Medical Policy

Policy Num:      08.001.052
Policy Name:    Intraoperative Radiotherapy
Policy ID:          [08.001.052]  [Ac / B / M+ / P+]  [8.01.08]

Last Review:      August 09, 2024
Next Review:      August 20, 2025
 

Related Policies: None

   Intraoperative Radiotherapy

Summary

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. 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.

Summary of Evidence

For individuals who have rectal cancer who receive adjunctive intraoperative radiotherapy (IORT) , the evidence includes randomized controlled trials (RCTs) , nonrandomized comparative studies, and systematic reviews with meta-analyses 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. Available meta-analyses on IORT, in addition to standard therapy, for rectal cancer have combined together studies on both locally advanced primary and recurrent disease. Of the 2 systematic reviews that quantitatively pooled results, there was no benefit with the addition of IORT in terms of survival, but there was conflicting results on local control with one demonstrating an improvement in 5-year local control, while the other found no benefit in locoregional reoccurrence. In individuals with locally advanced primary rectal cancer only, 2 RCTs failed to show benefit with the addition of IORT in terms of local control or survival. For individuals with locally advanced primary or recurrent colorectal disease, one meta-analysis evaluating these populations together showed a significant benefit with the addition of IORT on local control, disease-free survival (DFS) , and OS. More data are needed to determine the effect of adjunctive IORT in each specific population of locally advanced disease (ie, primary vs recurrent, rectal vs colorectal) with greater certainty. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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 external-beam radiotherapy (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 that the technology results in an improvement in the net health outcome.

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 that the technology results in an improvement in the net health outcome.

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 that the technology results in an improvement in the net health outcome.

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 that the technology results in an improvement in the net health outcome.

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. 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 that the technology results in an improvement in the net health outcome.

For individuals who have renal cell carcinoma (RCC) 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 that the technology results in an improvement in the net health outcome.

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 that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objectives of this evidence review are 2-fold: (1) to determine whether intraoperative radiotherapy (IORT) improves the net health outcome when used in conjunction with surgery and external-beam radiotherapy; and (2) to determine whether the use of IORT improves the net health outcome in individuals who cannot be treated with external-beam radiotherapy due to radiation toxicity.

Policy Statements

Use of intraoperative radiotherapy may be considered medically necessary in the following situation:

• Rectal cancer with positive or close margins with T4 lesions or recurrent disease.

Use of intraoperative radiotherapy is considered investigational for all other oncologic applications.

Policy Guidelines

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

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.

In the United States, certain racial/ethnic groups continue to be at an increased risk of developing or dying from particular cancers. Notably, Black men have the highest rate of new cancer diagnoses and Black men and women experience the highest rate of cancer-related death. Additionally, American Indians/Alaska Natives are disproportionally affected by kidney cancer and also have higher death rates from this cancer when compared to other racial/ethnic groups.

Regulatory Status

The INTRABEAM^® system was first approved for use by the U.S. Food and Drug Administration (FDA) for intracranial tumors in 1999 and was subsequently approved for whole body use in 2005. 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 radiotherapy or IORT treatments. In 1998, the Mobetron^® mobile electron beam accelerator, designed for use during surgery, was cleared for marketing by the FDA through the 510(k) process. Xoft^® Axxent^® electronic brachytherapy system is also available and was approved to deliver high dose rate X-ray radiation for brachytherapy in 2008.

FDA product codes: JAD, LHN.

This evidence review does not address the use of IORT for breast cancer (see review 8.01.13).

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 June 3, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a 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 a technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use 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. Randomized controlled trials 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Intraoperative Radiotherapy for Rectal Cancer

Clinical Context and Therapy Purpose

The purpose of intraoperative radiotherapy (IORT) is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with rectal cancer.

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

Populations

The relevant population of interest is individuals with rectal cancer undergoing tumor resection.

Classification of surgical resection margins is listed in Table 1.

Table 1. General Surgical Resection Margin Classification

Interventions

The therapy being considered is IORT. IORT delivers a fractional dose of radiation directly to the tumor/tumor bed while the area 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 electron beam IORT.

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 rectal cancer: surgery alone, multimodal therapies (EBRT plus surgery or chemotherapy).

Most individuals 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 2).

Table 2. Outcomes of Interest

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Primary, Advanced, and Recurrent Cancer

Four systematic reviews were identified that evaluated IORT for either primary locally advanced rectal cancer or locally recurrent colorectal or rectal 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).^1, 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 ).^2, Indications for IORT were locally advanced disease in 1792 patients and locally recurrent disease in 1211 patients with colorectal cancer. Liu et al (2021) included 3 RCTs and 12 observational studies (N=1460) that evaluated IORT in both locally advanced and locally recurrent rectal cancer.^3, Fahy et al (2021) included 7 studies of patients with locally advanced and locally recurrent rectal cancer (N=833).^4,

A comparison of the studies included in the systematic reviews is included in Table A-1. Characteristics and results of these reviews are summarized in Tables 3 and 4.

Table 3. Systematic Review Characteristics

IORT: intraoperative radiotherapy; RCT: randomized controlled trial.

Table 4. Systematic Review Results^a

aFormal meta-analysis not conducted in Wiig (2014), instead mean (range) for outcomes were presented for the publications included. CI: confidence interval; DFS: disease-free survival; HR: hazard ratio; IORT: intraoperative radiotherapy; NR: not reported; OR: odds ratio; OS: overall survival.

Mirnezami et al (2013) demonstrated significant survival and local control benefits with IORT in a mixed population of patients with locally advanced colorectal cancer (either primary or recurrent).^2, More recently, however, Liu et al (2021) did not demonstrate a 5-year OS or disease-free survival (DFS) benefit with IORT in patients with rectal cancer.^3, IORT did, however, demonstrate benefit in 5-year local control. Fahy et al (2021) also did not find a benefit with IORT for locoregional recurrence in a mixed population of patients with locally advanced and locally recurrent rectal cancer.^4, Wiig et al (2014) results suggested IORT provided no OS benefit for primary completely resected rectal cancers, with a possible reduction in local recurrence in cases of incomplete tumor resection.^1, There was no evidence that IORT affected OS or local recurrence when used to treat locally recurrent rectal cancer.

Some analyses also reported outcomes for complications following IORT. Mirnezami et al (2013) did not demonstrate an increased risk in total (odds ratio [OR]=1.13; 95% confidence interval [CI], 0.77 to 1.65), urologic (OR=1.35; 95% CI, 0.84 to 2.82), or anastomotic (OR=0.94; 95% CI, 0.42 to 2.1) complications with IORT; however, increased wound complications were noted after IORT (OR=1.86; 95% CI, 1.03 to 3.38; p =.049).^2, Liu et al (2021) did not find an increase in the risk of complications with IORT, including fistulae (OR=0.79; 95% CI, 0.33 to 1.89), wound complication (OR=1.21; 95% CI, 0.62 to 2.36), anastomotic leak (OR=1.09; 95% CI, 0.59 to 2.02), or neurogenic bladder dysfunction (OR=0.69; 95% CI, 0.31 to1.55).^3, Likewise, Fahy et al (2021) did not find an increased risk of complications with IORT, including wound infections (OR=1.13; 95% CI, 0.50 to 2.54), pelvic abscess (OR=1.01; 95% CI, 0.54 to 1.87), or anastomotic leak (OR=1.60; 95% CI, 0.51 to 2.81).^4, All 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.

Randomized Controlled Trials

Locally Advanced Cancer

The available RCTs evaluating IORT for locally advanced rectal cancer are summarized in Table 5. No RCTs were identified that evaluated IORT for the management of locally recurrent rectal cancers.

Table 5. Summary of Key RCT Characteristics

IORT: intraoperative radiotherapy; RCT: randomzied controlled trial. 

Health outcome results for RCTs are summarized in Table 6. Additionally, in the Dubois et al (2011) trial, postoperative complications were observed in 29.6% of patients in the IORT group and 19.1% of patients in the control group (p=.15).^5, 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.^6, 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 for less radical resection for advanced lower rectal cancer.

Table 6. Summary of Key RCT Results

CI: confidence interval; DFS: disease-free survival; IORT: intraoperative radiotherapy; OR: odds ratio; OS: overall survival; RCT: randomzied controlled trial.

The purpose of the limitations tables (see Tables 7 and 8) 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 conclusions on the sufficiency of evidence supporting the position statement.

Table 7. Study Relevance Limitations

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. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 8. Study Design and Conduct Limitations

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; 5. Other.b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.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); 7. Other.e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.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; 5. Other.

Section Summary: Rectal Cancer

The evidence for IORT as part of a multimodal treatment approach in patients who have locally advanced (colo-)rectal cancer includes RCTs, nonrandomized comparative studies, and systematic reviews with meta-analyses of these studies. Adjunctive use of IORT could permit an increase in radiation dose without increasing complications. Available meta-analyses on IORT, in addition to standard therapy, for rectal cancer have combined together studies on both locally advanced primary and recurrent disease. Of the 2 systematic reviews that quantitatively pooled results, there was no benefit with the addition of IORT in terms of survival, but there was conflicting results on local control with one demonstrating an improvement in 5-year local control, while the other found no benefit in locoregional reoccurrence. In individuals with locally advanced primary rectal cancer only, 2 RCTs failed to show benefit with the addition of IORT in terms of local control or survival. For individuals with locally advanced primary or recurrent colorectal disease, one meta-analysis evaluating these populations together showed a significant benefit with the addition of IORT on local control, DFS, and OS. More data are needed to determine the effect of adjunctive IORT in each specific population of locally advanced disease (ie, primary vs recurrent, rectal vs colorectal) with greater certainty.

For individuals who have rectal cancer who receive adjunctive intraoperative radiotherapy (IORT) , the evidence includes randomized controlled trials (RCTs) , nonrandomized comparative studies, and systematic reviews with meta-analyses 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. Available meta-analyses on IORT, in addition to standard therapy, for rectal cancer have combined together studies on both locally advanced primary and recurrent disease. Of the 2 systematic reviews that quantitatively pooled results, there was no benefit with the addition of IORT in terms of survival, but there was conflicting results on local control with one demonstrating an improvement in 5-year local control, while the other found no benefit in locoregional reoccurrence. In individuals with locally advanced primary rectal cancer only, 2 RCTs failed to show benefit with the addition of IORT in terms of local control or survival. For individuals with locally advanced primary or recurrent colorectal disease, one meta-analysis evaluating these populations together showed a significant benefit with the addition of IORT on local control, disease-free survival (DFS) , and OS. More data are needed to determine the effect of adjunctive IORT in each specific population of locally advanced disease (ie, primary vs recurrent, rectal vs colorectal) with greater certainty. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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.

Use of intraoperative radiotherapy may be considered medically necessary in the following situation:

• Rectal cancer with positive or close margins with T4 lesions or recurrent disease.

Population Reference No. 2

Intraoperative Radiotherapy for Gastric Cancer

Clinical Context and Therapy Purpose

The purpose of IORT is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with gastric cancer.

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

Populations

The relevant population of interest is individuals with gastric cancer undergoing tumor resection.

Classification of surgical resection margins is listed in Table 9.

Table 9. General Surgical Resection Margin Classification

Interventions

The therapy being considered is IORT. IORT delivers a fractional dose of radiation directly to the tumor/tumor bed while the area 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 electron beam IORT.

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 gastric 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 OS, disease-specific survival, and harms from treatment, specifically radiation toxicity (Table 10).

Table 10. Outcomes of Interest

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Review

A meta-analysis by Yu et al (2015) assessed 8 RCTs that used IORT for resectable gastric cancer.^7, 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. Hazard ratios (HR) 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 =.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 =.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 <.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.

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 external-beam radiotherapy (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 that the technology results in an improvement in the net health outcome.

Population Reference No. 3

Intraoperative Radiotherapy for Soft Tissue Sarcomas

Clinical Context and Therapy Purpose

The purpose of IORT is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with soft tissue sarcoma.

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

Populations

The relevant population of interest is individuals with soft tissue sarcoma undergoing tumor resection.

Classification of surgical resection margins is listed in Table 11.

Table 11. General Surgical Resection Margin Classification

Interventions

The therapy being considered is IORT. IORT delivers a fractional dose of radiation directly to the tumor/tumor bed while the area 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 electron beam IORT.

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 soft tissue sarcoma: 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 OS, disease-specific survival, and harms from treatment, specifically radiation toxicity (Table 12).

Table 12. Outcomes of Interest

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Review

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.^8,

Randomized Controlled Trial

One 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.^9, 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.^10, 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.^11, 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.^12, Median follow-up was 45 months. The 5-year local control rate for patients receiving surgery plus IORT was 89% versus 46% for the surgery-only patients (p =.03). Survival did not differ as both groups had a 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.

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 that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Intraoperative Radiotherapy for Gynecologic Cancers

Clinical Context and Therapy Purpose

The purpose of IORT is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with gynecologic cancer.

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

Populations

The relevant population of interest is individuals with gynecologic cancer undergoing tumor resection.

Classification of surgical resection margins is listed in Table 13.

Table 13. General Surgical Resection Margin Classification

Interventions

The therapy being considered is IORT. IORT delivers a fractional dose of radiation directly to the tumor/tumor bed while the area 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 electron beam IORT.

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 gynecologic 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 OS, disease-specific survival, and harms from treatment, specifically radiation toxicity (Table 14).

Table 14. Outcomes of Interest

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Observational Studies

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.^13, Between 2000 and 2007, 42 locally advanced cervical cancer patients were treated at a single center in Italy. 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).^14, 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.^15, All 45 patients in this series underwent optimal cytoreductive surgery at a single center in China. 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%) patients.

Chen et al (2022) evaluated the feasibility and safety of IORT as an adjuvant therapy for recurrent gynecological cancer in a case series of 5 women at a single center in Taiwan (cervical cancer, n=2; endometrial cancer, n=2; uterine leiomyosarcoma, n=1).^16, Three women died during follow-up, 2 of which had local recurrence or progression of disease. The median recurrence-free survival was 13.8 months (95% CI, 1.6 to not estimable) and the median OS was 16.4 months (95% CI, 4.7 months to not estimable).

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.

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 that the technology results in an improvement in the net health outcome.

Population Reference No. 5

Intraoperative Radiotherapy for Head and Neck Cancers

Clinical Context and Therapy Purpose

The purpose of IORT is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with head and neck cancer.

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

Populations

The relevant population of interest is individuals with head and neck cancer undergoing tumor resection.

Classification of surgical resection margins is listed in Table 15.

Table 15. General Surgical Resection Margin Classification

Interventions

The therapy being considered is IORT. IORT delivers a fractional dose of radiation directly to the tumor/tumor bed while the area 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 electron beam IORT.

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 head and neck 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 OS, disease-specific survival, and harms from treatment, specifically radiation toxicity (Table 16).

Table 16. Outcomes of Interest

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Observational Studies

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.^17, OS rates at 1, 3, and 5 years 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.^18, Recurrence-free survival rates at 1, 3, and 5 years were 82%, 69%, and 65%, respectively. Rates of OS 1, 3, and 5 years 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).^19, At a median follow-up of 23 months (range, 6 to 54 months), 8 patients were alive and without evidence of disease. The 1- and 2-year estimates for in-field local progression-free survival (PFS) rates were 66% and 56%, respectively, with 13 (34%) in-field recurrences. Distant metastases-free survival rates were 81% and 62%, respectively, with 10 (29%) patients developing distant failure. Rates of OS at 1 and 2 years 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.^20, All patients had previously been treated with surgery, and 82% had received postoperative EBRT. The 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).^21, 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 to 122 months). Estimates of in-field control after surgery and IORT at 1, 2, and 3 years 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.

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 that the technology results in an improvement in the net health outcome.

Population Reference No. 6

Intraoperative Radiotherapy for Pancreatic Cancer

Clinical Context and Therapy Purpose

The purpose of IORT is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with pancreatic cancer.

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

Populations

The relevant population of interest is individuals with pancreatic cancer undergoing tumor resection.

Classification of surgical resection margins is listed in Table 17.

Table 17. General Surgical Resection Margin Classification

Interventions

The therapy being considered is IORT. IORT delivers a fractional dose of radiation directly to the tumor/tumor bed while the area 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 electron beam IORT.

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 pancreatic 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 OS, disease-specific survival, and harms from treatment, specifically radiation toxicity (Table 18).

Table 18. Outcomes of Interest

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Review

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.^22, 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 19 and 20.

Table 19. Systematic Review Characteristics

IORT: intraoperative radiotherapy

Table 20. Systematic Review Results

CI: confidence interval; MSR: median survival rate; RR: relative risk; OS: overall survival.

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.^22, The incidence of postoperative complications between the groups were not significantly different from each other (relative risk=0.95; 95% CI, 0.73 to 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 21 and 22 below.

Table 21. Summary of Case Series Characteristics - Unresectable Disease

FOLIRINOX: folinic acid, fluorouracil, irinotecan, oxaliplatin; IORT: intraoperative radiotherapy; NR: not reported.

Table 22. Summary of Case Series Results - Unresectable Disease

DFS: disease-free survival; DMFS: distant metastasis-free survival; EBRT: external beam radiotherapy; FOLIRINOX: folinic acid, fluorouracil, irinotecan, oxaliplatin; IORT: intraoperative radiotherapy; IQR: interquartile range; LPFS: local progression-free survival; NR: not reported; OS: overall survival; PFS: 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 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, and another case series found that application of IORT following resection yields similar survival outcomes regardless of R0 (generally better prognosis) or R1 (generally worse prognosis) resection. RCTs in more diverse populations are needed to determine the effect of adjunctive IORT for resectable, locally advanced and metastatic pancreatic cancer 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 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. 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 that the technology results in an improvement in the net health outcome.

Population Reference No. 7

Intraoperative Radiotherapy for Renal Cell Carcinoma

Clinical Context and Therapy Purpose

The purpose of IORT is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with renal cell carcinoma (RCC).

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

Populations

The relevant population of interest is individuals with RCC undergoing tumor resection.

Classification of surgical resection margins is listed in Table 23.

Table 23. General Surgical Resection Margin Classification

Interventions

The therapy being considered is IORT. IORT delivers a fractional dose of radiation directly to the tumor/tumor bed while the area 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 electron beam IORT.

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 RCC: 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 OS, disease-specific survival, and harms from treatment, specifically radiation toxicity (Table 24).

Table 24. Outcomes of Interest

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Observational Studies

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 to 2010.^28, 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.^29,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 to 26 ). 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.^30, 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.

For individuals who have renal cell carcinoma (RCC) 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 that the technology results in an improvement in the net health outcome.

Population Reference No. 8

Intraoperative Radiotherapy for Glioblastoma or Neuroblastoma or Fibromatosis

Clinical Context and Therapy Purpose

The purpose of IORT is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with glioblastoma or neuroblastoma or fibromatosis.

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

Populations

The relevant population of interest is individuals with glioblastoma or neuroblastoma or fibromatosis undergoing tumor resection.

Classification of surgical resection margins is listed in Table 25.

Table 25. General Surgical Resection Margin Classification

Interventions

The therapy being considered is IORT. IORT delivers a fractional dose of radiation directly to the tumor/tumor bed while the area 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 electron beam IORT.

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 glioblastoma or neuroblastoma or fibromatosis: 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 OS, disease-specific survival, and harms from treatment, specifically radiation toxicity (Table 26).

Table 26. Outcomes of Interest

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Glioblastoma

Observational Studies

Nemoto et al (2002) reported on treatment with IORT for 32 patients with previously untreated malignant gliomas over a 10-year period.^31, 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).^32, All patients received standard of care therapy and adjuvant therapies that 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 PFS rates were 46.2%, 29.4%, and 5.9%, respectively (median PFS, 11.4 months). The median local PFS 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%.

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 that the technology results in an improvement in the net health outcome.

Population Reference No. 9

Neuroblastoma

Observational Study

Rich et al (2011) reported on their experience using IORT after re-resection in patients with locally recurrent or persistent high-risk neuroblastomas.^33, They retrospectively reviewed 44 consecutive patients who received IORT at a single institution between 2000 and 2009 after gross total resection of the recurrent 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 ), 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.

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 that the technology results in an improvement in the net health outcome.

Population Reference No. 10

Fibromatosis

Observational Study

Roeder et al (2010) reviewed the outcomes of 30 patients (31 lesions) with aggressive fibromatosis who were treated with IORT after surgery.^34, Treatment with IORT was undertaken to avoid mutilating surgical procedures when complete surgical removal seemed to be unlikely or impossible. The median age was 31 years (range, 13 to 59 ). Resection status was a close margin in 6 lesions, microscopically positive in 13, and macroscopically positive in 12. The median tumor size was 9 cm. Twenty-five (83%) patients received additional EBRT. After a median follow-up of 32 months (range, 3 to 139 ), 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 toward 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.

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 that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

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.

2009 Input

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

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Brachytherapy Society

In 2019, the American Brachytherapy Society consensus statement on intraoperative radiotherapy (IORT) provides recommendations for patient selection for IORT.^35, Table 27 summarizes their recommendations based on cancer type. The consensus statement did not rate evidence or strength of recommendations.

Table 27. Consensus statement on Use of IORT

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 28 lists the National Comprehensive Cancer Network guidelines on the use of IORT for the treatment of various cancers relevant to this evidence review.

Table 28. Recommendations for the Use of IORT

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.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 29.

Table 29. Summary of Key Trials

GBM: glioblastoma; IORT: intraoperative radiotherapy; NCT: national clinical trial.

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Policy History