Table of Contents  

Gallagher and Parks: Palliative and oncological management of pancreatic cancer

Introduction

Pancreatic cancer is possibly one of the most difficult cancers to treat. The combination of late symptom onset, proximity to and invasion of vital structures and early dissemination make for a poor prognosis in the majority of patients; 80% of patients are diagnosed with advanced unresectable disease and upwards of 80% of patients with resectable disease relapse. Therefore, the effective ‘cure rate’ is in the order of 4–5%. A more frustrating aspect, however, is that these figures have barely changed over the last 25 years despite advances in surgical technique and the conduct of many well-organized collaborative international oncology trials. Unlike breast cancer and colorectal cancer, which have seen substantial improvements in overall survival, outcomes for pancreatic cancer, unfortunately, lag significantly behind.

The aggression of this disease is related to a number of factors. There are no very early symptoms. Some authorities believe that pancreatic adenocarcinoma metastasizes early in its development.1 Similarly, there is good pre-clinical evidence supporting the hypothesis that it is the stromal component that makes these tumours so chemoresistant. Forming more than 80% of the tumour mass, the fibrotic stroma of pancreatic ductal adenocarcinoma is not a passive scaffold for malignant cells but an active player in carcinogenesis.2 The epithelial component, which is the target of many of our chemotherapeutic agents, is actually quite small compared with the surrounding desmoplasia, and it is possible that this stromal component is a barrier to therapy. Finally, this particular tumour is quite clearly able to debilitate its host by the elaboration of many cytokines so that the cachexia and pain seen in up to 80% of patients is unlike that seen with most other malignancies.3,4

The multifactorial reasons for poor overall survival in patients with pancreatic cancer means that, for most patients, treatment is palliative. Without treatment the median survival of patients with metastatic disease is approximately 3 months.

Definition and classification of pancreatic cancer

Although a formal tumour, node, metastasis (TNM) staging system does exist for pancreatic cancer,5 a more practical way to stage patients is to separate them into three primary categories: (1) those with localized, resectable disease, (2) those with locally advanced, unresectable disease and (3) those with evidence of metastases (Figure 1). Table 1 highlights the stage distribution of patients at the time of diagnosis, with associated long-term survival rates. An additional category is now increasingly being used between categories 1 and 2, termed ‘borderline resectable disease’; this includes patients with tumours that potentially may become resectable following neoadjuvant chemotherapy and/or radiation. For the purposes of this manuscript, the focus will be on categories 2 and 3.

FIGURE 1

Axial computed tomography image demonstrating bilobar liver metastases in the presence of a tumour in the body and tail of the pancreas.

8-2-7-fig1.png
TABLE 1

Stage at presentation and long-term survival rates based on Surveillance, Epidemiology and End Results (SEER) data6

Disease classification Proportion at diagnosis (%) 5-Year overall survival (%)
Localized 9 24
Regional (locally advanced) 27 9
Metastatic 53 2

Oncological management of metastatic pancreatic cancer

For many years, gemcitabine-based therapies have been the standard first-line therapy, as this was the first drug approved based on improvements in survival and performance status as well as reduced pain.7 Various gemcitabine-based regimens have been studied in large phase III trials7,8 and meta-analyses have demonstrated survival advantage with the use of gemcitabine in combination with certain classes of cytotoxic agents, including fluoropyrimidines and platinum analogues,9,10 although it must be stressed that these benefits are limited to patients with good performance status. The Molecular Profiling-based Assessment of Cancer Therapies (MPACT) trial showed an improved response and overall survival with gemcitabine in combination with paclitaxel protein-bound versus gemcitabine alone,11 although the combination was associated with higher rates of neutropaenia and peripheral neuropathy. Based on these data, in 2013, the United States Food and Drug Administration approved nab-paclitaxel (Abraxane®, Celgene, Uxbridge, UK) for use in combination with gemcitabine as first-line treatment of metastatic pancreatic cancer.

A number of non-gemcitabine-based frontline therapy regimens have been investigated. FOLFIRINOX chemotherapy results in superior overall survival and progression-free survival compared with gemcitabine monotherapy but does result in higher rates of grade 3 and 4 toxicities.12,13 Therefore, FOLFIRINOX is recommended as an appropriate option for patients with metastatic disease and good performance status.

Molecular research has led to the investigation of multiple potential targets and, as a result, gemcitabine has been studied in combination with various targeted therapies. The epidermal growth factor receptor inhibitor erlotinib (Tarceva®, Roche, Basel, Switzerland) is currently the only targeted agent approved for use in patients with locally advanced, unresectable or metastatic pancreatic cancer, and has been shown to be associated with improved overall survival.14

Patients who progress on first-line therapy have a very poor prognosis. There are no established therapies for second-line treatment and, indeed, fewer than 50% of patients who fail first-line treatment are fit enough for second-line therapy.15 It has been shown that patients who respond poorly to the majority of chemotherapy have an overall survival of less than 6 months, which is a 3-month benefit over supportive care.16 CONKO-003 combination oxaliplatin, 5-fluorouracil and leucovorin as second-line therapy in patients who had previously received gemcitabine monotherapy resulted in marginally improved survival compared with 5-fluorouracil/leucovorin alone.17 The general consensus is to give fluoropyrimidine-based chemotherapy to patients who have previously received gemcitabine-containing therapy and conversely to give gemcitabine-based treatment to patients who have previously received fluoropyrimidine-based therapy.

More recently, a nanoliposomal formulation of irinotecan, called MM-398 (Merrimack Pharmaceuticals, Cambridge, MA, USA), has been developed with enhanced pharmacokinetic and pharmacodynamic activity. MM-398 has demonstrated improved intratumoural accumulation in preclinical models,18 and an early clinical trial has shown that it is well tolerated and active in metastatic pancreatic cancer.19 A recent phase III trial reported that the combination of MM-398 with standard chemotherapy resulted in significant improvement to progression-free and overall survival, making this a promising therapy for patients with gemcitabine-treated metastatic pancreatic cancer.20

Oncological management of locally advanced pancreatic cancer

As discussed previously, approximately one-third of patients have locally advanced, unresectable tumours as defined by the degree of abutment, encasement or occlusion of surrounding vascular structures. Until relatively recently, patients with locally advanced and metastatic disease were treated identically, i.e. with systemic therapy. However, because of differences in biological behaviour and clinical outcome, it is now thought that these should be considered as two separate groups.

The selection of systemic agents for patients with locally advanced disease is similar to that for metastatic disease with the general consensus that in those with poor performance status, gemcitabine is safe to use and has proven benefit, whereas in those with good performance status, gemcitabine-based combination therapy or FOLFIRINOX may be used. Erlotinib combined with gemcitabine represents an additional option.

The role of chemoradiation in locally advanced disease, however, remains less well defined. Advocates argue that local control may correlate with a survival benefit, in addition to its important role in control of pain secondary to coeliac plexus infiltration. Early studies demonstrated the benefit of using radiosensitizing chemotherapy compared with radiotherapy alone in both overall and median survival.21 Outcome from trials performed subsequent to this have been conflicting,2225 to the point where induction chemoradiation for patients with locally advanced disease cannot be considered an absolute standard of care, based on currently available evidence. The dose and timing of radiation, as well as the chemotherapeutic agents used, varied widely between these studies.

In a potentially promising multicentre phase III trial (LAP-07), in which patients were randomized to receive gemcitabine with or without erlotinib and then randomized secondarily to undergo delayed chemoradiation or to continued chemotherapy without chemoradiation, patients who received chemoradiation had a lower rate of subsequent locoregional progression than those who did not receive chemoradiation.26 They also had a longer treatment-free interval before having to resume therapy, suggesting that a more refined approach to the choice, dosing and timing of chemotherapeutic agent may be of benefit and would be worth exploring in future studies.

Palliation of symptoms

Since the majority of patients with pancreatic malignancy have unresectable disease at the time of presentation, palliation to minimise symptoms and maximise quality of life has a major role in the care of these patients. This includes management of biliary obstruction, gastric outlet obstruction, pain, cachexia and minimizing the risk of thromboembolism.

Biliary obstruction

For patients with unresectable disease, progressive jaundice constitutes an immediate limitation to survival, in addition to significantly affecting quality of life because of pruritus, malaise and cholangitis.27 Although both surgical and non-surgical approaches are acceptable, results from the literature suggest that non-surgical palliation, i.e. stenting (Figure 2), can be achieved with a similar technical success rate to surgical bypass, but at reduced cost and with a trend towards a lower risk of short-term complications and mortality.28,29 Plastic stents occlude at a higher rate than metallic stents and require periodic exchange; therefore, selection of a plastic versus a metal stent is based, in part, on expected survival, with the longer expected patency and fewer complications associated with insertion of an expandable metal stent offering greater benefit in patients with better prognosis.28,30 For patients presenting with obstructive jaundice secondary to a localized resectable pancreatic cancer, the current opinion is to avoid pre-operative biliary drainage and proceed with urgent resection. Numerous studies have reported that such an approach is associated with lower rates of post-operative complications, infections and mortality.31,32 However, other series have reached different conclusions33 and if a delay to surgery is anticipated, stenting may be preferred.

FIGURE 2

Endoscopic retrograde cholangiopancreatography image taken after placement of a self-expanding metal stent in the presence of a locally advanced pancreatic tumour.

8-2-7-fig2.png

Surgical bypass may provide good medium-term palliation in terms of prevention of recurrent jaundice, and facilitates prophylactic gastrojejunostomy to prevent future gastric outlet obstruction, and therefore may be considered in patients with a longer expected survival. The cut-off point in survival time that has often been quoted in determining if palliative stenting or surgical bypass should be undertaken is 6 months.34,35 However, in practice, surgical bypass is more often performed when planned definitive pancreatic resection has been aborted because of finding unsuspected locally advanced or metastatic disease at laparotomy. Other determinants of poor survival rates include the presence of peritoneal or liver metastases and a low Karnofsky index of performance.36

Gastric outlet obstruction

The true incidence of symptomatic gastric outlet obstruction (GOO) remains unclear. Historically, it was considered that more than 25% of patients would develop GOO during the course of their illness and, therefore, prophylactic gastric bypass was recommended at the time of exploratory laparotomy. However, as the need for open exploration for staging purposes has decreased, the need for prophylactic bypass for the majority of patients has been questioned. In relation to pancreatic cancer, GOO is a late complication of advanced pancreatic cancer affecting 10–20% of patients who survive more than 15 months.3739 However, overall, fewer than 3% of patients develop GOO requiring surgical bypass.37,40,41 Most important, 60% of patients with advanced pancreatic cancer have delayed gastric emptying with no evidence of gastric or duodenal invasion and no mechanical obstruction. This may be explained by tumour infiltration of the coeliac plexus causing gastric stasis, nausea and vomiting.42 Espat and colleagues37 examined 155 patients undergoing laparoscopic staging in a prospective but non-randomized study. Following laparoscopy, 40 patients had locally advanced unresectable disease and the remainder had metastatic disease. In follow-up, only 3% of patients required a subsequent open operation for biliary drainage or GOO. This low percentage of patients requiring surgery for symptomatic GOO is consistent with data from the non-operative control groups in randomized trials of endoscopic biliary drainage versus surgery.

In 1995, Rhodes and colleagues43 reported one of the first series of patients who had undergone laparoscopic palliation for advanced pancreatic carcinoma. Of 16 patients, seven underwent laparoscopic cholecystojejunostomy, five had laparoscopic gastroenterostomy, three had both procedures and in one patient laparoscopic palliation failed. The median operating time was 75 minutes, the hospital stay was 4 days, the morbidity was 13% and the median survival in 10 patients was 201 days, with the remaining patients alive at the time of the publication.43 A randomized trial reported by Navarra and colleagues44 demonstrated that patients undergoing a laparoscopic gastrojejunostomy had significantly less intraoperative blood loss and resumed oral intake sooner than those patients undergoing an open palliative antecolic gastrojejunostomy. A technique for a transumbilical single-incision laparoscopic gastrojejunostomy has been reported.45 While this is technically feasible, the benefits compared with the conventional laparoscopic approach remain to be determined.

An alternative to the surgical approach for GOO is the endoscopic placement of a duodenal stent. In general, this is favoured whenever possible because of lower rates of complications and procedure-related mortality. Endoscopic palliative treatment of duodenal stenosis is safe and effective in the long term, including in patients with both biliary and duodenal obstruction. Use of such palliative management is justified as repeat procedures are rarely required even in patients who have a long survival.46

Cachexia

Cachexia is a complex metabolic disorder that involves features of anorexia, anaemia and loss of adipose and skeletal muscle mass, which develops in approximately 80% of patients with pancreatic cancer during the disease course. Up to one-third die from complications associated with cachexia through immobility, severe respiratory muscle impairment resulting in cardiopulmonary failure and impaired immunity.47 Therefore, an experienced dietitian should be involved early in a patient’s disease course to assist in management. In addition to nutritional supplements and pharmacological appetite stimulants, some studies suggest that eicosapentaenoic acids (found in fish oil supplements) can potentially help reverse cancer cachexia through modulation of proinflammatory cytokines.48 Depressive symptoms that often accompany pancreatic cancer (beyond the understandable reactive depression that may result from the initial diagnosis) may contribute to this picture and should prompt referral to a psychiatrist or psychologist specializing in the care of such patients.

Pain

Pain is almost always an issue in patients with advanced pancreatic cancer. Radiation may offer some palliation of a painful bulky or infiltrative primary pancreatic tumour involving the coeliac plexus, and even chemotherapy over time may reduce symptoms. However, for pain not adequately relieved with ongoing anticancer treatment or escalating doses of narcotic analgesics, a coeliac plexus block (with a steroid/local anaesthetic combination) and neurolysis (typically with alcohol plus a local anaesthetic) may be indicated. These procedures are generally performed under either fluoroscopic guidance or endoscopic ultrasound, with the latter approach associated with lower rates of neurologic complications.49 Pain relief is achieved in up to 80% of patients, although these effects begin to diminish beyond 3 months.50 Adverse events tend to be transient, including diarrhoea and hypotension. A double-blind controlled trial demonstrated that early endoscopic ultrasound-guided coeliac plexus neurolysis, performed at the time of initial cancer diagnosis and staging, produces greater pain relief than conventional pain management.51

Venous thromboembolism

Finally, it is well known that patients with pancreatic cancer are at high risk of venous thromboembolic events, with an incidence greater than 10%.52 The development of a venous thromboembolism (VTE) in itself is prognostic of poor survival.53 In the CONKO-004 trial, 312 patients with advanced pancreatic cancer were randomized to receive enoxaparin (Clexane®, Sanofi-Aventis, Paris, France) 1 mg/kg/day for the first 3 months, then 40 mg/day thereafter or placebo with gemcitabine-based chemotherapy.54 Unsurprisingly, patients receiving prophylactic enoxaparin had a significantly lower incidence of VTE at 12 months (5.0% vs. 15.3%; P < 0.05) with no corresponding increase in bleeding risk. After a median follow-up of 45 months, there were no significant differences between the two groups in terms of progression or overall survival. It seems reasonable to consider low-dose, low-molecular-weight heparin in patients without contraindications for anticoagulation, particularly those who are at significant high risk based on immobility or other factors.

Summary

The majority of patients with pancreatic cancer will require oncological and palliative care and, despite significant research into chemotherapeutic regimens over the years, the overall survival has not significantly improved. In what is currently an exciting time for pancreatic cancer research, there is hope for the future offered by a better understanding of the tumour stroma and by the targeting of specific signalling pathways. In the meantime, however, it is imperative to achieve optimal symptom control depending on performance status and personal wishes. A multidisciplinary approach involving surgeons, oncologists, dietitians, pain management specialists and palliative care physicians is of utmost importance to improve the quality of life of these patients.

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