Practical Questions in the Very Elderly
What are the goals of therapy?
The first clinical decision facing physicians who treat very elderly patients with DLBCL is whether the goal of therapy should be palliative or curative. Anthracycline-based chemo-immunotherapy programs have provided DLBCL patients with cure rates exceeding 50% depending on their pre-defined risk-stratification profile.[4] In younger patients, regimens that omitted anthracyclines compromised cure,[4] and full-dose intensity is considered to optimize chances for cure.
Deciding on the goals of therapy requires a full assessment of the patient’s physical condition and an accurate estimate of the life expectancy, as recent analysis has suggested that the overall expectation of life at birth is 77.7 years, with some variability between races and sexes.[57,58] If comorbidities and geriatric assessment suggest that patients cannot tolerate curative regimens, reduced-dose standard chemotherapy or non-anthracycline regimens may still be appropriate with a palliative intent. Some elderly patients present with a decline in their PS that is solely due to their lymphoma. In such instances, starting with a pre-phase treatment might be appropriate to improve patients’ functional status. The German Lymphoma Study Group suggested treating patients who present with ECOG PS of 2 or higher with 7 days of prednisone(Drug information on prednisone) and 1 mg of vincristine before the first chemotherapy cycle.[59] This might improve the patients’ PS and allow for safer chemotherapy administration. If a patient’s status improves, goals of therapy can then be modified.
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 4th cycle of anthracycline, although some have suggested more frequent monitoring.[60,61]
What is the best treatment for very elderly patients with DLBCL?
Generally, managing patients with DLBCL depends on the disease stage. In the very elderly, the optimal approach might be limited by the factors that have been discussed above. Historically, DLBCL patients with stage I or II disease have been managed with an abbreviated course of chemoimmunotherapy using R-CHOP, followed by involved-field radiation.[62] The debate over whether radiotherapy remains an essential part of treatment was ignited by long-term follow-up data from a randomized study showing late relapses in those who received radiation.[63,64] This debate was rekindled when Bonnet et al demonstrated that adding radiation to CHOP chemotherapy provided no survival benefit in DLBCL patients with good-risk limited-stage disease.[65] However, very elderly patients might have a limited life expectancy, in which case less cytotoxic therapy would be advisable to minimize the toxicity and adverse events associated with more chemotherapy cycles. If R-CHOP is judged to be overly toxic, alternative chemotherapy programs, as discussed previously, or alternative dosing schedules of R-CHOP can be implemented. In the absence of clear guidelines, the decision of how to proceed is usually left to the physician’s discretion. 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. Older studies that used radiation alone in DLBCL patients provided elderly patients with a cause-specific survival of 31% to 57% at 10 years.[66] When radiotherapy is used, doses of 30 Gy are usually utilized.[67]
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.[15,68-70] Prior to the widespread use of rituximab(Drug information on rituximab), studies that looked at the effect of adding etoposide(Drug information on etoposide) to standard CHOP showed improved outcomes in elderly patients aged 60 to 80 years.[59] While the German Lymphoma Study Group advocates R-CHOP given in a dose-dense fashion,[40] studies that compared dose-dense R-CHOP to standard R-CHOP failed to show improvement in outcomes with the dose-dense regimen.[71,72] We encourage the very elderly to be enrolled in prospective clinical trials specifically designed for this patient population. 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.
What about supportive care and CNS prophylaxis?
Current guidelines recommend primary prophylaxis with filgrastim(Drug information on filgrastim) (granulocyte colony-stimulating factor [G-CSF]) or pegfilgrastim (Neulasta) when the incidence of neutropenic fever after cytotoxic therapy is estimated at 20%.[73,74] Several studies have failed to demonstrate a survival benefit when growth factors are used in lymphoma patients.[75-77] Nonetheless, their use is associated with less hospitalization, shorter duration of neutropenia, fewer infectious complications, and possible healthcare cost savings.[46] Because bone marrow reserve decreases with advanced age, elderly patients are expected to be at increased risk for neutropenic fever, even if they are considered functionally fit.[78] Since the risk of infectious complications is greatest after the first cycle of therapy,[46] we recommend growth factors prophylactically from the onset of treatment. Furthermore, we recommend implementing prophylactic fluoroquinolones whenever the absolute neutrophil count is less than 500/μL, in a manner similar to that suggested by the German Lymphoma Study Group.[40] While no prospective studies have demonstrated the benefit of using trimethoprim(Drug information on trimethoprim)-sulfamethoxazole (TMP-SMX) prophylaxis, we routinely advise elderly patients to take TMP-SMX prophylactically in order to minimize the risk of Pneumocystis jiroveci infection, especially when prolonged courses of corticosteroids are anticipated. 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.
Reported Toxicities in Select Studies in Elderly DLBCL Patients
Unfortunately, approximately 5% of patients with advanced-stage DLBCL develop a secondary CNS recurrence followed invariably by rapid death.[79] Traditionally, patients with testicular involvement and those who have an elevated LDH level and involvement of one extra-nodal site have an increased risk of CNS disease and are usually offered prophylaxis.[80] Efforts to reduce the incidence of CNS relapse have yielded conflicting results. Adding to the controversy is the fact that over half of patients who present with CNS relapse also have systemic disease.[22] A population-based study by Villa et al suggested reduction in CNS relapse after the introduction of rituximab into DLBCL treatment programs.[81] While Abramson et al showed that intrathecal methotrexate(Drug information on methotrexate) can be administered safely with systemic R-CHOP,[82] and also showed that intrathecal methotrexate decreased CNS relapse, others were unable to duplicate these results.[83] Also, Bernstein et al reported on 20-year follow-up data in 899 patients with advanced-stage DLBCL, showing a cumulative incidence of CNS relapse of 2.8%.[84] CNS relapse occurred early, with the majority of relapsing patients manifesting disease during chemotherapy or within 6 months of completion. The number of extra-nodal sites and the IPI were predictive of CNS relapse. 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.[40]
A Suggested Approach to Treating DLBCL Patients Over the Age of 80
Concluding Remarks
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. If PS and functionality improve, then either R-CHOP or R-miniCHOP (in which lower doses of the CHOP components of the regimen are used) is recommended. 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.
