New treatments for metastatic pancreatic cancer

Cancer of the pancreas is one of the most difficult cancers to treat and is associated with a very poor prognosis for patients. It is the tenth most common cancer in the UK,¹ and ninth in Europe,² with a UK incidence of 8800 new cases per year. It the fifth most common cause of cancer death in the UK and Europe, the high death rate reflecting the very poor survival rate, with only 3% of pancreatic cancer patients surviving five years. Nearly all pancreatic cancers are ductal adenocarcinomas, originating from the exocrine (digestive enzyme-producing) part of the pancreas. There are also rare types of endocrine tumours – pancreatic neuroendocrine tumours – that are not discussed in this article. Surgery offers the greatest chance of survival, but this is only possible in early, limited stage, disease, and most pancreatic cancer is diagnosed as metastatic disease too late for curative surgery.

5-Fluorouracil (5-FU) was the standard of care up until 1997, despite having poor response rates and a median survival of only six months.³ In 1997, Burris et al demonstrated the superiority of gemcitabine over 5-FU, establishing gemcitabine as the standard treatment. The trial looked at gemcitabine 1000mg/m2 seven times weekly followed by one week of rest, then three times weekly every four weeks thereafter versus 5-FU 600mg/m2 once weekly.⁴ The median overall survival was 5.65 months in the gemcitabine arm versus 4.41 months for 5-FU (p=0.0025). The trial showed clinical benefit response in 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (p=0.0022) and survival at 12 months improved from 2% in the 5-FU arm to 18% in the gemcitabine arm.

Since 1997, many clinical trials have looked at combining gemcitabine plus ‘drug X’ versus gemcitabine in an effort to improve the standard of care; unfortunately most have failed. Chemotherapeutic agents that have failed to show significant benefit in combination with gemcitabine include capecitabine, cisplatin, irinotecan and oxaliplatin.^6–9 Trials with these drugs all showed some early promise, for example, improvements in time to disease progression, but none showed a statistically significant survival advantage over gemcitabine alone. For example, capecitabine, an oral pro-drug of 5-FU has some activity in pancreatic cancer. However the results of the trial looking at combination of gemcitabine with capecitabine versus gemcitabine monotherapy only showed a trend towards a median overall advantage, 7.1 months versus 6.2 months (five weeks). With a p value of 0.08, this trial failed to reach statistical significance.⁶

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Gemcitabine, difluorodeoxcytidine (dFdC), is a pyrimidine analogue that is converted intracellular by phosphorylation into its active metabolites the 5′-diphosphate (dFdCDP) and 5′-triphosphate (dFdCTP). It inhibits DNA synthesis through the actions of these two active metabolites. First, dFdCDP inhibits ribonucleotide reductase, an enzyme that catalyses reactions that generate the deoxynucleoside triphosphates required for DNA synthesis. Second, dFdCTP competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA and, after incorporation into DNA, appears to induce programmed cell death (apoptosis).⁵

Paclitaxel is an antimicrotubule agent that stabilises microtubule formation during cell division, resulting in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. Nab-paclitaxel contains human serum albumin–paclitaxel nanoparticles. Upon intravenous administration, the nanoparticles dissociate rapidly into smaller soluble, albumin-bound paclitaxel complexes. In vitro studies demonstrated that the presence of albumin in nab-paclitaxel nanoparticles enhances transport of paclitaxel across endothelial cells, optimising delivery of the drug. The use of albumin rather than organic solvents, for example, polyoxyethylated castor oil, in standard paclitaxel formulations also reduces the risk of an allergic reaction than with standard paclitaxel.

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These trials highlighted the fact that the majority of patients in metastatic pancreatic cancer trials gain little benefit, so there is an unmet need to be able to identify any subgroups of patients that are more responsive to treatment. In most other tumours, there have been significant developments in molecularly targeted therapies, with the aim of blocking the pathways that support the development, survival and progression of cancer cells. However, so far in pancreatic cancer, the early promise of pathways that could be targeted has not resulted in significant improvements. A high proportion of pancreatic cancers overexpress epidermal growth factor receptor (EGFR). Erlotinib (Tarceva®), an EGFR tyrosine kinase inhibitor, is licenced for treatment of patients with metastatic pancreatic cancer in combination with gemcitabine. The combination showed a statistically significant survival benefit over gemcitabine alone in locally advanced or metastatic disease (median overall survival 6.4 months versus 6 months, p=0.038).¹⁰ While of scientific interest, the clinical relevance of a survival difference of less than two weeks can be questioned. With such small benefit, it is hard to justify the additional drug acquisition cost and additional toxicities of the regimen. The effect of combining cetuximab (Erbitux®), another EGFR inhibitor, with gemcitabine was also studied but did not result in a statistically significant survival advantage compared with treatment with gemcitabine alone (6.3 versus 5.9 months, p=0.23).¹¹ Bevacizumab (Avastin®) is another novel therapy that targets the VEGF pathway inhibiting angiogenesis (the growth of new blood vessels) in many tumours. Bevacizumab in combination with gemcitabine failed to deliver any improvement in overall survival in metastatic pancreatic cancer compared with standard gemcitabine (5.9 months versus 5.8 months; p=0.54).¹²

Despite these failures, there are two successful treatments that have improved on gemcitabine alone, that is gemcitabine plus nab-paclitaxel and the FOLFIRINOX regimen, both of which have shown statistically significant improvements over single-agent gemcitabine.

The MPACT13 trial was a key Phase III study that randomised weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone. The trial was large: 861 patients with 431 patients randomised to nab-paclitaxel and gemcitabine arm; and 430 patients to gemcitabine alone. The dosing regimen used was IV nab-paclitaxel at 125mg/m2 on day 1, 8 and 15 of each 28 day cycle, followed by IV gemcitabine at 1000mg/m2 on day 1, 8 and 15 of each 28-day cycle compared with the standard gemcitabine 1000mg/m2 schedule.

The median overall survival was first reported as 8.5 months in the nab-paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (p<0.001).¹³ An updated analysis showed a slight increase in median overall to a two month advantage; 8.7 months versus 6.6 months hazard ratio (HR) =0.72 (95% CI, 0.62–0.83; p< 0.0001).¹⁴ The one-year survival rate was 35% in the nab-paclitaxel/gemcitabine group versus 22% in the gemcitabine group. The median progression-free survival was 5.5 months in the nab-paclitaxel/gemcitabine group, and 3.7 months in the gemcitabine group (p<0.001).

Nab-paclitaxel/gemcitabine was more toxic than gemcitabine with significant increases in neutropenia (38 versus 27%), fatigue (17% versus 1%), and neuropathy (17% versus 1%). Quality of life (QoL) data have not yet been published regarding this regimen, although the manufacturer has indicated this is being collected in an ongoing trial. QoL data can help payers, clinicians and patients to decide if combination therapy that offers a small increase in clinical benefit with expense of additional toxicity is worth pursuing. QoL assessment should be considered crucial in a disease with such poor outcomes as pancreatic cancer, but unfortunately many trials have not collected QoL data.

Nab-paclitaxel/gemcitabine combination therapy is being used as the first choice comparator arm for many pancreatic cancer clinical trials. At the time of writing, there were over 60 ongoing clinical trials listed on www.clinicaltrials.gov using nab-paclitaxel/gemcitabine as the comparator arm in metastatic pancreatic cancer.

The other combination regimen that has shown improvement versus single agent gemcitabine does not actually contain gemcitabine. A randomised Phase II/III trial of the FOLFIRINOX regimen versus gemcitabine showed significant survival advantage for the combination regimen; overall survival 11 months versus 6.8 months (HR 0.57; 95% CI 0.45–0.73, p<0.001).¹⁵ The FOLFIRINOX regimen is oxaliplatin 85mg/m2, irinotecan 180mg/m2, leucovorin 400mg/m2 and 5-FU 400mg/m2 given as a bolus followed by 5-FU 2400mg/m2 given as a 46-hour continuous infusion, every two weeks. The one-year survival for the combination regimen was 48%, which is considerably higher than any previously published figure. Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (p<0.001). However, FOLFIRINOX was more toxic than gemcitabine; 5.4% of patients in this group had febrile neutropenia.

Fortunately the trial also included QoL assessment, In this case the QoL data showed that despite FOLFIRINOX being more toxic, patients had a better quality of life, with significant increases in the time until definitive deterioration in the quality of life noted in the FOLFIRINOX group. At six months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of quality of life, versus 66% in the gemcitabine group.

One factor to consider with this trial is that the patient selection criteria were more rigorous than those in other pancreatic cancer studies. Patients had to have a good performance status (ECOG status score of 0 or 1). In the real world, patients may not be as well and have as good a performance status, and therefore some may not tolerate the FOLFIRINOX regimen, necessitating careful selection of patients. The toxicity profile increased means this regimen will only be suitable for patients who are able to manage the increased risk of toxicity.

One question we do not have the answer to is: which regimen – FOLFIRINOX or gemcitabine/nab-paclitaxel – should be first choice? Both can be considered standard treatment options for patients with advanced pancreatic cancer, but there is also a place for single agent gemcitabine, which is still widely used for patients, not fit enough to tolerate combination therapy.

In recent years, many poor prognoses cancers that have been traditionally difficult to treat (for example, lung cancer and renal cancer) have benefited from the development of targeted therapies. In metastatic pancreatic cancer, only two regimens, FOLFIRNOX and gemcitabine plus nab-paclitaxel, have demonstrated significant improvement over single agent gemcitabine, which has been the mainstay treatment of advanced disease for the last 15 years. Despite these advances, survival rates remain depressingly low. There is an unmet need to find biological targets that can be effectively targeted with novel therapies to improve survival in pancreatic cancer.

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