Almost one-third of newly diagnosed patients are over the age of Also, comorbidities that are common in the elderly might preclude the use of curative regimens that predispose some patients to life-threatening complications. These perceptions and observations have minimized the participation of elderly patients in the clinical trials that have shaped our current therapy of DLBCL, and have raised the question of how best to treat elderly patients with DLBCL.
We conclude by proposing an algorithm to help clinicians determine the optimal therapeutic strategy for treatment of DLBCL in very elderly patients, defined here as those over the age of 80 years. The International Prognostic Index IPI classifies patients over age 60 as elderly, but the IPI relied on clinical trials that included very few patients over the age of This, in turn, may deny them an opportunity for cure. The PS may complement a more comprehensive evaluation system. The comprehensive geriatric assessment CGA is a multidisciplinary evaluation of physical and psychological conditions that affect the choice of therapy for elderly patients with malignant disease.
The CGA evaluates the nutritional status, cognitive skills, and comorbidities of elderly patients. Several groups have adapted CGA-based approaches in making therapeutic decisions. Examples of such decisions include omitting anthracyclines in patients with cardiac dysfunction, or omitting vincristine in those with neuropathy.
Furthermore, using the CGA to help decide dose intensity and density of chemotherapy has resulted in excellent outcomes. Few trials were specifically designed for lymphoma patients. Nonetheless, these studies have shown that the domains evaluated in the CGA predict for morbidity and mortality in elderly cancer patients.
Rao et al demonstrated that elderly patients who were randomly assigned to inpatient geriatric assessment and management units experienced improved pain control and mental health scores. Tucci et al sought to determine whether the CGA could objectively identify elderly patients with DLBCL who could be effectively treated with anthracycline-based chemoimmunotherapy.
The outcomes of these patients were then analyzed according to both the treatment received and the results of the CGA. The response rates Among the unfit patients, 20 had received curative therapy and 22 palliative therapy.
Because the CGA can be time-consuming, requiring up to 45 minutes to conduct for each patient,[28,29] less cumbersome assessment scales have been utilized. Predictors of hematologic toxicity were the lymphocyte count, aspartate aminotransferase level, IADL score, lactate dehydrogenase LDH level, diastolic blood pressure, and the toxicity of the actual chemotherapy regimen.
Predictors of nonhematologic toxicity were the hemoglobin level, creatinine clearance, albumin level, self-rated health, ECOG-PS score, Mini-Mental State Examination score, Mini-Nutritional Assessment score, and the toxicity of the actual chemotherapy used. However, the patients studied were heterogeneous and received various chemotherapy regimens, and few had lymphoid malignancies.
In our opinion, decisions regarding treatment choice and goals in very elderly patients should rely more on these comprehensive predictive models than on the PS alone. However, prospective randomized studies in very elderly patients with DLBCL are needed to identify the most reliable system. Historically, the modified Charlson Comorbidity Index see Table 1 has been used to estimate risk of mortality, based on pre-existing morbid conditions.
Several studies have demonstrated how comorbid conditions adversely affect outcomes in patients with prostate, breast, and colon cancers, and suggest that similar trends are likely to be seen in lymphoma patients.
As patients age, organ dysfunction becomes more likely. Dysfunction may affect the kidneys, the liver, the heart, and bone marrow reserve. For example, platinum agents cannot safely be given in the presence of renal impairment.
The critical administration of anthracyclines to patients with DLBCL cannot be attempted when cardiac dysfunction is present. Peripheral neuropathy could preclude administration of vincristine at full doses. Most elderly patients receive several nonchemotherapy medications to control their chronic systemic illnesses, and these may impact hepatic and renal functions.
In fact, Marley et al showed that the decline in hematopoietic progenitor cell function may start at birth and continue throughout life. It is not surprising that studies have shown that advanced age is an independent risk factor for hospitalization and for the development of neutropenic fever. The difficulty of designing prospective studies in the population of very elderly patients with DLBCL has led researchers to analyze outcomes in the very elderly by conducting retrospective analyses.
Hasselblom et al performed a retrospective study of DLBCL patients median age, 73 years diagnosed in western Sweden between and Thieblemont et al retrospectively studied NHL patients over the age of 80 median age, 83 years to evaluate prognostic factors and outcomes. Median OS was 1. Dose density and intensity proved important in providing patients with better outcomes. Only half of the chemotherapy-treated patients were able to complete the full prescribed program.
Van de Schans et al retrospectively investigated data on patients with advanced-stage DLBCL, aged 75 years or older, who were diagnosed between and and were included in five regional population-based cancer registries in the Netherlands. Collectively, these studies demonstrate that very elderly patients are treated less frequently, experience more toxicity, and have less favorable outcomes, with worse OS and PFS, compared with younger patients. Importantly, progressive disease was a major cause of death in the very elderly.
However, these studies have significant limitations. Some studies reported on patients over age 65 while others suggested an age of 75 as a cutoff. Furthermore, not all studies evaluated these very elderly patients using CGA and other geriatric scales, since the data needed to comprehensively conduct these evaluations were missing due to the retrospective nature of these analyses.
Nonetheless, these trials paved the way for a few prospective phase II trials that have targeted this patient population. In the absence of prospective randomized studies, it is unclear whether one strategy is superior to another. Importantly, few prospective studies Table 2 have included exclusively patients older than 80 years, and all of these trials were small, phase II, single-institution studies. There were 58 deaths reported, 33 of which were secondary to lymphoma progression.
Others have also looked at reducing the intensity of CHOP. Importantly, despite the dose reduction, elderly patients still experienced more adverse events and toxicities, which were mainly hematologic. An alternative anthracycline-based program was investigated by Musolino et al when 23 patients 10 of whom were older than 80 years received dose-adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab DA-POCH-R.
The number of patients over the age of 80 in this cohort is too small to specifically form a conclusion regarding their outcomes, however. Non-anthracycline—based regimens were also studied. Three patients died of heart failure within 28 days of therapy.
Median OS was 10 months. Collectively, these studies demonstrate that anthracyclines can still be used in some patients and that other non-anthracycline—based regimens also have activity. Whether omitting anthracyclines in the very elderly has an adverse impact on their outcomes is yet to be seen and will depend on the results of future large prospective studies. Also, whether patients older than 80 years can be treated in a fashion similar to those between the ages of 70 and 80 remains unclear.
The first clinical decision facing physicians who treat very elderly patients with DLBCL is whether the goal of therapy should be palliative or curative. Some elderly patients present with a decline in their PS that is solely due to their lymphoma.
The German Lymphoma Study Group suggested treating patients who present with ECOG PS of 2 or higher with 7 days of prednisone and 1 mg of vincristine before the first chemotherapy cycle. After assessing organ function specifically cardiac ejection fraction , comorbidities, PS, and life expectancy, the physician should formulate an opinion as to whether an individual patient can tolerate full-intensity therapy.
If full-dose intensity and density are utilized, careful attention to supportive care measures is critical. It is our opinion that these patients should be seen frequently and be carefully monitored for side effects and adverse events. Frequent monitoring of cardiac function in those who receive anthracyclines is likely to minimize the chances of cardiac toxicity. We routinely reassess ejection fraction by performing an echocardiogram or a multigated acquisition MUGA scan after the 4 th cycle of anthracycline, although some have suggested more frequent monitoring.
In the very elderly, the optimal approach might be limited by the factors that have been discussed above. We favor using reduced doses of anthracyclines, as opposed to non-anthracycline—based programs-but always favor enrolling patients into prospective clinical trials when possible. Patients with advanced disease represent a true management challenge, since they require prolonged courses of systemic therapy.
R-CHOP has clearly demonstrated superiority to standard CHOP in all patient categories, but trials that looked at the very elderly have been limited, as discussed above. In the absence of clinical studies, we recommend a dose-reduced R-CHOP or a non-anthracycline—based program in those with compromised cardiac function or other comorbidity.
In fit patients with adequate cardiac reserve, full-dose R-CHOP is recommended with frequent response assessment so that unnecessary additional chemotherapy cycles can be withheld. Monitoring for other toxicities that can be encountered in elderly patients Table 3 is critical in order to optimize outcome. For some elderly patients who receive 5 days of prednisone as part of the CHOP regimen, stopping corticosteroids abruptly might cause significant fatigue and tiredness.
For these patients, we recommend a slow taper of the cortocosteroids to avoid withdrawal toxicity. Adding to the controversy is the fact that over half of patients who present with CNS relapse also have systemic disease.
Importantly, there was no significant benefit of CNS prophylaxis in patients with bone marrow involvement at diagnosis. These controversial findings, coupled with the potential toxicity of intrathecal therapy, lead us to suggest against routine use of prophylaxis.
In high-risk patients, systemic administration of intermediate-dose methotrexate seems to be as effective and less toxic and can be considered. Elderly patients with DLBCL are a rapidly growing population that represents a therapeutic challenge.
Guidelines on specifically how these patients should be treated are lacking. We recommend implementing the CGA as a measure to decide the best treatment strategy. The CGA should be followed by clear assessment of treatment goals, which requires open discussion with the elderly patient and his or her family. Regardless of treatment goals, we suggest preferential enrollment of elderly patients into clinical trials when available. When studies are not available and when a curative approach is deemed appropriate, we recommend R-CHOP at the full dose, with primary prophylaxis using G-CSF, antibiotics, and aggressive supportive measures in those who are found fit by the CGA Figure.
We suggest that patients who are deemed unfit or frail based on the CGA receive a pre-phase treatment with corticosteroids and vincristine. Those who do not improve despite pre-phase treatment are usually offered non-anthracycline—based therapy with palliative intent. Prospective clinical trials that are designed specifically for this patient population are in progress, and the results are eagerly awaited. Financial Disclosure: Dr.
Nabhan has received research grant support and honoraria from Genentech. The other authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. Mora O, Zucca E.
Management of elderly patients with hematological neoplasms. Ann Oncol. However, the disease remains the major cause of death. A recent review outlines the reasons for this. The treatment of older patients with NHL, and specifically the R-CHOP regimen, is associated with short-term toxicity: primarily hematologic toxicities with the increased risk of febrile neutropenia, cardiac toxicity and neurotoxicity. This regimen also results in long-term toxicity with secondary myelodysplasia or acute myeloblastic leukemia MDS or AML , functional and cognitive decline, and cardiomyotoxicity, leading to the loss of autonomy.
If the toxic death rate is important in all clinical trials, in older patients this rate is exacerbated. The prognostic factors associated with poor survival are discussed by Hamaker and are usually patient-related.
Soubeyran reviewed predictive factors for unacceptable toxicities such as early toxic death, loss of autonomy and unplanned hospitalization P Soubeyran, unpublished data, identified in 3 recent trials.
Marrow reserve is reduced in patients aged over 60 but their response to granulocyte-colony stimulating factor G-CSF is similar to that of younger patients. Another event causing early death is tumor lysis syndrome during the first cycle. This risk can be significantly reduced by a pre-phase treatment using steroids for one week with or without rituximab, 18 as confirmed at the Lymphoma Study Association LYSA meeting F Peyrade, unpublished data, Other concerns after treatment with R-CHOP are cardiovascular problems and late heart failure, diabetes and high sensitivity to neurotoxic drugs such as vincristine.
One should be very careful when monitoring heart rate, glycemia and searching for peripheral neuropathies. Older patients are also more sensitive to secondary tumors such as lung cancers and MDS. Pharmacokinetic data are dramatically lacking in very old patients and trials such as the GELA trial, with reduced doses of anthracycline leading to a similar CR rate and OS rate, suggest that older patients may have an increased half-life of drugs or drug metabolites.
Finally, as pointed out by Hamaker, most of the ongoing trials for elderly patients with hematologic malignancies are not addressing the right end points. As a scientific community, we must support patient-focused cancer care in RCT to further elucidate all these unresolved issues in order to significantly improve our knowledge of the optimal treatment of older patients. The treatment paradigm in aggressive NHL is, on the one hand, an effective conservative treatment that preserves quality of life and controls the disease, and on the other, an intensive potentially curative treatment with more toxicities.
A multidisciplinary approach using harmonized language is mandatory Table 3. Table 3. Unmet needs in the multidisciplinary approach of lymphoma patients. It is important to determine the risk-benefit ratio for each patient. We are entering an era in which the patient-physician relationship has evolved from paternalism to a face-to-face dialogue.
The patient is involved in the decision-making process and expresses his wishes regarding his quality of life. However, this patient involvement is conditioned by his ability to understand the risk-benefit ratio of the treatment, and to read and sign an informed consent. Today, the management of lymphoma in older patients is a multistep approach starting with the prognostic evaluation of the lymphoma and the potential severe adverse events induced by the treatment.
A second step evaluates the physical, physiological, cognitive and socio-economic status of the patient, raising the question of life expectancy with or without the tumor. Finally, and probably more importantly, the patient should express his expectations in terms of quality of life.
Unmet needs in the scientific approach to older patients with lymphoma. Article Information Vol. Pubmed Central. Published By. Ferrata Storti Foundation, Pavia, Italy. Print ISSN. Online ISSN. Article Usage.
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