As spinal fusion surgery continues to be associated with controversy, probes, and patient injuries, a recent North American Spine Society (NASS) annual meeting discussed cancer links to products such as Medtronic’s InFuse®.
Synthetic, or genetically engineered, recombinant human Bone Morphogenetic Protein (rhBMP-2)—manufactured by Medtronic under the brand InFuse®, was approved by the U.S. Food & Drug Administration (FDA) in 2002 to stimulate spine growth in patients suffering from lower spinal degenerative disease. Approved for use in one type of spinal surgery and some dental procedures, InFuse® is used, for the most part, in off-label procedures. Approval was based on Medtronic-funded research.
At this year’s annual meeting of the NASS in Chicago, renowned expert, Eugene J. Carragee, MD, and colleagues, discussed the increased cancer risk associated with the use of BMP-2 in fusion surgeries, said the Back Pain Relief Center citing the Society’s Back Letter. Although InFuse® manufacturer, Medtronic, maintains there is no link to cancer with the product, reporting in 2010 at FDA hearings that no statistically significant associations exist between cancer and the use of BMP-2 in the clinical trials submitted to the agency, Carragee disagrees, said the Back Pain Relief Center.
Carragee and colleagues presented new analysis revealing that patients who received BMP-2 in the trials performed under so-called “FDA auspices,” or pooled study data, were at least two times likelier to develop cancer when compared to control subjects. Also, patients treated with a higher dose in the AMPLIFY trial experienced a three-fold likelihood of developing cancer in the three-year follow-up when compared to control subjects, said the Back Pain Relief Center. AMPLIFY is a randomized trial evaluating BMP-2 in posterolateral fusion surgeries.
“Despite strict exclusion criteria in the AMPLIFY trial—which excluded patients with a history of serious cancer—a strong association between BMP-2 and cancer was seen by a variety of statistical methods,” Carragee reported. These differences were statistically significant, he added, noting that the strict exclusion criteria might mean that the BMP-2 cancer risk has probably been underestimated in typical spinal surgery, said the Back Pain Relief Center.
Carragee and colleagues are not the only experts to reach this conclusion. “The primary statistical concern is the apparent association with malignancy,” said the FDA. “I agree with the FDA’s analysis that there is a strong association with cancer,” Carragee said. “Proof of causation of cancer, however, requires a very high evidence bar—as 40 years of litigation from the tobacco industry about smoking and cancer have demonstrated.” Carragee noted that the association appears to increase with increased doses, in older patients who are less resistant to cancer, and in people with known cancer risk factors, said the Back Pain Relief Center. Carragee, answering questions at the event, noted that, “The tumors were all over the place…. In the BMP-2 group, there was an assortment of tumors—and not the mix you would expect to see in this population,” including lung, pancreatic, prostate, stomach, ovarian, and breast cancers.
What is causing the cancer remains unclear, said Carragee, “It is unlikely that these cancers stem from a direct carcinogenic effect [where BMP-2 is the root cause of the cancer…. The lead time is too short,” he explained, adding. “I think the most likely hypothesis is that there is a cancer-promotion effect related to the use of BMP-2.”
We previously wrote that late last year, a U.S. Senate Finance Committee report revealed that of some 13 Medtronic-funded clinical trials, none reported side effects with use of InFuse®. The Committee’s inquiry began in June 2011 and probed Medtronic-paid surgeons who never reported InFuse®-related complications.
The studies, presented InFuse® in a very positive light and as a major breakthrough in spine surgery; however, the significantly manipulated information downplayed serious complications linked to InFuse®, overstating its benefits. In truth, Medtronic employees, some from its marketing department, secretly worked with academic physician authors on 11 papers produced 2002 – 2009, according to the report. Although not against the law, this type of ghostwriting is considered far from ethical and is largely thought of as a breach of integrity and lacking in transparency. Such ghostwriting places doctors and patients in a position in which they must rely on incomplete, flawed data when making important medical decisions.
In 2011, the Spine Journal devoted a full issue to the matter, proving the InFuse® research wrong. “This sounds eerily familiar to many of the transgressions we’ve read about from the pharmaceutical industry,” Dr. Harlan Krumholz, a professor of medicine at Yale University, told MedPage Today when advised of the Senate report. “It paints a picture of a company very heavily involved in the science; marketing contaminating the science; and the medical profession and researchers being complicit. It’s no wonder the public has lost confidence in the drug and device industries,” Krumholz added.