INTRA OPERATIVE RADIOTHERAPY (IORT)

Dr Umesh V

INTRODUCTIONIntraoperative radiotherapy (IORT) is the delivery of a single large radiation dose to the tumor bed during surgical resection.

Intraoperative radiation therapy (IORT) is an intensive radiation treatment that's administered during surgery.

IORT is used to treat cancers that are difficult to remove during surgery and there is a concern that microscopic amounts of cancer may remain.

IORT allows direct radiation to the target area while sparing normal surrounding tissue.

IORT allows higher effective doses of radiation to be used compared to conventional radiation therapy.

It's not always possible to use very high doses during conventional radiation therapy, since sensitive organs could be nearby.

IORT also allows doctors to temporarily move nearby organs or shield them from radiation exposure.

HistoryThe initial clinical use of IORT dates back to the early 1900s, when IORT was performed using soft X-rays and moving patients from the operating room to the radiotherapy bunker.

The first IORT using electron beams (IOERT) was carried out in November 1976 at Howard University, in a bunker equipped with an operating room.

In the 1980s, in order to combine technical advantages of brachytherapy with logistic advantages of IORT, high dose rate brachytherapy IORT (HDR-IORT) was implemented at Memorial Sloan-Kettering Cancer Center, using a portable HDR machine (OMIT) .

Since the 1990s dedicated linear accelerators have been created to solve IORT logistical problems.

Currently, 220 mobile units are installed worldwide: 40% in the United States, 35% in Europe and 25% in Japan.

In 1998, a new professional society, the International Society of IORT (ISIORT) was created for the scientific and clinical development of IORT. The ISIORT has now over 1000 members from more than 20 countries and a scientific meeting is organized every two years. The first ISIORT meeting was held in September 1998 in Pamplona, at the University of Navarre, one of the most famous IORT centers

There are three principal models used in clinical practice :

Mobetron, from“Intraop Medical Incorporated”, California USA,

Novac7 , from “New Radiant Technology”, Italy and

Liac from “Sordina”, Italy.

These machines are small linear accelerators producing electron beams which can be positioned directly in the existing operating rooms, with no special shielding required

Intrabeam Photon Radiosurgery System (Zeiss Inc, Germany) is used for breast cancer treatment : it is a miniature electron beam-driven X-ray source that provides a point source of low-energy X-ray (50 kV maximum) at the tip of a 3.2 mm diameter tube.

The LIAC 12, LIAC 10 and NOVAC 11 accelerators, created by Sordina IORT Technologies, are the state of the art in this innovative therapy, developed to respond to the patient’s mental, physical and logistical needs.

IORT team should be:

1. The surgeon

2. The radiation oncologist

3. The radiation physicist

4. The radiotherapy technologist

5. The anesthesiologist

6. The nursing staff

The surgeon discusses clinical cases and the best surgical procedure with radiation oncologist and co-operates in setting up the patient during IORT

The radiation oncologist is clinically responsible for prescription and delivery of treatment and decides on IORT dose, field size, beam energy and technical approach according to disease extension and the closeness to organs at risk.

Along with the surgeon and the radiotherapy technologist, the radiation oncologist is responsible for the “docking” procedure.

The radiation physicist is responsible for dosimeter data acquisition and for machine quality control.

It is important that radiation physicists have dosimeters data readily available to calculate the monitor units required to deliver an adequate dose prescription.

The radiotherapy technologist is the professional profile dedicated to the mobilization of the IORT accelerator during docking procedure and to deliver the dose prescribed by the radiation oncologist.

Radiotherapy technologist is responsible for irradiation data registration and co-operates for quality assurance treatment.

The anesthesiologist must control the patient’s vital signs during irradiation through a remote system or by closed-circuit television; rapid access into treatment room is required to attend to patient in any instance.

Dose specificationsTraditionally, IORT procedures performed under the Radiation Therapy Oncology Group protocol have specified that the 90% isodose line covers the target volume, whereas the International Commission on Radiation Units and Measurements Report 3559 recommends that the dose be prescribed at dmax.

Therefore, TG-48 recommended that both the 90% dose and the maximum dose should be reported.

Since the publication of the TG-48 report, neither the ICRU nor any other institution has achieved a formal agreement on dose specification for IORT.

However most IORT groups follow the convention of prescribing to the 90% isodose level to ensure coverage of the target by the 90% isodose line.

This Task Group recommends that the dose be prescribed at the 90% isodose level and then the dose be reported at both the 90% level and dmax

Treatment delivery ParametersThe decision-making process will include consideration of intraoperative information by the pathologist concerning resection margins, tumor infiltration into surrounding tissues, histology, and other considerations such as risks to neighboring tissues and critical structures.

For some tumors, additional surgical preparation may be necessary to render the target accessible to electron irradiation (e.g., the preparation of a flat target area for IORT for breast cancers).

Definition of target depth and lateral extensions of the tumor and selection of beam energy will depend mainly on these criteria.

Intraoperative sonography to measure target depth or the distance of risk organs from the target has been suggested.

Beam energy is usually selected to place the 90% isodose line of the dose distribution of the chosen applicator at the distal depth of the target

Benefits of IORTSaves time: The entire therapeutic dose of radiation is given immediately at the time of surgery (removal of the tumor) while the patient is still under anesthesia. This allows the patient to complete the therapy sooner, allowing the patient to return to normal life more quickly.

Convenience for patients: Traditionally, patients would need to come back to undergo radiation therapy for five days a week for up to three to six weeks after they heal from surgery. For most patients who undergo IORT, there are typically no return trips for radiation.

Targeted radiation therapy: Radiation is given directly and internally to the sections of the sites with the biggest risks of cancer reoccurrence.

Team approach: The Radiation Oncologist is in the operating room with the surgeon.

Decreased side effects: IORT has been found to decrease side effects such as red rashes and skin irritations when compared to traditional radiation therapy.

Clinical Applications

Pancreatic cancers

Recurrent Rectal cancers

Retroperitoneal Soft tissue Sarcomas

Breast cancers

Vertebral metastasis

Pancreatic cancersPrognosis for pancreatic cancer remains poor with a high incidence of local relapse, even when disease is potentially resectable.

In order to overcome this problem, several studies have been conducted with the delivery of IORT to the tumor bed following pancreaticoduodenectomy, showing an increase in local control without a prolongation of survival .

Referred IORT doses are usually 10-15 Gy with a range from 10 to 30 Gy .

The treatment field includes retroperitoneum and tumor bed while the pancreatic remnant is usually excluded.

The major retroperitoneal blood vessel, i.e. aorta, celiac axis, superior mesenteric artery, superior mesenteric vein, portal vein and inferior vena cava can be included in IORT field because they are not particularly radiosensitive .

The most frequent postoperative complications are anastomotic leakage, peripancreatic abscess formation and pancreatic fistula

IORT is appreciated for the lasting effect in pain control in patients with unresectable disease

Recurrent Rectal CancerIsolated recurrences limited to the pelvis are the most frequent problem after resection of locally advanced rectal carcinomas.

IORT can be considered an ideal “boost” technique in order to obtain dose-escalation ; EBRT in combination with IORT, in fact, allows local delivery of a tumoricidal biological dose of up to 80-90 Gy .

The target volume is the “higher risk area” (i.e. where the tumor is fixed or where there is a macroscopic or possible microscopic residual).

In locally advanced rectal cancer as well as in recurrent rectal cancer, most studies referred an IORT median dose of 15 Gy (range 12.5–20 Gy) specified on 90% isodose .

The most frequent complications are urinary infections and symptomatic or objective neuropathy ; the ureter is not a dose-limiting structure but, as ureteral narrowing or obstruction can occur, stent positioning before surgery is suggested.

Peripheral nerves are the main dose-limiting structures for IORT but significantly fewer complications occur for doses of 12.5 Gy or less .

Retroperitoneal soft tissue sarcomasSurgery is the main treatment and provides the most favorable prognosis after complete resection (R0) but complete surgical resection is often difficult or impossible due to the anatomical location of these tumors and the frequent invasion of contiguous retroperitoneal structures .

In this scenario, IORT appears to be an appropriate treatment, associated with EBRT, with the aim of improving local control.

IORT can be delivered prior to as well as after EBRT and the median dose is 15 Gy with a range of 10-20 Gy ; the target is the tumor bed with a 1-3 cm safety margin and the dose is generally prescribed on the 90% isodose.

Potential side effects of intra-operative treatment are related to the site of the target volume.

Neurotoxicity is the most common side effect , particularly when the IORT dose is higher than 15 Gy.

Retroperitoneal abscess incidence is low while ureteral stricture may occur when ureter is included in irradiation field .

Vertebral metastasisIntraoperative radiotherapy (IORT) during kyphoplasty in order to regain immediate stability, sterilize the metastasis and continue with chemotherapy without a delay of several weeks.

Breast cancersThe idea of a single-shot treatment by IOERT, as proposed by the Milan Group, is tempting especially in low risk patients, but follow-up periods far beyond 5 years are mandatory to provide definitive evidence on long-term local control rates .

An interesting multicentre trial of Targeted Intraoperative Radiation Therapy (TARGIT) had as principal objective to determine whether IORT targeted to tumor bed could provide equivalent local control compared with whole-breast irradiation in patients with early-stage invasive breast cancer .

A total of 779 patients were accrued from 16 institutions all over the world: obviously definitive local control data need a longer follow-up

Moreover, IORT is an interesting option for patients with localized breast recurrences after previous EBRT .

Recently pooled analysis was performed by 6 ISIORT-Europe institutions: 1131 patients, treated from 1998 to 2005, were studied and IORT as “anticipated boost” showed an optimal accuracy in dose delivery and good local tumor control rates .

Technique IORT technique in breast cancer procedure:

After lumpectomy with satisfactory tumor-free margins dedicated aluminium-lead disks are placed above the pectoralis muscle in order to minimize irradiation to thoracic wall.

Then mammary parenchyma is sutured in surgery breach area and target volume thickness is measured.

Finally an applicator of proper diameter is placed in tumor bed and sterile gauze are positioned between skin and applicator’s edge.

Optimal energy is selected on the basis of measured target thickness.

Dose varies according to treatment “rationale” (single shot versus boost) and is prescribed on 90% isodose

Targeted intraoperative radiotherapy versus whole breast

radiotherapy for breast cancer (TARGIT-A trial): an

international, prospective, randomised, non-inferiority phase 3 trial

Jayant S Vaidya et al

Findings1113 patients were randomly allocated to targeted intraoperative radiotherapy and 1119 were allocated to external beam radiotherapy.

Of 996 patients who received the allocated treatment in the targeted intraoperative radiotherapy group, 854 (86%) received targeted intraoperative radiotherapy only and 142 (14%) received targeted intraoperative radiotherapy plus external beam radiotherapy.

1025 (92%) patients in the external beam radiotherapy group received the allocated treatment.

At 4 years, there were six local recurrences in the intraoperative radiotherapy group and five in the external beam radiotherapy group.

The Kaplan-Meier estimate of local recurrence in the conserved breast at 4 years was 1·20% in the targeted intraoperative radiotherapy and 0·95% in the external beam radiotherapy group (difference between groups 0·25%, –1·04 to 1·54; p=0·41).

The frequency of any complications and major toxicity was similar in the two groups (for major toxicity, targeted intraoperative radiotherapy, 37 [3·3%] of 1113 vs external beam radiotherapy, 44 [3·9%] of 1119; p=0·44).

Radiotherapy toxicity (Radiation Therapy Oncology Group grade 3) was lower in the targeted intraoperative radiotherapy group (six patients [0·5%]) than in the external beam radiotherapy group (23 patients [2·1%]; p=0·002).

Conclusions

For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered as an alternative to external beam radiotherapy delivered over several weeks

Another important IORT trial is the ELIOT trial conducted by Veronesi and co-researchers .

In this study, 590 patients affected by unifocal breast carcinoma up to a diameter of 2.5 cm received wide resection of the breast followed by IORT with electrons.

Ninety-seven percent of the patients in this study had IORT as the sole radiation treatment modality.

After a follow-up from 4 to 57 months (mean 24 months, median 20), 19 patients 3.2%) developed breast fibrosis – mild in 18, severe in 1 – which) resolved within 24 months.

Local recurrences developed in three patients (0.5%), ipsilateral carcinomas in other quadrants in three patients and contralateral breast carcinoma in five.

One patient (0.2%) died of distant metastases

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