Avastin and Fistulas

About two weeks ago the US FDA approved the use of Genentech's blockbuster drug Avastin (bevacizumab), a biologic, for treating patients with "persistent, recurrent or late-stage cervical cancer."

The FDA press release trumpeting Avastin's latest indication was by-the-book; it cited how many annual diagnoses of cervical cancer are estimated by the National Cancer Institute; it featured a quote from the head of the office issuing the approval, Richard Pazdur; it hyped the agency's priority review program; and lastly, it cited the pivotal clinical trial that led to the approval of the drug in question for the indication.

Safety and Effectiveness Paragraphs

The FDA always reserves one of the last paragraphs for the notable side effects observed in the pivotal trial. Seeing as how the paragraph prior to this one is the one that tells you the effectiveness of the drug in the treatment population, one ought to expect the safety or side-effect paragraph to be overshadowed by the effectiveness paragraph.

For cancer drug approvals, this is rarely the case. More often than not, the safety paragraph stays with you for much longer than the efficacy paragraph, and this recent Avastin approval offers an ideal example.

Fistulas

In the last line of the safety paragraph, the FDA throws in the following observation, making it feel like both an obligation and an afterthought:

"Perforations of the gastrointestinal tract and abnormal openings between the gastrointestinal tract and vagina (enterovaginal fistula) also were observed in Avastin-treated patients."

In fact, as has been detailed in so many studies involving Avastin, internal bleeding and fistulae are practically Avastin motifs.

What's a fistula? A fistula is an abnormal opening between organs. In this study, with a little extra effort, we will learn that it refers to an abnormal opening between either the vagina and the rectum (rectovaginal), or the vagina and the bladder (vesicovaginal). In either case, patients with this condition find they are involuntarily discharging waste products through the vagina—-a more psychologically and emotionally distressing side effect than this is difficult to imagine.

The FDA approved Avastin based on the following study: "Improved Survival with Bevacizumab in Advanced Cervical Cancer." The New England Journal of Medicine published this study in February, and it is there that we learn the occurrence of these enterovaginal fistulas: 14 in all, with 13 of them among the study group receiving Avastin.

Link to the PubMed abstract

In order to get a clearer picture of this group of patients, you have to go to the study's long and exhausting Supplementary Appendix. Once there, you must wade through over 50 PDF pages until you reach section 4 of the additional material for the bevacizumab analyses, a section given the stark, simple title, "Fistulas."

Link to the Supplementary Appendix (PDF)

(Actually, it appears that the section is mis-labeled as section 4. It really ought to be labeled section 5 since there are two section 3's: Health-Related Quality of Life and Dose Intensity)

So, here, in Table S17, we finally get to the details of those patients who received Avastin and who developed treatment-related fistulas. Seven are described as rectovaginal or RV and six as vesicovaginal fistulas or VV (It is no wonder UK-based charity The Vegetarian & Vegan Foundation changed their name to Viva! Health).

Vaginal fistulas like these are more commonly diagnosed as a consequence of childbirth—rather, they used to be, at least in developed countries. Outside of a minority of women with Crohn's disease, and according to information provided at the website for Forward, the Foundation for Women's Health Research and Development, vesicovaginal fistulas today remain horribly common among females who are subjected to female genital mutilation and/or child marriage. In fact, the condition is common enough that Fistula has become one of the organization's key priority areas.

According to the NEJM study, with two exceptions the fistulas were "managed supportively." Put another way, the patients received supportive care, or care meant to make them more comfortable. In the case of the two exceptions, one underwent colostomy and another, nephrostomy.

Confronting the odds

So there you have it: Six percent of the cervical cancer patients who received Avastin as part of the drug manufacturer's attempts to gain regulatory approval for this indication experienced an awful medical crisis that is typically associated with barbaric human rights violations performed on pre-teen African girls to prepare them for cultural acceptance.

For the record, the final analysis of Avastin in treating advanced cervical cancer showed that adding Avastin to two chemotherapy drugs improved overall survival from 13.3 months to 17 months. Such miniscule gains are absolutely typical of what Avastin delivers as a cancer treatment.

So is it reasonable to say that cervical cancer patients given Avastin in combination with other drugs have a six percent chance of experiencing an enterovaginal fistula? I don't know, but I do know that if the study showed complete remissions in six percent of the patients given Avastin, that Genentech would be shouting it from the rooftops.

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