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Pancreatic Cancer at the American Society of Clinical OncologyMay 20-23, 2000 annual meeting It was somewhere in the French Quarter when the cab driver began his lecture regarding the location strategies of large professional meetings in the United States. "N'awlns has the third biggest convention center in the U.S.of A., just behind Vegas and Chicago. There's only a few cities that can hold a big ol' convention like this." It was true. This year's Saturday to Tuesday meeting of the American Society of Clinical Oncology (ASCO) had well over twenty thousand attendees from all corners of the world. And the New Orlean's Ernest N. Morial Convention Center was HUGE. It was longer than Chicago's Sears Tower (if the Tower was to unfortunately fall on its side). It was longer even than Kuala Lampur's Twin Petronas Towers in Malaysia (though some people think that the antennae of these towers should not be counted to give them title as the world's tallest building). Over a third-of-a-mile long, the Morial center was hosting both the ASCO meeting and the International Jewelry Fair at this same time--with room to spare. In 2001, the AACR annual meeting (held earlier this year in San Francisco) -- will occur in New Orleans; while this ASCO meeting in New Orleans will be held in San Francisco! Truly enough to make your head spin. But roughly congruent with the implications of the cabby's ongoing lecture. By way of preparation, I had electronically searched the more than 2,600 ASCO meeting abstracts--there were 93 abstracts which directly referenced pancreatic cancer--but many many more that referenced drugs and treatment regimens which more indirectly touched upon all aspects of the treatment of cancer of the pancreas. This current paper is a companion piece to my earlier one which covered the year 2000 annual meeting of the American Association for Cancer Research--thus some of the more basic definitions and concepts will not be repeated here. The emphasis of this ASCO meeting had a more directed clinical orientation in regard to emerging treatments and clinical trials, as opposed to the more basic-science orientation of the AACR meeting. The jewel of the meeting (for my purposes) was the late afternoon Monday meeting entitled, "Update on the Treatment of Pancreas Cancer," hosted by three luminaries in the world of the treatment and research of pancreatic cancer (two of whom sit as scientific advisors to PanCAN): Margaret A. Tempero, MD, Chief of the Division of Medical Oncology at the University of California at San Francisco; Mace L. Rothenberg, MD, Associate Professor of Medicine, Division of Hematology and Oncology at the Vanderbilt University School of medicine; and Elizabeth M. Jaffee, MD, Associate Professor of Oncology, Pathology, Immunology and Cellular and Molecular Medicine at the Johns Hopkins University School of Medicine. Dr. Tempero spoke on the current state
of "cytotoxic" (non-surgical) approaches to treatment
(including chemotherapy, radiation and chemoradiation); Dr. Rothenberg
spoke to the updates in the "cytostatic" approaches
to treatment (including the new agents aimed, for example, at
molecular targets, cell-signaling cascades and angiogenesis);
and Dr. Jaffee spoke to the practice and promise of immunotherapies
(especially vaccines) in the treatment of pancreatic cancer.
I. Dr. Tempero In a sense, it fell to Dr. Tempero to outline the best current thinking about standard medical therapy in adenocarcinoma of the pancreas (the only type of pancreatic cancer that will be discussed in this paper). While showing which treatment approaches represent the standard of care--and which may possibly be tweaked for improvement at the margins--it also fell to her to show, despite progress, how poor the results of such efforts still remain. She indicated that at the time of diagnoses only about twenty percent of patients are candidates for surgery. The good news is that the peri-operative death-rate for such serious surgery (like the Whipple operation) has improved and remains low. Unfortunately however, only about twenty percent of such (surgery) patients survive for three years or longer. In patients who are found to have metastatic pancreatic cancer (and thus who are not eligible for surgery), and who are given no therapy, the median survival duration from the time of diagnosis is about 3 1/2 months. With chemotherapy for advanced cancer the median duration increases to 5-6 months. And when chemoradiation (chemotherapy + radiation therapy) is appropriate and given for advanced pancreatic cancer, the median survival duration is 6-12 months. A controversy arose at this year's meeting in regard to employing "adjuvant" chemoradiation therapy in regard to treating surgically resectable pancreatic cancer. Adjuvant therapy is a concept that connotes the practice of giving medical and/or radio therapy after surgery to help augment the effects of surgery. (Neoadjuvant is the term that describes the practice of giving such therapy prior to surgery for potentially resectable disease). Dr. Neoptolemos of Britain, on the first day of the meeting, gave an oral presentation outlining the results of a large 11-country multi-year ESPAC-1 (European-based) study which purported to show that receiving adjuvant chemoradiation in resectable pancreatic cancer confers no statistical advantage.1 Dr. Tempero spent some time on this matter and was firm in her presentation that the prevailing evidence demonstrates that adjuvant chemoradiation appears to increase survival measures. She cited data in this regard as far back as the 1985 work by the Gastrointestinal Tumor Study Group which indicated that adjuvant chemoradiation conferred almost twice the median survival advantage.2 Finally, she indicated that the conclusions of the ESPAC-1 study appeared, at least in part, to stem from misclassification error (ampullary carcinoma was included with pancreatic adenocarcinoma); that as the data of the trial are teased apart and examined more closely--the results of the study belie its conclusion and actually do appear to support the advantage of adjuvant chemoradiation in pancreatic adenocarcinoma. Dr. Tempero reported that there is an ongoing phase III trial (and which includes gemcitabine) sponsored by the Radiation Therapy Oncology Group (RTOG) which is further studying this issue. Dr. Tempero indicated that for nearly twenty years since the release of the results an even earlier study by the Gastrointestinal Tumor Study Group that most of her colleagues have considered chemoradiation as the standard of care in locally advanced unresectable adenocarcinoma of the pancreas. One recent change is the possible substitution of gemcitabine for 5-fluorouracil (5-FU). She indicated that gemcitabine acts as a very good tissue radiosensitizer. She further indicated that a number of phase I trials have been favorable in this regard, and the momentum of evidence is beginning to move consensus toward the use of gemcitabine as an agent in chemoradiation for locally unresectable pancreatic cancer. A number of problems regarding how to measure treatment response, as unique to cancer of the pancreas, were outlined. The first of these relates to the assessment of true tumor size--the apparent tumor size in pancreatic cancer by observation or radiography tends to be misleading: for as little as 1% of the apparent tumor "size" may be the true size of the malignant cell mass (in the pancreas there is a huge desmoplastic (not truly malignant) area surrounding the actual malignancy). This is compounded by possibilities of concurrent reactive pancreatitis and cyst formation which tend to demonstrate structural changes that may artificially appear as increased tumor size--and even interfere with the ability to identify the true margins of the tumor. Finally, loops of small bowel may distort the ability of radiography to accurately measure true tumor size. All of these challenges tend to make tumor size regression (as a measure of treatment response) less accurate than in other cancers. Additionally, it appears that chemotherapy may provide improvement in quality of life measures. These palliation effects are not so easily quantifiable, but they represent a critically important benefit to patients and must be considered in the evaluation of treatment. Of course, survival is the most "powerful" objective treatment response, but survival alone may not measure the full benefit of certain therapies. In regard to single chemotherapy-type treatment agents, Dr. Tempero reports her rule-of-thumb: to get her attention, an agent must confer at least a five-month median survival duration with metastatic pancreatic cancer. She reports that presently only the chemotherapy agents 5-FU and gemcitabine consistently demonstrate these results; as also do the hormonal agents tamoxifen and goserelin. 5-FU confers about a 5.5 month median survival rate with a 2% one-year survival. Gemcitabine is a "prodrug" (meaning that it only converts in the body into its activated form). Its most active metabolite is a tri-phosphate compound whose kinetic activity demonstrates rate formation that is both dose and dose-rate dependent. Gemcitabine tends to confer a slightly increased median survival rate as compared to 5-FU, and gives an 18% one-year survival rate. Additionally, studies have shown that quality of life indicators may be substantially improved with gemcitabine: in one study about a quarter of the patients treated with gemcitabine had less adverse adjudged tumor-related symptoms compared with five-percent of those treated with 5-FU. Dr. Tempero's lab has tried to take advantage of the pharmacokinetic properties of gemcitabine. In preliminary studies that are ongoing, she has found that a fixed-dose rate (dose-intensive) regimen of gemcitabine may be superior in effect (7.8 month median survival) in contrast to the standard 30-minute standard (high-dose) regimen (5.0 month median survival). These results need to be viewed with caution at present, as there were not enough participants in the study to give these results the statistical power to conclusively demonstrate that this apparent difference is meaningful. But, given the kinetics of the drug, these results are biologically plausible and intriguing. Two of the more promising new chemotherapies "in the pipeline" were singled out for discussion by Dr. Tempero. RFS 2000 (rubitecan) is currently in phase III clinical trials. This agent is a topoisomerase I inhibitor: an inhibitor of the enzyme that helps "un-kink" DNA during replication and cell division. The second is the novel mushroom-derived agent MGI-114, which has shown some activity against pancreatic cancer in early clinical trials, but also has shown a fair amount of toxicity-and thus has apparently required some recent adjustment to try and find a more appropriate dosage. There were a number of studies presented at this ASCO meeting involving these and other related agents. Before such studies are described in this paper, it is important to note that the results of these studies are not necessarily peer-reviewed in the sense that an article in a reputable medical journal might be. So it is important to be cautious in assigning any special importance to any single study or even to a series of studies. These agents are often in the early stages of clinical trials, and though they may sound very promising, they will need to wend their way through the entire process before more definitive conclusions can be drawn about them. The results of a phase II study with RFS 2000 against "refractory" pancreatic cancer by SuperGen and the Rubitecan Study Group demonstrated a 9% tumor response in patients who had not previously been treated or who had "failed" gemcitabine treatment; and 18% of patients showed a greater than 50% reduction in CA 19-9 levels.3 The results of a number of "new" topoisomerase agents were reported at the meeting. Phase I and phase II studies of the topoisomerase I inhibitor DX-8951f (exatecan) by researchers including those at the Cancer Therapy and Research Center in San Antonio, Texas showed activity and "manageable" toxicity in metastatic pancreatic cancer.4,5 The University of Chicago Cancer Center (among others) presented a status report concerning a phase I study which included four pancreatic cancer patients involving the agent karenitecin, a new topoisomerase I inhibitor. The results are preliminary, but one of the pancreatic cancer patients has shown stable disease.6 Researchers, including those from Bristol-Myers Squibb, found that BMS-247615, a topoisomerase II inhibitor (the enzyme topoisomerase II helps "re-kink" the DNA strand in cell division) was well-tolerated; this study included one pancreatic cancer patient.7 Finally, the results of a phase II clinical trial of MGI-114 (Irofulven) were presented. This study involved researchers from the Arizona Cancer Center (Dr. Daniel Von Hoff); the University of Colorado Health Sciences Center (Dr. Gail Eckhardt); and Dr. Tempero (among several others). The presentation related to this trial was an interim report and tentatively concludes that "MGI-114 has some antitumor activity in patients with gemcitabine-refractory pancreatic cancer."8 Dr. Tempero next discussed combination chemotherapy involving agents given in conjunction with 5-FU and/or gemcitabine. She indicated that observed extra benefit of combination therapy (as opposed to single agent therapy) in terms of survival is rather small, if it exists at all. And she concluded, based on an extensive review of the literature, that thus far, combination therapy has shown no real benefit over monotherapy. Potential promising future combination therapy, according to Dr. Tempero, per early clinical trial results, may include 5-FU + gemcitabine (although she indicated that we don't yet have a sense of what the right schedule might be); gemcitabine + cisplatin (platinum compound); and gemcitabine + Irinotecan (CPT-11, a topoisomerase I inhibitor). Dr. Tempero concluded by way of summary: chemotherapy is better than no therapy; gemcitabine (with caveats) appears to be better than 5-FU; fixed-dose-rate gemcitabine infusion is worthy of further attention; and combination therapy--though not yet proved out--appears to be promising. The Virginia Mason Clinic presented the results of a phase II trial involving adjuvant chemoradiation against resected cancer of the pancreas with 5-FU, cisplatin and alpha-interferon as sensitizing agents. Despite the toxicity, they judged this approach to have "promise" and indicated that it warrants further study.9 French researchers in a phase II trial found that 5-FU + oxaliplatin (platinum compound) was well tolerated and showed "objective responses" against advanced or metastatic pancreatic cancer.10 The results of a phase II trial of capecitabine (Xeloda) against advanced or metastatic pancreatic cancer by U.S. Oncology were presented. Xeloda is an orally administered prodrug, which essentially becomes 5-FU upon ingestion. Median survival was about seven months; there appeared to be symptom benefit and a good "safety profile."11 The results of a phase I study against advanced pancreatic cancer by Swiss researchers involving capecitabine (Xeloda) + gemcitabine were reported as encouraging, demonstrating acceptable safety and showing "response."12 Three studies looked at various combinations of gemcitabine + 5-FU in metastatic or advanced pancreatic cancer, demonstrating median survival times of 7.5 months and 8 months AND a one-year survival of 36% in one case. The combination in all three studies appeared to be well tolerated.13,14,15 A phase II study involving a four-drug combination regimen by Italian researchers against Stage IV pancreatic cancer with gemcitabine + 5-FU (via continuous infusion) + cisplatin + Epirubicin demonstrated a 9.4 month median survival duration with a greater than 40% one-year survival.16 Irinotecan + gemcitabine against locally advanced or metastatic pancreatic cancer was examined in a phase II multi-center trial sponsored in part by Pharmacia and Upjohn. This combination was found to be "active, and well-tolerated."17 And finally, Yale researchers conducted a series of three interrelated phase I/II trials with Irinotecan + taxane against advanced pancreatic cancer, demonstrating a median survival of 5 months with "encouraging evidence of activity."18 II. Dr. Rothenberg The daunting task of Dr. Rothenberg was to classify, update and summarize many of the emerging therapies which may be active against cancer of the pancreas. He provided admirable overview. His topics were the anti-ras agents, the matrix metalloproteinase inhibitors, anti-angiogenesis agents, the emerging gene therapies and alternative therapies. The ras gene mutation is found in more than 90% of patients with pancreatic adenocarcinoma. The mutation of ras appears to act as one of the potentially needed factors to stimulate the unregulated cell growth which is found in many pancreatic cancers. This gene appears to mutate early in the disease process--which makes it attractive as a treatment target. The related cascade which carries out ras "instructions," flows via signaling pathway. One aspect of this pathway is the enzyme farnesyl transferase which facilitates the necessary adherence of pathway proteins to the inner aspect of the cell wall. Thus, agents have been developed, called farnesyl transferase inhibitors (FTIs), which attempt to narrowly target for interruption this specific point in the ras signaling pathway. Despite the promise that the FTI's would beam directly at a single point in the ras pathway (with unalloyed effect), these agents appear to have secondary mechanisms of action which are less fully understood, and thus the FTIs may not be as narrowly targeted as originally thought, according to Dr. Rothenberg. Nonetheless, they have shown some promise--and research is proceeding apace. One alternative ras pathway (and which is not affected by the FTIs) involves the enzyme geranylgeranyltransferase. He also indicated that a potential alternate action point for the FTIs may be the RhoB protein which is ras independent. Four FTIs were highlighted and briefly discussed by Dr. Rothenberg, each of which had research presentations at the meeting: SCH66336 (Schering-Plough), R115777 (Janssen), L-778,123 (Merck) and BMS-214662 (Bristol-Myers Squibb). Two relevant phase I studies were presented in regard to SCH66336. Researchers at Duke University and UCLA presented results of a SCH66336 + gemcitabine trial against advanced cancers (which included 9 pancreatic cancer patients) which demonstrated "impressive disease stability."19 MD Anderson combined SCH66336 + paclitaxel (mainly against lung cancer) with apparently acceptable toxicities and the sense that the combination showed "activity."20 Dutch and Belgium researchers studied R115777 (including 5 pancreatic cancer patients), establishing a recommended dosage and noting that "hints of activity were observed in metastatic pancreatic cancer."21 Researchers from Japan and San Antonio, Texas found that R11577 + gemcitabine was well tolerated in a phase I pharmacokinetic study.22 Three phase I studies of L-778,123 were presented. Two appeared to be interim reports involving combination therapy with continuing patient accrual and dose escalation; the MD Anderson and Cancer Institute of New Jersey report (which included Dr. James Abbruzzese among other researchers) established a suggested appropriate dosage for the agent.23,24,25 Finally, there were two phase I studies of BMS-214662 against solid tumors presented by Dana-Farber (Harvard) researchers. One study included 12 pancreatic patients (of 38 total) and indicated that suggested dosage had not yet been established.26 The second outlined in more detail the pharmacokinetics of the drug.27 Another group of agents which act, at least in part, through their effect as ras signaling inhibitors, are the monoterpenes. The monoterpene perillyl alcohol, which is derived from certain organic substances including the lavender herb, appears to act against the ras pathway in such a manner as to affect geranylgeranyltransferase and the RhoB protein. Dr. Rothenberg indicated that perillyl alcohol is currently in phase II trials in the U.S. though the Eastern Cooperative Oncology Group (ECOG). As there had been a sense of promise about these agents, there was some rather disappointing news in the meeting regarding certain of the matrix metalloproteinase inhibitors (MMPIs). The Bayer MMPI, BAY12-9566 (temomastat) was found by Canadian researchers to be so remarkably less efficacious than gemcitabine that the study had to be stopped early.28 Dr. Rothenberg further indicated that the MMPI, marimastat (BB-2516) although it appeared to have some effect on decreasing the CA 19-9 marker, did not appear to show a survival advantage over gemcitabine according to recent studies including the latest findings per the British Biotech web-site. In discussing these findings, Dr. Rothenberg entertained several hypotheses. One that he considered was that though these agents may have inhibited the targeted enzymes as originally set out, certain of this family of over 20 enzymes have effects on angiogenesis. Therefore, it is physiologically feasible that the agents may have inadvertently additionally stimulated tumor angiogenesis, helping tumor to grow. He indicated that these enzymes may be especially active from an early stage in pancreatic cancer (beginning at a time when, for example, angiogenesis is not as much of a factor) -- and thus deploying a more targeted approach (with MMPIs) at an earlier stage in the disease may be a fruitful orientation for possible future research. There is uncertainty about the role of angiogenesis in pancreatic cancer. At the question period at the end of this session, one of the oncologists in the audience indicated that her clinic had seen a patient with pancreatic cancer who appeared to have responded extremely well to thalidomide (which has been reported to have anti-angiogenesis properties, but which is not officially approved for use in pancreatic cancer). In response, Dr. Tempero indicated that adenocarcinoma of the pancreas is one of the least vascular of the tumors; and that the jury was still out regarding any exceptional benefit of angiogenesis-inhibition in pancreatic cancer. There was one study presented at the meeting about the effects of positive and negative regulators of angiogenesis in pancreatic cancer cell-lines which concluded that pancreatic "tumor growth is dependent on the ability to obtain vascular support."29 There were encouraging phase I reports on two Sugen anti-angiogenesis drugs (SU5416 and SU6668) against advanced malignancies, including work by Dr. Rosen's group at UCLA.30,31 The phase I pharmacokinetics of the tyrosine kinase inhibitor, anti-angiogenesis agent ZD1839 was reported by Canadian researchers.32 And finally, there was quite a publicity buzz coming out of the meeting about the anti-angiogenesis, anti-epidermal growth factor, monoclonal antibody IMC-C225, which researchers at the University of Virginia indicated had a good safety profile; and which was adjudged to show "promising biological activity" by MD Anderson researchers (among others) in eight patients with relapsed or refractory solid tumors.33,34 The distinctions about what might constitute gene therapy are difficult, as almost all of these therapies ultimately operate at the molecular level. There was one phase I trial with the antisense ras-inhibitor ISIS 2503 + gemcitabine against advanced cancer which was reported out by the Mayo Clinic, demonstrating a suggested dosage for further trials.35 U.S. Oncology and related researchers reported in a phase I study that the Onyx-015 agent showed acceptable toxicity and evidence of replication in malignant tissue in patients with refractory cancers.36 Onyx-015 is a genetically altered adenovirus which when injected into a tumor-site selectively targets tumor cells for cell-death. MD Anderson and UCLA (including researchers Dr. Joel Hecht and Dr. James Abbruzzese, among others) reported on the results of a phase I/II study involving 18 patients with unresectable pancreatic cancer who were given up to eight sets of "intramural" injections with Onyx-015 via endoscopic guided ultrasound + gemcitabine. The results are reported as "possible activity" with this delivery system being adjudged as "feasible and tolerable."37 Finally, two favorable phase I studies of the proteasome inhibitor PS-341 against advanced malignancies were reported out of Memorial Sloan-Kettering and MD Anderson.38,39 Two ongoing clinical trials involving unconventional alternative therapies against pancreatic cancer were next discussed by Dr. Rothenberg. In a very cautious manner, he outlined the Kelly-Gonzalez regimen (a phase III trial occurring at the Columbia-Presbyterian hospital in New York city) which involves nutritional support, high-dose vitamins, pancreatic enzymes and coffee enemas. And he briefly discussed the Burzinski regimen phase II trial (at the Burzinski Research Institute in Texas) in which antineoplastons are prescribed. In summarizing the overall state of these non-cytotoxic approaches to the treatment of pancreatic cancer, Dr. Rothenberg indicated that they have been, to date, somewhat disappointing--but not without promise. He indicated that he thought that future work will try to exploit specific targets more narrowly, will try to target earlier disease, will combine these newer agents with more traditional chemotherapy and radiotherapy, and will explore combination therapy among these cytostatic agents themselves.
III. Dr. Jaffee Dr. Jaffee summarized the history of immunotherapy and gave a brief overview of the immune system. Her general discussion of immunotherapy led to a review of vaccine therapy. Under the topic of vaccines that activate T-cell responses, she discussed both cell-based strategies and antigen-specific cancer vaccines. As the tumor antigens which are expressed by most tumors are unknown at present, Dr. Jaffee indicated that the tumor cell itself remains the primary and best source of "immunizing antigens." And further, that at least one study had shown that the largest increase in systemic immunity (in mice) was produced via specialized exposure with the cytokine granulocyte-macrophage colony-stimulation factor (GM-CFS). GM-CSF is now understood to be a growth factor for the immune system's most deadly anti-tumor element: the dendritic cell. Dr. Jaffee briefly presented the methods and results of her phase I study of a GM-CSF tumor vaccine against pancreatic adenocarcinoma. 14 patients with stage I, 2, or 3 pancreatic cancer underwent a series of vaccinations after surgical resection and prior to receiving adjuvant chemoradiation. The researchers looked for signs of delayed type hypersensitivity (DTH) reactions (which might tend to indicate that the vaccine had "taken"). These DTH reactions were seen in all of the patients. Histologic examination of local skin biopsies also tended to confirm the reactions. Additionally, there appeared to be a correlation between DTH reactions and disease-free survival. The researchers conclusions are that the treatment appears to be safe and that it warrants further investigation.40 She indicated that she expects to begin (hopefully, later this year) to accrue patients for a phase II clinical trial at Johns Hopkins using these same or similar vaccine therapy techniques. Researchers from Austria presented the results of phase I trial using tumorlysate-pulsed dendritic cells in eight patients, five of whom had advanced pancreatic cancer. They found the procedure safe and feasible.41 Dr. Jaffee indicated that some of the more common antigenic targets for anti-tumor vaccine therapy (especially involving the pancreas) include: the mutated p53 gene, mutated ras, chorioembryonic antigen (CEA), the glycosylated protein Mucin-1 (MUC-1), heat-shock proteins, Her-2/Neu, and other specific antigens which are becoming recognized as expressed (or over-expressed) by pancreatic adenocarcinoma. Four anti-tumor ras vaccine studies were presented at the meeting. A multi-center phase II study from Europe found that ras peptide vaccine against unresectable pancreatic cancer was safe and immunologically effective (though survival rates were not yet available).42 The other three ras vaccine studies were phase I and pilot studies from Germany, Norway and the NCI; all were early and reported essentially positive findings.43,44,45 Researchers at the Fox Chase Cancer Center and the NCI presented the results of a phase I anti-CEA vaccine trial (in patients with advanced tumors which expressed CEA) with favorable results.46 A phase I study of a MUC-1 vaccine reported favorable results against advanced pancreatic cancer by researchers from the University of Pittsburgh.47 Another MUC-1 phase I trial (with Brevarex) against advanced solid tumors was reported as having favorable safety by researchers from San Antonio, including Dr. Gail Eckhardt and Dr. Daniel Von Hoff, among others.48 Her-2/Neu antigen over-expression was found in 17% of 123 patients with pancreatic adenocarcinoma by the Brown University Oncology Group.49 And finally, in 43 of 48 human pancreatic cancer tissue samples, cyclooxygenase-2 (COX-2) was strongly or moderately expressed as reported by Japanese researchers. Further, in the four cultured pancreatic cancer cell-lines which showed strong or moderate COX-2 expression (of six total), the addition of a COX-2 inhibitor dramatically reduced cell growth.50 Dr. Jaffee concluded her talk by indicating that substantial progress had been made in understanding many of the more subtle aspects of the immune system, that a number of successful phase I anti-tumor vaccine studies had been successfully reported and that more advanced trials are in progress. She suggested future directions which might include treating patients at earlier stages of disease, using vaccine therapy in combination with other therapies, and continuing to identify relevant antigens as will likely be accelerated by the new technologies which utilize phage-display libraries and by a further explication of the human genome. Dr. Jaffee indicated that these were early-days in the deployment of these vaccine strategies and that the overall effect of this generation of vaccine trials may not lead to immediate increased survival, but rather may lead researchers to more effective pancreatic cancer tumor antigenic targets (which in turn may lead to increased survival). And she was cautiously optimistic in indicating that "it is now feasible to design vaccines that are based on rational immunologic principles."
IV. Other There were some interesting studies presented involving the use of radiation. The Staten Island University Hospital presented three studies on body stereotactic radiosurgery, one which was specific to pancreatic tumors. The findings reported the procedure as being well tolerated and as showing a fair degree of control.51,52,53 A multi-center group presented an interim phase II report on the results of a trial involving chemoradiation including the use of the colloidal radioisotope implant 32P as brachytherapy in non-resectable pancreatic cancer. Tumor volume and tumor markers were down, while quality of life measures appeared to be improved.54 And finally, Italian researchers reported generally favorable results in regard to using radiofrequency ablation of malignant liver tumors (in over 300 patients). More than half of these represented tumor metastases.55 Symptom relief was also addressed in a number of studies. The results of two of the studies by both Czech and Austrian researchers verified the value of using GM-CSF in solution for mouthwash as a remedy for chemotherapy-induced oral mucositis.56,57 South African researchers demonstrated that the use of a locally applied cooling cap to the scalp (the Penguin Cold Cap System) tends to prevent or reduce chemotherapy-induced alopecia (hair loss).58 A multi-center trial indicated that transmucosal administered fentanyl was superior in pain relief compared to giving immediate release morphine for cancer pain.59 And finally, Argentine researchers studied the possible advantage (which they found to be beneficial) of using sublingual morphine as an option for cancer pain.60
The ASCO meeting came to a close and I was once again impressed by the magnitude of the progress and promise-of-progress of clinical research directed towards pancreatic cancer. One emblematic event stood out in my experience at the meeting. I was on an escalator going down to the main floor of Morial Center on the second day when I overheard two researchers talking about the time it would take to complete a certain project. The first fellow suggested that it would take about four years. The second fellow looked back at him for a long time and then laughed and said, "four years is OK, but let's make those dog years." I thought that this might be an appropriate motto for the state of affairs in cancer research. Research is accelerating to the speed of dog years. References
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