Pancreatic cancer

Pancreatic cancer (PC) remains a highly lethal malignancy. In the US, the 5-year survival rate at the time of diagnosis is 10% , since almost 80-85% of patients have unresectable or metastatic disease.

Even for the small subgroup of patients with resectable PC, the prognosis remains poor, since only 20% survive 5 years after surgery.

Advances in the last decade in diagnosis, perioperative management, radiotherapy techniques and systemic therapies for advanced disease have gained importance, but with a modest impact on patient outcomes.

The authors state that “new screening strategies for high-risk patients are desperately needed to detect pancreatic tumors in early stages, and thus have a clinically significant impact.

According to the American Cancer Society , PC is third in prevalence, behind lung and colorectal cancers. It is the seventh leading cause of cancer death in both sexes, worldwide. In Europe, PCa is expected to soon overtake breast cancer as the third leading cause of cancer death. Certain variables, such as race, marital status, and insurance level, have been found to affect outcomes in patients diagnosed with CP.

Modifiable risk factors associated with PC include obesity, type 2 diabetes, and smoking.

A National Institutes of Health cohort study showed that patients who were overweight or obese were more likely to develop CP, compared to patients with a normal body mass index. Fatty infiltration of the pancreas has been correlated with the development of pancreatic intraepithelial neoplasias (NIEP), precursors of pancreatic ductal adenocarcinoma (PDA).

CP has also been linked to genetic factors . BRCA2 mutations are the most common hereditary risk factor for CP, with a relative risk of 3.5 for developing the disease. Germline mutations in CDKN2A (atypical multiple mole familial melanoma) were also observed to be associated with a 17% increased risk of PCa.

Germline mutations in genes important for DNA damage response (e.g., ATM) and DNA repair (e.g., MLH1, H2, MSH6, as seen in Lynch syndrome, PALB2) also are associated with a higher risk of developing CP. Patients with Lynch syndrome have an almost 8.6-fold higher risk of PC at age 70 than the general population, with tumors exhibiting microsatellite instability, particularly sensitizing them to checkpoint inhibitor therapy.

Chronic pancreatitis is a well-known risk factor for CP. Patients with hereditary pancreatitis have a 40% lifetime risk of CP. There are other well-known inherited genetic alterations for CP. Thus, important American scientific entities recommend germline testing for all patients diagnosed with CP.

The majority of PCs are ductal adenocarcinomas and therefore represent malignancy of the exocrine pancreas, while a minority are neuroendocrine tumors.

Most ADPs originate in precursor lesions , called NIEP, which progress in a stepwise process, through the acquisition of genetic alterations, and culminate in the development of overt ADPs.

A minority of these adenocarcinomas arise from cystic neoplasms, such as intraductal papillary mucinous neoplasms. However, these neoplasms are often found to be localized as ADP and could have a different genetic signature, suggestive of divergent development.

The molecular characterization of grade 1 and 2 progression from NIEP to ADP has been well described in the literature; They are characterized by point mutations in the KRAS oncogene (found in almost 90% of ADPs). Grade 1 NIEP has the characteristic feature of telomere shortening, perhaps with cells that predispose to the development of mutations, through chromosomal instability.

Early NIEP, particularly grade 2 lesions, are associated with the inactivation of 2 specific chromosomally dependent inhibitors of cyclin-dependent kinases. The later stages of carcinogenesis, which represent grades 3 and 4 of the NIEP, have characteristic genetic identifying marks, as do 70% of the ADPs.

Genomic advances have facilitated attempts to promote PC subclassification according to different molecular signatures. Previous work using gene expression profiling of primary ADP samples, along with murine cell lines, identified 3 molecular subtypes of disease, each with different clinical outcomes: classical, quasi-mesenchymal, and exocrine-like.

Another aspect of the research identified 2 molecular subtypes : classical and a basal subset. The latter has clinical and molecular characteristics similar to basal subsets found in other solid tumors, such as breast cancer and bladder cancer. Another categorization scheme based on a genomic analysis of 456 ADP samples classified the tumors into 4 distinct subtypes: squamous, pancreatic progenitor, immunogenic, and aberrant differentiated exocrine-endocrine.

It has been proven that the molecular appearance of squamous-like, basal and quasi-mesenchymal cancers was similar, so it is likely that they represent the same subgroup of ADP. These tumors were also similar in their clinical outcomes, portending a poor prognosis and worse response to chemotherapy, compared with the pancreatic progenitor or classical subgroups. Finally, a molecular analysis of 309 resected ADPs confirmed the presence of the pancreatic and basal progenitor, squamous and quasi-mesenchymal subgroups.

A more in-depth study characterized the tumor microenvironment and identified 3 more subgroups: desmoplastic, classical immune, and stromal-activated. The clinical implications of this work are still in their early stages and these molecular data cannot yet be translated in a way that allows prediction and therapeutic decisions to be made.

> Presentation and symptoms 

Consistent with the fact that only a minority of patients diagnosed with PC have surgically resectable disease, it is frequently asymptomatic or symptoms are few until the advanced stage.

Unfortunately, the authors say, symptomatic patients often have nonspecific symptoms: epigastric or back pain, nausea, bloating, a feeling of abdominal fullness, or changes in stool consistency: Symptoms are often attributed to other benign causes, which can delay the diagnosis.

> Diagnostic imaging

The recommended initial imaging technique for accurate and timely diagnosis of PC is multi-effector computed tomography (CT) angiography, using a pancreatic protocol, which has a sensitivity of at least 90%.

In general, pancreatic tumors are hypodense compared to the pancreatic parenchyma, while the dual phase of the protocol allows visualization of regional vessels, to evaluate staging and resectability.

Magnetic resonance imaging ( MRI) is an alternative modality that can provide a detailed evaluation of the biliary tract (eg, MR cholangiopancreatography), and has greater sensitivity for the detection of liver lesions.

Endoscopic ultrasound has   frequently been used as a complementary tool to identify regional lymph nodes and evaluate the relationship of tumors to nearby vascular structures. For patients with potentially resectable disease, endoscopic ultrasound with fine needle aspiration is a safe, high-throughput method for tissue confirmation.

If malignancy cannot be confirmed after several biopsies, initial systemic therapy or resection should not be delayed. In situations where tumor infiltration causes biliary obstruction, a biliary stent can be placed using endoscopic retrograde cholangiopancreatography.

On the other hand, this method has a sensitivity and specificity for the diagnosis of PC >90%. Routine biliary decompression is not recommended for patients undergoing surgical resection due to increased complications.

PET-CT (positron emission-CT) is not indicated for the diagnostic evaluation of PCa, but should be considered in patients at high risk of occult metastatic disease, such as those with carbohydrate antigen (CA) concentrations19-9 , proportional to the suspected tumor stage.

> Serum biomarkers

CA19-9 is a well-documented and validated serum biomarker associated with PC. It has a sensitivity of 79-81% and a specificity of 82-90% for the diagnosis of the disease in symptomatic patients.

Carcinoembryonic antigen ( CEA) and CA125 are nonspecific markers that may be elevated in patients with PC. Serial measurement of CA19-9 is useful for monitoring response to systemic treatment, in the neoadjuvant or metastatic setting, and is often an early reflection of response on imaging.

Elevated preoperative CA19-9 may also help identify patients who are less likely to achieve an R0 level with surgery (microscopically negative margin resection) and, after resection, may predict long-term survival. CA-19 concentrations could have prognostic value in patients with inoperable PC. Importantly, CA19-9 may be elevated in patients with biliary obstruction, highlighting limitations in this setting.

> Screening

Currently, there is no recommendation for PC screening in asymptomatic adults, mainly due to the low incidence in an unselected population.

However, screening is beneficial in asymptomatic high-risk individuals, using endoscopic ultrasound, MRI, or CT. A comparative study showed that ultrasound and MRI were more sensitive than CT for the detection of abnormalities.

In 2011, the International Cancer of the Pancreas Screening Consortium recommended that high-risk individuals (e.g., carriers of germline mutations or with a positive family history, or both) be screened with endoscopic ultrasound or MRI, or both. . However, the age to start screening and the optimal follow-up intervals were not established.

> Staging

Patients with PC can be classified according to the 8th edition of the American Joint Committee Cancer Staging Manual e. However, most doctors use the 4-level staging system , based on the resectability of the tumor: resectable, borderline resectable, locally advanced, and metastatic.

In 2017, the International Association of Pancreatology published a modified classification that expands the anatomic definition of borderline resectability, taking into account biological and patient risk.

Although routine laparoscopic evaluation of patients with resectable tumors to rule out occult metastases is not recommended, it can be performed if the patient is at high risk, determined by equivocal radiographic findings or elevated CA19-9. The decision about the optimal management of patients with localized disease should be made by a multidisciplinary team of experienced clinicians.

> Resectable and borderline resectable

Despite 5-year survival rates of 10 to 25% for patients who can undergo surgical resection, surgery remains the only treatment that has curative potential.

A multidisciplinary team must determine the resectability status. Tumors of the head of the pancreas are generally resected by pancreaticoduodenectomy, which includes resection of the head of the pancreas, the duodenum and proximal jejunum, the gall duct and gallbladder, and a segment of the stomach.

Laparoscopic and robotic-assisted techniques have been comparable, in terms of safety, to traditional open surgery.

A Mayo Clinic study found that laparoscopic pancreaticoduodenectomy was associated with less blood loss, shorter length of hospital stay, and better disease-free survival compared to open surgery. On the other hand, there is evidence that institutions with a high volume of pancreaticoduodenectomy (at least 30/year) show lower postoperative mortality.

Tumors located in the body or tail of the pancreas can be treated with a distal pancreatectomy, often combined with splenectomy. Vascular resections at the time of tumor resection are frequently performed to achieve negative surgical margins. Unlike venous resection, arterial resection could be associated with greater postoperative morbidity and should only be considered in high-volume surgical centers.

The role of systemic therapy in patients with resectability and borderline resectability has been the most studied in the postoperative stage. A European study (ESPAC) established that adjuvant chemotherapy, with fluorouracil plus folinic acid (leucovorin), resulted in a moderate improvement in overall survival, compared with no postoperative chemotherapy.

After the ESPAC-3 trial confirmed the efficacy of adjuvant gemcitabine, the ESPAC-4 study of patients randomized to adjuvant gemcitabine with or without capecitabine, an oral fluoropyrimidine, showed a median increase in overall survival of 25.5 months to 28 months.

In 2018, the PRODIGE-24 trial was published that compared 6 months of adjuvant therapy with modified fluorouracil plus leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) to gemcitabine monotherapy.

Combination therapy increased disease-free survival from 12.8 to 21.6 months and median overall survival from 35 to 54.4 months. Based on these data, 6 months of adjuvant therapy with FOLFIRINOX is recommended for patients who may have good performance status after ADP resection, at any stage.

In 2019, the APACT study concluded that 6 months of adjuvant gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) did not improve disease-free survival compared to gemcitabine alone.

Gemcitabine with or without capecitabine remains a therapeutic option for patients with contraindications to mFOLFIRINOX, or for those with suboptimal performance status. It has been proven that patients who started adjuvant therapy between 28 and 59 days after surgical resection had better survival than those who started before 28 or after 59 days.

Despite little high-level evidence to support its use, many high-volume surgical centers use neoadjuvant therapy in patients with resectable and borderline resectable tumors.

Targets of preoperative systemic therapy include patients excluded for rapidly progressive disease who would likely not benefit from major surgery, increasing the chance of achieving an R0 resection.

A retrospective review of patients undergoing resection found that those treated with neoadjuvant therapy improved overall survival compared with those who received adjuvant therapy. In 2020, the phase 3 PREOPANC-185 study was announced, in which neoadjuvant chemoradiation with gemcitabine was compared with immediate surgery, in patients with resectable and borderline resectable ADP.

Although there was no statistically significant difference in survival, neoadjuvant chemoradiation was associated with a higher rate of R0 resection and prolonged disease-free survival. In a subgroup analysis, patients with resectable PC had better overall survival with neoadjuvant therapy. Comparative studies of neoadjuvant therapy with initial surgical resection followed by adjuvant therapy are currently being performed.

> Locally advanced disease

At least one third of patients with PC present with locally advanced disease, usually due to extensive vascular involvement that precludes surgical resection.

Treatment for this group of patients primarily involves chemotherapy, a systemic therapy that has been approved in the metastatic setting, with gemcitabine plus nab-paclitaxel or FOLFIRINOX. Although a small minority of these patients have an excellent response to chemotherapy, and may be eligible for surgical resection, in the vast majority the disease is incurable.

The multicenter phase 2 LAPACT study evaluated induction with gemcitabine plus nab-paclitaxel in patients with locally advanced disease, followed by continued investigator’s choice chemotherapy, chemoradiation, or surgery, for patients without disease progression. The median time to therapeutic failure was 9 months, with a median overall survival of 18.8 months. Notably, of 17 patients undergoing resection, 7 achieved an R0 resection.

The role of chemoradiation for patients with locally advanced disease is somewhat controversial, as studies have yielded mixed results. In 2020, the LAP07 study concluded that chemoradiation did not prolong the survival of patients with locally advanced PC after treatment with systemic chemotherapy (gemcitabine with or without erlotinib), although patients treated with chemoradiation experienced better local control rates and longer time without treatment.

It is not yet clear whether these conclusions can be applied in the context of new combination chemotherapy regimens and improved radiotherapy techniques, such as stereotactic body radiation and proton therapy.

> Metastatic disease

Almost 50% of patients present with metastases at the time of diagnosis. Systemic chemotherapy remains the main therapeutic modality, aimed at alleviating cancer-related symptoms, prolonging life. In untreated patients with metastases, the FOLFIRINOX combination performed better than gemcitabine alone, with an improvement in median overall survival from 6.8 to 11.1 months.

Although gemcitabine plus nab-paclitaxel has never been compared in a clinical trial, in the real world, retrospective analyzes indicate that younger and fitter patients are more likely to receive FOLFIRINOX, with a greater tendency to improve overall survival in comparison with gemcitabine plus nab-paclitaxel. Gemcitabine monotherapy remains an option for patients whose performance status or comorbidities preclude combination chemotherapy.

5-9% of CP patients have somatic or germline mutations in the BRCA1 and BRCA2 genes. Data on PC and ovarian cancer indicate that a response occurs to PARP inhibition.

Data on the benefit of PARP inhibition as maintenance therapy in patients with somatic or germline mutations of BRCA1 or BRACA2 could provide support for targeted therapy. These findings led to the Phase 3 POLO study, which evaluated the role as maintenance therapy of olaparib, a PARP inhibitor, in patients with germline BRCA1 or BRCA2 mutations who did not progress after at least 16 weeks of treatment with First-line, platinum-based chemotherapy.

Compared with placebo, olaparib improved median progression-free survival from 3.8 to 7.4 months. No difference in overall survival was found between the groups, although survival data had not reached maturity at the time of publication. In December 2019, olaparib was approved in the US for use as a targeted first-line drug for PCa.

The only second-line therapy for metastatic PC that has shown a survival advantage is the combination of fluorouracil plus leucovorin, with nanoliposomal irinotecan.

In the NAPOLI-1 trial, in patients with metastatic disease who had progressed on gemcitabine-based therapy, there was an increase in median overall survival with fluorouracil plus leucovorin with nanoliposomal irinotecan, compared with fluorouracil plus leucovorin. For patients who progressed during first-line chemotherapy with FOLFIRINOX, gemcitabine is an appropriate second-line option for patients with good function.

> Supportive care

Supportive care is a crucial component of the management of patients with advanced PC. Pain is an almost universal symptom, even in the early stages of the disease. Management options include opioids and interventions such as celiac plexus neurolysis.

Relieving biliary obstruction with the placement of a stent can reduce the risk of cholangitis and ensure the safety of chemotherapy, preferably using metallic stents, due to their better patency and lower potential risk of infection. Patients with cholangitis usually present with an acute condition, which can be confused with the progression of advanced PC and must be treated due to its potential reversible infection.

Venous thromboembolism is a source of potential morbidity and mortality in patients with ADP, and although evidence supports rivaroxaban prophylaxis, the decision should be made on an individual basis, after weighing the potential benefit against the risks of bleeding complications. Depression, anxiety, anorexia and weight loss are also common symptoms that must be addressed by treating physicians, including the use of medications.

Obstruction of the main pancreatic duct can result in exocrine pancreatic insufficiency, manifested by abdominal pain, bloating, and steatorrhea. Pancreatic enzyme supplementation may improve fat absorption and these symptoms. When making a diagnosis of metastatic disease, the American Society of Oncology recommends goals for care and discussion of management, following full evaluation of symptoms, psychological status, and social support, and generally need for Palliative Care consultation.

Participation in this specialty has been found to be associated with reductions in intensive care unit admissions, near-death chemotherapy, multiple emergency department visits, and hospitalizations.

PC remains one of the most lethal neoplasms, responsible for significant morbidity and mortality worldwide. The sad reality, the authors say, is that most patients have advanced or metastatic disease at the time of diagnosis and, therefore, there is great interest in improving early detection.

Current guidelines recommend screening only in patients at high risk for PC (defined as having 2 or more first-degree relatives with this cancer or being carriers of a known germline genetic variant associated with an increased risk of PC, or both). factors).

Several groups are determining the validity of liquid biopsies as a less invasive modality for early detection, but circulating tumor DNA is only detectable in approximately 50% of patients with localized disease. Therefore, until now, attempts to use circulating tumor DNA have been limited by low sensitivity and specificity.

Advances in surgical technique offer an opportunity to improve outcomes for patients with locally advanced disease. The advent of neoadjuvant chemotherapy and improvements in arterial and venous reconstruction have made some tumors previously designated as inoperable now candidates for operation.

Similarly, preoperative modern radiation therapy (e.g., stereotactic body radiation therapy) and ablative radiation therapy may also have a role in improving outcomes in patients with locally advanced disease.

Finally, the authors state that more effective systemic therapies are strongly required for patients with metastatic disease. To that end, patients with adequate performance status should be considered candidates for clinical trials.

Currently, active work is being done to put into practice the developments in the molecular characterization of PC and targeted therapeutics. Research aimed at identifying crosstalk between tumor cells and the tumor microenvironment remains promising.

Immune checkpoint inhibitors have demonstrated durable clinical benefit. in a wide range of malignancies, but this benefit has not been achieved in ADP due, in part, to the complex and highly immunosuppressive effect of the PC microenvironment, which contains a large number of suppressors derived from myeloid cells, regulatory T cells, macrophages alternatively activated (M2 macrophages) and cancer-associated fibroblasts, all of which function to effectively dampen anti-tumor immune responses, promoting tumor proliferation and cell invasion.

The myeloid compartment suppressor using a CD40 antibody agonist, which serves to activate and polarize macrophages toward an M1 (anti-tumor) phenotype and away from an M2 (pro-tumor) phenotype, has demonstrated preclinical benefit. The ADP tumor microenvironment is also characterized by a paucity of quality infiltrating effector T cells. Several vaccines are being studied to induce the infiltration of effector T cells.

One of these approaches uses allogeneic pancreatic tumor cells, secreters of granulocyte-macrophage colony-stimulating factor, to induce T cell action against a wide repertoire of PCa antigens, but improvements have not yet been obtained for the clinical results.

Effective immunotherapeutic strategies may require a multifaceted approach that incorporates strategies to induce T cell infiltration (e.g., vaccines), combined with immunostimulants (e.g., checkpoint inhibitors), as well as strategies to target the immunosuppressive microenvironment (e.g., CD40 antibody agonists).

The authors highlight the disappointing results of several recent clinical trials involving the addition of novel therapies to chemotherapy. These agents included PEGPH20, an enzyme targeting stromal hyaluronic acid, pegilodecakin, a pegylated IL-10, ibrutinib, a Bruton’s tyrosine kinase inhibitor, and napabucasin, a STAT3 inhibitor, aimed at targeting the called cancer stem cells.

Several other novel therapeutic targets are under investigation. One of those molecules, called CPI-613 (devimistat), is an inhibitor of 2 key enzymes of the tricarboxylic acid cycle, pyruvate dehydrogenase and α-ketoglutarate.

This approach exploits the relative dependence of CP cells on mitochondrial metabolism. The ongoing AVENGER 500 trial evaluates the efficacy of FOLFIRINOX with or without CPI-613 and another novel approach targets heterogeneously dense pancreatic stroma resulting in decreased vascular perfusion and drug release.

Losartan , an angiotensin receptor blocker, has been shown to decrease collagen and hyaluronan production in the PC stroma, which subsequently results in decreased cleavage stress by improving their release. It is currently being evaluated in clinical trials combined with chemotherapy, immunotherapy and radiation in patients with PC.