The role of chemotherapy in the treatment of pancreatic carcinoma

Patients with unresectable and metastatic pancreatic cancer are incurable and optimal palliation is the goal of therapy. If these patients have symptoms of biliary or duodenal obstruction they may benefit from palliative bypass procedures. Pain associated with local tumour infiltration may be palliated with radiation, with or without chemotherapy, or by coeliac nerve blocks or local neurosurgical procedures. Chemotherapy with gemcitabine has modest objective response rates, but can improve symptoms.

Pancreatic cancer remains one of the most feared gastrointestinal tract malignancies. There are 1800 new cases annually and the overall median survival is 3-5 months with a 12-month survival of 10% and a five-year survival of 3%.^1,2 Pancreatic cancer is usually diagnosed late, curative surgery is rare and requires specialised expertise found in few centres.³ It is characterised by early metastasis and resistance to all cancer treatment modalities.

The aetiology is not well understood, but risk factors thought to be associated with pancreatic cancer include smoking which increases risk twofold and chronic pancreatitis which increases the risk 5-15 fold. Hereditary cancer accounts for about 5%, but overall up to 60% of cases remain unexplained.⁴

An important minority of patients present with truly localised but inoperable disease. Local control remains an important issue in this group of patients in terms of symptomatic palliation of pain, and prevention of bleeding and obstruction. These patients may benefit from palliative bypass of biliary obstruction by endoscopic, radiologic or surgical techniques. Duodenal obstruction may require a surgical bypass.

Local radiation may palliate pain associated with unresectable cancer, but it has no impact on survival. An alternative approach is the use of coeliac plexus blocks. These are associated both with improved pain control in otherwise opioid-resistant patients and in one study with increased survival.

The role of combined local radiation and chemotherapy emerged some 30 years ago. The Gastrointestinal Tumor Study Group showed a doubling in median survival with chemo-irradiation compared to radiation alone⁵ There have been several conflicting studies, but there is promise that the therapeutic ratio will improve with modern radiotherapy techniques and three-dimensional planning systems. Patients should be invited to enrol in trials of these techniques to identify optimal strategies. Ultimately it remains to be proven whether chemotherapy alone or combined therapy can give this group of patients the greatest promise of tumour control, symptom palliation and survival with less toxicity.

There have been major changes in the management of patients with metastases. The improvements in supportive care used to manage the symptoms of locally advanced disease have dramatically altered quality of life. The use of anabolic drugs such as megestrol acetate, dexamethasone and pancreatic supplements may also improve quality of life.

Until 1995 there was little evidence that chemotherapy provided any benefit, as the drugs were toxic and did not significantly improve survival. In randomised trials no combination regimen was superior to 5-fluorouracil (5-FU) alone, however perceptions have changed after two small randomised studies showed improved survival over best supportive care.^6,7

Gemcitabine

Gemcitabine is a deoxycytidine analogue, which is converted by deoxycytidine kinase into an active triphosphate metabolite and induces its own activation intracellularly. It has substantial anticancer activity in non-small cell lung cancer, pancreatic cancer, ovarian cancer and non-Hodgkin's lymphoma. The first study in patients with pancreatic cancer refractory to 5-FU showed a response rate of 9.5%, a six-month survival of 31%, and a median survival of 3.9 months. A subsequent initial therapy study which randomised patients to receive gemcitabine or 5-FU showed a significant increase in one-year survival (18% versus 5%) and improved quality of life specifically focusing on the issues important in pancreatic cancer, namely pain, weight loss and performance status.⁸ Subsequent confirmation in a large phase IV report on over 3000 patients has reinforced this finding.⁹ Gemcitabine has subsequently been studied in a large number of randomised phase III studies. These studies, involving comparisons including both 5-FU and novel therapies, have confirmed the initial data.

An overview of all the large reported phase III studies shows that after a median 3-4 cycles of chemotherapy, the response rate is 15-25%, with a median survival of 5-6.7 months and one-year survival of 18%.¹⁰ Gemcitabine has consistently been superior to other single drugs. Attempts to improve upon this by combination with other drugs that are either synergistic in laboratory studies or other tumours have had mixed results. Neither cisplatin, nor a variety of permutations of 5-FU, nor any of a number of novel chemotherapy drugs have improved survival. As a result single drug gemcitabine remains the drug of choice for patients with metastatic pancreatic cancer who have a reasonable performance status and opt for chemotherapy.

The principal adverse effects of gemcitabine are nausea, vomiting and neutropenia. In an overview of 3000 patients only 4% discontinued because of drug-related adverse events.

New drugs

Novel targeted drugs have received extensive attention in view of the relative insensitivity of pancreatic cancer to conventional therapy. Metalloproteinase inhibitors to inhibit metastatic spread and an attempt to inhibit components of the tumour-activating pathway, such as ras, using a farnesyl transferase inhibitor have been ineffective. 5-FU in optimised schedules such as infusional 5-FU or in combination with leucovorin, or capecitabine, or new drugs such as irinotecan, does not increase survival over gemcitabine alone. Most recently, adding oxaliplatin has improved progressive-free survival, but not overall survival.¹¹

Other studies have been directed at inhibition of epidermal growth factor receptor. There has also been substantial interest in the role of angiogenesis inhibitors following reports of enhanced activity in colon cancer for 5-FU and irinotecan when combined with bevacizumab - a vascular endothelial growth factor ligand inhibitor. Other receptor inhibitors are also likely to be studied given the high expression of vascular endothelial growth factor receptor on pancreatic cancer cells. Some of these are in the early stages of clinical investigation.

Although the increased activity of combination therapy has not translated into improved overall survival, response rates are reaching 30% so further studies of combinations of newer drugs are likely. Outside of clinical trials, however, single drug gemcitabine remains the chemotherapy of choice for metastatic disease.

Adjuvant therapy

Perhaps most promising are recent data suggesting an improved outlook for those patients who undergo potentially curative surgery, all of whom remain at very high risk of relapse. The European Study Group for Pancreatic Cancer (ESPAC) 1 trial is the largest adjuvant therapy study ever performed. It was built in part upon the Gastrointestinal Tumor Study Group results and also a small Scandinavian study which randomised 47 patients to combination chemotherapy and found an increased median survival of 23 months compared with 11 months for observation.

The ESPAC was a 'pragmatic' study that randomised 541 patients from 11 European countries. It had four arms with a 2 x 2 factorial design that compared the effects of adjuvant chemoradiation, chemotherapy, chemoradiation followed by maintenance chemotherapy, and observation. Just over half of the patients were randomised to the 2 x 2 factorial design, the rest were recruited to a non-factorial arm. These complexities make accurate analysis of the findings quite difficult. When all the results were pooled, adjuvant chemotherapy was superior to no chemotherapy with a median survival of 19.7 months versus 14 months (p = 0.0005). The 2 x 2 factorial result is also significant; the five-year survival rate was 20% in those receiving chemotherapy and 8% in those not,¹², strengthening the conclusions. The study used 5-FU chemotherapy given for five days per month as a bolus injection, and this should now be regarded as the standard against which all new adjuvant studies should be performed.

Pancreatic cancer remains a formidable problem, but recent advances have at least resulted in a small but meaningful proportion of patients living longer. Similarly, a much larger group is now being offered a better quality of life through improved palliation. Promising new avenues of therapy are a reason for cautious optimism.

Associate Professor Goldstein has acted as an advisor on several occasions for Eli Lilly and for other oncologic pharmaceutical companies, including Pharmacia/Pfizer, Roche, Merck AG and Novartis. He is on the board of the Australasian gastrointestinal clinical trials group and the executive of the Clinical Oncology Society of Australia. He is principal investigator on a number of current and recent trials in pancreatic cancer.

The following statements are either true or false.
Click anywhere on the panel for the answers.

1. The pain of pancreatic cancer may be resistant to opioids.

2. Adjuvant therapy does not improve survival after surgical resection of pancreatic cancer.

Answers to self-test questions

1. True

2. False