Patients in 2010 with the deadliest form of brain cancer, glioblastoma, lived “significantly longer” than patients in 2008, reports a new population-based study in Cancer.
The apparent reason: the famous tumor blood-vessel blocker Avastin, which was conditionally approved for progressive glioblastoma by the Food and Drug Administration (FDA) in 2010.
“This study provides clear evidence that glioblastoma survival is improving,” says neuro-oncologist lead author Derek Johnson of the Mayo Cancer Center (Rochester, MN). While it “provides only indirect evidence Avastin is responsible for the improvement,” it provides a “new perspective on the issue.”
Furthermore, Avastin mixed with another key drug may boost survival even more, an earlier Mayo Clinic study has suggested. For, while Avastin in many cancers seems to shrink tumors temporarily, those cancers often roar back more vigorously. But Panos Anastasiadis, director of the Mayo (Jacksonville, Fla.) Cancer Center Cell Biology Program, reported this winter a drug added to the mix may capitalize on Avastin’s talents and weaknesses: Sprycel (dasatinib).
When Avastin blocks tumor blood vessel growth, it appears to create hypoxia (oxygen deprivation) in the tumor, shrinking it. But tumors appear to compensate by activating enzymes called SRC family kinases, which help tumor bits break off and escape the hypoxia: metastasize. Sprycel blocks such SRC-driven escapes, Anastasiadis’ study showed.
So Johnson’s new study “makes perfect sense,” says Anastasiadis. “Avastin retards glioblastoma tumors, and we are trying to improve on that. Our work showed tumor dissemination is one of these escape mechanisms that can be potentially targeted therapeutically.”
“For sure Avastin increases the motility of tumor cells,” says Emory University Cancer Cell Biology Program head Erwin Van Meir, who was not involved with either study. “Testing Avastin in combination with an agent blocking tumor cell migration is certainly worthwhile.”
A Phase 2 trial of exactly that— Avastin and Sprycel— is now ongoing through the Alliance for Clinical Trials in Oncology cooperative group.
But until such results are in, some will remain unsure of Avastin’s standalone survival edge. Johnson’s team, in the population-based study, looked at 5,607 adult patients from the National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database before, and after, the conditional 2009 FDA approval of Avastin for glioblastoma. The team reviewed data on 1,715 patients who died in 2006, 1,924 who died in 2008, and 1,968 who died in 2010.
The survival difference between 2008 and 2010— a median of two months— was “highly significant” offering “the strongest evidence to date” Avastin lengthens life, the team reported.
But the indirect evidence bothers some. “The real question is whether such a database approach provides more reliable answers than a rigorous clinical trial,” says Martin van den Bent, Erasmus Medical Center neuro-oncologist. In two noteworthy Avastin clinical trials, “no clear evidence of improved survival was present, although both trials suffered from cross over (from control to treatment arms when tumors progressed). A big deficit of the database study: treatment data are lacking. The conclusion is, therefore, quite speculative. “
Furthermore, van den Bent says, despite widespread U.S. Avastin use, not all glioblastoma patients received it. And half had “a median survival of only four months. It is quite likely many of those never received” Avastin. So for many the Avastin survival benefit “must have been even bigger…. (but) why that was not picked up in the randomized trials? It is good news that we see improved survival, but in view of the randomized trials that failed to show survival benefit, it remains difficult to attribute this” to Avastin.
Johnson responds that, “in this study, no improvement in survival was seen between 2006 and 2008, a period that serves as a control for incremental improvement in glioblastoma care over time.” Also: past population-based studies showed no improvement in glioblastoma survival— until there was an increase coinciding with temozolomide approval. He adds that larger failed trials issued the drug to newly diagnosed patients— not recurrent patients, whom the drug may help most.
The issue of whether Avastin alone helps or hinders became especially critical recently when the FDA revoked approval of the drug for breast cancer. Clinical trials had showed the drug helped manage breast cancer briefly--before tumors swiftly returned, conferring no survival benefit.
The Michigan University team of oncologist Max Wicha found, in pre-clinical work, this may be because Avastin’s hypoxic effects can prompt breast cancer stem cells to grow, not die. Yet even that group found Avastin mixed with synergistic drugs—cocktails— may work.
“Tumors are a dynamic adaptive system,” concludes Van Meir. “They change. Blocking a tumor is similar to trying to stop traffic in a city where people will adapt to any blocked roads by finding new ones. Cocktails are definitely the way to go.”