Update on management of pancreatic cancer: a literature review

Introduction

Approximately 85–95% of pancreatic cancers are pancreatic ductal adenocarcinomas originating from the exocrine part of the pancreas, and the term “pancreatic cancer” typically denotes this disease entity (1). It is an aggressive malignancy with increasing in incidence and with a high mortality. Globally, pancreatic cancer is currently the 7^th highest cause of cancer-related death, and with the current trend, pancreatic cancer is projected to be the 2^nd leading cause of cancer-related death by the year 2030 (2-4). Pancreatic cancer remains a disease with very poor prognosis (5-year survival rate, 2–10%) (5,6). In 2020, the number of mortalities from pancreatic cancer (n=466,003) was almost the same as the number of pancreatic cancer cases (n=495,773) (2). Radical surgery with adjuvant chemotherapy is the only chance of cure. However, approximately 80–90% of patients present with either locally advanced or metastatic disease at the time of diagnosis (6,7). A multidisciplinary approach is essential to optimize outcomes for both curable and advanced diseases.

This article aimed at reviewing the updated management of pancreatic cancer. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-23-94/rc).

Methods

We identified literature by searching Medline and PubMed from 1^st January 2010 to 30^th June 2023 using the keywords “pancreatic cancer”, “borderline resectable pancreatic cancer”, “metastatic pancreatic cancer”, “systemic chemotherapy”, “adjuvant treatment”, and “neoadjuvant treatment”. Only English language literature was considered. Case reports were excluded from analysis. Additional papers were identified by a manual search of the references from the key articles. There were no exclusion criteria for published information to the topics (Table 1).

Epidemiology & risk factors

Globally, pancreatic cancer is the 12^th most common cancer (7). The common age group with pancreatic cancer are 60–80 years of age. The highest incidence regions for pancreatic cancer include North America, Central and Eastern Europe. In last 10 years, increasing trends were observed in North America, Western Europe, and Australia (8,9). Although the incidence of pancreatic cancer varied in different country, its global burden has more than doubled over the last 25 years and the incidence of pancreatic cancer is increasing by 0.5–1.0% per year (10-12). Incidence and mortality rate in high human development index (HDI) countries are about 3–4-fold higher compared with low and medium HDI countries, and are slightly higher in male than in female gender (13). Pancreatic cancer is the 4^th most common cause of cancer-related deaths in most developed countries (14,15). Risk factors for developing pancreatic cancer includes modifiable and non-modifiable factors (4,16-19). Pancreatic cancer associated with familial pancreatic cancer or hereditary syndromes accounts for about 10% of cases (16,17).

Modifiable risk factors of developing pancreatic cancer included:

• Smoking.
• Obesity.
• Long-standing diabetes mellitus.
• Heavy alcohol use.
• Chronic pancreatitis.

Non-modifiable risk factors of developing pancreatic cancer included:

• Hereditary breast and ovarian cancer (pathogenic alterations in BRCA1 and BRCA2).
• Hereditary pancreatitis (pathogenic alterations in PRSS1).
• Lynch syndrome [pathogenic alterations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, & PMS2) and/or EPCAM].
• Peutz-Jeghers syndrome (pathogenic alterations in STK11/LKB1 gene).
• Familial atypical multiple mole syndrome (pathogenic alterations in the cell cycle gene CDKN2A).
• Li-Fraumeni syndrome (germline mutations in TP53 gene).
• PALB2 mutations.
• ATM mutations.
• Familial pancreatic ductal adenocarcinoma (those families have at least two 1^st degree relatives with pancreatic ductal adenocarcinoma, but do not have a known predisposing germline mutation).

Presentations

The presenting symptoms of patients with pancreatic cancer are often subtle and nonspecific. Majority of pancreatic cancers (almost 70%) originated at the pancreatic head. Pancreatic head cancer often present with progressive obstructive jaundice, decreased appetite, tiredness, weight loss, and pancreatic exocrine insufficiency. Typically, the jaundice is painless in nature.

On the other hand, pancreatic cancers originated from the body and tail of pancreas often present with nonspecific symptoms, such as epigastric pain, back pain, weight loss, decreased appetite and tiredness (6,20). Due to its anatomical location, the symptoms take longer to develop not until the pancreatic tumor grow to a certain size or metastasize.

Pain with radiation to back is a poor prognostic symptom as there is a possibility of tumor involvement of adjacent nerve plexus. Sometimes, new-onset of diabetes mellitus or worsening of pre-existing diabetes mellitus may be a sign of pancreatic cancer and warrants further investigation for underlying cause also (21).

Therefore, no matter the location of the main tumor, if preliminary investigations cannot sort out the cause of persistent abdominal pain, either computed tomography (CT) scan or magnetic resonance imaging (MRI) is needed to rule out the possibility of pancreatic cancer.

Diagnostic techniques and imaging

A high-quality fine cut pancreatic protocol CT scan including thorax, abdomen and pelvis is the primary imaging modality for: (I) diagnosis; (II) staging; (III) assess resectability of pancreatic cancer, including vascular anatomy, relationship of tumor and major vessels; and (IV) assess any complications due to pancreatic cancer including biliary obstruction, gastric outlet obstruction, and nerve plexus involvement. The circumferential tumor-vessel involvement by measuring the degree of contact between the pancreatic tumor and adjacent blood vessels [i.e., the portal vein (PV) and superior mesenteric vein (SMV) as well as the celiac artery, common hepatic artery (CHA), gastroduodenal artery (GDA) and superior mesenteric arteries (SMAs)] is categorized as either: (I) uninvolved; (II) abutted (abutment implies ≤180° of circumferential tumor-vessel involvement); or (III) encased (encasement implies >180° of circumferential tumor-vessel involvement) (Figures 1-3). MRI and CT scan in assessing resectability and vascular relationship for pancreatic cancer are comparable (22-24). However, MRI has advantages in better detection of small, non-contour-deforming tumors, in characterizing indeterminate pancreatic findings in CT scan and in diagnosis of liver metastases (25,26).

Figure 1 Pancreatic tumor encasing PV-SMV. PV, portal vein; SMV, superior mesenteric vein.

Figure 2 Pancreatic tumor abutting SMV & SMA. SMA, superior mesenteric artery; SMV, superior mesenteric vein.

Figure 3 T4 pancreatic tumor encasing PV & abutting CHA/CA. PV, portal vein; CHA, common hepatic artery; CA, celiac artery.

Visualization of an obstructed biliary tree can be performed by endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP). ERCP has the additional role in getting brush cytology of biliary stricture and insertion of biliary stent for biliary decompression.

¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT and endoscopic ultrasonography (EUS) are not considered a routine staging tool currently. They are supplementary investigations to CT scan or MRI (27). EUS has a role in obtaining a tissue diagnosis and getting tissue for molecular studies. Both fine-needle aspiration (EUS-FNA) and EUS guided fine-needle core biopsy (EUS-FNB) are safe and yield high diagnostic value (28,29). Even though the high diagnostic yield of EUS-FNA, it has potential limitations due to the cytological aspirations, such as inability to examine histologic architecture, and a small yield of tissue specimen for further immunohistochemical staining. EUS-FNB has the advantage of overcoming these potential limitations.

Serum carbohydrate antigen (CA) 19-9 (a cell surface glycoprotein complex), is a well-established biomarker for pancreatic cancer, and this tumor marker CA19-9 is routinely utilized during the diagnostic work-up of pancreatic cancer. CA19-9 is useful in monitoring treatment response and detecting recurrence. As a biomarker, its sensitivity is approximately 80%. It is well-known that Lewis and Secretor status can affect CA19-9 biosynthesis. CA19-9 has limitations for its clinical use for diagnosis and screening, including false positive elevation in patients with benign biliary, pancreatic and gastrointestinal disease, false negative results in patients with Lewis (a−b−) genotype, and its poor positive predictive value (72.3%) (30,31). These limitations make CA19-9 not a good cancer-specific biomarker. Recently, there is a promising development in the field of early detection of pancreatic cancer using diagnostic biomarkers, such as the detection of microRNA (miRNA) in serum and circulating tumour cells (32,33). However, this development is still in an initial phase.

Staging system

The staging system of pancreatic cancer is based on the American Joint Committee on Cancer (AJCC) Staging Manual (8^th edition) (34). Stages T1 to T3 are defined only by the size of tumor (T1: ≤2 cm; T2: >2 cm–4 cm; T3: >4 cm). T4 is defined when tumor involves large blood vessels (celiac axis, CHA, and/or SMA) [T1 further divided into T1a (≤0.5 cm), T1b (>0.5–<1 cm), and T1c (1–2 cm) to encompass those small invasive carcinomas increasingly detected in association with cystic neoplasms of pancreas].

The N classification is divided into N0, N1 (1–3) and N2 (>3).

AJCC staging groupings are defined as follow:

• Stage IA: T1N0M0;
• Stage IB: T2N0M0;
• Stage IIA: T3N0M0;
• Stage IIB: T1-3N1M0;
• Stage III: T1-3N2M0 or T4, any N, M0;
• Stage IV: any T, any N, M1.

Management

Pancreatic cancer basically divides into resectable disease, borderline resectable disease, unresectable locally advanced disease, and metastatic disease. Resectability for localized disease bases on the extent of adjacent arterial and venous involvement by tumor. For resectable pancreatic cancer, radical resection of pancreatic cancer with adjuvant systemic chemotherapy currently remains the standard treatment approach and is the only chance for long-term survival. A borderline resectable pancreatic cancer (5–10%) is a tumor with limited vascular involvement that is technically resectable but with a high chance of positive resection margins. Many groups have proposed various definitions of borderline resectable pancreatic cancers (35-41) (Table 2). The optimal treatment strategy for borderline resectable pancreatic cancer is still uncertain. Traditionally, “upfront surgery” is the main treatment of choice. Identifying borderline resectable disease is important because a vascular resection +/− reconstruction is more likely needed at the time of pancreatoduodenectomy, and instead of a traditional “upfront surgery” approach, these patients may benefit from neoadjuvant treatment to increase the chance of R0 resection and decrease the surgical morbidity. However, the role and advantages of neoadjuvant treatment in resectable pancreatic cancer and borderline resectable pancreatic cancer remains unclear. There is increasing evidence showing benefits of neoadjuvant therapy in borderline resectable pancreatic cancer. For unresectable locally advanced pancreatic cancer, and metastatic disease, systemic chemotherapy is the choice of treatment. Surgical resection can be considered for those down-staged from unresectable locally advanced disease to resectable disease.

Surgery

For resectable pancreatic cancer, radical resection of pancreatic cancer with adjuvant systemic chemotherapy remains the current standard treatment approach and is the only chance for long-term survival, even there is a high rate of recurrence (42). However, only small proportion of patients (10–20%) with pancreatic cancer are found to be resectable during the diagnosis. Tumors localised to pancreatic head or uncinate process can be treated with pancreaticoduodenectomy. Pancreaticoduodenectomy is the standard of surgical approach for pancreatic head cancer. Pancreaticoduodenectomy with vein resection and reconstruction is needed, in case of locally advanced tumor involving PV/SMV with adequate inflow and outflow veins for reconstruction, and the tumor does not involve SMA/CHA. Arterial resection with pancreatectomy remains controversial due to (I) increased surgical morbidity and mortality; and (II) unclear oncologic and survival benefit (43-45). Nevertheless, pancreatectomy with arterial resection continues to be performed at expert centers with acceptable reported outcomes in order to extend the indications and benefits of surgery to more patients. Importantly, combined venous/arterial resections should only be performed for extremely selected cases at expert centers. Its benefits and risks should be well balanced. Pancreatic cancer over the body and tail are treated with a radical distal pancreatectomy, often combined with splenectomy. Advances of pancreatectomy have been made over the past decade in the safety and efficacy of surgery and have resulted in surgical mortality of <3% and 5-year survival approaching 30% after resection with adjuvant systemic chemotherapy. The optimal number of lymph nodes for analysis and accurate tumor staging following standard pancreaticoduodenectomy and distal pancreatectomy were reported to be ≥15, and ≥20, respectively (46,47). Pancreaticoduodenectomy with extended lymphadenectomy of pancreatic head cancer does not offer any survival advantage over standard lymphadenectomy, but it increased surgical morbidity instead (48-50). A negative resection margin (R0) is one of the critical factors determining the oncological outcomes (51,52). Minimally invasive pancreaticoduodenectomy and distal pancreatectomy are being performed increasingly to treat pancreatic pathologies, including both robotic and laparoscopic approaches. Its indications have steadily broadened to encompass other conditions including pancreatic cancer, and it has gained increased acceptance and popularity. The advantages of minimally invasive approach include less blood loss and shorter hospital stay with comparable surgical mortality and morbidity to open approach (53-58). More and more studies showed similar oncological outcomes between minimally invasive and open approach when the techniques are applied in appropriate patients (53-58). The other potential advantage of minimally invasive approach may be earlier recovery with avoiding delay in adjuvant treatment. Larger sized and well-organized studies are needed to evaluate the surgical and oncological outcomes. However, the technique of minimally invasive approach of pancreatectomy is challenging and it is important to be performed by credentialed surgeons at experienced centers.

Adjuvant therapy after surgery for resectable pancreatic cancer

The European Study Group for Pancreatic Cancer-1 (ESPAC-1) (Neoptolemos et al.) trial was the 1^st multicenter, randomized large-scale study to establish the use and benefit of adjuvant chemotherapy in resected pancreatic cancer (59,60). ESPAC-1 trial showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant fluorouracil plus folinic acid. ESPAC-3 trial (Neoptolemos et al.) compared adjuvant gemcitabine (n=537) with fluorouracil plus folinic acid (n=551) in patients with resected pancreatic cancer (61). There were no significant differences in overall survival, progression-free survival, global quality-of-life scores between both groups. However, there were significantly fewer treatment-related serious adverse events in gemcitabine group. Ninety-seven treatment-related serious adverse events in 77 patients (14%) in fluorouracil plus folinic acid group were reported while 52 treatment-related serious adverse events in 40 patients (7.5%) in gemcitabine group were reported. CONKO-001 (Charité Onkologie 001) compared adjuvant gemcitabine (n=179) with no adjuvant treatment (control) (n=175) in patients with resectable pancreatic cancer (62). After a median follow-up of 53 months, disease recurrences were happened in 133 patients (74%) in gemcitabine group and 161 patients (92%) in control group. Gemcitabine group had significantly better disease-free survival than control group (median, 13.4 vs. 6.9 months). Estimated 3-year/5-year disease-free survival rate was 23.5%/16.5% in gemcitabine group, and 7.5%/5.5% in control group, respectively. There was no difference in overall survival between gemcitabine group and control group (median survival, 22.1 vs. 20.2 months; estimated 3-year survival rate, 34% vs. 20.5%; 5-year survival rate, 22.5% vs. 11.5%). Grade 3/4 adverse events rarely occurred. There was no difference in quality of life. In their follow-up report, at a median follow-up of 136 months, gemcitabine group had significantly longer disease-free survival than control group (median, 13.4 vs. 6.7 months) (63). Adjuvant gemcitabine treatment was shown to have better overall survival than control group (5-year overall survival rate, 20.7% vs. 10.4%; 10-year overall survival rate, 12.2% vs. 7.7%). A multicentre randomized trial ESPAC-4 (Neoptolemos et al.) compared the uses of adjuvant gemcitabine plus capecitabine (n=364) with monotherapy gemcitabine (n=366) in patients with resected pancreatic cancer (64). After a median follow-up of 43.2 months, gemcitabine plus capecitabine group had significantly better overall survival than gemcitabine group (median, 28.0 vs. 25.5 months). Estimated 5-year overall survival rate was 28.8% for gemcitabine plus capecitabine group and 16.3% for gemcitabine group. Six hundred and eight grade 3/4 adverse events were reported by 63% of the patients in gemcitabine plus capecitabine group while 481 grade 3/4 adverse events were reported by 53.6% of the patients in gemcitabine group. Adjuvant gemcitabine plus capecitabine group was found to have a 21% reduction of mortality following recurrence compared with gemcitabine group (65). A multicentre randomized trial by Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group (Conroy et al.) compared adjuvant modified-FOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, leucovorin) (n=247) with monotherapy gemcitabine (n=246) in patients with resected pancreatic cancer (66). At a median follow-up of 33.6 months, modified-FOLFIRINOX group had significantly better disease-free survival than gemcitabine group (median, 21.6 vs. 12.8 months). The 3-year disease-free survival rate was 39.7% and 21.4%, respectively. Modified-FOLFIRINOX group also had a significantly better overall survival (median, 54.4 vs. 35.0 months; 3-year overall survival rate, 63.4% vs. 48.6%). Grade 3/4 adverse events happened in 75.9% of the patients in modified-FOLFIRINOX group and in 52.9% of the patients in gemcitabine group. Mortality due to adverse event of interstitial pneumonitis was reported in one patient in gemcitabine group. Later, the follow report of 5-year indicated that adjuvant treatment with modified FOLFIRINOX had significantly better survival than gemcitabine in patients with resected pancreatic cancer (67). At a median follow-up of 69.7 months, there were 367 disease-free survival events. Modified-FOLFIRINOX group had significantly better disease-free survival than gemcitabine group (median, 21.4 vs. 12.8 months; 5-year disease-free survival rate, 26.1% vs. 19.0%). The overall survival was also significantly better in modified-FOLFIRINOX group (median, 53.5 vs. 35.5 months; 5-year overall survival rate, 43.2% vs. 31.4%). Modified-FOLFIRINOX group had significantly better metastasis-free survival than gemcitabine group (median, 29.4 vs. 17.7 months) and had significantly better cancer-specific survival (median, 54.7 vs. 36.3 months).

The current evidence is based on a limited number of well-designed randomized controlled trials for each treatment regimen. The current recommended adjuvant chemotherapy for resected pancreatic cancer is either modified FOLFIRINOX for patients with good well-being and functional status, or gemcitabine plus capecitabine or monotherapy with gemcitabine for patients with suboptimal functional status.

Neoadjuvant therapy for resectable pancreatic cancer and borderline resectable pancreatic cancer

The potential advantages of neoadjuvant therapy before surgery include: (I) early treatment of micrometastasis; (II) decreased lymph node involvement; (III) decreased the difficulties of surgery after downsizing of the tumor; (IV) improved R0 resection rates; and (V) selection of patients with favorable tumor biology. In addition, a significant proportion of patients after pancreatectomy cannot receive adjuvant therapy as planned due to surgical complications and prolong hospital stay (68,69). The benefit of neoadjuvant therapy will give chance of these patients for perioperative systemic treatment. The potential drawbacks of neoadjuvant therapy is the disease progression to an unresectable stage during the period of receiving neoadjuvant treatment, and the patient will lose the chance of curative resection. Neoadjuvant therapy has been tested in resectable pancreatic cancer and borderline resectable pancreatic cancer. Due to the great variations of the case selection, bias in the studies, variations in treatment regimens, and without comparison with upfront surgery groups, comparison of these studies with a valid conclusion are very difficult.

SWOG/NCI S1505 (Sohal et al.) randomized patients with resectable pancreatic cancer to neoadjuvant FOLFIRINOX group (n=55) and gemcitabine with nab-paclitaxel group (n=47). SWOG/NCI S1505 showed 2-year overall survival rate of 47% and 48%, respectively (70). Among the 102 patients, preoperative chemotherapy was completed in 84% and 85% of patients, respectively; 73% and 70% of patients underwent resection, and 49% and 40% completed all treatment, respectively. SWOG/NCI S1505 did not show an improved overall survival with perioperative chemotherapy, compared with historical data from adjuvant treatment studies in resectable pancreatic cancer. PANACHE01-PRODIGE48 evaluated the safety and efficacy of two neoadjuvant regimens of modified FOLFIRINOX (n=70) or FOLFOX (fluorouracil, oxaliplatin, leucovorin) (n=50) relative to the current standard treatment (upfront surgery and adjuvant chemotherapy) (n=26) in patients with resectable pancreatic cancer. There was no significant differences in 1-year survival rates (modified FOLFIRINOX—84.1%, FOLFOX—71.8%, and upfront surgery—80.8%) (71). There was a 10% increase in 1-year event-free survival rate (51.4% vs. 41.7%) and a 3-month improvement in event-free survival (median, 12.4 vs. 9.2 months) between neoadjuvant modified FOLFIRINOX group and upfront surgery group. NEONAX (Seufferlein et al.) studied the outcome of patients with resectable pancreatic cancer receiving gemcitabine plus nab-paclitaxel, either perioperatively (two pre-operative and four post-operative cycles) or adjuvant (six cycles) (72). The primary endpoint of disease-free survival rate (intention-to-treat population) of 55% at 18 months was not reached in both groups (33.3% vs. 41.4%). The secondary endpoint of median overall survival (intention-to-treat population) numerically favored the neoadjuvant group (25.5 vs. 16.7 months). There was a difference in chemotherapy exposure with 90% in perioperative chemotherapy group completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in adjuvant chemotherapy group.

In the RCT PREOPANC (Versteijne et al.) trial, 246 patients with resectable pancreatic cancer and borderline resectable pancreatic cancer were randomized to neoadjuvant chemoradiotherapy (n=119) (gemcitabine for 3 courses, the 2nd combined with 15×2.4 Gy radiotherapy, followed by surgery and adjuvant gemcitabine for 4 courses) and upfront surgery (n=127) (upfront surgery with adjuvant gemcitabine for 6 courses) (73,74). Both groups have similar resection rate (61% vs. 72%). Neoadjuvant chemoradiotherapy did not increase the incidence of surgical morbidity or mortality (75). Neoadjuvant group had a significantly better R0 resection rate (72% vs. 43%). In neoadjuvant group, 55 (81%) of the 68 patients started adjuvant chemotherapy and 34 patients (62%) finished all cycles. In upfront surgery group, 65 (79%) of the 82 patients started adjuvant chemotherapy and 35 patients (54%) completed all cycles. By intention to treat analysis, 46% of the 119 patients in the neoadjuvant chemoradiotherapy group started adjuvant chemotherapy, while 51% of the 127 patients in the upfront surgery group started adjuvant chemotherapy. The proportion of patients with serious adverse events was similar (52% vs. 41%). Neoadjuvant group had a significant better disease-free survival and locoregional failure-free interval. Neoadjuvant group also had a significant lower rates of pathologic lymph nodes, venous invasion and perineural invasion. After a median follow-up of 59 months, mortality was happened in 93 (78%) in neoadjuvant group and 117 (92%) in upfront surgery group. By intention to treat analysis, the median overall survival had no significant difference (15.7 vs. 14.3 months). Neoadjuvant group and upfront surgery group had an estimated 3-/5-year survival rates of 27.7%/20.5%, and 16.5%/6.5%, respectively. The limitation of this study was the use of adjuvant gemcitabine monotherapy, which is not considered as standard treatment regimen nowadays.

In phase 2 RCT ESPAC5 (Ghaneh et al.), 90 patients with borderline resectable pancreatic cancer were randomly assigned to immediate surgery (n=33), and three different types of short-course neoadjuvant therapy—gemcitabine plus capecitabine (n=20), FOLFIRINOX (n=20), and capecitabine-based chemoradiation (n=17) (76). Four patients were excluded from intention-to-treat analysis. No significant difference in resection rates (68% vs. 55%) and R0 resection rates (14% vs. 23%) between immediate surgery group and neoadjuvant therapy group. Surgical complication rate and 30-day mortality was 43% and 0% of patients who underwent surgery, respectively. Six (13%) of 46 had partial response among the 46 (84%) of 55 patients having neoadjuvant therapy available for restaging. At median follow-up of 12.2 months, there was significant difference in 1-year overall survival rate (39% vs. 78% vs. 84% vs. 60%) for immediate surgery, gemcitabine plus capecitabine, FOLFIRINOX, and capecitabine-based chemoradiotherapy groups. There was significant difference in 1-year disease-free survival from surgery (33% vs. 59%) for immediate surgery and combined neoadjuvant therapies. Two patients in immediate surgery group and 1 patient in FOLFIRINOX group had local recurrence. Nineteen (24%) of 78 patients (immediate surgery group, n=2 and combined neoadjuvant therapy groups, n=17) had a grade ≥3 adverse event. The most common adverse events were neutropenia, infection, and hyperglycaemia. ESPAC5 supported the use of short-course neoadjuvant chemotherapy (either gemcitabine plus capecitabine or FOLFIRINOX) for patients with borderline resectable pancreatic cancer.

Based on the current evidence, there is increasing evidence showing benefits of neoadjuvant therapy in borderline resectable pancreatic cancer. The optimal neoadjuvant treatment regimen was not certain yet. The use of neoadjuvant therapy in resectable pancreatic cancer has been restricted to clinical trials, as the data are limited and no clear benefits have yet been shown in resectable pancreatic cancer.

Systemic therapy for metastatic pancreatic cancer

At the time of diagnosis, approximately 50% of patients with pancreatic cancer present with distant metastases. Systemic therapy remains the primary treatment modality aiming at palliating symptoms and prolonging survival.

Von Hoff et al. randomized patients (Karnofsky performance-status score of ≥70) with metastatic pancreatic cancer to gemcitabine plus nab-paclitaxel (n=431) or monotherapy gemcitabine (n=430) (77). The median overall survival was significantly better in the gemcitabine plus nab-paclitaxel group (8.5 vs. 6.7 months). The 1-year survival rate (35% vs. 22%) and 2-year survival rate (9% vs. 4%) were significantly better in gemcitabine plus nab-paclitaxel group than gemcitabine group. Gemcitabine plus nab-paclitaxel group also had significantly better median progression-free survival (5.5 vs. 3.7 months), and response rate (23% vs. 7%). However, rates of grade 3/4 adverse events of peripheral neuropathy (17% vs. 1%), fatigue (17% vs. 7%) and neutropenia (38% vs. 27%) were increased.

Conroy et al. randomized patients (Eastern Cooperative Oncology Group performance status score of 0 or 1) with metastatic pancreatic cancer to FOLFIRINOX (n=171) or monotherapy gemcitabine (n=171) (78). As compared with gemcitabine, FOLFIRINOX group had a significant better overall survival (median, 11.1 vs. 6.8 months), progression-free survival (median, 6.4 vs. 3.3 months), and objective response rate (31.6% vs. 9.4%). Grade 3/4 adverse events of neutropenia, neutropenic fever, thrombocytopenia, sensory neuropathy and diarrhea were significantly higher in FOLFIRINOX group, whereas grade 3/4 adverse event of elevated alanine aminotransferase levels was significantly higher in gemcitabine group.

Adverse events of FOLFIRINOX and gemcitabine-plus-nab-paclitaxel often lead to dose-reductions and limit their long-term use. Maintenance therapies aim to prolong progression-free and overall survival without compromising quality of life. Mutations in breast- and ovarian-cancer-predisposing genes (BRCA1 and, especially, BRCA2) are also associated with increased risk of pancreatic cancer, and are present in 5–9% of patients with pancreatic cancer. The protein products of BRCA1 or BRCA2 genes are responsible in DNA damage response and repair of double-strand DNA breaks through homologous recombination. Golan et al. randomized metastatic pancreatic cancer patients with mutations in BRCA1 or BRCA2 genes that had not progressed during 1^st-line platinum-based chemotherapy to receive maintenance poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor—olaparib (n=92) or placebo (n=62) (79). The olaparib group had a significantly better progression-free survival than control group (median, 7.4 vs. 3.8 months). An interim analysis of median overall survival showed no difference between the 2 groups (18.9 vs. 18.1 months). The incidence of grade 3/4 adverse events in olaparib group and control group was 40% and 23%, respectively, and 5% and 2% of the patients were discontinued from the trial intervention due to adverse events, respectively.

Nanoliposomal irinotecan (nal-IRI) is a novel formulation of irinotecan, in which encapsulating drug molecules within long-circulating liposome-based nanoparticles with resulting favorable pharmacokinetic and biodistribution characteristics with a higher intra-tumoural levels of both irinotecan and SN-38 (an active metabolite of irinotecan) than traditional irinotecan. NAPOLI-1 Study Group (Wang-Gillam et al.) randomized patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy to either nal-IRI plus 5-fluorouracil and leucovorin (5-FU/LV) (n=117), monotherapy nal-IRI (n=151), or 5-FU/LV (n=149) (80,81). After 313 events, nal-IRI + 5-FU/LV group had a significantly better median overall survival better than 5-FU/LV group (6.1 vs. 4.2 months), while monotherapy nal-IRI group and 5-FU/LV group had similar median overall survival (4.9 vs. 4.2 months). The most frequently occurred grade 3/4 adverse events in nal-IRI + 5-FU/LV group were neutropenia (27%), fatigue (14%), diarrhoea (13%) and vomiting (11%). The survival benefits of nal-IRI + 5-FU/LV vs. 5-FU/LV were maintained over an extended follow-up. Estimated 1-year overall survival rates of nal-IRI + 5-FU/LV group and 5-FU/LV group were 26% and 16%, respectively.

The recommended first line chemotherapy for patients with metastatic pancreatic cancer is either FOLFIRINOX and gemcitabine plus nab-paclitaxel for patients having good functional status, or monotherapy gemcitabine for patients having suboptimal functional status. The evidence is based on a limited number of well-designed randomized controlled trials for each treatment regimen. Although modified FOLFIRINOX regimens have not been compared with traditional FOLFIRINOX in prospective randomized trials, it appears to be less toxic and data from retrospective studies showed similar outcomes (82,83). Nal-IRI + 5-FU/LV is a second line option of treatment for patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy. Recently, olaparib has been demonstrated to improve progression-free survival when used as a maintenance treatment in the subgroup of metastatic pancreatic cancer patients with BRCA1 or BRCA2 genes mutations had not progressed for at least 16 weeks during 1^st-line platinum-based chemotherapy. The decision to continue treatment with chemotherapy or change to maintenance therapy with olaparib should be based on a discussion between the patient and the oncologist, and the consideration of the response to chemotherapy and the tolerance and adverse events associated with chemotherapy.

Recently, the Food and Drug Administration (FDA) approved the use of pembrolizumab (an anti-programmed-death receptor 1, anti-PD-1) for patients with any microsatellite instability (MSI) high tumors, including pancreatic cancer. Phase 2 study KEYNOTE-158 recruited 233 patients with microsatellite instability-high (MSI-H)/DNA mismatch repair (dMMR) noncolorectal cancer (84). Among the study group, 22 patients (9.4%) had pancreatic cancer. Overall, 151 patients (64.8%) and 34 (14.6%) had treatment-related adverse events and grade 3 to 5 treatment-related adverse events, respectively. Eighteen patients (7.7%) had serious adverse events, and 22 (9.4%) discontinued trial intervention due to treatment-related adverse events. One patient (4.5%) and 3 patients (13.6%) with pancreatic cancer had complete response and partial response, respectively. Median progression-free survival, overall survival and duration of response were 2.1, 4 and 13.4 months, respectively. Follow up study showed that ≥3-year overall survival rate and ≥3-year progression free survival rate were 22.7% and 0%, respectively (85). Evidence about pembrolizumab usage for pancreatic cancer is still limited. More immunotherapy data in in pancreatic cancer treatment is pending.

At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first “tumor agnostic” drugs approved for pan-cancer use. Recently, FDA also approved the use of larotrectinib or entrectinib for patients with any tumors harboring a NTRK gene fusion in a second-line setting, including pancreatic cancer, in 2018 and 2019, respectively (86-89). However, the data for pancreatic cancer is still very limited.

In Drilon et al., a total of 55 patients (aged 4 months–76 years old) harboring 17 unique TRK fusion-positive tumor types were recruited and treated (86). The overall response rate according to independent review and investigator assessment was 75% and 80%, respectively (87). At 1 year, 71% and 55% of the responses were ongoing and maintained progression-free, respectively. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response were continuing treatment or had undergone operation with curative intent. Adverse events were mainly grade 1, and no grade 3/4 adverse event that was considered by the investigators to be related to larotrectinib occurred in >5% of patients. No patient discontinued larotrectinib owing to treatment-related adverse events. In a pooled analysis of three phase 1/2 clinical trials, 159 patients with TRK fusion-positive cancers were recruited and received larotrectinib. The objective response rate according to investigator assessment was 79% (complete responses—16%). In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3/4 larotrectinib-related adverse events were increased alanine aminotransferase level (3%), decreased neutrophil count (2%) and anaemia (2%). The most common larotrectinib-related serious adverse events were increased aspartate aminotransferase level (<1%), increased alanine aminotransferase level (<1%), and nausea (<1%). No treatment-related deaths occurred.

In a pooled analysis of three phase 1/2 clinical studies, a durable overall response rate of 57%, including a partial response rate of 50% and complete response rate of 7%, among 54 entrectinib-treated patients with 10 different tumor types and 19 different histologies harboring an NTRK fusion recruited after a median follow-up of 12.9 months (88,89). Median duration of response was 10 months. The most common serious treatment-related adverse events were nervous system disorders [3 of 68 patients (4%) in the NTRK fusion-positive safety population and in 10 of 355 patients (3%) in the overall safety-evaluable population]. The most common treatment-related grade 3/4 adverse events in both safety populations were increased weight [7 of 68 patients (10%) and 18 of 355 patients (5%)], and anaemia [8 (12%) and 16 (5%)]. No treatment-related mortality happened.

Palliation of complications of advanced pancreatic cancer

For patients with unresectable advanced pancreatic cancers, biliary obstruction, duodenal obstruction, and pain are the possible complications that needed to be managed. An appropriate modality of treatment should be chosen with consideration of the patient’s physical and functional status, the expected life expectancy, expertise availability, disease status and anatomical configuration. Psychosocial support to the patients and family is also important for patients with advanced disease.

Limitations

The main limitation of this review is that it is a narrative review rather than a systematic review. Currently, the treatment regimens and end-point measurements were too heterogenous to perform a systematic review. The number of studies for each treatment was small also. In future, if there is a greater number of randomized trials and well-designed nonrandomized comparative studies, systematic review with meta-analysis about pancreatic cancer treatment will be more useful.

Conclusions

Pancreatic cancer is a challenging disease for management. Radical surgery itself is not enough for prolong survival. The improvement of chemotherapy, target agents and immunotherapy with multidisciplinary approach for pancreatic cancer patients will be the only solution for improvement of their quality of life and survival outcomes.

The adoption of adjuvant treatment for operable disease and systemic treatment for inoperable disease is based on the published randomized trials. The adoption of neoadjuvant treatment and new treatment modalities such as target agents and immunotherapy is still limited by small number of studies with favorable outcomes. In the coming time, more well-designed large-scale studies are needed to give more evidence for the literature.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-23-94/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-94/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-94/coif). E.C.H.L. serves as an unpaid editorial board member of Chinese Clinical Oncology from December 2022 to November 2024. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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