Finally, after the usual quota of snafus, I am settling down in my new home in Columbia, Maryland. There are still a few unpacked cardboard boxes lurking around but the major headache of moving hearth and home is now behind me.
I hope you enjoyed your break from reading Updates about our favorite “good” cancer, because the next few weeks are going to be busy ones for you and me. The American Society of Clinical Oncology (ASCO) 2010 abstracts have been published online and there are a lot of interesting CLL papers presented. Here is the first one of the bunch that I will be reviewing for you.
FC versus FCR
It is official. There is no further justification for treating late stage CLL patients needing therapy with FC (fludarabine + cyclophosphamide), when FC+R is so much better. We are not talking about just response rates that researchers seem to find so fascinating. What impresses me is how long the remissions last (progression free survival or PFS) and how long patients live (overall survival OS) after completing therapy. Judging by both of these crucial metrics, patients do much better when treated with FC+R instead of just FC.
As you would expect, this important paper comes from M. D. Anderson, the center that has done the most work to establish FCR as the present day gold standard for treating CLL (both as front-line therapy as well as second line or salvage therapy). The full length ASCO abstract is given below for your convenience.
You should be aware this is not a double arm study done with patients randomly divided into the two protocols. Basically, the researchers compared their FCR clinical trial results with historical data available about how patients respond to FC. There can be inherent apples versus oranges problems associated with such comparisons. But it is the best we have, for now. The differences in response results are striking enough to wash over any minor discrepancies between the two groups.
The researchers point out that earlier studies have shown the advantage of FCR over FC in early stage and untreated patients. This study looks at late stage (Rai Stage III or IV) untreated patients. The two groups of patients are reasonably well matched, more or less. That makes the job of comparing the results a little bit easier.
Longer Lives, Longer Remissions
Please pay particular attention to the last four lines of the table at the end. The overall response rate was significantly higher with FCR (92% versus 79%). But even more telling, the percentage of patients getting the coveted “CR” (complete response) was more than double with FCR (66% versus 29%). That is a huge difference, and if you happen to be interested in statistical significance, the p value of 0.000 confirms it is indeed very, very significant.
But for patients and their families, what really matter is how long the hard won remission lasts, how long the patient lives after completing therapy. In the case of FCR, the median length of remission was 79 months, compared to 36 months for FC!! For a change, we have overall survival numbers too. Patients undergoing FCR therapy lived for median of 120 months (put in different words, half the patients lived more than 10 years). Compare that to the fact that the median overall survival was only 55 months for those undergoing FC therapy!! That is a whopping difference of 65 months or just under 5 ½ years!
Comparison of fludarabine (F) plus cyclophosphamide (C) versus FC plus rituximab (R) in previously untreated Rai stage III/IV chronic lymphocytic leukemia (CLL).
J Clin Oncol 28:7s, 2010 (suppl; abstr 6519)
Abstract No: 6519
Author(s): S. A. Parikh, W. G. Wierda, X. Badoux, S. M. O’Brien, A. Ferrajoli, S. Faderl, J. A. Burger, S. Lerner, H. Kantarjian, M. J. Keating; University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: A phase III study showed that treatment with FCR was associated with significant improvement in progression-free survival (PFS) and overall survival (OS) compared to FC in previously untreated patients (pts) with CLL. This benefit was clearly demonstrated for pts with Binet stage A and B; but was less clear for pts with Binet C disease. We report a historic comparison of pts with Rai III/IV CLL treated with front-line FC versus FCR at our institution. Methods: FC consisted of F: 30 mg/m2 and C: 300 mg/m2 on D1-3 ± GM-CSF 275 mg/m2 daily, every 4 weeks for 6 courses. FCR consisted of F: 25 mg/m2 and C: 250 mg/m2 on D2-4; R: 375 mg/m2 on D1 (for the first course) and 500 mg/m2 for courses 2-6, every 4 weeks for 6 courses. Indications for treatment and response assessment were according to 1996 NCI-WG guidelines for both groups. Results: Of 93 pts treated with FC, 38 (41%) had Rai III/IV CLL; and of 300 pts treated with FCR, 102 (34%) had Rai III/IV CLL. Baseline characteristics, complete remission (CR), overall response rate (ORR), PFS and OS of Rai III/IV CLL pts are shown (Table). There was a higher incidence of grade 3/4 neutropenia and thrombocytopenia with FCR compared to FC; however there was no significant difference in infectious complications between the two treatments. Conclusions: In pts with previously untreated Rai III/IV CLL, FCR was associated with significantly improved response rates and survival compared to historic patients treated with FC.
Don’t Get Stuck With the Short End of the Pointy Stick!
You see what I mean by saying there can be no further justification for using FC as frontline therapy in late stage patients needing therapy. FCR is clearly better, and everything I know about these two protocols says there is no additional increase in toxicity by the addition of Rituxan to F+C.
So, why do some patients still get treated with FC, even after the jury is in with the verdict? I can think of two reasons. The first reason has to do with money. Rituxan costs significant money. FC is a whole lot cheaper than FCR. I don’t want to get into politics of health-care or who pays for stuff – we follow a strict policy of no political discussions on this website. But this much is obvious to all of us – money makes the world go round and costs do matter. Eventually, consumers pay for everything, one way or another, through our taxes and our insurance policies.
The second reason why FC may be recommended is even more heartbreaking. Crucial information like this takes time to percolate down to the level of the local oncologists. No researcher at M. D. Anderson or any of the other expert centers would dream of using FC as front-line therapy any longer, not when FCR is available. But what about the strip-mall oncologists (you know, the guy who hangs out his shingle next door to the hair salon) who does not bother to attend ASH / ASCO, does not take the time to read articles in professional journals, the guys who make no effort to keep up to speed with new developments? Back when he went to medical school, FC was the standard of therapy and as far as he is concerned, what was good enough 20 years ago is good enough for today’s patients (Not!)
Don’t get me wrong. There are plenty of hard working local oncologists who make every effort to keep up with things and I take my hat off to these good professionals. I am talking about the ones that do not make this effort. If you have no choice but to be treated by such an oncologist, your protection lies in keeping up the learning curve yourself, so that you can educate your physician. I think of this as CME (Continuing Medical Education) from the bottom up, patients bringing their physicians up the learning curve when it becomes necessary.
If you are a late stage CLL patient looking at your therapy options and your guy tells you the best option is FC, please tell him you would rather have FCR. Or the FC+O combination, where the new monoclonal antibody ofatumumab (also known as Arzerra, Humax-cd20) replaces Rituxan. While ofatumumab has far less track record than Rituxan and that is an issue worth remembering, there are some reasons for hoping that being a fully humanized antibody, ofatumumab may have fewer adverse effects and may have higher efficacy. As you probably know, Rituxan has snippets of mouse protein in it and some patients develop hypersensitivity to it. My husband PC was one of them. Back then we had to go to the UK to get access to ofatumumab. Now that the FDA has approved it, patients can get access to it in the comfort of their home towns.