Clinical Investigation
Stereotactic Body Radiation Therapy for Locally Advanced Pancreatic Cancer: A Systematic Review and Pooled Analysis of 19 Trials

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Purpose

Although surgery is the standard of care for resectable pancreatic cancer (PC), standard-dose chemoradiation therapy and chemotherapy alone are suitable for patients with unresectable disease. Stereotactic body radiation therapy (SBRT) is an alternative, focused local therapy that delivers high radiation doses within a few fractions to the cancer, sparing the surrounding critical tissue. We performed a systematic review and pooled analysis of published trials to evaluate the efficacy and safety of this emerging treatment modality.

Methods and Materials

We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, SCOPUS, the Web of Science, and CINAHL for publications regarding SBRT for locally advanced PC. The 1-year overall survival (OS) rate was the primary endpoint, and the median OS, 2-year OS rate, 1-year locoregional control (LRC) rate, and grade 3 to 4 toxicities were the secondary endpoints. A multivariate random-effects meta-analysis was performed to calculate the aggregated OS rates at 1 and 2 years and the 1-year LRC rate.

Results

A total of 19 studies, encompassing 1009 patients, were included in the present analysis. The pooled 1-year OS was 51.6% in 13 trials with data available. The median OS ranged from 5.7 to 47 months (median 17). The LRC rate at 1 year was 72.3%. Overall, the occurrence of severe adverse events did not exceed 10%. LRC appeared to correlate with the total SBRT dose and the number of fractions.

Conclusions

The advantages of SBRT in terms of treatment time, satisfactory OS, and LRC indicate that it is an effective option for inoperable PC. However, a definitive validation of this treatment modality in large randomized studies is required, owing to the nonrandomized nature of the included studies and the limitations of small single-center series that include mixed populations.

Introduction

Pancreatic ductal adenocarcinoma is characterized by a poor prognosis, with a 5-year overall survival (OS) rate of about 6% (1). Surgery is the standard of care, with 5-year OS rates of 20% to 25%. The condition in most patients, however, is unresectable at the diagnosis, mainly because of locally advanced disease or distant metastases. In patients with locally advanced pancreatic cancer (LAPC), the integration of chemotherapy (CT) or chemoradiation treatment (CTRT) is a current therapeutic option but has been associated with a significant grade 3 to 4 toxicity rate and a median OS of 5 to 15 months (2).

In recent years, stereotactic body radiation therapy (SBRT) has been developed as a system for delivering a conformal high dose of radiation in 1 to 6 fractions to a tumor, with minimal dose to the surrounding critical tissue (3). This technique has been used in several sites, including the pancreas. The most significant advantage of SBRT compared with CTRT seems to be the short overall treatment delivery time, which avoids the need for prolonged systemic treatment breaks. Furthermore, focused irradiation might spare adjacent critical organs from acute and late toxicity. In contrast, the delivery of full or radiosensitizing doses of CT with SBRT has not been demonstrated to be safe and feasible compared with standard-dose CTRT, with which fluoropyrimidines are also usually prescribed. Concurrent CTRT might, therefore, improve both local control and systemic disease at the expense of increased in-field side effects and potentially delayed and complicated surgical treatment.

We investigated the role of SBRT in the treatment of unresectable pancreatic cancer (UPC) to confirm the hypothetical advantages of this innovative therapy compared with conventional CTRT. These possible advantages include greater local control related to the high doses used, the short overall treatment time, and, subsequently, optimal integration with systemic therapy (4).

To assess the efficacy of SBRT for patients with LAPC, we performed a systematic review and a pooled analysis of prospective trials or retrospective series exploring this type of locoregional treatment, with or without CT, in terms of OS (median OS and 1- to 2-year OS rates), locoregional control (LRC), progression-free survival (PFS), and toxicity.

Section snippets

Methods and Materials

The present meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (5).

Results

A total of 553 reports were retrieved from the electronic searches. After the removal of duplicates and screening by title, abstract, and full text, 19 full-text reports were included in the present meta-analysis 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 (Fig. 1, Table 1, Table 2). The treatment modalities included Cyberknife (8 studies), SBRT with a linear accelerator (6 studies), and different linear accelerator and Cyberknife techniques (4 studies). In 1

Discussion

The standard treatment of ULAPC, or initially BRPC, is challenging and differs to some extent. Surgical resection is the principal goal of neoadjuvant treatment of BRPC. Local disease control, OS improvement, and symptom palliation are the goals of ULAPC treatment. Despite the therapeutic progress of systemic and local treatment, ULAPC is associated with a dismal prognosis, similar to stage IV of the disease. Currently, the standard of care for patients who are unsuitable for surgery is the use

Conclusions

No evidence supports the claim that better outcomes result from SBRT compared with conventional RT. However, given the benefits of a shorter treatment time, the expected clinical advantage of dose escalation, and the increasing interest in SBRT in the oncologic field, our results provide meaningful aggregated information concerning the use of SBRT for patients with LAPC or BRPC.

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    Conflict of interest: none.

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