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A new licensed agent for pancreatic cancer is due to be launched this year as ongoing research starts to pay dividends, says Mark Greener

 

 

Pancreatic cancer (PC) has a dismal prognosis. During 2010, doctors diagnosed 8,463 cases in the UK and 7,901 people died from the malignancy, according to Cancer Research UK.

Between 2005 and 2009, only 3.7 per cent of adults with PC in England survived for at least five years. Pancreatic Cancer Action (PCA) says PC is the UK’s fifth largest cause of cancer deaths and could pass breast cancer to become the fourth biggest by 2030.

Early diagnosis and treatment offers the only hope of a cure. However a PCA survey found that GPs initially told half of PC patients that they had “nothing to worry about”. Nearly 40 per cent of patients waited at least four months between first reporting symptoms and referral to a pancreatic specialist. Thirteen per cent waited at least 12 months and one in 10 waited more than 18 months. Forty per cent made at least four GP visits before referral and nearly one in 10 visited their GP 10 times or more.

Pancreatic cancer has a dismal prognosis but is one of the most rapidly moving areas in oncology

Early detection

Until recently, scientists and clinicians had made little progress in understanding and tackling the malignancy, but delegates at a recent Pancreatic Cancer Forum in Madrid heard about numerous breakthroughs in basic biology, diagnosis and treatment.

“Pancreatic cancer is now one of the most rapidly moving areas in oncology. We’ve recently made huge leaps in our understanding and are starting to see the benefits,” said the forum’s co-chair Manuel Hidalgo, head of gastrointestinal cancer at the Spanish National Cancer Research Centre.

“The prognosis of most pancreatic cancer patients is poor due to their disease being diagnosed at an advanced stage, with many facing a life expectancy of only a few months,” Ali Stunt, founder of Pancreatic Cancer Action told Pharmacy Magazine. “However, for those who are diagnosed in time for surgery, their chances of surviving beyond five years increases 10-fold, which is why early diagnosis is crucial if we are to improve the currently dire survival rates.”

Unfortunately, detecting early PC is notoriously difficult. Many people, men in particular, put off going to their doctor until their situation becomes an emergency, says Stunt. “We need people to understand that if they have persistent symptoms that are not normal for them, they can bother their doctor. Community pharmacists can help get more people diagnosed sooner.”

Pharmacists should watch for signs and symptoms of PC, says Stunt. “Classic symptoms may indicate late-stage PC, but if suspected, patients need to be referred urgently to their GP. Other symptoms to look out for include newly diagnosed type 2 diabetes that is not associated with a metabolic condition – this can occur one to two years before the diagnosis of PC,” says Stunt. Indeed, having diabetes for more than three years increases PC risk by between 57 and 80 per cent¹.

Pharmacists also need to be suspicious of resistant dyspepsia. “Pharmacists are in a good position to discuss symptoms when conducting MURs and, in particular, to look out for patients with persistent dyspepsia that is not responding to proton pump inhibitors, who should be referredtotheirGP,” Stunt comments.

Catching early cases

Characterising biomarkers for early-stage disease is a major research goal, while genetic screening might help detect more early cases: a family history increases the risk of developing PC by 60 per cent¹. The forum heard about several potential genetic markers – for example, proteins encoded by BRCA have several critical roles, including repairing breaks in DNA. BRCA variants contribute to several malignancies including breast, fallopian tube, ovarian and peritoneal cancer². John McPherson of the Ontario Institute for Cancer Research told the forum that BRCA2 is associated with a 3.5-fold increased risk of PC and may account for approximately 4 per cent of cases.

Improving treatment

The bleak prognosis of pancreatic cancer also reflects its inherent resistance to treatment, partly because of the stroma: the dense ‘shell’ encasing the core of malignant cells. The stroma, which accounts for most of the tumour mass, acts a physical barrier to chemotherapy and reduces radiotherapy’s effectiveness. So the discovery that combining oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) was more effective than gemcitabine (the standard of care) in first-line therapy of metastatic PC proved a revelation.

Median overall survival (OS) was 11.1 months with FOLFIRINOX and 6.8 months with gemcitabine, a 43 per cent improvement. Median progression-free survival (PFS) was 6.4 and 3.3 months respectively – a 53 per cent improvement³.

“Anecdotally, some patients show a good response to FOLFIRINOX and some centres use it not only in the metastatic setting but also in the neo- adjuvant setting, sometimes with chemoradiation, to downstage tumours,” Stunt says. “The problem is toxicity. FOLFIRINOX can be given only to patients with excellent performance status”.

Some centres lower the dose to reduce toxicity but the forum heard that further studies need to assess the efficacy of ‘FOLFIRINOX-light’.

“Patients have reported that the side-effects are tough but ‘do-able’, but in other cases we know patients have had to be hospitalised with severe diarrhoea,” Stunt adds.

“FOLFIRINOX is a combination for only a select few.”

CHMP recommendation

In November, CHMP recommended approving nab-paclitaxel (currently used for metastatic breast cancer) with gemcitabine for first-line treatment of metastatic pancreatic adenocarcinomas, which account for about 95 per cent of PCs.

Nab-paclitaxel binds the taxane to nanoparticles of albumin. This allows nab- paclitaxel to use the cells’ active transport mechanisms for albumin to get more taxane through the stroma and into the tumour. Nab-paclitaxel and gemcitabine significantly improved, for example, median OS (8.5 versus 6.7 months respectively) and PFS (5.5 versus 3.7 months respectively) compared to gemcitabine alone⁴.

“Nab-paclitaxel and gemcitabine could have a place don’t have the performance status for FOLFIRINOX, as the toxicity is less,” Stunt comments. “However, peripheral neuropathy can be an issue for some patients”. (The forum heard that most cases of neuropathy are rapidly reversible.)

“Currently nab-paclitaxel is not licensed in the UK, but we hope it will be in early 2014,” Stunt adds. “If so, it will be the first new licensed agent for pancreatic cancer since gemcitabine in the 1990s. The lower toxicity could mean that nab-paclitaxel is an option for more patients than FOLFIRINOX.”

References

1. PloS one 2013; 8:e72311
2. The Journal of Pathology 2013; 230: 347-9
3. New England Journal of Medicine 2011; 364:1817-25

E-learning

• PCA has developed a free CPD-accredited e-learning module for GPs that might interest pharmacists.
• PCA can also provide pharmacies with free symptom awareness materials, including posters and leaflets. Contact www.pancreaticcanceraction.org or call 0303 040 1770