Pancreatic and hepatobiliary cancers: New treatment possibilities for pancreatic and biliary tumours

New treatment possibilities for pancreatic and biliary tumours Eric Van Cutsem, Karin Haustermans and Werner Van Steenbergen Department of Internal Medicine, University Hospital Gasthuisberg, 3000 Leuven, Belgium

Introduction

Chemotherapy for pancreatic cancer Many studies have been carried out with 5-fluorouracil (5-FU) in pancreatic cancer. Early trials

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Pancreatic adenocarcinoma is one of the most lethal cancers in the Western world with a median survival of approximately 3 months. Patient survival depends on the extent of disease and performance status at diagnosis. The extent of disease is best categorised as resectable, locally advanced or metastatic. Surgery is the only curative treatment. It is, however, an option in only 10-20% of patients. Long-term survival after surgical resection of pancreatic cancer is less than 20%. Local recurrence occurs in up to 85% of patients who undergo surgery alone. Local-regional tumour control is maximised with combined modality therapy in the form of chemoradiation and surgery. With improved therapy for local-regional disease, liver metastases become the predominant form of tumour recurrence and occur in 50 to 70% of patients following potential curative combined modality treatment. At the time of diagnosis, 40% of patients have locally advanced disease and more than 40% have visceral metastases, most frequently in the liver. Therefore, with new surgical and radiotherapeutic techniques improving locoregional control, we will face distant metastases being responsible for therapy failure more often and effective systemic treatment will become even more important for prolonging survival. Unfortunately results obtained with chemotherapy failed to have an important impact on the final outcome and have been the reason for scepticism among clinicians and oncologists for many years. However, a totally fatalistic approach is not justified, because a significant proportion of patients do achieve benefit from chemotherapy. Several new and innovative therapeutic modalities are in development and offer hope for an improved outcome for patients with pancreatic cancer in the future.

clearly overestimated the efficacy of 5-FU because of inadequate response criteria. The actual response rate is below 10%. Response evaluation, especially in locally advanced disease, is often troublesome. Accurate and reliable tumour measurements are often difficult to obtain. High numbers of patients with immeasurable disease are a major drawback of many clinical studies performed in pancreatic cancer. Liver and peritoneal metastases are often very small and local structures, such as normal pancreatic tissues, small bowel and stomach are sometimes difficult to distinguish from pancreatic tumour. There is also often a large amount of reactive fibrous tissue present in pancreatic cancer. Biochemical modulation of 5-FU with leucovorin and interferon did not show significantly better results. Combination chemotherapy with various combinations of 5-FU, mitomycin C, doxorubicin and streptozotocin (FAM and SMF regimens) has failed to yield clinically significant better results, despite some initial encouraging reports of early phase II studies [1,2]. A few studies have suggested that the activity of a protracted 5-FU infusion in combination with cisplatin is slightly more active [3,4]. It is how. ever not clear whether the increased toxicity justifies the use of these regimens in pancreatic cancer. The disappointing results obtained with 5-FU and 5-FU combination regimens underline the need for new active drugs in pancreatic cancer. Gemcitabine is a novel nucleoside analogue with activity across a broad range of solid tumours [5]. The activity of gemcitabine in pancreatic carcinoma was assessed first in phase II trials. In a United States study of 44 patients, an objective response rate of 11% and a median survival of 5.6 months were reported [6]. In a European study of 34 patients, a tumour response rate of 6.3% and a median survival of 6.3 months were found [7]. Both study groups reported symptomatic improvements in their patients which were beyond that suggested by the objective tumour response rates. These improvements were seen in pain (reductions in both pain severity and analgesic re-

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acceptable toxicity and show favourable results in terms of clinical benefit [25] and response [2]. Based on this information several other interesting combinations are presently being studied in phase II studies in advanced pancreatic cancer gemcitabine plus cisplatin, gemcitabine plus docetaxel, docetaxel plus cisplatin, and gemcitabine plus oxaliplatin. The EORTC-Gastrointestinal Tract Cancer Cooperative Group is performing a randomised phase II study of the combination of docetaxel plus gemcitabine versus docetaxel plus cisplatin. These randomised comparisons lead to more reliable conclusions than the earlier mentioned phase II evaluations. The question whether arterially delivered chemotherapy may be beneficial in locally advanced pancreatic cancer has been raised. Little information is available and most data are derived from small series of very selected patients. It seems highly unlikely that will lead to more promising data before more effective chemotherapy becomes available.

New therapeutic approaches in pancreatic cancer As systemic treatment of metastatic pancreatic cancer remains unsatisfactory. New treatment strategies are explored. Matrix metalloproteinases (MMPs) MMPs play a key role in the process of invasion and metastasis, by degradation of the adjacent extracellular matrix. Disruption in the tight control of MMP metabolism occurs in cancer, resulting in excessive destruction of the extracellular matrix, neovascularisation, tumour spread and metastases. Recent studies have shown that overexpression of MMPs is associated with poor prognosis. MMP inhibitors have shown not to affect tumour cells, but in vivo models have shown tumour growth delay and reduction in the number of metastases. Therefore endpoints such as objective tumour response are unsuitable for MMP inhibitors. A phase II study of marimastat demonstrated a reduced rate of increase of CA 19.9 [26] and a favourable survival in comparison to historical controls [27]. A randomised phase HI study of marimastat versus gemcitabine, however, did not show a significant difference. Moreover, preliminary results of a randomised study of gemcitabine plus marimastat versus gemcitabine failed to show any significant survival difference (press release). Tumour growth and its dissemination are angiogenesis-dependent processes. Angiogenesis is typically stimulated in response to tumour-secreted

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quirements) and in performance status [8]. Therefore 'clinical benefit response' was introduced as primary endpoint to evaluate the efficacy of gemcitabine [8,9]. Following these phase II evaluations, a randomised study was performed in 126 patients with advanced pancreatic cancer, in which patients were treated with gemcitabine or with 5-FU. Gemcitabine (1000 mg/m 2 ) was administered as a 30 minute infusion weekly for 7 consecutive weeks, followed by one week rest. Thereafter, the drug was given once weekly for 3 out of every 4 weeks. 5-FU 600 mg/m 2 was administered once weekly as a bolus. Fifteen of 63 patients randomised to gemcitabine experienced clinical benefit response (24%) with a median duration of 18 weeks versus 3 of 63 (5%) in the 5-FU treated patients and with a median duration of 13 weeks. In the gemcitabine group, 5.4% of the patients (3 of 56) with measurable disease had a radiologic response versus none in the 5-FU group. Gemcitabine also showed a modest survival advantage over 5-FU (1 year survival 18% versus 2%; median survival: 5.65 months versus 4.41 months) [9]. Although these were the first studies using clinical benefit response, and caution is justified in interpreting these results, gemcitabine seems to be the first agent that has demonstrated improvement of disease related symptoms and survival in advanced pancreatic cancer. As a result, the drug is proposed as the reference treatment for first-line treatment of advanced pancreatic cancer [10]. More recently pharmacologic studies have shown that increased levels of the active triphosphate metabolite of gemcitabine are achieved by prolonging the infusion time [11,12]. It has been suggested in a randomised phase II study that administering gemcitabine at a fixed dose rate infusion (1500 mg/m 2 at a rate of 10 mg/m 2 /min weekly x 3 every 4 weeks) results in more objective responses, longer median survival and higher 1 year survival than previously reported [13]. Of the newer agents the activity of topotecan, irinotecan, raltitrexed, MTA and temozolomide was limited with response rates of 7-15% in small phase II studies [14-18] and are usually considered as inactive in pancreatic cancer. Initial reports showed a promising activity for the taxoids. A response rate of 20% was shown with docetaxel (100 mg/m2) [19]. However, later phase II studies showed lower response rates [20-23]. Also, the activity of paclitaxel was very low [24]. The combination of 5-FU and gemcitabine has recently been studied phase I and phase II studies. In this combination 5-FU has been used both as bolus and in infusional regimens. Both are feasible, have

New treatment possibilities for pancreatic and biliary tumours

Clinical studies with several angiogenesis inhibitors that act on different mechanisms have therefore started in pancreatic cancer: e.g. SU5416, a selective inhibitor of the VEGF receptor; SU 6668, an inhibitor of the receptors for VEGF, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF); EMD 121974, a specific inhibitor of the avp3 integrin. Ras proteins These are guanine-nucleotide-binding proteins that play a crucial role in the control of normal and transformed cell growth. In 75-90% of pancreatic cancers a mutated K-ras gene has been found. Ras undergoes several post-translational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first — and most critical — modification is the addition of a famesyl isoprenoid moiety in a reaction catalysed by the enzyme farnesyltransferase (Ftase) [30]. It follows that inhibiting Ftase would prevent Ras from maturing into its biologically active form. Different classes of Ftase inhibitors have been identified that block famesylation of Ras, reverse Ras-mediated cell transformation in human cell lines and inhibit the growth of human tumour cells [30]. As single-agent therapy, Ftase inhibitors may be most efficacious against premalignant lesions and localised tumours that have not evolved significant resistance to apoptosis. In addition, the cytostatic properties of Ftase inhibitors may

be useful to block the growth of micrometastases after primary therapy. Combined modalities must therefore certainly be considered to enhance cytotoxicity. Preclinical data suggest that Ftase inhibitors will be useful as radiosensitizers and chemotherapy enhancing agents. Rl 15777 and SCH 44342 are 2 interesting Ftase inhibitors that are actually evaluated in phase II and m trials in pancreatic cancer as single agent and in combination with gemcitabine in pancreatic cancer. Other combination studies are also ongoing or planned. The Ras-Vaccination consists of a mixture of seven synthetic peptides which represent all currently known mutations in the Ras gene at positions 12 and 13. These two hot spots account for almost 100% of all Ras-mutations detected in gastrointestinal tract cancers. The agent is applied by intradermal injection in combination with GM-CSF. Early clinical trials have demonstrated that the currently applied vaccination schedule is capable to induce T-cell specific, T-cell mediated immune response in patients with advanced pancreatic cancer. Phase II trials are ongoing to evaluate the activity of this new approach. Other new and innovative approaches in preclinical and early clinical development in pancreatic cancer include gene therapy and immunotherapy. Genetic prodrug activation therapy using tumourselective gene promoters (virally directed enzyme prodrug therapy — VDEPT), replacement of tumour suppressor gene function using adenovirus to transfer wild-type p53 and pl6 genes, blockade of dominant oncogene function by antisense technology and genetic immunomodulation using cytokine genes as well as specific vaccines against tumour-associated antigens are examples of innovative approaches that are being examined for their role in pancreatic cancer [31]. Another new type of agent is ONYX-015, which is an E1B gene-attenuated adenovirus [32]. The deleted protein from the E1B region of the adenovirus normally binds to and inactivates the p53 gene. ONYX-015 can only be replicated in cells deficient for wt-p53 and kills only p53 abnormal cells. A phase I trial of intratumoural injection of ONYX-015 in unresectable pancreatic cancer showed clear hints of activity [33]. Biliary tract cancer Biliary tract cancers are rare tumours. The diagnosis of these tumours is most often made at an advanced stage of the disease. A complete surgical resection is the only curative option. Local relapse in the tumour bed or in regional lymph nodes is common after 'curative' resection. Both gallbladder and extrahepatic bile duct cancer, present often with

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angiogenesis factors such as vascular endothelial growth factor (VEGF). Several possible advantages and benefits of antiangiogenic drugs have been shown such as the fact that they might overcome some forms of intrinsic drug resistance caused by lack of sufficient penetration of drugs into the interior of solid tumours, because only the endothelial cells of the tumour's vessels would have to be targeted. Many drugs used to inhibit angiogenesis have been developed. Neutralising antibodies to VEGF, small molecule VEGF receptor antagonists or anti-VEGF receptor antibodies, soluble VEGF antagonists and endogenous protein inhibitors such as angiostatin or vasostatin are examples. Several of these drugs will be studied in pancreatic cancer. It has indeed been shown that VEGF was overexpressed in 64% of pancreatic tumours and the presence of VEGF overexpression is associated with an increased blood vessel number, large tumour size and enhanced local spread but not with a reduction in patient survival time [28]. It has been suggested that VEGF upregulation is due to mutations of the K-ras oncogene, which occur in 75-90% of pancreatic adenocarcinomas [29].

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obstructive jaundice and can be managed by stents placed endocopically or percutaneously. The results of palliative chemotherapy in biliary tract cancer are rather disappointing. Most of the reported studies are small phase II studies. Measurability of the lesions is also sometimes difficult because of the localisation of the tumour at the liver hilum. Response rates appear to be similar for advanced carcinomas of the gallbladder, bile duct — and intrahepatic cholangiocarcinomas. 5-FU is the most studied and the most active agent in these studies. Response rates vary from 10 to 20%. Drug . combinations such as a combination of 5-FU plus adriamycin and/or mitomycin C do not seem to increase response rates. No large randomised phase HI studies are available. A French phase II study that showed a response rate of 24% in 25 patients with the combination of infusional 5-FU and cisplatin [34], is the basis for a randomised phase II study of the EORTC-GITCCG that compares the activity of a weekly infusional regimen of 5-FU to infusional 5-FU plus cisplatin. The activity of other new agents such as gemcitabine, oxaliplatin, the taxoids and irinotecan have still to be studied prospectively in this tumour. Randomised phase II studies are probably the most appropriate way to further study these drugs. The occurrence of biliary obstruction with secondary jaundice might hamper the careful evaluation of some of these drugs in this cancer. The new approaches that are actually studied in pancreatic cancer are not evaluated in biliary tract cancer, mainly due to the low frequency of these tumours.

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Educational Session

SUPPORTIVE CARE Chairperson Robert E. Coleman

Co-Chairperson Piotr Siedlecki Marie Skledowska-Curie Institute Cancer Centre Warsaw, Poland

Speakers "Prevention of sterility possible in men?" John A. Radford Christie Hospital NHS Trust CRC Department of Medical Oncology Manchester, United Kingdom

"Prevention of infertility possible in women?" Luc Delbeke UZAntwerpen Centre for Reproductive Medicine Edegem, Belgium

"Uses and abuses of bisphosphonates" Robert E. Coleman Weston Park Hospital NHS Trust Yorkshire Cancer Research Department of Clinical Oncology Sheffield, United Kingdom

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Weston Park Hospital NHS Trust YCR Department of Clinical Oncology Sheffield, United Kingdom

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