CAM 80108

Intraoperative Radiotherapy

Category:Therapy   Last Reviewed:December 2020
Department(s):Medical Affairs   Next Review:December 2021
Original Date:December 2011    

Description:
Intraoperative radiotherapy (IORT) is delivered directly to exposed tissues during surgery and may allow higher radiation doses by excluding nearby radiation dose-sensitive tissues. IORT can be delivered by electron beams produced by linear accelerators or high-dose rate brachytherapy.

For individuals who have rectal cancer who receive adjunctive IORT, the evidence includes a randomized controlled trial (RCT), nonrandomized comparative studies, and systematic reviews of these studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related morbidity. Adjunctive use of IORT as part of a multimodal treatment could permit an increase in radiation dose without increasing complications. However, a phase 3 RCT and meta-analysis of IORT for locally advanced rectal cancer did not find improved outcomes with IORT in combination with external-beam radiotherapy (EBRT) and surgery. Nonrandomized comparative studies and a meta- analysis of these studies have shown some benefit in health outcomes with adjunctive IORT for recurrent rectal cancer, but these studies are limited by a high risk of selection bias, heterogeneous patient populations, and heterogeneous delivery of other treatments. Large RCTs are needed to determine the effect of IORT with greater certainty.

For individuals who have gastric cancer who receive adjunctive IORT, the evidence includes RCTs and a systematic review of RCTs. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related morbidity. A meta-analysis of 8 RCTs found a benefit of IORT in locoregional control (but not overall survival) when used with EBRT. When IORT was administered without adjuvant EBRT in patients with stage III disease, overall survival improved. Thus, IORT might be considered an alternative to EBRT in patients undergoing surgery for stage III gastric cancer. Randomized studies comparing benefits and harms of the 2 treatments are needed to determine the efficacy of IORT with greater certainty. It cannot be determined whether IORT provides any benefit for overall survival in this patient population (gastric cancer patients) when used with EBRT.

For individuals who have soft tissue sarcomas who receive adjunctive IORT, the evidence includes a systematic review, a small RCT, and several nonrandomized comparative studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related morbidity. Overall, the study quality is low. The limited data suggest that IORT might improve local control and overall survival, but adverse events might outweigh any treatment benefit. RCTs are needed to determine the risks and benefits of IORT for soft tissue sarcomas with greater certainty.

For individuals who have gynecologic cancers who receive adjunctive IORT, the evidence includes a nonrandomized trial and case series. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related morbidity. The contribution of adjuvant IORT cannot be determined from the available literature.

For individuals who have head and neck cancers who receive adjunctive IORT, the evidence includes case series. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related morbidity. The strongest evidence is from a retrospective analysis of patients who had recurrent salivary gland carcinomas and were at risk of radiation toxicity due to prior treatment with EBRT. Some patients received IORT plus salvage surgery, and multivariate analysis found that use of IORT was a significant predictor of improved outcomes. Although these findings suggested an improvement in health outcomes for head and neck cancers that cannot be treated with EBRT due to toxicity, there was a high risk of selection bias in this study. Comparative trials are needed to determine the efficacy of IORT with greater certainty.

For individuals who have pancreatic cancer who receive adjunctive IORT, the evidence includes large case series, cohort studies, and systematic reviews of these studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related morbidity. The systematic reviews found no evidence that IORT was more effective than other therapies in treating pancreatic cancer. No evidence was identified that evaluated outcomes when IORT was and was not added to multimodal therapy.

For individuals who have renal cell carcinoma who receive adjunctive IORT, the evidence includes case series. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related morbidity. No controlled trials were identified to determine whether adjunctive IORT improves health outcomes when added to multimodal therapy with surgical resection and EBRT. Grade 3 or higher toxicity after IORT has been reported in a substantial percentage of patients.

For individuals who have glioblastoma or neuroblastoma or fibromatosis who receive adjunctive IORT, the evidence includes case series. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related morbidity. Compared with other therapies, it is unclear whether IORT improves overall survival. However, compared with historical controls, IORT for patients with previously untreated malignant gliomas had no survival benefit when given in conjunction with multimodal therapy. In addition, complication rates may be high. Comparative trials are needed to evaluate the safety and efficacy of this treatment modality.

Background 
Intraoperative radiotherapy (IORT) increases the intensity of radiation delivered directly to tumors. The tumor and associated tissues at risk for micrometastatic spread are directly visualized during surgery. IORT is delivered directly to the tumor, and normal or uninvolved tissues are not exposed to radiation because they are removed or shielded from the treatment field.

Regulatory Status 
The INTRABEAM® system was first approved for use by FDA for intracranial tumors in 1999 and was subsequently approved for whole body use in 2005. The INTRABEAM® spherical applicators are indicated for use with the INTRABEAM® system to deliver a prescribed dose of radiation to the treatment margin or tumor bed during intracavity or intraoperative radiotherapy treatments. The Mobetron® mobile election beam accelerator designed for use in the operating room received 510(k) marketing clearance in 1998. FDA product codes: JAD, LHN.

This policy does not address use of IORT for breast cancer; for that indication, see related Policy No. 80113.

Related Policies
80113  Accelerated Breast Irradiation after Breast-Conserving Surgery for Early Stage Breast Cancer and Breast Brachytherapy as Boost with Whole-Breast Irradiation
 

Policy:
Medically Necessary:
External beam intraoperative radiation therapy (IORT) is considered medically necessary as the sole source of boost therapy at the time of surgical excision for colorectal cancer, pancreatic cancer, pelvic cancers (for example, cervical or uterine),or soft tissue sarcomas,  when either of the following criteria are met:

  • Tumor cannot be completely removed; or
  • Tumor has a high risk of recurring in surrounding tissues. 

Investigational and Not Medically Necessary: 
External beam intraoperative radiation therapy (IORT) is considered investigational and not medically necessary when the above criteria are not met, and for all other indications. 

Policy Guidelines
Effective in 2012, there are specific CPT codes for intraoperative radiotherapy: 

77424: Intraoperative radiation treatment delivery, X-ray, single treatment session
77425: Intraoperative radiation treatment delivery, electrons, single treatment session
77469: Intraoperative radiation treatment management. 

Prior to 2012, there was no CPT coding specific to radiotherapy given intraoperatively. The CPT codes for the radiotherapy (77261-77799) would have been used as appropriate. There was also a HCPCS code specific to intraoperative radiotherapy (S8049).

Benefit Application 
Blue Card®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all devices, drugs or biologics approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational, and, thus, these devices may be assessed only on the basis of their medical necessity.

Rationale
This evidence review was created in March 1996 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through May 19, 2020.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function -- including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Intraoperative Radiotherapy for Various Cancers
Clinical Context and Therapy Purpose
The purpose of IORT in patients who have cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does IORT improve the net health outcome when used as an adjunct to surgery and external-beam radiotherapy (EBRT) and when used to reduce radiation toxicity?

The following PICO was used to select literature to inform this review.

Patients
The relevant population of interest is patients undergoing tumor resection. The specific populations addressed in this evidence review are individuals with rectal cancer, gastric cancer, soft tissue sarcomas, gynecologic cancers, head and neck cancers, pancreatic cancer, renal cell carcinoma, glioblastoma, neuroblastoma, or fibromatosis.

Classification of surgical resection margins are listed in Table 1.

Table 1. General Surgical Resection Margin Classification 

Classification Definition
R0 Negative margins; no cancer cells detected in resected tissue
R1 Microscopic positive margin; cancer cells detected by microscope in resected tissue
R2 Macroscopic positive margin; tumor cells detected without microscope in resected tissue

Interventions
The therapy being considered is IORT. IORT delivers a fractional dose of radiation directly to the tumor/tumor bed while the areas is exposed during surgery with the intent to minimize exposure to surrounding healthy tissues. Different IORT modalities are available that impact both the dose distribution and method of application. IORT techniques include electron beam IORT, high-dose rate brachytherapy based IORT, and low-energy x-ray IORT. Most clinical experience involves intraoperative electron beam therapy.

IORT is performed with applicators and cones that attach to the treatment head of high-energy medical linear accelerators that are designed to direct radiation to defined surface structures. IORT can be used alone, but is more typically used in combination with other modalities such as surgical resection, EBRT, or chemotherapy.

Comparators
The following therapies and practices are currently being used for patients with cancer: surgery alone, multimodal therapies (EBRT plus surgery or chemotherapy).

Most patients receive preoperative or postoperative EBRT in addition to surgical resection of the tumor. Therefore, IORT would be considered an adjunctive treatment to multimodal treatment that includes surgery plus EBRT. For recurrent tumors already treated with EBRT, and tissue at risk for radiation toxicity (eg, head and neck cancers), IORT is being evaluated in conjunction with surgery alone.

Outcomes
General outcomes of interest are overall survival (OS), disease-specific survival, and harms from treatment, specifically radiation toxicity.

Table 1. Outcomes of Interest  

Outcomes Details Relevance
Overall survival Survival rate or proportion dead [Timing: 1 year-10 years ] Considered the most reliable and preferred cancer endpoint
Disease-specific survival Disease/recurrence-free survival [Timing: 1 year-10 years ] The most frequent use of this endpoint is in the adjuvant setting after definitive surgery or radiotherapy
Radiation toxicity Can be divided into acute, subacute, and chronic effects [Timing: Weeks (acute effects) or months (subacute, chronic) after treatment] Acute effects typically resolve within 2 weeks. Subacute and chronic effects include radiation pneumonitis, radiation-induced liver disease, fibrosis, and organ damage.

Rectal Cancer
Review of Evidence
Randomized Controlled Trials
Locally Advanced Cancer
The available RCTs evaluating IORT for locally advanced rectal cancer are summarized in Table 2. No RCTs were identified that evaluated IORT for the management of locally recurrent rectal cancers.

Table 2. Summary of Key RCT Characteristics 

Study Countries Sites Dates Participants Interventions
          Active Comparator
Dubois (2011)1 France 7 1993 to 2001 142 patients with locally advanced rectal cancer (infiltrative rectal adenocarcinoma; T3 or T4 or N+, and M0) treated with preoperative radiotherapy IORT plus surgical resection (n=73) Surgical resection alone (n=69)
Masaki (2020)2 Japan 1 Not reported. Terminated in 2017 76 patients with locally advanced rectal cancer (M0) IORT plus resection of rectum with total mesorectal excision (n=38) Resection of rectum with total mesorectal excision alone (n=38)

IORT: intraoperative radiotherapy

Health outcome results for RCTs are summarized in Table 3. Additionally, in the Dubois et al (2011) trial, postoperative complications were observed in the 29.6% of patients in the IORT group and 19.1% of patients in the control group (p=0.15).1 Specific, radiation-specific complications were not reported. In the Masaki et al (2020) trial, the primary outcome of the study was to compare the pelvic sidewall recurrence rate between the groups.2 The trial was prematurely stopped in July 2017 because distant metastasis-free survivals were found to be significantly worse in the IORT group compared to the control group. Therefore, the authors concluded that IORT should not be recommended as a standard therapy to compensate less radical resection for advanced lower rectal cancer.

The purpose of the limitations tables (see Tables 3 and 4) is to display notable gaps identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 3. Summary of Key RCT Results  

Study Overall survival Disease-free survival Local relapse
Dubois (2011)1 Median Median Local control at 5 years (%)
N 140 140 140
IORT + surgical resection 88 months 80 months 91.8%
Surgical resection 106 months 89 months 92.8%
Difference Not reported (p=0.2578) Not reported (p=0.6037) Not reported (p=0.6018)
Masaki (2020)2 5-year, 10-year, and 15-year overall survival 5-year, 10-year, and 15-year distant metastasis-free survival 5-year pelvic sidewall recurrence
N 76 76 76
IORT + surgical resection 71.5%, 61.7%, and 61.7% 57.5%, 53%, and 53% 12.4%
Surgical resection 81.8%, 73.8%, and 64.6% 76.8%, 76.8%, and 76.8% 8.3%
Difference (95% CI) OR=1.264 (0.523 to 3.051); p=0.603 OR=2.554 (1.041 to 6.269); p=0.041 OR=1.350 (0.302 to 6.034); p=0.694

CI: confidence interval; IORT: intraoperative radiotherapy; OR: odds ratio

Table 4. Study Relevance Limitations 

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Dubois (2011)1          
Masaki (2020)2 3. Staging of advanced rectal cancer not reported        

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 5. Study Design and Conduct Limitations  

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Dubois (2011)1   1. Patients and surgeons were not blinded to treatment assignment, though impractical for this study     3. Percent of local failures was smaller than expected, which may have reduced the power  
Masaki (2020)2   1. Patients and surgeons were not blinded to treatment assignment, though impractical for this study     3. Trial was terminated early likely reducing power  

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Systematic Reviews
Primary, Advanced, and Recurrent Cancer
Two systematic reviews were identified that evaluated IORT for either primary rectal cancer, locally recurrent rectal cancer, or advanced or recurrent colorectal cancer. Wiig et al (2014) reviewed 18 studies on primary rectal cancer (including 1 RCT, 5 comparative trials, 7 trials without IORT) and 18 studies on locally recurrent rectal cancer (including 5 studies without IORT).3 Meta-analysis of the data was not performed due to heterogeneity in study designs and reporting. Mirnezami et al (2013) included 29 studies (14 prospective, 15 retrospective) published between 1965 and 2011 (N=3003 patients).4, Indications for IORT were locally advanced disease in 1792 patients and locally recurrent disease in 1211 patients. A comparison of the studies included in the systematic reviews are included in Table A-1. Characteristics and results of these reviews are summarized in Tables 6 and 7.

Table 6. Systematic Review Characteristics 

Study Dates Trials Participants N (Range) Design Duration
Wiig (2014)3 1990-2013 Primary cancer: 15; Recurrent cancer: 18 Patients with locally advanced rectal cancer (either primary or recurrent) Primary cancer: 4272; Recurrent cancer: 1174 (ranges not reported) Randomized controlled trials (if available), comparative studies, non-comparative studies, non-IORT studies Up to 5 years
Mirnezami (2013)4 1991-2011 29 Patients with locally advanced colorectal cancer (either primary or recurrent) receiving IORT as part of a multimodal treatment 3003 (11-607) Randomized controlled trials (if available), prospective and retrospective observational studies Up to 5 years

IORT: intraoperative radiotherapy

Table 7. Systematic Review Resultsa 

Study Overall survival Disease-free survival Local relapse
Wiig (2014)3 Overall survival   5-year local control
Primary cancer      
Total N Not reported (20 studies)   Not reported (18 studies)
IORT, mean (range) 60 (28-76)   13 (2-35)
non-IORT, mean (range) 72 (52-85)   8 (5-9)
Locally recurrent cancer      
Total N Not reported (23 studies)   Not reported (12 studies)
IORT, mean (range) 25 (40-46)   49 (28-74)
non-IORT, mean (range) 19 (0-46)   81 (70-92)
Mirnezami (2013)4 5-year overall survival, IORT vs no IORT 5-year disease-free survival, IORT vs no IORT 5-year local control, IORT vs no IORT
Total N 370 288 482
Pooled effect (95% CI) HR: 0.33 (0.2 to 0.54) HR: 0.51 (0.31 to 0.85) OR: 0.22 (0.05 to 0.86)
I2 (p) 0 (0.85) 42% (0.161) 68% (0.007)
Range of N 19-167 37-167 19-167
Range of effect sizes 0.13-0.36 0.32-1.54 0.04-1.88

aFormal meta-analysis not conducted in Wiig (2014), instead mean (range) for outcomes were presented for the publications included.

CI: confidence interval; HR: hazard ratio; IORT: intraoperative radiotherapy; OR, odds ratio

Wiig et al (2014) results suggested ORT provided no OS benefit for primary completely resected rectal cancers, with a possible reduction in local recurrence in cases of incomplete tumor resection. There was no evidence that IORT affected OS or local recurrence when used to treat locally recurrent rectal cancer. Mirnezami et al (2013) also reported outcomes for complications following IORT.4 With IORT, no increase was observed in total (odds ratio [OR]=1.13; 95% confidence interval [CI], 0.77 to 1.65; p=0.57), urologic (OR=1.35; 95% CI, 0.84 to 2.82; p=0.47), or anastomotic (OR=0.94; 95% CI, 0.42 to 2.1; p=0.98) complications; however, increased wound complications were noted after IORT (OR=1.86; 95% CI, 1.03 to 3.38; p=0.049). Both reviews are limited by the risk of selection bias for IORT in nonrandomized studies, the variability in stages evaluated and IORT dosing, and high heterogeneity present for certain outcomes.

Section Summary: Rectal Cancer
The evidence for IORT as part of a multimodal treatment approach in patients who have locally advanced (colo-)rectal caner includes RCTs, nonrandomized comparative studies, and systematic reviews of these studies. Adjunctive use of IORT could permit an increase in radiation dose without increasing complications. For individuals with locally advanced rectal cancer who received IORT in addition to standard therapy, the evidence includes 2 RCTs and 1 meta-analysis, which all failed to show any benefit with addition of IORT in terms of local control or survival. For individuals with locally recurrent rectal disease, evidence is more limited. One systematic review evaluating locally advanced and recurrent rectal cancers together, has shown a significant benefit with addition of IORT on local control, disease-free survival and OS. More data are needed to determine the effect of adjunctive IORT for locally advanced rectal tumors with greater certainty.

Gastric Cancer
Review of Evidence
Systematic Reviews
A meta-analysis by Yu et al (2015) assessed 8 RCTs that used IORT for resectable gastric cancer.5 The literature search from 1990 through mid-2013 identified trials that assigned patients to surgery plus IORT or to surgery without IORT. Three studies also gave EBRT to both arms. HRs to describe the impact of adjuvant IORT on OS and locoregional control were obtained directly from the original studies or calculated from survival curves. Compiled data from 4 studies that reported OS revealed that IORT had no significant impact on OS (HR=0.97; 95% CI, 0.75 to 1.26; p=0.837). Notably, 3 of the 4 studies provided adjuvant EBRT. In another 3 studies that tested the efficacy of IORT for OS in patients with stage III disease, OS significantly improved (HR=0.60; 95% CI, 0.40 to 0.89; p=0.011). However, all 3 of these studies did not administer EBRT and used a higher dose of IORT than the other studies. The largest study in the meta-analysis included 292 patients with stage III disease. The HR for OS in this study was 0.54 (95% CI, 0.35 to 0.83). Significant improvement in locoregional control was observed in 4 studies that provided such data (HR=0.40; 95% CI, 0.26 to 0.62; p<0.001).

Section Summary: Gastric Cancer
A meta-analysis of 8 RCTs found a benefit of IORT in locoregional control but not OS when used in combination with EBRT. Three studies found improved OS in patients with stage III disease; however, none of the 3 studies provided EBRT. Randomized studies comparing the benefits and harms of IORT and EBRT are needed to determine the efficacy of IORT with greater certainty. It cannot be determined from the current literature whether IORT in patients with stage III disease provides any benefit for OS when used with EBRT.

Soft Tissue Sarcomas
Review of Evidence
Systematic Review s
A systematic review by Skandarajah et al (2009) highlights the potential value of IORT in the multimodal treatment of retroperitoneal sarcoma because these tumors are often close to dose-limiting structures, but reviewers noted that it is not without complications.6

Randomized Controlled Trials
One small randomized trial (n=35), reported by Sindelar et al (1993), compared IORT plus low-dose (35- to 40-gray) postoperative EBRT with high-dose (50- to 55-gray) EBRT alone.7 The local recurrence rate was lower (40%) in the combined therapy group than in the EBRT-only group (80%), with no difference in OS. Patients who received IORT had fewer radiation enteritis events but had more disabling peripheral neuropathies.

Nonrandomized Comparative Studies
In a nonrandomized comparative study of 251 patients, 92 of whom received IORT, Lehnert et al (2000) reported that IORT patients had more surgical complications and significantly more infectious complications; however, the IORT-treated patients had a 40% lower rate of local recurrence.8 IORT demonstrated effective tumor control in osteosarcoma.

A multicenter study by Calvo et al (2014) compared outcomes from 159 patients who had soft tissue sarcomas of the extremity treated using IORT plus multimodal therapy with 95 patients treated using multimodal therapy without IORT.9 IORT was administered to patients who had close (<1 cm) or positive surgical margins while patients with margins of 1 cm or greater were treated only with multimodal therapy. Use of IORT in the high-risk patients led to 5-year local control (82%) and OS rates (72%) that were similar to lower risk sarcoma patients treated without IORT. DFS (62%) remained modest due to the high-risk of distant metastases. In multivariate analysis, only surgical margin resection was significantly associated with local control.

Stucky et al (2014) reported on 63 consecutive patients with retroperitoneal sarcoma treated with surgery plus IORT (n=37) or surgery-only (n=26) between 1996 and 2011.10  Median follow-up was 45 months. The 5-year local control rate for patients receiving surgery plus IORT was 89% and 46% for the surgery-only patients (p=0.03). Survival did not differ as both groups had an actutimes 5-year OS rate of 60%. The contribution of IORT cannot be determined from this study.

Section Summary: Soft Tissue Sarcomas
The evidence on the use of adjunctive IORT for the treatment of soft tissue sarcomas includes a systematic review, a small RCT, and several nonrandomized comparative studies. Overall, study quality was low. The limited data available would suggest that IORT might improve local control and OS but adverse events might outweigh any treatment benefit. RCTs are needed to determine the risks and benefits of IORT for soft tissue sarcomas with greater certainty.

Gynecologic Cancers
Review of Evidence
The literature on IORT for gynecologic cancers consists primarily of case series.

In a phase 2 trial, Giorda et al (2011) examined the use of radical surgery with IORT after chemotherapy in extracervical, locally advanced cancer patients.11 Between 2000 and 2007, 42 locally advanced cervical cancer patients were treated. EBRT was administered to the whole pelvic region in combination with chemotherapy. After EBRT and chemotherapy, 35 (83%) of 42 patients underwent radical surgery and IORT treatment. Five-year DFS and OS rates were 46% and 49%, respectively. DFS and OS were significantly longer when the residual tumor was absent or limited to the cervix. At follow-up, only 3 (9%) of 35 patients were alive and free of disease.

A case series of 67 patients with locally advanced (n=31) and recurrent cervical cancer (n=36) treated with IORT at a Spanish center was reported by Martinez-Monge et al (2001).12 Previously unirradiated patients received preoperative chemoradiation. The 10-year control rate within the area treated with IORT was 69.4% for the entire group, 98.2% for the primary group, and 46.4% for the recurrent group. Control in the treated area correlated with margin status, amount of residual disease, and pelvic lymph node involvement. The overall incidence of toxic events attributable to IORT was 13.9%. The 10-year survival rate for the entire group was 34%, 58% for patients with primary disease, and 14% for those with recurrent disease. Patients, especially those with recurrent disease, with positive lymph nodes, parametrial involvement, and/or incomplete resection had poor local control, despite IORT at the doses used in the study.

Gao et al (2011) evaluated clinical outcomes and toxicity of IORT plus EBRT in advanced and recurrent ovarian carcinoma.13 All 45 patients in this series underwent optimal cytoreductive surgery. At 5-year follow-up, local control was observed in 68.9%, with OS and DFS rates of 64% and 56%, respectively. The major complication was peripheral neuropathy, affecting 5 (11%) of patients.

Section Summary: Gynecologic Cancer
The literature on IORT for gynecologic cancers consists of a nonrandomized trial and case series. The contribution of adjuvant IORT cannot be determined from these studies. OS rates in patients with locally advanced or recurrent disease are low and reported complications can be severe.

Head and Neck Cancers
Review of Evidence
Zeidan et al (2011, 2012) reported on 2 case series of head and neck cancers. In the 2011 publication, they reported on the use of IORT for 231 patients with advanced cervical metastasis.14 OS rates at 1, 3, and 5 were 58%, 34%, and 26%, respectively. Recurrence-free survival rates at 1, 3, and 5 years were 66%, 55%, and 49%, respectively. A second publication reviewed the use of IORT in 96 patients with primary or recurrent cancer of the parotid gland.15 Recurrence-free survival rates at 1, 3, and 5 years were 82%, 69%, and 65%, respectively. One-, 3-, and 5-year OS rates after surgery and IORT were 88%, 66%, and 56%, respectively. Complications developed in 26 patients.

Thirty-four patients with recurrent head and neck cancer treated with IORT at another center were reported by Perry et al (2010).16 At a median follow-up of 23 months (range, 6-54 months), 8 patients were alive and without evidence of disease. The 1- and 2-year estimates for in-field local progression-free survival rates were 66% and 56%, respectively, with 13 (34%) in-field recurrences. One- and 2-year distant metastases-free survival rates were 81% and 62%, respectively, with 10 (29%) patients developing distant failure. One- and 2-year OS rates were 73% and 55%, respectively, with a median time to OS of 24 months.

Chen et al (2008) reported on a retrospective study of 99 patients with locally recurrent salivary gland carcinomas treated surgically with or without IORT.17 All patients had previously been treated with surgery, and 82% had received postoperative EBRT. Median time from the initial surgery to local recurrence was 3.1 years. After salvage surgery, 37 (37%) patients received IORT. Reasons for IORT use were not clearly described in the report. For the entire patient population, the 1-, 3-, and 5-year estimates of local control were 88%, 75%, and 69%, respectively. Univariate analysis revealed predictors of local recurrence to be positive surgical margins, tumor size greater than 4 cm, and lack of IORT. Six of 37 patients treated with IORT experienced a local recurrence compared with 26 of 32 treated without IORT. At 5 years, the OS rate was 34%, and the DFS rate was 46%. The only predictor of DFS was the use of IORT, with a 5-year DFS rate of 61% in patients treated with IORT and 44% in patients without IORT. Complications were not analyzed.

A case series of 137 patients with persistent or recurrent salivary gland tumors treated with IORT after surgical resection was also reported by Chen et al (2007).18 There is a potential for overlap of patients with the Chen et al (2008) study described above. Eighty-three percent had previously received EBRT. Surgical margins were microscopically positive in 56 patients. Median follow-up among surviving patients was 41 months (range, 3-122 months). One-, 2-, and 3-year estimates of in-field control after surgery and IORT were 70%, 64%, and 61%, respectively, and positive margins at the time of IORT predicted in-field failure. Three-year rates of locoregional control, distant metastasis-free survival, and OS were 51%, 46%, and 36%, respectively.

Section Summary: Head and Neck Cancers
The evidence on the use of IORT for head and neck cancers includes case series. The strongest evidence is from a retrospective study of patients who had recurrent salivary gland carcinomas and were at risk of radiation toxicity due to prior treatment with EBRT. In this study, multivariate analysis found that the use of IORT was a significant predictor of improved outcomes. However, the reasons for using or not using IORT were not clearly described, and there was a risk of selection bias.

Pancreatic Cancer
Review of Evidence
Systematic Reviews
One recent systematic review by Jin et al (2020) was identified that evaluated clinical outcomes in patients with resectable pancreatic cancer with or without IORT.19 The meta-analysis identified 15 pertinent articles for inclusion representing 401 patients undergoing pancreatic resection with IORT and 433 patients undergoing pancreatic resection only. Characteristics and results are summarized in Tables 8 and 9.

Table 8. Systematic Review Characteristics

Study Dates Trials Participants N (Range) Design Duration
Jin (2020)19 1990-2019 15 Patients with resectable pancreatic cancer (not metastatic or locally advanced) undergoing surgery 834 (11-203) Non-randomized controlled trials Not reported

IORT: intraoperative radiotherapy

Table 9. Systematic Review Resultsa

Study Overall survival Disease-free survival Local relapse
Jin (2020)19      
Total N Not reported (13 studies)   Not reported (8 studies)
Pooled effect (95% CI) MSR: 1.20 (1.06 to 1.37)   RR: 0.70 (0.51 to 0.97)
I2 (p) 65.3% (p=0.00)   36.8% (p=0.135)
Range of N Not reported    
Range of effect sizes 0.57-3.54   0.14-0.96

CI: confidence interval; MSR: median survival rate 

Jin et al (2020) found that patients receiving IORT had an improved median survival rate and a reduced risk of local recurrence compared to those who did not receive adjuvant IORT with moderate heterogeneity.19 The incidence of postoperative complications between the groups were not significantly different from each other (relative risk, 0.95; 95% CI 0.73-1.23). Results of the meta-analysis were limited by the small sample sizes of the included studies, substantial heterogeneity, and the mostly retrospective design of the studies.

Case Series
Other larger retrospective evaluations of IORT in pancreatic cancer that evaluated patients with unresectable disease are summarized in Tables 10 and 11 below.

Table 10. Summary of Case Series Characteristics - Unresectable Disease  

Study Country Participants Follow-Up
Chen (2016)20 China 247 patients with nonmetastatic locally advanced pancreatic cancer median, 10.1 months
Cai (2013)21 United States 194 patients with unresectable locally advanced pancreatic cancer median, 11.6 months
Harrison (2020)22 United States 158 patients with borderline resectable/locally advanced pancreatic cancer (132 patients receiving FOLIRINOX were evaluated for survival analysis not reported

FOLIRINOX: folinic acid, fluorouracil, irinotecan, oxaliplatin

Table 11. Summary of Case Series Results - Unresectable Disease 

Study Treatment Overall Survival Progression-Free Survival
Chen (2016)20 IORT delivered after palliative surgical procedures; postoperative adjuvant therapy (eg, chemotherapy) was recommended for all patients Overall 1-, 2- and 3-year survival rates were 40%, 14%, and 7.2%. Median overall survival was 9 months. 1-, 2- and 3-year LPFS rates were 51.3%, 40.1%, and 34.6%. 1-, 2- and 3-year DMFS rates were 39.3%, 23.4%, and 11.9%.
Cai (2013)21 IORT as part of multimodal approach including pre-IORT EBRT and chemotherapy Overall 1-, 2- and 3-year survival rates were 49%, 16%, and 6%. Median overall survival was 12 months. 1-, 2- and 3-year LPFS rates were 61%, 41%, and 38%. 1-, 2- and 3-year DMFS rates were 49%, 28%, and 19%.
Harrison (2020)22 IORT as part of multimodal approach including neoadjuvant treatment prior to attempted resection with IORT Overall 1-, 2-, 4-year survival rates were 99%, 79%, and 47% for those receiving any form of resection plus IORT. Overall 1-, 2-, 4-year survival rates were 98%, 49%, 13% for those receiving IORT only. At time of study follow-up, 51% and 67% of patients had disease progression in the resection plus IORT and IORT only groups, respectively.

DMFS: distant metastasis-free survival; EBRT: external beam radiotherapy; IORT: intraoperative radiotherapy; LPFS: local progression-free survival

Section Summary: Pancreatic Cancer
The evidence on the use of IORT for pancreatic cancer includes large case series and a systematic review of non-randomized comparative studies. The systematic review found that in patients with resectable pancreatic cancer the addition of IORT to standard therapy was associated with improved median survival and reduced local recurrence; the evidence was limited by mostly smaller retrospective designs contributing to the review. However, the vast majority of patients present at diagnosis with more advanced disease, such as borderline resectable, locally advanced, or with distant metastases.One-year and 2-year OS rates of patients with unresectable pancreatic cancer ranged from 40% to 98% and 14% to 49%, respectively, in the large case series. Lastly, 1 case series found IORT combined with surgical resection to be associated with increased survival compared to IORT alone in patients with positive or close margins.RCTs are needed to determine the effect of adjunctive IORT for resectable, locally advanced and metastatic pancreatic cancer with greater certainty.

Renal Cell Carcinoma
Review of Evidence
The evidence on IORT for RCC includes case series. Paly et al (2014) reported on 98 advanced or locally recurrent RCC patients treated with IORT during nephrectomy at 9 different institutions during the period of 1985 and 2010.23 Pre- or postoperative EBRT was given to 62% of patients. Median follow-up time was 3.5 years for surviving patients. For advanced disease, the 5-year OS, disease-specific survival, and DFS rates were 37%, 41%, and 39%, respectively. For locally recurrent disease, the 5-year OS, disease-specific survival, and DFS rates were 55%, 60%, and 52%, and reported to be favorable to patients who had resection without IORT.

Calvo et al (2013) reported on 20-year outcomes in 25 patients with advanced (n=15) or recurrent (n=10) RCC treated with IORT.24 Fifteen (60%) patients received perioperative EBRT. Surgical resection resulted in negative margins (R0) in 6 (24%) patients and residual microscopic disease (R1) in 19 (76%) patients. Median follow-up for surviving patients was 22.2 years (range, 3.6-26 years). OS and DFS rates at 5 and 10 years were 38% and 18% and 19% and 14%, respectively. Locoregional control (tumor bed or regional lymph nodes) and distant metastases-free survival rates at 5 years were 80% and 22%, respectively. Six (24%) patients experienced acute or late toxicities of grade 3 or higher using National Cancer Institute Common Toxicity Criteria version 4.

Hallemeier et al (2012) reported on outcomes of a multimodality therapy combining maximal surgical resection, EBRT, and IORT for 22 patients with advanced or recurrent RCC.25 Surgical resection was R0 (negative margins) in 5 patients (23%) and R1 (residual microscopic disease) in 17 patients (77%). OS rates at 1, 5, and 10 years were 91%, 40%, and 35% and DFS rates at 1, 5, and 10 years were 64%, 31%, and 31%, respectively. Central recurrence (within the IORT field), locoregional relapse (tumor bed or regional lymph nodes), and distant metastases rates at 5 years were 9%, 27%, and 64%, respectively.

Section Summary: Renal Cell Carcinoma
The evidence on the use of IORT for RCC includes case series. No controlled trials were identified to determine whether adjunctive IORT improves health outcomes when added to multimodal therapy with surgical resection and EBRT. In a case series, grade 3 or higher toxicity was reported in 24% of patients after IORT.

Glioblastoma
Review of Evidence
Nemoto et al (2002) reported on treatment with IORT for 32 patients with previously untreated malignant gliomas over a 10-year period.26 Patients also had postoperative radiotherapy. Eleven patients had histologic diagnoses of anaplastic astrocytoma, and 21 had glioblastoma. Median survival time was 24.7 months in the anaplastic astrocytoma group and 33.6 months for matched historical controls. Differences in 1-, 2-, and 5-year survival rates between IORT-treated patients and historical controls were also not statistically significant. In the glioblastoma group, median survival was 13.3 months for IORT-treated patients and 14.6 months for matched controls. Data on 1-, 2-, and 5-year survival rates also did not differ significantly between groups.

Sarria et al (2020) reported on an international, retrospective, pooled analysis of patients with suspected glioblastoma/high-grade glioma treated with low-energy IORT, in addition to standard of care, across 5 institutions in 3 countries (Germany, Peru, and China).27 All patients received standard of care therapy adjuvant therapy, which included EBRT and temozolomide chemotherapy. A total of 51 patients were evaluated and followed for a median of 18 months. The 1-, 2-, and 3-year OS rates were 79.5%, 38.7% and 25.6% respectively (median survival time, 18 months). The 1-, 2-, and 3-year progression-free survival rates were 46.2%, 29.4%, and 5.9%. respectively (median progression-free survival, 11.4 months). The median local progression-free survival was 16 months. Radionecrosis was observed in 13 patients (25.5%).

Section Summary: Glioblastoma
Compared with historical controls, IORT for patients with previously untreated malignant gliomas had no survival benefit when given as an adjunct to surgery and EBRT. An international retrospective pooled analysis of patients treated with IORT in addition to standard of care reported 1- and 2-year OS rates of 79.5% and 38.7%.

Neuroblastoma
Review of Evidence
Rich et al (2011) reported on their experience using IORT after re-resection in patients with locally recurrent or persistent high-risk neuroblastomas.28 They retrospectively reviewed 44 consecutive patients who received IORT at a single institution between 2000 and 2009 after gross total resection of therecurrent or persistent tumor. Median follow-up after IORT was 10.5 months. Each patient had received prior chemotherapy and surgery, and 94.5% had received EBRT. Median OS was 18.7 months (95% CI, 11.7 to 25.6 months), with a 50.4% probability of local control.

Section Summary: Neuroblastoma
No controlled trials were identified. There is insufficient evidence to evaluate the efficacy of IORT as an adjunct to multimodal therapy for neuroblastomas.

Fibromatosis
Review of Evidence
Roeder et al (2010) reviewed outcomes of 30 patients (31 lesions) with aggressive fibromatosis who we
re treated with IORT after surgery.29 Treatment with IORT was undertaken to avoid mutilating surgical procedures when complete surgical removal seemed to be unlikely or impossible. Median age was 31 years (range, 13-59 years). Resection status was a close margin in 6 lesions, microscopically positive in 13, and macroscopically positive in 12. Median tumor size was 9 cm. Twenty-five (83%) patients received additional EBRT. After a median follow-up of 32 months (range, 3-139 months), no disease-related deaths occurred. Five local recurrences were reported, resulting in actutimes 3-year local control rates of 82% overall and 91% inside the IORT areas. Trends to improved local control were seen for age (>31 years) and negative surgical margins but none of these factors were statistically significant. Perioperative complications were found in 6 patients (wound healing disturbances in 5 patients, venous thrombosis in 1 patient). Late toxicity was seen in 5 (17%) patients.

Section Summary: Fibromatosis
Although the local control rate for aggressive fibromatosis is high in patients who have had incomplete surgery and EBRT, no controlled trials were identified that evaluated whether IORT improves survival. Late toxicity was observed with the combined treatment in 17% of patients.

Summary of Evidence
For individuals who have rectal cancer who receive adjunctive IORT, the evidence includes randomized controlled trials (RCTs), nonrandomized comparative studies, and systematic reviews of these studies. Relevant outcomes are overall survival (OS), disease-specific survival, change in disease status, and treatment-related morbidity. Adjunctive use of IORT as part of a multimodal treatment could permit an increase in radiation dose without increasing complications. However, a phase 3 RCT and meta-analysis of IORT for locally advanced rectal cancer did not find improved outcomes with IORT in combination with external-beam radiotherapy (EBRT) and surgery. One systematic review evaluating locally advanced and recurrent rectal cancers together, has shown a significant benefit with addition of IORT on local control, disease-free survival and OS. Additional data are needed to determine the effect of adjunctive IORT for locally advanced rectal tumors with greater certainty. National Comprehensive Cancer Network guidelines suggest use of IORT in patients with T4 or recurrent cancers as an additional boost. Outside of those parameters, the evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have gastric cancer who receive adjunctive IORT, the evidence includes RCTs and a systematic review of RCTs. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. A meta-analysis of 8 RCTs found a benefit of IORT in locoregional control (but not OS) when used with EBRT. When IORT was administered without adjuvant EBRT in patients with stage III disease, OS improved. Thus, IORT might be considered an alternative to EBRT in patients undergoing surgery for stage III gastric cancer. Randomized studies comparing the benefits and harms of the 2 treatments are needed to determine the efficacy of IORT with greater certainty. It cannot be determined whether IORT provides any benefit for OS in this patient population (gastric cancer patients) when used with EBRT. Further study is needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have soft tissue sarcomas who receive adjunctive IORT, the evidence includes a systematic review, a small RCT, and several nonrandomized comparative studies. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. Overall, the study quality is low. The limited data suggest that IORT might improve local control and OS but adverse events might outweigh any treatment benefit. RCTs are needed to determine the risks and benefits of IORT for soft tissue sarcomas with greater certainty. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have gynecologic cancers who receive adjunctive IORT, the evidence includes a nonrandomized trial and case series. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. The contribution of adjuvant IORT cannot be determined from the available literature. There is no evidence that IORT improves survival rates, and there may be severe complications related to the therapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have head and neck cancers who receive adjunctive IORT, the evidence includes case series. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. The strongest evidence is from a retrospective analysis of patients who had recurrent salivary gland carcinomas and were at risk of radiation toxicity due to prior treatment with EBRT. Some patients received IORT plus salvage surgery, and multivariate analysis found that the use of IORT was a significant predictor of improved outcomes. Although these findings suggested an improvement in health outcomes for head and neck cancers that cannot be treated with EBRT due to toxicity, there was a high-risk of selection bias in this study. Comparative trials are needed to determine the efficacy of IORT with greater certainty. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have pancreatic cancer who receive adjunctive IORT, the evidence includes large case series, cohort studies, and systematic reviews of these studies. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. The systematic review found that in patients with resectable pancreatic cancer the addition of IORT to standard therapy was associated with improved median survival and reduced local recurrence; the evidence was limited by mostly smaller retrospective designs contributing to the review. However, the vast majority of patients present at diagnosis with more advanced disease, such as borderline resectable, locally advanced, or with distant metastases, where comparative evidence is limited to case series. More data are needed to determine the effect of adjunctive IORT for resectable, locally advanced and metastatic pancreatic cancer with greater certainty. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have renal cell carcinoma who receive adjunctive IORT, the evidence includes case series. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. No controlled trials were identified to determine whether adjunctive IORT improves health outcomes when added to multimodal therapy with surgical resection and EBRT. Grade 3 or higher toxicity after IORT has been reported in a substantial percentage of patients. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have glioblastoma or neuroblastoma or fibromatosis who receive adjunctive IORT, the evidence includes case series. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. Compared with other therapies, it is unclear whether IORT improves OS. However, compared with historical controls, IORT for patients with previously untreated malignant gliomas had no survival benefit when given in conjunction with multimodal therapy. In addition, complication rates may be high. Comparative trials are needed to evaluate the safety and efficacy of this treatment modality. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 1 physician specialty society and 2 academic medical centers (6 reviewers) while this policy was under review in 2009. Input was quite variable, with some supporting use of intraoperative radiotherapy for multiple indications and others considering it investigational. The strongest support was for rectal cancer.

Practice Guidelines and Position Statements
The American Brachytherapy Society
In 2019, the American Brachytherapy Society consensus statement on IORT provides recommendations for patient selection for IORT.30 Table 12 summarizes their recommendations based on cancer type. The consensus statement did not rate evidence or strength of recommendations.

Table 12. Consensus statement on Use of IORT  

Cancer site Recommendation
Breast cancer Monotherapy should not be offered unless in the context of a prospective clinical trial. Use as a boost technique can be considered in patients requiring a tumor bed boost.
CNS, brain metastases Can be considered for selected patients
CNS, high-grade gliomas Can be considered for selected patients
Colorectal Consider in cases with concern for positive margins. "IORT can be considered at the time of surgical resection of locally advanced or recurrent colorectal cancer in cases with concern for a positive margin, particularly when pelvic EBRT has already been delivered. A dose of 15 Gy in a single treatment to 5 mm depth in tissue using IORT-HDR has been used"
Gynecologic Consider in recurrent cases with concerns for close/positive margins. "IORT can be considered at the time of surgical resection for isolated recurrent gynecologic cancer in cases with concern for residual microscopic disease. IORT after chemoradiation and surgery for primary management of locally advanced cervical cancer should not be used off protocol."
Head and neck Can consider in selected patients
Pancreas Consider in cases with concerns for close/positive margins
Pediatric cancers Consider for pediatric sarcomas upfront if concern for close/positive margins or in recurrent sarcomas
Sarcoma, extremity Consider in situations with close/positive margins or recurrence with reirradiation
Sarcoma, retroperitoneal Consider in conjunction with preoperative EBRT, especially if close/positive margins are expected
Thorax Can be considered in selected patients. "IORT can be considered at the time of surgical resection in cases with concern for a positive margin. Intraoperative LDR brachytherapy may improve local control outcomes in patients undergoing sublobar resections for stage I NSCLC when there is a concern for a positive margin."

CNS: central nervous system; EBRT: external beam radiation therapy; Gy: gray; HDR: high dose radiation; IORT: intraoperative radiation therapy; LDR: low dose radiation; NSCLC: non-small cell lung cancer

National Comprehensive Cancer Network
Table 13 lists the National Comprehensive Cancer Network guidelines on the use of intraoperative radiotherapy for the treatment of various cancers relevant to this evidence review.

Table 13. Recommendations for the Use of IORT  

Cancer Site Version Recommendation COR
Cervical v.1.202031 IORT "is particularly useful in patients with recurrent disease within a previously radiated volume. During IORT, overlying normal tissue (such as bowel or other viscera) can be manually displaced from the region at risk." 3
Colon v.3.202032 IORT "if available, should be considered for patients with T4 or recurrent cancers as an additional boost." 2A
Gastric v.2.202033 I IORT is not addressed NA
Head/neck v.1.202034 "In certain rare circumstances, reirradiation with IORT or brachytherapy may be considered in high-volume centers with expertise in these techniques." 2A
Ovarian v.1.202035 IORT is not addressed NA
Pancreatic v.1.202036 "Overall, there is no clear established role for IORT in patients with pancreatic cancer, and the panel believes it should only be performed at specialized centers." NA
Rectal v.3.202037 IORT "if available, may be considered for very close or positive margins after resection, as an additional boost, especially for patients with T4 or recurrent cancers." 2A
Renal v.2.202038 IORT is not addressed NA
Soft tissue sarcoma v.1.202039 For patients with resectable disease, consider boost with IORT for known or suspected positive margins "10-12.5 Gy for microscopic residual disease" and "15 Gy for gross residual disease". 2A
Uterine v.1.202040 "For patients with local or regional recurrences and previously treated with brachytherapy only at the recurrence site, surgery with (or without) IORT is recommended. For those previously treated with EBRT, recommended therapy for isolated relapse includes: 1) surgery with (or without) IORT (category 3 for IORT); and/or 2) systemic therapy with (or without) palliative RT." For local recurrence in the vaginal/pelvis that is negative for distant metastatic disease, surgical and RT treatment pathways are provided. Surgical options in patients without prior RT exposure includes the option for IORT. For local recurrence in patients with previous RT exposure, treatment options include "1) surgery with the option of IORT and/or systemic therapy (category 3 for IORT); 2) systemic therapy; 3) selected reirradiation with EBRT and/or brachytherapy." 3

COR: category of recommendation; EBRT: external beam radiation therapy; Gy: gray; IORT: intraoperative radiotherapy; NA: not applicable; RT: radiotherapy.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 14.

Table 14. Summary of Key Trials  

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing      
NCT02685605 A Multicenter Randomized Phase III Trial on INTraoperative RAdiotherapy in Newly Diagnosed GliOblastoma Multiforme (INTRAGO II) 314 Mar 2023

NCT: national clinical trial.

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Coding Section

Codes Number Description
CPT 77424 Intraoperative radiation treatment delivery, x-ray, single treatment session
  77425 Intraoperative radiotion treatment delivery, electrons, single treatment session
  77469 Intraoperative radiation treatment management
ICD-9 Procedure 92.41 Intraoperative electron radiation therapy
ICD-9 Diagnosis 154.1 Malignant neoplasm of rectum
  157.1  Malignant neoplasm of body of pancreas 
  157.2  Malignant neoplasm of tail of pancreas 
  157.3  Malignant neoplasm of pancreatic duct 
  157.4  Malignant neoplasm of islets of langerhans 
  157.8  Malignant neoplasm of other specified sites of pancreas 
  157.9  Malignant neoplasm of pancreas, part unspecified 
  171.5 Malignant neoplasm of connective and other soft tissue; abdomen (includes intra-abdominal soft tissue sarcoma)
  171.8 Malignant neoplasm of connective and other soft tissue; other specified sites (includes extremity soft tissue sarcoma)
  179  Malignant neoplasm of uterus, part unspecified 
  180.0  Malignant neoplasm of edocervix 
  180.1  Malignant neoplasm of exocervix 
  180.8  Malignant neoplasm of other specified sites of cervix 
  180.9  Malignant neoplasm of cervix uteri, unspecified site 
  182.0  malignant neoplasm of corpus uteri, except isthmus 
  182.1  Malignant neoplasm of isthmus 
  182.8  Malignant neoplasm of other specified sites of body of uterus 
ICD-10-CM (effective 10/01/15) C20 Malignant neoplasm of rectum
  C25 Malignant neoplasm of pancreas 
  C25.0  Malignant neoplasm of head of pancreas 
  C25.1  Malignant neoplasm of body of pancreas 
  C25.2  Malignant neoplasm of tail of pancreas 
  C25.3  Malignant neoplasm of pancreatic duct 
  C25.4  Malignant neoplasm of endocrine pancreas 
  C25.7  Malignant neoplasm of other parts of pancreas 
  C25.8  Malignant neoplasm of overlapping sites of pancreas 
  C25.9  Malignant neoplasm of pancreas, unspecified 
  C49.4 Malignant neoplasm of connective and soft tissue of abdomen
  C49.8 53.Malignant neoplasm of overlapping sites of connective and soft tissue
  C53 Malignant neoplasm of cervix uteri 
  C53.0  Malignant neoplasm of endocervix 
  C53.1  Malignant neoplasm of exocervix 
  C53.8  Malignant neoplasm of overlapping sites of cervix uteri 
  C53.9  Malignant neoplasm of cervix uteri, unspecified 
  C54 Malignant neoplasm of corpus uteri 
  C54.0 Malignant neoplasm of isthmus uteri 
  C54.1  Malignant neoplasm of endometrium 
  C54.2  Malignant neoplasm of myometrium 
  C54.3  Malignant neoplasm of fundus uteri 
  C54.8  Malignant neoplasm of overlapping sites of corpus uteri 
  C54.9  Malignant neoplasm of corpus uteri, unspecified 
  C55  Malignant neoplasm of uterus, part unspecified 
ICD-10-PCS (effective 10/01/15)   ICD-10-PCS codes are only used for inpatient services.
  DD073Z0 Radiation oncology, gastrointestinal system, beam radiation, rectum, electrons, intraoperative
Type of Service Therapy/Radiation  
Place of Service Inpatient  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2013 Forward     

12/01/2020 

Annual review, no change to policy intent. Updating rationale and references. 

12/02/2019 

Annual review, no change to policy intent. Updating rationale and references. 

12/31/2018

Annual review, no change to policy intent. Updating background, description, rationale and references. 

12/13/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

12/01/2016 

Annual review, expanding medical necessity to include: colorectal cancer, pancreatic cancer, pelvic cancers (for example, cervical or uterine), soft tissue sarcomas, updating coding. 

12/2/2015 

Annual review, no change to policy intent. Updating background, description, rationale and references.

12/01/2014 

Annual review. Added coding, regulatory status, policy guidelines, benefit applications. Updated description, background, rationale and references. No change to policy intent.

12/3/2013

Annual review. Added related policies and updated references. 


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