1. IORT AND RADIOBIOLOGY
What is IORT?
IORT and Radiobiology

2. What’s IOeRT?
Intraoperative electron irradiation (IOERT) in its broadest sense refers to the delivery of irradiation at the time of an operation.
IOERT evolved as an attempt to achieve higher effective doses of irradiation while dose-limiting structures are surgically displaced.
Intraoperative Irradiation: Techniques and Results L. Gunderson, C. Willet, L. Harrison, F. A. Calvo, Humana Press 2007 – ISBN: –

3. IOeRT – Clinical Indications
Breast cancer
Primary and recurrent colorectal
Pancreatic carcinoma
Liver metastasis
Sarcomas (retroperitoneal; soft tissue; bone)
Locally advanced and recurrent gynecologic malignancies
Bladder cancer
Prostate cancer
Lung cancer
Intraoperative Irradiation: Techniques and Results L. Gunderson, C. Willet, L. Harrison, F. A. Calvo, Humana Press 2007 – ISBN: –

4. Last ISIORT Pooled Analysis
IOeRT – Clinical Indications
Last ISIORT Pooled Analysis
More than patients including the European Institute of Oncology (EIO) in Milan, Italy (data not included in ISIORT database) treated with SIT dedicated accelerators.
ISIORT pooled analysis 2013 update: clinical and technical characteristics of intraoperative radiotherapy, Krengli M., Sedlmayer F., Calvo F. A., Sperk E., Pisani C., Sole C. V., Fastner G., Gonzalez C., Wenz F., Translational Cancer Research, Vol. 3, pp , 2014.

5. IOeRT – Clinical Indications
Most relevant IOeRT Clinical Results on non-breast districts
  CANCER
(Type)
INDICATION (Stages)
Locally advanced
INSTITUTION (ref)
RESULTS
Pancreas
Unresected
MGH (1)
16% 2 y OS (survivors > 5y)
Bordeline
Mayo Clinic (2)
84% LC;40%vs 0% 3 y OS
Resected
HGUGM (3)
58% 5 y LC
Esophago-gastric
HGUGM (4)
85% 5 y LC
Gastric
Systematic review (5)
St III IORT promoted OS
Rectal
cT2-4 N+
HGUGM (6)
96% LC 5 y
 Primary and recurrent
Systematic review (7)
IORT improved LC and OS
Prostate
Metastatic D1 and D2
Saitama Cancer C(16)
5-10 y OS 75/52%
Renal
Recurrent/Primary resected
US-Europe
Pooled-analysis (8)
OS 5y 37% (p) vs 55% (r)
Pediatric
Ewing/Rhabdomyosarcoma
Pooled-European (9)
5-10 y OS 74%-68%
Neuroblastoma + sarcoma incomplete resection
Heildelberg Univ (10)
1/18 local recurrences
Sarcomas
Retroperitoneal
Heildelberg Univ (11)
5 y LC 72%
Mayo Clinic (12)
5 y LC 89%
Extremity
Pooled- European (13)
5 y LC 82%
Osteosarcomas
Pooled-European (14)
10 y 82% LC, 73% OS
Oligo-recurrences
Gynaecologic, rectal, sarcomas
HGUGM (15)
5 y LC 53%, 46 % OS
MGH = Massachusetts General Hospital; HGUGM = Hospital general Universitario Gregorio Marañon; LC = local control; OS = overall survival; y = years; (p) = primary locally advanced disease; (r) = recurrent disease; St = stage; IOERT = intraoperative electron radiotherapy; (ref) = reference; C = Centre

6. IOeRT – Clinical Indications
Most relevant IOeRT Clinical Results on non-breast districts
  CANCER
(Type)
INDICATION (Stages)
Locally advanced
INSTITUTION (ref)
RESULTS
Pancreas
Unresected
MGH (1)
16% 2 y OS (survivors > 5y)
Bordeline
Mayo Clinic (2)
84% LC;40%vs 0% 3 y OS
Resected
HGUGM (3)
58% 5 y LC
Esophago-gastric
HGUGM (4)
85% 5 y LC
Gastric
Systematic review (5)
St III IORT promoted OS
Rectal
cT2-4 N+
HGUGM (6)
96% LC 5 y
 Primary and recurrent
Systematic review (7)
IORT improved LC and OS
Prostate
Metastatic D1 and D2
Saitama Cancer C(16)
5-10 y OS 75/52%
Renal
Recurrent/Primary resected
US-Europe
Pooled-analysis (8)
OS 5y 37% (p) vs 55% (r)
Pediatric
Ewing/Rhabdomyosarcoma
Pooled-European (9)
5-10 y OS 74%-68%
Neuroblastoma + sarcoma incomplete resection
Heildelberg Univ (10)
1/18 local recurrences
Sarcomas
Retroperitoneal
Heildelberg Univ (11)
5 y LC 72%
Mayo Clinic (12)
5 y LC 89%
Extremity
Pooled- European (13)
5 y LC 82%
Osteosarcomas
Pooled-European (14)
10 y 82% LC, 73% OS
Oligo-recurrences
Gynaecologic, rectal, sarcomas
HGUGM (15)
5 y LC 53%, 46 % OS
(1) Cancer. 2013; 119: ; (2) J Gastrointest Oncol. 2013;4:352-60; (3) Mol Clin Oncol. 2015; 3: ; (4) Radiother Oncol. 2014;112:52-8; (5) Surg Oncol. 2013;22:22-35
(6) Int J Radiat Oncol Biol Phys. 2014;88:618-23; (7) Int J Radiat Oncol Biol Phys. 2015;92: ; (8) Int J Radiat Oncol Biol Phys. 2006;64:235-41; (9) BMC Cancer. 2014;14:617
(10) J Surg Oncol. 2014;109: ; (11) Strahlenther Onkol. 2014;190:891-8; (12) Radiother Oncol. 2016; (13) Ann Surg Oncol Suppl 3: ; (14) Int J Clin Oncol. 2016
Additional references:
Pancreas: Semin Radiat Oncol. 2014; 24:126-31; Extremity recurrent sarcomas: Sarcoma. 2015;:91:3565; Rectal cancer: Am J Clin Oncol. 2015;38:11-6; Pediatric sarcomas: Int J Radiat Oncol Biol Phys. 2014;90:

7. Breast: IOeRT Clinical Results
ASTRO and ESTRO guidelines has been published for Partial Breast Irradiation. Patients are divided in 3 risk groups according to age, tumor size, lymphnodes status etc.
All low risk group patients can be treated with a single dose (ELIOT Protocol) and all the others can be treated with boost (HIOB protocol).
LOW RISK
MEDIUM RISK
HIGH RISK

8. IOeRT as BOOST - HIOB LOW RISK MEDIUM RISK HIGH RISK
Breast: IOeRT Clinical Results
IOeRT as BOOST - HIOB
LOW RISK
MEDIUM RISK
HIGH RISK
Such Patients Groups can be treated according to HIOB IOeRT Boost decrease significantly the EBRT fractions (33 to 15) and provide both excellent LR and OS at 5 years.

9. IOeRT as single dose - ELIOT
Breast: IOeRT Clinical Results
IOeRT as single dose - ELIOT
LOW RISK
Excellent LC at 5 years: 98.5%

10. ELIOT Advantages Breast: IOeRT Clinical Results
TIME SAVING: ONE MINUTE of irradiation inside the operating room avoids FIVE WEEKS of external radiotherapy.
Many women live far away from a
Radiotherapy institute:
How many km (and €) saved ?!
PATIENT QUALITY OF LIFE.
DRASTIC REDUCTION OF WAITING LISTS IN RADIOTHERAPY.

11. ELIOT Advantages Breast: IOeRT Clinical Results
Single Fraction Replaces 6 Weeks of Whole Breas Irradiation (WBI).
Less Normal Tissue Toxicity (Heart, Lungs, Ribs, Skin)
Very Short Treatment Time (1-2 minutes).
Allows for Immediate and Quicker Oncoplastic Reconstruction .
Allows Irradiation of Microscopic Disease that May Extend 2-3 cm Beyond the Original Tumor.
All Margins Receive a Minimum Dose of 18 Gy.
May Allow More Women to Choose Breast Conservation.
Better Cosmesis.
Silverstein MJ, Fastner G, Maluta S, Reitsamer R, Goer DA, Vicini F, and Wazer D. Intraoperative Radiation Therapy: A Critical Analysis of the ELIOT and TARGIT Trials. Part 1—ELIOT. Annals of Surgical Oncology (2014) 21:

12. Electrons vs. low energy X rays: a comparison
What is the clinical value of this radiation treatment?
Electrons 12 MeV applicator  60 mm
X ray 50 KV
applicator  25 mm
Consider a patient, who has a 2 cm tumor removed along with a small margin and her incision is sutured in such a way the target to be irradiated is 3 cm thick.
For LIAC the recommended settings would be 60 mm diameter applicator, 12 MeV energy and 21 Gy prescribed at 3 cm. The effective irradiated volume inside 90% isodose is a cylinder with a diameter about 50 mm and a depth of 32 mm, for a total volume of about 63 cm3.
The Electrons treatment takes less than 2 minutes.

13. Electrons vs. low energy X rays: a comparison
What is the clinical value of this radiation treatment?
Electrons 12 MeV applicator  60 mm
X ray 50 KV
applicator  25 mm
Consider a patient, who has a 2 cm tumor removed along with a small margin and her incision is sutured in such a way the target to be irradiated is 3 cm thick.
Intrabeam using a 25 mm applicator and 20 Gy at the surface of the applicator.
The volume treated within the 90% isodose is less about 2,1 cm3.
The volume treated within the 50% isodose is less than 7,4 cm3.
The soft X ray treatment takes between 35 and 50 minutes.

14. How a dedicated IOeRT accelerator must be?
Maximum mobility, able to move inside standard hospital space (elevators, doors…): mobile unit dimensions 210 x 76 x 180 cm.
Not isocentric but capable of performing easily and safely docking process; 5 degrees of freedom each other independent.
As small and light as possible; mobile unit weight 400 Kg. The impact on the OR is minimum: plug and play accelerator.
Different energies up to 12 MeV: a PTV with thickness up to 3.2 cm can be irradiated inside the 90% isodose (up to 3.8 cm inside the 80% isodose).
Multiple fields; biocompatible, sterilizable and transparent applicators, for a better treatment documentation.
Characterized by an easy, fast and safe docking procedure: all of this is hard docking.
Accessorized with radioprotection discs for shielding healthy tissues during breast cancer treatment.
User-friendly interface; dedicated software for dose evaluation according to international protocols, treatment documentation (ICRU 71) and LIAC Monte Carlo simulation. MU are 1 cGy with reference applicator.

15. How a dedicated IOeRT accelerator must be?
Maximum mobility, able to move inside standard hospital space (elevators, doors…): mobile unit dimensions 210 x 76 x 180 cm.
LIAC Dimensions

16. How a dedicated IOeRT accelerator must be?
Not isocentric but capable of performing easily and safely docking process by mean of 5 degrees of freedom each other independent.
LIAC Radiant Head Movements
Elevation 90 cm Roll angle ± 60° Pitch angle °, -15°
LIAC has got five degrees of freedom. The radiant unit moves in the plane and the radiant head has three independent degrees of freedom.
The remote control offers a selection between 4 different speeds, from the cruise one down to the very slow one designed for docking.

17. How a dedicated IOeRT accelerator must be?
Not isocentric but capable of performing easily and safely docking process by mean of 5 degrees of freedom each other independent.
LIAC movability in an Operating Room
Roll angle ±60°
Elevation 90 cm
Pitch angle °, -15°

18. How a dedicated IOeRT accelerator must be?
As small and light as possible; mobile unit weight 400 Kg […]
LIAC Technical Data Sheet

19. How a dedicated IOeRT accelerator must be?
[…] The impact on the OR is minimum: plug and play accelerator.

20. How a dedicated IOeRT accelerator must be?
[…] The impact on the OR is minimum: plug and play accelerator.
FROM DELIVERY TO THE FIRST TREATMENT
Delivery: LIAC is uncrated and driven to the OR
(OFFLINE) Signaling and interlocks system installation
DAY 1
Installation Check: LIAC is connected to the OR signaling and alarm system in order to check its correct behavior
DAY 2-3
LIAC dosimetric check
DAY 4
On-site Training for IOERT Operating Staff
DAY 5
First patient treatment

21. How a dedicated IOeRT accelerator must be?
As small and light as possible; mobile unit weight 400 Kg The impact on the OR is minimum: plug and play accelerator.
LIAC allows radiation therapy solutions for any Oncologic Surgical Center without requiring any specific facility, e.g. bunkers or any shielded Operating Room.

22. How a dedicated IOeRT accelerator must be?
Different energies up to 12 MeV: a PTV with thickness up to 3.2 cm can be irradiated inside the 90% isodose (up to 3.8 cm inside the 80% isodose)
LIAC Technical Data

23. How a dedicated IOeRT accelerator must be?
Multiple fields, biocompatible, sterilizable and transparent applicators, for a better treatment documentation.
Applicator drawing. Eight diameters (D) available:
30, 40, 50, 60, 70, 80, 100 and 120 mm.

24. How a dedicated IOeRT accelerator must be?
Multiple fields, biocompatible, sterilizable and transparent applicators, for a better treatment documentation.
Applicator terminal bevel angles: 0°, 15°, 30° and 45°diameter
100 mm is reported as an example
LIAC applicators are made in PMMA.

25. How a dedicated IOeRT accelerator must be?
Multiple fields, biocompatible, sterilizable and transparent applicators, for a better treatment documentation.
LIAC Applicator – why PMMA ?
It allows hard docking.
It is transparent.
It increases the surface dose up to 90% and higher  no need of bolus
It is fully compatible with X ray imaging.

26. How a dedicated IOeRT accelerator must be?
Characterized by an easy, fast and safe docking procedure: all of this is hard docking.
LIAC adopts an hard docking procedure for physically connect the applicator holder to the terminal.
This allows:
To execute the docking procedure in the easiest and fastest way: an experienced staff usually execute such process in less than 5 (five) minutes.
To apply the safest procedure: more than 20 (twenty) years of application and (fifteen thousand) treated patients.
Ever feasible in any condition and for any district (thanks to LIAC extreme mobility).
Reliable: certain and fully repeatable beam collimation.

27. How a dedicated IOeRT accelerator must be?
Accessorized with radioprotection discs for shielding healthy tissues during breast cancer treatment.
LIAC Accessories: Patient Radioprotection Disk PATENTED
Italian Patent
Device for healthy tissues radioprotection to be used in breast carcinoma Intra Operative Radio Therapy treatment. The device is very effective in shielding healthy tissues and is fully biocompatible.
6 mm of total tickness: 3 mm of PTFE and 3 mm of AISI 316L

28. How a dedicated IOeRT accelerator must be?
Easy and user-friendly interface; dedicated software for dose evaluation according to international protocols, treatment documentation (ICRU 71) and LIAC Monte Carlo simulation. MU are 1 cGy with reference applicator.
LIAC software tools:
SWL - LIAC Monte Carlo Simulation.
SWL - LIAC MU Calculus and QA stability check.
SWL - LIAC Dosimetric Tool KSAT
SWL - LIAC Dosimetric Tool KQ,Q’
SWL - LIAC PC interface.

29. How a dedicated IOeRT accelerator must be?
[…] LIAC Monte Carlo simulation.
LIAC Monte Carlo Simulation
It is based on a Monochromatic Beam Simulation Library.
LIAC Monte Carlo Simulation by means of optimization algorithm and four experimental PDD reconstructs LIAC Spectrum and generates the entire dosimetric characterization.
Greatly speeds up the Commissioning Process.
Only random checks are needed.

30. How a dedicated IOeRT accelerator must be?
[…] LIAC Monte Carlo simulation.
Example of LIAC Monte Carlo Simulation: LIAC Output Factor calculation

31. CONCLUSIONS
IOeRT has proven to be an efficient and effective technique for treating a wide class of malignancies.
For breast carcinoma treatment there are tw international recognized and successfully applied protocols for single dose application (ELIOT) and boost (HIOB).
LIAC is the dedicated IOeRT mobile linac which allows to perform any treatment inside any OR, thanks to its small dimensions/weight and its high mobility.
LIAC allows to deliver the treatment in the shortest time, less than two minutes.
LIAC, thanks to its four selectable energies, allows to treat any target with thickness up to 3.2 cm inside 90 % isodose (up to 3.8 cm inside 80% isodose).
LIAC is commissioned and installed in less than one week time
LIAC can be safely and easily moved between two (or more) hospitals in order to maximize quality of service offered to patients

32. SIT MAP - LIAC and NOVAC Installed

33. An added value to the technique:
the IOeRT Platform

34. IORT & Radiobiology: where do we stand ?

35. IORT & Radiobiology - open issues 1: LQ model
Is the linear quadratic model meaningful for a single fraction ?

36. IORT & Radiobiology : open issues - 1

37. IORT & Radiobiology : open issues - 1

38. IORT & Radiobiology - open issues 2: dose rate
IORT LINAC
EBRT LINAC
The dose per pulse generated by IORT linacs is up to times higher respect to the standard
S.I.T. S.p.A.