Pancreatic adenocarcinoma – emerging therapies

Pancreatic adenocarcinoma is the most common histological subtype of pancreatic malignancy, accounting for more than 90% of pancreatic tumours, and is the fourth most common cause of cancer-related death in the US. In Ireland, the recent National Cancer Registry annual report found that pancreatic cancer was the fifth most common cause of cancer death, with an average of 490 deaths each year between 2010 and 2012, and no improvement in mortality since 1994. It is often diagnosed at a late stage when tumours are either inoperable or metastatic, and therefore prognosis is extremely poor. 

Pancreatic cancer and female lung cancer were the only cancers to show increases in mortality rates between 2009 and 2013.¹ In 2013, 38,000 deaths were attributable to pancreatic cancer in the US. Five year survival rates are estimated at 5-20%, although with metastatic disease this decreases to 2%,^2,3 while median overall survival (OS) ranges between four and 22 months.⁴ The lifetime risk of developing pancreatic cancer is 1.49%, while the higher incidence is seen in older age groups, males, African-Americans and lower socioeconomic groups. 

Risk factors

Risk factors associated with the development of pancreatic adenocarcinoma include hereditary causes. Familial pancreatic cancer has been described in patients with at least two first-degree relatives with the disease and accounts for approximately 9% of pancreatic cancers.⁵ It is associated with an autosomal dominant inheritance pattern, some with germline mutations in BRCA2, PALB1 and ATM.⁶ Genetic conditions such as hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (HNPCC), familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), familial atypical multiple mole melanoma syndrome (FAMMM), hereditary pancreatitis (HP), cystic fibrosis (CF), and ataxia-telangiectasia (AT) increase the risk of developing pancreatic adenocarcinoma.⁷ Chronic pancreatitis is a strong risk factor for pancreatic cancer, with a 13-fold increased risk.⁸ Other environmental factors include cigarette smoking, excess alcohol use, increased body mass index and type 1 diabetes. Precursor lesions to invasive pancreatic cancer such as pancreatic intraepithelial neoplasms, mucinous cystic neoplasms, and intraductal papillary mucinous neoplasms are associated with improved outcomes after resection compared with invasive tumours.⁹ However, screening programmes for pancreatic neoplasms have not yet yielded promising results and there is no consensus on screening for high-risk patients.^7,10

Diagnosis and staging

Presentation of pancreatic cancer is varied, with symptoms including abdominal pain, weight loss, jaundice, dyspepsia, nausea and floating stools. New diagnosis of type 2 diabetes mellitus and hyperglycaemia are also associated with pancreatic cancer.¹¹ Diagnosis is usually by radiological imaging (CT or MRI) which demonstrates a pancreatic mass and is usually accurate in staging tumours as resectable or unresectable, although there are limitations to these including lymph node and peritoneal assessment.^12,13

Endoscopic ultrasound is increasingly being used as an adjunct to conventional imaging, especially in further assessment of involvement of lymph nodes or vascular structures prior to surgical intervention. PET/CT with standard CT is increasingly used as a staging investigation, having shown superior sensitivity for detection of metastatic disease compared with CT alone.¹⁴

EUS-guided fine needle aspiration is the standard method of obtaining tissue for histological confirmation. CT-guided FNA is an alternative technique. Staging of pancreatic cancer is by the AJCC TNM system developed in 2010, with a T4 tumour being unresectable at diagnosis. The tumour marker CA19.9 may be useful as a serum biomarker and for following response to treatment.

Surgery

Surgery is the only curative therapeutic option available for pancreatic adenocarcinoma. Unfortunately, only 10-20% of patients are deemed surgical candidates at diagnosis, with resectable or borderline resectable tumours.¹⁵ The surgical options are Whipples procedures, distal pancreatectomy for distal tumours, or total pancreatectomy. 

However, even in patients undergoing radical resection, the prognosis remains poor with median OS of 20 to 24 months due to the high rate of relapse after surgery.¹⁶ In one large study, of 175 patients who underwent resection of their tumours with no adjuvant treatment, 92% developed recurrent disease, with both local recurrence and distant metastases occurring at a median follow up of 53 months.¹⁷ The degree of margin clearance at surgery is predictive of outcome, with a resection with margins of greater than 1.5mm predicting improved survival (median 18.4 months), while involved margins predicted poor survival rates (median 13.2 months).¹⁸ Other factors which correlated with overall survival included tumour size, lymphovascular invasion, tumour location (pancreatic head tumours having improved survival) and lymph node involvement.

Neoadjuvant therapy

Neoadjuvant chemoradiation therapy has been used in recent years in an attempt to improve resectability rates. There have been no phase III trials examining neoadjuvant treatment in pancreatic cancer. A small phase II trial randomised 50 patients with potentially resectable tumours to either gemcitabine alone or gemcitabine and cisplatin in the neoadjuvant setting.¹⁹

Combination therapy was associated with higher rates of resection (70% versus 38%) and improved one-year survival (62% versus 42%) compared with gemcitabine therapy alone. In a retrospective review of 160 patients with borderline resectable tumours, 66 patients completed full neoadjuvant chemoradiation therapy and surgical resection.²⁰ The median OS in the treated group was 40 months, compared with a median OS of 13 months in patients who did not proceed to surgical resection. Of note, patients with a pathological response seen in their tumours or with a decline in CA19.9, had improved outcomes. 

A meta-analysis compared patients with upfront resectable tumours and those with initially unresectable tumours receiving neoadjuvant therapy.²¹ Approximately one third of patients with initially unresectable tumours were downstaged to be considered resectable, with combination chemotherapy resulting in higher response rates than single agent chemotherapy. 

Patients with locally advanced tumours at presentation may benefit from induction chemotherapy with gemcitabine, in order to distinguish the patients who may respond to full neoadjuvant treatment from those with rapidly progressive or unresponsive disease.^22,23

Adjuvant therapy

The CONKO-001 trial randomised patients who had an R0 or R1 resection of pancreatic cancer to either adjuvant gemcitabine chemotherapy for six months or observation alone.¹⁷ There was a significant advantage in favour of gemcitabine treatment with significantly improved disease-free survival (13.4 months versus 6.9 months). Three-year survival with gemcitabine was 36.5% compared with 19.5% with observation only. In final analysis in 2013, five year OS was 20.7% with gemcitabine compared with 10.4% with observation only.²⁴ Another randomised trial in Japan comparing surgery alone with surgery and adjuvant gemcitabine demonstrated improved disease-free survival, although this study did not show improved overall survival.¹⁶

The ESPAC-1 trial enrolled 289 patients, randomised to adjuvant chemoradiation, chemotherapy alone, both treatments or observation only.²⁵ This trial showed an improvement in OS with adjuvant chemotherapy compared with chemoradiation (20.1 months versus 15.9 months), with no differences in quality of life assessment. ESPAC-3 looked at 434 patients with resected periampullary carcinoma and found that there was a significant survival benefit with adjuvant chemotherapy (either gemcitabine or fluorouracil) compared with observation alone on multivariate analysis.²⁶ The ESPAC-3 trial also showed no advantage to gemcitabine treatment over fluorouracil treatment, although there were fewer serious adverse events with gemcitabine.²⁷ Adjuvant radiation therapy has been shown to improve outcomes in combination with chemotherapy.²⁸

Unresectable or metastatic disease

For many years chemotherapy using single agent gemcitabine has remained the standard of care in first-line treatment of unresectable or metastatic pancreatic cancer. Combinations of gemcitabine with other agents such as platinum-containing drugs or fluoropyrimidines did not yield improvements in overall survival in randomised trials.^29,30

However, a meta-analysis of chemotherapeutic regimens demonstrated a modest survival advantage with gemcitabine combination therapy compared with gemcitabine alone, with a hazard ratio of 0.91.31. A randomised trial of 557 patients treated with either gemcitabine alone or gemcitabine in combinations with erlotinib, an EGFR-targeted agent, demonstrated an increase in OS of just two weeks with combination therapy compared with single agent gemcitabine (6.24 versus 5.91 months).³²

The PRODIGE trial assigned 342 patients with metastatic pancreatic cancer to receive either FOLFIRINOX (oxaliplatin, irinotecan, leucovorin and 5-fluorouracil as a bolus followed by a 46-hour infusion) or gemcitabine.³³ Overall survival results were very promising, with an OS of 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group. Median PFS was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group, while objective response rates were 31.6% and 9.4% respectively. There were significant rates of grade 3 and 4 toxicities associated with FOLFIRINOX, including neutropaenia, diarrhoea and neuropathy. However, despite these adverse effects, the rates of degradation of quality of life were higher in the gemcitabine group (66%) than in the FOLFIRINOX group (31%). A further analysis of this data has been published, again demonstrating an increased time to deterioration in various quality of life factors, both physical and psychological, in patients treated with FOLFIRINOX compared with gemcitabine.³⁴

The SCALOP trial enrolled patients with locally advanced pancreatic tumours, who were treated with induction gemcitabine and capecitabine for 12 weeks.³⁵ If their disease was stable or responding, they were randomised to either gemcitabine and radiation therapy or capecitabine and radiation therapy. Median OS was 15.2 months in the capecitabine group compared with 13.4 months in the gemcitabine groups, with higher rates of haematological toxicity with gemcitabine, suggesting that capecitabine with radiation therapy may be a preferable treatment option in locally-advanced disease. 

The MPACT trial randomised 861 patients with metastatic pancreatic cancer to receive either gemcitabine alone or gemcitabine in combination with nab-paclitaxel (albumin-bound paclitaxel).³⁶ Overall survival was improved in the nab-paclitaxel group, with one-year survival 35% in the nab-paclitaxel group compared with 22% in the gemcitabine group, while response rates were 23% in the nab-paclitaxel group and 7% in the gemcitabine group. Grade 3 or 4 adverse events were more common in the nab-paclitaxel group, with the most common being neutropaenia, fatigue and neuropathy.

The recently published CONKO-001 trial examined second-line treatment in 168 patients who progressed through first-line gemcitabine treatment.²⁴ The study found improved OS with oxaliplatin in addition to fluorouracil and folinic acid compared with fluorouracil/folinic acid only (5.9 months versus 3.3 months). 

Future directions

A recent retrospective study found improved overall survival and recurrence free survival in patients who received two years of adjuvant capecitabine in addition to adjuvant chemotherapy compared with those who received adjuvant chemotherapy alone,³⁷ suggesting that this may be a future treatment option for long-term disease control. Newer agents in the setting of metastatic disease are also being investigated, such as evofosfamide, which has shown promising results when combined with gemcitabine.³⁸ MEK inhibitors, mTOR inhibitors and immunological therapies are also in phase I and II trials at present. In Ireland, the ICORG group has participated in several trials involving new agents or chemotherapy regimens for the treatment of pancreatic cancer, such as the Primo Vax trial examining use of a telomerase peptide vaccine, and the ICORG 08-39 trial which evaluated the combination of lapatinib and capecitabine in the treatment of metastatic pancreatic cancer.

Conclusion

Pancreatic adenocarcinoma remains a devastating cancer diagnosis, with the majority of patients unresectable at diagnosis and having a poor prognosis. For the small percentage of patients who undergo resection of their primary pancreatic tumour, recurrence rates are extremely high. However, newer treatment options are now available. Neoadjuvant chemoradiation therapy offers some patients the option of conversion from unresectable to resectable disease, while adjuvant chemotherapy improves outcomes. For patients with locally-advanced or metastatic disease, newer chemotherapy regimens such as FOLFIRINOX or gemcitabine and nab-paclitaxel are associated with longer overall survival with preserved quality of life. Ongoing studies of novel therapeutic agents may further improve outcomes for patients with pancreatic adenocarcinoma. 

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