An End to "Watch & Wait"?

"Watch & Wait" has got to be one of the stupidest phrases in medical history, guaranteed to provoke anxiety as much as any other response. The rationale is the same for all indolent lymphomas, like follicular lymphoma: decades ago, studies demonstrated that chemotherapy would have more or less the same effect whether it was started immediately upon diagnosis, or delayed until a later date when troubling symptoms developed or tumours grew to an unacceptable size. Since then, every new therapy is evaluated as a potential end to the watch and wait era.

Which brings us to Rituxan (rituximab), certainly the most important lymphoma drug of the last decade. One of the most important studies to emerge from the ASH conference in December 2010, judging from the flourish of congratulatory press coverage, is one claiming that rituximab is better with immediate, up-front treatment. So far, I'm just not buying it.


The study new study randomized several hundred patients into two main arms: the traditional watch and wait, and rituximab maintenance. Rituximab maintenance is a drawn-out regimen commonly used after induction chemotherapy, in which patients receive one dose every two or three months for two years. The study found that the patients who received rituximab maintenance upfront were able to delay, by an average of 2.5 years, having to take chemotherapy.

The fact that this study even exists is a result of rituximab's success – and that's what makes it a problem. With indolent lymphomas, scientists can no longer conduct full-length studies measuring overall survival of cancer patients, because we live too long (on average, 10-12 years and increasing). So they turn to intermediate measures, like disease progression and time to new treatment.

What this new study skips over, though, is that in this context rituximab maintenance IS treatment. Delaying additional treatment by 2.5 years is well and good, but it seems at least very possible that this approach will actually make the next round of drug therapy less effective. If the cancer progresses following rituximab maintenance, it is more likely to be resistant to rituximab (the technical term is "refractory" to rituximab). So rituximab won't be as useful in the next chemotherapy regimen. Make no mistake: rituximab maintenance therapy is still therapy. We already have rituximab monotherapy in our arsenal for older and less fit patients; rituximab maintenance is just an even lighter variant.

Is extending watch and wait by an average of 2.5 years really a good idea if the cost is reduced effectiveness of full therapy once the latter actually becomes necessary? This, of course, will require an additional study. If the team responsible for the current project is responsible, that's where they've already headed in their current work, but I don't see any indication of that in the press.