intraoperative radiotherapy

Intraoperative Radiotherapy (IORT)

Dr Sasikumar Sambasivam DNB ResidentDept. of Radiation Oncology

www.bmchrc.org--BMCHRC, Jaipur

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.


• 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)


Rationale for IORTAdvantages:1. Reducing the chance of residual disease at the

site of surgery by eliminating microscopic tumor foci;

2. Maximizing the radiobiological effect of a single high dose of radiation

with attainment of total dosage that exceed those of EBRT;

3. Optimizing the timing of the combined surgery and radiotherapy

earlier irradiation & avoidance of accelerated repopulation. www.bmchrc.org--BMCHRC, Jaipur

4. The combination of IOERT with EBRT – Improves the therapeutic ratio of local control versus

complications by:

(1) reducing the volume of the irradiation “boost” field by direct tumor/tumor bed visualization and conformal treatment;

(2) exclusion of part or all of dose-limiting normal structures by operative mobilization, direct shielding, or varying electron beam energy; and

(3) allowing the delivery of high-dose irradiation by the just-

mentioned methods.


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).


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 @ surfaceDose @ 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 setupLimited geometry

Relatively complexAny geometry

Cost Costlier Relatively cheaper

Sites Only superficial & accessibleAs electrons travel straight pathsUnsuitable 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


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.


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.


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 metswww.bmchrc.org--BMCHRC, Jaipur

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


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


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).


Normal Tissue Tolerance to IOERT (In Animals)

Tissue Max Tol Dose Tissue Effect Dose in GyIntact structure 30 Aorta, vena cava 50 Fibrosis of wall 20 Peripheral nerve 15 Neuropathy, sensory

motor25

Bladder 30 Contraction and ureterovesical narrowing

30

Ureter 30 Fibrosis and stenosis 20 Kidney 15 Atrophy and fibrosis 30 Bile duct 20 Fibrosis and stenosis 20 Small intestine 20 Ulceration, fibrosis, and

stenosis17.5

Esophagus

Full thickness 20 Ulceration, stricture 30

Partial thickness 10 No sequelae at this dose 40

Muscle (psoas) 23 50% decrement muscle fibers

38www.bmchrc.org--BMCHRC, Jaipur

Heart 20 Fibrosis 30

Lung 20 Fibrosis 20

Trachea 30 Submucosal fibrosis 30

Surgically manipulated

Aorta anastomosis 20 Fibrosis and stenosis 2045

Aortic prosthetic graft 25

Portal vein anastomosis

40 Graft occlusion 40

Biliary-enteric anastomosis

20 StenosisAnastomotic breakdown

20

Small intestine defuntionalized

45 Fibrosis and stenosisNo suture line breakdown

2045

Bladder 30 Healing but contraction 30

Bronchial stump 40 Absence of air leak 40www.bmchrc.org--BMCHRC, Jaipur

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


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.


• Breast• Pancreas• Stomach• Lung• Esophagus• Colorectum• Soft tissue Sarcomas• Paediatric tumors• Bladder & kidney• Gynaecologic sites

INDICATIONS WITH EVIDENCE IN


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


• 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 conventional-

fraction 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%)www.bmchrc.org--BMCHRC, Jaipur

• 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.


• 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.


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

• 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.

– 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 :• fibrosis and • liponecrosis • These complications resolved with

conservative care; one case required surgical curettage.


• The TARGIT trial– Targeted intraoperative radiotherapy vs whole breast radiotherapy for breast

cancer (TARGIT-A trial): an international,prospective, randomised, non-inferiority 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.


Pancreas Median survival

3y-actuarial survival

Local relapse rate

Remarks

Veronesi U. et al, 2005(IORT 10-40 Gy + EBRT +/- CT)

•Advanced unresectable 8 -16 m

•resectable disease:9-39 m

abdominal pain relief

=57-89%

M.D. Anderson(rapid-fractionation with chemotherapy (30 Gy/10 fraction + daily infusion of 5-FU]) and surgery together with IORT boost (10 to 15 Gy).

24m (resected group)

23% 10%

MGH(5-FU + EBRT + IORT)

17m better prognosis in: smaller applicator was used


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


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.www.bmchrc.org--BMCHRC, Jaipur

Esophagus

• Hosokawa M et al.:– IORT boosting of the upper mediastinum during

esophagectomy and lymphadenectomy with a nerve-sparing approach in esophageal

– Successful LC results (94% to 100%). – The main complication was tracheal damage with an

IOERT dose >20 Gy.


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+IORTEBRTSx EBRT

3Y DFS

55%24%

3Y LC

85%24%

European institutions (NART/NACTRT Sx+IORT boost)

81% versus 58% 93% versus 77%


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. www.bmchrc.org--BMCHRC, Jaipur

Retroperitoneal & pelvic soft tissue sarcomas

N LRR 5YS 5YLC REMARKS

NCI(EBRT35-40GyIOERT 20Gy orPhaseII 15Gy)

35

20%

80%

Mayo ClinicSx IOERTPrimary &Recurrent

87

7%39%

favorable impact on 5-YS:•Initial lesion size <10 cm and •surgeon's ability to achieve a gross total resection

MGHSx IOERT

37 50% 38% Increased LC & survival if gross total resection.


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 REMARKS

Technical University Munich IOERT boost

28 16%

University of InnsbruckIOHDR boost

39 None @ 8 Y

University of Navarra 45 20% peripheral neuropathy 11%

7-year actuarial survival rate of 75%


Extremity sarcoman 5y LR REMARKS

Technical University Munich IOERT boost

28 16%

University of InnsbruckIOHDR boost

39 None @ 8 Y

University of Navarra 45 20% peripheral neuropathy 11%

7-year actuarial survival rate of 75%


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)


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.www.bmchrc.org--BMCHRC, Jaipur

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.


• 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.


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.


Thank you.


intraoperative radiotherapy

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