TREATMENT CONSIDERATIONS IN THE ELDERLY PATIENT WITH LYMPHOMA

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TREATMENT CONSIDERATIONS IN THE ELDERLY PATIENT WITH LYMPHOMA Joseph M. Connors, MD, and Susan E. OReilly, MB, FRCPC

Two long-term trends hold major implications for clinicians caring for elderly patients with malignant lymphoma in North America: (1)the median age of the population is steadily increasing; (2) the incidence of lymphoma in the elderly is rapidly rising. Physicians caring for patients with lymphoma need to recognize the additional problems imposed by advanced age, and medical care planners should anticipate the increased demands these patients will impose on the medical care system. Examination of these trends and the evolving understanding of lymphoproliferative diseases and available treatments should provide practical information to guide therapeutic decisions for this group of patients with serious but treatable malignancies. TRENDS IN AGING OF THE POPULATION AND LYMPHOMA INCIDENCE

Over the next 25 years the proportion of the population of North America that is over the age of 65 years will increase from approximately 12% to 20%.15Thus, North American clinicians should expect an increase of nearly 60% to 70% in the number of lymphoma patients over the age of 65 years solely on the basis of demographics. If lymphoma were rare in the elderly, this change would have little consequence; however, the opposite is true. Malignant lymphomas are now the fourth or fifth most

From the British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 11 * NUMBER 5 * OCTOBER 1997

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common human neoplasm in in~idence?~ comprising between 3% and 4% of all newly diagnosed cancers.25Half of all new lymphomas are diagnosed in patients over the age of 60 to 65 years, despite the fact that such patients represent only a small minority of the population. Thus, any increase in the number of the elderly will cause disproportionate increases in the number of new lymphomas. Demographic shifts now underway will translate into a challenge for physicians and medical care planners. The increase in new lymphomas caused by aging of the population will be substantial on its own, but it will be considerably augmented by a second trend: the incidence of lymphoma itself is rising at a rate of approximately 3% per year and has been doing so for almost 50 years, suggesting that this trend will continue.33Furthermore, other than a modest contribution to increased incidence secondary to the AIDS epidemic, most of the increased incidence of lymphoma is occurring in the elderly.20Thus, we are witnessing the cumulative impact of multiple trends: the numbers of the elderly are increasing, and it is they who disproportionately develop lymphoma; the incidence of lymphoma is rising; and the greatest rise in incidence is occurring in the elderly. It is not unreasonable to expect more than a doubling of the absolute numbers of patients with lymphoma who are over the age of 65 years during the next 20 to 25 years. The physicians and medical care planners of North America will do well to anticipate these changes. CLASSIFICATION AND STAGING OF MALIGNANT LYMPHOMAS Classification

For more than a decade, the most widely used classification scheme for the malignant lymphomas has been the Working Formation,21outlined in Table 1. This scheme has been very useful because many of its subtypes are readily and reproducibly recognized and are homogeneous in terms of sites of presentation, natural history, response to treatment, and prognosis. Two influences, however-the identification of distinct new subtypes and a strong desire to integrate the Kiel classification, which is widely used in Europe-have led to proposals to adopt a new scheme with more subtypes, clearer linkage to immunophenotype, and a better incorporation of insights from molecular biology and cytogenetics. Although a generally accepted new scheme has not yet emerged, many elements of it have been anticipated in the Revised European-American Lymphoma (REAL) classification.l*Table 2 lists selected entities from the REAL classification that are widely recognized, traditionally considered with the malignant lymphomas, and necessary to identify when planning therapy. There are several changes important to clinicians as one shifts from the Working Formulation to the REAL classification. All the follicular

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Table 1. WORKING FORMULATION FOR THE CLASSIFICATION OF MALIGNANT LYMPHOMAS Low-grade Small lymphocytic with or without plasmacytoid differentiation Follicular, small cleaved cell Follicular, mixed large- and small-cell Intermediate-grade Follicular large-cell Diffuse small cleaved cell Diffuse mixed large- and small-cell Diffuse large-cell High-grade lmmunoblastic large-cell Lymphoblastic Small non-cleaved cell, Burkitt and non-Burkitt types

lymphomas-follicular small cleaved cell, follicular mixed large- and small-cell, and follicular large-cell-are collapsed into a single subtype. Two new B-cell entities are recognized. Marginal zone lymphoma, which includes the mucosa-associated lymphoid type ( M A L T o ~and ~ ) ~monocytoid B cell lymph0ma,2~is a small-cell lymphoma distinct from the chronic lymphocytic leukemia (CLL)-like small lymphocytic type, mostly in terms of sites of presentation and lesser tendency to disseminate. Mantle cell lymphoma,32which, before its recent recognition, was usually included in the diffuse small cleaved cell group, is a B-cell lymphoma with relatively poor prognosis, little evidence of curability, and an often relentless course with short duration responses and rapid relapses. The new subtype anaplastic large-cell lymphoma26is usually of T-cell phenotype but may be B or null cell and usually behaves similarly to B-cell large-cell lymphoma, but may occasionally present as an indolent lesion of the skin or soft tissue.26The immunoblastic and diffuse mixed B-cell subtypes are now considered variants of diffuse large-cell and are not listed separately, a lumping together justified by their similar natural history and response to treatmentJ8 The T-cell lymphomas are split into a number of recognizable subtypes but most are quite rare. The more common subtypes are listed in Table 2. The most commonly encountered type has the unwieldy name ”peripheral T-cell lymphoma, unspecified,” but it is most easily recalled as the Tcell variant of diffuse large-cell lymphoma. The purpose of a classification scheme for lymphomas is to separate subtypes with clinically relevant differences and group together subtypes with similar overall natural histories. Ideally, the subtypes should be unique and uniform in sites of presentation, natural history, response to treatment, and prognosis, and at the same time they should be readily and reproducibly identifiable by an experienced hematopathologist. The scheme shown in Table 2, although it falls short of this ideal, is a useful, practical way to divide the lymphomas, and it readily translates into therapeutic decisions. An overall approach to management of elderly

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Table 2. CLASSIFICATION OF THE LYMPHOMAS WITHIN THE REVISED EUROPEANAMERICAN LYMPHOMA CLASSIFICATIONSCHEME 0 Cell

T Cell

Low grade:

Small lymphocytic Plasmacytoid small lymphocytic (irnmunocytoma) Follicular lymphoma, including small cleaved-cell, mixed and large cell Marginal zone lymphoma, including mucosal-associated lymphoid tissue (MALT)

Mycoses fungoides

Intermediate grade:

Mantle cell lymphoma Diffuse large-cell, including immunoblastic Burkitt-like

Unspecified: Peripheral T-cell lymphoma Specified: Angioimmunoblastic Angiocentric T-cell Intestinal T-cell Anaplastic large-cell

High grade:

Lyrnphoblastic 6-cell Burkitt's

LymphoblasticT-cell

patients with lymphoma should start from classification of the diagnostic material into one of these categories. Staging

The stage or extent of dissemination of the malignant lymphoma is a major determination of treatment and strongly influences prognosis. Table 3 shows the standard diagnostic and staging evaluations that all patients should undergo unless precluded by frailty. Additional radiographs and scans, radionucleotide studies, samples of pleural or peritoneal effusions, and directed biopsies should be obtained to clarify suspicious lesions; however, additional testing is necessary only if it will alter the therapeutic plan. The traditional staging criteria for malignant lymphoma were arbitrarily and somewhat inappropriately borrowed from those for Hodgkin's disease, a more orderly lymphadenopathic disease with predictable patterns of spread. These Ann Arbor criteria4 are summarized in Table 4. In theory, eight different stages ranging from IA to IVB are possible, but in practice these can be collapsed with two broad categories of "limited" and "advanced" disease. The recognition that large bulk connotes a high tumor burden and indicates behavior more like that of advanced disease has led most authorities to include an assessment of tumor bulk in the staging as it applies to choice of therapy. Incorporation of Ann Arbor stage, symptomatic state, and tumor bulk allows assignment of the patient to one of two stages as shown in Table 5. This

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Table 3. STANDARD DIAGNOSTIC AND STAGING EVALUATION FOR ELDERLY PATIENTS WITH MALIGNANT LYMPHOMA Test

Reason Subclassification requires special experience and techniques and is a crucial determinant of treatment and prognosis B symptoms indicate advanced disease and worse prognosis Potential disease sites

Histopathologicreview by experienced hematopathologist History searching for B symptoms* or localized new abnormalities Physical examination searching for lymphadenopathyor visceromegaly CBC, serum creatinine, serum liver enzymes,

Bone marrow, renal and hepatic reserve affect choice and dosing of treatment.

lactate dehydrogenase (LDH)

LDH is a strong prognostic indicator Detection of monoclonal paraprotein lntrathoracic disease Intra-abdominaland retroperitoneal disease Common site of spread

Serum protein electrophoresis Chest radiograph CT scan of abdomen and pelvis Bone marrow biopsy

'B symptoms: weight loss exceeding 10% of baseline, persistent fever, night sweats.

Table 4. ANN ARBOR STAGING CRITERIA Stage

I II 111

IV A B

Criteria One area of nodal or extranodal disease Two or more nodal sites of disease or nodal and proximate extranodal sites on the same side of the diaphragm Two or more nodal sites of disease or nodal and proximate extranodal sites of disease on both sides of the diaphragm Disseminated extranodal with or without nodal sites of disease No constitutional symptoms Constitutional symptoms Weight loss > 10% of baseline Night sweats Persistent fever

Table 5. LYMPHOMA STAGING SIMPLIFIED FOR TREATMENT PLANNING Limited Stage Ann Arbor 1 or II and No B symptoms and Greatest single tumor diameter < 10 cm

Advanced Stage Ann Arbor stage 111 or IV or B symptoms or Diameter 2 10 cm

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simplified stage can be directly included in treatment planning, and it is useful across all the different types of lymphoma.

SPECIAL CONSIDERATIONS IN THE ELDERLY

Factors unique to the elderly population that may affect the results of treatment can be divided into those independent of and those intrinsic to the lymphoma. Changes unrelated to the disease include comorbid illnesses; cumulative consequences of long-term use or abuse of tobacco, alcohol, or medications; alterations in host immunologic integrity; loss of reserve in organs, which may be additionally damaged by chemotherapy or irradiation; alteration in absorption, distribution, activation, detoxification, metabolism, or clearance of drugs so that the pharmacodynamics of therapeutic and support medications are altered; and reduced emotional or physiologic tolerance for invasive procedures and toxic therapies. Commonly, many of these factors may be present in the same patient, reducing his or her ability to tolerate treatments and often leading to reduction in delivered doses or intensity of treatment or compromise in whatever participation is needed from the patient’s own immune, inflammatory, phagocytic, and other systems to help deal with the disease. The available literature strongly hints that the lymphomas seen in the elderly differ intrinsically from those seen in the younger population. Carbone and coworkers5could not detect statistically significant differences in the Working Formulation subtypes seen between elderly and younger patients, but they did find a striking preponderance of diffuse (85%) over nodular (15%)subtypes in the elderly. In two other studies2,14 and in our own results from the province of British Columbia (data not shown), we have found the same shift. Because all these observations may be affected by referral bias or patient selection, firm conclusions cannot be drawn; however, available data indicate that there is a clinically relevant shift to the more aggressive subtypes of lymphoma seen with advancing age. Another possible indicator of altered histology is the tendency of lymphomas in the elderly to involve extranodal sites more commonly. Several series have documented this increased likelihood of extranodal disease, especially to sites such as the gastrointestinal tract, brain, and testes.5,9, 11, 24 It seems reasonable to assert that the lymphomas in the elderly do have a different biology, based on the observations that the more aggressive histologic subtypes are more frequently encountered and extranodal disease is more common. Why might this be true? Although speculative, a reasonable explanation is that the lymphomas seen in the elderly have had more time to accumulate cytogenetic abnormalities and mutational events. These genetic changes may result in a more aggressive phenotype. Thus, it now appears that both host-related factors and changes intrinsic to the lymphomas militate against the elderly having as good an outcome when

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treated for lymphoma. This may help to explain the generally poorer outcomes seen in older patients, even when attempts have been made to give equipotent treatment.

RESULTS OF TREATMENT OF LYMPHOMA IN THEELDERLY Low-Grade Lymphoma Although the follicular lymphomas are encountered less frequently in the elderly, when the other subtypes are included this group of lowgrade lymphomas represents 30% to 40% of cases. There are no detailed reports of treatment of low-grade lymphoma focused solely on the elderly; such patients are often included in series with younger patients. A few lessons can be drawn from the available literature. Patients with limited-stage low-grade lymphoma constitute only about 10% of patients with low-grade disease, but they can be treated uniformly with involvedregion irradiation regardless of age. It is reasonable to hope to induce long-term remissions in at least 50% of such patients,” and many elderly patients can live out the rest of their lives free of lymphoma after such treatment. The special case of MALToma of the stomach in association with Helicobacter p y l ~ r i ’ also ~ applies regardless of age. Patients with low-grade MALTomas confined to the stomach and seen in association with H. pylori should have the organism eradicated with antibiotics. In many patients durable regression of the MALToma will ensue. If the lymphoma does not regress, more conventional irradiation or singleagent chemotherapy should be employed. Advanced-stage low-grade lymphoma has not been systematically evaluated in the elderly. The lessons available from series including patients of all ages probably apply. Given the shorter life expectancy, greater potential for toxicity, and understandable reluctance of patients to embark on an invasive evaluation or toxic treatments, the approach of watchful waiting and intervention with single alkylating agent chemotherapy when symptomatic or threatening disease develops is the current standard of treatment. Judicious use of involved-region irradiation can provide very helpful palliation. Resistant disease or transformation of the disease to a more aggressive subtype should prompt the use of more aggressive chemotherapy for selected patients who are otherwise well enough to tolerate increased toxicity.

Intermediate-Grade Lymphoma Although at least eight different histologic subtypes can be included in the intermediate-grade lymphomas (see Tables 1 and 2), by far the

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most common is B-cell large-cell lymphoma. Almost 50% of all lymphomas seen in the elderly fall into this one subgroup. About 30% of these elderly patients with diffuse large-cell lymphoma have limited-stage disease, and curative treatment can often be given within their tolerance for toxicity. Recently, a large Southwest Oncology Group (SWOG) study showed that a brief course of chemotherapy with CHOP followed by involved-region irradiation is the best approach and is superior to prolonged chemotherapy a10ne.I~We have used this brief chemotherapybased approach at the British Columbia Cancer Agency for the past 16 years and have found it routinely well tolerated by patients, even well into their ninth decade of life. Table 6 summarizes what we have been able to achieve when patients with limited-stage diffuse large-cell lymphoma and grouped by age are treated with brief chemotherapy and irradiation. Although the results for those over the age of 70 years are not quite as good as those for younger patients, they are nearly so. This demonstrates that when careful staging and efficacious treatment are offered to the elderly with diffuse large-cell lymphoma, most of the adverse impact of advanced age can be eliminated. Most clinical research into the treatment of lymphoma in the elderly population has focused on the variants of B-cell diffuse large-cell lymphoma in patients with advanced disease. Tables 7 and 8 list the findings from the phase I1 and phase I11 trials that have been published. The results shown in these tables reflect relatively short follow-up and are projected 3- to 6-year overall survivals. The overall survivals achieved in the phase I1 trials range from 21% to 45%, and the variation is more likely due to patient selection and immature follow-up than to differences in efficacy of the tested regimens. The results of the randomized trials demonstrate two important lessons. If overly toxic regimens are used, the net result will be inferior. Thus, MACOP-B produced a lower overall survival than did CHOP because of increased lethal toxicity, an outcome presaged in the experience of our group in Vancouver, where we excluded all patients over the age of 70 years from this protocol because of anticipated toxicity.16 The other lesson, however, is that too great a reduction in toxicity may well be accompanied by lower efficacy. CNOP, using mitoxantrone instead doxorubicin, reduced toxicity as compared with CHOP but also produced inferior results. Table 6. RESULTS OF TREATMENT OF LIMITED-STAGE DIFFUSE LARGE-CELL LYMPHOMA WITH BRIEF CHEMOTHERAPY AND INVOLVED REGION IRRADIATION ANALYZED BY AGE AT DIAGNOSIS Survival Age (yrs)

No.

10-yr Overall (“A)’

10-yr Disease-Specific (“A)’

16-69

197 100

76 38

85 73

> 70

’Overall survival includes all deaths from any cause; disease-specific survival censures patients at the time of death if it is unrelated to disease or toxicity and better reflects ability to cure the lymphoma.

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Table 7. RESULTS OF TREATMENT OF ELDERLY PATIENTS WITH ADVANCEDSTAGE DIFFUSE LARGE-CELL LYMPHOMA, PHASE I I STUDIES Regimen

No. Patients

Age (yrs)

Overall Survival (%)

66 52 40 32 63 26 81 67

>70 >70 65-85 65-85 65-85 >64 >64 65-80

21 25 38 43 45 36 32 40

TP + EP VMP LD-ACOP-B VABE DOCE BECALM CHOP P-VEBEC

Ref.

No.

30 31 23 23 22 18 8 3

TP + EP = teniposide, prednimustine, etoposide; VMP = etoposide, mitoxantrone, prednimustine; LD-ACOP-B = doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin; VABE = etoposide, doxorubicin, bleomycin, vincristine, prednisone; DOCE = doxorubicin, vincristine, cyclophosphamide, etoposide, prednisone; BECALM = bleomycin, etoposide, cyclophosphamide, doxorubicin, methotrexate, leucovorin; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; P-VEBEC = prednisone, vincristine, etoposide, bleomycin, epirubicin, cyclophosphamide.

Currently, the standard of practice for chemotherapy in elderly patients with advanced-stage diffuse large-cell lymphoma is CHOP. Both regimens that are more toxic and less toxic than CHOP have demonstrated reduced effectiveness, the former because of increased lethal toxicity, the latter because of reduced antineoplastic potency. CHOP, and virtually all of the preliminarily tested regimens exemplified by those listed in Table 6, seems to be able to cure about one half as many elderly patients as it can younger ones. Interestingly, this ratio of Table 8. RESULTS OF TREATMENT OF ELDERLY PATIENTS WITH ADVANCEDSTAGE DIFFUSE LARGE-CELL LYMPHOMA, PHASE 111 STUDIES ~~~~

~

~

Regimen

No. Patients

Age (yrs)

vs

273

>69

CTVP CVP CHOP

vs m-BACOD vs Pro-MACE-CYTABOM vs MACOP-B CHOP vs CNOP

Overall Survival (%)

Ref. No.

21

6

21 45

10

39 360

>60 41 23 42

72

29

>60 74

26

CTVP = cyclophosphamide,teniposide, vincristine, prednisone; CVP = cyclophosphamide,vincristine, prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; m-BACOD = methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone; Pro-MACECYTABOM = prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine; MACOP-B = methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin; and CNOP = cyclophosphamide, mitoxantrone, vincristine, prednisone.

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50% effectiveness matches the ratio of 5-year survival data from the Surveillance, Epidemiology, and End Results (SEER) study comparing older and younger patients with all non-Hod.gkin’s lymphomas,’ in which older patients have approximately 50% the chance of surviving 5 years from diagnosis as for younger patients.

Lymphoblastic and Burkitt’s Lymphomas The high-grade lymphomas are rare overall and quite rare in the elderly. Some types, such as T-cell lymphoblastic and Burkitt’s lymphoma, are only anecdotally encountered in those over 65 to 70 years of age. Thus, it is not surprising that there are no substantial reports of treatment outcomes for these most aggressive lymphomas in populations confined to the elderly. The types of intensive chemotherapy required to eradicate lymphoblastic lymphoma and Burkitt’s lymphoma in young patients are ill suited to the elderly and usually beyond their tolerance. All but the most exceptionally vigorous patients in this age range should be treated with palliative intent pending identification of better, less toxic treatments than are now available.

CONCLUSION Several subgroups of elderly patients with lymphoma can expect to tolerate currently available treatments and have nearly as good a chance of long-term survival as do those who are younger. These subgroups include patients with limited-stage low-grade lymphoma, initially asymptomatic patients with advanced-stage low-grade lymphoma, patients with H. pylori-associated MALTomas confined to the stomach, and patients with limited-stage large-cell lymphoma of B-cell type. Such patients should be carefully investigated and staged and then offered the same treatment as for younger patients. One large subgroup of elderly lymphoma patients does not have as good a prognosis as for younger patients but can still be cured sufficiently frequently that an attempt should be made-the patients with advanced-stage B-cell diffuse large-cell lymphoma. Such patients should be given CHOP, and they have approximately a 25% to 30% chance of cure. Patients in this group should be selected carefully. Those with advanced large-cell lymphoma in the setting of marked frailty, major symptomatic co-morbid illness, or substantial organ compromise should not be subjected to the toxicity of multiagent chemotherapy. It can be reliably predicted that they will not be able to complete the planned treatment. This choice between aggressive and palliative treatment cannot be reduced to simple criteria, and it requires careful clinical

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judgment and an informed choice on the part of the physician, patient, and family. Several subgroups of elderly patients with lymphoma should be approached with palliative intent from the time of diagnosis. In addition to the already mentioned frail, ill, and organ compromised groups, there are those whose lymphoma cannot be cured within the bounds of tolerable treatment. This includes most patients with aggressive histology T-cell neoplasms and those with lymphoblastic or Burkitt's lymphoma. Such patients are much better served by a caring but realistic explanation of their disease, judicious use of single-agent chemotherapy and local irradiation, and the best available supportive and palliative care. Over the past four decades tens of thousands of patients with lymphoma have been enrolled in clinical trials in Europe and North America. Despite the fact that nearly one half of all patients with these diseases are over the age of 65 years, such elderly patients have constituted only a small minority of those included in reported clinical trials. We are now living through an era during which the number of elderly patients with lymphoma may double in absolute numbers over only two to three decades. This group of patients needs focused clinical investigation specificalIy designed to increase treatment effectiveness within its narrower bounds of tolerable toxicity. Progress in this area of oncology will occur only in proportion to the willingness of investigators and clinicians to test novel approaches in well-organized, interpretable prospective trials.

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chemotherapy regimen in patients older than 70 years with unfavorable non-Hodgkin’s lymphoma. J Clin Oncol 10228-236,1992 32. Weisenburger D, Armitage J: Mantle cell lymphoma-an entity comes of age. Blood 8744834494, 1996 33. B a n g T, Mayne ST, Boyle P, et al: Epidemiology of non-Hodgkin’s lymphoma in Connecticut 1935-1988. Cancer 70:840-849, 1992 Address reprint requests to Joseph M. Connors, MD British Columbia Cancer Agency 600 West 10th Avenue Vancouver, BC V5Z 4E6 Canada