Oxford Case Histories in Oncology

Case 11

A patient presenting with painless jaundice

Elizabeth Liniker, Simon Johnston, Sara Custodio-Cabello, and Bristi Basu

Case history

A 51-year-old woman presented with a short history of painless jaundice. She had no significant past medical history and was not on any regular medications. She was otherwise well with an ECOG performance status of 0. On clinical examination her abdomen was soft and non-tender with no palpable masses. Blood test results were as follows: FBC, U&Es, calcium, clotting profile all normal; bilirubin 112μmol/L; alkaline phosphatase 387U/L; alanine aminotransferase (ALT) 267U/L; gamma-glutamyltransferase 245U/L; albumin 34g/L; CA 19.9—169U/ml (normal value 0–39). The patient had a contrast enhanced CT of the chest, abdomen, and pelvis (Fig. 11.1). She underwent an EUS-guided fine-needle aspiration biopsy of the pancreas. Subsequent cytology revealed cytological atypia (nuclear enlargement) in keeping with at least high-grade dysplasia.

Fig. 11.1

Questions

1. What does Fig. 11.1 show?

2. Outline your management if there were no distant metastases evident on staging imaging.

Answers

1. What does Fig. 11.1 show?

Axial contrast enhanced images of the abdomen show a mass in the head of the pancreas with biliary dilatation.

In light of a mass in the head of the pancreas and highly suggestive histology, the diagnosis is adenocarcinoma of the pancreas causing biliary obstruction. Histological confirmation is occasionally difficult in these tumours because of the surrounding stromal reaction. However, they often show positive immunohisto-chemical staining for CK19, CA19.9, and CEA.

2. Outline your management if there were no distant metastases evident on staging imaging.

The first question is does she have resectable disease which could be potentially cured with surgery. Fewer than 20% of patients have resectable tumours at diagnosis, 30–40% have locally advanced unresectable disease, and the remainder have metastases at presentation. Given that if the patient has a good performance status and no significant comorbidities to contraindicate major surgery, determination of resectability is appropriate and should be assessed using:

♦ Diagnostic imaging: triple-phase contrast-enhanced thin-slice (multidetector row) CT is the gold standard staging investigation and predicts resectability in 80–90% of patients.

♦ EUS: the presence or absence of vascular invasion can be visualized using EUS. In cases where small pancreatic tumours are suspected, EUS is able to detect these with a greater sensitivity than CT, MRI, or FDG-PET.

♦ Laparoscopy: in selected cases, where there is a higher than usual index of suspicion for occult metastases (e.g. a very high CA19.9 at diagnosis), laparoscopy may be performed to try to detect occult liver and peritoneal metastases.

Although distant spread represents an unambiguous contraindication to resection, there are differing opinions as to when a pancreatic cancer is technically resectable and when an attempt at resection is appropriate. In general, major arterial involvement (superior mesenteric, coeliac, and common hepatic arteries) remains a contraindication to resection due to the high risk of involved (R1) margins post-operatively and therefore an increased risk of loco-regional recurrence. However, the presence of short segment portal vein or superior mesenteric vein involvement no longer constitutes an absolute contraindication to resection due to the increasing use of vascular resection and grafts. In recognition of this fact, recently a new category of ‘borderline resectability’ has emerged (Table 11.1).

In the pre-operative setting, biliary drainage is only indicated in patients with cholangitis, those with significant liver dysfunction, and those who are symptomatic, such as with severe pruritus. Studies show that routine pre-operative biliary drainage for individuals with obstructive jaundice has a worse outcome than resection alone.

Table 11.1 Resectablility criteria for pancreatic cancer

SMA, superior mesenteric artery; SMV-PV, superior mesenteric vein–portal vein.

Source: Data from NCCN Guidelines Version 2.2012 Pancreatic Adenocarcinoma (Copyright © 2012 National Comprehensive Cancer Network, Inc. all rights reserved) and Callery et al. (2009) (Copyright © Society of Surgical Oncology 2009).

Question

3. What is the evidence for adjuvant chemotherapy after resection?

Answer

3. What is the evidence for adjuvant chemotherapy after resection?

Even completely resected (R0) pancreatic cancers have a poor prognosis, with 5-year survival rates in the range of 10–25% and median survival between 10 and 20 months. So a great proportion of patients who are currently regarded as resectable will have occult metastatic disease at the time of surgery. For those patients who undergo resection and remain fit, the current standard of care is to offer 6 months of adjuvant systemic chemotherapy. The ESPAC-1 and CONKO-001 (Oettle et al. 2007) trials demonstrated a significant benefit in 5-year survival (from <10% to around 20%) with adjuvant 5-FU/folinic acid and adjuvant gemcitabine, respectively, with the ESPAC-3 study then showing equivalence in survival between adjuvant gemcitabine and 5-FU/folinic acid (Neoptolemos et al. 2010). Current trials are evaluating whether there is additional benefit from the addition of agents such as capecitabine to gemcitabine. A new approach yet to be proven in large clinical trials may be to consider neoadjuvant treatment strategies. The period of neoadjuvant treatment may identify patients with early progression who are unlikely to benefit from upfront surgery with its associated morbidity and may also evaluate the feasibility of downstaging borderline unresectable disease to enable an R0 resection.

The patient underwent a laparotomy with a view to Whipple’s resection. However, at surgery, her disease was found to be inoperable on the basis of invasion of the common hepatic artery, which had been understaged by her diagnostic imaging. A palliative gastro-jejunostomy and hepatico-jejunostomy bypass was therefore performed. She made a very good postoperative recovery and her bilirubin normalized.

Question

4. What approaches to further treatment could you take in this case?

Answer

4. What approaches to further treatment could you take in this case?

In the absence of resectable disease, palliative treatments should be discussed with the patient. The optimal management plan for patients with locally advanced, unresectable pancreatic cancer is controversial and median survival in these cases is in the range of 6–10 months. Commonly used approaches involve chemotherapy, as for metastatic disease, or chemoradiation.

Gemcitabine is considered the benchmark palliative therapy following its comparison with bolus 5-FU because of an improvement in 1-year survival rate in one study (18% versus 2%) (Burris et al. 1997). There is also evidence that gemcitabine can provide symptomatic benefit with stabilization of weight and improvements in pain and performance scores. However, gemcitabine monotherapy does not provide a significant improvement in median survival duration, and unfortunately the addition of other chemotherapy drugs or targeted agents has largely not shown any additional benefit in a randomized phase III setting. A modest improvement in OS with addition of capecitabine to gemcitabine has been shown in a meta-analysis (Cunningham et al. 2009). Adding erlotinib to gemcitabine demonstrated a statistically significant improvement in OS in a randomized setting; the increase was only about 2 weeks (Moore et al. 2007).

Chemoradiotherapy can be used in locally advanced pancreatic cancer (LAPC). Phase III studies (FFCD/SFRO, ECOG) have shown that chemoradiotherapy is associated with greater toxicity than chemotherapy alone but can offer small improvements in outcomes. Different regimens and end-points (resectability, OS, local progression) have been studied without providing a definitive answer as to the optimum approach (Chauffert et al. 2008, Loehrer et al. 2011). However, given the increased toxicity of chemoradiotherapy and the early development of metastatic disease in many patients with locally advanced pancreatic cancer, there is evidence that preceding chemoradiotherapy with chemotherapy may spare those patients with rapidly progressive disease, thus selecting those patients who are most likely to benefit (Huguet et al. 2007).

The patient underwent 3 months of chemotherapy with gemcitabine plus capecitabine. Re-staging scans that showed stable disease so she was offered chemoradiation. A dose of 50.4Gy in 28 fractions with concomitant capecitabine was prescribed. A CT scan after treatment showed stable disease. However, 6 months following completion of chemoradiotherapy, she complained of right-sided abdominal pain and CT imaging revealed new liver metastases. The patient had an ECOG performance status of 1 and her blood tests were unremarkable apart from an aspartate aminotransferase (AST) of 70U/L and bilirubin of 19μmol/L.

Questions

5. What systemic therapy could be considered in this case?

6. Outline the principles of symptom control in patients such as this.

Answers

5. What systemic therapy could be considered in this case?

There is no standard chemotherapy regimen in this situation. Nevertheless, the pivotal PRODIGE 4/ACCORD 11 trial in metastatic pancreatic cancer patients, comparing first-line gemcitabine monotherapy with the FOLFIRINOX regimen demonstrated a significant advance in median OS from 6.8 months in the gemcitabine arm to 11.1 months with FOLFIRINOX (HR 0.56; 95% CI 0.45–0.73; P < 0.001) (Conroy et al. 2011). However, FOLFIRINOX was considerably more toxic, with more than 10% of patients experiencing grade 3/4 diarrhoea and 5.4% febrile neutropenia. The impressive response rates (31.6% versus 9.4%) seen in the trial have led to interest in evaluating this regimen in an earlier setting in the management of pancreatic cancer. However, the toxicity of the regimen necessitates careful patient selection for those with excellent performance status and fitness, limiting its role within the general population of patients diagnosed with metastatic pancreatic cancer. Therefore, wherever possible these patients should be offered enrolment into a clinical trial if they are eligible.

6. Outline the principles of symptom control in patients such as this.

Metastatic pancreatic cancer gives rise to symptoms that are challenging to palliate, and hence early referral to specialist palliative care is advised. Achieving and maintaining a good quality of life is the main aim of care, and early referral to a specialist palliative care team is recommended. Common problems such as pain, weight loss, jaundice, duodenal obstruction, ascites, and depression should be identified pro-actively and appropriate treatment and supportive measures instigated. Abdominal pain is a presenting symptom in 75–80% of patients. Although chemotherapy may improve pain scores, early approaches to address this should be based on the World Health Organization analgesic ladder with escalation to opiates as appropriate. Neuropathic pain from encroachment of the coeliac plexus may be targeted with medication (e.g. gabapentin) and coeliac plexus neurolysis. Cancer cachexia (weight loss >10%, anorexia, and systemic inflammation) is a typical feature of advanced pancreatic cancer. Secondary diabetes and steatorrhoea from pancreatic insufficiency may contribute to weight loss so early specialist dietetic support is recommended. Such support may help stabilize weight with institution of supplemental pancreatic enzyme replacement therapy, calories, and protein. Prokinetics such as metoclopramide may help gastric outflow obstruction (but can increase pain if there is subacute small bowel obstruction) whilst a duodenal stent may palliate duodenal obstruction. Procedures such as biliary stenting and paracentesis should be considered whenever appropriate, after careful consideration of the risk/benefit balance for such invasive measures.

Treatment and follow-up

The patient declined referral to a phase I/II clinical trial centre. Palliative care support in the community was instituted to manage her pain and fatigue. She deteriorated rapidly and died a month later.

Further reading

Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. Journal of Clinical Oncology1997; 15: 2403–2413.

Callery MP, Chang KJ, Fishman EK, et al. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Annals of Surgical Oncology 2009; 16: 1727–1733.

Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Annals of Oncology 2008; 19: 1592–1599.

Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. New England Journal of Medicine 2011; 364: 1817–1825.

Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. Journal of Clinical Oncology2009; 27: 5513–5518.

Huguet F, André T, Hammel P, et al. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. Journal of Clinical Oncology2007; 25: 326–331.

Loehrer PJ Sr, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. Journal of Clinical Oncology2011; 29: 4105–4112.

Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology 2007; 25: 1960–1966.

Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. Journal of the American Medical Association, 2010: 304: 1073–1081.

Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. Journal of the American Medical Association 2007; 297: 267–277.

Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. The Lancet 2011; 13: 607–620.