Abstract
Background:
Upfront resection (UR) followed by adjuvant chemotherapy remains the standard treatment for resectable pancreatic cancer. There is increasing evidence suggesting favourable outcomes toward neoadjuvant chemotherapy (NAC) followed by surgery.
Methods:
All clinical staging with resectable pancreatic cancer patients treated at a tertiary medical centre from 2013 to 2020 were identified. The baseline characteristics, treatment course, surgery outcome and survival results of UR or NAC were compared.
Results:
Finally, in 159 resectable patients, 46 patients (29%) underwent NAC and 113 patients (71%) received UR. In NAC, 11 patients (24%) did not receive resection, 4 (36.4%) for comorbidity, 2 (18.2%) for patient refusal and 2 (18.2%) for disease progression. In UR, 13 patients (12%) were unresectable intraoperatively; 6 (46.2%) for locally advanced and 5 (38.5%) for distant metastasis. Overall, 97% of patients in NAC and 58% of patients in UR completed adjuvant chemotherapy. As of data cut-off, 24 patients (69%) in NAC and 42 patients (29%) in UR were still tumour free. The median recurrence-free survival in NAC, UR with adjuvant chemotherapy and without adjuvant chemotherapy were 31.3 months (95% CI, 14.4–not estimable), 10.6 months (95% CI, 9.0–14.3) and 8.5 months (95% CI, 5.8–11.8), P=0.036; and the median overall survival in each group were not reached (95% CI, 29.7–not estimable), 25.9 months (95% CI, 21.1–40.5) and 21.7 months (12.0–32.8), P=0.0053. Based on initial clinical staging, the median overall survival of NAC was not significantly different from UR with a tumour less than or equal to 2 cm, P=0.29. NAC patients had a higher R0 resection rate (83% versus 53%), lower recurrence rate (31% versus 71%) and harvested median number lymph node (23 versus 15).
Conclusion:
This study demonstrates that NAC is superior to UR in resectable pancreatic cancer with better survival.
Keywords: neoadjuvant therapy, resectable pancreatic cancer, upfront surgery
Introduction
Highlights
Neoadjuvant therapy is more commonly adopted in the treatment of borderline resectable pancreatic cancer than in resectable pancreatic cancer.
Neoadjuvant therapy can increase the R0 resection rate, margin negative rate and lymph node negative metastasis rate.
In this real-world data, neoadjuvant therapy can improve recurrence-free survival and overall survival in resectable pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) accounted for 466 003 death worldwide in 2020 making it the seventh leading cause of cancer death globally1. PDAC is currently the third leading cause of cancer mortality in the United States and is predicted to be the second by 20262. Surgery is the curative treatment for PDAC, however, only 20% of patients with PDAC presented with resectable disease upon diagnosis3. After resection, the recurrence rate is high. Postoperative adjuvant chemotherapy has been proven its efficacy in reducing the recurrence rate. Upfront resection (UR) followed by adjuvant modified FOLFIRINOX (mFOLFIRINOX) achieved the best outcome in PDAC with a median overall survival (OS) of 54.4 months4. In fact, patients fit for adjuvant mFOLFIRINOX are a highly selected population that patients should be healthy enough to tolerate major surgery, surgical complication and recovery of nutrition. In the PRODIGE 24 trial, it took 4 years to enrol 493 patients from 77 centres (~1.6 patients per centre per year) which suggested selection bias could exist. Therefore, the application of adjuvant FOLFIRINOX to real-world practice remains not well-established5,6.
On the other hand, there is increasing evidence that PDAC had better be treated as a systemic disease since distant metastasis is seen in up to 30% of patients even with a small tumour size of 0.5 cm7,8. Theoretically, neoadjuvant chemotherapy (NAC) can eliminate radiographically occult metastatic disease and prevent an early recurrence6. The benefit of NAC is increasingly recognized in borderline resectable pancreatic cancer (BRPC)9–12. By contrast, previous randomization trials comparing NAC versus UR in purely resectable PDAC mostly terminated due to poor patient accrual13–15. Current evidence for NAC in resectable PDAC mostly came from meta-analysis or database analysis16–25, and trials included both BRPC and resectable PDAC26–28. Therefore, the role of NAC in resectable disease remains undetermined. To the best of our knowledge, no real-world experience of NAC versus UR in a purely resectable PDAC cohort had been reported. Herein, we reported our experience of NAC versus UR for resectable PDAC in a high-volume centre for pancreatic surgery in Taiwan.
Materials and methods
Patients and assessment
All patients with clinical stage I and II treated at a tertiary medical centre in Taiwan from 2013 to 2020 were identified by institutional PDAC tumour board registration (Fig. 1). All identified cases were manually reviewed for treatment course and surgery outcome. This retrospective study was approved by Institutional Review Board with a waiver of informed consent and followed the Declaration of Helsinki. This study was also registered on Clinicaltrials.gov with the registered number NCT05700188. All the work has been reported in line with the STROCSS criteria, Supplemental Digital Content 2, http://links.lww.com/JS9/A681. The initial radiological image before treatment was also reviewed for the determination of tumour size and resectability. The definition of resectability was based on the anatomical criteria from the international consensus of the International Association of Pancreatology which defined resectable disease as no tumour contact of coeliac trunk/superior mesenteric artery or contact of less than 180° of portal vein/superior mesenteric vein29.
Figure 1.
The flow chart of pancreatic cancer patients treated at a tertiary medical centre. PDAC, Pancreatic ductal adenocarcinoma.
Surgeons in our institute will explain the pros and cons of NAC and UR, including prognosis, surgical complication and adverse events of chemotherapy, to patients with newly diagnosed resectable PDAC. The treatment strategy (NAC or UR) and the regimen used in NAC was determined on the basis of shared decision-making after patients understood the possible adverse effects and outcome in the reported clinical trials30. If patients determined to receive NAC, endoscopic ultrasound-guided biopsy or computed tomography-guided biopsy was performed to acquire the definite pathological diagnosis31,32. Subclavian port-A was then inserted for chemotherapy. The planned courses and treatment period for NAC were 6 cycles of chemotherapy every 2 weeks in 3 months before the operation and another 6 cycles after the operation. In those patients who received upfront resection, postoperative adjuvant therapy was given according to practice guidelines in our hospital.
Radiological evaluation was done by computed tomography (CT) or MRI before treatment and every 8–12 weeks after treatment based on the national health insurance regulation and at the physician’s discretion. Tumour response was assessed by The Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Adverse events were retrospectively reviewed based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.3.
Statistical analysis
Descriptive statistics were presented as median, percentage and interquartile range where appropriate. The normality of data distribution was evaluated by the Kolmogorov–Smirnov test. The difference in proportion between groups was compared by Fisher’s exact test. The median duration of follow-up was estimated using the reverse Kaplan–Meier method. Progression-free survival (PFS) was calculated from the initial treatment to documented radiological or clinical progression, recurrence or death. PFS was censored at discontinuation of a regimen without progression (e.g. intolerance or patient choice), loss to follow-up or data cut-off. Overall survival was calculated from the initial treatment to death and censored at the date of loss to follow-up or data cut-off. Recurrence-free survival (RFS) was defined as the interval between surgery and recurrence or death while censored at loss to follow-up or data cut-off. Survival was estimated by the Kaplan-Meier method, and the survival difference was compared by the log‐rank test. To minimize selection bias, a propensity score matching was performed using a 2:3 nearest-neighbour matching algorithm for age, sex, tumour location, baseline albumin, baseline CA 19-9 and tumour size at diagnosis. The caliper of the propensity score matching was set to 0.2 as recommended by the previous study33. A Multivariate Cox regression model was also constructed to adjust the same baseline covariates for RFS, PFS and OS. All variables with P less than 0.05 were statistically significant. All statistical analyses were performed using R version 4.0.5 (R Core Team)
Result
Initial treatment pattern
Among the 159 patients (21%) with resectable PDAC (clinical stage I or II), 46 patients (29%) underwent NAC first while 113 patients received UR (Fig. 1). The baseline characteristics were not significantly different between the two groups except for age and clinical stage (Table 1). The median age was significantly lower in the NAC group (63.5 versus 68.4 years in the UR group, P=0.027). The NAC group had a significantly higher proportion of clinical stage IIB (67.4% versus 38.1% in the UR group, P=0.0004) and there was no patient with clinical stage IA in the NAC group.
Table 1.
Demographics of resectable pancreatic cancer patients.
| Characteristics | Neoadjuvant chemotherapy (N=46) | Upfront resection (N=113) | Overall (N=159) |
|---|---|---|---|
| Age, years, median (IQR) | 63.5 (56.3–69.0) | 68.4 (61.8–75.1) | 67.0 (58.1–73.4) |
| Sex, n (%) Female | 26 (56.5) | 50 (44.6) | 76 (48.1) |
| Male | 20 (43.5) | 63 (55.8) | 83 (52.2) |
| Location, n (%) Head | 41 (89.1) | 78 (69.0) | 119 (74.8) |
| Body | 3 (6.5) | 20 (17.9) | 23 (14.6) |
| Tail | 2 (4.3) | 15 (13.4) | 17 (10.8) |
| BMI, median (IQR) | 23.8 (21.6–25.1) | 22.7 (20.7–25.1) | 23.0 (20.8–25.1) |
| CA 19-9, U/ml Median (IQR) | 185 (53.8–558) | 189 (49.5–539) | 185 (49.6–558) |
| Not checked, n (%) | 1 (2.2) | 16 (14.3) | 17 (10.8) |
| Albumin, g/dl Median (IQR) | 4.10 (3.90–4.30) | 4.10 (3.60–4.40) | 4.10 (3.70–4.40) |
| Not checked, n (%) | 7 (15.2) | 23 (20.5) | 30 (19.0) |
| Neutrophil lymphocyte ratio | |||
| Median (IQR) | 3.05 (2.33–4.76) | 3.37 (2.16–5.63) | 3.27 (2.23–5.29) |
| Not checked, n (%) | 0 | 5 (4.5) | 5 (3.2) |
| Tumour size, cm, median (IQR) | 2.70 (2.23–3.30) | 3.00 (2.40–3.50) | 2.80 (2.30–3.50) |
| Clinical stage, n (%) | |||
| IA | 0 | 13 (11.5) | 13 (8.2) |
| IB | 12 (26.1) | 33 (29.2) | 45 (28.3) |
| IIA | 3 (6.5) | 24 (21.2) | 27 (17.0) |
| IIB | 31 (67.4) | 43 (38.1) | 74 (46.5) |
| No surgical resection, n (%) | 11 (23.9) | 13 (11.5) | — |
| Comorbidity | 4 | 1 | — |
| Double cancer | 1 | 0 | — |
| Locally advanced | 2 | 6 | — |
| Disease progression | 2 | — | — |
| Patient refusal | 2 | — | — |
| Occult metastasis | 0 | 5 | — |
| Not recorded | 0 | 1 | — |
IQR, interquartile range.
Thirty-seven of 46 patients (80%) in the NAC group proceeded to surgery but two patients were found to be unresectable intraoperatively, both due to severe tumour adhesion of the surrounding artery. Nine patients (20%) did not proceed to surgery primally due to comorbidity in four patients, two for progression disease and two for patient refusal. Among 113 patients in the UR group, 100 patients (89%) successfully underwent complete tumour resection while 13 patients (11%) were found to be unresectable intraoperatively, including locally advanced in 6 patients and distant metastasis in 5 patients (Table 1). During resection, there were 12 patients (34.3%) in NAC group and 15 patients (15%) in the UP group received venous resection to achieve adequate resection margin grossly. Finally, after resection, the R0 margin rate was 83% in the NAC group and 53% in the UR group, P=0.002 (Table 2).
Table 2.
Pathological characteristic.
| Neoadjuvant chemotherapy (N=35) | Upfront resection (N=100) | P | |
|---|---|---|---|
| Time to surgery, months, median (range) | 3.0 (1.3–6.4) | — | — |
| Resection margin, n (%) | 0.002 | ||
| R0 | 29 (82.9) | 53 (53.0) | |
| R1 | 6 (17.1) | 47 (47.0) | |
| SMV resection, n (%) | 12 (34.3) | 15 (15) | 0.06 |
| LN dissected, median (range) | 23 (9–45) | 15 (0–40) | 0.0001 |
| LN positivity, %, median (range) | 0 (0–33.3) | 6.9 (0–100) | 0.011 |
| LN involvement, n (%) | 0.088 | ||
| pN0 | 22 (62.9) | 42 (42.0) | |
| pN1 (1–3 LN involvement) | 10 (28.6) | 37 (37.0) | |
| pN2 (≥ 4 LN involvement) | 3 (8.6) | 21 (21.0) | |
| Pathological stage, n (%) | 0.011 | ||
| pTis/pCR | 3 (8.6) | 1 (1.0) | |
| IA | 7 (20.0) | 7 (7.0) | |
| IB | 10 (28.6) | 18 (18.0) | |
| IIA | 2 (5.7) | 18 (18.0) | |
| IIB | 10 (28.6) | 41 (41.0) | |
| III | 3 (8.6) | 15 (15.0) | |
| Tumour regression grade | 0.011 | ||
| TRG 0–1 | 11 (31.4) | — | |
| TRG 2–3 | 24 (68.6) | — | |
| Recurrence pattern, n (%) | 0.28 | ||
| Local | 1 (2.9) | 5 (5.0) | |
| Distant | 7 (20.0) | 36 (36.0) | |
| Both | 3 (8.6) | 21 (21.0) | |
| Occult (clinical) | 0 | 9 (9.0) |
LN, lymph node; TRG, tumour response grade; SMV, superior mesenteric vein.
Chemotherapy regimen
In the NAC group, the regimen used as neoadjuvant chemotherapy was the combination of S1, leucovorin, oxaliplatin and gemcitabine (SLOG) in 36 patients (78%), nab-paclitaxel plus gemcitabine in 4 patients (9%), modified FOLFIRINOX in 3 patients (7%) and the combination of gemcitabine, oxaliplatin, 5-fluorouracil and leucovorin (GOFL) in 3 patients (7%) (supplementary Figure S1A, Supplemental Digital Content 1, http://links.lww.com/JS9/A680). The median time from initial chemotherapy to surgery was 3 months. One patient refused treatment and lost to follow-up after 5 cycles of SLOG. For the remaining 45 patients, partial response was observed in 7 patients, including 6 of 36 patients (16.7%) with SLOG and 1 of 3 patients (33.3%) with mFOLFIRINOX (supplementary Figure S1B, Supplemental Digital Content 1, http://links.lww.com/JS9/A680). Two patients receiving SLOG had disease progression upon first image follow-up at 3 months after initial treatment. The regimens of adjuvant chemotherapy were the same as neoadjuvant chemotherapy in 31 patients while 2 patients switched to gemcitabine alone and 1 patient received S1 alone (supplementary Figure S1C, Supplemental Digital Content 1, http://links.lww.com/JS9/A680).
In the UR group, 42 of 100 resected patients (42%) did not receive adjuvant chemotherapy; 43 patients (43%) received S1 monotherapy, 5 patients (5%) received gemcitabine and 5 patients (5%) received gemcitabine plus S1 as adjuvant chemotherapy (supplementary Figure S1A, Supplemental Digital Content 1, http://links.lww.com/JS9/A680).
Treatment outcome
As of data cut-off on 31 December, 2021, the median duration of follow-up was 29.7 months (95% CI, 26.5–37.0). In the intention-to-treat population, the median PFS was 22.0 months (95% CI, 10.2–not estimable, NE) and 9.2 months (95% CI, 7.4–11.2) in NAC and UR groups, respectively (Fig. 2 A); the corresponding median OS was 35.3 months (95% CI, 29.7–NE) and 21.7 months (95% CI, 18.5–27.9) in NAC and UR group, respectively (Fig. 2 B). We further compared the outcome based on the tumour size in clinical staging. There was no patient with clinical stage IA (tumour ≤ 2 cm) in the NAC group. The median RFS of the NAC group was 22.0 months (95% CI, 10.2 months–not estimable, NE), which was significantly better than the UR group with tumour >2 cm (median RFS 8.7 months, 95% CI, 6.9–10.6, P=0.0057) and not significantly different from UR group with tumour less than or equal to 2 cm (median RFS not reached, 95% CI, 8.8–NE, P=0.29) (Fig. 2 C). The corresponding median OS was 35.3 months (95% CI, 29.7–NE) in NAC, which was significantly better than the UR group with tumour greater than 2 cm (median OS 19.5 months, 95% CI, 14.7–24.0, P=0.0092), and only margin different from UR group with tumour less than or equal to 2 cm (median OS not reached, 95% CI, 35.7–NE, P=0.097) (Fig. 2D). In the NAC group, the median OS was not reached (95% CI, 29.7–NE) in patients with resection while 10.4 months (95% CI, 6.5–NE) for those without resection; in the UR group, the corresponding median OS for patients with and without resection were 24.5 months (95% CI, 20.1–32.8) and 6.0 months (95% CI, 2.2–14.1)(supplementary Figure S2, Supplemental Digital Content 1, http://links.lww.com/JS9/A680).
Figure 2.
The Kaplan–Meier curve of progression-free survival (A) and overall survival (B) of the intention-to-treatment population in NAC and UR groups, and further stratified by tumour size (C, D). NAC, neoadjuvant chemotherapy; UR, upfront resection.
In the NAC group, 34 of 35 resected patients (97%) underwent adjuvant chemotherapy while only 58 of 100 resected patients (58%) in the UR group received adjuvant chemotherapy. The median RFS in the NAC group, UR with adjuvant chemotherapy and UR without adjuvant chemotherapy were 31.3 months (95% CI, 14.4–NE), 10.6 months (95% CI, 9.0–14.3) and 8.5 months (95% CI, 5.8–11.8), P=0.036 (Fig. 3A); and the corresponding median OS in each group were not reached (95% CI, 29.7–NE), 25.9 months (95% CI, 21.1–40.5) and 21.7 months (12.0–32.8), P=0.0053 (Fig. 3B). The median RFS and median OS of patients in the NAC group were significantly better than those in the UR group.
Figure 3.
Recurrence-free survival (A) and overall survival (B) in resected patients in NAC and UR groups. (C) Recurrence-free survival in the NAC group stratified by tumour response grade. (D) The change of clinical staging and pathological staging. Recurrence-free survival (E) and overall survival (F) in resectable pancreatic cancer patients based on the pathology staging. NAC, neoadjuvant chemotherapy; TRG, tumour response grade; UR, upfront resection.
Pathological characteristic
The median number of dissected lymph nodes (LNs) was significantly higher in the NAC group, 23 (range 9–45) than that in the UR group, 15 (range 15–40), P=0.0001. Patients in the NAC group had significantly lower node positivity (0 versus 6.9, P=0.011), a higher proportion of pN0 (62.9% versus 42.0%, P=0.088) and R0 resection rate (82.9% versus 53.0%, P=0.002). A total of 11 patients (31.4%) in the NAC group had a major pathological response (tumour regression grade 0–1) with a median RFS not reached as compared with 18.7 months in those without major pathological response (tumour regression grade 2–3), P=0.019 (Fig. 3C).
Twenty patients in the NAC group had early pathological stage (pCR/pTis in 3, stage IA in 7 and stage IB in 10) while 26 patients in UR had early pathological stage (pCR/pTis in 1, stage IA in 7 and stage IB in 18)(Table 2). There were 34 patients in the NAC group (74%) and 67 patients in the UR group (59%) with clinical stage II. The proportion of early pathological stage was significantly higher in the NAC group (20/46, 43%) as compared with in the UR group (26/113, 23%)(P=0.002)(Fig. 3D). In these resectable pancreatic cancer patients, the median RFS of patients with an early pathological stage (pCR/pTis/pT1/pT2) was not reached (95% CI, 10.2–NE) and 9.9 months (95% CI, 7.9–12.7) for patients beyond pathological stage I (Fig. 3E); the corresponding median OS was 40.5 months (95% CI, 29.7–NE) and 24.5 months (19.4–32.8) (Fig. 3F).
As of data cut-off, tumour recurrence was observed in 11 of 35 (31.4%) resected patients in the NAC group, which was significantly lower than 71 of 100 (71.0%) in the UR group (P<0.001) (Table 2). Distant failure was the most common recurrence pattern in both groups. Nine patients in the UR group were diagnosed with occult recurrence and underwent systemic chemotherapy according to the clinical symptom and elevated CA 19-9 without radiologically visible tumour.
Covariates adjustment
After propensity score matching, the baseline characteristic was more balanced between the NAC and the UR groups (supplementary Figure S3, Supplemental Digital Content 1, http://links.lww.com/JS9/A680). After matching, the benefit of NAC remained significant with a median PFS of 24.8 months (95% CI, 10.2–NE) versus 8.8 months (95% CI, 6.9–10.5), P=0.022 (Fig. 4A); a median OS of not reached (95% CI, 29.7–NE) versus 21.1 months (95% CI, 14.2–35.3), P=0.042 (Fig. 4B). The benefit of NAC was consistently observed in resected patients of the propensity score matched population with a median RFS of 31.3 months (95% CI, 20.5–NE) versus 9.7 months (95% CI, 7.4–14.3), P=0.012 (supplementary Figure S4A, Supplemental Digital Content 1, http://links.lww.com/JS9/A680).
Figure 4.
Treatment outcome after covariates adjustment. Progression-free survival (A) and overall survival (B) of upfront resection and neoadjuvant chemotherapy group after propensity score matching. (C) Forest plot of the Cox proportional hazard model of progression-free survival and overall survival. Blue dots represented hazard ratio (HR) and the grey line indicated a 95% CI. The grey dot indicated the reference group.
In the multivariate Cox proportional hazard model, baseline CA 19-9 greater than 500 U/ml and initial tumour size greater than 2 cm were independent poor prognostic factors of both PFS and OS (Fig. 4C). On the other hand, after adjustment of covariants, initial treatment with neoadjuvant chemotherapy significantly reduced the risk of progression by 56% [hazard ratio (HR) for PFS: 0.44; 95% CI: 0.27–0.74; P=0.002] and reduced the risk of death by 56% (HR for OS:0.44; 95% CI: 0.23–0.84; P=0.013)(Fig. 4 C). For resected patients in the propensity score matched population, NAC reduced the risk of recurrence by 67% (HR for RFS:0.33; 95% CI: 0.17–0.64; P=0.001) (Supplementary Figure S4B, Supplemental Digital Content 1, http://links.lww.com/JS9/A680).
Discussion
In the intention-to-treat analysis of the present study, we demonstrated NAC could achieve better median PFS (22.0 months versus 9.2 months) and median OS (35.3 months versus 21.7 months). The resection rate was not statistically significant different between NAC and UR groups (76% versus 88%, P=0.055). For patients who successfully underwent curative resection, NAC could significantly improve median RFS (31.3 months versus 10.6 months) and median OS (NR versus 25.9 months) compared with UR. NAC group patients also had a higher R0 resection rate (83% versus 53%), lower recurrence rate (31% versus 71%) and higher harvested median number of dissected LN (23 versus 15). Furthermore, there were 31% of patients had good pathological tumour response grade (TRG 0–1) following NAC.
Our results were compatible with the preliminary report of the randomized phase II/III Prep-02/JSAP-05 trial which demonstrated a median OS of 36.7 months in the NAC arm and a median OS of 26.6 months in the UR arm34. The randomized phase II PACT-15 trial also reported a similar result with a median OS of 38.2 months in the NAC arm and a median OS of 20.4 months (UR with adjuvant gemcitabine) and 26.4 months (UR with adjuvant cisplatin, epirubicin and gemcitabine)35. The resection rate in our intention-to-treat population was 76% in NAC and 88% in the UR group which was in line with other recently reported randomization studies comparing NAC versus UR in resectable PDAC (74–84.4% in NAC and 81–91.3% in UR group) (Table 3)34–37 We observed a higher R0 resection rate in NAC (82.9%) than UR group (53.0%), which was also compatible with the pooled data from 3 randomized controlled trials (70.2% in NAC and 53.8% in UR), the PACT-15 trial (63% in NAC, 27–37% in UR) and the NEONAX trial (87.8% in NAC and 67.4% in UR)24,35,37. The surgical outcome of our study was also compatible with another randomized SWOG S1505 trial comparing two different neoadjuvant regimens, mFOLFIRINOX or gemcitabine plus nab-paclitaxel38. In the SWOG S1505 trial, 77 of 103 (75%) eligible patients proceeded to surgery after NAC and 73 patients (71%) successfully underwent tumour resection with an R0 resection rate of 85%. The median number of dissected LN was 18 and a major pathological response was observed in 33% of patients38. The median RFS in the SWOG S1505 trial was 10.9 months in the mFOLFIRINOX arm and 14.2 months in the gemcitabine plus nab-paclitaxel arm with corresponding median OS of 23.2 and 23.6 months, respectively39. Although the median RFS and median OS were somehow slightly lower than expected, the SWOG S1505 trial still provided clinically meaningful evidence that NAC is feasible and has comparable survival as compared with the experiment arm in CONKO-001 (gemcitabine arm, median RFS of 13.4 months and median OS of 22.8 months) and ESPAC-4 (gemcitabine plus capecitabine arm, median RFS of 13.9 months and median OS of 28.0 months)40,41. The change of “standard of care” in guidelines usually requires high-level evidence derived from phase III trials. Two phase III trials (NCT02919787 and NCT04340141) is ongoing to compare neoadjuvant FOLFIRINOX versus adjuvant FOLFIRINOX and the results are expected to come out in 2026 and 2030. Although most of the previous randomization trials comparing NAC versus UR all terminated due to poor patient accrual, pooled meta-analysis confirmed the benefit of NAC over UR24. Our study further provides real-world evidence supporting NAC in resectable PDAC.
Table 3.
The collecting result of neoadjuvant therapy in resectable pancreatic cancer.
| Treatment arm | Resection rate | R0 resection | PFS | OS | |
|---|---|---|---|---|---|
| Prep-02/JSAP-0533 | NAC (n=182) | NR | NR | 36.7 months | |
| UR (n=180) | NR | NR | 26.6 months | ||
| PACT-1534 | NAC (n=32) | 84.4% | 63% | 16.9 months | 38.2 months |
| UR (arm A+ arm B, n=56)a |
87.5% | Arm A: 27% Arm B: 37% |
Arm A: 4.7 months Arm B: 12.4 months |
Arm A: 20.4 months Arm B: 26.4 months |
|
| NEONAX36 | NAC (n=63) | 80.0% | 87.8% | NR | 25.2 months |
| UR (n=64) | 91.3% | 67.4% | NR | 16.7 months | |
| PANACHE01-PRODIGE4835 | NAC (arm 1, n=70 arm 2, n=50)b |
Arm 1:74% Arm 2:68% |
Arm 1: 1 year-51.4% Arm 2: 1 year-43.1% |
Arm 1: 1 year-84.1% Arm 2: 1 year-71.8% |
|
| UR (n=26) | 81% | 1 year-41.7% | 1 year-80.8% | ||
| Present study | NAC (n=46) | 76% | 83% (97% cases with adjuvant therapy) |
31.3 months | NR |
| UR (n=113) | 89% | 53% (58% cases with adjuvant therapy) |
With adjuvant 10.6 months Without adjuvant 8.5 months |
With adjuvant 25.9 months Without adjuvant: 21.7 months |
NAC, neoadjuvant chemotherapy; NR, not reported; OS, overall survival; PFS, progression-free survival; UR, upfront resection.
Arm A (adjuvant gemcitabine), arm B (adjuvant cisplatin, epirubicin, gemcitabine and capecitabine, PEXG).
Arm 1 (mFOLFIRINOX), arm 2 (FOLFOX); arm 2 was terminated earlier due to futility.
An unsolved important issue is which NAC regimen is the best. As the key point of NAC in resectable PDAC is to eliminate micro-metastasis without delay of tumour resection, less toxicity is more important than a higher response rate. In the SWOG S1505 trial, gemcitabine plus nab-paclitaxel is equally toxic to mFOLFIRINOX with similar efficacy. Although cross-trial comparison is not recommended, the overall survival difference observed between the Prep-02/JSAP-05 trial and the SWOG S1505 trial still merits some attention. Gemcitabine plus S1, the NAC regimen used in the Prep-02/JSAP-05 trial, is generally considered not as effective as mFOLFIRINOX or gemcitabine plus nab-paclitaxel as it fails to demonstrate superior survival benefit over gemcitabine monotherapy42. However, the median OS of 36.7 months achieved by neoadjuvant gemcitabine plus S1 seemed to be better than the median OS of 23.2 in neoadjuvant mFOLFIRINOX and the median OS of 23.6 months in neoadjuvant gemcitabine plus nab-paclitaxel. Toxicities could possibly contribute to the discrepancy. In the present study, the most commonly used regimen SLOG was derived from previous studies which suggested that gemcitabine, oxaliplatin and 5-FU/leucovorin (GOFL) had synergism and non-overlapping toxicities43,44. Both SLOG and GOFL regimens had been proven to be as effective as mFOLFIRINOX with lower toxicities in advanced PDAC from multicenter randomized phase II trials and real-world experience45–47. Due to the limit of available studies, currently, it remains unclear which is the best regimen in the neoadjuvant setting. Further randomization studies are warranted.
The main limitation of the present study was its retrospective nature and patients were allocated to NAC or UR based on physician judgment and patient preference, not randomly which may contribute to selection bias. However, the benefit of neoadjuvant chemotherapy in PFS, RFS and OS remained significant after propensity score matching or covariates adjustment with multivariate Cox regression with baseline characteristics which suggested the benefit of NAC observed in the present study was not because of better baseline condition in the NAC group. Indeed, in the present study patients in the NAC group had more advanced disease and no clinical staging IA. The survival in the UR group was even slightly decreased after propensity score matching probably due to the removal of stage IA in the UR group after matching. Second, adjuvant chemotherapy was not applied to about 40% of patients resulting in an inferior survival in the UR group. But the survival provided by NAC remained significant even if compared to UR with adjuvant chemotherapy. A similar finding was also observed in the randomized NEONAX trial in which only 42.4% of subjects started adjuvant chemotherapy in the UR group37. Finally, the SLOG regimen was only evaluated in advanced PDAC but not in resectable PDAC and its application in resectable PDAC needs further validation study. A prospective multicenter study evaluating SLOG in resectable PDAC, BRPC and locally advanced pancreatic cancer (NCT05048524) is ongoing and will provide further insight into the use of SLOG regimen in the neoadjuvant setting.
Conclusion
In summary, the present study demonstrates NAC is feasible and tolerable without delaying curative resection in patients with resectable PDAC. This study provides real-world evidence that NAC is superior to UR and could be recommended to all patients with resectable PDAC larger than 2 cm. Which NAC regimen is the best remains undetermined and will be the next important issue in resectable PDAC.
Reporting checklist
The authors have completed the STROCSS reporting checklist48.
Ethical approval
The study is approved by NCKUH IRB and approval number is A-ER-108-113. Name of registry: Outcome of GI Cancer in NCKUH ClinicalTrials.Gov Identifier: NCT05700188. Hyperlink https://clinicaltrials.gov/ct2/show/NCT05700188.
Source of funding
This study did not acquire funding support from government, hospital, or industry.
Author contribution
Not available.
Conflicts of interest disclosure
All authors have no conflicts of interest.
Guarantor
Yan-Shen Shan is the guarantor to take response for this study.
Data statement
The author declared that all the data were produced in Department of Surgery, National Cheng Kung University Hospital. These patients received cares, including chemotherapy and operation were under the supervision of Prof Yan-Shen Shan, and this study was approved by the IRB of NCKUH.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Supplementary Material
Footnotes
Y.-Y.S., C.-J.W., Y.-J.C., Y.-S.S. and L.-T.C. contributed equally to this work.
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website, www.lww.com/international-journal-of-surgery.
Published online 7 June 2023
Contributor Information
Yung-Yeh Su, Email: yysu@nhri.org.tw.
Ying-Jui Chao, Email: surgeon.chao@gmail.com.
Chih-Jung Wang, Email: poemcage@gmail.com.
Ting-Kai Liao, Email: ltk1986@msn.com.
Ping-Jui Su, Email: cookieray1210@hotmail.com.
Chien-Jui Huang, Email: nelly91.huang@gmail.com.
Nai-Jung Chiang, Email: njchiang@nhri.org.tw.
Yu-Ting Yu, Email: ncku013@hotmail.com.
Hong-Ming Tsai, Email: sjfhmt@mail.ncku.edu.tw.
Li-Tzong Chen, Email: leochen@nhri.org.tw.
Yan-Shen Shan, Email: ysshan@mail.ncku.edu.tw.
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