In a landmark study, Gunderson et al. published the patterns of failure in patients with gastric cancer following resection based on second look surgeries. Locoregional failure occurred in 67% of patients, 54% of which were in the gastric bed and 26% in the anastomosis or stump5,6.
Japanese investigators sought to evaluate whether the addition of IORT to surgery improved outcomes. Patients were randomized to surgery alone or surgery with 28-35 Gy IORT. A long-term survival benefit with IORT was seen in a subgroup of patients with advanced disease7.
At the NCI, a small randomized study compared gastrectomy and 20 Gy IORT to the gastric bed to gastrectomy (either alone or followed by conventional postoperative EBRT) for advanced-stage lesions. Locoregional control was significantly improved in the patients who were treated with IORT8.
No randomized comparisons of IORT exist with adjuvant chemoradiation therapy as the control arm which is considered standard of care in advanced gastric cancer9.
A retrospective series from China compared outcomes of patients receiving 12-15 Gy IOERT followed by chemoradiotherapy to adjuvant chemoradiotherapy alone. IORT was well tolerated and associated with improvements in locoregional control and disease-free survival10.
Pancreatic cancers are characterized by high rates of both local and distant failure. In patients amenable to a potentially curative pancreaticoduodenectomy, rates of positive retroperitoneal margins are as high as 40%11. IORT has been investigated as an adjuvant therapy, with most reports limited to single institution series.
The available data suggest there is a consistent local control benefit with IORT, while the effect on survival has been variable12-14. With recent improvements in chemotherapy and increasing utilization of neoadjuvant chemoradiotherapy, the role of IORT in potentially resectable pancreatic cancers is not clear at present. In patients with locally advanced pancreatic cancer, local failure occurs in the majority of patients despite EBRT and chemotherapy15.
In part, this may relate to the inadequate doses administered to control gross disease. Dose escalation with IORT has been investigated as a means of improving local control and overall outcomes. A report from the Mayo Clinic investigating the addition of IORT to EBRT demonstrated an increase in local control but no improvement in survival16. The Radiation Therapy Oncology Group (RTOG) prospectively evaluated combination 20 Gy IORT followed by chemoradiotherapy to 50.4 Gy.
The results were disappointing with a median survival similar to conventional treatment17. Multiple single institution series have been published demonstrating high rates of local control but no consistent improvement in overall survival.
In patients experiencing pain related to their primary disease, IORT has been shown to effectively palliate this symptom18.
An area of active investigation with IORT is in the treatment of recurrent or primary locally advanced rectal cancers. Locally advanced rectal cancers typically involve fixation or adherence to adjacent structures such as the sacrum or pelvic side wall.
With no upfront therapy, these tumors are considered unresectable or have a high probability of gross/microscopic residual disease following resection. Even after preoperative EBRT and subsequent complete resection, these tumors have a high probability of recurrence. IORT has been utilized in this circumstance to improve local control.
Investigators at Massachusetts General Hospital (MGH) reported their experience with IOERT following preoperative EBRT for locally advanced rectal cancer. Patients at higher risk for recurrence (gross residual tumor, positive or close margins) were selected for IORT at doses ranging from 10-20 Gy depending on the extent of residual disease.
The local control rate in the IORT group compared favorably to the lower risk group not receiving additional radiation therapy19. The complication rate for those treated with IOERT was 15%. With a similar treatment approach, investigators at the Mayo Clinic also reported high rates of local control in this unfavorable patient population20.
IORT may also be utilized in the management of recurrent rectal cancers, most often using a multimodality approach. Experience from the Mayo Clinic suggests IOERT and EBRT following palliative surgical resection improves local control and survival outcomes compared to resection alone in locally recurrent rectal cancers21.
The likelihood of achieving margin negative resection is considerably less in this population, thus neoadjuvant chemoradiation prior to surgery should be pursued to increase the rate of R0 resection22. Despite this, R0 rates, local control and long-term survival are much lower compared to treatment in the primary setting.
IORT appears to be a useful technique in the combined modality management of locally advanced or recurrent gastrointestinal malignancies. Enhancement of the therapeutic ratio is achieved by the ability to exclude sensitive normal tissue from the operative bed. When conducted carefully, there are consistently improved rates of local control with low toxicity rates across several disease sites.
Overall survival improvements are variable which relates to the significant competing risk of distant failure in many of these malignancies. Improvements in systemic therapy may enhance the relative benefit of local control. The increasing mobility of modern IORT units is likely to increase utilization of this technique.
Prospective evaluation in the modern era will be necessary to determine efficacy, particularly as competing technology for dose escalation such as intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) become more prevalent.
Jordan A. Torok, Manisha Palta, Brian G. Czito, and Christopher G. Willett
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Correspondence to: Christopher G. Willett. Department of Radiation Oncology, Duke University, DUMC 3085, Durham, NC 27710, USA. Email: [email protected].
Disclosure: The authors declare no conflict of interest.
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Source: Translational Cancer Research.