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Intra Operative Radiotherapy

Intraoperative RT

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Intra Operative Radiotherapy

  1. 1. Intraoperative Radiotherapy (IORT) Dr Sasikumar Sambasivam DNB Resident Dept. of Radiation Oncology
  2. 2. Introduction • In many clinical situations the dose delivered by external beam radiation therapy (EBRT) techniques is limited by tolerance of surrounding normal tissues. • To overcome this, intraoperative irradiation has been employed as a technique facilitating tumor dose escalation.
  3. 3. • Intraoperative radiotherapy (IORT) is a technique where – a high, single-fraction radiation dose is delivered during a surgical procedure to macroscopic tumors or tumor beds with minimal exposure of surroundings tissues which are displaced and shielded during the procedure. – The radiation may be delivered using: • IOERT or • IOHDR (flab method)
  4. 4. Rationale for IORT Advantages: 1.Reducing the chance of residual disease at the site of surgery by eliminating microscopic tumor foci; 1.Maximizing the radiobiological effect of a single high dose of radiation with attainment of total dosage that exceed those of EBRT; 1.Optimizing the timing of the combined surgery and radiotherapy earlier irradiation & avoidance of accelerated repopulation.
  5. 5. 4. The combination of IOERT with EBRT – Improves the therapeutic ratio of local control versus complications by: • reducing the volume of the irradiation “boost” field by direct tumor/tumor bed visualization and conformal treatment; • exclusion of part or all of dose-limiting normal structures by operative mobilization, direct shielding, or varying electron beam energy; and • allowing the delivery of high-dose irradiation by the just- mentioned methods.
  6. 6. Shortcomings 1. Dedicated equipment (mobile linac/HDR machine). 2. Well equiped & shielded OT with appropriate radiation safety. 3. Multidisciplinary team work. 4. Higher risk of late effects, such as fibrosis, in late responding tissues (with alpha/beta values of <3).
  7. 7. IOERT HDR-IORT Pioneer Abe (kyoto, early 1960s) Munich (1991) Machine Betatrons  linacs(fixed/portable) HDR machine (portal) Source 3-12Mev (however not higher) Higher dose/pulse  shorter t/t time (2-3 min for 20 Gy). Iridium Dose prescription Dmax / 90% isodose curve 1 cm from the plane of implant (0.5 cm from implant surface) Dose lesser @ surface Dose @ depth •Higher •More homogenous Higher @ surface Applicators Electron cones •Cylindrical/square/rectangular •Sizes (upto 10-12 cm) •Flat end/ bevelled •Harrison-Anderson-Mick(HAM) applicator. •Superflab applicator •Transparent tansfer tubes Procedure Shorter t/t time & easier setup Limited geometry Relatively complex Any geometry Cost Costlier Relatively cheaper Sites Only superficial & accessible As electrons travel straight paths Unsuitable for: •pelvic locations, •anterior abdominal wall, •sub-diaphragmatic areas, •anterior and/or lateral interior chest wall, •Narrow cavities like the paranasal sinuses. Any site / surface
  8. 8. Impact on Local Tumor Control • Improved local control (LC) often improves survival. • If Microscopic residual disease + – EBRT doses necessary to achieve LC are >60 Gy in 1.8- to 2-Gy fractions. – The aggressive EBRT philosophy • May allow better local tumor control • But with severe treatment-related complications. • Preferred alternative in locally advanced malignancies – tolerable EBRT doses of 45 to 50 Gy preoperatively (1.8-Gy fractions) and IORT • Advantage over only EBRT – increase in LC – lower risk of complications.
  9. 9. Patient Selection Criteria • Appropriateness for IORT should be determined by the surgeon and radiation oncologist. • General criteria : 1. Surgery alone will not achieve acceptable LC. 2. Normal tissue tolerance (of OARs) to EBRT. 3. IORT will be performed at the time of a planned operative procedure. 4. There is no evidence of distant metastases or peritoneal seeding. 5. Surgical displacement or shielding of dose limiting structures can be accomplished allowing acceptable risks.
  10. 10. Patient Evaluation • A thorough history and physical examination, with attention to palpable disease and its relationship to anatomically immobile normal structures; • Tissue pathology proof. • CT,MRI and EUS aid in identifying adherence to structures. • Examination under anesthesia may be helpful • Routine blood chemistries & tumor-specific serum tests • PET CT – unsuspected distant mets
  11. 11. Sequencing • For patients with locally advanced tumors, preoperative EBRT (45 to 50 Gy )+/-CT f/b Sx and IORT offers theoretical and clinical advantage over resection and IORT followed by EBRT-----by – By postponing surgical resection until after preoperative therapy is completed. – may allow for tumor downstaging and facilitate resection with curative intent. – may reduce the risk of tumor seeding or dissemination during resection – intact vasculature, potentially improving the delivery of chemotherapy and improving oxygen delivery for EBRT. – morbidity and delayed recovery time by surgery delays adjuvant Rx
  12. 12. Radiation Doses and Techniques • IORT – Single dose of IORT is Biologically equivalent to 1.5 to 2.5 times the same total dose of fractionated EBRT – Concept of Shrinking field tecnique/ Boost 45 -50 Gy EBRT  Single IORT dose (Gy) Equivalent total dose by EBRT only (Gy) 10 70 to 80 15 75 to 87.5 20 85 to 100
  13. 13. Normal Tissue Tolerance • Tolerance for IOERT has been tested in animals particularly in dogs. • Late effects observed in animals suggest that 10 to 20 Gy of IOERT plus external fractionated irradiation (45 to 50 Gy) did not compromise the outcome of healthy young adult dogs. • Volume of tissue treated with IOERT is critical, in particular the length of tubular structures irradiated (such as large vessels and ureters).
  14. 14. Normal Tissue Tolerance to IOERT Tissue Intact structure Aorta, vena cava Peripheral nerve Max Tol Dose 50 15 (In Animals) Tissue Effect Fibrosis of wall Neuropathy, sensory motor Contraction and ureterovesical narrowing Dose in Gy 30 20 25 Bladder 30 30 Ureter Kidney Bile duct Small intestine 30 15 20 20 Fibrosis and stenosis Atrophy and fibrosis Fibrosis and stenosis Ulceration, fibrosis, and stenosis Full thickness 20 Ulceration, stricture 30 Partial thickness 10 No sequelae at this dose 40 23 50% decrement muscle fibers 38 20 30 20 17.5 Esophagus Muscle (psoas)
  15. 15. Heart 20 Fibrosis 30 Lung 20 Fibrosis 20 Trachea 30 Submucosal fibrosis 30 Aorta anastomosis 20 Fibrosis and stenosis 20 45 Aortic prosthetic graft 25 Surgically manipulated Portal vein anastomosis 40 Graft occlusion 40 Biliary-enteric anastomosis 20 Stenosis Anastomotic breakdown 20 Small intestine defuntionalized 45 Fibrosis and stenosis No suture line breakdown 20 45 Bladder 30 Healing but contraction 30 Bronchial stump 40 Absence of air leak 40
  16. 16. Dose Limiting Structures • Ureter : • Doses of 10 Gy administered intraoperatively resulted in a 50% incidence of ureteral obstruction, increasing to 70% with doses from 15 to 25 Gy .(Mayo) • Risk of obstruction ----time and dose • Other contributory causes like surgical manipulation,EBRT • Role of Stents • Peripheral nerve – Principal dose-limiting normal tissue for IOERT in pelvis, retroperitoneum, and extremities particularly sarcomas – the relative surgical “immobility & the inability to shield the nerve
  17. 17. Peripheral Nerve--Permissible doses: • When a full dose of EBRT option exists (i.e., 45 to 55 Gy fractionated EBRT), – an IORT boost dose of 10 to 20 Gy. • When EBRT doses must be limited because of prior treatment: – IORT doses ranging from 21 Gy to 25 Gy are used only. –Neuropathy was observed in patients surviving >5 years in avg doses > 20 Gy Second malignancies –described in animal experiments using IOERT. –development of undifferentiated (occasionally sarcomalike) tumors inside the IOERT field –Similar events have never been reported in clinical IOERT.
  18. 18. INDICATIONS WITH EVIDENCE IN • • • • • • • • • • Breast Pancreas Stomach Lung Esophagus Colorectum Soft tissue Sarcomas Paediatric tumors Bladder & kidney Gynaecologic sites
  19. 19. Breast • Increasing interest in the use of IORT as a supplement or alternative to EBRT in selected cases • IORT, given as a boost, – Higher ability to prevent LR in Early BC – Good cosmetic results – Prevents unnecessary radiation to the the breast tissue that can be spared • Landmark trials
  20. 20. • The Italian ELIOT trial(2000) – Randomized phase III trial comparing 21-Gy IOERT versus standard EBRT whole-breast/boost therapy – Mobile linear accelerator -the Novac7 – Veronesi and associates--reported on 237 patients with primary tumors 2 cm or smaller – Patients received IOERT using 3- to 9-MeV electrons with doses of 17 to 21 Gy – Median follow-up of 19 months, 1.7% developed breast fibrosis. – Follow up of 574 patients : 3 with LR and 3 additional with ipsilateral recurrence in other quadrants at median follow-up of 20 months. • A preliminary report : Italian collaborative breast IOERT group : – A multicenter trial comparing IOERT alone after lumpectomy to conventionalfraction EBRT in tumors less than 3 cm with negative margins. – IOERT --single 21-Gy fraction using 6- to 9-MeV electrons – Median follow-up of 31 m---no local recurrence was detected in either treatment group – a significant difference in the incidence of grade 1 to 2 late toxicity was seen in favor of the IORT group (3% vs. 63%)
  21. 21. • Montpelier (France): – – – – 50 patients with early breast cancer, 6 to 13 MeV electron beam at doses of 9 to 20 Gy to the 90% reference isodose. All patients received postoperative EBRT (50 Gy in 2-Gy fractions) – MFU: 9.1 years, – Results: • 2 LR within the primary tumor bed. • Cosmesis was good-to-excellent. • 6 patients had grade 2 late subcutaneous fibrosis on the boost area.
  22. 22. • Salzburg: – 156 women – IORT for stage I and II breast cancer; – single dose of 9 Gy was applied to the 90% reference isodose with – energies ranging from 4 to 15 MeV. – The applicator tubes were placed so that the whole tumor and surrounding tissue of approximately 2 to 4 cm were in the radiation target volume. – MFU18 moths, – Results: • no local recurrences were observed. • Cosmesis of the breast was very good • The late complications were two rib necroses.
  23. 23. The Milan experience • n=590 • received IOERT after BCS – as sole radiation treatment modality (574 patients) or – as an anticipated boost followed by external radiotherapy (16 patients). • INCLUSION CRITERION: • unicentric primary carcinoma • <2.5 cm – MFU:24 months – RESULTS: • 3 LR (0.5%); • 3 (0.5%) patients presented with ipsilateral second breast carcinoma and • (0.8%) with contralateral carcinoma; • 1 patient developed axillary lymph node metastases • 13 (2.2%) distant metastases. – The side effects : • The dose delivered was • 21 Gy in 559 patients, • 19 Gy in 6 patients, and • 17 Gy in 9 patients prescribed at the 90% using 3 to 10 MeV electron beams. • fibrosis and • liponecrosis • These complications resolved with conservative care; one case required surgical curettage.
  24. 24. • The TARGIT trial – Targeted intraoperative radiotherapy vs whole breast radiotherapy for breast cancer (TARGIT-A trial): an international,prospective, randomised, noninferiority phase 3 trial (Dr Jayant S Vaidya et al) – Women 45 y of IDC undergoing BCS were enrolled from 28 centres in nine countries. – The predefined non-inferiority margin was an absolute difference of 2·5% in the primary endpoint – 1113 patients—IORT, 1119-EBRT – 854/996 (86%) IORT alone, 14% IORT + EBRT – 92% in EBRT arm received allocated Rx – Results: At 4 years LC in IORT—6 and EBRT—5(Kaplan Mier Estim– 1.20% vs 0.95%) – Frequency of complications and major toxicity was similar – Radiation toxicity – lower in IORT than in EBRT – For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of TARGIT should be considered as an alternative to EBRT delivered over several weeks.
  25. 25. Pancreas Median survival Veronesi U. et al, 2005 •Advanced unresectable 8 -16 m (IORT 10-40 Gy + EBRT +/- CT) 3yactuarial survival Local relapse rate Remarks abdominal pain relief =57-89% •resectable disease: 9-39 m M.D. Anderson (rapid-fractionation with chemotherapy (30 Gy/10 fraction + daily infusion of 5FU]) and surgery together with IORT boost (10 to 15 Gy). MGH (5-FU + EBRT + IORT) 24m (resected 23% group) 17m 10% better prognosis in: smaller applicator was used
  26. 26. Stomach • Carter et al.: – IORT promotes LC • Calvo et al.: – Severe vascular toxicity has been reported in IORT gastric trial with an incidence of 3% to 12% • The IORT component has improved LC rates in – recurrent tumors (Henning et al.) & – locally advanced cases (Glehen et al. & Suit et al.). • Willet et al. – IORT boosts have been piloted in the context of neoadjuvant chemotherapy, surgical resection, and external-beam fractionated irradiation with acceptable tolerance
  27. 27. Lung  – • – • – Vujaskovic et al.: The intrathoracic high-risk regions for residual disease after lung cancer surgery that can be treated by an IOERT electron field • Unresectable tumors, • Post-resected right and left hilar region and/or mediastinum, and • Posterior or apex chest wall zones . Martinez et al.: IORT boost in Pancoast tumors • LC – 91% • OS – 56 % Rosenweig et al. Pleural mesothelioma : moderate results with HDR – IORT.
  28. 28. Esophagus • Hosokawa M et al.: – IORT boosting of the upper mediastinum during esophagectomy and lymphadenectomy with a nervesparing approach in esophageal – Successful LC results (94% to 100%). – The main complication was tracheal damage with an IOERT dose >20 Gy.
  29. 29. Colorectum Primary Locally Advanced Cancers 5y-DFS REMARKS MGH IOERT n=64 43% both LC and disease-free survival rates were higher if gross total resection was completed before the IOERT Gunderson et al. (Mayo Clinic ) Sx+IORTEBRT Sx  EBRT 3Y DFS 3Y LC 55% 24% 85% 24% European institutions (NART/NACTRT  Sx+IORT boost) 81% versus 58% 93% versus 77%
  30. 30. Colorectum Locally Recurrent Cancers – Atiken et al.: • 5-year survival improvement of 20% with the addition of IOERT to standard treatment – Willet et al.: • factors that impacted 5-year survival: – amount of residual tumor (microscopic vs. gross; 33% vs. 9%: p =.032) and – IOERT versus none (19% v 7%; p=0.0006) • Huber et al: HDR-IORT • Well-adapted boosting technique in the pelvic region for rectal cancer patients • Relatively frequent R2 resection biased the modality selection to IOERT to assure enough beam depth penetration.
  31. 31. Retroperitoneal & pelvic soft tissue sarcomas N NCI (EBRT35-40Gy IOERT 20Gy or PhaseII 15Gy) LRR 5YS 5YLC REMARKS 35 20% 80% Mayo Clinic Sx IOERT Primary & Recurrent 87 MGH Sx IOERT 37 favorable impact on 5-YS: •Initial lesion size <10 cm and •surgeon's ability to achieve a gross total resection 7% 39% 50% 38% Increased LC & survival if gross total resection.
  32. 32. Extremity sarcoma • Postresection radiotherapy for extremity preservation. – A component of the total radiation dose can be delivered as an intraoperative boost, IOERT or IOHDR n 5y LR Technical University Munich IOERT boost 28 16% University of Innsbruck IOHDR boost 39 None @ 8 Y University of Navarra 45 20% REMARKS peripheral neuropathy 11% 7-year actuarial survival rate of 75%
  33. 33. Extremity sarcoma n 5y LR Technical University Munich IOERT boost 28 16% University of Innsbruck IOHDR boost 39 None @ 8 Y University of Navarra 45 20% REMARKS peripheral neuropathy 11% 7-year actuarial survival rate of 75%
  34. 34. Paediatric tumors • A means of – improving precision in dose deposition, – protection of normal uninvolved tissues – Neuroblastoma (Haas – Kogan et al.) – high-risk category • IOERT component (7 to 16 Gy) • Addresses a total local failure rate (100%) in gross residual tumor postresection patients. • Bone sarcomas (Calvo et al.) – Ewing and osteosarcoma: • IOERT-augmented extremity preservation surgical management • high LC rates (95% Ewing and 95% osteosarcoma)
  35. 35. Bladder & kidney • Rostom et al. – IOERT in the radical treatment of infiltrating bladder cancer using chemoradiation and conservative surgery (TUR plus cystostomy for tumor exposure) – 5-year overall survivals of 53% – Cystectomy-free survival 48%. • Eble et al. – In locally advanced or recurrent renal cell cancer: • LC can be achieved using: – IOERT (15 to 20 Gy) – after incomplete tumor resection, • with minimal therapy-related side effects.
  36. 36. Gynaecologic sites • Locally recurrent gynecologic cancer in • the pelvic side walls, para-aortic nodes, or pelvic lymph nodes, the use of aggressive salvage surgery and IOERT with or without EBRT or chemotherapy may be beneficial – The 5-year survival ranges between 27% and 32%. • The University of Navarra (Pamplona) – L.A. primary cervical cancers – NACTRT (PF) resection+IOERT – 10-year in-field control rates: • 92% for primary and • 46% for recurrent disease.
  37. 37. • Stanford University – Recurrent Ovarian Ca • Cytoreductive surgery and • IORT – orthovoltage x-rays. – 9 to 14 Gy. • MFU 24 months – 5 patients remained free of disease and – 17 patients had recurrences, of whom 4 are alive with disease.
  38. 38. Conclusion • There is a large body of data supporting the use of IORT in various malignancy but relative paucity of phase III randomized trials. • Limited number of IORT facilities and cooperation from institutions . • Sequencing • Future treatment approaches could include “standard” courses of EBRT+/-concurrent chemotherapy and surgical resection with the integration of novel radiation sensitizers, protectors, and targeted biologic agents with IORT by appropriate case selection thereby prolonging DFS by better LC.
  39. 39. Thank you.