I've recently received some questions about the advantages and disadvantages of maintenance Avastin as a single agent for patients after completion of 6 cycles of first line chemo and avastin together for avastin-eligible patients. While this is generally considered to be a standard of care, many oncologists question whether it should be done. It's worth looking at how that standard came about and the strength of the evidence for it.

The trial that led to the FDA approval of avastin was called ECOG 4599 (NEJM abstract here), and in that trial 878 patients with previously untreated advanced NSCLC (limited to those with nonsquamous cancers, no brain metastases, no history of coughing up blood, and not on coumadin or other blood thinners) were randomized to carbo/taxol for six cycles or the same chemo with avastin 15 mg/kg every three weeks. For the patients who didn't show progression of their cancer after six cycles of chemo, the protocol had patients stop the chemo and continue on "maintenance" avastin every three weeks, until they showed evidence of progression of their disease. The trial design is as shown here:

(Click to enlarge)

Described in more detail elsewhere, the trial was positive, with a significantly higher response rate, progression-free survival, and overall survival seen in the recipients of chemo with avastin:

Based on the overall survival benefit, the FDA approved avastin in this particular population, to be given with carbo/taxol, then followed by maintenance avastin. How much of the benefit was from the chemo and Avastin combination, overlapping for 6 cycles, and how much of a contribution was from the maintenance avastin? We don't know. We just know that if you give avastin the way it was done on the ECOG trial, survival is improved, so that's the way most experts advocate doing it. We don't have trial results in which avastin is given with chemo but then there's no maintenance therapy.

For what it's worth, 53% of the patients on the trial had no progression of disease after 6 cycles of chemo/avastin and went on to receive maintenance avastin every three weeks. Half of those patients went on to receive more than 5 cycles of avastin before progressing. Importantly, some of the problematic side effects of the chemo/avastin combination, most notably the significant drops in blood counts and the associated risk of infection, pretty much went away when the chemo ended. Importantly, while we haven't seen responses of lung cancers (or really other cancers) to avastin as a single agent, we have seen patients who had prolonged lack of progression. In a smaller trial that led to the development of the larger ECOG trial (abstract here), patients who were assigned to a chemo alone arm could cross over to high-dose avastin (15 mg/kg IV every 3 weeks) after they progressed. Of the 32 patients on the chemo alone arm, 19 received avastin. They didn't show tumor shrinkage, but five of them went more than 6 months before showing progression, and one patient went twice as long on avastin alone without progression as he did on chemo as first line therapy before progressing (120 vs. 60 days). Here's a survival curve in which the horizontal lines at the bottom represent the length of time that cross-over patients remained on avastin without progression:

Overall, in both the smaller phase II and the larger phase III experience, some patients went a remarkably long time before progressing, far more than you'd expect with chemo alone, yet these patients stopped chemo after 6 cycles and were maintained on avastin alone.

But what we don't have is results of a trial in lung cancer in which patients received chemo/avastin and then no maintenance, to be compared with patients who went on to maintenance avastin (there was a European trial in colon cancer in which maintenance avastin was not included; the trial had less impressive results than expected, so some people extrapolate that the lack of maintenance avastin could be the reason). There are several potential downsides to ongoing avastin. First, there's the cost, which if you have a significant co-payment to make, can really add up. Then there's the safety risks, and while the decreased blood counts and infectious risks go down after chemo ends, risk of bleeding, high blood pressure, and other potentially problematic side effects can continue. And there's the open question of whether it would be better to stop avastin after the chemo and then restart it with a new chemo or tarceva once a patient moves to a new line of treatment. Does a cancer become completely resistant to avastin, or might avastin modify the activity of many different anti-cancer drugs it's given with? If the latter, it could be beneficial to continue it from one line of treatment to the next, the way oncologists routinely continue Herceptin for certain patients with breast cancer as they move from one chemo to another. But we have no data to answer these questions.

There are risks, there are costs, and there are potential benefits. Many oncologists are skeptical of the benefits of the maintenance avastin and think that the trial design for ECOG 4599 set up a convenient way to increase longer-term use of the very expensive avastin. It would be great to have a head-to-head trial of chemo/avastin without maintenance avastin to chemo/avastin followed by maintenance, but such a trial isn't coming anytime soon. Until then, the majority of experts are advocating treating patients the way they were treated in the ECOG trial. But it's possible that maintenance chemo doesn't add much, especially if it's restarted when a patient moves to their next line of therapy.

I'll let you know if we learn anything more. At this point, I'm continuing with avastin and not continuing the avastin after patients have progressed and are moving on to second-line therapy.