Neutron radiotherapy should continue.
Article Type: Letter to the editor
Subject: Radiotherapy (Forecasts and trends)
Radiotherapy (Management)
Oncology (Research)
Authors: Sauerwein, Wolfgang
Forman, Rita Engenhart-Cabillic Jeffrey D.
Gueulette, John
Hachem, Sabet
Jones, Dan
Krull, Andreas
Lukas, Peter
Mandrillon, Pierre
Petry, Winfried
Rosenberg, Ivan
Venimmen, Frederik
Welsh, James S.
Pub Date: 05/01/2012
Publication: Name: South African Medical Journal Publisher: South African Medical Association Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 South African Medical Association ISSN: 0256-9574
Issue: Date: May, 2012 Source Volume: 102 Source Issue: 5
Topic: Event Code: 010 Forecasts, trends, outlooks; 200 Management dynamics; 310 Science & research Computer Subject: Market trend/market analysis; Company business management
Geographic: Geographic Scope: South Africa Geographic Code: 6SOUT South Africa
Accession Number: 289216467
Full Text: To the Editor: Abratt's letter (1) needs a response. We are currently--or have been directly--involved in treating patients with fast neutrons for decades; some with more than 20 years' experience in proton therapy, and others working at major hospitals with modern, high-end facilities for radiotherapy with photons and electrons.

Prof Abratt's opinion was held in the late 1980s when severe late effects of fast neutron therapy (FNT) were recognised, resulting in the early enthusiasm for this modality abating. FNT was introduced into clinical practice after careful radiobiological work, particularly by LH Gray. FNT, the first high linear energy transfer (LET) radiation used in radiotherapy, has not fulfilled the early optimistic laboratory-based expectations. Initial treatment beams had inferior physical characteristics. However, clinical FNT now has facilities with high-energy beams, individually shaped fields, isocentric beam delivery and full 3D treatment-planning systems and image guidance, and it can be applied safely at dedicated centres. However, well-trained personnel are needed who understand the particles' biological effects and complex physical behaviour.

Proven indications for FNT are limited and will benefit few patients. However, for some indications, neutron therapy remains superior to other modalities, despite advances in oncology. The early closure of the one prospective clinical trial, (2) due to the unexpected demonstration of superior results of FNT over conventional low-LET radiotherapy for salivary gland tumours, precluded more patients being recruited. Had the trial continued, it may have led to a better understanding of the effects of neutrons on survival. Nevertheless, today, FNT is the standard and established evidence-based treatment for adenoid cystic carcinoma of the salivary glands, and should be maintained for patients who will benefit from high LET FNT. This knowledge is advantageous for such a rare disease; in most other similar situations, treatment is based on opinion rather than facts from randomised trials. Other FNT indications should be regarded as research or prescribed as an individual treatment decision.

Research is another important role for neutron therapy facilities, e.g. basic physics (interactions of neutrons with biological materials), dosimetry, technological developments and radiobiology, clinical trials and treatment application.

Few highly industrialised countries have the financial and technical capacity to explore carbon ion therapy, which combines a high LET effect with an excellent dose-distribution profile. Their clinical results will take time to guide the radiotherapy community in its use and prove the superiority of delivering expensive high LET radiation. (3,4) FNT history also shows that new developments which excite great enthusiasm may not always be justified; they need careful evaluation over time before becoming irrefutably beneficial for patients. The medical community must accept this less exciting period as essential. It is easier to demonise neutrons and conclude that they should not be used than to spend a long time learning how to use them safely.

Prof Abratt rightly notes the effective and safe use of proton (low LET) therapy but that is not a relevant argument against FNT. Different particles are needed for optimal treatment of different tumours.

iThemba LABS offers high LET radiation to South Africa and its neighbours at a fraction of the cost of carbon ion facilities. It has the infrastructure and knowledge to deliver this therapy safely, and its neutron therapy facility is regularly used for patients from Europe. Prof Abratt calls for fiscal responsibility--it would be fiscally irresponsible not to use South Africa's high LET facility and to send patients overseas for such therapy.

(1.) Abratt RP. The fast neutron therapy programme for patients in South Africa should come to an end. S Afr Med J 2012;102(2):58.

(2.) Laramore GE, Krall JM, Griffin TW, et al. Neutron versus photon irradiation for unresectable salivary gland tumors: Final report of an RTOG-MRC randomized clinical trial. Int J Radiat Oncol Biol Phys 1993;27(2):235-240.

(3.) Gueulette J, Slabbert JP, Bischoff P, Denis JM, Wambersie A, Jones D. Fast neutrons: Inexpensive and reliable tool to investigate high LET particle radiobiology. Radiation Measurements 2010; 45: 14141416. [http://dx.doi.org/10.1016/j.radmeas.2010.05.019]

(4.) Wambersie A, Jones DTL, Gueulette J, Gahbauer R, DeLuca PM. What can we learn from the neutron clinical experience for improving ion-beam techniques and high-LET patient selection? Radiation Measurements 2010; 45: 1374-1380. [http://dx.doi.org/10.1016/j.radmeas.2010.04.013]

Wolfgang Sauerwein

Strahlenklinik, University Hospital Essen, Germany

w.sauerwein@uni-due.de

Rita Engenhart-Cabillic

Klinik fur Strahlentherapie, Philipps-Universitat Marburg

Germany

Jeffrey D Forman

21st Century Oncology, and Radiation Oncology

Wayne State University, USA

John Gueulette

Department of Molecular Imaging and Radiological Oncology

Catholic University of Louvain, Brussels, Belgium

Sabet Hachem

Faculte des Sciences, University Nice Sophia Antipolis

France

Dan Jones

Constantia, South Africa

Andreas Krull

Ambulanzzentrum des Universitatsklinikum

Eppendorf, Hamburg, Germany

Peter Lukas

Univ.-Klinik fur Strahlentherapie-Radioonkologie

der Medizinischen Universitat Innsbruck, Austria

Pierre Mandrillon

The Cyclotron Laboratory, Centre Antoine Lacassagne

Nice, France

Winfried Petry

Forschungsneutronenquelle Heinz Maier-Leibnitz (FRMII)

Technische Universitat Munchen, Germany

Ivan Rosenberg

Department of Radiotherapy Physics

University College London Hospitals, UK

Frederik Venimmen

Previously: Radiation Oncology

Stellenbosch University and Tygerberg Hospital, South Africa

James S Welsh

Fermi National Accelerator Laboratory

University of Wisconsin, USA

Neutron radiotherapy: Abratt reply

To the Editor: The clinical fast neutron therapy programme in South Africa (SA) should be discontinued because:

(i) Many experimental and clinical studies show an increase in serious late normal tissue complications with neutron therapy, (1,2) which can be reduced in part by using the technology described in the letters by Laramore (3) and Sauerwein et al. (4) Nevertheless, its ability to deliver irradiation to tumours and spare normal tissue is inferior to that of other contemporary radiation modalities. More importantly, these complications arise from the interaction of neutrons with normal tissue, and are progressive with time. A patient's perspective of the debilitating morbidity after modern neutron therapy for adenoid cystic carcinoma of the parotid has been described. (5)

(ii) Continuation of the neutron therapy programme cannot be supported based on the results of Phase III studies. The authors of the aforementioned letters refer repeatedly to the 1993 study of 32 patients with salivary gland tumours, (6) but its data do not support the use of neutron therapy. In the study, neutron therapy was administered to 13 patients, resulting in severe toxicity in 9 patients and life-threatening toxicity in 2 patients. This toxicity was much higher than in the photon therapy arm. The trial was discontinued due to decreased referrals.

(iii) Due to the disappointing outcome of patients treated with fast neutron therapy, all such facilities--except for 2 in the USA--have been discontinued in England, Europe, Canada and the USA.

(iv) There are few peer-reviewed publications in the PubMed database on clinical studies of fast neutron therapy over the last 10 years.

Although the subject is the neutron therapy programme in SA, none of the 13 co-authors of the letter by Sauerwein et at. practice as a radiation oncologist in SA. They present no additional data to justify the continuation of this clinical fast neutron therapy programme. The radiobiological research programme is a separate matter.

Prof Laramore argues for further patient recruitment, continued resource allocation and for the neutron therapy programme to serve as a resource for Africa. The call for increased recruitment is unrealistic as the strong trend is of decreasing referrals to the programme. The average radiation oncology department in SA sees 150-300 new patients per month, whereas patient accrual to the neutron therapy programme is reportedly 1-2 patients per month in the last year.

Advocating the maintenance of resources for the programme is counter to our need for fiscal responsibility within our resource-constrained environment. Moreover, the failure of neutron therapy to meet its goals is not due to a lack of resources, but rather the biological nature of the therapy.

The neutron therapy programme, as a resource for Africa, has no basis; its shortcomings are as relevant to patients from Africa as they are elsewhere and are compounded by the distance of the site for patients. African studies give no weight to neutron therapy in cancer control programmes, but rather value conventional cancer prevention strategies and therapies. (7)

There have been exciting new developments in the technologies of other radiation modalities including proton particle therapy, and in the concurrent use of radiation with biological therapy and chemotherapy. The latter requires high precision radiation administration by contemporary radiation techniques with other modalities. Phase III studies with large numbers of patients document the safety and efficacy of these approaches for most of the common solid tumours, e.g. cancer of the cervix, lung, rectum, oesophagus,

brain and oral cavity. This has led to their widespread use in evidence-based patient management. Radiation oncologists in SA, as elsewhere, will seek to participate in clinical research based on these and other novel approaches.

Raymond Abratt

Radiation Oncology

Groote Schuur Hospital and University of Cape Town

raymond.abratt@uct.ac.za

(1.) Jones B, Dale RG and Carabe-Fernandez A. Charged particle therapy for cancer: The inheritance of the Cavendish scientists? Appl Radiat Isot 2009;67: 371-377.

(2.) Goitein M. Trials and tribulations in charged particle radiotherapy. Radiother Oncol 2010;95:23-31.

(3.) Laramore GE. Neutron radiotherapy in South Africa: A different perspective. S Afr Med J 2012;102:(5):269.

(4.) Sauerwein WAG, Engenhart-Cabillic R, Forman JD, et al. S Afr Med J 2012;102:(5):269-270.

(5.) Ebert R Life Itself: A Memoir. New York: Grand Central Publishing (Hachette Book Group), 2011.

(6.) Laramore GE, Krall JM, Griffin TW, et al. Neutron versus photon irradiation for unresectable salivary gland tumors: Final report of an RTOG-MRC randomized clinical trial. Int J Radiat Oncol Biol Phys 1993;27(2):235-240.

(7.) Sitas F, Parkin DM, Chirenje M, Stein L, Abratt RP, Wabinga H. Cancer in indigenous Africans. Part II. Epidemiology and control. Lancet Oncol 2008;9:786-795.
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