Coverage Policy Manual
Policy #: 1998112
Category: Radiology
Initiated: February 1998
Last Review: October 2018
  Intraoperative Radiation Therapy

Description: Intraoperative radiation therapy (IORT) is designed to increase the intensity of radiation directly delivered to tumors. The tumor and associated tissues at risk for micrometastatic spread are directly visualized at operation. 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.

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. Most patients are subsequently treated with high-dose external beam photon irradiation.

Policy/
Coverage:
Intraoperative radiation therapy meets primary coverage criteria for effectiveness and is covered in patients with pancreatic cancer, pelvic malignancies and colorectal cancer.
 
Any other use of IORT does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
 
For contracts without Primary Coverage Criteria, any other use of IORT is considered investigational and is not covered. Investigational services are an exclusion in the member benefit.

Rationale:
Partial breast irradiation has been tested in limited pilot studies and shown to provide acceptable cosmesis, minimal toxicity and adequate local control. In one study (Sacchini, 2008), 52 women with early-stage breast cancer were treated with breast-conserving therapy and intraoperative radiation therapy (IORT) between 2002 and 2006 with two different radiation doses.  Women treated with 18 Gy appeared to have a more favorable cosmetic outcome compared with those receiving 20 Gy.  This was a non-randomized study which only compared two doses of IORT.  The technique appeared feasible, but the therapeutic value is unknown.
 
A retrospective study (Tran, 2008) from the Stanford Cancer Center treated 50 patients with locally advanced and recurrent soft-tissue sarcomas in adults using IORT.  IORT after tumor reductive surgery was well-tolerated and seemed to confer infield control in selected cases, though clear comparative data with the historical group is not provided.  
 
Therapy of sarcoma with IORT was reviewed in 2000 (Hu KS, 2000). In summary, the preponderance of the data support the hypothesis that IORT can improve local control. When compared to the local recurrence rates of 41- 82% after gross total resection without IORT, five studies (including a randomized trial) indicate that IORT does appear to decrease local failure to rates of 19- 41%. However, with the exception of the 8-year follow-up of the randomized NCI trial, follow-up of most of the other studies is modest.  Local failure can commonly occur even in 5-year survivors at up to 5% per year. Thus, close surveillance is required to confirm the benefit of IORT on local control.   Theoretically, since local recurrence represents the primary mode of failure and underlies the cause of death in the majority of retroperitoneal sarcoma patients, it would seem that a survival benefit should be derived from the incorporation of IORT. Yet an obvious improvement in survival is not apparent. It may be that too few patients treated with IORT have been studied as data of only 183 patients have been reported or it is possible that follow-up is too short to make a firm conclusion. The improvement in local control without a survival benefit has been demonstrated for extremity sarcomas. However, given the morbidity and mortality associated with local failure, local control remains a worthy objective. IORT seems to be a promising new modality for the 50% of patients whose retroperitoneal sarcomas may be gross totally resected; however, its role in subtotally resected patients remains to be determined. New treatment approaches integrating IORT, possibly concurrently with new chemotherapeutic or other biological agents need to be investigated.
 
IORT appears to improve local control in other sites including colorectal, pancreatic and gastric cancers (Gunderson , 1997).
 
A study from Rome (Valentini, 2008) examined external radiotherapy + IORT in 26 patients with pancreatic cancer (often in combination with chemotherapy and subsequent radiation). The overall survival rate was 15.4%.  The incidence of local recurrence was 19.2% in the patients getting IORT external RT -- definitely less that that reported in other studies of adjuvant RT (about 50%), suggesting a benefit for “integrated adjuvant RT.”  
 
Acute toxicity of IORT delivered as an “early boost” after tumor resection in patients with locally advanced head and neck cancer was evaluated (Marucci, 2008).  IORT was deemed feasible, with no increase in acute toxicity directly attributable to radiation.  Outcomes were not evaluated.
 
Forty patients with colectomy or proctectomy and who underwent IORT were retrospectively reviewed (Williams CP, 2008).  All patients had local extension and incomplete resection.  Ten patients underwent IORT as an alternative to sacrectomy or exenteration.  Mean survival was 35 +/- 26 months, and 1 patient had local recurrence.  The writers conclude that IORT has allowed a selective treatment approach to locally advanced primary and recurrent neoplasms, which traditionally would have been unresectable.  Using IORT, extended resections may be avoided in selected high-risk patients with low risk of local recurrence and minimal morbidity.
 
A group in Germany reported (Drognitz, 2008) on patients treated from 1991 to 2001 for resectable gastric cancer and who were treated with IORT.  61 patients were retrospectively matched with 61 patients without IORT treatment.  Mean follow-up was about 5 years.  The use of IORT was associated with low locoregional tumor recurrence but had no benefit on long-term survival while significantly increasing surgical morbidity in patients with curable gastric cancer.
 
Memorial Sloan-Kettering reported (Caceres, 2007) on the results of multi-faceted therapy of 14 patients with recurrent uterine and cervical cancer who had extended pelvic resections there between 2000 and 2006.  Previous treatments had included hysterectomy, pelvic radiation, chemotherapy, and total pelvic exenteration.  Surgery was extensive, and 50% of the patients received high-dose rate IORT.  At medial follow-up of 26 months (5-84 months), 71% of the patients are alive and 29% have died of disease.
 
A review from Germany (Wilkowski, 2008) reviews advanced unresectable pancreatic cancer.  They conclude that IORT effects only pain palliation in most cases.  The median survival with this disease is a maximum of 6-8 months.
 
2010 Update
Evaluation of the effectiveness of IORT 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.” (Skandarajah, 2009) 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. 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.” (Ruano-Ravina, 2008)
 
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.  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.  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 to WBRT 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 From July 1999 to December 2003, 590 patients with unifocal breast carcinoma underwent wide resection followed by intraoperative radiotherapy (Veronesi, 2005).  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.
 
Nemoto et al reported results or treatment with IORT for 32 patients with previously untreated malignant gliomas over a 10-year period (Nemoto, 2002).  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 (Chen, 2007).   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, (Schuller, 2007) 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.
 
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.”
 
For colon cancer, the guidelines state that “Intraoperative radiotherapy (IORT) should be considered for patients with T4 or recurrent cancers as an additional boost.”  
 
For gynecological cancers, NCCN indicates that IORT is an option for patients with recurrent cervical cancer, recurrent endometrial cancer, and uterine sarcoma.  
 
The guidelines indicate that IORT is a treatment option for resectable retroperitoneal/intra-abdominal and extremity soft tissue sarcomas.
 
For breast cancer, NCCN recommends that partial breast irradiation should be performed only as part of a prospective trial.
 
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 (Sauer, 2007).  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.”
 
2012 Update
A search of the MEDLINE database was conducted through September 2012. There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the key literature identified.
 
Colorectal cancer
Cantero-Muñoz and colleagues conducted a systematic review on the efficacy and safety of IORT in colorectal cancer (CRC) (Cantero-Munoz, 2011). The scientific literature published between January 2000 and October 2009 was reviewed; study inclusion criteria included any study design, a minimum of 30 patients treated with IORT, adults diagnosed with any stage disease and a median follow-up period of greater than 3 months. Fifteen studies met the inclusion criteria and included one systematic review (Skandarajah, 2009); the majority of studies were case series, except for 3 which had a comparative design. The median follow-up was over 3 years in only 6 studies and in 2 studies it was 5 years. Sample size was over 100 patients in the majority of studies and over 200 patients in 2 studies. Study quality was judged to be low given the heterogeneous patient populations, lack of comparison groups, heterogeneous delivery of IORT doses, and the concomitant heterogeneous delivery of other treatments. Five-to-six-year local control was over 80% and 5-year overall survival was close to 65%. For recurrences, the 5-year overall survival was 30%. The main acute complications were gastrointestinal. The authors concluded that it was difficult to draw conclusions and to separate the attributing effects of IORT given the complexity of surgery, patient heterogeneity and because IORT was delivered as part of combined treatment, but that adding IORT to conventional treatment approaches appeared to reduce the incidence of local recurrence within the radiation area over 10%.
 
Pelvic Malignancy
A phase 2 trial examined the use of radical surgery with intraoperative high-dose radiotherapy after chemotherapy in extra cervical locally advanced cervical cancer patients (Giorda, 2011). Between 2000 and 2007, 42 locally advanced cervical cancer (stage IIA bulky-IVA) patients were treated. External beam radiation was administered to the whole pelvic region in combination with chemotherapy, and then radical surgery with IORT was performed 6-8 weeks after the end of the external beam radiation and chemotherapy treatment. After external beam radiation and chemotherapy, 35/42 patients (83%) underwent radical surgery and IORT treatment. At pathologic examination 8/35 (23%) patients showed complete response, while the rest (27/35) had residual disease, either microscopic (17/27) or gross (10/27). The 5-year disease free survival (DFS) and the 5-year overall survival (OS) were 46% and 49% respectively. There were significantly better DFS and OS when residual tumor was absent or limited to the cervix, respectively 78% versus 16% and 81% versus 20% (p < 0.001). At the time of the analysis, 17/35 (48%) of patients were alive but developed a relapse with a median of 22 months, and 15/35 (43%) of patients died of disease with a median of 33 months. Three of 35 (9%) patients were alive and free of disease. The authors concluded that external beam radiation and chemotherapy followed by surgery and IORT in locally advanced cervical cancer patients was effective in a subgroup of patients with pathological complete response to treatment or partial response with residual tumor limited to the cervix.
 
A retrospective study by Gao and colleagues evaluated clinical outcomes and the toxicity of intraoperative, whole pelvic electron beam radiation therapy in advanced and recurrent ovarian carcinoma (Gao, 2011). Forty-five women with epithelial ovarian carcinoma were treated with IOERT; twenty-five had primary disease without distant metastasis at IOERT, and 20 patients had an isolated local recurrence after surgery. All 45 patients in this series underwent optimal cytoreductive surgery. Thirty-three patients received postoperative intraperitoneal chemotherapy, while seven patients received intravenous chemotherapy. Five patients refused concurrent chemotherapy. Overall survival rates were analyzed using the Kaplan-Meier method. Tumor recurrence and metastasis were observed in 16 patients (35.6%). Of those, 14 patients (31.1%) relapsed and two patients (4.4%) had distant metastasis alone. Eight of 25 (32%) local failures were observed in the primary disease group, as compared to 6/20 (30%) in the isolated local recurrence group (p=0.885). Actuarial local control at five year follow-up was 31/45 (68.9%). Seventeen of the total 45 (37.8%) patients died; nine of 25 (36%) in the primary disease group, and 8 of 20 (40%) in the isolated local recurrence group. The 5-year OS and DFS rates were 28/45 (62.2%) and 25/45 (55.6%), respectively. In the primary disease group, the 5-year OS and DFS rates were 16/25 (64%) and 14/25 (56%) (p>0.05, vs. the isolated local recurrence group at 12/20 and 11/20, respectively). The OS and DFS in the IOERT plus intraperitoneal group were 25/33 (75.8%) and 23/33 (69.7%), respectively, which were superior to the rates achieved with IOERT plus intraoperative chemotherapy (p< 0.05). The major complication of IOERT was neuropathy. Five (11.1%) patients developed peripheral neurotoxicity.
 
Pancreatic Cancer
Zygogianni and colleagues conducted a systematic review of the literature on the effectiveness and safety of IORT in pancreatic cancer (Zyogianni, 2011). The review assessed the potential impact of IORT on local control, quality of life and overall survival. PubMed was searched from 1980 until 2010 and the search was restricted to articles published in English. Thirteen studies were included. The authors concluded that the results of their review found no clear evidence to indicate that IORT was more effective than other therapies in treating pancreatic cancer.
 
A 2008 systematic review of the literature from 1995 to 2007 by Ruano-Ravina and colleagues assessed the efficacy and safety of IORT in pancreatic cancer (Ruano-Ravina, 2008). Study inclusion criteria included a minimum of 30 patients and survival results based on a minimum 3-month follow-up. Fourteen papers were included, one was an IORT technology assessment report, 5 were cohort studies, and 8 were case series studies, 2 of which belonged to the same series. There were no published studies that assessed quality of life.  The authors concluded that, in general, the studies showed that IORT could slightly increase survival among patients with pancreatic cancer in localized stages. However, there was no clear evidence to indicate that IORT was more effective than other therapies in treating pancreatic cancer in locally advanced and metastatic stages.
 
Reports of 3 series of patients treated with IORT for pancreatic cancer were identified in the recent literature; in 2, IORT appeared to provide local control. The largest series, a retrospective analysis of results in 201 patients treated with IORT after resection of pancreatic cancer (R0 [negative margins]:147 patients; R1 [residual microscopic disease]: 63 patients), was performed by investigators in Japan (Ogawa, 2010). Fifty-four patients also had postoperative EBRT, and 114 patients had chemotherapy. Median follow-up of the surviving 62 patients was 26.3 months (range, 2.7-90.5 months). Fifteen percent of patients had positive margins, usually posterior. Median follow-up of surviving patients was 26.3 months (range, 2.7-90.5 months). At the time of analysis, 150 patients had disease recurrences, local failure was seen in 31 patients, and the 2- year local control rate was 83.7%. The median survival time and the 2-year actuarial overall survival in all 210 patients were 19.1 months and 42%, respectively. The authors concluded that IORT yields an excellent local control rate with infrequent severe late toxicity and that IORT combined with chemotherapy confers a survival benefit compared with IORT alone. Comparisons to other current management approaches are not made. A U.S. center reports a retrospective review of 23 patients treated between 1990 and 2001 (Bachireddy, 2010). Most tumors (83%) were located in the head of the pancreas. Most patients (83%) had IORT at the time of definitive surgery. Three patients had preoperative chemoradiation. Median and mean follow-up were 6.5 and 21 months, respectively. Kaplan-Meier 2-year infield control, locoregional control, distant metastasis-free survival, and overall survival were 83%, 61%, 26%, and 27%, respectively. Investigators at another U.S. center found that IORT did not improve locoregional control and did not alter survival in a 37 patients who underwent pancreaticoduodenectomy for periampullary tumors including pancreatic cancers (Showalter, 2009).
 
Breast
A review article in the Journal of the National Comprehensive Cancer Network (McCormick, 2012) discusses the status of several large randomized controlled trials either just recently completed or scheduled to complete in the near future.  Results of a prospective phase III trial designed by The Milan Cancer Institute were reported in May 2012 at the Barcelona ESTRO meeting. In this trial comparing WBRT with intraoperative partial breast irradiation, patients received either intraoperative PBI in a single dose of 21 Gy at the time of breast surgery or standard WBRT of 50 Gy over 5 weeks followed by a boost dose to the lumpectomy site. The local failure rate at 5 years in the WBRT arm was 0.7% compared with 5.3% in the PBI intraoperative radiation therapy arm.
 
The TARGIT-A trial, a randomized controlled trial assessing standard WBRT versus intraoperative radiation therapy, completed enrollment and results were presented at ASCO in 2010. Intraoperative radiation was given through a low-energy, 50-kV device called the Intrabeam. The radiation dose was 20 Gy at the surface of the applicator and 5 to 6 Gy at a distance of 1 cm into the breast tissue. Patients randomized to receive intraoperative PBI were allowed to receive additional WBRT for pathologic findings such as high-grade disease or lymphovascular invasion. Fourteen percent of the patients treated with PBI also received WBRT. At 4 years, 6 patients in the PBI group had local failure in the breast with 5 patients having failure in the WBRT group. McCormick indicates it is important to note that the study population had a median age of 63 years with 86 % of the patients having T1 tumors; more than 90% had an ER-positive cancer; and 87% were HER2/negative. Additionally, the median follow-up time was just 25 months. “With such a short median follow-up time and the use of the additional WBRT in 14% of the PBI study arm, the low rate of local failure is not unexpected, and additional analysis with more follow-up seems prudent” (McCormick, 2012).
 
McCormick concludes that the findings on the larger prospective randomized trials comparing WBRT with PBI are mixed. He further concludes that until more evidence is available favoring PBI over WBRT, hypofractionated WBRT seems to a reasonable option over the traditional 5-week course (McCormick, 2012). There remains a lack of scientific evidence that intraoperative PBI improves health outcomes compared with the standard of care, WBRT.
 
 
 
National Comprehensive Cancer Network Guidelines
2012 NCCN guidelines for treatment of rectal cancer (v3.2012) 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.” (category 2A) http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
 
For colon cancer (v3.2012), the 2012 guidelines state that “Intraoperative radiotherapy (IORT) should be considered for patients with T4 or recurrent cancers as an additional boost.” (category 2A)
 
For gynecological cancers, 2012 NCCN guidelines indicate that IORT is an option for patients with:
 
2012 NCCN guidelines do not address the use of IORT in ovarian cancer (v3.2012)
 
The 2012 guidelines indicate that IORT is a treatment option for soft tissue sarcomas (v2.2012).
 
For pancreatic cancer, 2012 NCCN guidelines (v2012) state that “ideally, patients should be treated on clinical trials when available” and “that sometimes IORT is used for resectable cases and may be best used when resection may result in close or involved margins.”
 
2013 Update
A search of the MEDLINE database through August 2013 did not reveal any new information that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
Colorectal Cancer
Mirnezami and colleagues conducted a systematic review and meta-analysis on the use of intraoperative radiotherapy in colorectal cancer (Mirnezami, 2013). The review included studies that were published between 1965 and 2011 and that reported outcomes after IORT for advanced or recurrent colorectal cancer (CRC). Study quality and design were assessed. The review included 29 studies, 14 prospective and 15 retrospective, with a total of 3,003 patients. Indications for IORT were locally advanced disease in 1,792 patients and locally recurrent disease in 1,211 patients. Comparative studies found a significant effect favoring IORT for improved local control (odds ratio [OR]: 0.22; 95% confidence interval [CI]:0.05-0.86; p=0.03), disease-free survival (hazard ratio [HR]: 0.51; 95% CI: 0.31-0.85; p=0.009), and overall survival (HR 0.33; 95% CI:0.2-0.54; p=0.001). With IORT, there was no increase in total (OR: 1.13; 95% CI:0.77-1.65; p=0.57), urologic (OR: 1.35; 95% CI:0.84-2.82; p=0.47), or anastomotic complications (OR: 0.94; 95% CI:0.42-2.1; p=0.98); however, increased wound complications were noted after IORT (OR: 1.86; 95% CI:1.03-3.38; p=0.049).
 
Gastric Cancer
Calvo and colleagues reported long-term outcomes in 32 patients with resectable locally advanced gastric adenocarcinoma treated with IORT (Calvo, 2013).  Between January 1995 and December 2010, 32 patients with primary gastric adenocarcinoma were treated with curative resection, either total gastrectomy (n=9; 28%), or subtotal gastrectomy (n=23; 72%) and lymphadenectomy, for disease confined to the locoregional area (stage: II [n=15; 47%], or stage III [n=17; 53%]). Patients were treated with IORT over the celiac axis and peripancreatic nodal areas. Sixteen (50%) patients also received adjuvant treatment (external-beam radiotherapy (n=6), chemoradiation (n=9), or chemotherapy alone [n=1]). Median follow-up was 40months (range, 2-60 months). Locoregional recurrence was observed in 5 (16%) patients. Overall survival at 5years was 54.6% (95% CI: 48.57-60.58). Postoperative mortality was 6% (n=2) and postoperative complications 19% (n=6).
 
Soft Tissue Sarcomas
Call and colleagues reported outcomes in 61 patients with upper-extremity soft tissue sarcomas treated with external-beam radiotherapy, surgery, and IORT, with or without chemotherapy (Call, 2012).  The median patient age was 50 years old (median age 13 to 95 years). The median follow-up was 5.9 years. Eleven patients had gross or microscopic disease at the time of IORT. IORT doses ranged from 7.50 Gy to 20.00 Gy and external-beam radiotherapy doses ranged from 19.80 Gy to 54.00 Gy. Overall survival at 5 and 10 years was 72% and 58%, respectively. Local control at 5 and 10 years was 91% and 88%, respectively. Distant control at 5 and 10 years was 80% and 77%, respectively. Patients who were treated for recurrent disease had inferior 5-year overall survival compared with patients with a first diagnosis (63% vs. 74%; p=0.02) and lower 5-year local control rate (67% vs. 94%; p<0.01). For patients with residual disease at the resection margin, local control at 5 and 10 years was 100% and 86%, respectively, whereas for patients without residual tumor after resection, local control was 89% at both 5 and 10 years (p=0.98). Limb preservation was achievable for most patients. Severe toxicity attributable to treatment was noted in 7% of patients.
 
Pancreatic Cancer
Jingu and colleagues reported 30-year experience with the use of IORT in pancreatic cance (Jingu, 2012). They retrospectively reviewed the records of 322 patients who received intraoperative radiotherapy with or without external-beam radiotherapy for localized pancreatic cancer. One hundred ninety-two patients had no distant organ metastases or dissemination at the time of laparotomy and were enrolled in the study. Eighty-three patients underwent gross total resection: 48 patients with all gross disease resected and margins microscopically free of disease (R0), and 35 patients with all gross disease resected with margins microscopically positive for disease (R1); 109 patients underwent only biopsy or palliative resection. Fifty-five patients underwent adjuvant EBRT, and 124 received adjuvant chemotherapy. The median follow-up was 37.5 months. At the time of the analysis, 166 patients had recurrent disease, and 35 had local failure. The 2-year local control and OS rates were 71.0% and 16.9%, respectively. A multivariate analysis showed that the degree of resection (R0-1 vs. R2 [partial resection with tumor left behind], hazard ratio: 1.97, p=0.001) and adjuvant chemotherapy (yes vs. no, hazard ratio: 1.54, p=0.028) had significant impacts on OS. Late gastrointestinal morbidity of Common Terminology Criteria for Adverse Events grade 4 or 5 was observed in 4 of the patients.
 
Renal Cell Cancer
Calvo and colleagues reported 20-year outcomes in 25 patients with locoregionally recurrent (n=10) renal cell carcinoma (RCC) after radical nephrectomy or locoregionally advanced primary RCC (n=15) who were treated with IOERT (Calvo, 2013).  Fifteen patients (60%) received perioperative EBRT. Surgical resection resulted in negative margins (R0) in 6 patients (24%) and residual microscopic disease (R1) in 19 patients (76%). The median follow-up for surviving patients was 22.2 years (range, 3.6-26 years). OS and DFS 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. One patient died within 30 days of surgery (4%). Six patients (24%) experienced acute or late toxicities of grade 3 or higher according to the National Cancer Institute Common Toxicity Criteria v4.
 
National Comprehensive Cancer Network Guidelines
NCCN guidelines for treatment of rectal cancer (v4.2013) 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.” (category 2A) (available online at: http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
For colon cancer (v3.2013), NCCN guidelines state that “Intraoperative radiotherapy (IORT) should be considered for patients with T4 or recurrent cancers as an additional boost.” (category 2A) (available online at: http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf )
 
For gynecological cancers, NCCN guidelines indicate that IORT is an option for patients with:
 
  • Cervical cancer (v3.2013): Central pelvic recurrent cervical cancer after radiation therapy should be considered for pelvic exenteration with or without IORT. (category 3 for IORT). Non-central recurrent cervical cancer after radiation therapy- resection with IORT for close or positive margins (category 3). Distant metastases, resectable, consider resection +/- IORT (category 3 for IORT). (available online at: http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf)
 
 
NCCN guidelines do not address the use of IORT in ovarian cancer (v2.2013)
 
NCCN guidelines indicate that IORT is a treatment option for soft tissue sarcomas (v1.2013). (available online at: http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf)
 
For pancreatic cancer, NCCN guidelines (v1.2013) state that “ideally, patients should be treated on clinical trials when available” and “that sometimes IORT is used for resectable cases and may be best used when resection may result in close or involved margins.” (available online at: http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf)
   
2014 Update
A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Colorectal Cancer
Several reviews have been published on IORT for colorectal cancer and have concluded IORT may confer some benefit in local control. One review by Wiig et al found no evidence IORT is beneficial (Wiig, 2014). This review included 18 studies on primary rectal cancer (including 1 randomized and 5 comparative) and 18 studies on locally recurrent rectal cancer. Twelve additional studies on treatment of rectal cancer without IORT were also reviewed. A meta-analysis wasn’t able to be performed due to heterogeneity in study design and reporting. The authors reported IORT provided no OS benefit for primary rectal cancers that were completely resected but there was a possible reduction in local recurrence in cases of incomplete tumor resection. IORT did not affect OS or local recurrence when used to treat locally recurrent rectal cancer.
 
Soft Tissue Sarcomas
Stucky et al reported on 63 consecutive patients with retroperitoneal sarcoma treated with preoperative
EBRT, surgery and IORT (n=37) or surgery only (n=26) between 1996 and 2011 (Stucky, 2014). Median follow-up was 45 months. The 5-year local control rate for patients receiving radiation therapy was 89% versus 46% for the surgery only patients (p=0.03). OS did not differ as both groups had an actuarial 5-year OS of 60%.
 
Pancreatic Cancer
Cai et al reported on 194 consecutive patients treated with IORT for unresectable locally advanced pancreatic cancer between 1978 and 2010 (Cai, 2013). The median OS was 12 months. Survival rates at 1-, 2-, 3- and 5-years were 49%, 16%, 6%, and 3% respectively. Favorable factors included IORT applicator diameter 8 cm, a Charlson age-comorbidity index 3 and treatment with chemotherapy. The median OS increased to 21.2 months in patients with all 3 factors.
 
Renal Cell Cancer
Paly et al reported on 98 advanced or locally recurrent renal cell carcinoma (RCC) patients treated with IORT during nephrectomy at 9 different institutions during the period of 1985 and 2010 (Paly, 2014). EBRT was given to 27% preoperatively and to 35% postoperatively. Median follow-up time was 3.5 years for surviving patients. For advanced disease, the 5-year OS, disease-specific survival (DSS) and DFS were 37%, 41% and 39%, respectively. For locally recurrent disease, the 5-year OS, DSS and DFS were 55%, 60% and 52% and reported to be favorable to patients treated with resection without IORT.
 
2015 Update
A literature search conducted through July 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Gastric Cancer
A meta-analysis published in 2015 compiled studies that involved the use of IORT for resectable gastric cancer (Yu, 2015). The literature search for this analysis encompassed the period January through July 2013. Hazard ratios (HRs) to describe the impact of adjuvant IORT on OS and locoregional control (LRC) were extracted directly from the original studies or calculated from survival curves. Compiled data from 4 studies that reported OS revealed that IORT had no significant impact on OS (HR=0.97; 95% CI, 0.75 to
1.26; p=0.837). In 3 studies that tested the efficacy of IORT for OS in a subgroup of patients with stage III disease, there was a significantly improved OS (HR=0.60; 95% CI, 0.40 to 0.89; p=0.011). Significant improvement in LRC was observed in 4 studies that provided such data (HR=0.40; 95% CI, 0.26 to 0.62; p<0.001).
 
In a retrospective series, 75 pediatric patients underwent HDR-IORT to treat a variety of sarcomas from May 1993 to November 2013 (Folkert, 2014). The median age of patients was 9 years old (36 patients were <6 years old). HDR-IORT was part of initial therapy in 37 patients (49%) and for recurrent disease in 38 patients (51%). Forty-one patients (55%) received HDR-IORT and postoperative external beam radiotherapy (PORT), and 22 patients (29%) were previously treated with EBRT to the IORT site. At a median followup of 7.8 years for surviving patients, 5-year projected rates of LC, EFS, and OS were 63% (95% CI, 50% to 76%), 33% (95% CI, 21% to 45%), and 43% (95% CI, 30% to 55%), with a median survival of 3.1years. The 5-year LC, EFS, and OS rates for patients with recurrent disease were 46% (95% CI, 28% to 64%), 30% (95% CI, 13% to 46%), and 36% (95% CI, 18% to 54%). Acute toxicity of grade 3 or higher occurred in 2 (2.5%) treatments; late toxicity of grade 3 or higher occurred in 4 (5.3%) patients 0.3 to 9.9 years after HDR-IORT. Although the incidence of toxicity of grade 3 or higher was not associated with HDR-IORT applicator size, HDR-IORT dose, prior RT or PORT, or prior or postoperative chemotherapy, all such toxicities occurred in patients age 6 years or less treated with HDR-IORT doses of 12 Gy or more.
 
The evidence for IORT as part of a multimodal treatment approach in patients who have rectal cancer with positive or close margins with T4 lesions or recurrent disease consists of systematic reviews, at least
1 randomized controlled trial, and other nonrandomized clinical studies. Clinical outcomes of interest include overall survival (OS) and treatment-related morbidity. In general, it is difficult to determine the incremental value of IORT because standard radiotherapy is often administered following IORT. However, good local control rates and good overall results, including toxicities, suggest that combined therapy including IORT might be beneficial in selected patients in this setting. Additional limitations of the evidence include low study quality given the heterogeneous patient populations; lack of comparison groups; heterogeneous delivery of IORT doses; and, the concomitant heterogeneous delivery of other treatments. Nonetheless, the body of evidence is sufficient to determine that use of IORT improves health outcomes in patients with rectal cancer with positive or close margins with T4 lesions or recurrent disease.
 
The evidence for IORT in patients who have solid tumors other than rectal tumors consists of nonrandomized clinical studies and some systematic reviews. Clinical outcomes of interest include OS and treatment-related morbidity. In general, whether IORT improves OS compared to other therapies is unclear. Furthermore, study quality was judged to be low given the heterogeneous patient populations; lack of comparison groups; heterogeneous delivery of IORT doses; and, the concomitant heterogeneous delivery of other treatments, particularly other radiotherapy. Therefore, the body of evidence is insufficient to determine that use of IORT improves health outcomes in patients with solid tumors other than rectal cancer.
 
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN) guidelines for treatment of rectal cancer (v.2.2015) 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.”
 
For colon cancer (v.2.2015), NCCN guidelines state that “Intraoperative radiotherapy (IORT) should be considered for patients with T4 or recurrent cancers as an additional boost.”
 
For gynecologic cancers, NCCN guidelines indicate that IORT is an option for patients with:
  • Cervical cancer (v.2.2015): Central pelvic recurrent cervical cancer after radiation therapy should be considered for pelvic exenteration with or without IORT. (category 3 for IORT). Noncentral recurrent cervical cancer after radiation therapy- resection with IORT for close or positive margins (category3). Distant metastases, amenable to local treatment, consider resection ± RT or local ablative therapies ± RT or TR ± concurrent chemotherapy.
  • Uterine endometrial adenocarcinoma (v.2.2015)42: recurrent endometrial cancer, for patients previously treated with external-beam radiation at the site of recurrence, resection ± IORT.  
 
NCCN guidelines do not address the use of IORT in ovarian cancer (v.1.2015).
 
NCCN guidelines indicate that newer techniques such as brachytherapy, IORT, and intensity-modulated radiotherapy have led to improvement of treatment outcomes in patients with soft tissue sarcomas (v.1.2015) (NCCN, 2015).
 
For pancreatic cancer, NCCN guidelines (v.2.2015) (NCCN, 2015) state that “the role of IORT for unresectable and resectable cases is controversial and should only be performed at specialized centers. It is sometimes used in cases where surgical resection may result in close or involved margins.
 
2017 Update
 
A literature search conducted using the Medline database through August 2017. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
RECTAL CANCER
The only randomized controlled trial (RCT) identified was a 2011multicenter study on intraoperative radiotherapy (IORT) for locally advanced rectal cancer by Dubois et al (Dubois, 2011). It was included in the meta-analyses described next. Patients (N=142) with locally advanced rectal cancer were treated with preoperative radiotherapy and randomized to surgical resection alone or surgical resection plus IORT. Mean duration without local relapse, based on Kaplan-Meier analysis, was 107 months with surgery plus IORT and 126 months with surgery alone (p=NS). There was no significant difference between groups in the incidence of local control or overall survival (OS).
 
In 2015, Zhang et al reported on a nonrandomized comparative study with 148 patients who had primary locally advanced rectal cancer treated with IORT plus external-beam radiotherapy (EBRT) or EBRT alone (Zhang, 2015). Use of IORT was based on patient preference and technology availability . Thus, there was a high risk of selection bias. Five-year local control was 89.7% for IORT plus EBRT compared to 79.2% for EBRT alone (p=0.032). DFS was also increased in the IORT group (69%) compared to IORT alone (58.5%; p=0.049). However, OS rates did not differ significantly between groups. Multivariate analysis found a significant impact of tumor size classification and staging, with a trend (p=0.079) for improved locoregional control with IORT, and no significant differences between groups in acute and late toxicity.
 
SOFT TISSUE SARCOMAS
One small randomized trial (N=35) from 1993 compared IORT plus low-dose (35- to 40-gray [Gy]) postoperative EBRT to high-dose (50- to 55-Gy) EBRT alone (Sindelar, 1993). 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.
 
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.  

CPT/HCPCS:
19294Preparation of tumor cavity, with placement of a radiation therapy applicator for intraoperative radiation therapy (IORT) concurrent with partial mastectomy (List separately in addition to code for primary procedure)
77424Intraoperative radiation treatment delivery, x-ray, single treatment session
77425Intraoperative radiation treatment delivery, electrons, single treatment session
77469Intraoperative radiation treatment management

References: 1988 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; p 93.

1992 Blue Cross Blue Shield Association Technology Evaluation Center Evaluation and Coverage; p 402.

AMA TechBrief; May 1995.

Bachireddy P, Tseng D, Horoschak M et al.(2010) Orthovoltage intraoperative radiation therapy for pancreatic adenocarcinoma. Radiat Oncol 2010; 5:105.

Caceres A, Mourton SM, et al.(2007) Extended pelvic resections for recurrent uterine and cervical cancer: out-of-the-box surgery. Int J Gynecol Cancer. 2007 Dec 5. [Epub ahead of print].

Cai S, Hong TS, Goldberg SI, et al.(2013) Updated long-term outcomes and prognostic factors for patients with unresectable locally advanced pancreatic cancer treated with intraoperative radiotherapy at the Massachusetts General Hospital, 1978 to 2010. Cancer. Dec 1 2013;119(23):4196-4204. PMID 24006012

Call JA, Stafford SL, Petersen IA et al.(2012) Use of Intraoperative Radiotherapy for Upper-extremity Soft-tissue Sarcomas: Analysis of Disease Outcomes and Toxicity. Am J Clin Oncol 2012 [Epub ahead of print].

Calvo FA, Sole CV, Martinez-Monge R et al.(2013) Intraoperative EBRT and resection for renal cell carcinoma : twenty-year outcomes. Strahlenther Onkol 2013; 189(2):129-36.

Calvo FA, Sole CV, Obregon R et al.(2013) Intraoperative radiotherapy for the treatment of resectable locally advanced gastric adenocarcinoma: topography of locoregional recurrences and long-term outcomes. Clin Transl Oncol 2013; 15(6):443-9.

Calvo FA, Sole CV, Polo A, et al.(2014) Limb-sparing management with surgical resection, external-beam and intraoperative electron-beam radiation therapy boost for patients with primary soft tissue sarcoma of the extremity: a multicentric pooled analysis of long-term outcomes. Strahlenther Onkol. Oct 2014;190(10):891-898. PMID 24715241

Cantero-Munoz P, Urien MA, Ruano-Ravina A.(2011) Efficacy and safety of intraoperative radiotherapy in colorectal cancer: a systematic review. Cancer Lett 2011; 306(2):121-33.

Chen AM, Bucci MK, Singer MI et al.(2007) . Intraoperative radiation therapy for recurrent head-and-neck cancer: the UCSF experience. Int J Radiation Oncology Biol Phys 2007; 67(1):122-9.

Chen AM, Garcia J, Bucci MK, et al.(2008) Recurrent salivary gland carcinomas treated by surgery with or without intraoperative radiation therapy. Head Neck. Jan 2008;30(1):2-9. PMID 17828788

del Carmen MC, McIntyre JF, Goodman A.(2000) The role of intraoperative radiation therapy (IORT) in the treatment of locally advanced gynecologic malignancies. Oncologist 2000; 5:18-25.

Dowdy SC, Mariani A, Cliby WA et al.(2006) Radical pelvic resection and intraoperative radiation therapy for recurrent endometrial cancer: technique and analysis of outcomes. Gynecol Oncol 2006; 101(2):280-6.

Drognitz O, Henne K, et al.(2008) Long-term results after intraoperative radiation therapy for gastric cancer. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70:715-21.

Dubois JB, Bussieres E, Richaud P, et al.(2011) Intra-operative radiotherapy of rectal cancer: results of the French multi-institutional randomized study. Radiother Oncol. Mar 2011;98(3):298-303. PMID 21339010

Folkert MR, Tong WY, LaQuaglia MP, et al.(2014) 20-year experience with intraoperative high-dose-rate brachytherapy for pediatric sarcoma: outcomes, toxicity, and practice recommendations. Int J Radiat Oncol Biol Phys. Oct 1 2014;90(2): 362-368. PMID 25304795

Gao Y, Liu Z, Chen X et al.(2011) Intraoperative radiotherapy electron boost in advanced and recurrent epithelial ovarian carcinoma: a retrospective study. BMC Cancer 2011; 11:439.

Gemignani ML, Alektiar KM, Leitao MM Jr. et al.(2001) Radical surgical resection and high-dose intraoperative radiation therapy (HDR-IORT) in patients with recurrent gynecologic cancers. Int J Radiat Oncol Phys 2001; 50(3):687-94.

Giorda G, Boz G, Gadducci A et al.(2011) Multimodality approach in extra cervical locally advanced cervical cancer: chemoradiation, surgery and intra-operative radiation therapy. Eur J Surg Oncol 2011; 37(5):442-7.

Gunderson LL, et al.(1997) Intraoperative irradiation: current and future status. Semin Oncol, 1997; 24:715-31.

Gunderson LL.(1994) Rationale for and results of intraoperative radiation therapy. Cancer 1994; 74:573-41.

Hui KS, Harrison LB.(2000) Adjuvant radiation therapy of retroperitoneal sarcoma: the role of intraoperative radiotherapy (IORT). Sarcoma. 2000;4:11-6.

Jingu K, Tanabe T, Nemoto K et al.(2012) Intraoperative radiotherapy for pancreatic cancer: 30-year experience in a single institution in Japan. Int J Radiat Oncol Biol Phys 2012; 83(4):e507-11.

Martinez-Monge R, Jurado M, Aristu JJ et al.(2001) Intraoperative electron beam radiotherapy during radical surgery for locally advanced and recurrent cervical cancer. Gynecol Oncol 2001; 82(3):538-43.

Marucci L, Pichi B, et al.(2008) Intraoperative radiation therapy as an "early boost" in locally advanced head and neck cancer: preliminary results of a feasibility study. Head Neck. 2008 Jun;30:701-8.

McCormick B.(2012) Hypofractionated whole breast radiation and partial breast radiation for early-stage breast cancers: an update on progress. JNCCN 2012;10:1061-1164.

Mirnezami R, Chang GJ, Das P et al.(2013) Intraoperative radiotherapy in colorectal cancer: systematic review and meta-analysis of techniques, long-term outcomes, and complications. Surg Oncol 2013; 22(1):22-35.

National Comprehensive Cancer Network (NCCN).(2015) Pancreatic Adenocarcinoma V2.2015. http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed June 18, 2015.

National Comprehensive Cancer Network. Practice Guidelines in Oncology. V.2.2009. Accessible online at http://www.nccn.org (Last accessed 01/15/10).

Nemoto K, Ogawa Y, Matsushita H et al.(2002) Intraoperative radiation therapy (IORT) for previously untreated malignant gliomas. BMC Cancer 2002; 2:1.

Ogawa K, Karasawa K, Ito Y et al.(2010) Intraoperative radiotherapy for resected pancreatic cancer: a multi-institutional retrospective analysis of 210 patients. Int J Radiat Oncol Biol Phys 2010; 77(3):734-42.

Paly JJ, Hallemeier CL, Biggs PJ, et al(2014) Outcomes in a multi-institutional cohort of patients treated with intraoperative radiation therapy for advanced or recurrent renal cell carcinoma. Int J Radiat Oncol Biol Phys. Mar 1 2014;88(3):618-623. PMID 24411190

Ruano-Ravina A, Almazan Ortega R, Guedea F.(2008) Intraoperative radiotherapy in pancreatic cancer: a systematic review. Radiother Oncol 2008; 87(3):318-25.

Ruano-Ravina A, Almazán Ortega R, Guedea F.(2008) Intraoperative radiotherapy in pancreatic cancer: a systematic review. Radiother Oncol 2008; 87(3):318-25.

Sacchini V, Beal K, et al.(2008) Study of quadrant high-dose intraoperative radiation therapy for early-stage breast cancer. Br J Surg. 2008 Sep;95:1105-10.

Sauer R, Sautter-Bihl ML, Budach W et al.(2007) Accelerated partial breast irradiation – consensus statement of 3 German oncology societies. Cancer 2007; 110(6):1187-94.

Schuller DE, Ozer E, Agrawal A et al.(2007) Multimodal intensification regimens for advanced, respectable, previously untreated squamous cell cancer of the oral cavity, oropharynx, or hypopharynx. Arch Otolaryngol Head Neck Surg 2007; 133(4):320-6.

Shasha D, Harrison LB, Enker W.(1999) Brachytherapy in the treatment of colorectal malignancies. Hematol Oncol Clin N Am 1999;13:559-75.

Showalter TN, Rao AS, Rani Anne P et al.(2009) Does intraoperative radiation therapy improve local tumor control in patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma? A propensity score analysis. Ann Surg Oncol 2009; 16(8):2116-22.

Sindelar WF, Kinsella TJ, Chen PW, et al.(1993) Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial. Arch Surg. Apr 1993;128(4):402-410. PMID 8457152

Sindelar WF, Kinsella TJ.(1999) Studies of intraoperative radiotherapy in carcinoma of the pancreas. Ann Oncol 1999; (sup 4):226-30.

Skandarajah, AR, Lynch AC, Mackay JR et al.(2009) The role of intraoperative radiotherapy in solid tumors. Ann Surg Oncol 2009; 16(3):735-44.

Stucky CC, Wasif N, Ashman JB, et al.(2014) Excellent local control with preoperative radiation therapy, surgical resection, and intra-operative electron radiation therapy for retroperitoneal sarcoma. J Surg Oncol. Jun 2014;109(8):798-803. PMID 24862926

Tran PT, Hara W, et al.(2008) Intraoperative radiation therapy for locally advanced and recurrent soft-tissue sarcomas in adults. Int J Radiat Oncol Biol Phys. 2008 Apr 2. [Epub ahead of print].

Valentini V, Morganti AG, et al.(2008) Intraoperative radiation therapy in resected pancreatic carcinoma: long-term analysis. Int J Radiat Oncol Biol Phy, 2008;70:1094-9.

Veronesi U, Orecchia R, Luini A et al.(2005) Full-dose intraoperative radiotherapy with electrons during breast-conserving surgery – experience with 590 cases. Ann Surg 2005; 242(1):101-6.

Wiig JN, Giercksky KE, Tveit KM.(2014) Intraoperative radiotherapy for locally advanced or locally recurrent rectal cancer: Does it work at all? Acta Oncol. Jul 2014;53(7):865-876. PMID 24678823

Wilkowski R, Wolf M, Heinemann V.(2008) Primary advanced unresectable pancreatic cancer. Recent Results Cancer Res, 2008; 177:79-93.

Williams CP, Reynolds HL, et al.(2008) Clinical results of intraoperative radiation therapy for patients with locally recurrent and advanced tumors having colorectal involvement. Am J Surg. 2008 Mar;195:405-9.

Yu WW, Guo YM, Zhang Q, et al(2015) Yu WW, Guo YM, Zhang Q, et al. Benefits from adjuvant intraoperative radiotherapy treatment for gastric cancer: A meta-analysis. Mol Clin Oncol. Jan 2015;3(1):185-189. PMID 25469292

Zhang Q, Tey J, Yang Z, et al.(2015) Adjuvant chemoradiation plus intraoperative radiotherapy versus adjuvant chemoradiation alone in patients with locally advanced rectal cancer. Am J Clin Oncol. Feb 2015;38(1):11-16. PMID 25616201

Zygogianni GA, Kyrgias G, Kouvaris J et al.(2011) Intraoperative radiation therapy on pancreatic cancer patients: a review of the literature. Minerva Chir 2011; 66(4):361-9.


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