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Description

Policy

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

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

Policy Guidelines

Benefit Application

Rationale

The policy was extensively updated in 2009 based on a MEDLINE search through May 2009. Because the literature consists mainly of retrospective reports of small case series with historic controls from single institutions published over a period of more than 20 years, recent systematic reviews, when available, were relied on for summary information.

Intraoperative radiation therapy (IORT) was first performed in the early 1900s and has been used for treatment of a variety of primary and recurrent solid tumors since the 1960s. Nevertheless, evaluation of its effectiveness is limited by the absence of randomized controlled trials (RCTs). A number of phase 1 and phase 2 trials of IORT in the treatment of soft tissue sarcomas and rectal, breast, brain, head and neck, and upper gastrointestinal cancers are underway at this time. A study of targeted intraoperative radiotherapy for the management of ductal carcinoma in situ of the breast is recruiting at the Norris Comprehensive Cancer Center at the University of Southern California (NCT00556907). Six more studies of IORT for treatment of breast cancer at U.S. sites are active, but not recruiting. Studies of multimodal therapy including IORT for sarcoma are underway at the M.D. Anderson Cancer Center (NCT00004123) and the Mayo Clinic (NCT00652860). A study of multimodal therapy including IORT for sarcoma is also ongoing. A complete list can be accessed at http://clinicaltrials.gov/ct2/results?term=intraoperative+radiotherapy.

Skandarajah and colleagues performed a systematic review of the literature to review indications, applications, and outcomes of IORT in non-gynecological solid tumors and concluded that “current studies in all common cancers show an additional benefit in local recurrence rates when intraoperative radiotherapy is included in the multimodal treatment. However, intraoperative radiotherapy may not improve overall survival and has significant morbidity depending on the site of the tumor.” (1) Their review is summarized here.

Major series of IORT for locally advanced or recurrent colorectal cancer were reviewed in their paper including large series (>100 patients) from the Mayo clinic and Massachusetts General Hospital. In the Massachusetts General study of IORT for locally advanced colorectal cancer, for example, patients with negative tumor margins (R0) had local control of 89% and disease-free survival at 5 years of 69%. Local control and disease-free survival for patients with an R1 (microscopic involvement) margin were 68% and 40%, respectively, and for R2 (macroscopic involvement), it was 57% and 14%. These results were reported to be better than those for historical controls. In all of the studies, disease-free survival was associated with complete surgical resection. Complete resection was also the most important prognostic factor in patients with recurrent rectal cancer for whom prior operation complicates surgery and extended resections may be required. Some, but not all, studies of multimodality treatment with IORT and preoperative external beam radiotherapy demonstrate improvement in local control in patients who received IORT. The authors note that the most extensive experience with IORT for recurrent rectal cancer is reported by the Mayo Clinic. Of 304 patients who underwent resection, 131 received IORT, 52% with palliative intent and 33% with curative intent. The Mayo clinic reported 5-year survivals of 21% for the palliative group and 27% in the patients for whom the treatment was intended to be curative. The possibility of selection bias prevents firm conclusions; good local control rates and good overall results suggest that combined therapy might be applied in selected patients.

Skandarajah et al observe that few studies of IORT for gastric cancer have been published in the last decade, suggesting that there is minimal efficacy for this indication and that is achieved only with potential toxicity to other organs. (1) Three RCTs and case series with historic controls were reviewed; all demonstrate only a small survival benefit at any cancer stage and with high complications rates in the IORT-treated patients. Evaluation of IORT for pancreatic cancer is hampered by the small number of patients eligible for resection. In the single RCT reviewed by Skandarajah et al (12 patients and 12 controls), IORT decreased local recurrence rates (33% vs. 100% in the control group) but had no impact on overall survival. Ruano-Ravina and colleagues concluded from their review of the literature that there is “no clear evidence to indicate that IORT is more effective than other therapies in treating pancreatic cancer in locally advanced and metastatic stages”. (2)

Regarding soft tissue sarcomas, the systematic review by Skandarajah et al highlights the potential value of IORT in the multimodal treatment of retroperitoneal sarcoma because these tumors are often close to dose-limiting structures but notes that it is not without complications. (1) One randomized study compared IORT combined with postoperative external beam radiation therapy (EBRT) with EBRT alone. The local recurrence rate was 40% in the combined therapy group versus 80% in patients who received EBRT only, but there was no difference in overall survival. Patients who received IORT had fewer radiation enteritis events but more disabling peripheral neuropathies. In a non-randomized study of 251 patients of whom 92 received IORT, IORT patients had more surgical complications and significantly more infectious complications; however, the IORT-treated patients had a 40% lower rate of local recurrence. IORT has demonstrated effective tumor control in osteosarcoma but fracture of irradiated bone can be significant.

Standard treatment for early breast cancer is breast-conserving surgery and whole breast radiation (WBRT). IORT has been studied as an adjuvant to standard treatment or to replace WBRT. Skandarajah et al caution that local recurrence is strongly associated with positive margins and that standard treatment in breast-conserving surgery is to re-excise positive margins before EBRT. (1) IORT without pretreatment pathology, including knowledge of margins and predictors of local recurrence such as ductal carcinoma in situ and extensive intraductal component suggest that IORT may be given inappropriately. The authors found 1 RCT comparing IORT (n =79) to WBRT (n =69) in patients with T1 and T2 tumors. There were no differences in local occurrences or local toxicity at 3 years. IORT has also been proposed for treatment of local breast recurrences after previous external beam therapy. The systematic review concludes that “despite promising early results, the data supporting IORT is premature, and outside the setting of a clinical trial, use of IORT in early breast cancer or in local recurrence is as yet not recommended.” A large case series was reported by Veronesi et al (3) From July 1999 to December 2003, 590 patients with unifocal breast carcinoma underwent wide resection followed by intraoperative radiotherapy. After mean follow-up of 24 months (range, 4 to 57 months), 3 developed local recurrences, 3 ipsilateral carcinomas in other quadrants, and 5 contralateral breast carcinoma. One patient died of distant metastases. Nineteen patients developed breast fibrosis that resolved in 24 months. Results of RCTs are expected in the near future.

No systematic reviews of IORT for gynecological cancers were identified in the literature search. Reports of single institution case series published in the past 10 years are summarized here. 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. (4) 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 to 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 The authors conclude that IORT is a valuable boosting technique particularly in the management of advanced but resectable cervical cancer. Patients, especially those with recurrent disease, with positive lymph nodes, parametrial involvement, and/or incomplete resection have poor local control despite IORT at the doses used in the study.

Gemignani et al report on 17 patients with recurrent gynecologic cancers treated with radical resection and high-dose intraoperative radiation therapy (HDR-IORT) at the Sloan-Kettering Cancer Center. (5) The site of the primary tumor was the cervix in 9, the uterus in 7, and the vagina in 1 patient. In patients with complete gross resection (n =13), the 3-year local control rate was 83% vs. 25% in patients with gross residual disease. The overall 3-year survival rate was 54%.The overall distant metastasis-free rate was also 54%; 7 patients, all of whom had microscopic residual, developed distant metastases. The authors conclude that radical surgical resection with IORT appears to provide a reasonable local-control rate in patients who have failed prior surgery and/or definitive radiation; however, only patients with complete gross resection at completion of surgery appear to benefit. Two of the authors state in a later review that for most patients with recurrent cervical cancer, pelvic exenteration is the only therapeutic option that offers the possibility of long-term survival, and patients for exenteration are those with central local recurrences that have not extended to the pelvic sidewalls. (6) They suggest that HDR-IORT combined with radical resection makes this option available to more patients, and those with recurrences that extend close to the pelvic sidewalls should be referred to centers where HDR-IORT is available. Dowdy and colleagues report on a series of 25 patients who received radical resection and IORT for recurrent endometrial cancer at the Mayo Clinic; 56% received radiation and 48% had either secondary surgery or chemotherapy before referral. (7) Seven patients required exenteration with resection of the pelvic sidewall. Overall 5-year survival was 47% versus 71% for those with a gross total resection but close margins. The most common complications were peripheral neuropathy, functional ureteral obstruction, and fistula formation. External beam radiotherapy, tumor size after resection, grade, and patient age were associated with improved survival.

Nemoto et al reported results or treatment with IORT for 32 patients with previously untreated malignant gliomas over a 10-year period. (8) Patients also had postoperative radiation therapy. Eleven patients had histological diagnoses of anaplastic astrocytoma (AA) and 21 had glioblastoma (GBM).  Median survival time was 24.7 months in the AA group versus 33.6 months for matched historical controls. Differences in 1-, 2-, and 5-year survival between IORT-treated patients and historical controls were also not significant. In the GBM group, median survival was 13.3 months in the IORT-treated patients versus 14.6 months in the matched controls. Data on 1-, 2-, and 5-year survival were also not significantly different between groups.

The literature search also found recent reports of single institution case series of patients treated with IORT for head and neck tumors, however comparisons with conventional treatment were not found. A large case series of patients was reported by Chen et al. (9) Between 1991 and 2004, 137 patients underwent gross total resection and IORT for recurrence or persistence of locoregional cancer of the head and neck. Eighty-three percent of them had previously received EBRT. Surgical margins were microsopically 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 overall survival were 51%, 46%, and 36%, respectively. A series of phase 2 clinical trials of three multimodal intensification regimens consisting of perioperative cisplatin chemoradiotherapy, surgical resection with intraoperative radiotherapy, and postoperative paclitaxel and cisplatin chemoradiotherapy for advanced, resectable, previously untreated squamous cell cancer of the oral cavity, oropharynx, or hypopharynx were conducted at Ohio State University, (10) and 123 patients were treated. Compliance (patients receiving full doses of chemotherapy and radiation within the prescribed time without delay or dose reduction and receiving all courses of treatment in the protocol) was 61%. Overall 5-year survival by Kaplan-Meier analysis was 57% (46% in the first regimen, 56% in the second, and 68% in the third). Overall disease-specific 5-year survival was 73%, with 60% for the first regimen, 78% for the second, and 80% for the third. The overall locoregional disease control rate was 91%, and the rate of distant metastases was 13.8%. The precise contribution of IORT cannot be established from these data.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
In response to requests, input was received through 1 Physician Specialty Society and 2 Academic Medical Centers (6 reviewers) while this policy was under review for October 2009. 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. The input obtained was quite variable with some supporting use of IORT for multiple indications and others considering it investigational. The strongest support was for rectal cancer.

In summary, there is evidence that IORT, as part of multimodal treatment of solid tumors, provides an additional benefit in local recurrence rates for many tumors. However, the impact of its use on survival rates is less clear and, for some tumors, is achieved at the price of significant treatment-related morbidity. In addition, the impact of this modality compared with some of the newer radiation therapy techniques (that allow better targeting of tumor) and chemotherapy regimens is not known. Given the available evidence, and the strength of the evidence, along with the clinical input, this may be considered as a medically necessary treatment option in patients with rectal cancer with very close or positive margins after resection. All other uses, including use in breast cancer, are considered investigational given the limited evidence.

Technology Assessments, Guidelines and Position Statements

National Comprehensive Cancer Network Guidelines (2009)

A search of the National Comprehensive Cancer Network (NCCN) guidelines for the term “intraoperative radiation therapy” found IORT referenced in only the following guidelines.

The NCCN guidelines for treatment of rectal cancer indicate that “IORT, if available, should be considered for very close or positive margins after resection, as an additional boost, especially for patients with T4 or recurrent cancers.” (11)

For colon cancer, the guidelines state that “Intraoperative radiotherapy (IORT) should be considered for patients with T4 or recurrent cancers as an additional boost.” (12)

For gynecological cancers, NCCN indicates that IORT is an option for patients with recurrent cervical cancer, recurrent endometrial cancer and uterine sarcoma. (13, 14)

The guidelines indicate that IORT is a treatment option for resectable retroperitoneal/intra-abdominal and extremity soft tissue sarcomas. (15)

For breast cancer, NCCN recommends that partial breast irradiation should be performed only as part of a prospective trial. (16)

The German Society of Radiation Oncology, the German Society of Senology, and the Working Group for Gynecological Oncology of the German Cancer Society published a consensus statement on accelerated partial breast irradiation (APBI) in 2007. (17) They state that “follow-up times mostly do not yet permit a definite judgment concerning the long-term effectiveness and side effects of APBI. The relevant societies in Germany support randomized clinical studies comparing APBI and WBRT in a well-defined subset of low-risk patients. However, the authors expressly discourage the routine use of APBI outside clinical trials. Until definite results show that APBI neither impairs therapeutic outcome nor cosmetic results, WBRT remains the gold standard in the treatment of early breast cancer.”

References:

Index

Policy History