Life Raft study presented at CTOS annual meeting Starting vs. actual dose significant

A groundbreaking study of cancer patients done by the cancer patients and caregivers themselves was presented at the Nov. 11-13 meeting of the Connective Tissue Oncology Society’s in Montreal, Canada.

The study undertaken by the Life Raft Group was presented Friday afternoon, Nov. 12, to over 300 sarcoma and GIST specialists from around the world. It affirmed preliminary results of a large European study on dose levels of Gleevec (imatinib) for GIST (gastrointestinal stromal tumor), and also tackled the thorny issue of clinical trial patients who begin a clinical trial at a certain dose, but then change that dose.

The results of clinical trials are usually based upon the starting, or “intent to treat” dosages – even though patients sometimes have their dosage reduced due to side effects or changed by the patients themselves without notifying the trial clinician. Researchers generally do not take into account these dosage changes when reporting their findings.

The Life Raft study, however, suggests that cancer patients, particularly those on long term oral therapy, might be better served if dosage changes were considered as well. In the LRG study of 169 patients with metastatic GIST receiving Gleevec, there was a significant difference in the observation of resistance when the actual dose being taken was considered versus the “intent to treat,” or starting dose.

The patients studied all had metastatic GIST, had been on Gleevec one year or longer, and had experienced initial tumor shrinkage. The objective of the study was twofold: to see if there’s a correlation in this group between dose and the cancer becoming resistant to Gleevec; and to evaluate the difference in methodology between using starting dosage (“intent to treat”) vs. actual dosage.

Of the 169 patients, 91 reported continued stable disease following shrinkage. The other 78 had experienced tumor growth after their initial response. Forty percent of the 169 patients were initially prescribed 600 mg. or more of Gleevec daily, while 60 percent were prescribed less than 600 mg.

When considering starting dosage alone, the LRG study did find a correlation between dosage and relapse, but it was not statistically significant (p = 0.265). The relapse rate for patients taking 600 mg. or more was 41.2 percent, while it was 49.5 percent for those taking less than 600 mg. It is interesting that this 8.3 percent higher relapse rate is not far off the 6 percent higher relapse rate reported in the European/Italian/Australian (EORTC, ISG, AGITG) Phase III study of 946 GIST patients of patients taking 400 mg. or 800 mg. of Gleevec daily. The companion American/Canadian study of a somewhat smaller group of patients has failed to report any relationship between dosage and resistance thus far. In looking at the starting dose vs. actual dose issue, the Life Raft study found that 38 percent of patients had a reported change of dosage, most because the clinician had changed the dosage but some because the patient had changed the dosage themselves without notifying the clinician. Most (30.2 percent) reduced their dosage but some (7.7 percent) had a dosage increase.

When the actual dose was considered, the difference in relapse rates between the higher and lower dosage groups was dramatic. Based upon actual dosage there was a significantly lower relapse rate for higher versus lower dose (p = .001)

Going by “intent to treat” dosage, the relapse rate was 49.5 percent for those on less than 600 mg., and 41.2 percent for those on 600 mg. or more. But when the actual dose was considered, the relapse rate was 52.9 percent for those on the lower dose, and just 30 percent for those on the greater dose. Put another way, the lower dose group had an 8% higher relapse rate based upon starting dose but a 23% higher relapse rate based upon actual dose. Further, although not statistically significant, likely due to small numbers, the actual dosage data does suggest a gender difference that needs to be watched in future studies.

When the study looked at relapse rates based upon actual dosage over time, relapse rates were relatively consistent in five six month time periods starting with month 13 (the first study month). Relapse rates overall and separately by gender were significantly lower for higher dose. What this means is that patients on lower doses who have not relapsed cannot take any comfort in that fact and face the same risk of resistance in each six month time period evaluated thus far.
Conclusions:
When looking at actual dosage, patients on 600 mg or more of Gleevec are significantly more likely to have lower relapse rates than do patients on less than 600 mg.

Actual dosage produces substantially different results than starting dosage.

It is important to note that the methodology used by the Life Raft Group is subject to bias in that there was not a non-random assignment of subjects to dosage groups. On the other hand the Life Raft Group methodology takes into consideration the actual dosage that patients were on, including those situations in which the patients themselves changed their dosage without reporting this to their clinicians.

The Life Raft Group study was led by Norman Scherzer, executive director, with science coordinator Jerry Call, research assistant Pamela Barckett, biochemist David Josephy, Ph.D.; mathematician Michael Josephy, MSc., and statistician Richard Singleton, Ph.D.

This was a milestone event for CTOS and the LRG. For CTOS it was the first patient led scientific study and presentation. Dr Larry Baker commented at the end that this was an “extraordinary event. …that much other retrospective work had been presented at the CTOS meeting and the LRG’s was as provocative as any”. For the LRG this was a major learning event.

By Richard Palmer, Norman Scherzer and Jim Hughes