The limitations of progression-free survival as an endpoint – NPR addresses

On the NPR Shots blog, Scott Hensley addresses, “Avastin For Breast Cancer: Hope Versus False Hope.” Excerpt:

Any day now FDA Commissioner Margaret Hamburg is expected to make a final decision on Avastin’s fate. Women who said Avastin helped their breast cancer were out in force at a June hearing of an appeal of FDA’s proposal. At this point, it would be a big surprise if the agency let the approval, granted on an accelerated basis back in 2008, stand.

Now, one of the cancer specialists on the expert panel, which voted unanimously against the Avastin appeal, invokes a hypothetical conversation with a breast cancer patient to explain why.

In a letter published in the latest New England Journal of Medicine, Dr. Mikkael Sekeres, who heads the leukemia service at the Cleveland Clinic, asks what sort of chat he would have with a woman, if he was the doctor leaning toward Avastin for breast cancer.

The bottom line:

“Well, I can offer you a drug that will not make you live longer, won’t make you feel better, and may have life-threatening side effects, but it will keep your cancer from worsening by an average of 1 to 2 months.”

Hensley also addresses the limitations of progression-free survival as an endpoint.

Should this progression-free survival “in the absence of an overall survival advantage or any improvement in quality of life” sway a patient? In the end, Sekeres saw it as a Pyrrhic victory for the drug and decided it wasn’t enough to keep the approval for the drug intact.

His letter concludes:

“We did not make this decision because we do not care about women with breast cancer or because we want to deny them therapy for a terrible disease but because we do not want people to be hurt by a drug that does not work that well. We do not want to provide false hope.”

In another example of political rhetoric on medical evidence (earlier this week we cited Newt Gingrich’s recent example), we reported back in July, 2010 that:

Senator David Vitter of Louisiana says that an FDA advisory committee’s vote to revoke the approval of Roche-Genentech’s Avastin for treating breast cancer is “essentially government rationing.”

Be ready for a firestorm of more of this if and when the FDA rules as expected.

Meantime, more background on the mounting questions about progression-free survival as an endpoint is provided in a New England Journal of Medicine perspective piece.

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Angelina Lenahan

October 13, 2011 at 5:57 pm

My sister has metastatic breast cancer and was treated with Avastin for 4.5 years. One can only speculate what her quality of life would be had she not been given Avastin. She’s in her mid 70’s and was still driving up until last year. She was able to return to college and study Chinese, American literature, and do some wonderful things with her great grandchildren before the bone and brain mets.

Elaine Schattner

October 13, 2011 at 8:12 pm

You ignore (or doubt, but why would that be?) that a few, very-real humans with MBC do well with Avastin and either don’t or haven’t thrived with other drugs, despite their and their oncologists’ best efforts. Medicine is not so neat and tidy as that. Exceptions exist, and the woman in the hypothetical leukemia doc’s office might, if she were real, benefit and not be harmed particularly by Avastin.
Progression free survival can mean the difference between living without with bone pain, without coughing up blood from malignant lung infiltrates and not having seizures from brain mets, or living with all of those symptoms, and more. The NEJM perspective was a bureaucratic take, essentially saying the FDA shouldn’t do the right thing because it would be an administrative embarrassment and a bad precedent.
I am a firm believer in evidence and science. But I am also an advocate for compassionate, patient-centered health care.

Gary Schwitzer

October 13, 2011 at 10:24 pm

No, Elaine, I neither ignore that a few benefit nor doubt it.
Please don’t make up things I did not write and did not imply or intend to convey.
And what exactly is meant by your parenthetical comment – (or doubt, but why would that be?)? What are you implying? It wasn’t clear to me and I’m sure it’s not clear to anyone else.

Gregory D. Pawelski

October 14, 2011 at 1:32 am

We are being told that dedicated physicians, empowered to scrutinize the best data, could not prove beyond any doubt that Avastin improved survival. The progression-free survival data was favorable and the survival data also “trended” in a favorable direction. But, the final arbiter of clinical approval – the survival advantage for the Avastin-based therapies in breast cancer – has not met statistical significance.
The progression-free survial in the confirmatory trials were less, there were more treatment-related deaths and the overall survival was less. Progression-free survival does not address the patient’s quality of life during those additional months of some serious side effects a number of women experience.
The FDA’s “intent” was that in first-line therapy, it wants to see an overall survival benefit. The reason that Avastin was approved without showing overall survival was the progression-free survival benefit was great. The confirmatory trials found that not to be.
In regards to the few patients with MBC that do well with Avastin, the problem is that doctors don’t know which patients will respond favorably in terms of overall survival, and you do not want to give it to every patient with MBC. One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit.
There should be an inclusive effort to study and utilize technologies which are based on both the sub-cellular (molecular) level and at the cellular (cell function) level. Because what may benefit one individual cancer patient may not benefit another.

Elaine Schattner

October 16, 2011 at 6:23 pm

Hi Gary,
I was away for a few days. My issue is with the leukemia specialist’s over-confidence, i.e. the lack of doubt – a quality that’s troubling in doctors as it can be in journalists.
What you highlight as “the bottom line” are words offensive in their commanding, all-knowing, patronizing tone:
“Well, I can offer you a drug that will not make you live longer, won’t make you feel better…” But how is he, the doctor, so certain the drug won’t help that particular woman or make her feel better? The only explanation would be that he dismisses the Avastin outliers as false or untrue.
If you don’t agree with him, or don’t support his hypothetical statement to a patient, I’m reassured and regret my inference.