Using Chemotherapy On Patients With Pancreatic Cancer
Pancreatic ductal adenocarcinoma is one of the top five causes of mortality in oncology. It is viewed as a chemotherapy resistant tumour. Exocrine pancreatic cancer is the most common form of this cancer. A second endocrine form of tumour affects Islet cells (1% of cases) and it may be benign or malignant. For the purpose of this article, I will be focusing only on the treatment of ductal cell adenocarcinoma of the pancreas. The development of early detection tools and strategies as well as improvements in imaging and use of tumour markers has helped to revolutionise the treatment of this silent killer. A steady and incremental progress in this area, over the last three decades has led to the conduction of studies surrounding combination therapies. Most current therapies for locally advanced and metastatic disease use gemcitabine-based platforms. However as a general concept, pancreatic adenocarcinoma is a chemoresistant tumour and trials showing response rates of more than 20% are uncommon (1). Therefore, the aim of treatment is almost always palliative and side effect profile of treatment regimes should be taken into account when selecting protocols for patients.
This article reviews and examines the evolution of change in diagnosis and treatment of pancreatic cancer (ductal cell adenocarcinoma) particularly in unresectable locally advanced and metastatic disease. An audit on the palliative chemotherapy for unresectable pancreatic cancer was conducted and the results obtained are portrayed at the end of this paper. The audit reviews the appropriateness and effectiveness of local chemotherapy treatment protocols for patients treated at the Royal Lancaster Infirmary.
Aims of Evidence Review
This review aims to examine the evolution of change in treatment of pancreatic cancer, in resectable, unresectable, locally advanced and metastatic disease. Analysis of the clinical studies from the past thirty years has helped interpret the results of treatment options for pancreatic cancer. The current evidence for gemcitabine as a chemotherapy platform for pancreatic cancer has also been explored.
This analytical study was needed, despite the existing evidence base, for several crucial reasons. Firstly, the disease carries a very poor prognosis and has a relatively common nature. Secondly and more importantly the current treatment has a relatively low efficacy. These areas amongst the current evidence-base will be critically analysed and reflected upon.
A glossary of all abbreviations/acronyms used in this paper can be found in ‘Appendix 6’.
Literature Search Strategy
A systematic literature search strategy was employed to obtain data from medical databases such as PubMed, Medline, EMBASE, Web of Science, Elsevier Science Direct and The Cochrane Library. Extended searches were made using the University MetaLib via the ‘Health and Medicine’ research category. Recently published, well-conducted systematic reviews, primary studies and updated NICE guidelines were selected for inclusion in this systematic review.
Using MeSH and searching different fields by applying limits has refined search results back from databases. Most articles found within this search were then critically appraised; their relevance to this review of evidence was also then decided.
These systematic searches were performed from February 2011 to May 2011 in order to identify suitable studies and meta-analyses published between 1980 and the present day. Although some robust randomised controlled studies have been included which were dated back beyond this period. In this review, only patients with pancreatic ductal adenocarcinoma were included as it has a worse prognosis compared to other pancreatic cancers (2).
Pancreatic cancer treatment Chemotherapy Gemcitabine Fluorouracil
Pancreatic ductal adenocarcinoma is a common cancer with age-standardised incidence rates (per 100,000) of 10.1(males) compared to 7.7(females)(1998-2006) (3). One-year survival for pancreatic cancer is 14.2% (15% males, 13.5% females) and less than 3% of patients have a 5-year survival (3, 4). Pancreatic cancer is the fourth cause of cancer death in the developing world (5). The majority of these tumours are ductal adenocarcinomas (85%)(6). Although surgery offers the chance of cure, the majority of patients present with unresectable disease hence requiring medical intervention.
Aetiology of pancreatic cancer is poorly understood (7). Fewer than 20% of cases are localised to the pancreas itself, meaning a higher cure rate. For those who also have a <2cm tumour and no lymph node involvement with no extension beyond the pancreatic capsule, complete resection yields a 5 year survival rate of 18-24% (8). Symptoms of pancreatic cancer may depend on the site of the tumour in the pancreas and the degree of involvement.
Imaging advances help diagnose the location, stage and identify resectable and unresectable cases (9). For those that are at an advanced stage of cancer, the overall survival (OS) rate of all stages is less than 1% at 5 years, most patients die within 12 months (10-12).
Patients are considered for clinical trials at all stages of pancreatic cancer primarily due to the poor response to current treatments. Palliative treatment, whether it be surgical, radiological biliary compression or gastric outlet obstruction pain relief, they may improve the QoL whilst not affecting the OS (13, 14). Palliation may also improve disabling psychological events associated with the diagnosis and treatment of pancreatic cancer (15).
Aetiology and potential risk factors
Potential risk factors and possible causes for pancreatic cancer can be viewed in table 1 in appendix 2.
Pancreatic cancer is known as the silent killer due to its asymptomatic and non-specific nature in the early stages of disease. Therefore, diagnosis is often when the cancer is advanced stage and the presence of symptoms significantly reduces the patients’ QoL. Common signs and symptoms can be viewed in table 2 appendix 2. The more serious signs and symptoms should result in urgent referral to a specialist team. NICE guidance states referral should be within two weeks for further investigation and management.
Tests examining the pancreas are able to detect, diagnose and stage pancreatic cancer. Accurate staging (TNM Staging) and diagnosis is essential in estimating the chance of resection.
Initial investigations include; FBC, U&Es, LFTs (indicate obstruction of the bile duct due to raised; bilirubin, Gamma GT and ALP levels), Coagulation Profile, Calcium, Albumin, Glucose, CRP should all be checked. A useful tumour marker, Carbohydrate Antigen 19-9 (CA 19-9) is elevated in over 80% of advanced disease patients (16) (80.8% sensitivity and 89.1% specificity) (17). However, CA-19-9 is an ineffective screening tool due to its elevation in numerous other malignancies and even benign conditions (18). Thus, it is not a diagnostic tool for pancreatic cancer.
Pancreatic ultrasound is useful as a first line investigation as it can reveal obstruction of the bile duct suggestive of head of pancreas cancer (50% cases and US has 90% sensitivity) (19). Multi-slice CT is 90% accurate in diagnosing a focal or diffuse pancreatic cancer. CT is helpful in diagnosing adjacent organ invasion, vascular involvement and liver metastases in approximately 50% of patients (20).
Further imaging, such as MRCP is effective for visualising the pancreatic duct and biliary tree for pre-operative patients. ERCP imaging of the bile ducts and pancreatic duct is mainly used to treat incurable cases, as a stent can be placed to relieve deep jaundice (21).
EUS enables the US probe to be placed close to the pancreas, allowing clear imaging and visualisation of small tumours. Definitive diagnosis is made by EUS needle biopsy or surgical excision, by confirming cell-type. Tissue diagnosis is made by EUS guided FNAC (22).
Recent interest in PET scanning with glucose analogue FDG, provides the advantage of full body scan for distant metastases (23). However, CT imaging is the primary method for diagnosing pancreatic cancer and monitoring therapy response.
OS of patients at all stages of exocrine pancreatic cancer is poor (24). Before any treatment is initiated, resectability should be assessed using imaging techniques (25). Wherever possible, surgical resection should be the primary mode of treatment as it leads to an improved OS as well as allowing effective palliation (26). Approximately 15-20% of diagnosed patients receive potentially curative resection. However, despite resection, the 5-year survival rate is less than 20% and the majority of patients develop recurrent disease (27).
Postoperative therapy with or without chemoradiation remains controversial. Most of the RCT data is statistically underpowered and offers conflicting conclusions (28). Malabsorption due to exocrine insufficiency may cause malnutrition hence pancreatic enzyme replacement is used. Nerve blocks such as coeliac plexus blocks provide long-term pain control.
Treatment depends on the stage of pancreatic cancer. Whipple procedure is most commonly used for head of pancreas tumours. A pancreatoduodenectomy followed by a gastro-jejunostomy and finally a cholecysto-jejunostomy is performed. Conditions for the procedure include local disease, non-invasion of adjacent structures and no metastases. Pancreatic tail cancers are resected by a distal pancreatectomy (29).
Several large RCTs have shown adjuvant chemotherapy with gemcitabine increases 5-year survival from 10% to 20% (30, 31). Surgery can be performed as a form of palliation to improve the QoL but is not curative.
Many attempts have been made to develop effective therapies for pancreatic cancer. Unresectable cancer can be treated with palliative chemotherapy to improve the QoL and gain a modest OS, by controlling symptoms and complications. For advanced disease, adjuvant treatment can be in the form of chemotherapy, chemoradiation or both, depending on which protocol is implemented.
5-Fluorouracil and gemcitabine, are the two major active drugs used to treat pancreatic cancer. Wherever possible, patients should be offered treatment within an RCT.
5-Fluorouracil has been studied comprehensively, as a chemotherapeutic drug. It has provided response rates ranging from 0-19% (32). However, not all the studies are complete. This could be due to poorly differentiated and circumscribed tumour outline, inaccurate evaluation techniques as a result of the tumour mass containing inflammatory cells and fibrosis. Thus it can be difficult to assess and unreliable results are produced.
For over a decade, gemcitabine has been the platform drug of choice after Burris et al’ clinical trial reported improvements in QoL and OS. Gemcitabine is a nucleoside analogue with activity against solid tumours (33). Its mechanism of action is via inhibition of DNA synthesis. Gemcitabine has a wide spectrum of anti-tumour activity against pancreatic tumours. NICE guidelines recommend the current standard of care to be single-agent gemcitabine chemotherapy (4), administered via intravenous infusion in those with advanced or metastatic pancreatic cancer. According to NICE, patients must also have a Karnofsky performance (see appendix 3) score of more than 50 for gemcitabine to be administered. It should not be used in patients who may be suitable for a potentially curative resection or in those that score below 50 on the KPS (see appendix 3).
Treatments for Stage I and II Pancreatic Cancer
(Evidence for Adjuvant treatment from clinical trials)
Approximately 10-20% of patients presenting with pancreatic cancer are locally resectable cases (34). Complete resection yields median survival of 20 months and 5-year survival of 10-15%, but ultimately there is high incidence of local and distant tumour recurrence (35).
In North America, adjuvant chemoradiotherapy was the standard approach in resectable disease based on the positive results of a phase III trial (GITSG) despite being terminated early due to low accrual and large survival difference between the two study groups (36). In contrast EORTC, also comparing split dose chemoradiotherapy with observation group, failed to find a significant improvement in median survival from adjuvant chemoradiotherapy (37).
A Norwegian study, showed the benefit of adjuvant combination chemotherapy versus observation, which reported a significant difference in median survival of 23 and 11 months respectively. Results of the ESPAC-1 study have elaborated the roles of adjuvant chemoradiotherapy and chemotherapy in pancreatic cancer (38). It was initially designed as a two-by-two factorial design in which patients were randomly assigned to four treatment groups. At median follow-up of 47 months, those who received 5-fluorouracil chemotherapy alone showed improvement. On the contrary, no benefit was shown for patients receiving chemoradiotherapy, in whom it may have been harmful compared to those not receiving chemoradiotherapy (Median survival 15.9 versus 17.9 months respectively) (28, 38). However, this study has been criticised for its lack of cycle completion, lack of delivery of radiotherapy quality control and the two-by-two factorial design (39).
A meta-analysis of five published RCTs including ESPAC-1, EORTC, GITSG, Japanese and Norwegian studies investigating adjuvant therapy, have provided the largest series of patient data (40). This meta-analysis accumulated a total of 875 data available patients and highlighted the role of adjuvant chemoradiotherapy concluding no significant survival benefit. Norwegian, Japanese and ESPAC-1 studies concluded a significant survival benefit with the use of chemotherapy in established prognostic factor subgroups.
Overall, the results of this meta-analysis correlates with the large ESPAC-1 study of patients benefiting from adjuvant chemotherapy after resection. On the other hand, a benefit from chemoradiotherapy post-resection could not be found and indeed patients receiving chemoradiation may be at a disadvantage.
The ongoing controversy surrounding whether adjuvant treatment is beneficial for patients with resectable tumours, particularly post-operative chemoradiotherapy remains. In the USA, 5-fluorouracil and chemoradiotherapy are considered as the standard of care. Evidence for this is based on the small GITSG study (43 patients) and large case series from the Mayo Clinic and John Hopkins (41, 42). Despite, two larger studies failing to replicate the same OS benefit, yet the bias still continues.
In contrast, adjuvant chemotherapy alone is widely recommended in Europe and UK based on ESPAC-1 (however flawed) and the CONKO-001 trials, which both showed survival benefit using 5-fluorouracil (plus folinic acid) or gemcitabine, respectively (38). As a result of this, these two regimes are now advocated as standard adjuvant treatment in Europe (43).
Despite all this, the potential role of chemoradiotherapy should not be dismissed for future trials. Chemoradiotherapy may downstage a tumour and allow for complete tumour resection (44, 45).
For now, there is strong evidence of a survival benefit using adjuvant chemotherapy as a standard of care for patients with resectable pancreatic cancer. However, the results of the analysis reiterate the need for further RCT’s to find the optimal chemotherapy regimen for the early stages of pancreatic cancer.
Treatment for Stage III Pancreatic Cancer
(Evidence for Adjuvant and Palliative treatment from clinical trials)
Stage III pancreatic tumours are essentially unresectable due to local vessel impingement or due to tumour invasion. Palliation by endoscopic, radiological or surgical means may be beneficial for relieving pain caused by biliary obstruction or impingement (13).
Three trials (GITSG-9173, EST-8282 and FFCD-SFRO) all investigated combined modality therapy versus radiotherapy alone (46-48). However, they had many deficiencies in design. Based on the first two studies chemoradiation became the standard of practice in the US.
Modern radiotherapy techniques have improved vastly. For instance, IMRT a form of conformal radiation is being used in studies underway today. Results of these trials are still awaited.
FFCD-SFRO, a mature study involving patients with locally advanced disease, assigned randomly to chemoradiotherapy with 5-fluorouracil, followed by gemcitabine or gemcitabine alone reported a median follow up of 31 months in the chemoradiation arm and 33 months in the gemcitabine arm (48). These results proved that chemoradiotherapy did not improve OS. Again this demonstrates chemoradiotherapy is not beneficial and may even be a harmful adjunctive treatment.
Publication of the FFCD study has caused the standard of practice to change in the UK and gemcitabine-based therapy to be used for locally advanced or metastatic pancreatic cancer. Chemoradiotherapy therefore remains a controversial area for stage III pancreatic cancer.
The ESPAC-3 study is the largest adjuvant study conducted for resected patients, randomly assigned 5-fluorouracil or gemcitabine, concluding no significant difference in survival between the two-adjuvant arms. Thus the regimen of choice is based on the individual patients’ toxicity profile.
The CONKO-001 trial found a significant improvement in median disease-free survival for gemcitabine (13.4 months) compared to observation (6.9 months). Overall median survival was 22.1 months for gemcitabine group and 20.2 for the surgery alone group. At the time, CONKO-001 concluded treatment with gemcitabine offered the best benefit and risk ratio of all available adjuvant treatment options (43). Furthermore, the toxicity profile of gemcitabine in this trial appeared to be lower than 5-fluorouracil (28, 38).
Conclusions of ESPAC-1 and other adjuvant trials suggest no statistically beneficial evidence for chemoradiotherapy in pancreatic cancer (48, 49). The apparent failure of chemoradiation in treating this disease may be due to interference of chemotherapy scheduling. It could also be because of significant pro-metastasising effects of ionised radiation. In conclusion, current evidence for advanced stage disease and ESPAC-3 results is supportive of using gemcitabine. Further studies continue in the search for an optimal treatment protocol for advanced disease.
Treatment for Stage IV Pancreatic Cancer
(Evidence for Palliative treatment from clinical trials)
Metastatic pancreatic cancer is a highly aggressive and lethal chemoresistant neoplasm that has posed a considerable challenge to oncologists for decades. A low response rate coupled with a lack of survival benefit using current chemotherapy clearly indicates that clinical trials are appropriate for all those newly diagnosed with stage IV pancreatic cancer.
Chemotherapy such as 5-fluorouracil allows some patients to have palliation from their symptoms. Gemcitabine has yielded superior activity over 5-fluorouracil as a useful palliative agent (50-52).
Over a decade ago, Burris et al conducted a phase III trial of first line gemcitabine monotherapy versus 5-fluorouracil in 126 patients with advanced or metastatic pancreatic adenocarcinoma (KPS of 50+). Burris also included a high proportion of patients with a poorer performance status (KPS 50-70) compared to most other studies with KPS of 80-100. These results therefore, are a better representation of treatment efficacy, as most ill patients were included.
It reported a significant improvement in OS amongst patients treated with gemcitabine. The one-year survival was 18% with gemcitabine compared to 2% with 5-fluorouracil (50). However, 5-fluorouracil was given by bolus injection as opposed to the usual intravenous infusion, which was a newer administration technique.
This breakthrough trial also evaluated the impact of gemcitabine on QoL in terms of clinical benefit response (CBR) (defined as an assessment of performance status, pain and weight and a responder is one who has a sustained improvement in CBR) (53). CBR was higher in the gemcitabine group compared to 5-fluorouracil alone (23.8% vs 4.8%) (54). However, CBR is not a validated tool for measuring the effectiveness of palliative chemotherapy, but could be considered a proxy for QoL analysis. This study indicated that objective criteria to evaluate new pancreatic cancer treatments could be used. The evaluation of QoL in some form should be part of all trials as palliation of symptoms is the main aim in treatment of advanced pancreatic cancer.
Overall, there was a statistically significant improvement in OS for the gemcitabine patients. Although additional improvement is required, these were encouraging results as gemcitabine was the first drug in 30 years to improve OS against single agent 5-fluorouracil (50, 55), hence the search for better regimens was the next logical step.
A preliminary report of another phase III trial comparing gemcitabine alone versus gemcitabine plus erlotinib in patients with advanced or metastatic disease showed the erlotinib group prolonged survival slightly than gemcitabine alone. The OS for the erlotinib group was favoured. Median survival rates for patients receiving erlotinib versus gemcitabine alone were 6.24 months versus 5.91 months. Adverse effects of grade 1/2 were more evident in the erlotinib plus gemcitabine group and can lead the clinician to think if the modest gain of 2 extra weeks is clinically meaningful (56, 57).
A Swiss study and NCRI UK, investigated whether the addition of capecitabine and gemcitabine would improve survival versus gemcitabine alone in patients with advanced disease (58). Results should have been reported independently of other studies, however the investigators of GEM/CAP published a meta-analysis along with their results. These favoured GEM/CAP, but this inevitably clouded the results of their own trial, which turned out to be statistically insignificant for GEM/CAP. The study did not statistically achieve its primary endpoint of improved one-year OS (59). However, there was a trend towards improved OS. Secondary outcome measures (response rate and PFS) on the other hand, were met. A meta-analysis cannot guarantee QoL was measured uniformly throughout the three trials. To conclude, the addition of capecitabine to gemcitabine can be considered as one of the treatment options available for patients. However, it cannot replace gemcitabine alone for all patients with locally advanced or metastatic pancreatic cancer.
FOLFIRINOX, a multiagent regimen has been compared to single agent gemcitabine showing encouraging results. A phase III ACCORD-11 randomly assigned FOLFIRINOX multiagent regimen or gemcitabine to 342 metastatic disease patients. The trial was stopped early as it had only enrolled only 250 patients and had reached its endpoint of improved OS. FOLFIRINOX group had a much-improved objective response rate of 31.6% compared to 9.4% in the gemcitabine group. OS was 11.1 versus 6.8 months respectively. WHO grade 3/4 toxicities were experienced amongst the FOLFIRINOX group. However due to improved response rate and OS, FOLFIRINOX can be a treatment option for patients with metastatic pancreatic cancer and a good performance status. It does however require cautious utilisation due to its reported toxicities (60).
Other agents combined with gemcitabine are docetaxel, cisplatin, irinotecan and cetuximab. When used alongside gemcitabine there has been no clear supportive evidence to suggest an improved OS (54, 61), despite some support showing combination for gemcitabine and cisplatin (62). However, the standard of care in the UK and the rest of Europe remains as gemcitabine alone (4).
Treating pancreatic cancer with gemcitabine-based platforms has been the mainstay for treating this deadly malignancy. A possible treatment exploration is a neoadjuvant approach to identify those unlikely to benefit from surgery, as patients with progressive disease after this neoadjuvant therapy have refractory disease and are more likely to recur after resection. In the neoadjuvant setting, treatment with FOLFIRINOX, to shrink the tumour with two cycles prior to resection, may provide improved OS (KPS of 80-100 due to heavy toxicity and careful observation in palliative setting). Patients can be followed up with gemcitabine alone in the adjuvant setting. This may improve surgical resectability, hence post-operative survival.
Studies for patients with locally advanced disease (not metastatic disease) can be redone using low-dose IMRT at a dose of 10-20 Gy plus standard dose of gemcitabine alone. Intensely radiosensitising gemcitabine may only need low-dose IMRT to make it a more effective treatment. Chemoradiotherapy in the neoadjuvant setting is a tempting option, except it may do more harm than good.
Metastatic disease and palliative treatment modalities require inspiration from basic science and by going back to the drawing board. The search for specific target therapy is required for the palliative setting.
As discussed, the study and analysis of treatment for pancreatic cancer is imperative due to the abysmal rates of survival this disease carries. The aims of this review have been met by critically analysing most of the evidence in the literature to date. Exploring the change in the treatment of pancreatic cancer over the past three decades has helped interpret the results of treatment options available today. Complete remission is rare (63) and the median survival from diagnosis is 3-6 months (metastatic disease) and 6-11 months (locally advanced disease) (64).
ESPAC-1 and ESPAC-3 findings led to worldwide change in clinical practice, this was reflected in national and international guidelines on the management of pancreatic cancer. Future studies such as ESPAC-4 are now set to determine how survival associated with adjuvant chemotherapy can be further improved through combination regimens.
Incremental progression in treatment options has led clinicians to some recent important advances. Research for new agents to target specific signal pathways in pancreatic tumours continues. In the meantime pancreatic cancer continues to be as deadly in most patients, as its mortality rate shows. The best standard of care for patients of any stage pancreatic cancer will continue to be an international controversy. Nonetheless, the enrollment in a clinical trial can be a useful alternative until a much more significantly beneficial OS is found for this lethal disease.
Local Results - Audit of the Palliative Chemotherapy for Pancreatic Cancer
Aims: This audit was intended to review the appropriateness and effectiveness of local chemotherapy treatment protocols for patients treated at the Royal Lancaster Infirmary.
Audit Methodology: An Audit on the palliative treatment for pancreatic cancer patients was undertaken. The study group was a cohort of 78 patients collected retrospectively from the Somerset Cancer Registry and the Lorenzo patient system, during the period, 1st January 2009 – 31st December 2011. The QoL and survival time of patients’ after treatment was collected along with histology, MDT outcome and many other analytical areas using the proforma outlined in appendix 4. The mortality rates after treatment were then analysed and are portrayed in the survival graph below.
Recorded management plans have been trawled through and the necessary data extracted for audit purpose. This is to see the level of clinician compliance against the NICE guidance set out in 2001. I include in my audit presentation the proportions of treatments adhering to the NICE guidance. This means the audit should be more effective in improving patient care in the future. See Appendix 5 for the Keynote presentation of the Clinical Audit and further results and conclusions than outlined here.
Percentage Survival in Gemcitabine treated patients – Kaplan Meier Curve (Local Results).
Results: This Kaplein-Meir death/survival curve is a good representation of the management protocol at the RLI, demonstrating the excellent figures in comparison to the evidence base and the national guidelines. Outlined below are the survival results for the period 1st January 2009 – 31st December 2010.
Median survival Results
Overall pancreatic cancer population = 87 days (3.1 months)
Median Survival with GEM = 221 days (7.9 months)
Compare Burris et al. results:
Overall median survival 5.65 months for patients given gemcitabine
Survival duration for patients on GEM (n=26)
6 months ~55%
9 months ~33%
12 months ~22.5%
Conclusions: Dr Fyfe and his patients mostly opted for the gemcitabine alone protocol, it offered an improved QoL compared to the extra couple of weeks in which patients usually have a deteriorating QoL.
Clinicians should review their clinical management of pancreatic cancer against the NICE guidance. Relevant guidelines and protocols should be reviewed and revised according to these NICE guidelines. Dr Fyfe and the network guidelines for pancreatic cancer abide by NICE guidance. Single-agent gemcitabine is the standard of care, although GEM/CAP and GEM/CIS can be considered in patients with a good performance status. The excellent toxicity profile of gemcitabine alone meant Dr Fyfe and his team used GEM throughout the time period of the audit conducted (2 years).
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