Neoadjuvant Chemotherapy Switch in Borderline Resectable/Locally Advanced Pancreatic Cancer

All patients had biopsy-confirmed pancreatic adenocarcinoma, with tissue collected via endoscopic ultrasound (EUS) fine needle aspiration. For any patients presenting with previous outside biopsies, those tissue blocks were formally interpreted by institutional gastrointestinal pathologists prior to initiating systemic chemotherapy. For patients undergoing resection after NAC, the College of American Pathology (CAP) protocols were used for tumor, margin, and nodal assessments.^16,17 Pathologic treatment response was scored according to the CAP criteria: complete response, score 0 (no viable cancer cells); near complete response, score 1 (single/rare groups of cancer cells); partial response, score 2 (residual cancer with regression); poor/no response, score 3 (no tumor regression). For subsequent analyses, we grouped a score of 0 or 1 as major pathologic response and a score of 2 or 3 as minor pathologic response.

All patients underwent standardized radiographic imaging at the time of diagnosis, which included non-contrast chest computed tomography (CT) and triple-phase (arterial, pancreatic, portal) abdomen/pelvis CT per pancreas protocol with axial, coronal, and sagittal reconstructions. All imaging was reviewed by both gastrointestinal radiologists and study surgeons, and patients were anatomically categorized as either BR/LA per Intergroup (Alliance) criteria based on the extent of extrapancreatic extension with venous and/or arterial involvement.¹⁸ In recent years, the majority of patients also underwent baseline positron emission tomography (PET) metabolic imaging (PET/CT or PET/MRI) prior to the initiation of induction chemotherapy. All patients underwent identical radiographic restaging following NAC after the completion of FL therapy and after CS prior to surgical resection. All patients had serum CA19-9 levels drawn at diagnostic baseline (after biliary stenting/drainage and just prior to the initiation of NAC) and serial levels were drawn throughout NAC. CA19-9 normalization (response) was determined at the conclusion of all systemic NAC and was dichotomized per previous methods.¹⁵

All patients received modern combinatorial NAC with either 5-fluorouracil-based chemotherapy (FOLFIRINOX/FOLFOX) or gemcitabine-based (gemcitabine/nab-paclitaxel) regimens, according to institutional protocols, with or without dose modifications, as deemed appropriate by treating oncologists. Chemotherapy was administered on a 2-week or 4-week cycle dependent on the specific regimen. Total cycles of chemotherapy were counted based on the total number of cycles administered during induction chemotherapy treatment. For those patients who underwent CS, we counted the total of all regimen cycles. Patients underwent routine restaging, typically every 2–3 months during induction chemotherapy treatment to evaluate for objective responses to treatment. Components of an objective response included clinical (improved pain, weight gain), biochemical (CA19-9 decrease), radiologic (decreased tumor size or less vascular involvement), or metabolic responses (decrease in tumoral PET avidity/viability). The majority of CSs were performed after the first restaging examination, typically after 2–3 months of FL chemotherapy, while a minority of patients underwent CS after the second or third restaging visits. Select patients received chemoradiation (CRT) following NAC and this was determined according to surgeon/oncology recommendations based on margin risk. CRT consisted of photon/proton external beam with a 50 Gy dose delivered in 25–28 daily fractions over 5 weeks, or a 45 Gy dose delivered in 15 fractions over 3 weeks, as per an institutional protocol with three-dimensional conformal or intensity-modulated techniques with concurrent radiosensitizing chemotherapy.

Patients were deemed candidates for surgical resection following NAC in the absence of metastatic disease after completion of therapy, technical feasibility for potentially achieving a negative margin resection with or without en bloc vascular and/or multivisceral resection and reconstruction as deemed by the operative surgeon, and patient fitness and condition permissible for surgery with general anesthesia. Radiologic anatomical downstaging was not a requirement for proceeding to resection if anatomy was favorable; however, other measures of objective response (clinical, biochemical, or metabolic response) were typically required as surrogates of chemotherapeutic treatment response. Surgical resections included pancreaticoduodenectomy, distal/subtotal pancreatectomy, and total pancreatectomy. Formal en bloc vascular resections were routinely performed with or without formal revascularization dependent on anatomical circumstances.

Postoperative complications were graded according to the standard Clavien–Dindo classification, as minor (grade 2 or lower) or major (grade 3A or higher) and reported as 90-day outcomes.¹⁹ Pancreas-specific complications such as delayed gastric emptying (DGE), postoperative pancreatic fistula (POPF), and post-pancreatectomy hemorrhage (PPH) were graded according to the International Study Group of Pancreatic Surgery (ISGPS) definitions, as clinically significant (grade B/C).²⁰ Operative mortality was calculated as any death within 90 days after surgery, either as an inpatient or outpatient and either at our center or an outside facility. Postoperative surveillance occurred every 3–4 months for the first 3 years, every 6 months for years 4–5, and annually beyond 5 years. For those patients receiving follow-up at local facilities, laboratory and imaging records were faxed and uploaded into our electronic medical record and updated within our cancer registry. Follow-up phone calls to all living patients included in this cohort were performed every 3 months to confirm patient status.

Continuous variables were summarized using mean and standard deviation or median and interquartile range, while continuous variables were summarized using frequency and percentage. Differences between chemotherapy groups were analyzed using either a t test or Wilcoxon rank-sum test for continuous variables and Chi-square test or Fisher’s exact test for categorical variables. All statistical tests were two-sided and differences were considered significant when p < 0.05. Recurrence-free survival (RFS) was measured from the date of resection until detection of local, peritoneal, or distant metastases, or death, and overall survival (OS) was measured from the date of tissue diagnosis until death or unless otherwise specified. Median RFS and OS were estimated using the Kaplan–Meier method with 95% confidence intervals. Statistical analysis was performed using MedCalc Statistical Software version 20.0.0 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org, 2020) or GraphPad 8.2.0 for Windows (GraphPad Software, San Diego, CA, USA; www.graphpad.com).

After exclusions, we identified 468 patients with BR/LA PDAC who received initial FL NAC chemotherapy without development of metastatic disease on initial restaging examinations (Fig. 1). Of this initial cohort, 70% (329/468) continued with the FL chemotherapy regimen and subsequently underwent surgical resection. The median number of chemotherapy cycles in the FL cohort was six, the median number of FL 5-fluorouracil-based cycles was six, and the median number of FL gemcitabine-based cycles was four. The remaining 30% (139/468) of patients underwent chemotherapy switch (CS) following initial FL chemotherapy with a median of four cycles of initial FL chemotherapy. The number of patients undergoing CS steadily increased over the study period (Fig. 2). Of the 139 patients who underwent CS, 89% (124/139) switched from 5-fluorouracil-based chemotherapy to gemcitabine-based chemotherapy, while 11% (15/139) switched from gemcitabine-based chemotherapy to 5-fluorouracil-based chemotherapy (Fig. 3). Indications for CS included non-metastatic radiologic progression in 42% (58/139) of patients, biochemical (CA19-9) progression in 39% (54/139) of patients, no objective response in 25% (35/139) of patients, and chemotherapy toxicity/intolerance in 19.4% (27/139) of patients. There were 38 patients (27%) with more than one indication. The median number of total chemotherapy cycles in the CS cohort was eight. Of the patients undergoing CS, 28% (39/139) did not undergo subsequent resection for the following reasons: 54% (21/39) of patients developed metastatic progression after CS, 38% (15/39) had anatomy precluding resectability despite CS, and 8% (3/39) of patients were deemed conditionally unfit for resection. Overall, 72% (100/139) of patients who underwent CS underwent surgical resection.

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Perioperative and oncologic outcomes were assessed comparing patients undergoing successful resection following either FL or CS. Patient cohort demographics and variables of the 429 patients who underwent resection after FL (329 patients) or CS (100 patients) are shown in Table 1.

There were no significant differences in sex, age, or baseline CA19-9 levels in either the FL or CS cohorts. CS patients received a higher number of cycles of chemotherapy compared with the FL group (8 vs. 6, p = 0.0001) and were more likely to receive CRT after induction chemotherapy treatment than FL patients (92% vs. 80.2%, p = 0.005). Overall, the FL and CS groups had a similar proportion of patients with normalization of CA19-9 levels after completion of all NAC (55.3% vs. 64%, p = 0.13).

Patients in the FL cohort were more likely to have laparoscopic resections (17% vs. 6%, p = 0.006), while total pancreatectomy was more common in CS patients and pancreaticoduodenectomy was more common in FL patients. There was no difference in the rate of en bloc vascular resections between the FL and CS cohorts (60% vs. 60%, p = 0.93), however multivisceral resection was more common in the CS patients (16.4% vs. 35%, p = 0.0001). The median estimated blood loss and perioperative transfusion was lower in the FL group compared with the CS group (550 mL vs. 700 mL, p = 0.03; 32% vs. 48%, p = 0.003). Perioperative outcomes were similar between groups, with similar 90-day major morbidity (29% vs. 37%, p = 0.34), 90-day operative mortality (5.2% vs. 5.0%, p = 0.95), and 30-day readmission rate (25% vs. 29%, p = 0.52) between the FL and CS cohorts, respectively. The median length of stay in patients following FL chemotherapy was shorter than CS (8 vs. 10 days, p = 0.004).

The rates of margin-positive resections (8.8% vs. 7%, p = 0.57) and lymph node positivity (28% vs. 33%, p = 0.33) were similar, as were major pathologic treatment response scores (CAP score 0/1) [31.3% vs. 30%, p = 0.45], between the FL and CS cohorts, respectively. There was no difference in receipt of adjuvant chemotherapy between groups, i.e. 38% of FL patients compared with 32% in the CS group, which was not significantly different (p = 0.28).

Median follow-up for the resected cohort was 29.5 months, and there was no difference in recurrence rate between the FL and CS groups (50.4% vs. 57%, p = 0.19). On subset recurrence analysis, there was no difference in local, peritoneal, or distant recurrence between both cohorts, with distant metastases being the most common recurrence pattern in both groups. At the time of last follow-up, 46% of the entire cohort was alive, which was similar between groups (p = 0.36). There was no statistically significant difference in the median RFS between the FL and CS cohorts (30 vs. 19.1 months, p = 0.1332). Similarly, there was no significant difference in median OS between FL and CS patients (41.4 vs. 36.4 months, p = 0.9391). The median OS for those patients who underwent CS but did not ultimately undergo resection was 19 months, which was significantly worse than those patients who did undergo resection after either FL or CS (p ≤ 0.0001) (Fig. 4).

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Univariate predictors of RFS and OS are shown in Table 2. CS was not associated with detrimental survival outcomes. Tumor grade, lymph node status, CA19-9 response, and pathologic treatment response were associated with RFS, while chemotherapy duration, perioperative blood transfusion, multivisceral resection, major complications, tumor grade, margin status, lymph node status, CA19-9 response, pathologic treatment response, and adjuvant chemotherapy were associated with OS. On multivariate analysis (Table 3), chemotherapy duration, margin status, major complications, and adjuvant therapy were independent predictors of OS only, while CA19-9 response and pathologic treatment response were independent predictors of both RFS and OS (Fig. 5)

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