IORT State of the Art and Beyond

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1 IORT State of the Art and Beyond Marco Krengli Dept. of Radiotherapy University of Piemonte Orientale A. Avogadro University Hospital Maggiore della Carità Novara, Italy

2 No conflicts of interest

surgical procedure while sparing the surrounding healthy tissues Dose

3 IORT Definition IORT (Intra-Operative Radiation Therapy) is a Radiotherapy Technique allowing to deliver a relevant dose during the surgical procedure while sparing the surrounding healthy tissues Dose intensification Normal tissue protection Better tumor control Less side effects

IORT Historical Notes March 11 1905: first IORT treatment (with orthovoltage) of cervical carcinoma in a 33 y/o woman

4 IORT Historical Notes March : first IORT treatment (with orthovoltage) of cervical carcinoma in a 33 y/o woman operated by hysterectomy, pelvic node dissection, and partial cystectomy. The treatment was performed by Comas and Prio in Barcelona.

5 IORT Historical Notes (courtesy of F. Calvo)

6 IORT Technical Aspects

7 IORT Organizational Aspects Conventional Linac with patient s transportation Conventionl Linac in operating room Dedicated mobile Linac mobile operating room Targit Brachiterapia (peri-operatoria)

8 IORT Organizational Aspects Guidelines for Quality Assurance in IORT Istituto Superiore di Sanità, Rome - Structural aspects - Machines - Professionals - Organization of clinical activity WEBSITE: - Analysis of costs

9 IORT Biological Aspects Effect of Single High Dose (Fuks, Cancer Cell, 2005)

10 IORT Biological Aspects Effect of Single High Dose Target = membrane of endothelial cells Dose >8 Gy kills cript stem cells (Potten 1990) Dose >10 Gy causes endothelial cell apoptosis (max effect 25 Gy) (Garcia-Barros 2003)

11 IORT - Biological Aspects Normal Tissue Tolerance (animal models) Vessels (aorta and vena cava) Peripheral nerves Surgical anastomosis

12 IORT - Clinical Indications Breast cancer Rectal cancer Gastric cancer Pancreatic cancer Biliary tract cancer Esophageal cancer Lung cancer Soft tissue sarcoma Head & Neck cancers Brain glioma Gynecological cancer Bladder cancer Renal cancer Prostate cancer Pediatric cancers

13 IORT - Clinical Indications IORT as a boost (dose escalation) IORT as a single treatment (dose de-escalation)

14 IORT - Clinical Indications Breast Cancer (Ruano-Ravina, Cancer Letters, 2011)

15 IORT - Clinical Indications Breast Cancer (Ruano-Ravina, Cancer Letters, 2011)

$single fraction Inclusione criteria: Age 45, T2-T3 tumour, N0-N1$

16 Vaidya S. et al. Intrabeam - low energy x-rays - 50 kv maximum IORT dose: 20 Gy in single fraction Inclusione criteria: Age 45, T2-T3 tumour, N0-N1 nodal status 28 centres in 9 countries (UK, USA, Germany, Italy, Poland, Switzerland, Denmark, Canada, Australia)

17 Vaidya S. et al. The local recurrence rate in the targeted intraoperative radiotherapy group was not significantly different from that in the external beam radiotherapy group (1.2% vs 0.95%, p=0.41 at 4 years). This large, international randomised trial provides robust and mature evidence that targeted intraoperative radiotherapy is safe.

18 IORT - Clinical Indications Rectal Cancer

19 Preop. EBRT: 40 Gy + IORT: 18 Gy Preop. EBRT: 40 Gy

Pts: 605 with local advanced rectal cancer (LARC) who underwent multimodality treatment up to 2005.

20 Pts: 605 with local advanced rectal cancer (LARC) who underwent multimodality treatment up to The basic treatment principle was preoperative (chemo)radiotherapy, intended radical surgery, IORT and elective adjuvant chemotherapy (act). Results: Chemoradiotherapy lead to more downstaging and complete remissions than radiotherapy alone (P < 0.001). It is difficult to study the quantitative effect of IORT, but 5-year LR rate of 12% is very low in this high-risk group of patients. Further, 55% of the patients with positive surgical margins did not develop LR, suggesting that these residual tumor cells were sterilized.

21 IORT - Recurrent Rectal Cancer Series Pts IORT EBRT *OS *Local year (Gy) (Gy) 5 yrs Control Haddock (42pts) % 60% 2001 (5-FU) Lindel % 47% 2001 (5-FU) Alektiar (HDR) +/ % 43% 2000 (5-FU) Mannaerts % (3ys) 73% (3 y) 2001 Valentini % 79% 1999 (5-FU) * microscopic positive margins

22 IORT - Clinical Indications Gastric Cancer Randomized Trials: Surgery vs S+IORT (28-35Gy) Takahashi M and Abe M, 86 Surg +RT (50 Gy) vs p= (Local Control) Surg +IORT (20 Gy) Sindelar WF et al Surgery vs p=ns (OS) p=0.04 in N+ Preop 20Gy+S+IORT(20Gy) Skoropad VY et al. 2000

23 IORT - Clinical Indications Gastric Cancer

24 IORT as a single modality or in combination with low dose of preoperative radiotherapyfailed to show a statistically significant benefit.studies without IORT showed a statistically significant improvement in survival at both 3 and 5 years of follow-up.

25 IORT - Pancreatic Cancer (Ruano-Ravina, Radiother Oncol, 2008)

26 IORT - Pancreatic Cancer (Ruano-Ravina, Radiother Oncol, 2008)

Local Control Overall Survival Overall survival stratified on the basis

increases the effects of IORT in terms of local control and overall

27 Local Control Overall Survival Overall survival stratified on the basis of the freedom from local recurrence <2 years (blue line) or >2 years (red line). From this joint analysis emerges the fact that preoperative radiotherapy increases the effects of IORT in terms of local control and overall survival (theory of filter-induction ). The 5-year local control of 23.3% confirms the beneficial sterilizing effect of IORT on the tumor bed.

29 IORT - Clinical Indications Biliary Tract Cancer CENTER TUMOR CHARACTERISTICS TREATMENT SURVIVAL Todoroki, Tsukuba University Japan, pts IVA Klatskin tumours 47 pts micr. res. tumour S+/-IORT+/- EBRT vs 33.9% 5y (39.6% 5y IORT+EBRT) 13.5% 5y Surgery alone Lindell, 20 pts S+IORT+EBRT 47% 5y Lund Hospital, Sweden, 2003 Locally advanced (10 IORT) vs Surgery alone 13% 5y

30 Author Tot. Pts IORT - Esophageal Cancer Site of IORT Surgery Toxicity of IORT Loco-regional rec. (%) Survival (%) 2 aa 3 aa 5 aa FEASIBILITY STUDIES WITH VARIOUS IORT DOSE Arimoto et al N MEDIAST. IORT: 25Gy o 20 Gy o 15 Gy o 18 Gy Tracheal ulcer in 6 pts with 25Gy none Hosokawa et al N MEDIAST. IORT :20-25 Gy o Gy o 12 Gy Tracheal ulcer with 25 Gy none Miller et al N ABDOMINAL IORT: 10-25Gy nv CT-RT + SURGERY AND IORT VS CT-RT EXCLUSIVE Murakami et al (T1-T2) N ABDOMINAL IORT : Gy none nv - 90% CT-RT+ S + IORT vs 80% CT-RT excl. - Murakami et al (T3-T4) N ABDOMINAL IORT : Gy none nv - 30% CT-RT+ S + IORT vs 48% CT-RT excl. - SURGERY+IORT VS SURGERY ALONE Murakami et al N ABDOMINAL IORT : Gy none N abdominal : 8% S + IORT vs 24% S alone 46% CT- RT+ S + IORT vs 56% CT-RT excl. - -

31 IORT - Esophageal Cancer mediastinum Limit: subclavian artery Field about 8 x 4 cm Lower to the tracheal biforcation Anteriorly to trachea and posteriorly to vertebrae

32 IORT - Esophageal Cancer

33 IORT Lung Cancer (NSCLC) Series Pts IORT EBRT OS Local year (Gy) (Gy) 5 yrs Control Martinez-M* % (4ys) 91% (4ys) 1994 Aristu % (IIIA) DDP-based CT Van Geel* % (2ys) 85% (2ys) Jaske % (3ys) 68% (3ys) 2007 * Superior sulcus tumor Phase II Study Preop CT-Surg/IORT-Postop RT

34 IORT Retroperitoneal STS Series Pts EBRT IORT OS Local year (Gy) (Gy) 5 yrs Control Sindelar % 60% % 40% Petersen % 59% 2002 Alektiar* (HDR) 45% 62% 2000 Gieschen** % 59% 2001 Azinovic % 53% 2001 Krempien % 40% 2006 Randomised study (P<0.001) *IORT-HDR; **Pre-op RT

35 IORT Extremity STS Series Pts year EBRT IORT OS Local (Gy) (Gy) 5 yrs Control Rochbauer (HDR) - 100%(2ys) 2003 Azinovic *75% 88% 2003 Kretzler % 84% 2004 Krempien % 78% 2006 *Primary tumors

36 IORT Head & Neck Cancer Advanced T-stage Nag 1997 (Ohio University) (40 pts) Larynx 32%, oral cavity 26%, oropharynx 8%, hypopharynx 8%, paranasal sinus 8% 20 pts IORT (6-9 MeV e-), Dose Gy 20 pts HDR-IORT, Dose Gy EBRT 50 Gy was added in 28 pts LC and OS 50% and 33% vs. 79% and 88% with EBRT No stat. difference between IORT by e- and by HDR Pinheiro 2002, Mayo Clinic (34 pts, 56% skull base, 44% neck) Dose IORT Gy, (6-15 MeV) SCC vs. non-scc : LC 46% vs. 52%; OS 32% vs. 50%, DFS 21% vs. 40% IORT safe with dose of 20 Gy or less (one neuropathy in pt treated with 22.5 Gy)

37 IORT Recurrent H&N Cancer after RT Chen (UCSF) 2007 (137 pts) Sites: oropharynx 24%, oral cavity 23%, 12% paranasal sinuses, 7% hypopharynx, 6% salivary glands, 6% skin, 3% nasopharynx, 3% larynx, 2% ear, 2% others IORT dose Gy (median 15 Gy), e- 6 MeV LC In-field IORT at 1,2,3 anni: 70, 64, 61% Positive margins are predictive for recurrence in IORT field (p=0.002) OS correlates with site of recurrence (44% T 19% N, p=0.001) Loco-regional control, DMFS and OS at 3 yrs: 51, 46, 36% No perioperatory mortality Complications in 7% (infections, fistolae, necrosis, trismus, neuropathy)

IORT Brain Glioma (recurrent) Author # IOERT dose Shibamoto 1994 Histology Median survival (months) 9 23 40 Gy AA / GBM 12 Matsutani 1994

39 IORT Brain Glioma (recurrent) Author # IOERT dose Shibamoto 1994 Histology Median survival (months) Gy AA / GBM 12 Matsutani 1994 Willich 1997 Ortiz de Urbina 1999 Schueller Gy GBM Gy AA / GBM Gy AA / GBM Gy AA / GBM 12.5

40 IORT Gynecological Cancer CENTRE # pts TUMOUR CHARACTERISTICS TREATMENT LOCAL CONTROL SURVIVAL Mahe, 70 Recurrent cervix S+IORT 75% 3y 8% 3y French Intraop.Gr., 1995 (10-25 Gy) +/- EBRT+/-CT No sign. diff. with IORT No sign. diff. with IORT Martinez- Monge, Univ.Navarra Cervix: 31 primary 36 recurrent EBRT+CT (primary)+ S+IOERT (12-15 Gy) 69% 10y 93% prim. 46% rec. 15% tox. pain and neuropathy Liu, Xi an Jiaotong University (China), Cervix, stage IIB EBRT +S + IORT (18-20 Gy) RT only EBRT+BRT - 95% 5y (91% adenoca) 88% 5y (33% adenoca) Dowdy, Mayo Clinic, Recurrent endometrial S+IORT (10-25 Gy) +EBRT(84%) - 47% 5y Tran, Stanford, CA Recurrent S+IORT ( Gy) +EBRT(53%) 44% 5y 47% 5y (DSS)

41 HDR-IORT Gynecological Cancer CENTRE # pts TUMOUR CHARACTERISTICS TREATMENT LOCAL CONTROL SURVIVAL Gemignani, MSKCC, Recurrent Cervix 53% Uterus 41% Vagina 6% S+HDR- IORT (mean 14Gy) 67% 3y (83% gross resection, 25% partial resection) 54% 3y (OS) Orr, Ft.Myers,FL Persistent/Recurrent S+HDR- IORT (mean 20Gy) 86% mos (mean OS)

42 IORT Bladder Cancer Bladder-preservation protocol Radiotherapy + cystotomy and IOERT The bladder has been opened superiorly and the treatment cylinder is angled laterally to avoid irradiating the right ureteral orifice and the rectum. Electron beams of 15 to 18 MeV, that penetrate 4 to 5.5 cm are necessary to treat the extra-vesical extensions of these advanced tumors. The treatment cylinder is angled latero-inferiorly so that the anus, rectum, and prostate or lower vagina are not in the path of the exit beam. (Shipley WU, Cancer 1987)

43 IORT Bladder Cancer Brachytherapy or IOERT Author # Clinical stage Treatment 5 year Local Control 5 year Survival van der Werf-Messing et al 328 T2 EBRT, Ra % 56% Batterman et al 85 T2 EBRT, Ra % 55% Mazeron et al 24 T2 Resection, Ir-192, EBRT 92% 58% Matsumoto et al 28 T2 IOERT, EBRT 82% 62% Nieuwenhuijzen et al 108 T1-T2 EBRT, Ir % 62% van Onna et al 111 T1-T2 EBRT, Ir % van der Steen-Banasik et al 76 T1-T2 EBRT, Cs-137, Ir % 57% Blank et al 122 T1-T2-T3 EBRT, Ir % 73% Rostom et al 27 T2-T3 IOERT, EBRT 81% 53% Preservation of bladder function in more than 75% of patients with solitary tumors that invade into but not beyond the bladder muscle

IORT Bladder Cancer Intra/Peri-Operative Brachytherapy This technique was introduced and developed in the Netherlands by Brigit Van der Werf- Messing and has

44 IORT Bladder Cancer Intra/Peri-Operative Brachytherapy This technique was introduced and developed in the Netherlands by Brigit Van der Werf- Messing and has been employed mainly in France (Hoffstetter 1998, Mazeron 1988, Pernot 1996, Rozan 1992) and in Belgium (Soete 1997, Van Poppel 2000). (Courtesy of J.P. Gerard)

122 pts; pathologic stage distribution was: 30 pt1, 81 pt2, and 11 pt3 Tx: EBRT SURGERY BRT (99 LDR, 23 PDR) 5-yr local was 76% and distant relapse-free survival 83% 5 and 10-yr relapse-free survival

45 122 pts; pathologic stage distribution was: 30 pt1, 81 pt2, and 11 pt3 Tx: EBRT SURGERY BRT (99 LDR, 23 PDR) 5-yr local was 76% and distant relapse-free survival 83% 5 and 10-yr relapse-free survival were 69% and 66%, respectively 5 and 10-yr OS were 73% and 49%, respectively Toxicity was low. No differences were found between the LDR and PDR groups. In the Netherlands, a nationwide evaluation of bladder-saving techniques is underway.

46 IORT - Clinical Indications Renal Cancer Institution # pts Dx Tx Local control Survival Comment Santos 1989 Univ. Navarra 11 Stage III- IV S+IOERT (10-20 Gy)+EBRT 5/11 long survivors 3/11 long survivors No toxicity Eble 1998 Univ. Heidelberg 11 3 primary 8 recurrent S + IOERT(15-20 Gy) + EBRT 100% 4y No toxicity Master 2005 UCSF 14 Locally advanced S +/- IOERT - 5y No difference for IOERT Hallemaier 2012 Mayo Clinic 22 3 primary 19 recurrent S + IOERT (10-20 Gy) + EBRT 73% 5y 10y 23% grade III-V toxicity In patients with LR recurrent or LR advanced primary RCC, a multimodality approach of perioperative EBRT, maximal surgical resection, and IOERT yielded encouraging results. This regimen warrants further investigation (Hallemaier, 2012).

47 IORT - Clinical Indications Prostate Cancer High risk, locally advanced Conventional approaches (S/EBRT/HT): 37-62% Relapse-Free 5 yrs 40% Local Failure after radical prostatectomy

48 IORT - Clinical Indications Prostate Cancer Low α/β value for prostate cancer Analysis of 5,969 pts: α/β = 1.4 (95% CI = ) Gy (Miralbell, IJROBP, 2011) High sensitivity to dose/fraction (rationale for single dose and hypofractionated protocols) The administration of high doses per fraction may represent a potential advantage for local control for prostate cancer.

49 IORT - Prostate Cancer Author # Patients selection Takahashi Stage B2-D2 Surgical approach IORT Energy / Dose EBRT Perineal No RP MeV / Gy (single dose) Gy combined with EBRT 50 Gy to pelvic lymph nodes Abe Stage B2-D2 Perineal No RP 8-14 MeV / Gy (single dose) or Gy combined with EBRT 50 Gy to pelvic lymph nodes Higashi Stage B-C Perineal/retropubic No RP Gy 30 Gy, 2 Gy/fx Kato Stage B2-D1 Perineal/retropubic No RP Gy 30 Gy, 2 Gy/fx Orecchia Interm.- high risk Retropubic IORT-RP 8-10 MeV / 12 Gy 45 Gy, 1.8 Gy/fx Saracino Interm. risk Retropubic RP-IORT 7-9 MeV / Gy (dose escalation) no Rocco Interm.- high risk Retropubic IORT-RP 8-10 MeV / 12 Gy 45 Gy, 1.8 Gy/fx Krengli Interm.- high risk Retropubic IORT-RP 9-12 MeV / Gy Gy, 2 Gy/fx

50 IORT - Prostate Cancer High risk, locally advanced No prostatectomy - Japanese series: (Takahashi, 1985) - Kyoto University (first report by Abe in 1975) - Saitama Cancer Center

51 IORT - Prostate Cancer Intermediate and High risk, locally advanced - Italian series : (Saracino, 2008) (courtesy of R. Orecchia) - Inst. Regina Elena, Rome (after prostate removal) - EIO, Milan; UH of Novara (before prostate removal)

52 Author Local control and F/U Takahashi % (4-140 mos) Abe yrs IORT - Prostate Cancer Survival Higashi % (stage B), 87% (stage C) 5 years Toxicity - Delayed wound healing of perineal incision No severe IORT related 72% 5 years 100% early hematuria 10% early pollakiuria 1 chronic cystitis, 1 late urethral stricture No critical cystitis, proctitis, anal bleeding Kato yrs 89% DSS, 74% 5 yrs 20% early rectal G3-G4 (without rectal spacer) 7% early rectal G3 (with rectal spacer) Orecchia Peri-operative: 1 lymphocele, 3 anastomotic leakage Saracino % (19-59 mos) Rocco % 2 yrs, 100% OS (3-24 months) Krengli % (6-46 mos) 77% 3 years No urinary or rectal toxicity G1 82% BRFS, 100% OS (6-46 months) GU: 17% G 2 (early), 7% G 2 (late) GI: 10% G 2 (early), 0% G 2 (late) Peri-operative: lymphocele 16%, hematoma 6%; After EBRT: 11% G2 early rectal G2 11%, early urinary G2 4%; bladder neck stricture 7%

CLINICAL SERIES From September 2005 to February 2011: 70 pts with prostate ca., high-risk Median ipsa (IQR, min-max), ng/ml Mean post-op. PSA Pathological GS (median) Positive surgical margins pn+ 17.

53 CLINICAL SERIES From September 2005 to February 2011: 70 pts with prostate ca., high-risk Median ipsa (IQR, min-max), ng/ml Mean post-op. PSA Pathological GS (median) Positive surgical margins pn ( , ) 0.04 ng/ml 9 44/70 (62.8%) 19/70 (27.1%) Inclusion Criteria (at least 2 of the following) PSA tot. > 10 ng/ml Gleason Score 7 Stadio Clinico ct2c 24% Stadio Patologico pt2c 30% Clinical Stage ct2c > 2/3 positive biopsies Probability of organ confined disease < 25% (Kattan nomogram MSKCC) > ct2c 76% Basato su DRE, TRUS o TC > pt2c 70%

54 METHOD Prostate exposure ANTERIOR CAUDAL APEX Intra-op. US RECTUM Diameter of collimator: cm Energy of electrons: 9 (47%) - 12 (53%) MeV TARGET VOLUME: Prostate with 5-10 mm margin Mobetron, Intraop Dose (12 Gy, isodose 90%) as anticipated boost

55 Rectal Dosimetry Mean dose to the anterior rectal wall was 4.8 Gy (range: Gy) Rectal probe (diameter: 2.5 cm) Anterior Posterior 4 radio-chromic films positioned on the surface Laterals

Results after S + IORT + EBRT (pts with more that 12 mos F/U) G3

2% Tossicità GU acuta G2 17% G1 24% Acute GU toxicity G0 57%

tardiva GU G3 4% Late GU toxicity Biochemical Recurrence Free

56 Results after S + IORT + EBRT (pts with more that 12 mos F/U) G3 2% Tossicità GE Acuta G2 15% G1 15% Acute GI toxicity G0 68% G3 2% Tossicità GU acuta G2 17% G1 24% Acute GU toxicity G0 57% Late GI toxicity 1,0 G1 2% G2 2% G2 9% G4 G3 4% 9% Tossicità tardiva GU G3 4% Late GU toxicity Biochemical Recurrence Free Survival 0,8 0,6 0,4 0,2 0,0 5 yrs follow-up (months) 60 G0 85%

IORT Pediatric Cancer 2000-2009: 44 consecutive patients IORT after gross total resection of recurrent/persistent tumor.

57 IORT Pediatric Cancer : 44 consecutive patients IORT after gross total resection of recurrent/persistent tumor. IORT after re-resection of locally recurrent/persistent neuroblastoma results in a reasonable rate of local control with acceptable morbidity and survival. This approach should be considered in this high-risk population.

58 Future Perspectives Treatment Planning Coordination of multicenter prospective clinical trials Biological Research in IORT

59 Future Perspectives Treatment Planning Multiplanar reconstruction in pancreatic cancer

60 Future Perspectives Treatment Planning Multiplanar reconstruction in solitary fibrous tumor

61 Future Perspectives Treatment Planning Multiplanar reconstruction and volume rendering Simulation Previsional dosimetry (courtesy of Radiance )

62 HOW IS IT DONE? FIX THE APPLICATOR IN THE OR TRANSPORT TO THE SCAN SCAN OF THE PATIENT INTRA IMAG

WORKFLOW SEGMENTATION SIMULATION DOSE COMPUTATION

Organs to protect Resected Volume (surgery) Tumor bed

and bevel Cone position and orientation Select enery

images to confirm that the dose at the selected

63 WORKFLOW SEGMENTATION SIMULATION DOSE COMPUTATION Gross Tumot Volume (GTV) Clinical Tumor Volume (CTV) Organs to protect Resected Volume (surgery) Tumor bed (PTV) Surgical frame Patient orientation Cone diameter and bevel Cone position and orientation Select enery which covers the target volume Use the DVH and 2D/3D images to confirm that the dose at the selected percentage covers the target area protecting the risky healthy areas

64 Future Perspectives Coordination of Clinical Trails by ISIORT? ISIORT EUROPE Registry Joint analysis of data from centers within the ISIORT- Europe program to investigate the role of intraoperative radiotherapy (IORT) by collecting information on tumour presentation and treatment modalities.

65 ISIORT EUROPE Registry Available data ( ): 3,754 cases

66 ISIORT EUROPE Registry Available data ( ): 3,754 cases

67 Future Perspectives Biological Research in IORT

68 Conclusion Available data show a favourable impact on local control and, in selected tumour sites, in OS when IORT is used as dose-intensification treatment The use of IORT as a single radiation treatment requires specific validation by prospective controlled clinical trials as in breast cancer Technological and biological advances may allow a development of IORT clinical activity in the frame of customized protocols based on biological knowledge of tumour cell characteristics

69 7 th International Conference June 22-24, 2012 Grand Hotel Dino, Baveno, Italy

ISIORT Conference September 25-27, 2014 Cologne/Germany Cologne Marriott Hotel

8th International ISIORT Conference September 25-27, 2014 Cologne/Germany Cologne Marriott Hotel IORT for genitourinary malignancies Marco Krengli Dept. of Radiotherapy University of Piemonte Orientale