12.1 Introduction
Hadrontherapy, a form of radiation therapy dealing with heavy charged particles, has become one of the most sophisticated and attractive approaches in the management of cancer, since it deals with two essential aspects of modern radiation oncology: 1/ ballistic aspects, that allows optimisation of the dose to the tumour volume, along with maximal sparing of surrounding normal anatomical structures; 2/ biological aspects, due to an increased radiobiological effectiveness (RBE) on interposed tissues, related with a high linear energy transfert (LET) along their path. If the ballistic properties are not far different for most particles, i.e. protons (P) and light ions, the biological advantages are only shared by heavier ions, represented nowadays almost exclusively by carbon ions (CI). The interest for particle therapy has paralleled the technological evolution of “conventional” photon (XR) therapy: introduction of compact dedicated commercial accelerators in place of former nuclear physics prototypes; development of isocentric rotating gantries that allow sophisticated beams’arrangements, and easier patients’ set- ups (mainly for P); image guided radiotherapy (IGRT), including mobile targets tracking; pencil- beam scanning (continuous or by spots), able to generate intensity modulated P therapy (IMPT); Accurate dose-calculations methods (Monte Carlo) that progressively replace less sophisticated ones (ray-tracing, pencil beam), along with in vivo QA (gamma-prompts, on-line PET). These innovations have considerably stimulated the exploration of new clinical indications, from a few in the early 80s to more than 60 recorded recently on the PSI website dedicated to P alone. We summarize below the clinical experience accumulated in proton and carbon ion therapy. Detailed informations can be found in recent articles and textbooks [1-4]
12.2 Proton therapy indications
P, whose clinical experience exceeds 100,000 patients worldwide, have proven advantageous in two settings:
- 1/ Delivering an escalated dose to a “radio-resistant” tumour process, situated close to, or abutting a radiosensitive organ:
Ocular malignancies, esp. uveal melanomas, represent the main indications in the P literature, with highly hypofractionated doses being administered to a maximum of 50-60 GyE (i.e. Physical dose X estimated RBE of 1.1 for P). Remarkable results have been brought out by most groups: approx. 95% local control (LC), 80% overall survival (OS), 50% eye-preservation, and sometimes salvage programs including P Re-irradiation .
Skull base and cervical canal low grade sarcomas: chordomas (CH) and chondrosarcomas (CS) have been extensively explored since the late 70s . Recent advances have concerned the genetic profile of these malignancies, and the introduction of biological agents in metastatic presentations. But charged particles remain of crucial importance in achieving permanent LC. Optimal dose has been set to about 70 GyEq in CS, and ≥ 75 GyEq in CH. Late failures (i.e. > 10 years) can occur, and make protracted follow-up necessary.
Spinal, para spinal and sacral sarcomas/CH are particularly challenging conditions due to the cord and/or cauda equina proximities, and the frequent interposition of metallic surgical material in the beams’ path. These lead to a severe selection of patients. Further improvements could be achieved using CI (see below).
Head and neck carcinomas have also long been highly challenging due to the interposition of bone-air cavities, in sino-nasal sites. This introduces uncertainties in dose-distribution. The development of Monte Carlo calculations has made their management much safer. Remarkable results have been brought out esp. in adenoid cystic carcinomas, approaching 80% [10]. But the outcome of malignant gliomas has not been definitely improved despite dose-escalation studies.
2/ Improved sparing of normal tissues from radiation effects.
-In children, this advantage is particularly important, due to the exquisite sensitivity of organs under development. In the mid-80s, the dramatic improvement of paediatric tumours that followed the introduction of efficient polychemotherapy programs, made RT almost obsolete in the mind of many investigators. Actually RT has remained crucial in most clinical situations, and gained even in popularity when P facilities became available. Nowadays these indications should be considered in priority. Using P, one can expect to reduce long term sequelae, esp. those affecting bone growth, and brain maturation in youngsters. The potential risk-reduction of radiation-induced secondary malignancies has also been recently addressed. - In adults, P have proven beneficial for multiple anatomical organs, such as parotids in ENT
sites, or rectum/bowel in pelvic sites, in terms of improved physical dose-sparing. But clinical benefits still remain partially unknown. It is interesting to mention that not only long term side-effects can be spared using particles, but also acute toxicity on mucosa, and bone marrow that make them attractive in chemo-radiations combinations. It is also important to stress that optimal “conformality” to the target, along with sparing of critical structures can only be achieved using modern dose-delivery techniques (see intro).
12.2 Development of carbon ions indications
The clinical experience has concerned approx. 15,000 patients worldwide, most in Japan. Biologically, maximal increased RBE is observed in the distal peak, where tumour is located, and not in the plateau located upstream, where normal tissues are interposed. This makes them highly attractive in most challenging tumours. But variations are observed according to tissue-types, biological and clinical endpoints, and fractionation of the dose (not to mention alternating types of particles), that make further intensive physical and biological research programs necessary. Japanese have derived their CI experience from formerly tested neutrons (N), a neutral high-LET particle, which applied to slow-growing, intrinsically radio-resistant, hypoxic, and/or non- operable malignancies, administered with unusually high doses per fractions. These included salivary, and prostatic primaries (= slow growing), and sarcoma/glioma histological subtypes (= radio-resistant). Unfortunately N clinical experiments were discontinued in the mid-90s, due to the excessive toxicity reported on healthy tissues, related with their poor dose-distribution. On an other hand, the CI dose-profile somewhat similar to P, has stimulated the interest for similar indications, with the hope to improve their outcome further: 70-85% LC has been reported in skull base CH, a benefit confirmed in a recent multivariate analysis; 50% OS, in selected cases of pancreatic carcinomas, known for their usual lethal outcome; 80% in unresectable spinal/para spinal sarcomas; 80% in some series of aggressive melanomas (generally not ocular nor cutaneous, but of mucosal origin). Prostate carcinomas have also been largely explored… The European experience, initiated more recently in Germany (Darmstadt, 1997, Heidelberg, 2009), and Italy (Pavia, 2012) has been based on more “conventional” fractionation of the dose (compared with XR), that might help put in perspective particles with XR-therapy. First randomized trials are also being conducted. There are also CI projects under development in Austria (Wiener-Neustadt), and France (Lyon and Caen).
12.3 Perspectives
Recent evaluation by the French ETOILE group in Lyon assessed that P and CI could be beneficial in approx. 12 and 5% of cancer patients respectively. This would represent about 20 to 25,000 new cases per year in countries such as France, Italy or Germany. These values exceed by far the current capacities of hadron-therapy programs. As far as P, facility-cost has been substantially cut-down for the past few years, and makes them relatively “accessible” to major cancer centers. This might favour comparative P vs XR evaluations, highly suitable in the context of dramatic technological progress, for both. As far as CI, it will remain for long, beyond the scope of most oncological groups, with hopefully the exception of few dedicated centers, able to promote advanced research programs.
References
[1] J. Lundkvist, M. Ekman, S.R. Ericsson, B. Jönsson, B. Glimelius, Proton therapy of cancer:
potential clinical advantages and cost-effectiveness. Acta Oncol. 44 (2005) 850-61.
[2] J.S. Loeffler, M. Durante, Charged particle therapy – optimization, challenges and future
directions. Nat. Rev. Clin. Oncol. 10 (2013) 411-424.
[3] U. Linz (Editor), Ion Beam Therapy. Springer Verlag, Heidelberg, 2012
[4] T.F. DeLaney, H.M. Kooy (Editors), Proton and Charged Particle Radiotherapy. Lippincott
Pub, Philadelphia, 2008.
[5] C.M. Charlie Ma, T. Lomax, Proton and Carbon Ion Therapy. CRC Press, Taylor & Francis,