When Can R-CHOP Not Be Used in an Elderly Patient?

Latta and colleagues have written a nice review of the current data on diffuse large B-cell lymphoma (DLBCL) in very elderly patients. The only problem is that we do not have a lot of good data on such patients. In their review, the authors base arguments on studies done in elderly patients, and the conclusions they draw may not hold for very elderly patients. While they may have correctly defined “elderly patients,” they have not given a definition of “very elderly patients.” They correctly make the point that age alone is not a good criterion for defining “elderly” or “very elderly”; rather, what is important is the capacity to tolerate a curative treatment for DLBCL. And this capacity is defined by the presence of other diseases that alter the function of the various bodily organs. Young patients do not have disease or have only one disease (although that may be severe). Around the age of 60 years, other diseases appear and the number of these diseases increases with a person’s calendar age. Elderly patients may have several such comorbidities, but their impact on normal life is minimal-and so most of these patients may receive a curative treatment such as R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone). Very elderly patients have more comorbidities with greater impact, with the result that some of their vital organs exhibit functional deficiency.

There are very few studies that look at the cutoff that defines the passage from elderly to very elderly; this cutoff can probably be defined in terms of the nature of the patient’s disease and the therapeutic options that realistically can be used to treat it. The best definition of when a patient should be considered “very elderly” is probably the point at which the physician must change from standard treatment to adapted treatment because of functional deficiencies. Clearly, this definition is dependent on the disease and treatment objectives. A geriatric assessment may help with this determination, as suggested by Latta et al, but it will not be specific for the disease in question and also must be interpreted in light of the objectives of treatment. These are probably among the reasons few physicians do such an assessment in elderly lymphoma patients before initiating treatment.[1] In patients with DLBCL, the relatively involved geriatric assessment may be replaced by the serum albumin level at diagnosis. Patients with a low albumin level have a high risk of complications and death during the first cycles of treatment.[2]

DLBCL is the most common lymphoma in elderly and very elderly patients.[3,4] Most of the other lymphomas, except for Burkitt lymphoma and peripheral T-cell lymphoma, are clinically indolent and do not need treatment-or a single-drug treatment will result in a stabilizing disease course in these very elderly patients. Burkitt lymphoma needs more aggressive therapy that is rarely possible in very elderly patients; thus the outcome is poor. DLBCL can be cured with standard R-CHOP even in elderly patients.[5] So, the question that is really important is: when can R-CHOP not be used in a given patient?

Currently, as described by Latta et al, there is no good study that will allow one to give a definitive response to this question. Existing studies have defined inclusion criteria as older than 80 years or older than 75 years.

Another related question regarding DLBCL patients is: when will adapted R-CHOP chemotherapy produce a good outcome without too much toxicity? The objective of treatment in young patients with DLBCL is cure. Cure is also the main objective for elderly patients. In Europe, expected survival for a person aged 80 years who does not have DLBCL is 7 to 9 years; this decreases regularly as age increases, with the expected survival for a person aged 85 years being 5 to 6 years, and 3 years or less for a person over 90 years of age. If treatment does not cure the DLBCL, relapse will occur within 1 or 2 years following therapy, and death from lymphoma less than a year after that, with a total survival of less than 2 or 3 years. So clearly, for “young very elderly” DLBCL patients (aged 75 to 85 years), cure must be the main objective of treatment. For patients of more advanced age, complete clinical response might be considered an acceptable objective. In any case, the physician must discuss the situation with his or her patient and choose the best objective on the basis of patient expectations and altered functional status resulting from comorbidities.

Good phase II studies have shown that adapted R-CHOP is associated with good long-term outcomes in DLBCL patients.[6,7] There are no data showing that another regimen will produce the same outcome but with less toxicity. Thus, these other regimens must be reserved for patients with altered organ function that does not allow the use of R-CHOP-ie, for those with severe cardiac dysfunction. If the cardiac dysfunction is not major, it may be in part the result of lymphoma evolution and may improve with response to adapted R-CHOP chemotherapy in the first cycles. In such a case, cardiac function must be re-evaluated after one or two cycles. When cardiac function is too altered to use doxorubicin, a combination of rituximab plus other agents (such as ifosfamide, etoposide, cyclophosphamide, or bendamustine [Treanda]) can replace R-CHOP, but such combinations are usually associated with poorer results.[1]

Once these very elderly patients have relapsed, a second complete response is possible only in those few patients with a limited number of comorbidities and a long-lived response to first-line treatment. For the rest, palliative treatment is the best option, since median survival after relapse is around 3 months.[5]

In conclusion, very elderly DLBCL patients are defined as those with altered organ function secondary to the presence of comorbidities. The majority of these need to be treated with the intent of achieving a complete response and a cure. With such an approach, these patients will have a quality of life comparable to their quality of life before the lymphoma diagnosis and will die from something other than lymphoma or its treatment. A palliative intent for first treatment must be reserved for only those patients with major organ dysfunction.

Financial Disclosure:Dr. Coiffier serves on the advisory boards of Roche and Celgene.

References:

REFERENCES

1. Sarkozy C, Coiffier B. Diffuse large B-cell lymphoma in the elderly: a review of potential difficulties. Clin Cancer Res. 2013; in press.

2. Peyrade F, Gastaud L, Re D, et al. Treatment decisions for elderly patients with haematological malignancies: a dilemma. Lancet Oncol. 2012;13:e344-52.

3. Thieblemont C, Grossoeuvre A, Houot R, et al. Non-Hodgkin’s lymphoma in very elderly patients over 80 years. A descriptive analysis of clinical presentation and outcome. Ann Oncol. 2008;19:774-9.

4. Thieblemont C, Coiffier B. Lymphoma in older patients. J Clin Oncol. 2007;25:1916-23.

5. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116:2040-5.

6. Peyrade F, Jardin F, Thieblemont C, et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12:460-8.

7. Hasselblom S, Stenson M, Werlenius O, et al. Improved outcome for very elderly patients with diffuse large B-cell lymphoma in the immunochemotherapy era. Leuk Lymphoma. 2012;53:394-9.