Special issue on intraoperative radiotherapy—guest editor’s preface

The considerable technical advancements of irradiation techniques over the past decade lead to an increased use of high(er) single doses with less side effects. In some cancers, stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) with high single doses to one or more lesions have proved to be equally (or even more) effective as surgery. However, the delivery of ablative doses in a single fraction bears more advantages than instantaneous sterilization of the treated volume: a variety of effects on non-irradiated cells that are located adjacent (bystander effect and cohort effect) and distant (abscopal effects) to the initial tumor site have been observed (1-3). Corresponding to this, there is also increasing evidence for systemic effects after high-dose radiotherapy in metastasized malignancies (4,5), whereas this effect may be further augmented by checkpoint inhibitors such as ipilimumab (6,7).

The application of intraoperative radiotherapy (IORT) resembles the most effective approach to spare healthy tissue and at the same time to deliver extraordinarily high single doses of radiotherapy to (microscopically or macroscopically) remaining tumor cells. Modern devices resemble portable miniature linear accelerators, that are either using low-energy photons or electrons and thus require similar shielding requirements as c-arm fluoroscopy (8). The facilitated room-to-room portability can also be seen as a powerful metaphor for an interdisciplinary use of these devices. Beside the most widely known application in early-stage breast cancer, where IORT turned out to be non-inferior to postoperative external beam radiation therapy in two large phase III trials (9,10), IORT is to date increasingly used by multiple disciplines to treat a broad variety of tumors, including sarcoma, high-grade gliomas, brain and spinal metastases, head-and neck carcinomas or cervical cancer (11-20).

Although for most of these indications, IORT does not bear the requirements of expensive study drugs or complicated resection techniques, randomized clinical trials that generate level I evidence are still lacking for most indications (except breast cancer). In the light of ever-increasing costs for targeted molecular therapies and tighter budgets for healthcare, targeted radiotherapy in the form of IORT carries the excitement of a low-cost-high-efficiency approach. The IORT community is therefore encouraged to follow the example of IORT in early-stage breast cancer in creating high level evidence in order to modify clinical guidelines for cancer treatment in the era of evidence-based medicine.

With the objective of forming such an interdisciplinary community that may collaboratively set up prospective trials and, as a consequence of the positive response to the first special issue on IORT in 2014, Translational Cancer Research has deiced to once more provide a forum, in which IORT experts give insights on their views and where researchers publish novel developments in this moving field.

In this issue, Emami et al. address normal tissue complications after (high-dose) IORT and question the use of the linear-quadratic formalism for predicting such. Tallet and her colleagues staged patients planned for IORT using pre-operative MRI and report ipsilateral second breast cancer in 4%. Reis et al. present their approach of combined intraoperative radiotherapy and kyphoplasty (Kypo-IORT) and also provide an outlook on an upcoming phase III trial. Massarut and colleagues give an overview on the current knowledge about wound response(s) after surgery and Veldwijk et al. contributed a brief report on their findings when analyzing growth promoting effects of wound fluids collected from breast cancer patients with and without IORT.

Münter et al. provide a comprehensive review on various techniques including HDR-brachytherapy, intraoperative electron radiation therapy (IOERT) or IORT with low-energy photons in head and neck carcinomas. Sethi et al. investigated the impact of commonly encountered tissue heterogeneities on measured dose in heterogeneous media. Potemin et al. report on outcome after IORT in patients with locally advanced or recurrent rectal cancer.

As adequate documentation of IORT is still a major challenge the introduction of a treatment planning software for IORT displays a major advantage for the community. Valdivieso-Casique et al. introduce the software and review the process of establishing it.

We wish to thank all contributors and the editorial office for supporting this special issue and hope that it resembles an inspiring source not only to physicians and physicists practicing in IORT, but also for those interested IORT.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research for the series “Intraoperative Radiotherapy II”. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.3978/j.issn.2218-676X.2015.04.09). The series “Intraoperative Radiotherapy II” was commissioned by the editorial office without any funding or sponsorship. FAG and PCL served as the unpaid Guest Editors of the series. FW served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Translational Cancer Research. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Herskind C, Wenz F. Radiobiological aspects of intraoperative tumour-bed irradiation with low-energy X-rays (LEX-IORT). Transl Cancer Res 2014;3:3-17.
2. Lara PC, López-Peñalver JJ, Farias Vde A, et al. Direct and bystander radiation effects: a biophysical model and clinical perspectives. Cancer Lett 2015;356:5-16. [PubMed]
3. Park B, Yee C, Lee KM. The effect of radiation on the immune response to cancers. Int J Mol Sci 2014;15:927-43. [PubMed]
4. Cheung P, Thibault I, Bjarnason GA. The emerging roles of stereotactic ablative radiotherapy for metastatic renal cell carcinoma. Curr Opin Support Palliat Care 2014;8:258-64. [PubMed]
5. Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol 2013;14:e28-37. [PubMed]
6. Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol 2009;10:718-26. [PubMed]
7. Sologuren I, Rodríguez-Gallego C, Lara PC. Immune effects of high dose radiation treatment: implications of ionizing radiation on the development of bystander and abscopal effects. Transl Cancer Res 2014;3:18-31.
8. Schneider F, Clausen S, Jahnke A, et al. Radiation protection for an intraoperative X-ray source compared to C-arm fluoroscopy. Z Med Phys 2014;24:243-51. [PubMed]
9. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet 2014;383:603-13. [PubMed]
10. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol 2013;14:1269-77. [PubMed]
11. Abo-Madyan Y, Goessler U, Vent J, et al. Intraoperative radiotherapy (IORT) for recurrent head and neck squamous cell carcinoma (SCC) using a mobile 50 kilovoltage (KV) mini-accelerator. Strahlenther Onkol 2013;189:99-100.
12. Call JA, Stafford SL, Petersen IA, et al. Use of intraoperative radiotherapy for upper-extremity soft-tissue sarcomas: analysis of disease outcomes and toxicity. Am J Clin Oncol 2014;37:81-5. [PubMed]
13. Calvo FA, Sole CV, Polo A, et al. Limb-sparing management with surgical resection, external-beam and intraoperative electron-beam radiation therapy boost for patients with primary soft tissue sarcoma of the extremity: a multicentric pooled analysis of long-term outcomes. Strahlenther Onkol 2014;190:891-8. [PubMed]
14. Giordano FA, Abo-Madyan Y, Brehmer S, et al. Intraoperative radiotherapy (IORT)—a resurrected option for treating glioblastoma? Transl Cancer Res 2014;3:94-105.
15. Giordano FA, Brehmer S, Abo-Madyan Y, et al. INTRAGO: intraoperative radiotherapy in glioblastoma multiforme—a phase I/II dose escalation study. BMC Cancer 2014;14:992. [PubMed]
16. Guo S, Reddy CA, Kolar M, et al. Intraoperative radiation therapy with the photon radiosurgery system in locally advanced and recurrent rectal cancer: retrospective review of the Cleveland clinic experience. Radiat Oncol 2012;7:110. [PubMed]
17. Reis T, Schneider F, Welzel G, et al. Intraoperative radiotherapy during kyphoplasty for vertebral metastases (Kypho-IORT): first clinical results. Tumori 2012;98:434-40. [PubMed]
18. Roeder F, Ulrich A, Habl G, et al. Clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma: interim analysis. BMC Cancer 2014;14:617. [PubMed]
19. Schneider F, Fuchs H, Lorenz F, et al. A novel device for intravaginal electronic brachytherapy. Int J Radiat Oncol Biol Phys 2009;74:1298-305. [PubMed]
20. Weil RJ, Mavinkurve GG, Chao ST, et al. Intraoperative radiotherapy to treat newly diagnosed solitary brain metastasis: initial experience and long-term outcomes. J Neurosurg 2015;122:825-32. [PubMed]

Frank A. Giordano

Pedro Carlos Lara

Prof. Frederik Wenz