Colette N. Owens, MD
As the population continues to age, the interplay between aging and cancer increasingly shows cancer to be a disease of older people. By the year 2030, there will be an increased incidence of non-Hodgkin lymphoma (NHL) in older individuals.1 The median age of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) is 70 years old, and given these demographic changes, oncologists will increasingly be required to manage older patients with DLBCL in the context of comorbidity and age-related organ dysfunction.
DLBCL is an aggressive NHL that is curable with front-line therapy with an anthracycline-based chemoimmunotherapy, with overall survival rates of 60% to 70%.2,3 However, this represents the best opportunity for cure, as those with relapsed or refractory disease often die of the disease.
Stuart M. Lichtman, MD
Given this context, there are significant challenges in optimizing therapy for older patients in the context of disease and patient factors. From a practical standpoint, the initial assessment of older patients with DLBCL is evolving not only to include disease staging and biologic risk factors, but also oncogeriatric risk assessments.
CONSIDERATION OF life expectancy is important in choosing a therapy for older patients. The average 80-year-old has a predicted life expectancy of approximately 5 years, and thus, DLBCL is most likely the greatest risk to the patient, except for the frailest patients with a life expectancy of less than 1 year.4
Thus, curative options should be made available to these patients. Life expectancy tables are available from the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®), and the Lee-Schonberg calculator is also a practical web-based tool for determining life expectancy.
An anthracycline-based chemotherapy regimen has the best opportunity for cure, and the decision to proceed with this treatment is central to the treatment of DLBCL. R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) is the standard of care. However, this regimen has a treatment-related mortality of between 6% and 12% and a cardiac toxicity risk in older individuals.2,3 Dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) is an infusional chemotherapy regimen that may have improved efficacy in certain subtypes of DLBCL, may be useful for treating proliferative tumors (eg, MYC-positive, high Ki67, double-hit), and is potentially less cardiotoxic due to the infusional doxorubicin. Both of these regimens are given with pegfilgrastim (Neulasta) for primary prophylaxis.
CLINICAL PROGNOSTIC scores are important to understanding prognosis and help to frame treatment decisions in older patients. Age figures prominently into these models, with one analysis suggesting a more relevant inflection point for worse outcomes among elderly patients between the ages of 70 and 75, rather than 60 years as in earlier reports.5 The International Prognostic Index (IPI) is used for DLBCL: age > 60, stage III/ IV, performance status > 1, lactate dehydrogenase (LDH) level > the upper limit of normal, and extranodal disease > 2. The age-adjusted IPI uses three factors (stage, LDH level, performance status) that are also predictive.
Comorbidity is prevalent in older patients, with 60% to 70% of older patients with NHL having some comorbidity. Comorbidity in these patients has been associated with increased treatment-related mortality, toxicity, dose reductions and treatment failures.6,7 The Charlson comorbidity score and the Cumulative Illness Rating Score for Geriatrics offer information that is distinct from the aforementioned lymphoma prognostic indices and can also independently identify patients at risk.
“From a practical standpoint, the initial assessment of older patients with DLBCL is evolving not only to include disease staging and biologic risk factors, but also oncogeriatric risk assessments.”— Colette N. Owens, MD
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Ideally, comprehensive geriatric assessments should be performed in older patients. Tucci et al demonstrated that a comprehensive geriatric assessment was better at distinguishing those at risk for toxicity and aggressive treatment than clinician judgment alone.8 However, because comprehensive geriatric assessments may be more time-consuming, screening assessments, such as for activities of daily living or instrumental activities of daily living, should be employed in all patients. Additionally, the use of the CARG (Cancer and Aging Research Group) and CRASH (Chemotherapy Risk Assessment for High-Age Patients) models are time-efficient and predictive of serious hematologic and nonhematologic toxicities.9,10 Although prospective trials integrating these tools into disease-specific dose modifications and/or treatment choices is needed, in practice those with the highest risk for toxicity should be considered for modifications or reduced-intensity regimens.
Strategies for Mitigating Toxicity
TO MITIGATE the impact of decreased functional status pretreatment, a strategy of “prephase” can be utilized. The goal is to improve functional status and thereby reduce the risk of treatment toxicity. The German NHL study group demonstrated that a week of steroids and a single dose of vincristine reduced treatment-related mortality by 50%.3 In clinical practice, a week of prednisone at 100 mg daily with or without a single dose of rituximab is often used to start to treat the underlying lymphoma and improve functional status in anticipation of starting chemotherapy.
THE ANTHRACYCLINES are associated with a defined risk of anthracycline-induced cardiomyopathy at a cumulative dose (although rarely idiopathic) in excess of 400 mg/m2. Hypertension is an established risk factor. An echocardiogram is always assessed prior to treatment with R-CHOP. Infusional doxorubicin or liposomal doxorubicin may be a safer alternative, and there are also nonanthracycline regimens for patients with an absolute contraindication who are treated with curative intent. The cardioprotective agent dexrazoxane is not frequently used, given a lack of data in NHLs.
Vinca alkaloids or platinum agents are also associated with peripheral and autonomic neuropathy. In older patients with baseline neuropathy, dose reductions and/or omissions should be considered. Dose reduction of vincristine or flat doses of 1 mg can be used in regimens with vincristine. It is important to note that even grade 2 neuropathy may inhibit daily function, increase the risk for falls, and impact quality of life.
Reduced-Intensity and Nonanthracycline-Based Regimens
IF R-CHOP is not feasible, there are dose-reduced regimens with dose intensities of 50% to 70% and nonanthracycline regimens that are curative. R-miniCHOP (50% dose reduction) has been shown to have 2-year progression-free and overall survival rates of 47% and 59%, respectively.11 Nonanthracycline regimens include R-GCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone), R-CEPP (rituximab, cyclophosphamide, etoposide, procarbazine, and prednisone), R-CEOP (rituximab, cyclophosphamide, epirubicin, vincristine, and prednisone), R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone), and rituximab/bendamustine. Fields et al demonstrated that a regimen of R-GCVP yielded 2-year progression-free and overall survival rates of 49.8% and 55.8%, respectively.12 Nonetheless, with these regimens, there is some reduction in efficacy but with the benefit of less toxicity and treatment-related mortality.
TYPICALLY, SALVAGE chemotherapy followed by high-dose therapy/autologous stem cell rescue is the treatment in the relapsed or refractory setting. However, given the significant risk of morbidity and mortality with high-dose therapy/autologous stem cell rescue, there must be careful patient selection. In the absence of high-dose therapy/autologous stem cell rescue, second-line therapy is generally not curative in DLBCL, and the goals become palliative. Second-line regimens include clinical trials, R-CVP, rituximab/ gemcitabine/oxaliplatin, rituximab/bendamustine, R-CEPP, and rituximab with lenalidomide (Revlimid).
“In aggressive lymphomas, curative treatments should be considered, with modifications as appropriate….”— Colette N. Owens, MD
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More recently, CAR (chimeric antigen receptor) T-cell therapy (axicabtagene ciloleucel [Yescarta], tisagenlecleucel [Kymriah]) has been approved for relapsed or refractory DLBCL. It is a genetically modified immunotherapy with activity against the DLBCL cells (CD19 targeted). While this provides another option besides transplant in the relapsed setting, it is also associated with significant complications, including cytokine-release syndrome, which can be life-threatening, and significant neurotoxicity. Careful consideration is also necessary in patient selection for this treatment.
AGE ALONE should not be the determinant of treatment recommendations for NHLs. In aggressive lymphomas, curative treatments should be considered, with modifications as appropriate when the lymphoma is the greatest risk to a patient’s life. Several factors, including disease biology, physiology, comorbidity, as well as social and psychologic considerations, should be integrated to help delineate those for whom curative treatment is possible and those for whom noncurative options would be more appropriate. ■
Dr. Owens is a medical oncologist and hematologist at the Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York.
DISCLOSURE: Dr. Owens reported no conflicts of interest.
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