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Intraoperative Radiotherapy (IORT)
Dr Sasikumar Sambasivam
Dept. of Radiation Oncology
• 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
– 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
– The radiation may be delivered using:
• IOERT or
• IOHDR (flab method)
Rationale for IORT
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
1.Optimizing the timing of the combined surgery
earlier irradiation & avoidance of accelerated
The combination of IOERT with EBRT
– Improves the therapeutic ratio of local control versus
• 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-
1. Dedicated equipment (mobile linac/HDR
2. Well equiped & shielded OT with appropriate
3. Multidisciplinary team work.
4. Higher risk of late effects, such as fibrosis, in late
responding tissues (with alpha/beta values of
Abe (kyoto, early 1960s)
HDR machine (portal)
3-12Mev (however not higher)
Higher dose/pulse shorter t/t time (2-3 min for 20
Dmax / 90% isodose curve
1 cm from the plane of implant (0.5 cm from implant surface)
Dose lesser @ surface
Dose @ depth
Higher @ surface
•Sizes (upto 10-12 cm)
•Flat end/ bevelled
•Transparent tansfer tubes
Shorter t/t time & easier setup
Only superficial & accessible
As electrons travel straight paths
•anterior abdominal wall,
•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
– 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
4. There is no evidence of distant metastases or peritoneal
5. Surgical displacement or shielding of dose limiting
structures can be accomplished allowing acceptable risks.
• A thorough history and physical examination, with attention to
palpable disease and its relationship to anatomically immobile
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
• 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
– may reduce the risk of tumor seeding or dissemination during
– intact vasculature, potentially improving the delivery of
chemotherapy and improving oxygen delivery for EBRT.
– morbidity and delayed recovery time by surgery delays
Radiation Doses and Techniques
– 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)
70 to 80
75 to 87.5
85 to 100
Normal Tissue Tolerance
• Tolerance for IOERT has been tested in animals particularly in
• 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
Normal Tissue Tolerance to IOERT
Aorta, vena cava
Max Tol Dose
Fibrosis of wall
Dose in Gy
Fibrosis and stenosis
Atrophy and fibrosis
Fibrosis and stenosis
Ulceration, fibrosis, and
No sequelae at this dose
50% decrement muscle
Fibrosis and stenosis
Aortic prosthetic graft
Fibrosis and stenosis
No suture line
Healing but contraction
Absence of air leak
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
Peripheral Nerve--Permissible doses:
• When a full dose of EBRT option exists (i.e., 45 to 55 Gy
– 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
–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.
INDICATIONS WITH EVIDENCE IN
Soft tissue Sarcomas
Bladder & kidney
• Increasing interest in the use of IORT as a
supplement or alternative to EBRT in selected
• 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
– Mobile linear accelerator -the Novac7
– Veronesi and associates--reported on 237 patients with primary tumors 2 cm
– 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
– a significant difference in the incidence of grade 1 to 2 late toxicity was seen in
favor of the IORT group (3% vs. 63%)
• 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
– MFU: 9.1 years,
• 2 LR within the primary tumor bed.
• Cosmesis was good-to-excellent.
• 6 patients had grade 2 late subcutaneous fibrosis on the
– 156 women
– IORT for stage I and II breast cancer;
– single dose of 9 Gy was applied to the 90% reference isodose
– 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,
• no local recurrences were observed.
• Cosmesis of the breast was very good
• The late complications were two rib necroses.
The Milan experience
• received IOERT after BCS
– as sole radiation treatment
modality (574 patients) or
– as an anticipated boost followed
by external radiotherapy (16
• INCLUSION CRITERION:
• unicentric primary carcinoma
• <2.5 cm
– MFU:24 months
• 3 LR (0.5%);
• 3 (0.5%) patients presented
with ipsilateral second breast
• (0.8%) with contralateral
• 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
• These complications resolved
with conservative care; one
case required surgical
• 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
– 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
– 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.
Veronesi U. et al, 2005
8 -16 m
10-40 Gy + EBRT +/- CT)
abdominal pain relief
chemotherapy (30 Gy/10
fraction + daily infusion of 5FU]) and surgery together with
IORT boost (10 to 15 Gy).
(5-FU + EBRT + IORT)
24m (resected 23%
better prognosis in: smaller
applicator was used
• 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
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
• 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.
• 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.
Primary Locally Advanced Cancers
both LC and disease-free
survival rates were
higher if gross total
resection was completed
before the IOERT
Gunderson et al.
(Mayo Clinic )
81% versus 58%
93% versus 77%
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
Retroperitoneal & pelvic soft tissue
IOERT 20Gy or
favorable impact on 5-YS:
•Initial lesion size <10 cm and
•surgeon's ability to achieve a
gross total resection
Increased LC & survival if gross
• Postresection radiotherapy for extremity preservation.
– A component of the total radiation dose can be delivered
as an intraoperative boost, IOERT or IOHDR
None @ 8 Y
University of Navarra
survival rate of 75%
None @ 8 Y
University of Navarra
survival rate of 75%
• 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
• 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.
• Locally recurrent gynecologic cancer in
• the pelvic side walls, para-aortic nodes, or pelvic lymph
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
– 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.
• 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 .
• 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.