Treatment of Pancreatic Cancer: Current Limitations, Future Po Published on Cancer Network (http://www.cancernetwork.com)

Treatment of Pancreatic Cancer: Current Limitations, Future Possibilities Review Article [1] | March 01, 1996 | Gastrointestinal Cancer [2], Pancreatic Cancer [3] By A. William Blackstock, Jr, MD [4], Adrienne D. Cox, PhD [5], and Joel E. Tepper, MD [6] In an attempt to improve the grave prognosis associated with the diagnosis of pancreatic cancer, researchers have explored a number of novel therapies. These include hormonal therapy, immunotherapy, radiopharmaceuticals, and novel chemotherapeutic agents.

Introduction Few malignancies have frustrated the persistent efforts of the oncologist as has pancreatic cancer. In a review of 61 published studies that included over 37,000 patients with pancreatic cancer, Gudjonsson observed an overall survival rate of 3.5% for the 4,100 patients who had undergone resection [1]. More recent data indicate continued poor results, with survival rates ranging from 2% to 5% [2]. The annual incidence and overall number of deaths from pancreatic cancer in developing countries are virtually identical; in 1994, an estimated 81,000 new cases were diagnosed, resulting in 78,000 deaths [3]. The incidence of pancreatic cancer rose 1% per year from 1937 until 1973, and has remained unchanged since then [2]. The dismal reports in the literature result, in part, from the stage of disease at diagnosis [4]. Computed tomography (CT) and magnetic resonance imaging (MRI) have made it easier to define disease stage and determine the diagnosis. Needle biopsies and laparoscopy guided by CT have resulted in fewer unnecessary laparotomies, while biliary stenting, either endoscopically or, when necessary, transhepatically, can lessen the need for a surgical procedure in patients with advanced tumors. Unfortunately, these imaging and diagnostic advances have not yielded detection of earlier-stage disease. Approximately half of all patients with pancreatic cancer have metastatic disease at the time of diagnosis [4,5], while most of the rest have locally advanced, unresectable disease [6,7]. In general, the overall curative resection rate is 10% to 15%, with most authors reporting an overall 5-year survival rate of 10% [4,8]. The national cancer data base reported a 10% overall survival rate for patients with pancreatic cancer diagnosed since 1990 [9]. It is clear from more recent surgical data that the survival rate following a Whipple procedure has improved. Several major centers are reporting perioperative mortality of less than 1% for a procedure that some authors previously suggested abandoning due its high complication and death rates [10-12]. This improvement is due, in part, to increased surgical experience, advanced postoperative intensive care techniques, and better preoperative selection with the preopera tive use of abdominal CT, MRI, and laparoscopy to assess local disease extent and resectability. At Johns Hopkins, perioperative survival for resected patients has shown a steady improvement. In-hospital mortality for patients treated with resection in the 1970s was 30%, vs 0.9% for patients similarly treated in the 1990s. As reported by Yeo et al, this decrease in operative mortality has led, in part, to increased median survival: 7.5 months for patients treated during the 1970s vs 17.5 months for patient treated since 1990 [10]. This improvement in median survival also results from the increased use of adjuvant postoperative radiation and chemotherapy. Radiation therapy alone, chemotherapy alone, or the two in combination provides palliative therapy for patients with locally advanced, unresectable disease. Radiation alone has been shown to increase median survival from 3 to 6 months [13], while concurrent radiation and 5-fluorouracil (5-FU) may further increase median survival to 10 months (Table 1) [14]. Yet, reports of 5-year survival among patients managed with nonsurgical therapies remain anecdotal. At present, the most active single-agent chemotherapy agents are 5-FU and mitomycin (Mutamycin), with each demonstrating response rates in the range of 10% to 30% [15,16]. Data from a number of groups have shown little survival benefit with various single-agent and combination chemotherapies for locally advanced or metastatic pancreatic cancer [17,18]. Palmer et al, however, using 5-FU, Page 1 of 10

Treatment of Pancreatic Cancer: Current Limitations, Future Po Published on Cancer Network (http://www.cancernetwork.com) Adriamycin, and mitomycin (FAM), reported a median survival of 33 weeks, vs 15 weeks for no treatment, and they suggested that previous studies were negative because they lacked a no-chemotherapy treatment arm [19]. Our current arsenal of chemotherapeutic agents modestly prolongs life while providing little possibility for cure. Of the reported 150 ten-year survivors of pancreatic cancer in the world literature, only 12 have been cured with nonsurgical therapies [1]. Despite these poor results, many experts consider radiation delivered concurrently with 5-FU to be standard therapy for patients with locally advanced pancreatic cancer. There have been limited advances toward improving the overall survival rate after resection with adjuvant therapies. Tepper et al observed a local tumor recurrence rate of 50% in curatively resected patients, suggesting a possible survival advantage to improving local control with radiation therapy [20]. In randomized data from the Gastrointestinal Tumor Study Group (GITSG), postoperative radiation given concurrently with 5-FU not only resulted in a local control advantage over surgery alone but also produced a median survival advantage (Table 2) [21]. Data from this trial at 5 and 10 years continue to show a survival advantage for patients receiving adjuvant therapy; 5and 10-year survival rates for the surgery-alone arm were 5% and 0%, respectively, vs 19% at both 5 and 10 years for patients receiving adjuvant chemoradiation [22]. These data showing benefit with adjuvant therapy are supported by nonrandomized studies from the University of Pennsylvania and Johns Hopkins [10,23]. Numerous clinical trials have been performed with other innovative radiation treatment techniques aimed at improving local control, including neutron therapy [24], iodine-125 implantation [25], and intraoperative radiation therapy [26,27]. Often, an improvement in local control over conventional external-beam therapy has been observed, but this has not translated into an overall survival advantage. Although the gains with surgery plus adjuvant therapy have been modest, most consider standard therapy for patients with operable pancreatic cancer to be resection followed by postoperative radiation therapy with concurrent 5-FU. Because of the marginal advances made thus far with standard oncologic therapies, a number of researchers have focused on developing other strategies for the treatment of pancreatic cancer. In this article, we will discuss some of the more innovative of these approaches and their potential limitations in the management of pancreatic cancer.

Hormonal Therapy Somatostatin and its Analogs Somatostatin is a cyclic peptide hormone widely distributed throughout the gastrointestinal system [28], and can act as a potent inhibitor of tumor cell growth [29]. It has been postulated that somatostatin and its analogs inhibit cell growth by triggering signal transduction pathways that negatively control cell growth or by downregulating the stimuli responsible for tumor growth [29]. Szende et al recently demonstrated that somatostatin may induce tumor regression through a mechanism associated with programmed cell death [30]. Unfortunately, clinical experience has demonstrated no significant benefit of somatostatin monotherapy in the treatment of pancreatic cancer [31,32]. More compelling clinical results were reported by Ebert et al with high-dose octreotide (Sandostatin), an analog of somatostatin with an increased duration of action. In a cohort of patients with advanced pancreatic cancer, a low-dose octreotide regimen resulted in a median survival of only 3 months, whereas the high-dose produced a median survival of 6 months [33]. Antiestrogens The presence of estrogen receptors in neoplastic mammary tissue and the subsequent tumor responses observed following antiestrogen treatment have been well documented in the literature [34]. Pancreatic carcinomas also possess estrogen receptors; therefore, it is plausible that a similar approach would result in an effective therapy for pancreatic cancer [35]. Unfortunately, most of the clinical data, including a randomized trial reported by Taylor et al, have not demonstrated an improved median survival with tamoxifen alone over placebo [36]. One of the few positive results comes from a case-control study of 80 patients with metastatic pancreatic cancer reported by Wong et al, which demonstrated a modest improvement in median survival for patients receiving tamoxifen therapy (7 vs 3 months) [37]. Rosenberg et al reported a median survival advantage for patients receiving a combined octreotide-tamoxifen regimen (12 months, vs 3 months) for an untreated matched cohort) [38]. Although these data are somewhat encouraging, tamoxifen and octreotide do not appear to have great overall effectiveness in Page 2 of 10

Treatment of Pancreatic Cancer: Current Limitations, Future Po Published on Cancer Network (http://www.cancernetwork.com) pancreatic cancer. Luteinizing Hormone-Releasing Hormone Agonist The use of leuprolide (Lupron), a luteinizing hormone-releasing hormone agonist, alone or in combination with somatostatin, has demonstrated in vitro and in vivo activity in pancreatic cancers in hamsters [39]. In light of these and other supporting data [40], Zaniboni et al conducted a phase II trial to test the combination of leuprolide and tamoxifen in 15 patients with pancreatic cancer. No objective responses were observed, and median survival was a disappointing 5 months [41]. In conclusion, the clinical impact of hormonal therapy in pancreatic cancer, either alone or in combination with other agents, appears limited.

Immunotherapy IL-2/LAK Therapy Other researchers have investigated the use of lymphokine-activated killer (LAK) cells in the treatment of pancreatic cancer. LAK cells have demonstrated cytotoxic activity in a number of carcinoma and sarcoma cell lines [42,43], and in vivo in combination with interleukin-2 (IL-2) [44]. Interleukin-2 is a glycoprotein produced by activated T-lymphocytes that is thought to induce LAK cell activity. This activity requires direct contact with target cells. Researchers have recently determined that certain surface molecules, such as adhesion molecules and major histocompatibility complex (MHC) antigens, play important roles in LAK cell/target cell interactions [45]. Takahashi et al observed in vitro that LAK cell attachment was mediated by specific surface molecules associated with the pancreatic cell line, PCI-24, suggesting a possible role for IL-2/LAK therapy in pancreatic cancer [46]. Because several clinical trials utilizing high-dose IL-2 and LAK cells have demonstrated objective responses in renal-cell carcinoma and melanoma [44], a phase II trial was conducted by Sparano et al in patients with pancreatic cancer. Unfortunately, the authors observed no objective response in eight patients treated with standard IL-2/LAK cell therapy [47]. Based on the data reported thus far, IL-2/LAK cell based immunotherapy is not likely to provide substantial benefit for patients with pancreatic cancer. Anti-CEA Vaccine Another therapy being investigated involves the development of a recombinant anti-human carcinoembryonic antigen (anti-CEA) vaccine using an attenuated strain of vaccinia virus. Vaccination of mice with the anti-CEA vaccine rendered them resistant to subsequent transplantation of CEA-expressing tumors. In addition, mice vaccinated within 7 days of the tumor injection showed reduced or no tumor growth [48]. Although the immunologic mechanisms remain unknown, these animal data demonstrate that an attenuated vaccinia strain used extensively in humans is an efficient vehicle for inducing a range of immune responses, including antitumor activity [48]. Viral Gene/CEA Coupling Related work to attain tumor-specific gene expression was achieved by coupling the promoter for CEA to a gene, herpes simplex virus thymidine kinase (HSV-tk), which phosphorylates and converts ganciclovir (Cytovene) to a potent DNA synthesis inhibitor. Retroviral vectors were constructed to contain the CEA promoter coupled to HSV-tk and were used to transduce the CEA-expressing pancreatic carcinoma cell line BxPC-3. Recombinant pancreatic carcinoma cell lines expressing HSV-tk were then tested for the toxic effects of ganciclovir after engraftment into athymic immunodeficient mice. The study demonstrated a significant reduction in tumor size with ganciclovir therapy when compared to controls [49]. This approach warrants further investigation.

Chemotherapy A vast number of chemotherapeutic agents have been evaluated in the treatment of advanced pancreatic cancer; most of these regimens have contained 5-FU because of its reported 10% to 30% activity [50]. The overall response rate with multiagent chemotherapies containing 5-FU remains in the range of 20% to 40% [51]. Modulation of 5-FU A number of investigators have attempted to modulate 5-FU to enhance its antitumor effects. Marsh et al evaluated the use of circadian rhythm-modulated, continuous-infusion 5-fluoro- uracil deoxyribonucleoside (5-FUdR) given concurrently with megestrol acetate in 13 patients with advanced pancreatic cancer. No patient was observed to have tumor regression, and the addition of megestrol did not improve the nutritional status of any of the patients [52]. Although the response data are contradictory [53], several authors, delivering 5-FU in conjunction Page 3 of 10

Treatment of Pancreatic Cancer: Current Limitations, Future Po Published on Cancer Network (http://www.cancernetwork.com) with interferon-alfa-2a (Roferon-A) and folinic acid, have reported enhanced activity [54,55]. The administration of 5-FU given via continuous infusion or concurrently with methotrexate or leucovorin has also demonstrated only limited benefit. A potential future modulator of 5-FU may be 3'-azido-3'-deoxythymidine (AZT, zidovudine [Retrovir]), an agent clinically used in patients with the AIDS. Chandrasekaran et al have demonstrated in vitro that AZT, when given in conjunction with 5-FU, can induce a cell-cycle synchronization that leads to a synergistic cytotoxic effect [56]. Improving the cytotoxicity of 5-FU through modulation may lead to improved objective response rates, but its ability to alter the overall survival of this disease is unlikely. Novel Chemotherapeutic Agents Other more novel chemotherapeutic agents have also been investigated in pancreatic cancer. Anthracycline Analogs--THP-Adriamycin (pirarubicin) is an anthracycline that is reported to have antitumor activity superior or equal to that of its parent compound, doxorubicin, but lower cardiotoxicity. Mondher et al enrolled 18 patients with advanced pancreatic cancer into a phase II clinical trial of pirarubicin and demonstrated acceptable tolerance but no objective responses and a dismal median survival of 3.5 months [57]. In a phase II trial, the Eastern Cooperative Oncology Group (ECOG) evaluated the efficacy of two other anthracycline analogs, dihydroxyanthracinedione (DHAD) and aclacinomycin A. Dihydroxyanthracinedione avoids anthracycline cardiotoxicity by replacing the amino sugar moiety with an alkyl amino group, and yet its ability to bind DNA and intercalate between base pairs and inhibit nucleic acid synthesis is left unaltered. Aclacinomycin A exhibits greater inhibition of RNA than DNA or protein synthesis and may have a different mechanism of action than doxorubicin and much less cardiotoxicity. Unfortunately, no complete or partial responses were observed with either agent [58]. Gemcitabine--Several groups are currently investigating gemcitabine (2',2'-difluorodeoxycytidine [Gemzar]), a fluorine-substituted cytarabine analog. Once gemcitabine is converted intracellularly to its active forms, gemcitabine diphosphate and gemcitabine triphosphate, these metabolites reduce cellular deoxycytidine triphosphate levels. This facilitates both increased gemcitabine phosphorylation and decreased elimination, resulting in continued inhibition of cellular DNA synthesis. In a randomized, multicenter, single-blind trial, which evaluated gemcitabine vs bolus 5-FU in 126 patients with locally advanced or metastatic pancreatic cancer, a clinical benefit response rate of 23.8% was obtained for patients receiving gemcitabine, as compared with a rate of 4.8% for those given 5-FU [59]. Clinical benefit was defined as a clinical change in patients' pain intensity, analgesic consumption, weight, and performance status. More objectively, however, 5.4% of the gemcitabine-treated patients demonstrated a partial response. Median survival durations for the gemcitabine and 5-FU groups were 5.7 and 4.4 months, respectively. Additional efforts will be directed at assessing the activity of gemcitabine in combination with other cytotoxic agents or possibly as a radiation sensitizer. Paclitaxel and Docetaxel--Finally, phase II trials evaluating paclitaxel (Taxol) and docetaxel (Taxotere) in patients with pancreatic cancer have reported equally disappointing data. Brown et al reported a response rate of only 13% in a small cohort of patients treated with paclitaxel [60], while Rougier et al observed a more encouraging 27% response rate in 26 patients treated with docetaxel but a median response duration of only 3.0 months [61].

Radiopharmaceuticals Infusional brachytherapy has also been advocated in the treatment of patients with pancreatic cancer. This modality evolved from the application of radiolabeled monoclonal and polyclonal antibodies, but, as reported by Larson et al and others, the tumor dose with systemic infusion was often inadequate [62]. Order et al recently reported phase I results with the interstitial infusion of radioimmunoconjugates directly into the target volume in 16 patients with locally advanced, nonmetastatic pancreatic cancer. The technique entails the initial infusion of macroaggregated albumin (MAA) directly into the tumor. The MAA obstructs the venular capillaries and lymphatics and thus provides greater retention of the radioactive chromic phosphate phosphorus-32 colloid. Following the initial brachytherapy treatment, patients are treated with a full course of external-beam radiation (60 Gy) delivered with concurrent 5-FU. Infusional phosphorus-32 brachytherapy produced tumor doses in the range of 23,000 to 500,000 cGy with very little toxicity [63]. The overall median survival for patients who Page 4 of 10

Treatment of Pancreatic Cancer: Current Limitations, Future Po Published on Cancer Network (http://www.cancernetwork.com) completed therapy was 8 months.

Molecular-Based Therapy Researchers attempting to uncover new targets for therapy have sought to determine which molecules have different expression levels and/or activity in normal and cancerous pancreatic cells. It has been shown in both cell and animal model systems that correction of a single defect can significantly affect the aberrant behavior of tumor cells [64,65]. Genetic defects commonly associated with pancreatic cancers include loss or inactivation of the tumor-suppressor proteins p53, p16, and DCC and mutational activation of the K-ras proto-oncogene [66,67]. Between 75% and 90% of all pancreatic cancers contain a mutation in codon 12 of K-ras [68]. Since it is far more practical to destroy the activity of a protein than to replace a defective one, one obvious target for therapy relates to the exceptionally high incidence of specific activating mutations in the K-ras proto-oncogene. H-, N-, and K-ras proteins are small (21-kd) proteins that normally serve as guanosine triphosphate(GTP)-regulated switches to control an incredibly diverse array of cellular signals that modulate highly regulated programs of proliferation, differentiation, and death. The mutations at codon 12 render ras constitutively GTP-bound, or active, and this deregulated form of ras is therefore unable to switch off growth signals. Using in vitro model systems, it has been demonstrated that reducing the activity of the mutated K-ras protein, either by homologous recombination to delete the mutated K-ras oncogene in human colorectal carcinoma cells [64] or by direct microinjection of neutralizing antibody into cultured fibroblasts [69], significantly reduces both tumorigenicity in animal models and proliferation in cell culture. How might interference in K-ras function be accomplished in a clinical setting? Efforts to date have focused on two types of pharmacologic agents that either target the expression of K-ras protein or interfere with the biologic activity of the protein. K-ras Antisense Therapy In the first approach, antisense molecules created specifically against the mutated form of K-ras are used to suppress the expression of the protein. Used with varying degrees of success in different tumor types, antisense development has suffered from considerable technical difficulties in delivery, toxicity, and lack of specificity [70]. Advances are being made in all of these areas, particularly in the development of more stable analogs of the short oligonucleotides necessary to inhibit protein expression. A typical example of the frustrations encountered was presented by a group that tested antisense oligonucleotides both on a panel of five pancreatic tumor lines and on H- or K-ras-transformed fibroblasts in vitro. Although dose-dependent antiproliferative effects were seen, these were neither correlated with reduced levels of K-ras protein nor found to be sequence-specific [71]. In a recent, more promising study [72], an antisense K-ras expression plasmid was transduced into pancreatic tumor cell lines. It inhibited both the levels of K-ras protein expression (80% inhibition) and the growth (45% to 87%) of two lines containing mutated K-ras, but did not affect either parameter for a third line containing only wild type K-ras. When the antisense plasmid was delivered as a liposome complex directly into the peritoneal cavity of nude mice 3 days after inoculation, only 2 of the 12 mice treated with the antisense construct developed tumors, whereas 9 of 10 untreated mice developed pancreatic and/or mesenteric tumor nodules by 4 weeks. The authors reported additional preliminary data in which the antisense constructs were also effective when administered to mice at day 14 or 15 after tumor cell inoculation, a time interval that was ample for peritoneal dissemination. Delivery of the plasmid to other organs (except the brain) without toxicity was reported. If reproducible, this approach has the potential to produce a major impact on a disease such as pancreatic cancer, which readily metastasizes. Inhibition of K-ras Modification Farnesyl Transferase Inhibitors--A second approach to interference in ras function has resulted from the discovery that, in order to target correctly the plasma membrane and be biologically active, ras proteins must be modified by a lipid moiety called a farnesyl isoprenoid, an obligate intermediate in the cholesterol biosynthetic pathway [73]. The development of peptidomimetic inhibitors of farnesyl transferase (FTase), the enzyme that accomplishes this modification, has led to a novel group of rationally designed compounds that have the potential to become anticancer chemotherapeutic agents for tumors dependent on ras function. These FTase inhibitors (FTIs) are now under intense investigation. First demonstrated to selectively reduce the anchorage-independent growth of ras-transformed cells in vitro, FTIs have recently been shown to cause slowing or even regression of tumor growth in Page 5 of 10

Treatment of Pancreatic Cancer: Current Limitations, Future Po Published on Cancer Network (http://www.cancernetwork.com) mouse xenograft and transgenic models of lung [74], bladder [75], fibrosarcoma [75], and mammary carcinomas [76]. Since these compounds act by preventing the modification of newly synthesized ras proteins, they are predicted to be cytostatic rather than cytotoxic, but the mechanism of regression is unclear. Surprisingly, given the central role of ras in growth regulation, but fortunately, given the probable necessity for chronic, long-term treatment, FTIs appear to be only minimally toxic. Because these agents are new, experience with them in pancreatic cancer is minimal. In one study in which the overall sensitivity of a panel of 44 tumor cell lines was more than 70%, 2 of 3 pancreatic tumor lines with a mutated K-ras were sensitive to FTI growth inhibition, and a fourth line with wild type K-ras was resistant [77]. Since there are multiple mechanisms, in addition to mutation of ras, by which tumors may be dependent on ras function, attempts to correlate FTI sensitivity to ras mutation status may not be focusing on the relevant parameters. Another study [78] tested a different FTI on a panel of 19 tumor cell lines, of which 52% were sensitive; of these, a fifth pancreatic tumor line was partially sensitive to inhibition of anchorage-independent growth. Overall, the degree of inhibition of the tumor cell lines correlated with the type of ras mutation, with H- and N-ras being substantially more sensitive than K-ras. This is not surprising, since K-ras is a substantially better substrate for the FTase enzyme, and its modification is therefore much more difficult to inhibit. At present, there is a great deal of controversy over whether K-ras, under conditions of FTI treatment, may escape inhibition by using an alternate lipid modification pathway [79]. If this is indeed the case, such a finding has major implications for the potential utility of FTIs in treating tumors dependent on mutant K-ras. These initial findings are promising, but it remains unclear whether these agents will make the transition to clinical application. A recent finding indicates that another unidentified protein may be an even more important target for FTIs than ras [80]. Major efforts are underway to characterize the precise mechanism of tumor inhibition by FTIs before clinical trials are undertaken. HMG-CoA Reductase Inhibitors--A review of the literature found no published data of FTI treatment of pancreatic tumor models in vivo. However, another class of agents that can inhibit ras modification has shown some efficacy in pancreatic cell lines and pancreatic tumor xenograft models [81,82]. These agents are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors--a drug class long used to modify cholesterol blood levels. Because HMG-CoA reductase inhibitors, such as lovastatin (Mevacor) and simvastatin (Zocor), act by blocking the production of mevalonate, the precursor of all isoprenoid and cholesterol biosynthesis, they are much less specific than FTIs. Known to affect a variety of molecules required for the cellular replication machinery, the inhibitory actions of these compounds are not attributable to their ability to block ras processing [83]. However, as with FTIs, the ability of these agents to demonstrate inhibition of pancreatic tumor cell lines in vitro and in xenograft models in vivo, at clinically relevant doses, makes them worthy of further testing.

Conclusions The management of pancreatic cancer has improved relatively little in the past few decades; the major advances have been better preoperative staging and a decrease in surgical morbidity and mortality. The data suggest an advantage to adjuvant (postoperative) radiation therapy and 5-FU chemotherapy. For patients with locally advanced, nonmetastatic tumors, the combination of radiation and chemotherapy improves median survival but has minimal chance of producing long-term cure. At present, most chemotherapeutic approaches have produced only modest benefit in metastatic disease. Newer techniques, such as modification of the ras signal transduction pathway in the large percentage of pancreatic cancer patients with ras mutations and immunotherapeutic approaches, are important avenues for continued clinical investigation.

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