Large B-cell non-Hodgkin’s lymphoma: Optimising therapy for elderly patients
Prof Pierre-Louis Soubeyran - Institut Bergonié, Regional Cancer Center, Bordeaux, France
Now, you’re looking at frail, elderly patients with diffuse large B-cell lymphoma, what specifically are the issues that you are raising with these patients who have an aggressive lymphoma?
Diffuse large B-cell lymphoma is indeed aggressive but it’s also curable with a standard regimen that is very much standard, that’s R-CHOP, a combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. The rate of cure is quite high but the problem with this regimen is this regimen has some toxicity that may be not affordable for frail patients. This regimen can kill in these patients from toxic death or induce so many toxicities that the patients don’t remain independent, for example.
So what did you do in the study that you’re now reporting?
The problem is in these patients R-CHOP is not feasible so we are searching for a regimen that may be the right choice in terms of efficacy-toxicity ratio. We are hesitating, I would say, with two strategies: one may be a very cautious strategy with omitting the doxorubicin or another strategy is to use a reduced dose of less toxic doxorubicin, in this case liposomal doxorubicin. So we proposed a randomised phase II between R-COP, very cautious, and R-COPY with 40mg/m2 of liposomal doxorubicin which is more aggressive but more risky, I would say.
How did you define your frailty in these elderly patients?
That’s a very important question that is not easy to answer indeed. If you are looking in the literature about the different ways of selecting the frail patients you find a lot of different approaches. Patients may be selected on geriatric grounds with a geriatric questionnaire, for example, or they may be selected on oncological or haematological grounds, that is select the feasibility of a treatment. This is what we have chosen so we have selected patients not able to receive R-CHOP according to a series of factors and to the opinion of the haematologist. This includes performance status so they had to have at least one of these factors to come and to be accrued in this trial: performance status 3; low creatinine clearance, below 50ml/min; low left ventricle or ejection fraction below 50%; high bilirubin, high serum bilirubin or several comorbidities that did preclude the use of R-CHOP, but this is how we selected. At the end, I would say that about 50% of the patients had performance status 3 and 50% had low creatinine clearance and the other factors were much lower indeed. This selected a population that is both of adverse prognosis in terms of lymphoma and also with adverse features in terms of geriatric assessment.
How many patients did you look at and what did you find?
We had 67 patients accrued, we had 47 in the R-COP arm, that’s the cautious regimen and 20 in the R-COPY arm because we had to stop the R-COPY arm, the most risky one, because of toxicity. We defined severe toxicity as either toxic death, such is evident, but also febrile neutropenia with the knowledge we approached in previous studies that febrile neutropenia is very much life threatening in these patients because half of them died in the previous studies most of the time. But indeed with the help of geriatric management that was added in this trial, also the geriatricians were allowed to help the medical oncologists or haematologists do their job, indeed febrile neutropenia didn’t kill patients, I would say. So we had to stop it because of febrile neutropenia, not because of toxic death. But at the end the observation is that indeed although the R-COPY arm is more risky it appears that more patients go to the end of treatment with response and toxicity is really higher but it’s very much manageable. So at the end probably, this is a randomised phase II, it’s not randomised phase III so the conclusion should be very much cautious, but I would say that R-COPY is probably more appropriate for these patients and probably to be proposed but still remains risky so you have to manage patients with the help of the geriatrician. For the R-COP probably it’s not the right choice right now but this is more cautious so we have to think to other approaches and probably a possible solution but it’s the place for research, clinical research, is to add to R-COP some targeted therapies at the place that we can use.
What should doctors be making of these cautious interpretations at this stage?
As much as possible they depend on clinical judgement but as much as possible you should prescribe some anthracycline containing regimen, some R-CHOP, R-CHOP derived regimen. You may use a less toxic anthracycline, likely for example; you may discuss about omitting some drugs with, for example vincristine, if the patient has a risk of falls, but I think that anthracycline up to now should be part of the regimen, that’s the first conclusion. Then, depending on factors that remain to be identified, you have to select for some patients that should not be treated curatively but select patients that should be treated palliatively, it may be best supportive care but it may be a very much reduced regimen which in some cases may be also efficient. So R-COP may be efficient in some patients but it should be restricted to really the patients with poor status, probably.
And the brief bottom line message, then, for doctors? What should they take home very briefly?
I became more thinking that anthracycline was something very much dangerous in these patients; it appears that anthracycline is not that dangerous if you perform correctly so that R-CHOP or R-CHOP reduced regimens should remain the standard for the management of the elderly with diffuse large B-cell lymphoma, even frail patients.
Thank you very much.