Chemo-immunotherapy dosing in older patients with diffuse large B-cell lymphoma: is this how we should treat our parents?

Despite acceptance that rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is the optimal known therapy for diffuse large B-cell lymphoma, delivering R-CHOP in elderly patients remains a common and significant challenge. Twentieth century studies suggested that the oldest of older patients received lower dose intensities of CHOP and experienced inferior survival. New data presented in this issue compare detailed dosing information with R-CHOP in patients over age 70 with that in younger patients and analyze disease-specific clinical outcomes. This information coupled with future studies may help attain personalized dosing strategies for older patients.

Delivery of R-CHOP in elderly patients with diffuse large B-cell lymphoma is a significant issue of public health. Prospective studies from research centers have left little debate that R-CHOP is the best known therapy for the disease in fit elderly patients [1,2]. There is a long-held presumption with partial supporting evidence from the CHOP literature that more intense chemotherapy is better than less [3,4]. Studies of Medicare billing records suggest that a troubling fraction of older people do not receive R-CHOP – presumably due to concerns on behalf of patients or physicians that full-dose R-CHOP would be too toxic [5,6]. Would that change if lower doses of R-CHOP were found to be effective? Would that change if we understood better the reasons why older patients do not receive R-CHOP? The untreated population is elusive to study because, at least in the United States, they do not often attend centers generating most of the published literature. Perhaps we can achieve partial insight into why some older patients receive no R-CHOP by studying those who receive “less.” The article in this issue by Huntington et al. provides that opportunity [7].

Huntington and colleagues retrospectively interrogated the medical records of Vanderbilt patients completing R-CHOP for diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma grade III. They compared 37 patients over age 70 with 65 subjects under age 70, with an emphasis on quantitative chemotherapy delivery and experienced toxicities. The former objective is quite achievable, although the latter is likely weakened by the retrospective approach and the reliance of the Vanderbilt records on experienced toxicities reported from home. As acknowledged by the authors, this patient population is not likely representative of the general population, but at least there is internal age diversity for comparisons.

Their careful study of dosing found that 16% of the older cohort received less than 70% relative dose intensity (RDI) of doxorubicin and cyclophosphamide, compared to only 3% of the younger cohort, despite the fact that the older cohort was relatively fit, with only 19% having a performance score of >1. The lower RDI seemingly stems from more dose reduction, as dose delays and mean number of cycles were not clearly dissimilar between the two age groupings. Age greater than 70, higher morbidity score and lower body surface area (BSA) were associated with greater odds of dose reduction when all patients were analyzed, but no regression analysis restricted to the older cohort is presented. Hospitalizations and neuropathy were more common in the elderly, while emesis was less common. Finally – and perhaps interestingly – the authors observe that despite a higher frequency of dose reductions in the older patients, there was no appreciable difference in complete response rate or failure-free survival in this small number of patients.

This article starts to address two important questions for R-CHOP dosing in the elderly. First, what are dosing realities in patients over age 70 who actually attempt therapy? Huntington provides a very nice, detailed description of how much chemotherapy was delivered in older patients at Vanderbilt. Although confirming that even this relatively fit population of older patients has a higher frequency of reduced RDI, the analysis does not allow an understanding of whom within the older population is at highest risk for incomplete dosing. Did these patients start at optimal dosing and then experience a reduction because of toxicities? Did the subjects who died of treatment-related complications have poorer performance status or identified comorbidities?

Second, how important is it to give full dose intensity in the elderly? Although some studies suggest that full-dose chemotherapy in the very elderly is not necessary to achieve satisfactory results, most comparative effectiveness studies find an association between decreased dose intensity and survival [8–11]. These studies generally do not take a precise look at lymphoma-specific survival, and of course the addition of immunotherapy could result in different conclusions from those of 20th century studies. Huntington’s study notably failed to find a difference in response rates or progression-free survival between the two age groups, although a more instructive analysis might include comparing outcomes in higher versus lower RDI in the elderly cohort.

How has this taken us forward? The authors provide strong evidence that age remains a factor in chemotherapy delivery for this potentially curable disease, and provide an important observation with detailed response data in the immuno-chemotherapy era that challenges the paradigm that this is detrimental. Their conclusion that very elderly patients with no comorbidities should be started at full-dose intensity therapy is not directly supported by the results of their study, and in fact is brought into question by the two observed treatment-related fatalities and the observation that the older cohort – with a lower RDI – did not have observably inferior disease-specific outcomes.

Future studies, as called for by the authors, should seek baseline clinical, serologic or genetic factors within the elderly population that allow for prediction of therapy tolerance so that “personalized dosing” can begin appropriately [12]. Prospective studies, or larger comparative effectiveness research designs, should attempt to clarify the importance of achieving full dose intensity in the elderly with careful focus on disease-specific outcomes.

Potential conflict of interest

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