Factors Predicting Response, Perioperative Outcomes, and Survival Following Total Neoadjuvant Therapy for Borderline/Locally Advanced Pancreatic Cancer

Abstract

Objective: To identify predictive factors associated with operative morbidity, mortality, and survival outcomes in patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) undergoing total neoadjuvant therapy (TNT). Background: The optimal preoperative treatment sequencing for BR/LA PDA is unknown. TNT, or systemic chemotherapy followed by chemoradiation (CRT), addresses both occult metastases and positive margin risks and thus is a potentially optimal strategy; however, factors predictive of perioperative and survival outcomes are currently undefined. Methods: We reviewed our experience in BR/LA patients undergoing resection from 2010 to 2017 following TNT assessing operative morbidity, mortality, and survival in order to define outcome predictors and response endpoints. Results: One hundred ninety-four patients underwent resection after TNT, including 123 (63%) BR and 71 (37%) LA PDAC. FOLFIRINOX or gemcitabine along with nab-paclitaxel were used in 165 (85%) and 65 (34%) patients, with 36 (19%) requiring chemotherapeutic switch before long-course CRT and subsequent resection. Radiologic anatomical downstaging was uncommon (28%). En bloc venous and/or arterial resection was required in 125 (65%) patients with 94% of patients achieving R0 margins. The 90-day major morbidity and mortality was 36% and 6.7%, respectively. Excluding operative mortalities, the median, 1-year, 2-year, and 3-year recurrence-free survival (RFS) [overall survival (OS)] rates were 23.5 (58.8) months, 65 (96)%, 48 (78)%, and 32 (62)%, respectively. Radiologic downstaging, vascular resection, and chemotherapy regimen/switch were not associated with survival. Only 3 factors independently associated with prolonged survival, including extended duration (≥6 cycles) chemotherapy, optimal post-chemotherapy CA19-9 response, and major pathologic response. Patients achieving all 3 factors had superior survival outcomes with a survival detriment for each failing factor. In a subset of patients with interval metabolic (PET) imaging after initial chemotherapy, complete metabolic response highly correlated with major pathologic response. Conclusion: Our TNT experience in resected BR/LA PDAC revealed high negative margin rates despite low radiologic downstaging. Extended duration chemotherapy with associated biochemical and pathologic responses highly predicted postoperative survival. Potential modifications of initial chemotherapy treatment include extending cycle duration to normalize CA19-9 or achieve complete metabolic response, or consideration of chemotherapeutic switch in order to achieve these factors may improve survival before moving forward with CRT and subsequent resection.

Vascular Resection for Pancreatic Cancer: 2019 French Recommendations Based on a Literature Review From 2008 to 6-2019

“…Regarding survival rates, a Japanese monocentric comparative study including 375 patients, including 142 classified as "borderline resectable" who underwent upfront resection, showed that the rate of R0 resections was lower in case of VR (n = 91) (69 vs. 77%) including when preoperative CT scan demonstrated unilateral venous contact (Nakao Type B) (77). Moreover, the N+ rate was higher (80 vs. 65%) and the prognosis was poorer than that in patients with "clearly" resectable tumors (median cancer-specific survival: 14.4 vs. 24.4 months and median recurrence-free survival: 12 vs. 16.5 months; p = 0.0038). Survival was correlated with the severity of venous involvement observed on preoperative CT scan (Nakao Types B, C, or D: median specific survival 26, 12, and 16 months, respectively).…”

“…Both the Mayo Clinic group (24,120) and Bachellier et al (121) reported more than 100 ARs (LE 4). In 2018, the Mayo Clinic group reported results in 111 patients who underwent pancreatectomy with AR [HA (n = 60), celiac (n = 49), SMA (n = 15), multiple ARs (n = 15)] including 55% with reconstruction and 51% with simultaneous VRs (120).…”

“…A recent study (17) has shown that a standardized pathological protocol R0-resection based on 1 mm clearance was rarely achieved after upfront venous resection due to microscopic involvement of the SMV-groove (LE 4). It is important to note that patients considered to be at high risk of R1 resection and/or those with an unfavorable clinical and/or "biological" status are now candidates for neoadjuvant therapy (18)(19)(20)(21)(22)(23)(24)(25)(26) (LE 3). In one North American study (27) the benefits of neoadjuvant therapy were found to be significant in the presence of "unilateral" venous involvement (Ishikawa II-III) (LE 3).…”

Response to Preoperative Therapy in Localized Pancreatic Cancer

“…In a recent study by Truty and colleagues, among 194 patients with BR or LAPC PDAC treated with "total neoadjuvant therapy" with FOLFIRINOX or GA, 28% had radiographic downstaging (37). A similar rate of radiographic downstaging, strikingly higher than that reported in the past, maybe due to a higher efficacy of modern chemotherapy regimens, but it may also simply reflect artifact of study conduct (such as, in this case, the exclusion of patients who did not undergo surgery).…”

“…In 2017, a study from MD Anderson showed that baseline factors including young age, pretreatment CA 19-9 level, and use of gemcitabine as a radio-sensitizer were associated with pMR. Two other studies correlated positron emission tomography (PET) complete metabolic response and CA 19-9 response to pCR (37,52,53).…”