Neoadjuvant Strategy as Initial Treatment in Resectable Pancreatic Cancer: Concrete Evidence of Benefit

Summary of Staging

Most pancreatic carcinomas (approximately 90%) are adenocarcinomas. Due to different natural history, other histological types are not considered in this review.

The definition of staging criteria for pancreatic cancer are based on the tumor/node/metastasis (TNM) system (7). However for clinical purposes, pancreatic cancer is usually staged as resectable, borderline-resectable and unresectable disease (Table I). Considering our purpose, we only introduce specific information to determine resectable status. Definition of resectable disease includes a tumor extending beyond the pancreas but without encasement of the celiac artery or the superior mesenteric artery, and an unobstructed portal vein and superior mesenteric vein.

The Background to Neoadjuvant Treatment

Since 1935, pancreatoduodenectomy remains the gold standard surgical treatment for resectable pancreatic cancer (8). The high risk of local recurrence after surgery is linked to the clinical anatomical relationships of the gland, as well as to the intrinsic invasive nature of pancreatic carcinoma. The pancreas is a retroperitoneal structure of the upper abdomen, strictly related to the mesenteric vessels. Even though significant improvement has been obtained in the characterization of primary stage disease, the tendency for lymphatic spread and hematogenous dissemination often culminate in non-radical resection, whether macro- or microscopic (9, 10). Unlike curative surgical resection of rectal, gastric and esophageal cancer, pancreato-duodenectomy necessitates complete biliodigestive reconstruction. This implies protracted postoperative hospitalization, hindering prompt adjuvant treatment. Literature data report a rate of 22% to 30% of patients who did not receive planned therapy (11-12). Consequently, the impact on survival may be significantly influenced by the slow accrual in trials testing appropriate adjuvant therapy (13,14). High local failure rates and the high risk of relapses due to delay of adjuvant treatment justify the interest in testing preoperative treatment as a new approach.

The Rationale for Neoadjuvant Treatment

In patients with potentially resectable pancreatic cancer, neoadjuvant therapy i.e. radiation therapy, with or without chemotherapy, given before surgery, aims to minimize local recurrence and to maximize survival. A down-staging effect, in this context, is not the main objective because the disease is considered surgically-resectable at the time of diagnosis.

There is a strong rationale for a neoadjuvant approach based on several fundamental assumptions. Notable advantages of preoperative radiation therapy include its effectiveness on well-vascularized tissue due to the oxygen effect. Moreover, preoperative radiation therapy potentially sterilizes the surgical field, with an increased probability of negative microscopic margins, especially retroperitoneally. Preoperative radiation treatment carries the advantage that all patients can receive neoadjuvant treatment, with an improved ability to tolerate it. Moreover, combined therapy is not associated with toxicity that delays surgery. On the contrary, considering distant metastases as a component of failure, preoperative therapy can potentially improve the control of micrometastatic disease and identifies rapidly progressive disease, reducing pancreatic resection for patients with no probability of cure.

Although preoperative radiotherapy can produce changes in tissues in the surgical bed, the choice of appropriate timing of surgery (not more than 45-60 days after the end of neoadjuvant therapy) can significantly reduce surgical problems, as demonstrated in neoadjuvant rectum radiotherapy (15).

Despite these theoretical considerations explaining the potentially favorable impact of neoadjuvant treatment on survival, whether radiation therapy should be delivered before or after pancreaticoduodenectomy remains unclear.

The Clinical Evidence Neoadjuvant Treatment

Promising results from several prospective trials (12, 16-18) and retrospective studies (19, 20) of preoperative chemoradiotherapy in localized and potentially resectable pancreatic cancer are available in the literature. The heterogeneity of data and a statistically underpowered analysis are the major factors restricting validation of the theoretical advantages of this strategy.

A role for preoperative multimodality therapy in resectable cancer is supported by some studies that combined radiation therapy with 5-fluoruracil-based chemotherapy. These single-Institute experiences confirmed excellent locoregional control, with a median overall survival of 15.7 to 25 months in patients treated with combined modality therapy (16-18).

Hoffmann et al. conducted a clinical trial of preoperative multimodality therapy (16). Out of 53 patients, 24 underwent tumor resection, with a median survival of 15.7 months vs. 9.7 months for the entire group. Pisters et al. reported overall survival of 25 months in patients who underwent neoadjuvant therapy compared with 7 months in those not submitted to surgery (17). Staley et al. evaluated survival in 39 patients treated by preoperative chemoradiation; it resulted in improved local control, with a median survival of 19 months (18).

Based on radiosensitizing properties of gemcitabine and on its efficacy in advanced pancreatic cancer (19, 20), a few trials investigated gemcitabine in association with radiation therapy as an alternative approach in the neoadjuvant setting. Talamonti et al. reported the results of a phase II trial testing preoperative gemcitabine and radiation therapy in 20 patients with resectable pancreatic carcinoma, which led to a median overall survival of 26 months (21).

There are no randomized data from randomized phase III trials comparing neoadjuvant treatment with adjuvant strategies. A recent multi-Institutional study provided a large retrospective database analysis comparing effects of neoadjuvant and adjuvant approach on patient survival. Colbert et al. reported data from 5,414 patients submitted to preoperative (277 patients) or postoperative (5,137 patients) chemoradiotherapy (22). This cohort study reported overall survival not to be inferior (18 months vs. 19 months), with higher rates of negative margins (82% vs. 72%), and lower rates of lymph node positivity at resection (41% vs. 65%) in patients receiving neoadjuvant therapy. Data from the study by Spitz et al. suggested no statistically significant difference in median survival (19.2 and 22 months, respectively) between pre- and postoperative chemoradiation strategies in 142 patients with localized pancreatic cancer (12). A significant survival benefit for the use of neoadjuvant radiation therapy over adjuvant therapy (23 months vs.17 months) was reported by Stessin et al. (23), but due to limitations of SEER database analysis, definitive results must be validated. Again, a significantly better overall survival after neoadjuvant therapy compared with adjuvant treatment (33.8 vs. 19 months) was demonstrated by Artinyan et al. (24). Table II shows a review of the literature.

The Current Status of Neoadjuvant Treatment

Neoadjuvant treatment has been tested extensively in the management of gastrointestinal cancer (15, 26, 27). Despite a significant improvement on local control being detected in rectal (15, 25) and esophageal cancer (26), neoadjuvant radiation, with or without chemotherapy, still remains experimental for pancreatic cancer. At the current time, neoadjuvant chemoradiotherapy ensures similar resection frequencies and survival rates to those of adjuvant treatment (6). On the basis of data from trials, considering that patients submitted to preoperative chemoradiotherapy may have had initially more adverse prognostic features,assessing the real therapeutic value of neoadjuvant treatment is complicated. Better patient selection would probably increase the survival rate. Therefore, future trials should enroll homogeneous patient populations to clarify definitive conclusions. Randomized trials focusing on the impact of survival after neoadjuvant chemoradiotherapy are in progress (27-29). Open areas of investigation include advanced irradiation techniques – such as radiosurgery, proton beam therapy, intra-operatory radiotherapy) – and more effective combinations of drugs – such an oxaliplatin, irinotecan, 5-fluorouracil, bevacizumab, and nab-paclitaxel.