Advances in Radiation Therapy

M. Guckenberger, S. E. Combs, D. Zips

• Éditeur: S. Karger
• Année: 2018
• ISBN:
  9783318063622
• Sujet: Medicine
• Sous-sujet: Oncology

Developments in radiation oncology have been key to the tremendous progress made in the field in recent years. The combination of optimal systemic treatment and local therapy has resulted in continuing improved outcomes of cancer therapy. This progress forms the basis for current pre-clinical and clinical research which will strengthen the position of radiation oncology as an essential component of oncological care. This book summarizes recent advances in radiotherapy research and clinical patient care. Topics include radiobiology, radiotherapy technology, and particle therapy. Chapters cover a summary and analysis of recent developments in the search for biomarkers for precision radiotherapy, novel imaging possibilities and treatment planning, and advances in understanding the differences between photon and particle radiotherapy. Advances in Radiation Therapy is an invaluable source of information for scientists and clinicians working in the field of radiation oncology. It is also a relevant resource for those interested in the broad topic of radiotherapy in general.

Guckenberger M, Combs SE, Zips D (eds): Advances in Radiotherapy.
Prog Tumor Res. Basel, Karger, 2018, vol 44, pp 89–104 (DOI: 10.1159/000486997)

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Clinical Rationale and Indications for Particle Therapy

Constantin Dreher · Stephanie E. Combs

Department of Radiation Oncology, Technische Universität München (TUM), Klinikum rechts der Isar, Munich, Germany

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Abstract

Particle therapy is characterized by distinct physical properties leading to a reduction of integral dose compared to photons. While protons have an almost comparable biological effect, carbon ions and other heavier charged particles offer an increased relative biological effectiveness. The potential clinical benefit has been pointed out by several groups. Most likely, for protons, children have the largest margin of benefit since their normal tissue is very sensitive to radiation, and curative treatments lead to extremely long-term survivors having a lot of scope for long-term side effects. Many clinical studies, mostly of a retrospective nature, have shown promising results for various tumor types being treated with proton and heavy ion radiotherapy. Further clinical trials are needed in order to evaluate the opportunities of ion beam therapy and its prognostic influence on the general outcome, and many studies are currently recruiting patients. The aim here is to summarize current knowledge, possible clinical rationales, and indications for ion beam therapy.

© 2018 S. Karger AG, Basel

Early treatment trials were restricted to tumors that were difficult to irradiate. Due to the physical properties of particle beams, the idea was to increase the dose to the tumor, which is possible due to their dose distributions. Based on the inverted depth-dose curve, the reduction of dose exposure to the normal tissues has mainly been the rationale for the use of ion beam therapy. With promising results in terms of increased dose application and the enhanced radiobiological effectiveness of both protons and heavy ions, the early indications of ion beam therapy were mainly limited to radioresistant tumors. Recently, other tumor types have also begun to be investigated. Generally, the rationale for carbon ions is often seen in radiation-resistant, sometimes slow-growing tumors, such as chordomas. As for protons, indications are set a little wider, focusing on tumor types of various histologies generally with the aim to reduce long-term side effects.

Central Nervous System Tumors

Gliomas and Meningiomas

High-grade glioma and atypical meningioma are characterized by high radioresistance, which is why these tumors may profit most from ion beam therapy. For low-grade tumors, the benefit of a reduction in integral dose has the potential to reduce acute as well as long-term side effects. Therefore, protons have a certain rationale, especially in low-grade gliomas and benign meningiomas. With high-linear energy transfer (LET) particles, such as carbon ions, one may exploit the radiobiological properties of these beams for a potential increase in outcome. This might be a promising concept in high-grade meningiomas as well as high-grade gliomas.

Japanese facilities have produced promising results, showing the superiority of combined photon and carbon ion radiotherapy versus photon radiotherapy alone in patients with WHO III and IV gliomas after resection [1]. On the basis of a retrospective analysis of postoperative combined photon and carbon ion radiotherapy with concurrent temozolomide (demonstrating the potential benefit of this concept), the CLEOPATRA trial with postoperative radiochemotherapy with temozolomide (photon radiotherapy of 50 Gy) followed by a carbon ion (18-Gy relative biological effectiveness [RBE]) versus proton boost (10-Gy [RBE]) at Heidelberger Ion-Beam Therapy Center (HIT) has been set up [2, 3]. Two Japanese trials on combined high-dose photon and proton boost radiotherapy (50.4 + 46.2 Gy [RBE] or 50.4 + 23.1 Gy [RBE] + 23.1 Gy [RBE]) with concurrent temozolomide or nimustine hydrochloride had satisfying 2-year overall survival rates of 45.3% [4, 5].

Besides high-grade gliomas, low-grade gliomas have also been successfully treated with proton radiotherapy of 54 Gy (RBE) with 3- and 5-year progression-free survival rates of 85 and 40% and only few side effects [6, 7]. Hasegawa et al. [8] could also show that overall survival and progression-free survival were higher with carbon ion radiotherapy of 55.2 Gy (RBE) than with smaller doses, while at same time showing acceptable toxicity. A study on pediatric patients with low-grade gliomas could even demonstrate 8-year progression-free survival rates of 82.8% after proton radiotherapy with a median of 52.2 Gy (RBE) [9].

Meningiomas account for about 15% of all primary central nervous system tumors, of which only 10% are atypical ones. The treatment of choice is resection, but skull base and recurrent meningiomas profit from high-dose radiotherapy. In general, photon irradiation with a cumulative dose over 60 Gy leads to satisfactory survival, but there is no advantage of combined photon and proton irradiation over high-dose photon radiotherapy of benign meningiomas in terms of local control rates [10–13]. This may be explained by reduced robustness due to sharp dose gradients or the fact that mainly atypical, skull base, and recurrent meningiomas profit from radiotherapy. However, this is not fully understood and needs to be reevaluated in prospective trials, directly comparing photon and particle radiotherapy. With regard to recurrent and atypical meningiomas, radiotherapy has to be improved in order to increase the local control and overall survival rate. Small trials with photons could show that doses exceeding 60 Gy are required [11]. Dose escalation trials, especially in the case of skull-base tumors, should be conducted by ion beam therapy. Radiotherapy with heavy ions can possibly overcome the results of proton or high-dose photon radiotherapy. On the basis of first results of the Gesellschaft für Schwerionenforschung (GSI) in Germany, a clinical trial of combined photon and carbon ion radiotherapy (50.4 Gy photon radiotherapy + 18 Gy [RBE] carbon ion radiotherapy boost) has been initiated at HIT [14, 15]. To date, proton data are comparable to photons; however, randomized trials are still missing to confirm any superiority.

Skull Base Cancer

Skull-base tumors are characterized by highly radiosensitive normal tissues surrounding the tumor, which is why conformal radiotherapy is of utmost importance. The proximity of tumor and cranial nerves or major vessels results in oncologically incomplete resections with additive radiotherapy afterwards, which is why Fossati et al. [16] concluded that proton radiotherapy plays a major role in skull-base malignancies. Here, especially the potential to dose-escalate is the strongest argument for particles.

Ion beam therapy shows superior results compared to photon irradiation with regard to both dose distribution and clinical results, especially in the case of chordomas and chondrosarcomas [17–22]. The Paul Scherrer Institute (PSI) showed actuarial 5-year local control rates of 81 and 94% after proton radiotherapy of chordomas and chondrosarcomas (73.5 Gy [RBE] and 68.4 Gy [RBE]). At HIT, carbon ion radiotherapy of a median 60 Gy (RBE) leads to local control and overall survival rates of 72 and 75% after 5 years [23]. On top of that, HIT could show the safety and efficacy of reirradiation with carbon ions (51.0 Gy [RBE]) of recurrent skull-base chordomas and chondrosarcomas [24].

Irradiation after surgery is even more important in patients with chordomas, as chordomas frequently recur after incomplete resections. The combination of precise head immobilization, and the physical and the biological characteristics of ion beam therapy allows high-dose applications in the target volume of the skull base. This is important, as a clear dose-response relationship was found in chordoma patients and the local control rate probability improved with a cumulative dose exceeding 60 Gy (RBE) – at least 57.36 Gy (RBE) should be recommended [17, 20, 21, 25, 26]. As described before, PSI showed actuarial 5-year local control rates of 81% after proton radiotherapy with 73.5 Gy (RBE). The GSI showed actuarial 5-year local control rates of only 70% after carbon ion radiotherapy of skull base chordomas with 60 Gy (RBE) [17]. However, the National Institute of Radiological Sciences (NIRS) could show superior local control rates (5-year local control rate of 100%) by the use of carbon ion radiotherapy of up to 60.8 Gy (RBE) in a phase II trial on chordomas [21].

With regard to chondrosarcoma, the ideal therapy has not yet been found, but postoperative high-dose ion beam thera...