**Definitions and Scope:**

This policy addresses intraoperative radiation for the treatment of cancer.
Intraoperative radiation for the purposes of this Local Coverage Determination
(LCD) is any method of radiation administered to the patient in the operating
room (OR), such that the initiation of radiation exposure begins following the
surgical exposure of the tumor or tumor bed, and the cessation of radiation
exposure occurs prior to the patient leaving the OR. This includes radiation
that is delivered by a beam from a device or placement of a radioactive
material in tissues. Therapeutic radiation delivered as defined by this time
frame should be coded using the codes in the related billing and coding
article. Therapies termed "brachytherapy" in the medical literature that
involve removal of the radiation source prior to the patient leaving the OR
should be considered "intraoperative radiation" rather than "brachytherapy"
for the purposes of this LCD.

This policy does not address general diagnosis or management of malignancies,
nor does it address specific surgical or chemotherapy treatments. Radiation
delivered outside of the OR and brachytherapy are not specifically covered
here either.

**Background:**

For many cancers, surgical resection is an established method to either
achieve a prolongation of life or a cure. Radiation delivered in conjunction
with surgery improves outcomes for some types of cancer presumably through its
ability to reduce tumor volume, kill grossly visible neoplastic tissue that
was not resected due to technical infeasibility, and destroy microscopic foci
of cancer surrounding the known tumor site. However, radiation is toxic not
only to the neoplastic but also to healthy tissues, and in some cases
mortality benefits due to cancer related deaths appear to be attenuated by
non-cancer related mortality from complications of radiation to healthy
tissue. Intraoperative radiation has been posed as a radiation delivery method
that allows providers to deliver a large dose of radiation focally to the
tumor bed, thereby aggressively treating the tumor but sparing healthy
tissues.

**General Indications and Principles**

 Surgical resection of the tumor must be reasonable and necessary for the
treatment of the patient's malignancy based on all available information at
the time that the decision to put the patient through surgery is made. As
such, the medical record should reflect that surgical resection was indicated.
Palmetto GBA recognizes that intraoperative findings may change the course of
treatment, and resection may not be carried out or completed in such cases.

 Surgery strictly for the sake of delivery of intraoperative radiation is not
supported by the evidence and is not considered reasonable and necessary.

 This LCD is not intended to provide recommendations regarding treatment.
Radiation treatment should be reasonable and necessary for a patient's
individual case, in light of that patient's cancer diagnosis and cancer stage
or grade, as well as the patient's comorbid clinical conditions.

 The choice of radiation dose and areas to irradiate should be derived from
evidence-based treatment protocols. The relevant evidence should be on hand
for review if requested.

 Radiation treatment planning and delivery should be handled by an
experienced and qualified team with the necessary knowledge and skills to
ensure that appropriate precautions are taken to protect the patient,
healthcare providers, and the public from the hazards of radiation in the OR
environment. The relevant professionals with such skills and knowledge who are
involved in the case must be documented. All federal, state, and local laws
governing the use and handling of radiation must be followed.

**General Procedure Requirements:**

 Pre-procedural documentation must include a complete initial evaluation,
including history and an appropriately focused physical examination with
review of relevant pathology and imaging results. Treatment plans formulated
in conjunction with other providers (e.g., medical oncologist, surgeon, tumor
board, etc.) should be included if these discussions support that the
procedure is reasonable and necessary.

 A procedure note must be legible and include sufficient detail to allow
reconstruction of the procedure. Required elements of the note include a
description of the mode of radiation delivered, anatomic sites to which it is
delivered, dose of radiation (in Gray), as well as any necessary pre- and
post-procedural assessments. This note must have a legible signature, time,
and date.

**_Information pertaining to specific malignancies based on anatomic location
and tissue type_**

**Breast Cancer**

Intraoperative Radiation Therapy (IORT) in breast cancer should be used only
in patients in whom there is a reasonable expectation at the time of surgery
that Accelerated Partial Breast Irradiation (APBI) may be appropriate. Even in
patients who meet these criteria, clinicians should provide appropriate
informed consent regarding the fact that whole breast irradiation is still
considered standard treatment. Palmetto GBA considers patients to be
appropriate for APBI based on the criteria set forth by the National
Comprehensive Cancer Network (NCCN) to describe candidacy for use of APBI
outside of a clinical trial. These criteria are as follows:

1\. A woman who meets all of the following criteria:

 50 years or older

 Invasive ductal carcinoma

 Tumor size <= 2cm (T1 disease)

 Negative margins >= 2mm

 No lymphovascular invasion

 Estrogen receptor (ER) positive

 BRCA negative

**or**

2\. A woman who meets all of the following criteria:

 Low or intermediate nuclear grade

 Screen-detected ductal carcinoma in situ (DCIS)

 Tumor size <= 2.5 cm

 Negative margins >= 3 mm

Palmetto GBA recognizes that new findings following surgery, including but not
limited to final pathology results, may be found, and that based on such
findings the patient would be determined not to be a suitable candidate based
on the above criteria after the IORT dose has already been given. As long as
information is available at the time of surgery that indicates it is
reasonable to expect that the patient did meet the above criteria, IORT may
still be considered reasonable and necessary. If further radiation treatment
is deemed necessary based on the new information learned after IORT is given,
further radiation should be provided as clinically appropriate.

Intraoperative radiation is not considered reasonable and necessary in women
who undergo a complete or a radical mastectomy.

**Colon and Rectal Cancer**

Intraoperative radiation for colon cancer may be reasonable and necessary in
patients who warrant surgical resection and at least 1 of the following:

 T4 tumor

 Recurrent cancer

 Positive or close surgical margins

Intraoperative radiation may be given as a boost dose in conjunction with pre-
or post-operative external beam radiation.

**Soft Tissue Sarcoma**

Intraoperative radiation may be considered reasonable and necessary in the
treatment of soft tissue sarcomas for which there is a substantial risk that
surgical resection will be insufficient to avoid local recurrence because of
the tumor's location, surrounding anatomy, or other technical aspects of the
procedure which may limit surgical effectiveness.

**Uterine and Cervical Cancer**

Intraoperative radiation may be considered reasonable and necessary in
patients with recurrent tumor burden following external beam radiation.
Intraoperative radiation may also be considered reasonable and necessary in
patients without metastatic disease for whom surgical resection by itself
would be unlikely to achieve adequate local disease control.

**Gastric and Gastroesophageal Junction Cancer**

Intraoperative radiation is not currently considered reasonable and necessary
in the treatment of gastric and gastroesophageal junction cancers.

**Pancreatic Cancer**

Intraoperative radiation is not currently considered reasonable and necessary
in the treatment of pancreatic cancer.

**Esophageal Cancer**

Intraoperative radiation is not currently considered reasonable and necessary
in the treatment of esophageal cancer.

**Lung Cancer**

Intraoperative radiation is not currently considered reasonable and necessary
in the treatment of lung cancer.

**Brain Cancer**

Intraoperative radiation is not currently considered reasonable and necessary
in the treatment of brain cancer.

**Breast Cancer**

For many women with breast cancer, surgical resection is an important
component of treatment. This resection may involve either mastectomy or
breast-conserving therapy (BCT) depending on the tumor histology and disease
stage. For some women, breast conserving surgery in conjunction with radiation
may offer similar cancer-related outcomes as mastectomy.1-5 The standard of
treatment has conventionally been post-operative external beam whole breast
radiation delivered over roughly 3 weeks. However, APBI has started to gain
interest as a possible therapeutic approach that may increase accessibility of
adequate radiation treatment and BCT to women.6 Intraoperative radiation in
breast cancer is among potential APBI delivery methods.

Initial research has provided some evidence that IORT may be non-inferior to
and equivalent to whole breast irradiation in women who have had BCT with
regards to tumor recurrence, potentially offering reduced radiation
toxicity.7-9 However, whole breast irradiation is still considered the
standard treatment option per NCCN guidelines.

NCCN guidelines generally consider APBI including IORT experimental and
recommend its use in clinical trials. But note that it may be appropriate for
women who meet specific criteria.10 These criteria are as follows:

1\. A woman who meets all of the following criteria:

 50 years or older

 Invasive ductal carcinoma

 Tumor size <= 2cm (T1 disease)

 Negative margins >= 2mm

 No lymphovascular invasion

 ER positive

 BRCA negative

**or**

2\. A woman who meets all of the following criteria:

 Low or intermediate nuclear grade

 Screen-detected DCIS

 Tumor size <= 2.5 cm

 Negative margins >= 3 mm

**Colorectal Cancer**

For decades, a treatment for colorectal cancer has been surgical resection.
However, recurrence rates post-operatively and mortality are quite high,
particularly among rectal carcinomas.11 The use of pre-operative and post-
operative adjuvant therapies has been tried to improve outcomes. A large study
of externally applied radiation in rectal cancer found that while external
beam radiation enhanced outcomes related to the primary cancer, an overall
mortality benefit, while present, was attenuated by a rise in the rate of non-
rectal cancer related deaths among radiation treated patients. This suggested
that benefits of radiation could be improved if the safety of radiation could
be enhanced.12  

Intraoperative radiation has been developed as a potential method of
delivering a high dose of radiation to a focused area of concern for
malignancy, while limiting radiation exposure and toxicity to non-cancer
tissue.

There are no large randomized controlled trials (RCTs) of intraoperative
radiation in colorectal cancer, and 2 smaller RCTs showed local tumor control,
but no 5 year mortality benefit of intraoperative radiation in populations
with a large proportion of T3 cancers.13-14 However, a number of non-
randomized comparative and non-comparative studies have collectively indicated
that IORT provides both enhanced local tumor control and a mortality benefit,
particularly in patients with T4 tumors and not unresectable or positive
margin tumors.15

NCCN guidelines for the treatment of colon and rectal cancers recommend
consideration of intraoperative radiation in patients who have at least 1 of
the following characteristics of their cancer16-17:

 T4 tumor

 Recurrent cancer

 Positive or close surgical margins

**Soft Tissue Sarcoma**

Soft tissue sarcoma is relatively rare, but treatment is difficult. Surgical
resection is a mainstay of treatment.18 However, for retroperitoneal sarcomas,
which can be quite large and involve numerous anatomic areas, complete
resection is often not achievable, and even with complete resection,
recurrence rates are still quite high.19 This prompted interest in the use of
radiation, which must be applied to a large area near many organs that are
potentially quite sensitive to radiation.

This prompted an interest in intraoperative radiation in the treatment of soft
tissue sarcomas. There is limited evidence on the use of intraoperative
radiation with only a single RCT studying its effect in retroperitoneal
sarcomas, which showed a significant reduction in local disease recurrence at
5 years.20 A number of observational studies have also suggested that
intraoperative radiation may have a benefit in the treatment of
retroperitoneal sarcomas.21

**Uterine and Cervical Cancer**

The management of uterine and cervical cancer has variation among oncologists,
though surgical resection is often an important component in the treatment of
endometrial cancer. While no large RCTs exist, smaller studies and
observational studies suggest that intraoperative radiation may be an
appropriate means of delivering a sufficiently large dose of radiation to
involved tissues while sparing healthy tissues of the pelvis in appropriately
selected patients with uterine cancer and may be an appropriate treatment
option in patients with recurrent cervical cancer.22-24

NCCN guidelines recommend that intraoperative radiation be considered in
patients with recurrent tumor burden following external beam radiation or in
patients for whom surgical resection by itself would be unlikely to achieve
adequate local disease control.25-26

**Gastric and gastroesophageal junction cancers**

Surgical resection has been a mainstay of treatment for gastric cancer.
External beam radiation, when combined with chemotherapy, has been shown to
improve survival.27-28 Due to concerns for toxicity, intraoperative radiation
has been an area of interest, but data from recent RCTs and trials comparing
intraoperative radiation to external beam radiation are lacking. Observational
and single-arm studies have not consistently shown that intraoperative
radiation provides a clear benefit in relation to well proven treatment
options.29

Guidelines from NCCN recommend the use of external beam radiation where
radiation is appropriate.30-31

**Esophageal cancers**

Surgical resection has been a mainstay of treatment for esophageal cancer.
External beam radiation in conjunction with chemotherapy has been shown to
improve survival and has become an important component of surgically treated
esophageal cancers.32-35 However, there is a paucity of high quality research
examining the benefits of intraoperative radiation.

**Pancreatic Cancer**

Most pancreatic cancers are unresectable, and among those that are, the
prognosis for 5 year survival is still quite poor. Radiation has been pursued
as a way to enhance survival, including IORT. NCCN guidelines explicitly
indicate that there is no known role for IORT in pancreatic cancer.36

There have been observational studies employing IORT, but there have been no
large RCTs, and the evidence that has been published does not suggest a
mortality benefit.29,37 NCCN guidelines note that there is no clearly
identified role for intraoperative radiation in the treatment of pancreatic
cancer.

**Lung Cancer**

Surgical treatment is an important component of many patients with non-small
cell lung cancer.38-41 However, there is a lack of evidence regarding the use
of intraoperative radiation.

Surgical treatment is generally not considered indicated in small cell lung
cancer, which would preclude the use of intraoperative radiation. In the
subpopulation of patients with small cell lung cancer for whom limited
evidence suggests surgery may offer appropriate treatment, there is a paucity
of evidence regarding the use of intraoperative radiation.42-43

Intraoperative radiation is not considered reasonable and necessary in the
treatment of lung cancer.

**Brain**

While whole brain radiation has become a recognized component of high grade
gliomas, studies using intraoperative radiation have been limited to small
observational studies, with inconsistent results.44-45 While there is a phase
I/II trial currently underway, intraoperative radiation for brain cancer is
presently an experimental treatment and not reasonable and necessary.46

Intraoperative radiation has been studied in a variety of conditions and has
been shown to offer specific benefits over alternative radiation delivery
methods for some conditions.

In the treatment of breast cancer, evidence supports the use of a single dose
of IORT in lieu of a course of external beam radiation to the whole breast in
selected women who undergo breast-sparing surgery, producing similar disease
recurrence outcomes as whole breast irradiation with potentially less toxicity
to healthy tissues and may be an appropriate treatment approach for
appropriately selected women.

In colon and rectal cancers, evidence supports the role of intraoperative
radiation for reducing local disease recurrence and potentially prolonging
life in colon and rectal cancers for which there is significant concern that
surgical resection will be incomplete.

Soft tissue sarcomas can be difficult to treat in their entirety surgically,
leaving small amounts of malignant tissue, and they may be close to radiation-
sensitive tissues. There is evidence that intraoperative radiation may reduce
local disease recurrence in these tumors.

For recurrent uterine and cervical cancers, in which there is a role for
surgery, and in cancers for which there is a reason to be concerned about
surgical resection not getting all malignant tissue, evidence suggests that
IORT may have a treatment benefit.

For gastric and esophageal cancers, evidence supports a benefit of treatment
regimens using combined external beam radiation and chemotherapy. These
findings in conjunction with a lack of data supporting the use of
intraoperative radiation, mean that intraoperative radiation is not currently
reasonable and necessary in the treatment of gastric cancer and esophageal
cancer.

There is a paucity of evidence regarding the use of IORT in the treatment of
pancreatic cancer, lung cancer, and brain cancer. At this time, intraoperative
radiation for these diagnoses is not considered reasonable and necessary.