical proton therapy centers may enable researchers to conduct prospective trials on a large scale and may help change this.

The authors applaud the establishment of the U.S Pediatric Proton Consortium Registry (PPCR), which will be able to track patient outcomes. They also recommended that a European Hadron Therapy Registry be established.(3)

In addition, the authors are hopeful that the ANDANTE project (www.andanteproject.eu) will eventually provide data relating to long-term toxicities. They state that “it is extremely important to quantify the secondary cancer risk related to secondary neutron exposure.” The ANDANTE project is investigating the risk of cancer from exposure to low doses of neutrons. Medical physicists, radiobiologists, and epidemiologists are working together to develop a risk model that will be tested in a prospective study on the incidence of second cancers following exposure to scattered neutrons occurring after pediatric proton therapy.

The authors acknowledge that “as childhood cancer is a rare and heterogeneous disease and the number of children with cancer requiring radiotherapy as part of their treatment is small, randomized clinical trials may not be reasonable. The feasibility of randomized clinical trials should be evaluated on a case-by-case basis.”

“Prospective comparative clinical trials, preferably conducted in an internationally coordinated fashion, are clearly needed,” the authors conclude.

*The 15 cancers under study were: skull base chondrosarcoma, skull base and (para) spinal chordoma, craniopharyngioma, ependymoma, esthesioneuroblastoma, Ewing sarcoma, CNS germinoma, low-grade glioma, medulloblastoma/primitive neuroectodermal tumors (PNET), nonresectable osteosarcoma, pelvic sarcoma (ie, nonrhabdomyosarcoma, non-Ewing sarcoma, pineal parenchymal tumors, retinoblastoma, rhabdomyosarcoma, and (para) spinal “adult-type” soft-tissue sarcoma.

References

  1. Leroy R, Benahmed N, Hulstaert F, et al. Proton therapy in children: A systematic review of clinical effectiveness in 15 pediatric cancers. Int J Radiat Oncol Biol Phys. 2016; 95(1(267-278.
  2. Guyall G, Oxman AD, Sultan S, et al. Grade guidelines. 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. J Clin Epidemiol. 2013;66:151-157.
  3. Leroy R, Benahmed N, Hulstaert F, et al. Hadron therapy in children - an update of the scientific evidence for 15 paediatric cancers - Synthesis. Health Technology Assessment (HTA) Brussels: Belgian Health Care Knowledge Centre (KCE). 2015. KCE Reports 235Cs. D/2015/10.273/03. Open access(https://kce.fgov.be/sites/default/files/page_documents/KCE_235CsHadron%20therapy_Synthesis.pdf).

 

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Proton Therapy: Presumed initial positive benefit in 15 pediatric cancers, long-term proof needed.  Appl Rad Oncol. 

By Cynthia E. Keen| August 09, 2016

About the Author

Cynthia E. Keen

Cynthia E. Keen

Cynthia E. Keen is a medical writer and regular contributor to Applied Radiation Oncology. She is based in Sanibel Island, Florida.

 



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