Prognostic factors of recurrence in patients with recurrent postoperative pancreatic cancer treated with adjuvant TS-1 as the main outcome

doi:10.21203/rs.3.rs-4890491/v1

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Research Article

Prognostic factors of recurrence in patients with recurrent postoperative pancreatic cancer treated with adjuvant TS-1 as the main outcome

https://doi.org/10.21203/rs.3.rs-4890491/v1

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Purpose

Prognosis of pancreatic cancer is improved by combining postoperative adjuvant chemotherapy and preoperative adjuvant chemotherapy with surgery, while the importance of extended dissection surgery has decreased. Here, to better understand prognostic factors of recurrence, we focused on the timing of postoperative adjuvant chemotherapy in patients with pancreatic cancer.

Materials and Methods

One hundred patients who underwent pancreatectomy or pancreaticoduodenectomy and chemotherapy for pancreatic cancer were classified into early and late postoperative adjuvant therapy initiation groups. Prognosis was evaluated retrospectively using known prognostic factors.

Results

On receiver operating characteristic analysis, optimum cut-off between the early (< 52 days; n = 60) and late adjuvant initiation groups (≥ 52 days; n = 40) was 52 days. The two groups were well-matched, except the early initiation group had more surgeries with D2 lymph node dissection (75% vs 48%; p = 0.01); fewer postoperative complications (17% vs 59%; p = 0.04), including less postoperative pancreatic fistula (13% vs 35%; p = 0.03); and longer disease-free survival (0.7 years v 0.5 years; p = 0.02). On multivariate evaluation, early initiation of adjuvant therapy and completion of adjuvant therapy were associated with increased overall survival, while early initiation was associated with prolonged disease-free survival.

Conclusion

Prognosis of patients with pancreatic cancer is improved by earlier rather than later initiation of postoperative adjuvant therapy. While surgery remains a key treatment approach, its main contribution to prognosis may derive from minimization of dissection and complications.

TS1

adjuvant chemotherapy

pancreatic cancer

The value of postoperative adjuvant chemotherapy (AC) for pancreatic cancer is widely recognized, and the combination of surgery and chemotherapy to control potential micrometastatic lesions is now the standard of care [1]. Worldwide, AC for resectable pancreatic cancer (RPC) is based on 5-fluorouracil plus folinic acid or gemcitabine. While RPC treated with surgery alone has a 5-year survival rate of about 20% [2], the addition of AC prolongs 5-year survival by about 10–21% [2, 3]. Metastasis, a progressive form of disease, occurs relatively early in the development of pancreatic cancer [4]. Resection of the primary tumor can stimulate tumor cells to release growth factors, and the immunocompromised state of patients can promote the establishment and growth of micrometastasis at distant sites [5]. Against this background, delayed initiation of adjuvant therapy may lead to the establishment of drug-resistant micrometastases [6] and increased angiogenesis in the vascular layer surrounding the metastases [7]. In contrast, early postoperative initiation of adjuvant therapy may inhibit these factors, leading to decreased recurrence and prolongation of OS.

Pancreatectomy is one of the most invasive and complicated procedures in the field of gastrointestinal surgery [8]. Clinical decision making is hampered by the lack of clarity on the optimum interval between pancreatectomy and adjuvant therapy, and the fact that approximately 30% of patients are unable to receive adjuvant therapy due to postoperative complications, early metastasis, or poor performance status [9]. It remains unclear whether AC should be initiated as soon as possible after surgery, and whether initiation can be safely subordinated to the requirements of surgical therapy and need for adequate postoperative recovery. This lack of clarity often results in a delay in AC in favor of postsurgical care. Further, the few studies to date have been conflicting: some suggest that a delay in adjuvant therapy has no influence on prognosis [10, 11], whereas Ma et al. reported that early initiation improved prognosis [12]. Moreover, cutoff values for the optimum number of days before initiation of chemotherapy in these studies also varied. Thus, a conclusive understanding of the indications and scheduling of AC in postoperative pancreatic cancer is long overdue. With regard to adjuvants, the JASPAC-1 trial reported that TS-1 showed better survival than gemcitabine, with 5-year OS of 44.1% and 24.4%, respectively [13], and TS-1 is now the standard of care in Japan. However, the timing of initiation of adjuvant therapy with TS-1 has not been investigated in Japan, and is often at the discretion of the attending surgeons and medical oncologists. Recurrence remains high, however, at 56–62% even after surgery [14], suggesting that scheduling of AC should be determined with consideration to treatment of recurrence.

Here, to better understand the timing of AC following surgery for pancreatic cancer, we retrospectively analyzed the timing of TS-1 in patients with postoperative recurrence of pancreatic cancer with TS-1 and compared results with other known prognostic factors in these patients.

Patients

The study was conducted under a retrospective design at two institutions, The Jikei University Hospital and The Jikei University Kashiwa Hospital. Consecutive patients (N = 100) who underwent pancreatectomy for pancreatic cancer between January 2011 and December 2020 and postoperative adjuvant therapy with TS-1, followed by chemotherapy for postoperative recurrence of disease, were retrospectively compared to identify prognostic risk factors. Inclusion criteria included: 1. pancreatic cancer histologically determined to be adenocarcinoma or adenosquamous carcinoma; 2. unresectable recurrent pancreatic cancer, with or without measurable lesions - patients with measurable lesions had to undergo diagnostic imaging studies within 28 days prior to enrollment; 3. no previous radiotherapy for pancreatic cancer; 4. age 20 to 79 years; 5. Eastern Cooperative Oncology Group Performance Status of 0 or 1; and 6. adequate function of major organs as defined by laboratory tests performed within 14 days prior to enrollment, including white blood cell count ≥ 3500/mm³, neutrophil count ≥ 2000/mm³, hemoglobin ≥ 9.0 g/dL, platelet count ≥ 100000/mm³, total bilirubin ≤ 2.0 mg/dL (or ≤ 3.0 mg/dl for patients treated with obstructive jaundice and biliary drainage), aspartate aminotransferase and alanine aminotransferase ≤ 150 U/L, serum creatinine ≤ 1.2 mg/dL, and creatinine clearance ≥ 50 mL/min; 6. ability to take oral medication; and 7. no clinically abnormal ECG findings within 28 days before registration. Exclusion criteria included 1. pulmonary fibrosis or interstitial pneumonia confirmed by chest X-ray within 28 days before enrollment; 2. watery diarrhea; 3. active infection, excluding viral hepatitis; 4. serious complications such as heart failure, renal failure, hepatic failure, hemorrhagic peptic ulcer, intestinal paralysis, intestinal obstruction or poorly controlled diabetes; 5. moderate or severe (requiring drainage) ascites or pleural effusion requiring treatment; 6. metastasis to the CNS; and 7. active double cancer (synchronous double cancer or asynchronous double cancer with a disease-free duration of 3 years or less). Pancreatic cancer is recognized as a systemic disease, and the balance and combination of resection and chemotherapy are considered important. We focused on AC after pancreatectomy with TS-1. We evaluated risk for prognosis with early and late initiation of AC by retrospective comparison with known prognostic factors, including (1) use of TS-1 or another adjuvant, (2) time from surgery to the start of adjuvant therapy (days), and (3) whether TS-1 administration was completed. The study was approved by the ethics committee of The Jikei University School of Medicine (approval number: 27–177(8062)). The study was conducted under a retrospective design and, in accordance with Japanese national guidelines, informed consent was not required.

Treatment and patient follow-up

All study subjects had undergone pancreatectomy for pancreatic cancer and received adjuvant therapy, and then developed recurrence which was treated with chemotherapy.

Pancreatectomy included open pancreaticoduodenectomy with lymph node dissection or pancreaticoduodenectomy (with splenectomy). In principle, drains were placed at the pancreatic jejunal anastomosis and bile duct jejunal anastomosis for pancreaticoduodenectomy, and at the pancreatic fragment and under the left diaphragm for pancreaticoduodenectomy. Cefmetazole sodium 2 g/day was administered daily from the day of surgery. When infection control was judged insufficient, administration was escalated to a broad-spectrum antibacterial agent. When fever or elevated inflammation was observed, detailed examination, including contrast-enhanced computed tomography (CT) imaging and drain biochemistry measurements, was performed to determine complications, and additional treatment was given if necessary.

Following discharge, patients were initially followed on an outpatient basis, with outpatient visits every 3 weeks during TS1 administration and once a month during non-TS1 administration. Follow-up evaluation items included confirmation of progress without complications, food intake, ADLs, and satisfactory resolution of subjective symptoms. If outpatient evaluation of health status revealed no problems, adjuvant therapy with TS-1 was started with timing at the discretion of the attending physician. Doses were calculated in accordance with the package insert based on body surface area and given by twice daily administration for 2 consecutive weeks followed by a 1-week rest, continued for 6 months where possible regardless of disease stage. When significant adverse events (Clavian Dindo 3 or higher) occurred, TS-1 was discontinued or the dose was reduced. Postoperative followup also included measurement of blood samples (including tumor markers) once a month, and contrast-enhanced CT every 3 months to check for recurrence. When recurrence was confirmed, chemotherapy was introduced based on regimens described in the Japanese Pancreatic Association’s Clinical Practice Guidelines for Pancreatic Cancer 2022 (5FU + Irinotecan + Oxaliplatin combined therapy, GEM + nab-PTX, GEM + TS1, GEM only, or TS1 only) at the discretion of the attending physician. Following induction, adverse events, performance status, and disease status were evaluated, doses were reduced or stopped in a timely manner, and prognosis was investigated.

Assessment

Sarcopenia (SP) was measured by CT scan of the cross-sectional area of the iliopsoas muscle at the level of the L3 lumbar vertebrae at the time recurrence was confirmed (Fig. 1). Patients were classified based on median value into high SP (SP+) (N = 70) and low SP groups (SP-) (N = 30). Osteoporosis (OP) was measured at the same time by pixel value at the center of the body of the 11th thoracic vertebra (Fig. 2). Patients were classified based on a cut-off value of 160 HU (37–39) into positive OP (OP+) (N = 47) and negative OP (OP-) groups (N = 53). Patient background and surgical outcomes were evaluated using the following endpoints: 2-year survival (time since surgery), recurrence, perioperative complications (pancreatic leak), length of hospital stay, overall survival (OS), disease-free survival (DFS), chemotherapy regimen, preoperative adjuvant therapy, pathological evaluation (resectability [R], stage, histological type [well, moderate, or poor], and number of lymph node metastases), and tumor diameter.

Statistical analysis

Standard statistical analyses were used to evaluate descriptive statistics, such as means, medians, frequencies, and percentages. Continuous variables were compared using the Mann-Whitney U test. Categorical variables were analyzed using the chi-squared test or Fisher's exact test. Univariate and multivariate survival analyses were performed using Cox proportional hazards models on selected variables as appropriate. Cumulative overall survival (OS) and recurrence-free survival (RFS) rates were calculated using the Kaplan-Meier method, and differences were evaluated using the log-rank test between curves. OS was calculated in days from the date of surgery to the date of last follow-up or death, whichever occurred first. P values less than 0.05 were considered to indicate statistical significance. All analyses were conducted using IBM® SPSS statistics version 20.0 (IBM Japan, Tokyo, Japan).

Cutoff value of time from surgery to TS-1 initiation.

Receiver operating characteristic curve analysis of the distribution of the number of days until initiation of postoperative adjuvant therapy (time from surgery to TS-1 initiation) revealed a cutoff value of 52 days (area under the curve = 0.700; Fig. 1). Patients were divided accordingly into early (n = 60) and late (n = 40) initiation groups.

Patient characteristics

The two groups are characterized in Table 1. The groups were well-matched with regard to age, cancer location, chemotherapy regimen at recurrence, and degree of cancer differentiation, but less well-matched regarding sarcopenia, adjuvant chemotherapy drug or completion of AC. In particular, compared to the late initiation group, the early group had (1) a lower rate of No lymph node dissection (D0) or Group 1 lymph node dissection (D1) lymph node dissection (lymph node dissection range (D0 + D1: Group 2 lymph node dissection(D2)) 15:45, 25% versus 21:19, 53%; p = 0.01), (2) lower rates of surgical complications (-ve:+ve) (50:10, 17% vs 23:16, 41%; p = 0.004) and pancreatic leakage (-ve:+ve) (52:8, 13% vs 26:14, 65%; p = 0.02), and (3) tended to have a higher rate of Stage 1 or 2 disease at recurrence (Stage 1/2:3/4) (50:10, 83% vs 26:14, 65%; p = 0.07).

Table 1

Patient characteristics
	Time from surgery to TS-1 initiation < 52 (n = 60)	Time from surgery to TS-1 initiation ≧ 52 (n = 40)	p-value
Gender (male:female)	37:23(62%:38%)	24:16(60%:40%)	0.21
Age, years*	70	71	0.94
Sarcopenia (no:yes)	18:42(30%:70%)	12:28(30%:70%)	0.1
Osteopenia (no:yes)	32:28(53%:47%)	21:19(53%:47%)	0.41
Cardiopulmonary disease (no:yes)	44:16(73%:27%)	32:8(80%:20%)	0.18
Multiple primary cancers (no:yes)	50:10(83%:17%)	35:5(88%:12%)	0.2
Nutritional therapy (no:yes)	44:16(73%:27%)	36:490%:10%)	<0.01
Cancer location (head:body or tail)	39:21(65%:35%)	26:14(65%:35%)	0.58
Neoadjuvant chemotherapy (no:yes)	52:8(87%:13%)	35:5(88%:12%)	0.18
Preoperative CEA, ng/mL *	5.5	5.5	0.63
Preoperative CA19-9, U/mL *	86.5	108.5	0.23
Operation time, min. *	471	485	0.91
Blood loss, ml *	445	510	0.39
Lymph node dissection range (D0 or D1:D2)	15:45(25%:75%)	21:19(53%:47%)	0.01
SMA lymph nodes dissected (no:yes)	26:34(43%:57%)	13:27(33%:67%)	0.29
Postoperative complications (no:yes)	50:10(83%:17%)	23:16(58%:42%)	0.04
Postoperative pancreatic fistula (no:yes)	52:8(87%:13%)	26:14(65%:35%)	0.02
Number of post-operative days in hospital *	25	36	0.06
Pathological Stage (1 or 2:3 or 4)	50:10(83%:17%)	26:14(65%:35%)	0.07
Degree of differentiation of cancer (well.:mod. or por.)	15:45(25%:75%)	8:32(20%:80%)	0.62
Tumor diameter, mm *	35	35	0.96
Portal vein invasion (no:yes)	37:23(62%:38%)	26:14(65%:35%)	0.88
Pathological cancer remnant (no:yes)	46:14(77%:23%)	26:14(65%:35%)	0.35
Recurrent form (local recurrence:metastasis)	20:40(33%:77%)	12:18(30%:70%)	0.13
Completion of adjuvant chemotherapy (no:yes)	29:31(48%:52%)	15:25(38%:62%)	<0.01
Disease-free survival, years *	0.7	0.5	0.02
Chemotherapy regimen at recurrence (GnP:FOLFIRINOX:Other)	18:14:28 (30%:23%:47%)	8:11:21 (20%:28%:52%)	0.68
* median; min.: minutes; CEA: carcinoembryonic antigen; CA19-9: carbohydrate antigen 19 − 9; D0: no lymph node dissection; D1: group 1 lymph node dissection; D2: group 2 lymph node dissection; SMA: superior mesenteric artery; wel.: well-differentiated adenocarcinoma; mod.: moderately differentiated adenocarcinoma; por.: poorly differentiated adenocarcinoma; GnP: gemcitabine + nab-paclitaxel combined therapy; FOLFIRINOX: 5FU + irinotecan + oxaliplatin combined therapy

Kaplan-Meier curve: Relationship between induction of adjuvant chemotherapy and OS, DFS

Figure 2 shows that the early initiation group had significantly better OS than the late group (p = 0.02). Figure 3 shows that the OS of patients who completed AC was significantly better than that of patients who did not (p = 0.01) Fig. 4 shows that the group with earlier postoperative initiation of AC had significantly better DFS than the later group (p = 0.02), consistent with the better OS in this group (Fig. 2).

Univariate and multivariate analyses of risk factors for OS in patients with recurrent postoperative pancreatic cancer

Evaluation of risk factors for OS (Table 2) identified a number of factors that were significantly associated with OS. On univariate analysis, elevated hazard ratios for OS were seen for D2 lymph node dissection range (HR, 2.39; 95% confidence interval

Table 2

Univariate and multivariate analyses of risk factors for OS in patients with recurrent postoperative pancreatic cancer.
	OS univariate analysis		OS multivariate analysis
Parameter	Hazard ratio (95% CI)	p-value	Hazard ratio (95% CI)	p-value
Sarcopenia (yes)	3.58 (1.26–10.2)	0.02	0.13 (0.03–0.46)	<0.01
Osteopenia (yes)	2.45 (1.21–4.96)	0.01	1.08 (0.47–2.47)	0.85
Cardiopulmonary disease (yes)	1.02 (0.42–2.48)	0.95
Multiple primary cancers (yes)	1.05 (0.51–2.18)	0.89
Nutritional therapy (no)	1.57 (0.68–3.61)	0.28
Cancer location (head)	1.20 (1.53–2.38)	0.6
Neoadjuvant chemotherapy (yes)	0.39 (0.19–0.81)	0.01	0.73 (0.33–1.61)	0.44
Preoperative CEA >6	1.15 (0.58–2.25)	0.67
Preoperative CA19-9 >67.5	1.19 (0.58–2.44)	0.63
Operation time >471 min	0.99 (0.50–1.95)	0.99
Blood loss >330 ml	1.31 (0.64–2.69)	0.46
Lymph node dissection range (D2)	2.39 (1.21–4.69)	0.01	1.48 (0.65–3.34)	0.34
Number of lymph nodes dissected >25	0.88 (0.44–1.72)	0.71
SMA lymph nodes dissected (yes)	1.54 (0.78–3.10)	0.21
Postoperative complication (yes)	1.27 (0.65–2.49)	0.48
Postoperative pancreatic fistula (yes)	1.86 (0.72–4.81)	0.2
Number of post-operative days in hospital >29.5	1.84 (0.91–3.72)	0.09
Pathological stage (3 or 4)	4.00 (1.28–8.13)	0.03	2.56 (1.10–5.56)	0.03
Degree of differentiation of cancer (mod. or por.)	1.25 (0.54–2.87)	0.6
Tumor diameter>33.5 mm	1.43 (0.71–2.86)	0.31
Number of lymph node metastases ≥ 5.5	2.35 (1.02–5.43)	0.04	2.67 (1.10–6.49)	0.03
Portal vein invasion (yes)	1.69 (0.85–3.32)	0.13
Pathological cancer remnant (yes)	3.22 (1.62–6.45)	<0.01	2.87 (1.30–6.33)	<0.01
Completion of adjuvant chemotherapy (no)	7.68 (3.15–18.76)	<0.01	8.45 (3.32–21.50)	<0.01
Time from surgery to TS-1 initiation ≥52 days	2.26 (1.15–4.44)	0.02	3.50 (1.57–7.75)	<0.01
CEA: carcinoembryonic antigen; CA19-9: carbohydrate antigen 19 − 9; SMA: superior mesenteric artery; mod.: moderately differentiated adenocarcinoma; por.: poorly differentiated adenocarcinoma

(CI), 1.21–4.69), number of lymph node metastases ≥ 6 (HR, 2.35; 1.02–5.43), pathological stage 3 or 4 (HR, 4.00; 1.28–8.13), positive for pathological cancer remnant (HR, 3.22; 1.62–6.45), failure to complete adjuvant chemotherapy (HR, 7.68; 3.15–18.76), presence of sarcopenia (HR, 3.58; 1.26–10.2) and osteopenia (HR, 2.45; 1.21–4.96), and late initiation of AC after surgery (HR, 2.26; 1.15–4.44). On multivariable analysis, however, elevated HR was seen only for pathological stage 3 or 4 disease (HR, 2.56; 1.10–5.56), number of lymph node metastases ≥ 6 (HR, 2.67; 1.10–6.49), positive for pathological cancer remnant (HR, 2.87; 1.30–6.33), failure to complete AC (HR, 8.45; 3.32–21.50) and late initiation of AC after surgery (HR, 3.50; 1.57–7.75).

Univariate and multivariate analyses of risk factors for DFS in patients with recurrent postoperative pancreatic cancer

Risk factors for DFS were also evaluated (Table 3). On univariate analysis, significant risk factors were neoadjuvant chemotherapy (HR, 0.65; 95% CI, 0.48–0.88), preoperative Carbohydrate antigen 19 − 9 (CA19-9) > 67.5 (HR, 1.35; 95% CI, 1.05–1.98), number of post-operative days in hospital > 29.5 (HR, 1.36; 95% CI, 1.10–1.68), pathological stage 3 or 4 (HR, 1.76; 95% CI, 1.37–2.26), number of lymph node metastases ≥ 5.5 (HR, 1.68; 95% CI, 1.08–2.61), pathological cancer remnant (HR, 1.49; 95% CI, 1.19–1.86), completion of AC (no) (HR, 0.75; 95% CI, 0.62–0.92), and time from surgery to AC ≥ 52 (HR, 1.44; 95% CI, 1.16–1.78). In multivariate analysis, pathological stage 3 or 4 (HR, 1.61; 1.21–2.11), pathological cancer remnant (HR, 1.32; 1.03–1.61), completion of AC (no) (HR, 0.73; 0.58–0.91), and time from surgery to AC ≥ 52 (HR, 1.32; 1.02–1.71) remained and were identified as risk factors.

Table 3

Univariate and multivariate analyses of risk factors for DFS in patients with recurrent postoperative pancreatic cancer.
	DFS univariate analysis		DFS multivariate analysis
Parameter	Hazard ratio (95% CI)	p-value	Hazard ratio (95% CI)	p-value
Sarcopenia (yes)	3.58 (1.26–10.2)	0.02	0.13 (0.03–0.46)	<0.01
Osteopenia (yes)	2.45 (1.21–4.96)	0.01	1.08 (0.47–2.47)	0.85
Cardiopulmonary disease (yes)	1.02 (0.42–2.48)	0.95
Multiple primary cancers (yes)	1.05 (0.51–2.18)	0.89
Nutritional therapy (no)	1.57 (0.68–3.61)	0.28
Cancer location (head)	1.20 (1.53–2.38)	0.6
Neoadjuvant chemotherapy (yes)	0.39 (0.19–0.81)	0.01	0.73 (0.33–1.61)	0.44
Preoperative CEA >6	1.15 (0.58–2.25)	0.67
Preoperative CA19-9 >67.5	1.19 (0.58–2.44)	0.63
Operation time >471 min	0.99 (0.50–1.95)	0.99
Blood loss >330 ml	1.31 (0.64–2.69)	0.46
Lymph node dissection range (D2)	2.39 (1.21–4.69)	0.01	1.48 (0.65–3.34)	0.34
Number of lymph nodes dissected >25	0.88 (0.44–1.72)	0.71
SMA lymph nodes dissected (yes)	1.54 (0.78–3.10)	0.21
Postoperative complication (yes)	1.27 (0.65–2.49)	0.48
Postoperative pancreatic fistula (yes)	1.86 (0.72–4.81)	0.2
Number of post-operative days in hospital >29.5	1.84 (0.91–3.72)	0.09
Pathological stage (3 or 4)	4.00 (1.28–8.13)	0.03	2.56 (1.10–5.56)	0.03
Degree of differentiation of cancer (mod. or por.)	1.25 (0.54–2.87)	0.6
Tumor diameter>33.5 mm	1.43 (0.71–2.86)	0.31
Number of lymph node metastases ≥ 5.5	2.35 (1.02–5.43)	0.04	2.67 (1.10–6.49)	0.03
Portal vein invasion (yes)	1.69 (0.85–3.32)	0.13
Pathological cancer remnant (yes)	3.22 (1.62–6.45)	<0.01	2.87 (1.30–6.33)	<0.01
Completion of adjuvant chemotherapy (no)	7.68 (3.15–18.76)	<0.01	8.45 (3.32–21.50)	<0.01
Time from surgery to TS-1 initiation ≥52 days	2.26 (1.15–4.44)	0.02	3.50 (1.57–7.75)	<0.01
CEA: carcinoembryonic antigen; CA19-9: carbohydrate antigen 19 − 9; SMA: superior mesenteric artery; mod.: moderately differentiated adenocarcinoma; por.: poorly differentiated adenocarcinoma

In this study, we showed that early postoperative initiation of TS1 as AC after pancreatic resection for pancreatic cancer in patients with subsequent chemotherapy-treated recurrence was associated with longer recurrence-free survival than later initiation, and with longer overall survival and disease-free survival. Further, completion of adjuvant therapy was also associated with overall survival. These findings suggest the importance of early scheduling of postoperative AC in the treatment of recurrent pancreatic cancer. To our knowledge, this is the first study to focus on the scheduling of AC in these patients.

In patients with recurrent chemotherapy after pancreatic resection for pancreatic cancer, time (in days) to the initiation of post-resection AC (TS-1) and completion of adjuvant therapy were associated with prolonged OS. In addition, TS-1 tended to be initiated earlier by avoiding lymph node dissection, and thereby minimizing surgical complications and pancreatic leakage. In addition, earlier TS-1 tended to prolong DFS, which in turn tended to prolong OS. Pancreatic cancer is a systemic disease, and while surgery is important, it is also important to combine treatment with chemotherapy. Indeed, the contribution of surgery to longer prognosis might be more accurately attributed to the minimization of dissection and complications. To our knowledge, this is the first study to focus on the scheduling of AC in these patients. Pancreatic cancer remains an extremely challenging condition. Factors previously associated with survival include resection margin (R factor), smoking, pre- and postoperative CA19-9 serum levels, preoperative C-reactive protein concentration, tumor differentiation, presence of lymph node metastases, maximum tumor diameter, tumor stage, presence of varices, tumor diameter, venesection, local invasion, and sarcopenia [15–17]. In our study, OS was consistent with these previous findings, showing associations for number of lymph node metastases ≥ 5.5, tumor stage, pathologic cancer remnant (R factor), and the presence of sarcopenia. Notably, however, our study newly adds adjuvant-related items as factors in OS, namely early initiation of AC and completion of AC. Among previous studies of AC after resection for pancreatic cancer, analysis has been hampered by heterogenous patient selection and treatment. For example, some studies reported that early administration of postoperative AC, defined by a cutoff of around 8 weeks, was not a significant independent prognostic factor, whereas completion of AC was a factor[16, 18]. However, the chemotherapy regimens used in these previous papers varied, and included 5FU, GEM, nafamostat and TS-1. Further, selection criteria for adjuvant therapy in previous clinical trials were rigorous, and included full recovery from surgery. This rigor introduced a degree of selection bias. Even among these selected populations, completion rates of AC ranged from as low as 54–79%^{19. 20}. These findings indicated both the difficulty and importance of completing AC in patients with recurrent pancreatic cancer, but the differences in patient selection and type and scheduling of postoperative AC makes it difficult to draw any conclusions to support clinical decision making for treatment. In contrast, our present study retrospectively evaluated risk factors for recurrence in consecutive patients who underwent pancreatectomy for pancreatic cancer, subsequent postoperative AC with TS1 or another agent, and chemotherapy for postoperative recurrence. This methodology decreased the selection bias seen in these previous studies. Further, our early and late adjuvant groups were reasonably similar in background factors. Together, these characteristics support our comparison of these two groups for risk factors of recurrence, and likely allow greater confidence in decision making toward earlier timing of adjuvant initiation. In this regard, it is notable that patients who received AC even as late as 12 to 36 weeks after surgery had improved OS compared to those who received surgery alone, suggesting that AC should still be administered even if long delayed after surgery [10, 11] .

Among other cancers, delayed initiation of AC and longer duration of AC have been associated with worse survival in a wide range of cancers, including colorectal cancer[21], head and neck cancer [22], cervical cancer [23], breast cancer [24], and gastric cancer [25]. Effective regimens for these conditions are well-established, however, and it is unsurprising that the outcome of any divergence from them would be unfavorable. A similar situation might be expected for pancreatic cancer once localized and effective chemotherapy regimens have been established, and likely also if earlier diagnosis becomes common. Further, taking these previous and our present results together, it appears likely that, assuming effective postoperative care (completion of TS-1 therapy), both the timing and completion of AC are prognostic of recurrence of pancreatic cancer. The efficacy of postoperative AC for pancreatic cancer varies by regimen. In a 2019 report from the phase III APACT trial, adjuvant use of nab-paclitaxel (Abraxane) in combination with gemcitabine did not improve disease-free survival compared with gemcitabine alone (mDFS 19.4 months vs 18.8 months), but did improve overall survival (mOS 40.5 months vs. 36.2 months) [26] as well as 5-year survival (38% vs 31%) [27]. The adverse event rate with nab-paclitaxel (Abraxane) plus gemcitabine is relatively high, however, and initiation of this regimen in the first few weeks after surgery can be difficult.

TS-1 has shown a superior survival rate compared to gemcitabine [13], and is now the standard of care for postoperative AC for pancreatic cancer in Japan. TS-1 monotherapy can be continued on an outpatient basis, has relatively few adverse events [28], is easily introduced after surgery in many cases, and is highly effective. In the present study, 65% of patients in the early group received adjuvant therapy with TS-1 versus another regimen versus 83% in the late group, with this difference not being significant (p = 0.107). The only study to date on the timing of TS-1 therapy in GS (gemcitabine plus TS-1) reported that early intervention led to a significant improvement in 5-year OS (52%) [29]. However, cutoff for early versus late adjuvant administration in that study was 20 days. The feasibility of this early cutoff is unclear, and will depend on the incidence of postsurgical complications after pancreatectomy. In addition, the late AC group had a low 5-year OS of 26%, which is comparable to the 5-year survival rate for pancreatic cancer in the US, and may indicate selection bias in patient background [29]. Allowing that this is the only report on the timing of TS-1 adjuvant therapy after pancreatic cancer surgery and further confirmation is required, these results nevertheless appear positive for early initiation. Among other factors possibly impacting OS, early introduction of adjuvant therapy was associated with decreased lymph node dissection range, reduced incidence of surgical complications and pancreatic effusion on univariate analysis. Allowing that none of these remained significant on multivariate analysis and patient numbers were low, they are consistent with the general trend toward less invasive surgery and chemotherapy, and to the extent they can be achieved, will facilitate clinical decision making toward early introduction of TS-1, and thereby prolong DFS and OS. Our preferred strategy in this study was to prolong DFS by reducing the number and range of lymph node dissection, surgical complications, and postoperative pancreatic fistula, thereby reducing the number of patients who had to undergo repeat surgery. Several limitations of our study warrant mention. First, it was conducted under a retrospective design. Second, there is a degree of bias in patient background, specifically with regard to nutritional therapy, lymph node dissection range, postoperative complications, and postoperative pancreatic fistula. Third, the stage of cancer was not specified.

This study shows that the prognosis of patients with pancreatic cancer is improved by earlier rather than later initiation of postoperative AC. These findings suggest the importance of early scheduling of postoperative AC in the treatment of recurrent pancreatic cancer. Surgery remains a key treatment approach, but its main contribution to prognosis may derive from minimization of dissection and complications.

Authors’ contributions:

TI oversaw the entire study. The others contributed to analysis and interpretation of data. KA designed the study and wrote the initial draft of the manuscript.

Acknowledgement

The authors would like to thank the staff of the Jikei University Daisan Hospital and Jikei University School of Medicine.

Compliance with Ethical Standards

Funding:

This work was supported by JSPS KAKENHI Grant Number JP 23K15506.

Conflict of Interests:

The authors declare that they have no conflict of interest.

Ethical approval:

This study was approved by the Ethics Committee of the Jikei University School of Medicine (review number: 27-177(8062)). All procedures were performed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients prior to inclusion in the study.

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No competing interests reported.

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Prognostic factors of recurrence in patients with recurrent postoperative pancreatic cancer treated with adjuvant TS-1 as the main outcome

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