in pancreatic cancer

Aliment Pharmacol Ther 1998; 12: 949±964.

Review article: current treatment and optimal patient management in pancreatic cancer A. HAYCOX*, M. LOMBARD , J. NEOPTOLEMOS & T . W ALLEY* Prescribing Research Group, Department of Pharmacology and Therapeutics, University of Liverpool; and Pancreatic Research Group, University of Liverpool & Royal Liverpool University Hospital, Liverpool, UK Accepted for publication 26 May 1998

SUMMARY

This review analyses the current state of knowledge and understanding concerning the optimum treatment and therapeutic management of patients who suffer from pancreatic cancer. It outlines recent advances in scienti®c understanding and assesses their potential future value to clinicians in confronting this disease. Despite a signi®cant expansion in scienti®c knowledge relating to factors underlying the early development of pancreatic carcinoma, the clinician continues to be restricted to a severely limited therapeutic armoury for this disease. Local therapies (surgery and radiation) are inevitably of limited value in the face of a disease that is normally encountered at a stage where metastasis is already highly developed. Despite such limitations, however, surgery performed in specialist units may be of value for 10±20% of patients, with a 5-year survival rate in such units of between 10 and 24%. This may be improved even further by appropriate use of adjuvant treatment. The advanced stage of the disease when

INTRODUCTION

A recent study1 identi®ed a number of major problems underlying the quality of reporting of published results on the treatment of pancreatic cancer. Many studies accrued patients opportunistically rather than in accordance with a scienti®c entry criteria and the Correspondence to: Dr A. Haycox, Prescribing Research Group, The Inirmary, 70 Pembroke Place, Liverpool L69 3GF, UK. E-mail: [email protected] Ó 1998 Blackwell Science Ltd

normally encountered emphasizes the potential value of systemic treatment in this therapeutic area. Unfortunately systemic treatment (chemotherapy) has been found to be ineffective to date in signi®cantly extending survival, with a low rate and duration of remission being identi®ed in most trials. The challenge for both the health service and the pharmaceutical industry is to harness recent and future developments in scienti®c knowledge to the practical bene®t of clinicians. Where cure is possible it should be vigorously pursued; where it is not, in this ®eld above all others, clinicians have a duty of care. To achieve this it is necessary to abandon the therapeutic nihilism that has characterized the attitudes of clinicians towards this disease in the past. It is time that such nihilism was replaced by a recognition of the challenges and the opportunities available to clinicians in enhancing the quantity and quality of life available to patients. The dictum of `curing whenever possible but caring always' should be the future therapeutic philosophy used to guide clinicians in this important and rapidly changing therapeutic area.

majority of studies did not provide crucial data on patient and tumour characteristics (age, sex, disease stage, lymph node metastasis, tumour size, tumour site, histological grade) or undertake a histopathological veri®cation of pancreatic cancer. Studies frequently ignored long-term survival and made little or no effort to evaluate the level of quality of life experienced by patients. Perhaps of greatest concern was the fact that in one out of six of the studies examined patients were lost to follow-up without explanation. Such limitations in published studies cause signi®cant problems to both 949

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researchers and clinicians given that progress depends upon careful evaluation of comparable evidence concerning the value of different therapeutic strategies. Only by standardizing the reporting of results is it possible to effectively evaluate the comparative value of the range of therapeutic strategies currently used or proposed for the treatment of pancreatic cancer. Despite these weaknesses, however, it is important that the extensive and rapidly growing body of research evidence generated in this area is effectively synthesized and reviewed to assess its practical value in informing current and future clinical decision-making with regard to treatment strategies for pancreatic cancer. Providing such a practically focused review is the purpose of this article. THE DUAL AIMS OF TREATMENT

The dual aims of treatment for pancreatic cancer are to maximize quality of life by ensuring effective symptom palliation for jaundice, pruritus, pain, diarrhoea and weight loss, and other complications, while simultaneously controlling or curing the underlying cancer. Surgery currently provides the best potential for cure in pancreatic cancer. However, this potential must be placed in the joint context of a relatively late presentation and the generally poor ability of the patient to withstand radical surgery due to general age and in®rmity. Effective palliation requires the sensitive management of the patient's physical symptoms in an integrated management strategy to improve survival and quality of life.2 Symptom palliation is often commenced during the course of making a diagnosis and consideration of the role of surgery or other treatment follows once the diagnosis is con®rmed. Given a median survival in pancreatic cancer of only 5±7 months,3 the speed and the manner in which palliation is achieved become crucial. Unfortunately, palliation involving courses of chemotherapy4, 5 or radiotherapy may take 6 weeks to administer. In such circumstances the time commitment and side-effects related to such courses would be likely to dominate remaining survival.6 The need to `trade off' improvements in `quantity' of life against the impact upon the `quality' of the patients' remaining life represents a key issue in identifying optimal palliative strategies for each patient. The range of strategies available to control the major symptoms of pancreatic cancer are outlined below.

ACHIEVING EFFECTIVE SYMPTOM PALLIATION

Weight loss Weight loss is a frequent symptom encountered in the early stages of pancreatic cancer and is often due to systemic cachexia caused by tumour growth. However, it is important not to overlook the possibility of malabsorption caused by pancreatic enzyme de®ciency. Pancreatic enzyme supplements may be of value in a minority of patients but are frequently omitted from the care package provided to the patient. Similarly these can be valuable in controlling diarrhoea due to pancreatic insuf®ciency but again are often forgotten. Pain Pain is another frequent and debilitating symptom with 70±80% of patients presenting with severe back or abdominal pain.7 Adherence to the WHO guidelines for cancer pain relief (oral administration of analgesic commencing with non-narcotics followed by weak and then strong narcotics in association with adjuvant drugs) provides adequate pain relief in approximately one-half of patients. Pain can also be effectively treated with chemical splanchnicectomy8 or through neurolytic coeliac blockade9 which provides effective relief for 3± 4 months.10, 11 A new approach to the management of intractable pain in pancreatic cancer is bilateral thoracic sympathectomy by excision or ablation of the splanchnic nerve. This innovative approach has been found to be an effective treatment for chronic pancreatic pain12 but requires further evaluation. Obstructive jaundice Obstructive jaundice occurs in 60±70% of patients.13 The role of surgical bypass has been challenged by the development of endoscopic or percutaneous transhepatic stenting which can relieve obstructive jaundice and pruritus in 90% of patients. The high rates of postoperative mortality together with limited post-operative survival combine to make the advantages of surgical bypass highly questionable.14 Equally however, the lower procedure-related mortality exhibited by stenting (»1%15) must be balanced against the need for frequent stent replacement in patients with lengthy post-operative survival. Newer metal stents which expand following deployment to a ®nal diameter of almost 10 mm are much less prone to occlusion from debris, which was a Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 949±964

REVIEW: TREATMENT OF PANCREATIC C ANCER

disadvantage of 10 and 12 French gauge plastic endoprostheses. However, tumour in-growth causing occlusion can still be a problem and these new stents are also much more expensive. From a cost-effectiveness perspective, while the initial costs associated with surgical intervention are higher, the bene®ts will probably last until the patient dies. As a consequence, surgical intervention is likely to be costeffective when targeted upon the minority of patients that are likely to experience more prolonged survival. However, a number of randomized studies16±19 have shown that stenting is superior for patients who are either a poor operative risk or who have a limited life expectancy. Bypass surgery should be restricted to patients who have longer anticipated survival, given that in such patients any advantages of stenting may be outweighed by the need for stent replacement due to occlusion, tumour in-growth or because of gastric outlet obstruction. The comparative impact of surgery and stenting must therefore be evaluated not only in terms of patient survival but also in terms of the post-operative quality of life experienced by patients. To date the only quality of life comparisons undertaken have been restricted to complication rates, hospital utilization or physical performance status.20±25 Gastric outlet obstruction Gastric outlet obstruction can develop in patients with pancreatic carcinoma provided with biliary bypass alone. The development of gastric outlet obstruction implies that the patient will subsequently require gastroenterostomy. It could be argued therefore that both biliary bypass and gastroenterology should be routinely performed together as a means of palliation. However, as the addition of a gastroenterostomy to surgical biliary bypass doubles the mortality rate but is ultimately needed by only about 10% of patients, some have concluded that patients should be palliated by biliary bypass alone.26, 27 THE ROLE OF SURGERY

The pancreas is dif®cult to access surgically because of its deep-seated location and close proximity to vital vascular structures. High post-operative mortality in the past has contributed to the notion that this was `the cancer which gave cancer a bad name'.28±30 Indeed, a long-term analysis of the outcome of partial pancreatÓ 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 949±964

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icoduodenectomy (Whipple's resection) concluded that the impact on survival was so small that this procedure should be abandoned.31 Such nihilism, however, is seriously outdated as recent improvements in surgical techniques and technology32 have signi®cantly enhanced safety and ef®cacy so that 5-year survival of between 19%33 and 24%34 can be attained with postoperative mortality being reduced from 18% to less than 5%.35, 36 The situation has improved because of better patient selection and peri-operative and post-operative management together with the increasing concentration of pancreatic surgery in the hands of specialists who can achieve minimal operative mortality.37 In the UK, this trend is exempli®ed by a reduction of 30-day post-operative mortality from 45% in the ®rst decade and 28% in the second decade of a longitudinal analysis of 13 560 patients38 to 5.9% in a recent UKPACA study.39 An improvement in the surgical management of pancreatic cancer is also demonstrated by a Norwegian study40 which identi®ed an overall operative mortality of 9%. Only » 10% of patients have disease con®ned to the pancreas upon initial assessment41 and even when the disease is detected at this stage, the general in®rmity of the patient population may contraindicate radical surgery.42±44 Age by itself, however, should not represent a contraindication to surgical intervention. A recent review found advanced age insigni®cant in predicting surgical outcome,45 which contradicted the ®ndings of earlier studies. Size of tumour at presentation, histological grade and clear resection margins at surgery are the key features which signi®cantly determine outcome.33, 46±48 A study which recruited patients from the whole of Japan found that patients with small carcinomas exhibited a resectability rate of 99%, an operative mortality of only 4% and a 5-year survival of 30%.49 Furthermore, the early onset of obstructive jaundice in ampullary and lower bile duct carcinomas is likely to lead to more rapid diagnosis and a much higher 5-year survival following resection of 25±30%.50 Conversely, symptoms of tumours located in the head, corpus and tail of the pancreas are more commonly identi®ed at a much later stage, by which time often the tumour has in®ltrated adjacent structures. Alternative operations have been proposed with the aim of either improving long-term survival51 (total pancreatectomy, regional pancreatectomy, extended or subtotal resection) or improving quality of life52 (pylorus-preserving surgery). In general there is a paucity of

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published data on the quality of palliation provided by the more extensive operations but they appear to provide little bene®t in terms of enhanced survival while signi®cantly increasing intra-operative and postoperative complications.40, 53 The less radical operations proposed54, 55 have been found to provide signi®cant bene®ts for only a small subset of the patient population. In general therefore the role of these newer procedures remains controversial, and further evidence is required concerning their impact upon survival and quality of life in broader subgroups of patients. For locally advanced disease, no generally accepted guidelines are available concerning the boundaries for resectability and the approach taken will be dependent

on the attitude of the surgeon.46, 56±61 The only clearcut contraindication to surgical intervention is when distant metastases are demonstratively present. However, even in these circumstances bene®cial results have been obtained in the surgical treatment of solitary liver metastasis.62 One study however, found that physical performance following pancreatectomy was signi®cantly better than following palliative bypass surgery,63 potentially justifying its use as a planned palliative intervention. More recently, laparoscopic bypass has been utilized in an attempt to achieve good surgical palliation whilst avoiding the disadvantages of major debilitating abdominal surgery in these patients.64

Table 1. Results of surgery Reference

Patient group analysed

Outcome of surgery

Gudjonsson31

Patients provided with Whipple resection

5-year survival (3.8%) abandon curative resection

Patients provided with palliative bypass

1970sÐmortality 17% survival 5 months 1980sÐmortality 14% survival 7 months

Cameron45 Cameron45 Pellegrini34 Pellegrini34 Livingston55 Satake68 Satake68 Bakkevold40 Bakkevold40 Edge65

Patients Patients Patients Patients Patients Patients Patients Patients Patients Patients

5-year survival of 19% 5-year survival of 57% 5-year survival of 24% 5-year survival of 57% 5-year survival of 9% 80% surgical cure rate 17% surgical cure rate Median survival 17 months Median survival 18 months Post-operative mortality 6% Major complications 21%

Wade48

Patients in Stage I±II provided with resection Patients in Stage III provided with resection

Additional 9-month survival No survival advantage

Bakkevold40

Patients with carcinoma of the pancreas and papillar of Vater

Operative mortality 9%

Bramhall38

Patients treated in the West Midlands of the UK over 20-year period

Post operative mortality First decade 45% Second decade 28%

Tsuchiya49

Patients with carcinoma of less than 2 cm

Resectability rate 99% Operative mortality 4% 5-year survival 30%

Watanapa32

Patients provided with operations for surgical palliation (1971±90)

First decade: Mortality 17%, survival 5 months Second decade: Mortality 14%, survival 7 months

provided with Whipple resection without metastasis provided with Whipple resection without metastasis treated surgically in the USA with carcinomas of less than 2 cm in stage IV of their disease provided with Whipple resection provided with total pancreatectomy provided with surgical resection

Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 949±964


Multi-institution analyses of outcomes for pancreatic surgery are of value in identifying the extent to which improvements in outcome achieved in single specialist centres can be generalized throughout the hospital sector. Such studies inevitably combine a wide range of surgical practice and expertise and must therefore be interpreted with caution. One such analysis of American University Centres65 identi®ed a post-operative mortality rate of 6% and a major complication rate of 21%, which coincided with results achieved in another recent series.66 In this study no association could be identi®ed between post-operative mortality and either the surgeons' caseload or patients' age,67 and while resection was found to provide signi®cant bene®ts for localized pancreatic cancer, such bene®ts were not apparent when the cancer was more extensive.48 In evaluating surgical outcomes it is imperative that outcome is assessed in the context of the patient population being analysed. In general, despite recent improvements, the prospect of bene®cial surgical intervention in the treatment of pancreatic carcinoma for the majority of patients remains poor, and therefore it is important to evaluate the effects of more systematic means of treating this aggressive carcinoma (Table 1). THE ROLE OF CHEMOTHERAPY

Fluorouracil (5-FU) remains the most effective and most frequently used single chemotherapy agent in the treatment of pancreatic carcinoma. 5-FU works partly by interference with enzymes such as thymidylate synthase, and partly by incorporation of metabolites into RNA and DNA interfering with cell proliferation. Continuous infusion of 5-FU or 5-FUdR (5-¯uorouracil deoxyribose) is more effective than administration by bolus and less toxic.69±71 The use of circadian infusion has also shown further improvement in the therapeutic/ toxic ratio which may facilitate further dose intensi®cation.72±74 Most studies analysing 5-FU and the simultaneous use of folinic acid75±79 have identi®ed a marginal survival bene®t over 5-FU alone but on no occasion was the resulting improvement found to be signi®cant. The addition of recombinant human granulocyte-macrophage colony-stimulating factor (rhGMCSF) to this combination80, 81 however, led to severe toxicity and no improvement in survival or quality of life.82 Conversely the combination of 5-FU with cisplatin is highly active in advanced pancreatic cancer with an acceptable level of toxicity in the majority of cases.83 Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 949±964

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Only one randomized controlled trial has shown signi®cant survival bene®t using 5-FU in combination with doxorubicin and mitomycin C.84 Gemcitabine is a ¯uorinated pyramidine nucleoside analogue that inhibits DNA synthesis through a number of mechanisms but essentially is incorporated into DNA in place of dCTP and interferes with cell division. A Phase II trial of gemcitabine identi®ed signi®cant improvements in cancer-related symptoms and performance status for a number of patients with pancreatic carcinoma.85 A prospective, multicentre Phase II trial was initiated in a cohort of patients who had failed to respond to 5-FU.86 In this trial an outcome dimension was developed entitled `clinical bene®t response' to evaluate the palliative impact of gemcitabine. A clinical bene®t response was de®ned as having occurred if patients experienced a 50% reduction in pain, a 50% reduction in analgesic requirement or a 20 point improvement in Karnofsky performance score for over 4 weeks without any adverse change in any other measured characteristic. Seventeen out of 63 patients entered into the trial (27%) displayed a clinical bene®t response, which appears to indicate that gemcitabine can play a signi®cant role as a palliative agent in the treatment of pancreatic carcinoma. A further randomized trial that compared gemcitabine and 5-FU as ®rst line therapy in advanced pancreatic carcinoma87 found that average survival was 5.65 months for gemcitabine in comparison to 4.41 months for 5-FU. In addition, 24% of gemcitabine patients were alive at 9 months in comparison to only 6% of 5-FU patients. The proportion of patients displaying an improvement in `clinical bene®t response' was 24% for gemcitabine in comparison to only 5% in 5-FU. Unfortunately, gemcitabine was also associated with signi®cantly higher toxicity. A wide range of other single agents have been evaluated to assess their effectiveness in the treatment of pancreatic cancer. However, all such trials to date have met with very limited success. The majority of single agents evaluated have been found to be either ineffective or to lead to signi®cant levels of toxicity which makes their routine use of limited value.88±107 A selection of the results obtained in these trials is provided in Table 2. The lack of activity displayed by single agents is re¯ected in the results obtained for combination chemotherapy. None of the principal combinations evaluated to date have been found to be consistently superior to 5-FU alone while all exhibit

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Table 2. Outcome of chemotherapy in pancreatic cancer Reference

Drug regimen

Outcome

Rougier83

5-FU and cisplatin

Overall response rate 26% Mean duration of response 10 months Palliative effect in 45% of patients Concluded to be active and well tolerated

Tajiri74

5-FU and leucovorin

Response rate 7% Median duration of response 3 months Concluded no therapeutic bene®t over 5-FU alone

Cascinu79

5-FU and leucovorin

Response rate 8% Median survival 5 months Severe toxicity led to trial being stopped

Weinerman77

5-FU and leucovorin

Mean survival of treated group 16 weeks Mean survival in matched controls 12 weeks

Moore87

Gemcitabine vs. 5-FU

Gemcitabine survival 6 months, clinical bene®t 24% 5-FU mean survival 4 months, clinical bene®t 5%

Hubbard90 Jones91 Moore82 Mahjoubi92 Leichmann94 Ebert99

Iproplatin Merbarone 5FU ± rhGM-CSF Pirarubicin Amona®de Octreotide

Concluded to be ineffective Concluded to be ineffective No survival or quality of life advantage over 5-FU alone Concluded to be ineffective Severe toxicity and ineffective Low dose: median survival 3 months (ineffective) High dose: median survival 6 months. No signi®cant side-effects and improved quality of life

Friess103 Casper104 Jenkins106 Kajanti107

Octreotide Edatrexate Piroxantrone Oral carmofur

Concluded to be ineffective at low dose Minor therapeutic activityÐineffective as a single agent Signi®cant toxicity and ineffective Median survival 8 months (3% partial response, 23% stable disease). Moderate toxicity

Decaprio108

5-FU & folinic acid

Median time to progression 3 months (7% partial response, 47% stable disease). No improvement over 5-FU alone

signi®cantly greater levels of toxicity.108±114 Again the results obtained for the principal combinations evaluated to date are provided in Table 2. Research evidence linking pancreatic cancer to sex hormones has led to signi®cant interest in the potential role of anti-oestrogen and anti-androgen treatments.115 The potential value of hormone therapy in the regulation of pancreatic cancer has been investigated98 with the hormone CCK being of particular interest.116 The CCK receptor antagonist MK-329 is highly selective for the predominant receptor present in pancreatic tissue117±119 and signi®cantly enhances the effect of cisplatin in animal models but at the cost of increased toxicity.120 Application of this approach to humans requires greater understanding of the role of CCK receptor blockade and further control of levels of toxicity. In general, analyses undertaken to date

emphasize that while certain patients may bene®t from such treatments,121 there is little evidence of a generalized improvement in survival.122 The generally disappointing results obtained from chemotherapy arise in part because it is dif®cult to increase the intratumour concentration of an anticancer drug to a therapeutic level by systematic administration alone.123, 124 Early experience with the intratumoural administration of anti-cancer agents has found them to be more effective and less toxic than systemic administration.125 Early work in animal models has shown that intratumoural administration was successful in completely suppressing tumour growth at a dose that would be ineffective via the intravenous route.126 Whilst such early results are encouraging they require much greater validation prior to their generalized use in pancreatic carcinoma. Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 949±964


THE ROLE OF RADIOTHERAPY OR CHEMORADIOTHERAPY

The survival bene®ts provided by radiotherapy alone have been generally disappointing.127 The location of the pancreas (surrounded by crucial radiosensitive structures) limits access and the intensity of radiotherapy that can be applied. Radiotherapy is therefore of greatest value in patients who present with disease localized to the pancreatic bed.128 For such patients a number of small studies have identi®ed survival and palliation ®gures for radiotherapy that are comparable to those obtained through surgery, although no direct comparison of these modalities has been undertaken to date.129±132 Adjuvant use of external beam radiotherapy after surgical resection has been reported to signi®cantly improve patient survival133 while the combination of 5-FU with external beam radiotherapy has also been found to extend survival in comparison to either 5-FU or radiotherapy alone.134, 135 Unfortunately the majority of comparative analyses of patient outcome have been generated in comparatively small studies using a non-randomized research design. It is imperative that high-quality randomized controlled trials of the comparative outcome of radiotherapy are undertaken to effectively determine its role and value in the treatment of pancreatic carcinoma. The combination of radiotherapy and chemotherapy aims to combine the enhanced local control obtained through radiotherapy with the wider systemic bene®ts of chemotherapy.136±139 Unfortunately while 5-FU signi®cantly increases the radiosensitivity of pancreatic tumours the tolerable dose of 5-FU in combined therapy is reduced below optimum levels and such suboptimal dosing may adversely affect patient outcome.140 The combination of 5-FU and split course radiotherapy has led to modest improvements in palliation and survival and has become ®rst line therapy in many hospitals. A range of variations of combined modality therapy have been evaluated including radiotherapy and simultaneous multi-drug chemotherapy consisting of 5-FU, streptozotocin and cisplatin (RT-FSP).141 The RT-FSP trial con®rms the ability of clinicians to achieve bene®cial therapeutic goals for patients with locally advanced pancreatic cancer using chemotherapy (Table 3). Further trials are essential to evaluate the potential contribution of new drugs to the radiotherapy/5-FU combination.


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A range of other strategies have been proposed to enhance the effectiveness of radiotherapy in improving survival or palliation in patients with pancreatic cancer. Such strategies include wide area radiation,149 radioactive implants,150 intra-operative radiation therapy,143 conformal radiation techniques151 and hyperfractionated radiation therapy.152 Wide Area Radiation Therapy (WART) was developed to more effectively meet the treatment needs of the 95% of patients with pancreatic cancer that develop hepatic metastases. A number of non-randomized trials142, 143 have identi®ed signi®cantly increased survival in certain patient groups through the use of chemoradiation to the primary tumour supported by wide ®eld irradiation. The potential bene®ts of this approach, however, while promising, require con®rmation in large-scale randomized trials. Direct implantation of radioactive sources enables the delivery of intensive but localized doses of radiation which, when combined with external beam radiation therapy and chemotherapy, has been found to produce signi®cant improvements in local disease control. One study144 found that implantation led to enhanced survival (Table 3), and signi®cantly improved local control of the disease and effective palliation of symptoms. Unfortunately, radioactive implantation is associated with complications such as deep vein thrombosis, gastrointestinal haemorrhage and sepsis and also exhibits an operative mortality as high as 33%.153 Thus although implantation radiotherapy may improve local control of pancreatic cancer, its associated morbidity and mortality make it a potentially dangerous procedure.154 Pre-operative radiotherapy aims to reduce the size and spread of tumour so as to enhance the possibility and ef®cacy of curative resection. Pre-surgical radiotherapy has the theoretical advantages of increased vulnerability of the cancer cells to radiotherapy given that vascularity has not been interrupted by surgery and patients are likely to be in better general health. Hoffman et al.155 concluded that the method was safe and effective in downstaging lymph nodes and resection margins but that the implications of such changes upon patient survival requires further evaluation in the form of a controlled clinical trial. This result mirrors other studies146, 147, 156, 157 that have supported the value of pre-operative irradiation in increasing the overall resectability rate and thus improving patient survival.

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Table 3. Outcome of radiotherapy/chemoradiotherapy in pancreatic cancer Reference

Nature of treatment

Outcome

Komaki142 Gunderson143 Goertz144

Wide ®eld irradiation Local vs. wide ®eld irradiation Implantation and XRT compared to XRT and surgical resection

Survival (1 year, 67%; 2 year, 47%) 2-year survival 6% (local), 20% (wide ®eld) Median survival 8 months (Implant & XRT) 7 months (Surgery) 5 months (XRT alone)

Sindelar145

IORT compared to conventional therapy External beam irradiation following resection

Major complications (35%) No signi®cant difference in survival Local recurrence rate 50% Disease free survival 12 months Overall survival 23 months

Pre-operative radiotherapy on unresectable patients Preoperative chemoradiation on unresectable patients IORT with post-operative chemotherapy compared to XRT Surgery vs. split course radiotherapy and 5FU

35% of patients found at 6 week assessment to be resectable (2 survived 5 years and 1 for 7 years) 48% of patients provided with resection leading to a `signi®cant increase in survival' SurvivalÐno signi®cant difference Local relapse rate IORT (25%)Ðcontrol (55%) Median survival: Surgery 11 months CombinationÐ20 months 2-year survival: SurgeryÐ15% CombinationÐ42%

Moertle137

EBRT vs. combination therapy

Blitzer136

Radiotherapy vs. combined therapy

Median survival: Radiotherapy aloneÐ6 months Combination therapyÐ10 months One year survival: Radiation aloneÐ25% Combination therapyÐ44%

Gastrointestinal Tumour Study Group134

Adjuvent chemoradiation following resection

Median survival: No chemoradiationÐ11 months ChemoradiationÐ21 months Two year survival: No chemoradiationÐ18% ChemoradiationÐ43%

Bruckner141

Combination therapy (RT-FSP)

Remission: completeÐ33%, partialÐ33% Signi®cantly improved local control

Bossett127

Pilepich146 Coia147 Fossati148 Kalser135

Unfortunately none of the studies was undertaken in the form of a randomized control trial and therefore the results of such studies should be interpreted as being indicative rather than providing conclusive evidence. Intraoperative radiation therapy (IORT) facilitates the safe delivery of higher radiation doses to pancreatic tumours than can be given by external beam techniques.158±161 It has been suggested that this technique may lead to improved survival and a reduction in local recurrence rates151 without signi®cantly increasing surgical complications.162 A number of studies have also found signi®cant improvements in the palliation of severe pain.148, 160, 163 Local control rates may be further improved by the use of a boost technique such as intraoperative electron beam irradiation (IOEBRT); however, a prospective randomized study comparing IOEBRT with conventional radiotherapy145 found no

signi®cant difference in either local control or median survival. However, the combination of extended radical pancreatectomy with intraoperative radiation therapy seems to signi®cantly increase long-term survival.164 Unfortunately, IORT may also inhibit the activity of tumour in®ltrating lymphocytes. The restriction of this natural killer activity means that IORT is best provided with biological response modi®ers to counter such inhibition of local immunity165 if the theoretical advantages provided by IORT are to be fully translated into survival bene®t for patients. THE ROLE OF TUMOUR CELL BIOLOGY

The development of an enhanced knowledge of the causative agents and mechanics underlying genetic mutation has provided valuable clues to tumorigenesis Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 949±964


and the process of tumour development. However, despite the fact that recent studies have begun to generate information concerning the genetic pro®le underlying pancreatic adenocarcinoma, little is currently known of the genetic alterations arising in the very earliest stages of such tumours. The identi®cation of `early' tumours that are amenable to resection still remain genetically at a late stage of tumorigenesis and hence can provide little indication of preceding changes. The development of a detailed understanding of the process and time sequence of molecular changes in preneoplastic lesions and early pancreatic tumorigenesis represents a crucial gap in our knowledge. Improved understanding of such molecular changes would provide the potential to develop entirely new therapeutic strategies to correct or assuage the damage caused by such molecular mutations.166 Interference with regulatory factors and signals is another potential strategy for future treatments. It is known, for example, that pancreatic cancer overexpresses epidermal growth factor receptor (EGFR)167 as well as producing transforming growth factor a (TGF-a). This combination enables cells to proliferate in an anchorage independent manner168 through an autocrine loop which provides cancer cells with a signi®cant growth advantage. Their normal function becomes usurped by the cancer cells, leading to activation of growth-promoting pathways. Growth control and dif-

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ferentiation is in¯uenced by components of the extracellular matrix and within this matrix cytokines regulate the recruitment of effector cells in tumour tissue by changing cell adhesion and chemotaxis. Combined treatment with cytokine TNF-a and an EGFR-speci®c monoclonal antibody can modulate antigen expression and provoke an effective immunotherapeutic response.169 A range of further pharmacological interventions directed at changing the function of this growth regulatory gene are currently under development.170 Promising results obtained in mice171 have stimulated trials in patients suffering from unresectable pancreatic cancer. Such trials strongly suggest that cytokines can modulate antigen expression and provoke an effective immunotherapeutic response with a monoclonal antibody in pancreatic cancer patients.172 The role of angiogenesis in tumour sustenance173 also provides possibilities of adjuvant treatment by its inhibition by cytokines.174 Tumour invasion requires in®ltration of cells into adjacent tissues and degradation of extracellular barriers represents an important feature underlying the aggressive nature of pancreatic cancer.175 The process of overcoming such barriers involves matrix metalloproteinases (MMP) which are a family of 15 proteolytic enzymes which enable abnormal cells to spread by overcoming the barriers formed by the ECM. A range of biotechnology companies are currently engaged in

Table 4. Outcome of palliative treatment in pancreatic cancer Reference

Nature of palliative treatment

Outcome

Klassen139

Biliary by-pass

Post-operative mortality 19% Median survival 5 months

Huibregtse15

Endoscopic stents

Post-operative mortality 1% Successful palliation 85%

Sharp10 Ventafridda9

Operative celiac plexus block WHO guidelines Subsequent use of neurolytic coeliac block Operative celiac plexus block

Successful palliation: (1±2 months duration 83%) Successful palliation 49% Successful palliation 100% Successful palliation 85% Pain free at death 50%

Bypass alone compared with bypass plus gastroenterostomy

Successful palliation by biliary bypass alone 90% (little additional bene®t from gastroenterostomy)

Analysis of post-operative mortality for operations of surgical palliation

Whipples 5±10% Biliary by-pass 12% Gastrojejunostomy 14%

Gemcitabine

`Clinical bene®t response' experienced by 27% of patients

Costamagna11 Holbrook26 Watanapa

Casper85

32


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developing MMP inhibitors with the aim of reducing the ability of cancer cells to invade adjacent cells. One of the ®rst synthetic compounds to enter clinical trials is marimastat (British Biotech) which is being tested in a variety of protocols in the treatment of advanced pancreatic cancer as well as in the adjuvant setting. This is a novel approach with interesting possibilities for extending survival176 in a therapeutic area characterized by the extreme aggressiveness of the underlying growth of the carcinoma. CONCLUSIONÐCONFRONTING THE CLINICAL CHALLENGES

The short-term challenge is to alter clinical attitudes away from therapeutic nihilism, in order to take full advantage of advances in drug therapy177 and other new therapeutic innovations.86 The extent of this shortterm challenge is emphasized by studies that question the reliability of even the minimal 5-year survival rates for pancreatic adenocarcinoma presented in the literature. One study178 found that the majority of such `survivors' had a histologically uncon®rmed tumour with diagnosis being based entirely upon macroscopical ®ndings, or radiological or clinical evidence alone. The authors concluded that the true 5-year survival rate for pancreatic (extra-ampullary) adenocarcinoma is close to zero. The medium-term challenge is to optimize the use of currently available therapeutic strategies. Most patients will continue to present, for the foreseeable future, with advanced disease, posing the dual therapeutic challenge of local and distant tumour control. Improving local control requires effective surgical, chemotherapeutic and radiotherapeutic interventions. Therapeutic strategies must also take adequate account of the impact of treatment strategies upon the quality of a patient's remaining life. Quality of life evaluation must therefore become integral to the evaluation of therapeutic strategies for this patient group. The long-term challenge is to effectively translate scienti®c advance into clinical practice. In this way innovative therapeutic strategies can be developed to interfere with the fundamental pathways that initiate and promote pancreatic carcinoma. Improved understanding of the role of mutated ras proteins and autocrine/paracrine growth factors offers examples of areas in which an improved understanding of methods of

modulating pancreatic carcinoma cell growth offers the potential for signi®cant improvements in patient care. In confronting these challenges it is important that clinicians make optimal use of the skills and expertise of other health professionals and scientists. This is best achieved through close collaboration and af®liation with an expert multidisciplinary team. Undoubtedly, further advances in unravelling the biology of pancreatic cancer and improving both palliative and curative treatment options will depend on channelling and concentrating patients through protocols in multidisciplinary centres of excellence. In this way a `bespoke' treatment can be tailored to the individual patient which provides the best method of improving the quality and quantity of life experienced by the current and future patient population in this important therapeutic area (Table 4). ACKNOWLEDGEMENTS

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