Management is highly dependent on:
- The stage of disease
- The age of the patient
Rarer tumour types are managed differently.
Localised disease (T1-T3, N0-1)
Once the diagnosis and stage are confirmed, patients with this stage of disease should proceed with pancreato-duodenotomy (Whipple's procedure) if medically fit. This offers the only chance of cure. Median survival after surgery approaches 1 1/2 years in these patients; 5 year survival is 20%. Modern surgical techniques have reduced the mortality of pancreato-duodenotomy to < 5%.
Regardless of the surgical outcome, there remains a high risk for both local and distant recurrence following surgical resection. This has prompted a number of studies looking at the role of adjuvant chemotherapy, radiotherapy or both. There is some overlap in the use of chemotherapeutic agents and radiotherapy between resected and non-resectable disease.
Controversy exists regarding neo-adjuvant and adjuvant therapies for patients with resectable disease.
- The initial study by the gastro-intestinal tumour study group (GITSG) suggested improved survival for patients who received adjuvant chemoradiotherapy (40 Gy + adjuvant bolus 5-FU)
- Only 43 patients were randomised, but the treatment group's median survival was significantly longer at 20 months vs 11 months; 2 year survival improved from 15 to 42%.
- Unexpectedly, local failure occurred in 33% of untreated versus 47% of treated patients. This is an argument against radiotherapy.
- An EORTC study also demonstrated improved median survival in patients receiving chemoradiotherapy
- 2 year survival was 37 vs 23% in the chemoradtiotherapy versus no treatment arm, falling to 20% vs 10% at 5 years. The results were not significant.
- The ESPAC-1 study was a doubly randomised trial (observation vs adjuvant chemo vs chemo-RT vs chemo-RT + adjuvant chemo) demonstrated improved survival with adjuvant 5-fluorouracil but worse outcomes with chemoradiotherapy alone
- Observation alone: 17 months
- Chemoradiotherapy: 14 months
- Chemoradiotherapy + Adjuvant chemo: 20 months
- Adjuvant chemotherapy alone: 21.5 months (significantly longer)
These trials are all compromised by inferior radiotherapy technique with a split course of 40 Gy in 20 fractions.
The GITSG trial has led to widespread adoption of chemoradiotherapy throughout the United States. The negative European trials have enshrined chemotherapy alone as the treatment choice in Europe. The Americans claim the European trials were flawed (EORTC had a number of patients in the treatment arm with no treatment, the ESPAC trial was 'overly complicated' and had no quality assurance). The Europeans counter with the low numbers of patients in the initial GITSG trial and the statistically significant survival advantage seen with adjuvant chemotherapy alone in ESPAC-1.
The standoff has led to the development of research along different lines. In the USA, researchers are trying to find methods to improve outcomes on top of chemoradiotherapy. The RTOG 97-04 study randomised patients to gemcitabine or 5-fluorouracil before and after chemoradiotherapy (50.4 Gy in 28# with 5-FU). 3 cycles of chemotherapy were delivered prior to and 2 cycles after the chemoradiotherapy. Subset analysis of patients with pancreatic head cancers demonstrated a trend towards improved survival with gemcitabine (31 vs 22% 3 year survival).
In Europe, the CONKO-001 study evaluated the benefit of gemcitabine versus observation. Although median survival was similar (22 vs 20 months, significantly longer) the 5 year overall survival was significantly longer (21 vs 9%) in the gemcitabine arm.
The use of gemcitabine in place of 5-fluorouracil with chemoradiotherapy is under exploration in phase II studies but is not yet mainstream.
This standoff has meant that further trials to determine the role of radiotherapy have had difficulty in being proposed. Currently, the RTOG 08-48 study is accruing patients to examine the role of both the addition of erlotinib to gemicitabine chemotherapy and a second randomisation between an additional cycle of chemotherapy vs chemoradiotherapy with 5FU.
In summary:
- There is no consensus of opinion
- Active treatment should either be:
- Chemotherapy with gemcitabine (as per CONKO-001)
- Adjuvant gemcitabine with chemoradiotherapy (50.4 Gy in 28# with 5-FU 225 mg/m2) after 3 weeks of weekly gemcitabine, as per RTOG 97-04
Neo-Adjuvant Therapy (Resectable Disease)
Neoadjuvant therapy has never been evaluated in randomised controlled trials. A significant volume of phase 2 data exists. The premise of therapy in the resectable setting is to improve the likelihood of negative margins (particularly vascular). The role of neoadjuvant therapy in the resectable setting remains unclear and should only be used in clinical trials.
Locally advanced disease
Locally advanced disease (50% of presentations) presents with an unresectable mass but no distant metastases.
Unresectability depends on the origin of the tumour within the pancreas and the degree to which it has invaded nearby vascular structures - invasion of over half of the superior mesenteric artery, or invasion of the coeliac axis or aorta represent unresectable disease. Tumours that have metastasised to distant lymph nodes or viscera are also unresectable.
The options for treatment in this scenario are:
- Surgical debulking can improve survival but is associated with significant morbidity
- Radiotherapy alone has been used in the past but has proven inferior to chemoradiotherapy (GITSG trial)
- The GITSG unresectable pancreatic cancer trial demonstrated superiority of chemoradiation over radiation alone (median survival 5 months vs 10 months). A follow on study demonstrated superiority of 5-FU with radiotherapy to 54 Gy over chemotherapy alone
- 10% of patients receiving chemoradiotherapy will be converted to an operable state,
- Chemoradiotherapy is popular in the United States; it has proven benefits over radiotherapy alone but there is conflicting evidence on chemoradiotherapy versus chemotherapy alone
- Chemotherapy alone has also been used and remains a popular choice in Europe. Gemcitabine is the most commonly used agent; combination schedules are not well established. The FFCD-SFRO trial examined gemcitabine alone vs with a course of concurrent chemoradiotherapy (using 5-FU and cisplatin). Outcomes were worse for the chemoradiotherapy + gemcitabine arm; critics argue that the dose was too high (60 Gy) and that cisplatin would have caused added toxicity.
Outcomes are poor regardless of treatment approach and chemotherapy, chemoradiotherapy or supportive care all remain viable options that require discussion with patient.
A popular approach is to give several cycles of gemcitabine, and if metastatic disease has not developed deliver a course of chemoradiotherapy. This has been evaluated in retrospective studies but has not been tested in a randomised controlled trial. This approach spares patients potentially toxic radiotherapy treatment if they are going to perish due to gemcitabine resistant metastases regardless.
Summary
Patients should receive gemcitabine, and be restaged at the end of cycle 2. If there is no disease progression, plans should be made to commence chemoradiotherapy (54 Gy + 5-FU) at the end of cycle 3. In patients unable to tolerate infusional 5-FU, capecitabine makes an acceptable alternative.
Metastatic Disease
A landmark trial is the ACCORD 11 trial, which randomised patients between gemcitabine (standard) and 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOL-F-IRIN-OX, note that leucovorin is called xxxxx in America). Response rates of 32% were seen with FOLFIRINOX versus conventional gemcitabine. It is used for patients with good performance status. Gemcitabine is reserved for patients where FOLFIRINOX would not be tolerated.
Rare Histology
Subtopics
Specific management issues for surgery, radiotherapy and chemotherapy are discussed seprately.
