Treating GIST: Which Target, What Agent,
How Much, When To Treat?

By Bob Spiegel

The “New Challenges in Treating GIST” satellite meeting was held in conjunction with the 2008 ASCO Gastrointestinal Cancers Symposium in Orlando in late January. The ASCO conference and numerous satellite meetings were held in The Orlando World Center Marriott Resort & Convention Center, smack dab in the middle of all the Central Florida parks that teach people how to avoid reality. The hotel, bigger than the town I live in, and where staff use Segways to get from place to place, was a daunting maze of halls and meeting rooms and restaurants. But during this symposium, it served merely as the setting in which to teach medical professional how to deal with the reality of cancer. And do it better.

The GIST satellite meeting had about half the attendees of the previous night’s 100-physician meeting on redefining targeted therapies for treatment of the more common carcinoma variety of GI cancers, a reflection of the general interest in this cancer ‘variation’ because of its rarity. But a veritable Who’s Who of GIST researchers and MDs made this Friday evening exchange of ideas a treasure of information, both prescribed by program, and ‘off-label’ by buttonholing attendees who wanted more.

The ‘lineup’ of faculty included:

• Dr. George Demetri, Director of The Ludwig Center at Dana Farber Cancer Institute and Harvard Medical School in Boston
• Dr. Ron DeMatteo, Chief of Surgical Oncology at Memorial Sloan-Kettering Cancer Center in NYC
• Dr. Burton Eisenberg, Director of the Norris Cotton Cancer Center and and Professor of Surgery at Dartmouth Medical School, both in New Hampshire.

A sudden illness interfered with the appearance on the program by Dr. Jonathan Fletcher, Associate Professor of Pathology and Pediatrics at Harvard Medical School in Boston. Thus, Fletcher’s part of the program, the Molecular Pathogenesis of GIST, was ably covered by the remaining panelists/speakers.

The affable Dr. Demetri chaired this session and led with his take on managing advanced GIST with kinase inhibitors and just how to do it most appropriately. The talk was peppered with advice on the variances among exon mutations and his belief that KIT gene mutation simply doesn’t explain ‘the whole thing’ and simple KIT testing is often not enough on which to base treatment decisions. After pointing out that 98% of exon 9 mutation are in the small intestine, roughly the same percentage of PDGFRA mutations are in the stomach, and, what most of us GSI ‘frequent flyers’ know…tumors over 10cm in size and higher than a 5/50 HPF mitotic count have an 86% chance of tumor progression.

On the up side, Demetri pointed out that imatinib (Gleevec, the commercial name for imatinib, was never mentioned, even though this CME meeting was sponsored by maker Novartis) actually triples the survival rate of GIST patients and THERE IS LITTLE DIFFERENCE IN THE PROGRESSION-FREE SURVIVAL RATE BETWEEN THE 800mg AND 400 mg DOSES. This will be music to the ears of those having troublesome side effects on the 800mg doses, though some circumstances may still require it. An example would be exon 9 mutations, for which 800 is optimal.

Demetri mentioned that 35 out of 100 whole stomach GISTS had 35 tiny GISTS (micro-Gists) remaining after surgery and familial GISTS, though rare, are becoming an increasingly ‘interesting’ aspect of GIST treatment protocol. As for tumor ‘architecture’ his statistics show that 2/3 of all GISTS are spindle cell, with the remaining being epithelioid, but often there’s a mixture. Those of us with exon 11 mutations, per Demetri, have a 75-80% chance of secondary mutations developing on imatinib treatment. And he made it clear to his audience that it is becoming increasingly important to consider combinations of drugs and there are many clinical trials in progress to acquire that information to best treat a patient.

Dr. DeMatteo opened with a presentation on the surgical principles for primary tumors, including but not limited to;
1. Complete resection
2. Avoiding rupture
3. The ‘wedge resection’ of organs
4. Laparoscopic surgery for small tumors
5. Assessing the tumor for metastatic disease

"By far, the mitotic rate is the greatest indicator of survival" DeMatteo opined. A puzzling statistic regarding clinical trials was expressed by DeMatteo, claiming that the toxicity was almost equal between trial patients on Gleevec and those on placebo. "Are we delaying or preventing recurrence with the use of adjuvant Gleevec?" he offered, then honestly answered his own question with an "I don’t know." But at 1 ½ years (following 1 year on adjuvant imatinib), the recurrence rate does increase, the exon 9 mutation at a historically higher rate. But he insisted that the 400mg dose of Gleevec is safe, well tolerated and increases the rate of recurrence-free survival.

Dr. Burton Eisenberg addressed multimodal treatment options for localized GISTS and led a panel discussion with Doctors DeMatteo and Demetri. Dr. Eisenberg cautioned attendees that a biopsy must almost always be done prior to adjuvant therapy, but ‘core’ biopsies of primary GISTS should be used sparingly because of the high risk of subjecting the patient to ‘spill’. Eisenberg also mentioned that if a patient should relapse, if early enough, many of the new growths are resectable, depending on size and location.

The meaning of ‘clear margins’ took on some new meaning when, during the panel discussion, Dr. DeMatteo cautioned that most surgeons are using staples for incision closure and, unfortunately, pathologists often remove the ‘staple lines’ prior to testing, thereby complicating the true definition of clear margins during surgery. "It therefore behooves the surgeon to instruct the pathologist what the true margins are," he said.

The panel closed with a brief Q & A period about how important the site of the tumor is when considering adjuvant therapy…a 50/50 split here, but the clock expired before the esteemed panelists could explain their differences.

Webcasts of the presentations can be found on the internet by going to http://www.cancerlectures.com/other_solid_tumors/gist_08_1706/.

Some post-session private conversations provided lots of additional information from the panel members and the GSI contingent of Brad Clark, Bill Davis, Penny Duke and myself were warmly greeted by Demetri, who proudly proclaims, "I love GSI!". I suspect GSI listers return the favor.