Case-Based Review

Locally Advanced Pancreatic Cancer


 

References

INTRODUCTION

Pancreatic cancer is one of the most rapidly rising causes of mortality in the United States. In 2016, the number of deaths from pancreatic cancer exceeded those from breast cancer, making it the third leading cause of cancer-related death in the United States.1 It is projected that by 2020 pancreatic cancer will overtake colorectal malignancies to become the second most common cause of cancer death in this country.1,2 The term pancreatic cancer encompasses both exocrine and endocrine tumors. However, since 80% of pancreatic cancers are classified as pancreatic ductal adenocarcinoma (PDA), when speaking about pancreatic cancer most clinicians and scientists are referring to PDA.

Even with advances in chemotherapy and radiotherapy over the past decade, the only curative option for PDA is surgical resection. Unfortunately, only 20% of patients are appropriate surgical candidates at the time of diagnosis.3 Considering the lack of screening options and the ambiguity of symptomatology, roughly 4 out 5 patients with PDA are diagnosed as having locally advanced or metastatic disease that is initially not amenable to surgery.

Locally advanced pancreatic adenocarcinoma presents unique challenges in management and treatment. Treatment options include multi-agent chemotherapy, chemoradiation, or radiotherapy. Some patients can be successfully down-staged with these therapies and be deemed surgical candidates. Other challenges include selecting the appropriate sequence of therapies and stratifying therapies based on comorbidities. In this article, we review the epidemiology, biology, and diagnostic approach to PDA and focus on current treatment strategies for locally advanced pancreatic cancer (LAPC).

EPIDEMIOLOGY

In 2012, GLOBOCAN estimated that PDA caused 331,000 deaths per year, accounting for 4% of all worldwide mortality.4,5 Despite high incidence rates internationally, PDA is a disease of Western and industrialized nations. In the Unites States, PDA is a malignancy of middle to late adulthood, with a sharp upsurge in incidence after age 50 years.6 More than one third of new cases are diagnosed in patients older than 70 years, and more than half of patients diagnosed are older than 60 years of age.2 The incidence of pancreatic cancer is fairly equal among men and women, with a slightly higher rate for the male sex. It has an incidence preference for African-Americans by 4.8 cases per 100,000 persons nationally.7

Risk factors for the development of exocrine pancreatic cancer include hereditary disposition, underlying medical conditions, and environmental factors. One of the most significant environmental risk factors for the development of PDA is smoking,8 which is associated with up to 25% of all cases.9 Smoking cessation leads to a rapid reduction in risk for pancreatic cancer, with the risk among former smokers approaching that for never smokers less than 10 years after quitting.9 Other environmental factors that contribute to the development of pancreatic cancer include increased body mass index, a high-salt and high-saturated fat diet, heavy alcohol intake, and increased utilization of nonsteroidal inflammatory drugs.10–13

There is a strong association between new-onset diabetes and increased risk for developing PDA.14,15 Data also suggest that diabetes may be a risk factor and/or a consequence of tissue destruction that arises during the development or progression of PDA.16,17 Interestingly, ABO blood grouping is another underlying medical disposition that confers an altered risk profile. Studies have shown that patients with blood group O were less likely than those with type A, B, or AB to develop pancreatic cancer.18

Genetic predisposition syndromes can elevate an individual patient’s risk for developing PDA. Genetic syndromes and gene alterations that increase the risk for PDA include BRCA1/2, Peutz-Jeghers syndrome, and Lynch syndrome risk.19–21 Up to 10% to 15% of PDA cases may be due to an inherited familial cancer.22 Having a first-degree relative with PDA increases the odds of developing PDA 1.76-fold compared to those without a family history.23 The exact biologic and molecular mechanisms of familial pancreatic cancer are unclear. It is estimated that about 10% of patients with familial pancreatic cancer (FPC) carry BRCA2 mutations.24 Individuals at risk for FPC should undergo genetic screening for the presence of the most frequently inherited pancreatic cancer susceptibility genetic defects: BRCA2, PALB2, and ATM germline mutations.25 Carriers of BRCA2, who are also at increased risk for developing breast, ovarian, and prostate cancer, should be monitored closely. Of all hereditary conditions, hereditary pancreatitis confers the highest risk for developing PDA, with an approximate risk elevation of 40% to 50%.26,27 Although several genetic predisposition syndromes have been identified, most cases of pancreatic adenocarcinoma are thought to be sporadic.

CANCER BIOLOGY AND PATHOLOGY

The pathologic predecessor of PDA is pancreatic intraepithelial neoplasia (PIN). With further dysplastic changes that result from increasing genetic alterations, these precancerous lesions progress from low- to high-grade and finally to adenocarcinoma. More than 90% of all PINs across all grades have oncogenic KRAS mutations.28 Additionally, inactivating mutations in the tumor suppressor genes SMAD4, p53, and CDKN2A are found with increasing frequency in higher grade PINs. The frequency and presence of mutations in both oncogenes and tumor suppressor genes in precursor neoplasias mirror the genetic mutations noted in advanced PDA.29 Among all mutations, KRAS is the most common and most functionally important for pancreatic cancer cell survival. KRAS mutations not only have profound effects on downstream mediators of tumor growth and metastasis, but they are implicated in reprograming of cellular metabolism.30,31

Pancreatic adenocarcinoma has a unique microenvironment that makes it a difficult target for current therapeutic modalities. First, it is one of the most stroma-rich malignancies. The dense stroma surrounding pancreatic tumor cells leads to increased tumor pressures and alterations in tumor vascular perfusion.32 It also serves as a barrier that prevents chemotherapeutic drugs from reaching the tumor cells. Thus, clinical trials are under way to investigate agents such has hyaluronidase, which may degrade components of the extracellular matrix that supports thestromal environment. Additionally, there is data to suggest that the microenvironment of PDA downregulates immune monitoring, leading to further tumor growth.27,33 The molecular, cellular, and immunologic complexity of PDA may contribute to its resistance to traditional therapeutics.

EVALUATION AND DIAGNOSIS

CASE PRESENTATION

A 61-year-old man with a history of type 2 diabetes mellitus and chronic tobacco use presents to the emergency department (ED) with a 4-month history of progressively worsening abdominal discomfort and fatigue. He has also noticed darkening of his urine and slight yellow discoloration of his eyes. His weight measured 5 months ago in his primary care physician’s office was 91 kg (200 lb, BMI 29.5) and in the ED is 75 kg (165 lb, BMI 24.4). He has noticed bulky, malodorous, oily stools for about 2 months. Preliminary laboratory studies reveal elevated levels of total bilirubin (2.7 mg/dL) and alkaline phosphatase (204 IU/L). Transabdominal ultrasound (US) is obtained and reveals a 3-cm pancreatic mass with biliary tract dilation.

  • Does this patient have pancreatic cancer?

CLINICAL SIGNS AND SYMPTOMS

Establishing the diagnosis of pancreatic cancer in a patient who presents with a high index of suspicion is critical. Patients with pancreatic cancer usually present after a period of nonspecific and vague symptoms, which typically are experienced as abdominal discomfort, weight loss, and weakness. It is estimated that approximately 25% of patients may complain of vague abdominal pain up to 6 months prior to diagnosis. Up to 15% of patients may seek medical attention more than 6 months prior to establishing a diagnosis of PDA.34 The most common symptoms associated with pancreatic cancer in order of decreasing reported frequency are weight loss, anorexia, abdominal/epigastric pain, dark-colored urine, jaundice, nausea, back pain, and diarrhea with associated steatorrhea.35 Upwards of 15% of patients present with painless jaundice, a term that is often associated with pancreatic cancer.36 On exam these patients may have scleral icterus, sublingual jaundice, epigastric pain on palpation, weight loss, hepatomegaly, lymphadenopathy and a nontender, distended, palpable gallbladder (also known as Courvoisier sign).34 Abdominal signs and symptoms arise from tumor growth into surrounding vessels, tissues, and ducts within the abdominal cavity. Compression of the common bile duct accounts for the development of jaundice. Tumor growth around the stomach and duodenum can lead to delayed gastric emptying and subsequently nausea and vomiting. Constriction of the pancreatic duct leads to pancreatic insufficiency, precipitation of weight loss, and steatorrhea. Pancreatic insufficiency can worsen abdominal pain, and lead to increased weight loss and flatulence.

Less common symptoms include pain, erythema, and edema involving the lower extremities, which may be reflective of migratory thrombophlebitis (commonly known as Trousseau syndrome). Thromboembolic disease, including pulmonary embolism, portal vein, and deep vein thromboses are frequently encountered complications of pancreatic cancer. The incidence of thromboembolic events in patients with PDA has been reported to be as high as 54%.37 Of all signs encountered, weight loss is the most common and most profound. Patients with advanced PDA have severe degrees of cachexia. Some patients present with as much as a 5 kg/m2 decrease in their BMI from pre-illness baseline BMI, and lose another 3 to 4 kg/m2 through disease progression.38 At the time of diagnosis, many patients have already undergone significant weight loss, which can have substantial implications on treatment planning and clinical outcomes.

  • What other studies can be done to assist in making the diagnosis?

LABORATORY ABNORMALITIES AND TUMOR MARKERS

Elevations in alkaline phosphatase, γ-glutamyltransferase (GGT), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), and direct fractions of bilirubin are common in patients with PDA. Patients will usually have an obstructive pattern on their liver panel, with predominant elevations in direct bilirubin, alkaline phosphatase, and GGT, as compared with AST and ALT. Other baseline laboratory studies, including a complete blood count and basic metabolic panel, should be obtained because patients commonly have thrombocytosis, anemia, and electrolyte abnormalities due to the tumor itself and pancreatic insufficiency (Table 1).

Table 1 Diagnostic Tests used in the Evaluation of Pancreatic Adenocarcinoma

Measurement of glycated hemoglobin (HBA1C) is an emerging and important diagnostic test in the diagnosis of pancreatic cancer. Recently, data has emerged to suggest that new-onset diabetes is present in about 50% of patients diagnosed with pancreatic cancer.39 The temporal relationship of pancreatic cancer and diabetes is supported by evidence showing that patients who undergo resection commonly have resolution of their diabetes.17 This study suggested that hyperglycemia, elevated HBA1C, and symptoms of diabetes in patients older than 50 years may identify patients who have early pancreatic cancer. The entity of pancreatic cancer–associated diabetes needs to be better defined and the algorithmic approach to evaluation and diagnosis, utilizing signs, symptoms, and laboratory values associated with diabetes, needs to be clearly established.

The only serum marker for PDA is carbohydrate antigen 19-9 (CA 19-9), also known as sialylated Lewis antigen or cancer-associated antigen. It was first identified in pancreatic cancer patients in 1981.40,41 The sensitivity and specificity of CA 19-9 ranges from 70% to approximately 90%.42,43 Hereditary predispositions and comorbid disease cross-reactivity contribute to the diminished sensitivity and specificity of CA 19-9. In about 5% to 10% of the population, CA 19-9 is not expressed (Lewis antigen A and B negative). Additionally, since CA 19-9 is expressed in the cells that line the biliary tree, diseases that lead to pancreatic or liver inflammation may falsely elevate CA 19-9.44 As a result, CA 19-9 is not an ideal screening test. However, data has shown that CA 19-9 may have prognostic value postoperatively and serve as a marker for therapeutic response.45,46

  • Is biopsy needed for this patient and if so, what is the most appropriate technique?

ENDOSCOPIC ULTRASOUND

Generally, diagnosis with tissue is not necessary for patients who clearly have resectable disease and will proceed directly to surgery for management. Nevertheless, it is still commonly obtained in this group of patients. However, in patients with LAPC or with features suggestive of LAPC, such as tumor approximation to critical vessels such as the superior mesenteric artery (SMA) or celiac axis, biopsy is necessary. These patients will receive neoadjuvant therapy, and biopsy is important in establishing a diagnosis. The ideal way to obtain a biopsy is through fine-needle aspiration (FNA) or biopsy (FNB) utilizing endoscopic ultrasound (EUS). Percutaneous and computed tomography (CT)–guided FNB can also be used to obtain a biopsy for diagnosis. In comparison to percutaneous and CT-guided FNB, EUS-FNA/FNB has low rates of complications, a decreased rate of peritoneal seeding, and is cost effective.47,48

CASE CONTINUED

Abdominal CT obtained following abdominal ultrasound reveals a 3.5-cm mass in the head of the pancreas in close approximation to the SMA and celiac axis.

  • Does the patient have borderline resectable or unresectable disease?

IMAGING

Abdominal ultrasound is a reasonable, inexpensive, and safe alternative to abdominal CT as it does not utilize ionizing radiation. It is particularly useful in patients who present with jaundice or have concern for biliary obstruction based on laboratory evaluation. It is particularly sensitive for detecting tumors greater than 3 cm in size.49,50 In patients whose abdominal ultrasound is unrevealing and whose index of suspicion remains high for PDA, abdominal CT should be the next imaging modality.

Abdominal CT obtained utilizing a pancreatic protocol is ideal for detection and staging of pancreatic tumors. By implementing a triple-phase protocol with arterial, late arterial, and venous phases, tumors, which have a density different from that of the pancreatic parenchyma, are accentuated. Abdominal CT is also able to provide critical information about tumor resectability.51 By revealing the degree of tumor encasement around the aorta, level of destruction of the superior mesenteric vein, or degree of involvement of the SMA or celiac vessels, abdominal CT determines if a patient should be deemed resectable, borderline resectable, or unresectable (Table 2).52,53 Resectability is based on thorough imaging evaluation, expert opinion of a multidisciplinary team, and guidelines proposed by American Hepatopancreaticobiliary Association, Society of Surgical Oncology, Society for Surgery of the Alimentary Tract, and the NCCN.54

Table 2 Definition of Resectability

Other imaging modalities have a less clearly established role in the diagnostic approach to PDA. In patients who have contraindications to obtaining CT, magnetic resonance imaging can be utilized as a secondary imaging modality.55 The role of positron emission tomography 18F-fluorodeoxyglucose (PET-FDG) is not clearly defined among clinicians, nor reflected in consensus guidelines by the National Comprehensive Cancer Network (NCCN). In clinical practice, it is still often combined with CT to detect metastatic disease, particularly in high-risk patients such has those with LAPC. The role of PET-CT in staging and its impact on clinical outcomes has not been fully established.

Endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) can also assist in the diagnosis and management of PDA. In patients with obstructive jaundice, both MRCP and ERCP visualize obstructions and dilations within the biliary tree, with the latter having the ability to intervene. ERCP allows for the collection of tissue to aid in diagnosis, and has the ability to relieve biliary obstruction via stenting.56

TREATMENT

CASE CONTINUED

After an abdominal CT is obtained, the patient is referred to an outpatient oncologist because of concern for pancreatic adenocarcinoma. After consultation, the patient is advised to obtain EUS with biopsy and to return immediately afterwards for further treatment planning. The pathology report following EUS confirms that the mass is a poorly differentiated PDA. The patient’s case is discussed at a multidisciplinary meeting with radiation, surgical, and medical oncology. The abdominal CT and PET-CT scan are thoroughly reviewed. After imaging review, the multidisciplinary team concludes that the tumor is in contact with the SMA at 120° and with the common hepatic artery without extension in the celiac axis and without evidence of metastasis.

  • What is the appropriate management of borderline resectable pancreatic cancer?

BORDERLINE RESECTABLE CANCER

Patients who have nonmetastatic disease and are deemed resectable and without contraindications to surgery or high-risk features, as defined by NCCN guidelines, should proceed directly to surgery. A large body of evidence suggests that complete surgical resection with negative margins is a significant predictor of survival and currently provides the only option for cure.57–59 Despite the curative intent of surgery, the rate of recurrence remains high in patients who undergo surgical resection. Even in patients with negative resection margins (R0 resection), the 5-year survival is 20% to 30%, with a median survival ranging from 12 to 25 months, suggesting the presence of regional and distant occult disease at the time of diagnosis.60–62

Additionally, in half the patients who undergo surgical resection with resultant positive microscopic (R1 resection) or gross (R2 resection) margins, the median survival is no greater than 12 months. In this subset of patients, clinical outcomes are similar to outcomes in patients with locally advanced and metastatic pancreatic cancer, suggesting that upfront surgery and adjuvant therapy may not be the ideal therapeutic option. This raises 2 important points: first, resectability should be assessed carefully in all patients with LAPC, and second, for those patients who are deemed borderline resectable, neoadjuvant therapy should be considered.63 Borderline resectability is defined as tumor abutment ≤ 180° of the celiac artery, and tumor abutment of the superior mesenteric vein /portal vein of > 180° or abutting ≤ 180° with irregularity of the vein with or without thrombosis with anatomical structures that still allows for safe and complete resection and vein reconstruction (Table 2).

Neoadjuvant Therapy

The goal of neoadjuvant therapy is to minimize the negative impact of upfront surgery in patients who have a high likelihood of having microscopic or grossly positive margins. Research has suggested that neoadjuvant therapy may improve resectability, decrease the rate of recurrence, and improve overall survival.64–66

There is no clear consensus on the ideal management of patients with borderline resectable disease. However, expert guidelines are in agreement that upfront surgery in patients with LAPC is not appropriate, as most patients will not be able to achieve an R0 resection.67 As staging and management of patients with LAPC is difficult, expertise of a multidisciplinary team can be helpful.68

Several studies and the NCCN guidelines support the use of neoadjuvant therapy in patients deemed borderline resectable.69,70 Treatment of borderline resectable disease is similar to unresectable LAPC and generally involves 2 chemotherapy treatment backbones: FOLFIRINOX (folinic acid [leucovorin], fluorouracil [5-FU], irinotecan, and oxaliplatin) or gemcitabine-based therapy.

Phase 1 to 2/3 clinical trials conducted by Conroy et al from 2005 to 2011, including the landmark ACCORD-11 trial, established the safety and role of FOLFIRINOX in metastatic pancreatic cancer and also demonstrated an improved overall survival with the use of this therapy in these patients.71,72 These findings led to interest in FOLFIRINOX as a neoadjuvant therapy for patients with LAPC. Since then, multiple prospective and retrospective studies have shown that 54% to 100% of patients with borderline resectable LAPC who were treated with FOLFIRINOX were down-staged significantly enough to undergo resection. Of those patients, more than 90% had a R0 resection following surgery (Table 3).73–79

Table 3 Pancreatic Cancer

Data over the past 7 years suggests that neoadjuvant FOLFIRINOX improves overall survival and resectability in patients with borderline disease. However, treatment with FOLFIRINOX is not without limitations. FOLFIRINOX is associated with higher rates of febrile neutropenia, thrombocytopenia, diarrhea, and sensory neuropathy as compared with gemcitabine-based therapy.72 Other less commonly observed toxicities associated with FOLFIRINOX include mucositis, hand-foot syndrome, pulmonary toxicity, and alopecia. Dose-attenuated FOLFIRINOX-based regimens, including those that exclude the bolus fluorouracil dose and augment upfront filgrastim, have demonstrated improved safety and comparable efficacy as compared to standard FOLFIRINOX.80

Gemcitabine has been the fundamental treatment backbone for PDA since the results of the phase 3 CONKO-001 trial were published.81 Gemcitabine is a pyrimidine antimetabolite and potent inhibitor of DNA polymerase and ribonucleotide reductase.82 In recent years, multiple combination therapies with gemcitabine have been investigated, including regimens with nab-paclitaxel, oxaliplatin, or docetaxel. Resection rates and negative margin outcomes have been shown to be comparable to patients who received FOLFIRINOX in the neoadjuvant setting with borderline locally advanced disease.83–85 In addition to having a more tolerable side effect profile in comparison to fluorouracil-based regimens, gemcitabine is considered to be a potent radiosensitizer.86 For this reason, studies have also investigated the role of radiotherapy in conjunction with gemcitabine, revealing negative margin resection rates above 80% in patients with borderline resectable disease.87,88

Because very few studies directly comparing FOLFIRINOX with gemcitabine-based combination regimens have been completed, there is no clear consensus on the preferred treatment regimen, in both borderline and unresectable LAPC. Decisions to treat are influenced predominantly by comorbidities, adverse effect profiles, and performance status of patients, as FOLFIRINOX is the more toxic of the 2 treatment backbones. Therefore, FOLFIRINOX has mostly been utilized in patients with relatively good functional status (Eastern Cooperative Oncology Group [ECOG] performance status 0 to 1).89 In elderly patients and those with poor functional status, ECOG 2 to 4, gemcitabine as a single agent is a reasonable alternative in the neoadjuvant setting of borderline resectable disease.

The exact role of radiation therapy in addition to induction chemotherapy in borderline resectable pancreatic cancer has not been clearly established because of the lack of prospective studies in this area. Multiple large retrospective series have identified high rates of conversion to margin-negative resection with neoadjuvant chemoradiation alone.90 Based on available data, it is reasonable for patients with borderline resectable disease to proceed with any of the following treatment options: chemotherapy, chemoradiation, or induction chemotherapy followed by chemoradiation (Figure). Chemotherapy and chemoradiation are generally more appropriate with patients with high CA 19-9 levels or those at an elevated risk of having positive margins or occult metastatic disease.91 Obtaining negative margin resections is the predominant goal of neoadjuvant radiotherapy.89 Many studies have identified margin status to be one of the most significant prognostic factors in PDA.57,59,92,93 Additionally, several studies have highlighted that radiotherapy in the neoadjuvant setting could improve negative margin resection rates, local control, and clinical outcomes in patients with borderline resectable locally advanced disease.94–97 A common multimodal regimen utilized in the neoadjuvant setting combines capecitabine, an oral prodrug that is converted to fluorouracil, with radiation therapy. This combination has also been shown to improve resectability rates and long-term clinical outcomes in patients with borderline resectable disease.98 Additionally, neoadjuvant radiation therapy can potentially downstage patients with unresectable disease at the time of diagnosis to become surgical candidates.99 Despite the paucity of data, interval scans utilizing CT following neoadjuvant therapy should be obtained 2 to 4 months after completion of therapy to determine therapeutic response, evaluate for disease progression, and, most important, reassess surgical stage/resectability. It is clinically acceptable to proceed to resection with radiographically stable disease post-neoadjuvant therapy.

Many patients classified as borderline resectable are able to proceed with surgery following neoadjuvant therapy. Unfortunately, specific data on adjuvant therapy following neoadjuvant chemotherapy or chemoradiotherapy and surgical resection in borderline resectable patients is scarce. Clinical practice guidelines are extrapolated from studies where upfront resection in clearly resectable patients was followed by adjuvant therapy. Based on these data, approximately 6 months of perioperative chemotherapy with or without chemoradiotherapy is a reasonable consideration. Nevertheless, about 80% of patients at the time of diagnosis are deemed to be unresectable, and a smaller number do not proceed to surgery despite an initial classification as borderline resectable. Of the 80% of patients with advanced disease, about half are metastatic at presentation and the remaining 30% to 40% are defined as having unresectable LAPC.100

CASE CONTINUED

The patient is deemed borderline resectable. He receives neoadjuvant therapy with gemcitabine and nab-paclitaxel. Two months after therapy, interval imaging with abdominal CT does not show improvement in tumor size and there is now evidence that the tumor has invaded the celiac axis and is abutting more than 180° of the SMA. The patient presents to the oncologist to discuss further management. He has lost about 15 lb since his last evaluation, is capable of self-care, but is unable to carry on with any work activities.

  • What is the appropriate management of unresectable nonmetastatic LAPC?

UNRESECTABLE LOCALLY ADVANCED CANCER

As in the case of borderline resectable disease, there are many treatment options for patients with unresectable LAPC. Timing, optimal chemotherapy regimen, and the addition of regularly and hypofractionated radiotherapy are issues currently under investigation. However, there are some general considerations and principles that are followed as reflected in the NCCN guidelines and recent studies. The primary therapeutic aims in patients with unresectable locally advanced disease are to increase survival and improve palliation.

The elderly comprise a large percentage of the patients diagnosed with unresectable locally advanced disease. Pharmacokinetics and toxicity profiles are altered in the elderly population.101,102 Therefore, it is important to assess functional status and comorbidities as these are critical factors in determining treatment regimens, similar to patients with borderline resectable disease. Currently, the most common first-line therapies in advanced pancreatic cancer are gemcitabine alone, gemcitabine and nab-paclitaxel, FOLFIRINOX, gemcitabine/capecitabine, and gemcitabine/oxaliplatin.103 The overall treatment approach to unresectable locally advanced pancreatic adenocarcinoma closely mirrors that of patients with borderline resectable disease and metastatic disease. Much of the data supporting treatment regimens in unresectable LAPC is extrapolated from clinical trials looking at advanced or metastatic pancreatic cancer.

Consensus opinions domestically and from Europe recommend that patients with locally advanced unresectable disease undergo upfront chemotherapy (Figure).104 This is based on the premise that initial chemotherapy may destroy occult metastatic cells and increase the efficacy of consolidative chemotherapy, particularly with radiation in the future. Upfront chemoradiotherapy has only been investigated in a small series of trials in which no clear survival benefit was observed and has the added consequence of treatment-related toxicity.105 However, data is limited in this regard, with variations in treatment protocols and cohort compositions contributing to the inconclusive findings.

Despite advances in immunotherapy, targeted therapies, and gene sequencing, initial chemotherapy for unresectable disease is still either gemcitabine-based combination therapy or FOLFIRINOX. Across numerous studies, patients with unresectable LAPC receiving FOLFIRINOX have a median progression-free survival of 3 to 20 months and a median overall survival of 10 to 32.7 months.106 As with borderline resectable patients, FOLFIRINOX (Table 4) is generally reserved for unresectable patients with good functional status (ECOG 0–1 or Karnofsky Performance Status 90–100) and those at low risk for developing grade 3 or 4 systemic toxicities.103 For these reasons it has generally not been frequently combined with other chemotherapeutic agents. However, FOLFIRINOX has been combined with radiation therapy in the consolidative neoadjuvant setting after induction chemotherapy. There have also been studies where traditional FOLFIRONIX was modified to improve tolerability, as evidenced by Gunturu et al’s study, which dose-reduced both fluorouracil and irinotecan by 25%, without compromising efficacy and simultaneously increasing tolerability.107 Additionally, FOLFIRINOX requires infusional administration of the fluorouracil component, which may not be practical in certain patients. In that subset, capecitabine can be substituted. Among radiosensitizers during neoadjuvant therapy for unresectable LAPC, capecitabine has been shown to be as efficacious and less toxic than even gemcitabine.108

Table 4 Pancreatic Cancer
As in borderline resectable disease, gemcitabine-based combination therapy is a standard treatment option in patients with unresectable disease (Table 5). In the phase 3 clinical trial by Van Hoff et al, the addition of nab-paclitaxel to gemcitabine versus gemcitabine alone led to significant improvements in overall and progression-free survival in metastatic patients. The objective response occurred at the expense of increased toxicity with peripheral neuropathy and myelosuppression, but the treatment was overall well tolerated.109 This data led to the use of gemcitabine combined with nab-paclitaxel in patients with unresectable LAPC. Despite the improvements in objective response rates (ORR) with gemcitabine plus nab-paclitaxel, gemcitabine alone still has a role in LAPC (ORR of 23% with gemcitabine plus nab-paclitaxel versus 39% with FOLFIRINOX versus 10% with gemcitabine alone).100 In elderly patients with poor functional status, significant comorbidities, or increased risk for developing toxicities, single-agent gemcitabine may be better tolerated than gemcitabine plus nab-paclitaxel or FOLFIRINOX with or without radiation therapy in LAPC. However, numerous clinical trials support the use of combination chemotherapy with FOLFIRINOX or gemcitabine plus nab-paclitaxel as reasonable options in LAPC patients with good functional status and adequate pain control and nutritional intake.103

Table 5 Pancreatic Cancer

No head-to-head studies investigating FOLFIRINOX versus nab-paclitaxel and gemcitabine in patients with locally advanced disease have been published, but clinical trials are under way. Other combination therapies have been looked at through small retrospective or prospective studies, but no robust, large-scale clinical trials have been completed. For this reason, NCCN guidelines recommend enrollment of patients with LAPC into active clinical trials.

  • What is the role of radiation therapy in unresectable LAPC?

Despite the reported advantages of neoadjuvant radiation in patients with potentially resectable disease, there is significant debate regarding the timing and role of neoadjuvant radiation in patients with unresectable disease. Numerous comprehensive analyses and studiest indicate that chemoradiotherapy leads to significantly better overall survival compared to no therapy or radiation therapy alone in LAPC.68,110,111 However, conflicting data support the use of upfront chemoradiotherapy in unresectable LAPC when compared to chemotherapy alone. Unfortunately, most prospective studies investigating the role of radiotherapy were performed following administration of single-agent gemcitabine, which is no longer considered standard of care for patients with LAPC. In spite of this, ECOG 4201 identified a statistically significant improvement in median overall survival following the addition of gemcitabine-based radiotherapy. Huguet et al in his review pointed out that upfront chemoradiotherapy was not superior to chemotherapy only and was associated with increased treatment toxicity.105 Additionally, a recent phase 3 study looking at chemoradiotherapy versus chemotherapy alone in patients treated with gemcitabine found no difference in overall survival.112 This can potentially be attributed to the fact that about 30% of patients with LAPC develop metastatic disease in the early phases of treatment due to poor control of local and systemically occult disease.113 Given the propensity for high rates of occult metastatic disease in LAPC, treatment paradigms and consensus guidelines recommend multi-agent systemic chemotherapy followed by chemoradiotherapy in select patients.

Based on current studies and until further clinical investigations are completed, consensus opinion indicates that the most appropriate approach in unresectable LAPC is to begin with induction chemotherapy (with either gemcitabine plus nab-paclitaxel, FOLFIRINOX, capecitabine, or other treatment combinations), followed by chemoradiation in the absence of disease progression when the first repeat imaging evaluation is completed (Figure). One important caveat regarding reimaging with CT in the neoadjuvant setting is that radiologic response may not correlate with pathologic response.114 PET-CT may have a role in predicting response to neoadjuvant therapy. Overall, induction chemotherapy followed by consolidative chemoradiation may confer numerous benefits: it removes the unnecessary burden and toxicity associated with radiotherapy in the nearly one third of patients who have pervasive disease progression during initial treatment; it allows testing and increases the chances of tolerating full-dose systemic chemotherapy; and it raises the likelihood of converting patients who do not progress to metastasis during the initial phase of treatment from unresectable to resectable status.103,115 Despite the lack of strong conclusive data, the general agreement is that neoadjuvant chemoradiotherapy converts about one third of borderline and unresectable LAPC to an R0 resection.95,103 There are very specific rationales for the addition of radiotherapy in LAPC, and these functions need to be better defined through further clinical trials.

Figure 1

PALLIATIVE CARE

CASE CONTINUED

The patient is unable to tolerate his first round of second-line therapy with modified FOLFIRINOX. His overall treatment plan is transitioned to palliation. He continues to have pain, despite increasing doses of narcotics.

  • What is the next step for patients in whom second-line therapy fails and who have intractable pain while on high-dose narcotics?

A subset of patients with unresectable LAPC may not be amenable to chemotherapy with or without radiation due to significant comorbidities or because they present with or progress to ECOG scores 3 or 4. The goal in these patients should be palliation. Pain is one of the most predominant and difficult to manage symptoms in progressive LAPC. Opioid-based medications are the primary treatment for pain in LAPC. However, patients sometimes become refractory to opioid medications. In this group of patients, it is reasonable to consider palliative radiation as an alternative method for pain control.116

An alternative to palliative radiation in the setting of progressive pain in PDA is celiac plexus block or neurolysis. By injecting an anesthetic or alcohol into the celiac plexus, neural signaling pathways involved in the propagation of pain are inhibited without leading to significant nerve destruction. Additionally, chemical splanchnicectomy allows for reduced opioid medication use and associated side effects.117

In general patients with LAPC have profound weight loss prior to and during treatment. This has significant implications prognostically and on treatment options. The underlying etiology is multifactorial, but one of the primary driving factors is pancreatic insufficiency. An estimated 65% of pancreatic cancer patients have fat malabsorption, and 50% have protein malabsorption, leading to steatorrhea and weight loss.118 Patients diagnosed with pancreatic cancer should be given enzyme replacement with formulations that include lipase, amylase, and protease. A minimum dose of enzyme replacement should include 40,000 to 50,000 U of lipase during meals and 25,000 U during snack intake. If maldigestion, symptoms, or nutritional endpoints (BMI, albumin, prealbumin, cholesterol) do not improve, the pancreatic enzyme dose should be escalated and a proton-pump inhibitor (PPI) added. In patients with pancreatic insufficiency, PPIs have been shown to improve fat absorption.119 Enzyme replacement therapy has been shown to prevent weight loss in patients with unresectable pancreatic cancer.120

As most patients with LAPC go on to develop progressive disease, palliative care becomes an integral aspect of the therapeutic paradigm. Palliation in LAPC has a significant role in determining quality of life and ensuring patient’s goals of care have been meet. Studies have suggested that pancreatic cancer is second only to lung cancer in terms of the number of emergency department visits in the later stages of disease.120 Additionally, aggressive care in the setting of incurable diseases such as LAPC has been associated with poor quality of life.121 More recently it has been shown that involvement of palliative care in patients with advanced pancreatic is associated with less aggressive care near death.122 Therefore, the incorporation of palliative or supportive care teams in the treatment of patients with progressive LAPC can improve quality of life and alleviate suffering associated with increasing symptom burden.

CONCLUSION

LAPC is a difficult disease for both provider and patient. There is a paucity of robust clinical trials in the neoadjuvant setting for LAPC. Current research is complicated by varying consensus definitions of resectability and the varying treatment configurations across studies. The optimal type, timing, and sequence of treatment and whether to add radiation therapy in LAPC have not been clearly defined. However, based on the available studies and consensus guidelines, patients who are deemed to have LAPC should have neoadjuvant therapy. FOLFIRINOX or gemcitabine with nab-paclitaxel should be considered first-line treatments. Patients with LAPC who respond to chemotherapy or are ineligible for multi-drug chemotherapy may benefit from chemoradiotherapy. In patients with unresectable disease, chemoradiotherapy has been shown to enhance survival as compared to best supportive care or radiation alone. For borderline resectable disease, it is reasonable to treat patients with either chemoradiotherapy, chemotherapy alone, or chemotherapy followed by chemoradiotherapy.

Considering the invasive nature of LAPC and the controversy around neoadjuvant treatment protocols, enrollment of patients with LAPC into clinical trials is important and will help determine the optimal treatment regimen for future patients.