Impact of therapeutic management and geriatric evaluation on patient of eighty years and older with diffuse large B-cell lymphoma on survival: A systematic review.

80 and over aged anthracyclines antineoplastic combined chemotherapy protocols diffuse large B-Cell lymphoma frail elderly geriatric assessment systematic review

Journal

European journal of haematology
ISSN: 1600-0609
Titre abrégé: Eur J Haematol
Pays: England
ID NLM: 8703985

Informations de publication

Date de publication:
Jan 2022
Historique:
revised: 24 08 2021
received: 13 03 2021
accepted: 26 08 2021
pubmed: 9 9 2021
medline: 15 3 2022
entrez: 8 9 2021
Statut: ppublish

Résumé

Diffuse large B cell lymphoma (DLBCL) is an aggressive disease. The first-line treatment is well defined in young patients; however, in oldest old patients treatment remains unclear. To investigate the impact of therapeutics management and geriatric evaluation on survival in aged patients with DLBCL. We performed a systematic review of PubMed and COCHRANE databases of published report on elderly patients (median age 80 and above) with DLBCL, from January 2002 to January 2020. We included 32 studies (6 prospective and 26 retrospective). Patients treated with anthracyclines-containing chemoimmunotherapy had a 2-year overall survival (OS) of 59%-74.3% in prospective studies and 48.1-64.6% in retrospective studies. With less intensive treatment without anthracyclines, 2-year OS was 28%-53%. Without specific treatment, median OS was 2 months. History of falls and severe comorbidities were associated with a decreased survival. Chemoimmunotherapy with anthracyclines increases survival in selected very elderly patients in comparison with less intensive regimen. Geriatric assessment, in particular altered mobility disorders and severe comorbidities, is predictive of survival and should be associated with the therapeutic decision. More comparative studies are needed to guide the management of frailer patients.

Sections du résumé

BACKGROUND BACKGROUND
Diffuse large B cell lymphoma (DLBCL) is an aggressive disease. The first-line treatment is well defined in young patients; however, in oldest old patients treatment remains unclear.
OBJECTIVES OBJECTIVE
To investigate the impact of therapeutics management and geriatric evaluation on survival in aged patients with DLBCL.
METHODS METHODS
We performed a systematic review of PubMed and COCHRANE databases of published report on elderly patients (median age 80 and above) with DLBCL, from January 2002 to January 2020.
RESULTS RESULTS
We included 32 studies (6 prospective and 26 retrospective). Patients treated with anthracyclines-containing chemoimmunotherapy had a 2-year overall survival (OS) of 59%-74.3% in prospective studies and 48.1-64.6% in retrospective studies. With less intensive treatment without anthracyclines, 2-year OS was 28%-53%. Without specific treatment, median OS was 2 months. History of falls and severe comorbidities were associated with a decreased survival.
CONCLUSIONS CONCLUSIONS
Chemoimmunotherapy with anthracyclines increases survival in selected very elderly patients in comparison with less intensive regimen. Geriatric assessment, in particular altered mobility disorders and severe comorbidities, is predictive of survival and should be associated with the therapeutic decision. More comparative studies are needed to guide the management of frailer patients.

Identifiants

pubmed: 34496073
doi: 10.1111/ejh.13704
doi:

Substances chimiques

Biomarkers 0

Types de publication

Journal Article Meta-Analysis Systematic Review

Langues

eng

Sous-ensembles de citation

IM

Pagination

3-17

Informations de copyright

© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Références

Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Diffuse large B-cell lymphoma. Pathology and genetics of tumours of the haematopoietic and lymphoid tissues. World Health Organization Classification of Tumours. France: IARC Press; 2001:171-174.
Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808.
Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27(17):2758-2765.
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235-242.
Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9(2):105-116.
Morrison VA, Hamlin P, Soubeyran P, et al. Approach to therapy of diffuse large B-cell lymphoma in the elderly: the International Society of Geriatric Oncology (SIOG) expert position commentary. Ann Oncol. 2015;26(6):1058-1068.
Bellera C, Praud D, Petit-Monéger A, McKelvie-Sebileau P, Soubeyran P, Mathoulin-Pélissier S. Barriers to inclusion of older adults in randomised controlled clinical trials on Non-Hodgkin’s lymphoma: a systematic review. Cancer Treat. 2013;39(7):812-817.
Scher KS, Hurria A. Under-representation of older adults in cancer registration trials: known problem, little progress. J Clin Oncol. 2012;30(17):2036-2038.
Lichtman SM. Physiological aspects of aging. Drugs Aging. 1995;7(3):212-225.
Kirkhus L, Šaltytė Benth J, Rostoft S, et al. Geriatric assessment is superior to oncologists' clinical judgement in identifying frailty. Br J Cancer. 2017;117(4):470-477.
Wedding U, Ködding D, Pientka L, Steinmetz HT, Schmitz S. Physicians' judgement and comprehensive geriatric assessment (CGA) select different patients as fit for chemotherapy. Crit Rev Oncol Hematol. 2007;64(1):1-9.
Soto-Perez-de-Celis E, Li D, Yuan Y, Lau YM, Hurria A. Functional versus chronological age: geriatric assessments to guide decision making in older patients with cancer. Lancet Oncol. 2018;19(6):e305-e316.
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(5):460-468.
Shi Z, Tang X, Shen Q, et al. Clinical characteristics, treatment patterns and outcomes of patients older than 80 years diagnosed with DLBCL in China over a 10-year period. Cancer Chemother Pharmacol. 2019;84(1):127-137.
Storti S, Spina M, Pesce EA, et al. Rituximab plus bendamustine as front-line treatment in frail elderly (>70 years) patients with diffuse large B-cell non-Hodgkin lymphoma: a phase II multicenter study of the Fondazione Italiana Linfomi. Haematologica. 2018;103(8):1345-1350.
Park SI, Grover NS, Olajide O, et al. A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma. Br J Haematol. 2016;175(2):281-289.
Olivieri A, Gini G, Bocci C, et al. Tailored therapy in an unselected population of 91 elderly patients with DLBCL Prospectively evaluated using a simplified CGA. Oncologist. 2012;17(5):663-672.
Lu X, Yang B, Yu R, et al. Clinical study of autologous cytokine-induced killer cells for the treatment of elderly patients with diffuse large B-cell lymphoma. Cell Biochem Biophys. 2012;62(1):257-265.
Lee S, Fujita K, Negoro E, et al. Impact of relative dose intensity of standard regimens on survival in elderly patients aged 80 years and older with diffuse large B cell lymphoma. Haematologica. 2020;105(8):e415-e418.
Eyre TA, Martinez-Calle N, Hildyard C, et al. Impact of intended and relative dose intensity of R-CHOP in a large, consecutive cohort of elderly diffuse large B-cell lymphoma patients treated with curative intent: no difference in cumulative incidence of relapse comparing patients by age. J Intern Med. 2019;285(6):681-692.
Cox MC, Pelliccia S, Marcheselli L, et al. The metronomic all-oral DEVEC is an effective schedule in elderly patients with diffuse large b-cell lymphoma. Invest New Drugs. 2019;37(3):548-558.
Kayamori K, Shono K, Onoda M, Yokota A. Efficacy and tolerability of rituximab and reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy for elderly patient with diffuse large B-cell lymphoma. Hematology. 2019;24(1):52-59.
Zeremski V, Jentsch-Ullrich K, Kahl C, et al. Is bendamustine-rituximab a reasonable treatment in selected older patients with diffuse large B cell lymphoma? Results from a multicentre, retrospective study. Ann Hematol. 2019;98(12):2729-2737.
Schelker RC, Herr W, Reichle A, Vogelhuber M. Low-dose trofosfamide plus rituximab is an effective and safe treatment for diffuse large B-cell lymphoma of the elderly: a single center experience. BMC Cancer. 2018;18(1):1000.
Cheng C-L, Liu J-H, Chou S-C, Yao M, Tang J-L, Tien H-F. Retrospective analysis of frontline treatment efficacy in elderly patients with diffuse large B-cell lymphoma. Eur J Haematol. 2018;101(1):28-37.
Witte HM, Riecke A, Mayer T, et al. Trofosfamide in the treatment of elderly or frail patients with diffuse large B-cell lymphoma. J Cancer Res Clin Oncol. 2019;145(1):129-136.
Arakaki H, Nakazato T, Osada Y, Ito C, Aisa Y, Mori T. Comparison of R-CVP with R-CHOP for very elderly patients aged 80 or over with diffuse large B cell lymphoma. Ann Hematol. 2017;96(7):1225-1226.
Laribi K, Denizon N, Bolle D, et al. R-CVP regimen is active in frail elderly patients aged 80 or over with diffuse large B cell lymphoma. Ann Hematol. 2016;95(10):1705-1714.
Williams JN, Rai A, Lipscomb J, Koff JL, Nastoupil LJ, Flowers CR. Disease characteristics, patterns of care, and survival in very elderly patients with diffuse large B-cell lymphoma. Cancer. 2015;121(11):1800-1808.
Eyre TA, Salisbury R, Eyre DW, Watson C, Collins GP, Hatton CS. Results of a large retrospective analysis of the effect of intended dose intensity of R-CHOP on outcome in a cohort of consecutive, unselected elderly patients with de novo diffuse large B cell lymphoma. Br J Haematol. 2016;173(3):487-491.
Hamlin PA, Satram-Hoang S, Reyes C, Hoang KQ, Guduru SR, Skettino S. Treatment patterns and comparative effectiveness in elderly diffuse large B-cell lymphoma patients: a surveillance, epidemiology, and end results-medicare analysis. Oncologist. 2014;19(12):1249-1257.
Alvarez R, Esteves S, Chacim S, et al. What Determines Therapeutic Choices for Elderly Patients With DLBCL? Clinical Findings of a Multicenter Study in Portugal. Clin Lymphoma Myeloma Leuk. 2014;14(5):370-379.
Aoki K, Takahashi T, Tabata S, et al. Efficacy and tolerability of reduced-dose 21-day cycle rituximab and cyclophosphamide, doxorubicin, vincristine and prednisolone therapy for elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma. 2013;54(11):2441-2447.
Juul MB, Jensen PH, Engberg H, et al. Treatment strategies and outcomes in diffuse large B-cell lymphoma among 1011 patients aged 75 years or older: a Danish population-based cohort study. Eur J Cancer. 2018;99:86-96.
Gobba S, Moccia AA, Gulden-Sala W, et al. Outcome of patients older than 80 years with diffuse large B-cell lymphoma (DLBCL) treated with « standard » immunochemotherapy: a large retrospective study from 4 institutions. Hematol Oncol. 2018;36(1):84-92.
Chihara D, Westin JR, Oki Y, et al. Management strategies and outcomes for very elderly patients with diffuse large B-cell lymphoma. Cancer. 2016;122(20):3145-3151.
Carson KR, Riedell P, Lynch R, et al. Comparative effectiveness of anthracycline-containing chemotherapy in United States veterans age 80 and older with diffuse large B-cell lymphoma. J Geriatr Oncol. 2015;6(3):211-218.
Hedström G, Hagberg O, Jerkeman M, Enblad G, Swedish Lymphoma Study Group. The impact of age on survival of diffuse large B-cell lymphoma - a population-based study. Acta Oncol. 2015;54(6):916-923.
Shah BK, Ghimire K, Pendharkar D. survival trends in very old adults with advanced diffuse large B-Cell lymphoma-a population-based study. J Am Geriatr Soc. 2015;63(3):605-607.
Boslooper K, Kibbelaar R, Storm H, et al. Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone is beneficial but toxic in very elderly patients with diffuse large B-cell lymphoma: a population-based cohort study on treatment, toxicity and outcome. Leuk Lymphoma. 2014;55(3):526-532.
Varga C, Holcroft C, Kezouh A, et al. Comparison of outcomes among patients aged 80 and over and younger patients with diffuse large B-cell lymphoma: a population-based study. Leuk Lymphoma. 2014;55(3):533-537.
Smith SD, Chen A, Spurgeon S, et al. Diffuse large B-cell lymphoma in adults aged 75 years and older: a single institution analysis of cause-specific survival and prognostic factors. Ther Adv Hematol. 2013;4(6):349-353.
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(3):394-399.
van de Schans SAM, Wymenga ANM, van Spronsen DJ, Schouten HC, Coebergh JWW, Janssen-Heijnen MLG. Two sides of the medallion: poor treatment tolerance but better survival by standard chemotherapy in elderly patients with advanced-stage diffuse large B-cell lymphoma. Ann Oncol. 2012;23(5):1280-1286.
Oberic L, Peyrade F, Puyade M, et al. Subcutaneous rituximab-MiniCHOP compared with subcutaneous rituximab-miniCHOP plus lenalidomide in diffuse large B-Cell Lymphoma for patients age 80 years or older. J Clin Oncol. 2021;39(11):1203-1213.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383.
Sonnevi K, Wästerlid T, Melén CM, Harrysson S, Smedby KE, Wahlin BE. Survival of very elderly patients with diffuse large B-cell lymphoma according to treatment intensity in the immunochemotherapy era: a Swedish lymphoma register study. Br J Haematol. 2021;192(1): 75-81.
Peyrade F, Bologna S, Delwail V, et al. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol. 2017;4(1):e46-55.
Zhou D, Li L, Bao C, et al. Replacement of conventional doxorubicin by pegylated liposomal doxorubicin in standard RCHOP chemotherapy for elderly diffuse large B-Cell lymphoma: a retrospective study in China. Int J Clin Exp Med. 2015;8(12):22497-22502.
Luminari S, Viel E, Ferreri AJM, et al. Nonpegylated liposomal doxorubicin combination regimen in patients with diffuse large B-cell lymphoma and cardiac comorbidity. Results of the HEART01 phase II trial conducted by the Fondazione Italiana Linfomi. Hematol Oncol. 2018;36(1):68-75.
Fridrik MA, Jaeger U, Petzer A, et al. Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: a randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14). Eur J Cancer. 2016;58:112-121.
Tilly H, Morschhauser F, Bartlett NL, et al. Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Lancet Oncol. 2019;20(7):998-1010.
Hutchings M, Carlo-Stella C, Bachy E, et al. Glofitamab step-up dosing induces high response rates in patients with hard-to-treat refractory or relapsed non-hodgkin lymphoma. Blood. 2020;136(Supplement 1):46-48.
Olszewski AJ, Avigdor A, Babu S, et al. Single-agent mosunetuzumab is a promising safe and efficacious chemotherapy-free regimen for elderly/unfit patients with previously untreated diffuse large B-cell lymphoma. Blood. 2020;136(Supplement 1):43-45.
Shen Q-D, Zhu H-Y, Wang L, et al. Gemcitabine-oxaliplatin plus rituximab (R-GemOx) as first-line treatment in elderly patients with diffuse large B-cell lymphoma: a single-arm, open-label, phase 2 trial. Lancet Haematol. 2018;5(6):e261-9.
Mounier N, El Gnaoui T, Tilly H, et al. Rituximab plus gemcitabine and oxaliplatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. a phase II lymphoma study association trial. Haematologica. 2013;98(11):1726-1731.
Ionescu-Ittu R, Shang A, Velde NV, et al. Second-line rituximab-bendamustine versus rituximab-gemcitabine-oxaliplatin in diffuse large B-cell lymphoma in the real world. J Comp Eff Res. 2019;8(13):1067-1075.
Joshi M, Taper J, Forsyth C, et al. Outpatient rituximab, ifosfamide, etoposide (R-IE) in patients older than 60 years with relapsed or refractory diffuse large B-cell lymphoma who are not candidates for stem cell transplantation. Leuk Lymphoma. 2020;61(1):91-97.
Wang M, Fowler N, Wagner-Bartak N, et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia. 2013;27(9):1902-1909.
Zinzani PL, Pellegrini C, Gandolfi L, et al. Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk. 2011;11(6):462-466.
Cox MC, Musuraca G, Battistini R, et al. Aggressive lymphomas of the elderly: the DEVEC metronomic chemotherapy schedule fits the unfit. Br J Haematol. 2018;183(5):819-822.
Pfreundschuh M. How I treat elderly patients with diffuse large B-cell lymphoma. Blood. 2010;116(24):5103-5110.
Lakshmaiah KC, Asati V, Babu KG,, et al. Role of prephase treatment prior to definitive chemotherapy in patients with diffuse large B-cell lymphoma. Eur J Haematol. 2018;100(6):644-648.
Liu MA, DuMontier C, Murillo A, et al. Gait speed, grip strength, and clinical outcomes in older patients with hematologic malignancies. Blood. 2019;134(4):374-382.
Soubeyran P, Fonck M, Blanc-Bisson C, et al. Predictors of early death risk in older patients treated with first-line chemotherapy for cancer. J Clin Oncol. 2012;30(15):1829-1834.
Jørgensen TL, Hallas J, Friis S, Herrstedt J. Comorbidity in elderly cancer patients in relation to overall and cancer-specific mortality. Br J Cancer. 2012;106(7):1353-1360.
Søgaard M, Thomsen RW, Bossen KS, Sørensen HT, Nørgaard M. The impact of comorbidity on cancer survival: a review. Clin Epidemiol. 2013;5(Suppl 1):3-29.
DuMontier C, Liu MA, Murillo A, et al. Function, survival, and care utilization among older adults with hematologic malignancies. J Am Geriatr Soc. 2019;67(5):889-897.
Merli F, Luminari S, Rossi G, et al. Outcome of frail elderly patients with diffuse large B-cell lymphoma prospectively identified by comprehensive geriatric assessment: results from a study of the fondazione Italiana linfomi. Leuk Lymphoma. 2014;55(1):38-43.
Nabhan C, Smith SM, Helenowski I, et al. Analysis of very elderly (≥80 years) non-hodgkin lymphoma: impact of functional status and co-morbidities on outcome. Br J Haematol. 2012;156(2):196-204.
Kanesvaran R, Li H, Koo K-N, Poon D. Analysis of prognostic factors of comprehensive geriatric assessment and development of a clinical scoring system in elderly Asian patients with cancer. J Clin Oncol. 2011;29(27):3620-3627.
Dubruille S, Libert Y, Roos M, et al. Identification of clinical parameters predictive of one-year survival using two geriatric tools in clinically fit older patients with hematological malignancies: major impact of cognition. J Geriatr Oncol. 2015;6(5):362-369.
Park S, Hong J, Hwang I, et al. Comprehensive geriatric assessment in elderly patients with newly diagnosed aggressive non-Hodgkin lymphoma treated with multi-agent chemotherapy. J Geriatr Oncol. 2015;6(6):470-478.
Aaldriks AA, Giltay EJ, Nortier JWR, et al. Prognostic significance of geriatric assessment in combination with laboratory parameters in elderly patients with aggressive non-Hodgkin lymphoma. Leuk Lymphoma. 2015;56(4):927-935.
Lee S, Fujita K, Morishita T, et al. Prognostic utility of a geriatric nutritional risk index in combination with a comorbidity index in elderly patients with diffuse large B cell lymphoma. Br J Haematol. 2021;192(1):100-109.
Frasca M, Soubeyran P, Bellera C, et al. Alterations in comprehensive geriatric assessment decrease survival of elderly patients with cancer. Eur J Cancer. 2018;90:10-18.
Paillaud E, Soubeyran P, Caillet P, et al. Multidisciplinary development of the Geriatric Core Dataset for clinical research in older patients with cancer: a French initiative with international survey. Eur J Cancer. 2018;103:61-68.
Beygi S, Sadashiv S, Reilly JB, Khan C, Lister J. Frontline treatment of diffuse large B-cell lymphoma in elderly: a systematic review of clinical trials in post-rituximab era. Leuk Lymphoma. 2018;59(12):2847-2861.
Tucci A, Martelli M, Rigacci L, et al. Comprehensive geriatric assessment is an essential tool to support treatment decisions in elderly patients with diffuse large B-cell lymphoma: a prospective multicenter evaluation in 173 patients by the Lymphoma Italian Foundation (FIL). Leuk Lymphoma. 2015;56(4):921-926.
Romano PS, Roos LL, Jollis JG. Adapting a clinical comorbidity index for use with ICD-9-CM administrative data: differing perspectives. J Clin Epidemiol. 1993;46(10):1075-1079.

Auteurs

Marguerite Briand (M)

Geriatric Department, Internal Medicine and Oncogeriatry Unit, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

Stephane Gerard (S)

Geriatric Department, Internal Medicine and Oncogeriatry Unit, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

Martin Gauthier (M)

Department of Hematology, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France.
Department of Internal Medicine, Centre Hospitalier de Cahors, Cahors, France.

Marie Garric (M)

Geriatric Department, Internal Medicine and Oncogeriatry Unit, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

Zara Steinmeyer (Z)

Geriatric Department, Internal Medicine and Oncogeriatry Unit, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

Laurent Balardy (L)

Geriatric Department, Internal Medicine and Oncogeriatry Unit, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

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