Dana-Farber Hosts Celebration for GIST Patients and Families
By Terry Jennings
“Uplifting” is the word my husband, Lou, used to describe the Dana-Farber celebration: Living with GIST, 10 Years of Molecular Targeted Therapy. It was truly uplifting to hear the physicians relate stories of the battle with our rare cancer; to be in the same room with 10-year veterans of the fight and folks who have just barely started; to learn that it was through the persistence and caring of their doctors and loved ones that the veterans were now alive. We heard how many of those veterans had literally “cheated” death with the help and collusion of their physicians. What could be better than knowing that ten years ago, many GIST diagnoses (even if they were correctly identified) meant death, but now there is hope. And the beginning of that hope came with the trial known as B2222, a trial of a drug now known as Gleevec and first known as STI-571, which began in the summer of the year 2000.
The celebration was hosted by Drs. George Demetri and Suzanne George of Dana-Farber Cancer Institute (DFCI). Presenters included doctors and researchers involved in the trial—Dr. Meg Von Mehren, Director of the trial at Fox Chase Cancer Center (FCCC), Dr. Charles Blanke, Director of the trial at Oregon Health Science Center (OHSC) at the time, Dr. Chris Corless, pathologist; Dr. Annick van den Abbeele, imaging and nuclear medicine radiologist. It also included a panel of “veterans”—patients who began taking STI-571 ten years ago and were part of the original trial. From the doctors and researchers we heard the amazing story of the discovery and trial of Gleevec. From the veterans we heard their stories and what living with GIST, courtesy of Gleevec has meant. From a group of DFCI specialists, we heard about different modalities to help us cope.
The Story: GIST Before Gleevec
10 years ago GIST was often diagnosed as other types of sarcoma—in particular, leiomyosarcoma— and treated as such. Surgery is still the first line of defense, but then it was the only hope. Surgery can be curative for very small GISTs, less than 5 cm with low mitotic rate (slow growing). But since GIST is a very silent cancer, by the time it is found, it is often large and has a high risk of recurrence. So, like Dr. Burton Eisenberg (formerly of FCCC and now at Dartmouth’s Lebanon Cancer Center) told us, “very adequate surgery” can still result in recurrence.
Whether or not GIST was correctly identified, if surgery wasn’t curative or if surgery was not possible, nothing else worked. George Demetri characterized the treatment of GIST before STI-571 as having a “very low risk-to-benefit ratio.” With various chemotherapies and radiation, patients experienced significant side effects, but no benefits, yet oncologists had no other tools; so they kept using those modalities anyway in the hopes that something would work, and in the hopes of extending life even just a little bit.
The Story: Discovery Of Molecular Therapies Targeted At GIST
The usual culprit in the development of GIST is a mutation in the KIT gene. A virus hijacked molecules in that gene, a gene that builds tyrosine kinase, the protein which receives growth signals for cells, and caused a mutation. The mutation gave the cells the impetus to grow uncontrollably. According to Chris Corless, Director of Medical Pathology at OHSC, the virus was discovered in the 1980s in, of all things, kittens!
The idea in trying to stop the cancer was to find something to stop the kinases from giving that growth signal: a kinase inhibitor. It would be an enzyme. But making a kinase inhibitor drew few researchers. It is difficult to produce enzymes, and biologists felt that since the body makes 600 different kinases, a kinase inhibitor might kill every molecule in the body, not just the troubled ones. It was not until Dr. Brian Druker, then a post-doctoral student, developed a way to produce the enzymes for testing, that biologist Chuck Styles was able to begin research to find enzymes that would stop kinases from giving the growth signal, and lead to cell death. Research continued and in 1998 a Japanese research group including Dr. Seichi Hirota showed that GIST contained the mutated KIT protein. This protein, labeled CD117, became a tool to identify GIST.
The same year of Dr. Hirota’s discovery, Dr. Brian Druker (now a full-fledged physician and researcher at OHSC) found that a tyrosine kinase inhibitor —STI 571—was very successful in treating chronic myeloid leukemia (CML). Physicians like George Demetri and other scientists knew that there were similarities between the mutation that causes CML and the mutation that causes GIST. In early 2000 Dr. Jonathan Fletcher of DFCI found that GIST cells would die if given STI-571, the compound we now know as imatinib and Gleevec, the first molecularly targeted cancer therapy.
It would have been great to start giving GIST patients the drug right away, or to start a human trial of STI-571, but Novartis was overwhelmed with CML demand. Despite Dr. Demetri’s and other researchers’ best efforts, Novartis was unable to divert the drug for trials on a cancer as rare as GIST. It took a patient in Finland, aware of STI-571 and with a huge GIST tumor load, to coax Novartis into giving her some of the drug. It worked dramatically. But even with that knowledge, there was still no drug available for FDA trials in the United States. It took another persistent patient, Chris Carley, who contacted the drug company through a family connection with The Wall Street Journal to get Novartis to release enough drug for a trial. This was July 2000.
The actual study was a collaborative effort between Dr. Demetri and Drs. Meg non Mehren (FCCC) and Charles Blanke (OHSC). Originally 36 patients participated in a phase I trial to test efficacy of the drug, and the initial success soon led to a phase II trial with 147 patients to compare the effect of different doses. According to Dr. Blanke, 90% of patients were back to normal within two weeks. When Chris Carley’s scans became available after the first dose, the change was so dramatic that Dr. van den Abbeele at first thought a mistake had been made. Then she called Demetri. “George,” she said. “You’d better come down, something is working.” When Becky Harper, another GIST patient, had a PET scan after just one dose, all metabolic activity in the tumors had stopped.
It was obvious in listening to these doctors that they were totally focused on their patients’ welfare. They just wanted to be able to offer GIST patients access to the drug. Dr. Blanke even confessed to having admitted people into the trial without meeting all criteria just to make the drug available to them. In fact, it was so important for researchers to get STI-571 out for general use that the protocol for a large scale trial, which is necessary for FDA approval and which can take years to develop, was completed by George Demetri and his team in about a month.
Since this first trial, other trials have rounded out researchers’ knowledge of the drug. We now know that pre-operative Gleevec can make surgery easier and shrink tumors to operable size. Post-operative Gleevec delays GIST recurrence significantly. Stopping Gleevec after 1, 3, or 5 years results in recurrence in metastatic GIST patients. And as time passed, we found that after about two years of Gleevec treatment, many tumors develop a resistance to Gleevec. At this point the offending tumor can be resected or ablated and Glee
vec continued, or drugs like Sutent, Nexavar and Tasigna can be used to stem the growth of GIST.
The Stories From The Veterans (B2222 Trial Patients): What it means to live with GIST
It is safe to say that had this drug not become available when it was, the patients on the stage for this celebration would not be alive today. They were part of the original B2222 trial and many were at death’s door when they first received the drug. Most of them had been originally misdiagnosed. Most had been fighting the dragon since the 90’s—one, Becky Harper, since 1983. We heard from veterans who had begun to give away their possessions, had been in hospice for months, had 38 tumors, had a very short life expectancy. And we heard stories of gratefulness for the gift of life.
Now What? How To Cope
Dana Farber has a center for integrative oncology, previously known as complementary and alternative medicine. Dr. David Rosenthal, its director, spoke on the modalities practiced at the DFCI—manipulative therapies such as massage; mind-body therapies such as yoga, prayer and meditation; alternative medical systems such as homeopathy and naturopathy; energy therapies such as Reiki, magnets and Qui Gong; and biologically based systems such as diet and herbs.
A couple of websites may be interesting. For diet and nutrition, access www.dana-farber.org/nutrition. For family issues, access www.dana-farber.org/familyconnections
What a Day!
In all, it was a wonderful experience. My take-away from the meeting was the caring that the professionals had for their patients. It was palpable. I believe that without the commitment of the doctors present at that meeting and some who were not there, without their constant striving to get the drug and make it available to patients through whatever means, without their willingness to bend the rules, and without their sheer hard work, many of the veterans would not have been there. Eventually the drug would have been found, but many more would have died. We are all lucky to have such a stellar group in our corner.