Although pancreatic cancer accounts for only two percent of all newly diagnosed cancers each year, it is the fifth leading cause of cancer deaths nationwide. Historically, clinicians have had few tools in their treatment armamentarium for fighting this devastating disease. That reality is reflected in the most recent statistics from the American Cancer Society: Of the estimated 30,300 new cases expected to be diagnosed this year, an estimated 29,700 people will die, mostly within the first six months or less of diagnosis.
I often say to patients that, unlike the situation for other diseases like breast cancer, lymphoma, or leukemia, our tool box is very shallow for pancreas cancer, says James L. Abbruzzese, MD, Chairman of the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston.
Because of advances in genomics and tumor cell biology, physicians like Dr. Abbruzzese, a leader in pancreatic cancer research, believe the field may be poised to address the challenge posed by this particularly resistant group of tumors.
Coupled with a new initiative resulting from a February 2001 NCI Pancreatic Cancer Progress Review Group Report (Pancreatic Cancer: An Agenda for Action, available at: http://osp.nci.nih.gov), oncologists may finally get a purchase on both diagnosis and treatment of pancreatic cancer. (See box below)
Reexamination of Combination Chemotherapies
The majority of malignant pancreatic tumors are the adenocarcinomas, which have been notoriously resistant to the standard cytotoxic regimens, such as fluorouracil (5-FU). If diagnosed in the earlier stages, of course, the tumor can be curable by resection.
And, with improvements in surgery with the Whipple technique, postoperative mortality can be less than one percent if patients are treated at a center for excellence. Unfortunately, however, these cases account for only 10 to 20 percent of annual pancreatic cancer diagnoses.
Accordingly, researchers in the 1980s began to test the use of combination radiation and chemotherapy in the adjuvant setting for the disease. Studies such as those by the Gastrointestinal Tumor Study Group (GITSG) and the European Organization for Research and Treatment of Cancer, both of which compared resection alone to some form of 5-FU-based adjuvant chemoradiation after resection, were emblematic of this line of investigation.
The GITSG trial demonstrated a modest survival benefit for split-course radiotherapy given at a dose of 40 Gy with bolus 5-FU during and after the completion of radiotherapy. This multimodal therapy resulted in a median survival duration of 20 months compared with 11 months for those receiving surgery alone.
The EORTC trial demonstrated a trend toward increased survival with adjuvant therapy compared with surgery alone, but was not able to replicate the results of the GITSG trial.
In addition, as Dr. Abbruzzese pointed out in a review at last year's ASCO Annual Meeting of the current status of adjuvant therapies in pancreatic cancer, the two trials had methodologic problems that necessitate caution against using the results to establish adjuvant chemoradiation as a standard of care.
The GITSG trial introduced a major selection bias, since 21 patients randomized to the chemoradiation arm had extended postsurgical recovery periods (more than 10 weeks). Only patients with good performance status and who recovered rapidly from surgery were entered into the treatment protocol. In his ASCO summary, Dr. Abbruzzese also brought up similar concerns with the EORTC trial, including the fact that neither follow-up methods nor precise anatomic distinctions between pancreatic and periampullary adenocarcinoma were defined in the study.
Figure. John S. Macd...Image Tools
Finally, noted John S. Macdonald, MD, Medical Director of Physician Organizations for Salick Health Care, Inc., and Professor of Medicine and Director of Gastrointestinal Oncology at St. Vincent's Cancer Center in New York City, the ESPAC-1 (European Study Group for Pancreatic Cancer-Trial 1) study reported last November in Lancet (Neoptolemos JP et al: Lancet 2001;358(9293):1576-1585) suggested that radiation therapy did not add much to surgery alone.
In fact, Dr. Abbruzzese agreed, Recent analysis and presentation of the ESPAC-1 trial and the improved ability to accurately stage patients with pancreatic cancer preoperatively suggest that many of the gains ascribed to post- or preoperative adjuvant therapy may simply be the result of better patient selection and improved surgical technique.
Using these same three trials as examples, David H. Ilson, MD, PhD, of Memorial Sloan-Kettering Cancer Center, writing in (the Lippincott Williams & Wilkins journal) Current Opinion in Oncology (2001,13:287-290) noted that, with the exception of the GITSG trial, there are only limited randomized clinical trial data to support the use of postoperative therapy in resected pancreatic cancer.
Dr. Abbruzzese concurs with this assessment of the pancreatic cancer literature, a review of which reveals, he said, small trials that report extremely high response rates and other signs that patients benefited from therapy, but when studied more broadly, or in larger randomized trials, it was much harder to see a big difference. That has led to a lot of the pessimism and even nihilism about pancreatic cancer.
Changes with Gemcitabine
Gemcitabine has been used to treat pancreatic cancer since its approval for that indication by the Food and Drug Administration in 1995.
When gemcitabine came along, said Simon R. Bramhall, MD, a Lecturer in the Department of Surgery at Queen Elizabeth Hospital in Birmingham, UK, and a member of the Marimastat Pancreatic Cancer Study Group, we suddenly had something to offer these patients. But nevertheless, the data from gemcitabine, whilst encouraging, is not earth-shattering.
A trial comparing gemcitabine plus radiation with 5-FU plus radiation initiated in 1998 by the Radiation Therapy Oncology Group has been steadily accruing patients and will have approximately 500 patients when it closes this year.
The hope is that results from that trial, in which Dr. Abbruzzese is involved as a member of the Southwest Oncology Group, will provide some definitive answers about adjuvant chemoradiation. Perhaps the most important sign from this current national trial, he said, is that its investigators were able to enroll large numbers of patients, underscoring the viability of conducting other randomized trials with pancreatic cancer patients.
Dr. Bramhall said that from the point of view of therapies that are currently available, combination chemotherapy is probably the best treatment. Gemcitabine alone is not a powerful enough agent, but it is extremely well tolerated, he noted.
It also has a slightly different mode of action than many chemotherapy agents. Therefore, it can be combined with other standard and novel agents with different side effect profiles. Combination chemotherapy is probably the most exciting way forward.
New Agents & 'Hints of Activity'
In light of the high resistance of pancreatic adenocarcinomas to chemotherapy, the areas of real interest are in understanding and unlocking the key (or keys) to the tumors' molecular biology.
Pancreatic cancers are the ideal candidates for novel and targeted therapeutic approaches, the researchers interviewed for this article noted, because of the high incidence of genetic alterations identified to date in invasive pancreatic cancer.
For instance, in more than 90 percent of pancreatic adenocarcinomas, the K-ras oncogene is overexpressed; p16, p53, DPC4 and BRCA2 tumor suppressor genes are inactivated; and invasive tumors are also characterized by a high percentage of expression of epidermal growth factors.
A recent study published in the Journal of the National Cancer Institute (2002;94:120-142) detailed an examination by immunohistochemistry of 106 human pancreatic tissue specimens.
The researchers from Germany found that the retinoblastoma tumor-suppressor gene pRB was overexpressed in pancreatic ductal adenocarcinomas and may partly explain why pancreatic cancer cells are able to evade chemotherapy-induced apoptosis.
Speaking from his office in Berlin, Stefan Rosewicz, MD, principal investigator of that study and Professor in the Department of Hepatology and Gastroenterology at Humboldt University, expressed satisfaction with the group's work, which builds on an earlier paper published in 2000 in the Journal of Cell Biology (2000;150:1467-1477) showing that restoration of p16 expression, which is functionally inactivated in 95 percent of human pancreatic cancers, results in a complete loss of tumorigenicity of human pancreatic cancer cells.
The inactivation or loss of p16, which occurs in virtually all pancreatic cancer, results in upregulation of pRB, Dr. Rosewicz explained.
To take advantage of this discovery, his team is now following several different avenues of investigation, he reported. One of the avenues we are pursuing is to try to establish RB expression as a differential diagnostic marker.
It is often difficult to differentiate between chronic pancreatitis and pancreatic cancer by conventional diagnostic means, such as computed tomography or magnetic resonance imaging. Since RB overexpression is restricted to pancreatic cancer, this might be useful in making the diagnosis and planning a course of treatment.
A second avenue would be to evaluate patients' RB expression level and try to correlate this with a response prediction to chemotherapy, he said. A third avenue would be to try to find ways to inhibit RB expression and thus render the tumor more sensitive to chemotherapy.
Dr. Bramhall cautions that hopeful results in the laboratory do not always pan out in clinical settings. His group, which last summer published results of a large randomized trial comparing the broad spectrum matrix metalloproteinase inhibitor (MMPI) marimastat to gemcitabine in 414 patients with unresectable pancreatic cancer, found no significant survival benefit between the two treatments (JCO:2001;19:3447-3455).
I think one has to bear in mind that over the years there have been other attempts [to translate laboratory findings to the clinic], Dr. Bramhall said. It may not be as simple as it looks. In the basic science work on metalloproteinase expression in pancreatic cancer, we found that MMPs are massively overexpressed [in pancreatic cancer]. We were all very excited. Then when it was an orally active inhibitor, everyone was even more excited. But in clinical practice, it's often difficult to translate that into a benefit.
In an editorial accompanying the study, Drs. Abbruzzese and Kenneth R. Hess, also of MD Anderson, wrote: The hint of activity produced by marimastat in pancreatic cancer described in this report suggests that this agent should be investigated further…in patients with nonoperable, nonmetastatic pancreatic cancer, or potentially in the adjuvant setting.
Marimastat studies are currently on hold, Dr. Bramhall reports, as its partner-owners Schering-Plough and British Biotech are currently in discussion with the FDA about whether further studies need to be done before licensing to address musculoskeletal side effects (which were severe in eight percent of patients in the study).
Because this is such a complex disease, from the standpoint of genetics and wiring inside the cells, we have not been able so far to identify good compounds, Dr. Abbruzzese said. He and his group at MD Anderson are putting finishing touches on a protocol for a large Phase III trial looking at the epidermal growth factor receptor blocker C-225 in combination with gemcitabine in patients with pancreatic cancer.
This is just the beginning of attempts by various groups to target signaling in these cells, he said. It would be exciting to see that there's some real benefit to the combination of gemcitabine with C-225.
'The Cinderella of Cancers'
Dr. Bramhall and the others interviewed for this article believe that targeted research money is the key to advancing targeted therapies.
Pancreatic cancer has been the 'Cinderella' of cancers, for a host of reasons, Dr. Bramhall remarked. Twenty years ago, general surgeons were operating on these patients, and many were dying of postoperative complications.
Here in the UK, we have realized in the last 10 years that these patients must be sent to a specialized unit to improve [surgical] results. That's been happening in the United States for a lot longer than in the UK. There has been a slow change in mood and in approach to patients with pancreatic cancer. We have [Eli] Lilly to thank as well. In this country, prior to gemcitabine, patients were not getting chemotherapy. So things are improving slowly.
Organizations: PanCan & The Lustgarten Foundation for Pancreatic Cancer Research
Since OT's last Special Report on pancreatic cancer about five years ago, there are more available resources for patients as well. Two new national organizations, Torrance, California-based PanCAN (Pancreatic Cancer Advocacy Network - www.pancan.org), and New York City-based The Lustgarten Foundation for Pancreatic Cancer Research (www.lustgartenfoundation.org) were founded (in 1999).
Both organizations have been working to put pancreatic cancer on the map: PanCAN in the areas of patient services and advocacy, public policy, and research awareness, and The Lustgarten Foundation in the area of privately funded pancreatic cancer research.
The Lustgarten Foundation awarded 12 one-time $125,000 basic science research grants in February 2001. Working with former President Jimmy Carter, the foundation is also involved in raising public awareness of the disease. The foundation is named for the late Marc A. Lustgarten, who was the vice president of Cablevision and chairman of Madison Square Garden when he died of pancreatic cancer at the age of 52, and who helped establish the organization before he died.
When the father of PanCAN's co-founder and CEO, Paula Kim, was diagnosed with pancreatic cancer in December 1997, she was unable to find a patient advocacy organization to help her family through their crisis. When her father died 75 days after diagnosis, in March 1998, she began networking with others whose family members had died of the disease. Following a successful black-tie dinner organized in late 1998, Ms. Kim and others moved quickly to establish PanCAN as the first national patient-based nonprofit entity for the disease in early 1999.
Figure. Paula Kim, C...Image Tools
With a full-time staff of six and Team Hope affiliates in 27 other locations, and growing, PanCAN now offers a range of patient services via their Web site and toll-free number (877-2-PANCAN).
In addition, they are currently launching a new patient support service called PALS (Patient And Liaison Services), which pairs newly diagnosed patients and their families with a PALS associate who will act as a navigator and source of information for the course of the patient's illness.
Most pancreatic cancer patients, unfortunately, follow a predictable trajectory of diagnosis, treatment, failure to treatment, failure to another treatment, and then go into end of life, Ms. Kim said.
Our goal with the PALS program is to provide patients with options, information, and education in order to make informed decisions. Our PALS associate is there to help them as they go through these very difficult sequences.
In addition to its patient support arm, PanCAN has also consciously developed a strong public policy arm to target agencies (NCI, National Institute of Diabetes and Digestive and Kidney Diseases, and CDC) responsible for funding research at the national level.
As Dr. Bramhall notes, Pancreatic cancer doesn't have the same media grip that breast cancer, for instance, does. Both PanCAN and the Lustgarten Foundation have set out to change that reality.
Early on, Ms. Kim recalled, our board of directors looked at the picture for pancreatic cancer and asked, 'how can we make the biggest impact on this disease?' We looked at funding levels at the NCI, which have been low. The latest figures place total NCI FY 01 funding for pancreatic cancer at $21.5 million. We have a disease that is much more chemoresistant, presents itself at advanced stages, and the odds are against us. In an effort to change this poor funding history, we made a very deliberate decision to focus on developing a solid public policy arm that works to educate our public policy makers and private funders about the needs for pancreatic cancer research.
Science Follows Money
In response to PanCAN's public policy efforts and recommendations made in the Report of the Pancreatic Cancer Progress Review Group, the NCI has increased its projected budget for pancreatic cancer in FY (fiscal year) 2002 to $23.5 million, a 36% increase since FY 99's budget of $17.265 million for the disease.
And, for investigations focused 100 percent on pancreatic cancer, the NCI is proposing to increase the pay line by 50 percent.
If we can get the research dollar base up into the $50 million range, I am hopeful we can make some significant progress, as has been demonstrated in other diseases. But we don't want to take away from other diseases; the entire budget needs to be increased, Ms. Kim stated.
The Pancreatic Cancer Progress Review Group (PRG) Report grew out of the Pancreatic Cancer PRG Roundtable, which met in September 2000 in Chantilly, VA, and spells out the current state for research in this disease: Pancreatic cancer has been understudied in both basic research laboratories and the clinic. In terms of total research dollars, total numbers of researchers, and numbers of researchers who are highly focused on this disease, pancreatic cancer lags significantly behind all of the most common tumors, despite their far more favorable survival rates.
Paula Kim puts it this way: In every area, whether it's diagnostic imaging, tumor biology, [availability of] mouse models, health services research, or critical treatment, we are not even at the starting line.
Researchers express optimism about the current NCI initiatives in pancreatic cancer. We've got some interesting, basic knowledge now about the tumor, and the question becomes, how do you exploit that clinically? This kind of targeted resource allocation makes a lot of sense, Dr. Macdonald said.
Growing New Investigators
Ms. Kim calls it the chicken or the egg phenomenon. The PRG clearly identified a dearth of full-time investigators who are focused on pancreatic cancer. As NCI continues to increase its funding to investigators, as is planned for FY 2002 and beyond, there may be a lack of investigators to take up the challenge.
Accordingly, PanCAN will begin to sponsor two-year Young Investigator Awards with both ASCO and AACR in order to nurture more investigators.
Our goal is to hatch the breeding ground for young investigators, she said. If we can help them for the first two years, then hopefully, by the third year, they will be ready for NCI funding.
Funding and advocacy at the public policy level are strongly linked to nurturing of grassroots constituents as well. As we train our grassroots volunteers how to communicate our concerns and raise awareness to the Congress, our public policy efforts will gain momentum, she said.
The Congress listens carefully to their constituents, and these messages have the potential to be translated into directives that NCI and the public agencies will follow through on with increased research funding and program initiatives.
Dr. Abbruzzese is also optimistic about increased NCI research funding. It's a great opportunity for groups working in the area which may not have had sufficient funding to obtain a critical mass of investigators. Hopefully, [this funding] will attract either young investigators or even established people who are thinking of branching out a bit.
NCI'S New 'Agenda for Action'
Following publication of the Pancreatic Cancer Progress Review Group (PRG) report, Pancreatic Cancer: An Agenda for Action in February 2001, the National Cancer Institute announced it will take the following 10 steps to address the challenges for further research in pancreatic cancer:
1. Increased Pay Lines: Beginning with fiscal year (FY) 2002, the NCI intends to increase the pay line by 50 percent for research grants devoted 100 percent to investigations in pancreatic cancer. To be considered for these grants, applicants are instructed to include the following in the background section of the grant application: The research described in this application is 100% relevant to pancreatic cancer.
2. New SPORES: NCI will fund three new Specialized Programs of Research Excellence (SPOREs) in FY 2002, and may require all new gastrointestinal SPOREs to include at least one pancreatic cancer project. As part of the SPORE effort in pancreatic cancer, the NCI may ease human endpoint requirements for this disease until translational research in pancreatic cancer matures. Pancreatic SPOREs may be allowed to exceed the current budget cap to develop expanded tissue collections, banking activities, and data from high-risk individuals.
3. Mouse Models: The NCI will provide supplements to investigators within the Mouse Models Consortium for the development of pancreatic cancer models.
4. Other Models: The NCI will evaluate the need for supplements to develop alternative models of pancreatic cancer that are complementary to mouse models.
5. Tissue Samples: Feasibility of providing greater access to pancreatic tissue samples will also be explored by the NCI.
6. Patient Data, Samples: The need for uniform data collection instruments and data sampling protocols will be addressed. Ultra rapid access to tissue samples will be considered.
7. Early Detection: The Early Detection Research Network and the Center for Proteomics will focus on identification of early detection markers for pancreatic cancer.
8. Development of Drugs: The NCI will expand the Rapid Access to Intervention Development (RAID) in response to high demand.
9. Increased Patient, Provider Education: Education materials and information will be developed in conjunction with advocacy groups and posted on the Internet.
10. Palliative Care and End-of-Life Support: NCI will expand research on palliative care and end of life through the Centers of Excellence in Cancer Communication.
The PRG report, Pancreatic Cancer: An Agenda for Action, is available online in pdf at http://osp.nci.nih.gov
© 2002 Lippincott Williams & Wilkins, Inc.