Enhancement of Oncological Patient’s Quality of Life through Intraoperative Radiotherapy (IORT)

Aim:

To assess changes in health-related quality of life (HRQOL) in oncological patients as an outcome of intraoperative radiotherapy considering relationship with age, cancer stage and presence of any comorbidity.

Project Team Leader:           Prof. Dr. med. Mikhail Janjalia

International Partner:           Carl Zeiss Meditec AG,

Represented by its CEO in Georgia Mrs. Nino Lomuashvili

Project Team Members:         Assistant Professor MD Tsotne Samadashvili,

                                            Assistant Professor MD Beqa Samkharadze,

                                            Assistant Professor MD Besarion Metonidze,

                                            MD Besarion Sokurashvili.

Short Description

Intraoperative radiotherapy (IORT) refers to the delivery of a high dose of radiation at the time of surgical intervention. IORT achieves highly effective radiation doses to a specific target while dose-limiting healthy structures are surgically displaced or shielded. This procedure uses a multidisciplinary approach in the treatment of cancer emphasizing an interaction between surgery and radiotherapy by minimizing surgical residue, maximizing the radiobiological effects of a single high dose of radiation and optimizing the duration of the treatment (Gunderson LL, Willet CG, Calvo FA, Harrison LB. Intraoperative irradiation: techniques and results. 2nd ed. New York: Human Press; 2011).

The modern approach to IORT began in the early 60 s with studies by Abe at the University of Kyoto using single high dose of gamma-rays of cobalt unit and electrons of betatron. In 1970, special IOERT facilities with in-room conventional linear accelerators were equipped at the Howard University Hospital and the Massachusetts General Hospital.

In the early 1990s the Christie hospital trial tested index quadrant irradiation with encouraging results; these results helped identify two types of breast cancer unsuitable for such an approach: lobular cancers and those with an extensive intraductal component (EIC). However, the latter factor may lose its importance if tumour-free margins are well clear. To test the hypothesis that localized radiotherapy might be sufficient, was needed to have an elegant means to provide such radiation. In early 1996 was received a fortuitous enquiry from the Photoelectron Corporation (Lexington, MA, USA) asking whether researchers would be interested in developing a radiotherapy device for breast cancer. From October 1996 to July 1998 they developed the device and the operative technique and treated the first patient on 2 July 1998 in Middlesex Hospital, University College London, with so called TARGIT (TARGeted Intraoperative radioTherapy), in which low-energy X-rays are delivered to the tumor bed directly – a single dose of radiotherapy given at the time of the initial lumpectomy to replace several weeks of treatment, travel and stress (HEALTH TECHNOLOGY ASSESSMENT VOLUME 20 ISSUE 73 SEPTEMBER 2016 ISSN 1366-5278).

These X-rays are delivered using the INTRABEAM® system, originally developed in collaboration with the Photoelectron Corporation, USA, and now manufactured by Carl Zeiss (Oberkochen, Germany). The INTRABEAM uses an electron beam to generate a point source of low-energy X-rays (50 kV maximum) at the tip of a 3.2-mm diameter tube. A personalized spherical applicator is then used to accurately target the tissues of the tumor bed for 20–35 minutes. The physics and dosimetry of this device have been well studied; the applicator delivers a uniform 20 Gy to the surface of the tumor bed and, as X-rays attenuate rapidly, spares lower tissues by delivering to them a much lower dose.

In the early 90s, dedicated mobile electron linear accelerators and a miniaturized low-energy X-rays machine were introduced to the clinical practice in a number of radiotherapy centres worldwide (Gunderson LL, Calvo FA, Willet CG, Harrison LB. Rationale and historical perspective of intraoperative irradiation. In: Gunderson LL, Willet CG, Calvo FA, Harrison LB, editors. Intraoperative irradiation: techniques and results. 2nd ed. New York: Human Press; 2011. p. 3–26). The Intrabeam radiotherapy system was granted a CE (Conformité Européene) mark in 1999 for use in radiotherapy.

INTRABEAM is a radiation therapy device specifically developed for intraoperative radiotherapy (IORT). The mobile miniaturized radiation source of INTRABEAM accelerates electrons through the 100 mm drift tube with a maximum power of 50 kV and 40 μA onto a gold target where the low-energy X-ray radiation is generated and is then emitted isotropically. Depending on the clinical application various types and sizes of applicators can be attached to the X-ray source.

The INTRABEAM® radiotherapy delivery system:

•  Converts electricity into low-energy X-rays

•  Delivers radiation treatment through a special spherical applicator

•  Ensures that the radiation beams come into direct contact with the targeted tissue

•   Irradiates a tumor site for several minutes while a patient is under anesthesia for surgery

Starting Date and Duration:

Starting date of research project is March 1, 2017.

There is no limit as to the duration of the project.

Budget (Approved NVU Share so far): GEL 1 820 000:

2017: GEL 756 340, 20;

2018: GEL 600 000;

2019: GEL 463 659, 80 (allocated for in forthcoming budget).

Primary results of studies will be published in 2 (two) years after the implementation of the project – in March, 2019.

INTRABEAM® from ZEISS radiotherapy indication:

• Brain Tumors -Intraoperative radiation therapy for brain tumors is a pragmatic and effective approach to sterilize the margins from persistent tumor cells, abrogate post-injury proliferative stimuli and to bridge the therapeutic gap between surgery and radiochemotherapy (Giordano, F. A., Wenz, F., & Petrecca, K. (2016). Rationale for intraoperative radiotherapy in glioblastoma. Journal of Neurosurgical Sciences, 60(3), 350–6; Han, X., Fu, B., Wu, M., Zhang, H., Li, D., Zhang, J., … Sun, S. (2014). Intraoperative Radiotherapy with INTRABEAM in primary brain tumors after resection: Preliminary reports of 26 cases. Neuro-Oncology, 16)
• Breast Cancer -radiotherapy with the INTRABEAM® from ZEISS irradiates the tumor bed targeted so that the surrounding healthy tissue is spared. During the operation and immediately after the tumor is excised a circa 30-minute irradiation procedure is performed. As a result, the standard approximate six weeks of post-op irradiation is reduced and can be eliminated for selected patients with a low risk profile (Vaidya, J. S., Wenz, F., Bulsara, M., Tobias, J. S., Joseph, D. J., Keshtgar, M., Baum, M. (2014). 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. The Lancet, 383(9917), 603–613)
• Gastrointestinal Tumors -By using intraoperative radiation with the INTRABEAM® local control of colorectal tumors, locally advanced and recurrent rectal cancer can be improved compared to EBRT (Guo, S., Reddy, C. A., Kolar, M., Woody, N., Mahadevan, A., Deibel, F., Suh, J. H. (2012). Intraoperative radiation therapy with the photon radiosurgery system in locally advanced and recurrent rectal cancer: retrospective review of the Cleveland clinic experience. Radiation Oncology, 7(1), 110)
• Head & Neck Tumors – Due to radiation scattering effects of conventional radiotherapy treatments for head and neck tumors, the risk of damaging various anatomically sensitive structures such as nerves, aorta, muscles or vocal cords is relatively high. Intraoperative radiation therapy (IORT) enables the delivery of radiation immediately after surgical resection and therefore directly into the tumor bed, minimizing scattering effects (De Felice, F., Musio, D., Tombolini, V. (2016). Intraoperative radiation therapy (IORT) in recurrent head and neck cancer. Oral Oncology, 55(March), e1.;2 Roopashri, G., & Baig, M. (2013). Current advances in radiotherapy of head and neck malignancies. Journal of International Oral Health, 5(6), 119–23; 3 Chen, A. M., Bucci, M. K., Singer, M. I., Garcia, J., Kaplan, M. J., Chan, A. S., & Phillips, T. L. (2007). Intraoperative radiation therapy for recurrent head-and-neck cancer: The UCSF experience. International Journal of Radiation Oncology*Biology*Physics, 67(1), 122–129.
• Skin Cancer – the treatment of non-melanoma skin cancer, kilovoltage irradiation is an important therapy option which is also suitable for patients with a high operative risk (Cognetta, A. B., Howard, B. M., Heaton, H. P., Stoddard, E. R., Hong, H. G., & Green, W. H. (2012). Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients. Journal of the American Academy of Dermatology, 67(6), 1235–41; Tward, J.D., Anker, C, J,. Gaffney, D.K., Bowen, G. . (2012). Radiation Therapy and Skin Cancer. Modern Practices in Radiation Therapy, 207–246;  Chan, S., Dhadda, A.S. (2007) Swindell, R., Single fraction radiotherapy for small superficial carcinoma of the skin. Clin Oncol (R Coll Radiol), 19(4), 256-9)
• Spinal Metastases -The first clinical trial experiences of this approach have yielded very promising results with an intraoperative risk profile comparable to cement augmentation alone yielding increased patient convenience by reducing both the treatment time and hospitalization time when compared to conventional multifraction radiation treatment (Wenz, F., Schneider, F., Neumaier, C., Kraus-Tiefenbacher, U., Reis, T., Schmidt, R., & Obertacke, U. (2010). Kypho-IORT – a novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases. Radiation Oncology, 5(1), 11; Schmidt, R., Wenz, F., Reis, T., Janik, K., Bludau, F., & Obertacke, U. (2012). Kyphoplasty and intra-operative radiotheray, combination of kyphoplasty and intra-operative radiation for spinal metastases: technical feasibility of a novel approach. International Orthopaedics, 36(6), 1255–1260)

The project is also designed to create networking opportunities and boost collaborations between University, industry and the healthcare sector in order to develop better strategies for cancer treatment with radiotherapy and thus contributing, with a variety of technological platforms, to develop effective therapeutic strategies to combat cancer.

Methodology and Approach

Collecting information about all patients having treatment with Intrabeam at a national level (New Vision University Hospital, Innova Medical Center). Clinicians should enter details about all patients who choose to have the Intrabeam radiotherapy system for adjuvant treatment. They should audit, review and document clinical outcomes locally, and consider the relationship between outcomes and patients’ characteristics.

The data and clinical outcomes to be collected include:

• histology of the cancer and patients’ characteristics including: type, size and grade of the tumor; side of the body affected; lymph node status; estrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 status; and age of the patient

• local recurrence
• treatment after local recurrence
• metastatic disease
• disease-free survival
• overall survival
• adverse effects of treatment
• health-related quality of life (including EQ‑5D).