Respectful Insolence

The saga of Avastin and breast cancer

One of the most frustrating aspects of taking care of cancer patients is that in general, with a handful of specific exceptions, we do not have good curative therapies for patients with stage IV cancer, particularly solid tumors. Consequently, we are forced to view patients with stage IV cancer as “incurable” because, the vast majority of the time, they are incurable. Over the years, we have thrown everything but the kitchen sink at patients with stage IV disease, largely with dissapointing results. That’s not to say that the few specific exceptions to which I alluded are not a reason for hope. After all, patients with colorectal cancer and liver metastases used to have a median survival of around 6 months, but these days, with newer chemotherapeutic regimens like FOLFOX plus Avastin, median survival has more than tripled. While expecting to live less than two years is cold comfort to cancer patients with this particular clinical situation, the prognosis is far better than it was.

Of course, I specifically mentioned Avastin because it’s been in the news a lot recently with respect to my area of clinical specialty, breast cancer. Specifically, beginning in July there started appearing a spate of stories about the FDA considering revoking the approval of Avastin for advanced breast cancer based on recent studies that demonstrate that it does not prolong survival in these patients. Many lay people and patients find this reconsideration of Avastin to be quite puzzling, given that the drug was granted accelerated approval in 2008 and has since gone on to be used fairly widely. Given that the case of Avastin in breast cancer is rapidly becoming a classic case study of how messy science-based medicine can be when practiced in the public eye and debated among pharmaceutical companies, the government, and patient advocacy groups.

The promise of angiogenesis inhibitors

Avastin (generic name: bevacizumab) is a class of drug that attacks cancer by attacking its blood supply. Basically, Avastin targets a protein called vascular endothelial growth factor (VEGF), which is growth factor that stimulates the cells lining the blood vessels to undergo a process of angiogenesis, sprouting out new blood vessels in the direction of the cells secreting VEGF. Angiogenesis is a normal physiological function used during embryogenesis and pregnancy, wound healing, during the proliferative phase of the female menstrual cycle, and a variety of other processes. Diffusion of oxygen and nutrients through an aqueous medium is limited to around 1 mm, and malignant tumors get around this limitation by hijacking the normal process of angiogenesis by secreting large amounts of pro-angiogenic factors like VEGF in order to provide themselves with the oxygen and nutrients that they need to grow. During the 1990s, largely inspired by the work of one of my scientific heroes, Judah Folkman, scientists discovered strategies to target the process of angiogenesis to treat cancer. After spectacular results in mouse models of various cancers, however, as is all too often the case the use of angiogenesis inhibitors in humans produced far less dramatic results and, in some cases, didn’t work at all. However, for some cancers, such as colorectal cancer, combining Avastin with conventional chemotherapy has been effective. To those of us “in the biz” since the mid-1990s, this is not a revelation or surprise. In fact, I was involved with some of the first research demonstrating that combining anti-angiogenic therapy with radiation resulted in synergistic anti-tumor effects.

Over the last decade, Avastin has tended to be a magnet for controversy. The major reason that Avastin has attracted a lot of attention is that it’s so expensive (up to $100,000 a year per patient), and part of the reason it’s so expensive is that it is a protein rather than a small molecule. Basically, Avastin is an antibody directed against human VEGF. More specifically, it’s a humanized monoclonal antibody against VEGF. What that means is that the antibody has been modified to get rid of most of the mouse sequences that can provoke an immune reaction against the protein in humans. In any case, developing and producing such a molecule, which is a large protein, are not cheap. Even so, there has been considerable criticism of Genentech, the manufacturer of Avastin, for allegedly overpricing it. In addition, Genentech has pulled some highly dubious stunts to protect its profits with regard to some off-label uses of Avastin, for example, for macular degeneration.

Be that as it may, the number of uses of Avastin have expanded to a number of cancers, now including colorectal, lung, breast, and renal cell cancers. Perhaps the most controversial expansion occurred in 2008, when the FDA approved Avastin on what is known as the “fast track” for use in metastatic breast cancer. This allows certain promising drugs for life-threatening conditions to be granted in essence provisional approval quickly, so that patients can have access to them before the usual large phase III randomized, double-blind trials are completed. To understand why this decision was controversial and why it is now being reconsidered, a brief review of terminology is required.

How to evaluate an anticancer therapy

Cancer therapies are generally evaluated using a number of endpoints. The most commonly used include overall survival (OS) and progression-free survival (PFS). There are, of course, other endpoints related to survival that are measured, but these two are the most relevant for this discussion. Overall survival is what it sounds like: How long do patients survive their cancer after diagnosis? Period. It’s hard for an endpoint to be more objective than that: Either the patient is alive or he is dead. This number is usually expressed in terms of median survival, which is the period of time after which half of the patients under study are still alive and half have died. This includes all causes, not just cancer. If a patient with cancer under study dies of a heart attack that is not related to his cancer or his cancer treatment, that counts. Traditionally, OS has been the “gold standard” endpoint in measuring the efficacy of a cancer therapy, because the primary goal has been to prolong survival, the ideal case being prolonging survival to the point where it is indistinguishable from life expectancy if the patient never had cancer in the first place. PFS is survival without progression; i.e., how long the patient with cancer survives before his or her tumor starts measurably growing again or metastasizes. While PFS is often measured as well as OS, it’s generally considered less useful because it is entirely possible for a treatment to prolong PFS without prolonging OS. This sort of result can happen when the treatment is effective at shrinking a tumor or slowing its growth but its toxicities can result in death. Thus, PFS improves with no improvement in OS.

Which brings us to Avastin.

In 2008, that’s exactly the sort of data upon which the FDA’s fast track approval of Avastin was based. Back in 2005, the National Cancer Institute (NCI) announced that in a randomized trial Avastin combined with paclitaxel had increased PFS approximately 4 months over the use of paclitaxel alone. Eventually, by the time an FDA panel voted to approve Avastin in 2007, the E2100 study published in the New England Journal of Medicine had reported encouraging results that Avastin improved PFS in women with metastastic breast cancer. Unfortunately, E2100 also failed to find any benefit in terms of OS. Specifically, Paclitaxel plus Avastin significantly prolonged progression-free survival compared to paclitaxel alone (median, 11.8 vs. 5.9 months; hazard ratio for progression, 0.60; P<0.001). Adding Avastin to paclitaxel also increased the objective response rate (36.9% vs. 21.2%, P<0.001). Unfortunately, however, the overall survival rate (median, 26.7 vs. 25.2 months; hazard ratio, 0.88; P=0.16). Complications were also more frequent in the group receiving Avastin. Grade 3 or 4 hypertension (14.8% vs. 0.0%, P<0.001), proteinuria (3.6% vs. 0.0%, P<0.001), headache (2.2% vs. 0.0%, P=0.008), and cerebrovascular ischemia (1.9% vs. 0.0%, P=0.02), all complications common from antiangiogenic therapies, were more frequent in patients receiving paclitaxel plus Avastin. Infection was more common in patients receiving paclitaxel plus Avastin (9.3% vs. 2.9%, P<0.001).

These data were thin gruel indeed to approve Avastin for the indication of metastatic breast cancer, which the FDA did in February 2008. Although the increase in PFS was impressive, the lack of effect on OS was very disturbing, strongly suggesting that drug toxicity was "taking back" all the benefit the addition of the drug was providing against the cancer. Also, there were serious concerns about the E2100 trial. For example, there was 34% loss to follow up, 10% missing data, and discordance between radiological and clinical progression findings. The discordance between disease progression findings was of particular concern, given that it was the primary endpoint upon which Genentech's claim of efficacy was based.

Nonetheless, despite these concerns and despite the recommendation of the FDA's Oncologic Drugs Advisory Committee (ODAC) that Avastin not be approved, the FDA gave provisional approval to Genentech to market Avastin for metastatic breast cancer using the "fast track" program designed in the 1990s to speed the approval of promising drugs for life-threatening conditions, with the reasonable condition that Genentech had to perform additional studies to verify the results upon which the original approval had been based. At the time, there was a great deal of argument over whether this was a wise decision, particularly given how expensive Avastin is and the lack of evidence that it improved quality of life or overall survival. Indeed, I recall attending a talk at ASCO in June 2008 in which the approval of Avastin was strongly defended and the speaker (who it was now escapes me) attacked the use of OS as the basis upon which to approve drugs and argued that PFS should be enough, given the potential improvements in quality of life that can result from a longer period of time without tumor progression.

In the press at the time, Dr. Kathy Albain at Loyola University defended the approval of Avastin thusly:

Dr. Kathy Albain, a breast cancer specialist at Loyola University Medical Center in Maywood, Ill., polled colleagues and patients and found overwhelming support for approving drugs based on delaying tumor progression. It would be ideal to show that a drug also prolongs life, but that may not be realistic, she said. The reason is that when a woman’s cancer progresses, doctors change the drugs they use, hoping to slow the cancer. That dilutes any impact of the first drug — in this case Avastin.

Personally, although I can see where Dr. Albain is coming from, I’ve always been uneasy with this view. Yes, I can see the utility of a drug that slows tumor progression but does not prolong survival. However, I can see its usefulness in only one situation: There must also be good evidence that that drug also improves quality of life, evidence that was lacking for Avastin. In fact, the evidence that existed was suggestive of increased complications due to Avastin. Now, it may be a bit of a judgment call whether it is worth it to slow down tumor progression if there is no improvement in survival and there are drug-related complications, but I remained unenthusiastic about a drug that didn’t prolong OS but did appear to produce markedly more complications. How is that improving the quality of life of a cancer patient? I can also understand the argument, which was made in 2008, that perhaps Avastin benefits certain subsets of patients; we just don’t know who they are yet. My response to that would be that we should be doing the studies to identify those patients rather than exposing large numbers of women to the risk of the drug outside the auspices of clinical trials that could identify them.

Avastin does not live up to even its modest promise

In any case, the followup studies, known as the AVADO and RIBBON-1 trials were indeed performed, and the results published. The AVADO trial was a phase III randomized double-blind clinical trial (N=736 subjects) comparing docetaxel with docetaxel plus Avastin in women with stage IV HER2-negative breast cancer. Its results were less than impressive. While it did demonstrate a decrease in PFS due to the addition of Avastin, PFS did not improve anywhere near the five months it did in the E2100 trial; rather it improved from 8.2 months to 9.0 months, a mere 0.8 month or 24 days. As in E2100, there was no detectable effect on OS. There was, however, a troubling trend towards a shorter OS in women who received Avastin. Even though the difference was not statistically significant, women who did not receive Avastin survived a median of 31.9 months; those who received the lower dose survived a median of 30.8 months; and those who received the higher dose level of Avastin survived a median of 30.2 months. In contrast to E2100, in the AVADO study Avastin did not increase the toxicity of treatment measurably. In the discussion, the authors of the AVADO study concluded:

Taken together with the results of the E2100 study, these data suggest that the combination of bevacizumab with taxane chemotherapy should be considered as an option for the first-line treatment of HER2-negative MBC.

I’m nots sure why one would recommend this based on such results. There is a difference between statistically and clinically significant improvements in DFS. Just because a small measurement can be measured does not mean that a drug has meaningful effects.

In any case, the initial results of the RIBBON-1 trial were reported at the American Society of Clinical Oncology (ASCO) meeting last year and were similarly disappointing. In the trial, Avastin was tested in a randomized, double-blind study enrolling 1,237 patients. Oncologists could choose from capecitabine, taxane, or anthracycline-based chemotherapy, and patients would be randomized to that plus or minus Avastin. The results were that Avastin improved PFS by 2.9 months when added to capecitabine, and 1.2 months when added to anthracycline-based chemotherapy. Again, there was no improvement in OS in women receiving Avastin. In fact, it was these studies that led the FDA advisory panel to vote 12-1 to revoke FDA approval for Avastin for use in breast cancer:

An FDA advisory committee voted 12 to 1 on July 20 to withdraw Avastin’s authorization for advanced breast cancer based on two new studies that the advisers concluded had not shown that the drug extends life. Not only that, the committee concluded that the studies indicated the drug slowed tumor growth for even less time — perhaps as little as about a month. “The vast majority opinion of the committee was that the drug was not doing very much, and what it was doing was more than offset by the negative,” said Wyndham Wilson of the National Cancer Institute, who chaired the committee. Avastin can cause a variety of potentially serious side effects, including blood clots, bleeding and heart failure. “In our best judgment, we did not feel this drug was safe to give relative to its benefits,” Wilson said.

The recommendation has been praised by many cancer experts and by advocates for breast cancer patients.

“The FDA should never have approved Avastin for breast cancer to begin with,” said Fran Visco of the National Breast Cancer Coalition. “We don’t see evidence of benefit, but we do see evidence of harm.”

I tend to agree, although I must admit that back in 2008 I was ambivalent about the FDA approval of Avastin rather than necessarily opposed to it. Now, I’m more of the opinion that the FDA would be justified, based on science alone, in revoking Avastin’s approval, although I can also understand, if not agree, with a lot of the multitude of opinions in the breast cancer oncology world regarding the FDA’s decision. However, there is more than science at work, which is why where the rubber hits the road practicing science-based medicine in intersection with public policy can be so messy and contentious. Just practicing SBM alone is contentious enough, but add a biotech company trying to protect its profits and expand its market, regulatory agencies trying to fulfil their mandate in the case of ambiguous data, and advocacy organizations trying, well, to advocate for their members, and the whole debate can turn into a huge kerfuffle in a hurry. In this case, the FDA is scheduled to make a final determination in September. In the meantime, patients receiving Avastin are afraid, because if the FDA revokes its approval using Avastin for breast cancer will become and off-label use, and insurance companies will no longer pay for it.

Wingnut politics and burning stupid intrude

The whole controversy, where science, economics, politics, and dying cancer patients intersect in what are sometimes very ugly ways, is taking an even uglier turn, thanks to the entire healt insurance reform debate and the intrusion of partisan politics and the unrelenting opposition of Republicans to what they often derisively term “Obamacare.” The reason is that right wing bloggers have jumped on the bandwagon of criticizing the FDA’s decision on Avastin as “evidence” of the impending arrival of socialized medicine-style rationing (“Oh, noes, teh socializm!”), thanks, of course, to “Obamacare.” For example, Senator Dave Vitter (R-LA) characterized the decision thusly:

Reviving allegations of government death panels, Sen. David Vitter of Louisiana said Wednesday that an FDA advisory panel’s negative recommendation on a contested breast cancer drug amounts to rationing health care. “I shudder at the thought of a government panel assigning a value to a day of a person’s life,” Vitter said in a press release about the drug Avastin. “It is sickening to think that care would be withheld from a patient simply because their life is not deemed valuable enough.”

Several right wing and rightward-leaning blogs, such as Red State, Hot Air, and Big Government characterized the decision as the FDA being made complicit in “rationing” health care. Perhaps the most despicable post I’ve seen about AVastin is this one by Moe Lane at Red State, entitled Obamacare worth 17.5K dead women a year? Burning stupid does not even begin to describe the drippy turd consisting of utter demagoguery of the most vile and despicable sort. Avastin, even under the most optimistic scenario imaginable, only prolongs disease-free survival; it does not save lives of stage IV breast cancer patients, at least not as far as we can tell. It’s possible that it may save lives for other indications in breast cancer, such as inflammatory breast cancer that is still curable, but such results will await clinical trials. Also at Red State, Ed Morrissey resorted to exaggerating the benefits and downplaying the results of clinical trials that failed to find much, if any, benefit and did find potential evidence of harm, even going so far as to accuse the FDA thusly:

With the new ObamaCare regime in place, the issue of cost has now become openly part of the FDA process. This is a perversion of their mission, which is supposed to only involve product safety and effectiveness, not bean-counting. If Medicare doesn’t want to cover Avastin, that should be a separate issue handled by CMS and HHS. This strongly suggests that the FDA has become politicized to a degree where their recommendations lose credibility — a dangerous situation for consumers and providers alike.

The Wall Street Journal chimed in with a fallacy- and demagoguery-filled editorial whose deconstruction would be worthy of a separate post of its own if it weren’t already over two weeks old, entitled The Avastin Mugging, in which the anonymous editorialist harped on the earlier E2100 trial and cherry picked the very best numbers out of the AVADO and RIBBON-1 trial, completely ignoring the fact that OS was no different with Avastin and that it might even be worse. He or she made liberal use of straw men arguments and even misquoted findings, at one point even claiming, “At any rate, even the 31% reduction in the risk of disease progression or death is better than the status quo.” The problem is that none of the studies showed a 31% decrease in the risk of death–or any decrease in the risk of death for that matter. The editorialist also referred to to chemotherapy as “savagery” and asserted:

The Avastin mugging is really an attempt to undermine regulatory modernization like accelerated approval that offends the FDA’s institutional culture of control and delay. It is also meant to discourage innovations like Avastin that the political and medical left has decided are too costly, with damaging implications for the next generation of cancer drugs.

No, the reconsideration of decisions like the decision to approve Avastin is an absolutely necessary part of the fast track approval of drugs. If we are going to approve drugs on the basis of relatively scarce preliminary evidence with the quite reasonable requirement that more studies be done and the issue of FDA approval be revisited after those studies are completed, we have to expect that we will find in at least some cases where follow up studies will suggest that FDA approval wasn’t justified, that the drug isn’t particularly useful, and that FDA approval should be revoked. If that doesn’t happen from time to time, then why bother requiring additional studies? Just use fast track approval and forget it, which is, of course, what the pharmaceutical companies would very much like to see.

Although it may not be unreasonable to be concerned that the law may evolve to consider cost more strongly, as the law exists now and as has been reported in the Wall Street Journal and the AP, FDA advisory panels do not consider the costs of the drugs they are evaluating, only the evidence. Whether they should or not is certainly something we as a nation will have to decide. I don’t consider it at all unreasonable to ask whether it’s worth over $8,000 a month to produce a 1.2 month increase in DFS, no increase in OS, and an increased risk of complications such as bleeding, stroke, hypertension, and bowel perforation.

FDA approval, science-based medicine, and politics

So how will this all play out on September 17, which is when the FDA is expected to make its final determination. The FDA could decide to side with the panel recommendation to revoke approval for Avastin, ignore the recommendation, or chart a middle course, continuing approval and asking for still more studies. It wouldn’t surprise me if the FDA chose that last option. It is also important to remember that Avastin may well have uses in breast cancer other than in stage IV disease. One area where it shows promise is in the neoadjuvant therapy (therapy before surgery) of inflammatory breast cancer.

Whatever the FDA decides in this particular case, determining which drugs to approve for metastatic breast cancer (or nearly all metastatic solid malignancies) is a particular challenge to SBM because SBM cannot cure the disease. Consequently, the goals in treatment must be palliative; i.e., to relieve symptoms and prolong survival as much as possible. Sometimes these goals are in conflict. In the case of Avastin, this may well be the case. The drug improves PFS very modestly, but there must be a cost in terms of complications that decrease quality of life. The Avastin saga is a saga the likes of which we are probably going to see with increasing regularity.

Another lesson of the ongoing Avastin saga is about the very nature of science-based medicine itself. We have stated that we believe that medical care should be science-based. However, although medicine should be based on science, medicine itself can never be a pure science because so many non-science-based considerations impact on it. On the patient level, there is patient choice and how the doctor and patient weigh the patient’s personal situation and personal considerations in choosing from among science-based therapies. At the national level, considerations of cost, politics, and values cannot be separated from medical policy considerations. Science can tell us that Avastin does not prolong overall survival in breast cancer patients and that it only very modestly prolongs progression-free survival. It can tell us that even that modest increase in PFS comes at a cost of complications that prevent improved PFS from translating to improved OS. What science can’t tell us is whether that modest benefit is worth the cost. That’s a value judgment that must be made both at the level of society as a whole and at the level of each patient and physician.

With more research, I can only hope that science will soon be able to tell us which women with breast cancer are most likely to benefit the most from Avastin.

Comments

  1. #1 disgruntledphd
    September 3, 2010

    Great post. I cant remember who said it, but this stuff brings to mind a saying that if there were a commercial interest, even the law of gravity would be brought into disrepute.

  2. #2 Pablo
    September 3, 2010

    I tend to agree, although I must admit that back in 2008 I was ambivalent about the FDA approval of Avastin rather than necessarily opposed to it.

    Actually, I think the FDA kind of felt the same way. And in a way, I think what they did was appropriate.

    If you have something that is very PROMISING in lots of ways in a new area, I don’t think it is a bad idea to give the go ahead to try it even if the initial small trials might not have lived up to expectations. Still, the FDA says, give it a try. There is hope, and we’ll monitor the situation. A couple years later, when more data have come to light, they reevaluate the case and say, hey, it worked! Or, nope, it’s not happening. Don’t waste the money on a non-effective treatment.

    What makes David Vitter or other lawmakers experts on the effectiveness of anti-cancer drugs? What makes them better people to evaluate them than, for example, the folks on the ODAC? Oh, I know. Call it “ObamaCare” and make it a political issue.

    But in the end, I don’t fault the FDA for giving the drug preliminary approval. Given it’s promise, use it until it can be shown to actually fail, as opposed to denying patients the opportunity. Of course, when it has failed, pull the plug.

    Looks like the process worked.

  3. #3 Mu
    September 3, 2010

    I’m sure Ed Morrisey and co would have commented the other way around if the FDA panel ruled for Avastin; as waste of tax payer money for support something left wing. The FDA can do no right by them.
    BTW in While it did demonstrate a decrease in PFS due to the addition of Avastin, PFS did not improve anywhere near the five months it did in the E2100 trial you mean increase

  4. #4 jay.sweet
    September 3, 2010

    “I shudder at the thought of a government panel assigning a value to a day of a person’s life,

    So if it costs $300 billion to extend a 96-year-old’s life by one day, then this guy say “Go for it”, eh?

  5. #5 Pablo
    September 3, 2010
    “I shudder at the thought of a government panel assigning a value to a day of a person’s life,

    So if it costs $300 billion to extend a 96-year-old’s life by one day, then this guy say “Go for it”, eh?

    Yeah, this guy needs to talk to people in the field of medical ethics. This question is contemplated ALL THE TIME, how much is life worth?

    The last I heard, the general actions of our society put the price at about $50K for each year of life saved. That was why I was actually a little surprised to hear Avastin costs $100K a year. It’s a little steep, but I think the reason it is paid is because of the direness of it, and maybe because the value of younger lives is higher.

    But to suggest that there isn’t a value that is assigned to a person’s life is really idiotic. That is absolutely done already.

  6. #6 Ian
    September 3, 2010

    I work as a health economist – a position that is common in Canada and Europe, but not so much in the US. I find the accusation of ‘rationing’ to be a real stinker. There are a finite amount of available resources in the world, whether they’re funded by the private sector or the public fund.

    With government-sponsored health insurance, the decision becomes a balancing act around maximizing benefit while minimizing cost. After all, every dollar that is spent on treatment A is money that can’t be spent on treatment B. Is this “rationing”? Sure, absolutely.

    In the private sector, however, there exist the same limitations of available resources. In order to make insurance companies profitable, they kick people off the rosters for being too sick, deny coverage, and increase rates. That is no less an act of “rationing” than is done in the public sector.

    I am not at all sure why people think that insurance companies are going to do a better job of looking out for people than the government is. The evidence doesn’t support that idea.

    I’ve been opposed to Avastin for a few years, based on the so-so outcomes and the extreme cost. I want people to have quality care, and bevacizumab isn’t that yet. The decision was made on good evidence, and I’m glad for that.

  7. #7 jay.sweet
    September 3, 2010

    I may have to stop reading about anything the American Right has to say, just for my own personal health and happiness.

  8. #8 mj
    September 3, 2010

    Thanks for this post, Orac! Though I’m a big fan of your takedowns of quackery in all it’s guises, I relish balanced discussion of other serious medical topics. It’s nice to see that science-based medicine can always bring something to the table, i.e. reason.

  9. #9 Scott
    September 3, 2010

    The last I heard, the general actions of our society put the price at about $50K for each year of life saved.

    Another interesting figure that needs to be factored into calculations is how much it costs to save lives by spending money other ways (law enforcement, for instance, or even education). Depending on who does the calculation and how, it’s arguable that even $50k of medical care for a year of life is grossly overpaying. But it’s also arguable the other way. Which is why it’s such a hard question, that needs a lot more careful consideration than it usually gets.

  10. #10 Alison
    September 3, 2010

    Every time I read your blog I get smarter. Wonderful post.

    Just had to say, though, that whenever I hear Republicans hollering about rationing health care, it does serious damage to my irony meter.

  11. #11 Scott
    September 3, 2010

    In some cases those doing such hollering really mean rationing by the government which is a defensible position. But yes, it usually means the person in question just doesn’t get that health care is now, has always been, and cannot ever NOT be “rationed” via one mechanism or another. It’s simply an inevitability in the presence of limited resources.

    Too bad it drowns out the discussion of what’s the fairest and most effective way to do that rationing. You know, the one we really should be having instead.

  12. #12 Pablo
    September 3, 2010

    Another interesting figure that needs to be factored into calculations is how much it costs to save lives by spending money other ways (law enforcement, for instance, or even education). Depending on who does the calculation and how, it’s arguable that even $50k of medical care for a year of life is grossly overpaying.

    I’m not sure that the $50K number doesn’t already account for such things. I don’t know it doesn’t, at least.

    I know it absolutely DOES include things like medical screening, and not just treatment. IOW, how much are we willing to pay for prevention and early detection? You could screen everybody every year for everything, but it would be costly and even though you might catch a couple extras, the number you would save would be small comparatively. So that is why we now focus on risk factors so much, and chose a limit in those, and recommend that they are the ones we focus our resources on. Not because others can’t have the problem (in fact, given the large statistical sample, they certainly WILL have some), but because it isn’t cost efficient to scan everyone. In order to make that decision, though, we have to draw a cost line.

    See: mammography.

  13. #13 JRB
    September 3, 2010

    I was going to say something similar to what mj said up at #8 but I won’t bother since he already said it better.

    A really excellent article, even by the high standards I already expect from Orac.

  14. #14 medonc
    September 3, 2010

    You fail to mention that in 2008, the advisory panel actually voted against it, but the FDA approved it anyway. In 2008, as in 2010, Avastin should not have been approved. The data was clear then to me as a medical oncologist cynical of most drugs (You think Avastin is overhyped, there’s Herceptin, called “a cure” in the New England Journal of Medicine).

  15. #15 Scott
    September 3, 2010

    I’m not sure that the $50K number doesn’t already account for such things. I don’t know it doesn’t, at least.

    Some such calculations try, but most I’ve encountered have not. Such issues are why the numbers themselves are worthless without details, regardless of how they’re tossed around. (Not that I’m saying you tossed them around inappropriately – “I’d heard X which seemed inconsistent with Y and was surprised” is perfectly reasonable even without getting into the details of the source behind X.)

    Also, the recent mammography kerfluffle wasn’t considering cost (at least as I recall Orac’s posts on the matter). Though I thought it really should have, regardless of whether that would have provoked even more of a to-do.

  16. #16 rob
    September 3, 2010

    Orac, this is a bit off topic, but there is this article

    http://www.msnbc.msn.com/id/38990966/ns/technology_and_science-science/

    about anti-biotic use 2000 yrs ago. in beer.

    the ancients *were* wise!

  17. #17 Orac
    September 3, 2010

    You fail to mention that in 2008, the advisory panel actually voted against it, but the FDA approved it anyway.

    Your reading comprehension is lacking. From my post:

    Nonetheless, despite these concerns and despite the recommendation of the FDA’s Oncologic Drugs Advisory Committee (ODAC) that Avastin not be approved, the FDA gave provisional approval to Genentech to market Avastin for metastatic breast cancer using the “fast track” program designed in the 1990s to speed the approval of promising drugs for life-threatening conditions, with the reasonable condition that Genentech had to perform additional studies to verify the results upon which the original approval had been based.

  18. #18 neurondoc
    September 3, 2010

    When the FDA makes device approval decisions, they do not take the cost of treatment into account. The advisory panels may do that, but the final approval/non-approval decision is based on the scientific evidence, not economic information. I suspect that the same holds true for drugs. CMS’s decisions on whether to cover a treatment is a completely separate process and does involve cost-benefit analyses.

  19. #19 Ian
    September 3, 2010

    That $50k threshold is from a panel of health economists and was published almost 15 years ago. With inflation, it’s about $65k today. It’s a highly-criticized value (I share the criticism), because it came about years before some of the major advances in currently-used technology (the rise of MRI, CT, newer drug therapies).

    As far as the costs of screening go, there’s a lot of controversy about that due to something called ‘discounting’, referring to the fact that people are less willing to pay now for things that happen in the future (irrespective of inflation). Screening programs tend to find benefits way down the line, and are almost never truly cost-effective under classical definition. It’s a problem in the field.

    @Pablo – it was also approved with such a high price tag because patients really wanted it, and lobbied the government hard to get it.

  20. #20 acm
    September 3, 2010

    “What science can’t tell us is whether that modest benefit is worth the cost. That’s a value judgment that must be made both at the level of society as a whole and at the level of each patient and physician.”

    Where to draw the lines for what is a “reasonable cost” for the society to bear for an individual (and conversely for an individual to owe to society), and what rights individuals have in the medical choices they make as compared to the responsibility of their physicians to direct them in getting the best care for their patients?

    So often we forget that after practicing the best science and medicine, these considerations, among many others, are what ultimately makes the practice worthwhile.

    Thanks for meticulously going through the definitions, history, and multiple perspectives, and especially for ending with those sentences.

  21. #21 Chris
    September 3, 2010

    Ian:

    I work as a health economist – a position that is common in Canada and Europe,

    Are you going to give a talk at the Vancouver Skepticamp? It looks like you would have lots to say on the medical cost/alt med arena. Part of me wants to sneak up and see what one is like.

  22. #22 garry
    September 3, 2010

    maybe if you shook up some water really hard, that’d help.

  23. #23 Vicki
    September 3, 2010

    I also note that people who talk about how no price is too high to save a life back off fast if you suggest that we as a society should spend enough to feed everyone properly.

  24. #24 Chance Gearheart, AAS, NREMT-P
    September 3, 2010

    “I also note that people who talk about how no price is too high to save a life back off fast if you suggest that we as a society should spend enough to feed everyone properly.”

    Or if you point out that extension of life without quality of life is very cruel. People want to ignore that one too. Sometimes, there’s nothing that can be done. Until we get to a point, as a society, where we are technologically advanced enough to use nanotechnology to perform surgery at the cellular level on patients, you’re still going to have people dying despite recieving the best treatments. That doesn’t mean that science and medicine are flawed, it means that you did the best you could with what you had at the time. (Yes, I’m a futurist. Thanks for pointing that out.)

    It’s really amazing how organ donation, advanced directives for care, and hospice care all equal Death Panels to people.

  25. #25 Donna B.
    September 4, 2010

    As the reaction to the mammogram recommendations earlier indicated, a lot of people are simply not rational where boobs are concerned. I wonder if the reaction would have been the same if the effectiveness had been reversed with that shown in colon cancer and the FDA was considering “unapproval” for use there.

    Though I didn’t read the specific “wingnut” sites you provided on the topic of Avastin, I did read two others and participated in the comments sections on those. I was certainly not alone in providing the perspective that the drug didn’t turn out to work very well and that bad side effects negated at least part of the good. I got my information from the Genentech site.

    I also pointed out that was likely the best spin possible to put on the data about the drug’s effectiveness. And I was not alone in defending the panel’s recommendation. Yes, Virginia there are reasonable conservatives out there!

    One of three things happened: 1) Commenters that had previously agreed it was a harbinger of death panels came back and wrote that with the additional information they’d changed their minds; 2) Commenters usually up for a good argument disappeared; 3) A few fools stuck to their guns.

    What didn’t happen is that the bloggers didn’t update their posts, write a new post, or participate in the comments. (Both are bloggers known to regularly do both.) This was very disappointing and it certainly informs my estimation of their reliability.

  26. #26 Kristjan Wager
    September 4, 2010

    Great post Orac. Given the fact that I live outside the US, I hadn’t heard much about this before reading your post.

    In the private sector, however, there exist the same limitations of available resources. In order to make insurance companies profitable, they kick people off the rosters for being too sick, deny coverage, and increase rates. That is no less an act of “rationing” than is done in the public sector.

    Ian, it’s actually even worse in the private sector. The same limits exist, plus they have to make a profit (something which the public health sector doesn’t have to), which reduces the available resources even more. On top of that, you have to put in extra layers of administration, which is estimate to cost as much as 1/3 of the total health care cost (see my post on it here).

  27. #27 KODAK
    September 4, 2010

    Hmm, it looks like I’m having a dejavu.
    David Gorski at SBM tells exactly the same verbatim: http://www.sciencebasedmedicine.org/?p=6674 And it was posted on August, 30.
    So who is the author of this piece?

  28. #28 JS
    September 4, 2010

    This is a great post. I’m a regulator myself (disclaimer: I work on oncology products, but have no role in the Avastin review or decision-making process) and have been looking for somewhere to point friends and acquaintances to familiarize them with the Avastin issues. This is the place.

    Two small points:

    1. I think the post confuses the regulatory mechanisms of “Fast Track” and “Accelerated Approval.” The key thing here is Accelerated Approval: That’s the mechanism by which promising therapies can receive preliminary approval based on efficacy on a surrogate endpoint. Fast Track is a more general designation for products intended for unmet needs / serious and life-threatening conditions, and it entitles a sponsor to several benefits, including more handholding from FDA and rolling review. Fast Track products are often eligible for Accelerated Approval, but the two mechanisms aren’t identical. (For one thing, you can have Fast Track designation for products with no acceptable surrogate endpoint on which to base Accelerated Approval.)

    2. There is, to my mind, exactly one reasonable argument made by advocacy groups and some oncologists against revoking approval for Avastin: The “options” argument. It may sound like empty rhetoric to say that patients and practitioners should have options, when we know that this particular option doesn’t improve median survival. But clinical trials are generally only capable of measuring average effects in a population, and don’t rule out the possibility that the drug really does work for specific patients in specific circumstances. Before approving a product, we’d certainly like to know who those patients are and what those circumstances are, but that’s sometimes an unrealistic goal, and it’s likely that hypothetically useful products have never made it to market because their usefulness was more subtle than an overall effect on median survival.

    I don’t personally find this argument persuasive in the Avastin case, because the decision under consideration is whether to remove one of several indications; the product will still be available for clinical use for oncologists who want to incorporate it in their breast cancer arsenal (and for patients with plenty of cash). And, if there is a way to use Avastin to improve an existing treatment algorithm, hopefully it will trickle back up in the form of case reports, etc. But I think it’s a reasonable enough argument to address seriously.

  29. #29 Pablo
    September 4, 2010

    It may sound like empty rhetoric to say that patients and practitioners should have options, when we know that this particular option doesn’t improve median survival. But clinical trials are generally only capable of measuring average effects in a population, and don’t rule out the possibility that the drug really does work for specific patients in specific circumstances.

    As you note, if you actually knew who were the ones who would benefit, it would be great and you could use it.

    But the problem is, you can’t. We don’t know who is going to respond favorably to avistin, and who is going to actually respond unfavorably (not “no response” but actual adverse response).

    The thing to remember is that for something with no net benefit, as soon as you postulate that there is some subset of the crowd that has a real, positive benefit, then there also must be a subset that has a real, negative benefit.

    Unless you can identify which is which, your “options” are a 50/50 shot of providing benefit or killing them early.

  30. #30 JS
    September 4, 2010

    The thing to remember is that for something with no net benefit, as soon as you postulate that there is some subset of the crowd that has a real, positive benefit, then there also must be a subset that has a real, negative benefit.

    That’s more or less true, but the negative and positive benefits aren’t necessarily of the same value, even if they balance out mathematically in the median survival. You have to remember that medians are, by design, insensitive to extreme values.

    To take a contrived example, suppose that exactly 51% of all patients on or off Avastin die in exactly 32 months, but that after that, patients on Avastin live for 20 more years while patients off Avastin live for 20 more days. Those two populations have the same median survival, but Avastin is obviously effective.

    It’s a silly example for a number of reasons, not least because, you know, we’d notice something like that if it were happening. But it’s not unheard of for a drug to have no effect on the median survival, but to have a small but real effect on a “cure rate.” Indeed, there could be cases of very toxic treatments that kill a substantial proportion of patients outright, have no effect on the majority of the rest of the patients, but seem to give 10% or so of patients an extra 3-5 years of life. That might be a drug with a negative effect on median survival but which, nevertheless, could be seen as a valuable option in some circumstances. Such effects are extremely hard to detect statistically.

    We can’t go around approving products that have no evidence of efficacy just because the evidence might exist if we were hypothetically looking in the right place, and I wasn’t arguing otherwise. But a case like this, where the product is already approved with some tepid evidence on a surrogate and some reasonable biology, has some ambiguity, and it’s not crazy to propose adopting a more permissive attitude in situations where the patients in question are dying, pretty much one and all, from their disease. People with a terminal diagnosis often understandably have a different view of risk-benefit than those without, and that should be taken seriously.

    But, as I already said or implied, my own opinion is that striking the breast cancer indication is the appropriate public health decision here. I just would encourage everyone to understand all sides of the issue.

  31. #31 PRN
    September 4, 2010

    “patients with colorectal cancer and liver metastases used to have a median survival of around 6 months, but these days, with newer chemotherapeutic regimens like FOLFOX plus Avastin, median survival has”

    FOLFOX+Avastin are expensive rat droppings. Given all the side effects, rats with buboes…

    By 1996 the Japanese demonstrated that cimeditine with cheap, continuous, oral, low dose 5FU showed great survival improvement. That could cost under $1/day. By 2002, the Japanese (Masumoto, 2002) showed that ca 2/3 of stage III colorectal patients, those overexpressing sialyl Lewis ligands (e.g. CA 19-9, sLEX biomarkers), quadrupled survival with cimetidine at 10 yrs for those (~2/3, a large majoity) with above average CA 19-9 readings.

    Ca 1999, the Japanese began replacing oral 5FU with UFT, a DPD inhibited Tegafur (Tegafur alone is similar to Xeloda), the lowest side effect 5FU product on the world market, a generic under $5 per day. Vs Avastin plus FOLFOX / XELOX for $15,000-$20,000 per month. For 400 mg cimetidine, we pay under $1.50 per 100 tablets, for 25-50 days, for unsubsidized generics.

    The NIH and FDA must be hopelessly incompetent and/or corrupt to not have publicly funded studies and approved UFT here for such a common, deadly need by now. And Avastin is a “poor (performing) relation” to cimetidine’s selective VEGF inhibition and great immune modulation for a longer list of off-label uses.

    Some advanced breast cancers but not yet too highly disseminated, properly selected for stage and biomarkers, controlled for prolactin, estradiol, and estrone, added to a 3 component cocktail, might be a similar winner. It is very impressive at pathology and interview if a massive granulocyte attack nukes a lot of the invasive material.

  32. #32 John Thomson
    September 4, 2010

    “medonc”‘s comment at 14 caught my eye. Here in NZ we have (of course) a socialized medical system although patients are free to purchase treatment privately, as we call it here, if they wish. At our last general election, the National opposition at the time and who are now the government were high jacked by pressure groups over the issue of public funding of Herceptin. Although, thankfully, here we do not (yet) have the right wing screaming bullsh*t that you in the USA seem to have to deal with, Herceptin was funded fully because pressure groups (including one called Boobs for Herceptin, no less) indicated that our drug buying agency in NZ (Pharmac) – our state agency that funds pharmaceuticals which some of you might be interested at looking at – as being parsimonious, nay even sexist, by refusing to fund Herceptin for 12 month treatment instead of 9 weeks. We had the same repeated claims here about H being a “cure” Those of you who have more experience in oncology, esp Orac will be more expert about the science of this, but from the view of a community pharmacist in NZ the evidence (at least,at the time 2006-8) seemed to be on Pharmac’s side. The opposition promised that if they got into power they would fund Herceptin and on duly being elected (not just on this issue of course) set aside money for such. Presumably they were assisted in this by the manufacturers of Herceptin who of course are those (ahem) nice people who brought us Valium and Tamiflu. Pharmac was over-ruled and voila! My understanding is that the money has not all been taken up as the world of pharmaceutical science has moved on – but others here will be much more knowledgeable and informed.
    My post here is not to argue about the efficacy of Herceptin or not – but to illustrate that these sorts of medical issues that become politicized are world wide and not just confined to the USA. In addition, I think that most in NZ have realised that to fund one expensive thing means that lots of other less expensive things can’t be funded.
    I have some reservations about the transparency of some of the “deals” that Pharmac does, including a current one about the continued funding of “Lipitor” brand of atovastatin but ….. another time.
    Those of you who are interested in our drug buying agency – look at their extensive web site http//: pharmac.govt.nz

  33. #33 DLC
    September 4, 2010

    So, if I can summarize for the non-medical types:
    Avastin doesn’t seem to work very well on late stage breast cancer, or at least not as well as some hoped it would, but it may continue to be used in treatment due to political manipulations ?

  34. #34 Jay Gordon
    September 4, 2010

    Orac, excellent exposition of one of the most difficult issues in medicine. I understand the Avastin debate far better now. Thank you.

    Best,

    Jay

  35. #35 Kipper
    September 5, 2010

    The news about Avastin broke while I was visiting a relatively young relative who was taking the drug as part of a last-ditch effort to slow a breathtakingly fast recurrence of breast cancer, which ultimately claimed her life only a few weeks later.

    The choice to pursue aggressive treatment — and undertake its effects — despite poor odds of slowing the disease was hers, and I respect that even if it is not the choice I would have made for myself. But it was a hard, hard thing to hear that some part of the suffering before my very eyes, of my very own loved one, was the result of not a long-shot treatment with a faint glimmer of hope but a misfire that really could never have extended her life, even a bit.

    The FDA is doing the right thing. If a patient is going to make the choice to surrender some portion of the quality of her life on the hope of extending that life slightly, that gamble should be made on a treatment that is worth the trade-off. We have learned that Avastin is not that treatment for this application. Personally I wish this had come to light in April, but better late than never.

  36. #36 Elihphile
    September 5, 2010

    @John Thompson

    It’s exactly the same situation here in the UK. We have the prototypical drugs rationing agency NICE (see this article in the NYT for a good description) and it has been the target for relentless pressure from drug companies and patient advocacy groups.
    The dispute over the approval of Herceptin for the treatment of breast cancer was one of the most bitter examples and in the end the government backed down. Breast cancer in patricular seems to be more politicised and provoke more emotion than any other cancer and I’m not really sure why that is. Sarah Bosely wrote in the Guardian, about how most of the patient advocacy groups involved were backed by the pharmaceutical companies, who prefer to work cancer patients into a fervour about how the evil, evil goverment wants them to die, than have to reduce prices. There’s also the additional benefit of gaining lots of media coverage of their new “wonder drug” which in reality is often marginally effective and/or has serious side effects.
    Avastin was another drug that has been a source of major controversy, when it was rejected by NICE to treat advanced bowel cancer, but the government itself Ordinary link: has had to refer it to be assessed for use against age related macular degeneration because Roche preferred to create and market Lucentis, for the same use, at 100 times the price.

  37. #37 Calli Arcale
    September 7, 2010

    PRN @ 30: cimetidine as an anti-cancer agent? I’m intrigued. As a long-time sufferer of acid reflux disease (and with a daughter who was diagnosed with the same at age 6) I mostly know this drug as a treatment for chronic heartburn. (I haven’t taken it. My daughter uses ranitidine, another H2 blocker, and I have to go for the heavier-duty stuff — I’m on prescription-strength omeprazole.) Could you tell me more? I find it surprising that such an affect could have hidden all this time, given how popular cimetidine is for acid reflux and how many people suffer from that. It’s sound very interesting, and I’d love to hear more!

  38. #38 NP
    September 8, 2010

    Even if the FDA revokes the breast cancer indication, oncologists will still be able to prescribe it off-label, since it is still an efficacious agent for colorectal cancer, and may also be effective for glioblastoma multiforme and ovarian cancer. What might change is that few, if any, insurance companies will cover it for breast cancer.

  39. #39 NP
    September 8, 2010

    @PRN (#30)

    Orac is referring to the use of FOLFOX + Avastin for Stage IV colorectal cancer. The 2002 Matsumoto paper evaluated cimetidine in patients with earlier stage colorectal cancer. So you’re essentially comparing apples and oranges. A drug that is effective for localized cancer may not be effective for metastatic cancer, and vice versa.

  40. #40 califorme
    September 27, 2010

    I am in a Stage 3 Avastin trial for early Breast Cancer. I am in the Avastin arm. I wish I had known in June what I know today. I am not at all sure I would have chosen to be in this trial. I can only hope that there is a a use for Avastin with the type of cancer I have. But, only time will tell, and I don’t want to find out I went the wrong direction when I end up with a recurrence. Would I have had that recurrence had I not taken Avastin. That is a question I never want to face.

    There are women with stage 4 breast cancer that does respond well to Avastin. I agree with the author. They should be trying to figure out what these subtypes are and what these women have in common.

    I don’t know what to think when it comes to Avastin and breast cancer. Should it have gone the accelerated route? I wish it hadn’t, because it has resulted in an expansion int early breast cancer, and, from what I am reading I may have put myself at great risk of metastasis, especially since I have a particulary aggressive form of bc, which does tend to recur. Yet, I am sure that there are many women who have been helped who have few choices of drugs to treat their stage 4 cancer. At any rate, I wish my timing had been better. I did google and look into the information on Avastin, but the information was mostly positive at that time, with a few negatives. Plus, the oncologists at the group I go to were still excited about it’s use for early breast cancer.

    I will add one more thing. The politicization of this very complicated, damned if you do, damned if you don’t is disgusting. I don’t believe for a minute that these GOP politicians, Rush, and the Rightwing Blogs care one bit about me or any other breast cancer patients. They want to attack health care reform right at the time some provisions that benefit those with serious diseases or illnesses take affect.

  41. #41 PRN
    October 2, 2010

    There is some limited stage IV cancer data for cimetidine that is very promising for colorectal(Gan To Kagaku Ryoho. 2003 Oct;30(11):1794-7. Effect of cimetidine with chemotherapy on stage IV colorectal cancer) and ovarian cancer (MOLECULAR MEDICINE REPORTS 1:119-122, 2008 Prognostic implications of cimetidine on advanced serous ovarian carcinoma related to cyclooxygenase-2 expression). Since cimetidine is both a VEGF inbibitor and interferes with EGFR signaling as well as allowing dendritic cells to unleash a large scale granulocyte attack, one might consider the possiblity that cimetidine is an unsung hero, unadvertised, equal or better than Avastin and Erbitux combined, without the huge side effects. Lack of cost and side effects mean cimetidine, could theoretically, be used very long term.

  42. #42 Xplodyncow
    October 18, 2010

    Got this in my work e-mail today:

    NCCN Guidelines for Breast Cancer Updated; Bevacizumab Recommendation Affirmed

    The National Comprehensive Cancer Network® (NCCN®) recently updated the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Breast Cancer to affirm its recommendation regarding the use of bevacizumab (Avastin®, Genentech/Roche) in the treatment of metastatic breast cancer.

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