Document GmXYqZ5zbE7RgdrqzeQjwKVYV

.- "? Seminars in Oncolo&' Nursing. Vol 14, No 4 (November), 1998:pp 273-283 M O R ~ O W N , .-- 26506 OBJECTIVES: ay ~ ~ ~ ~ R LIAWG H(TITLE 17 US. corn To revim the etiology, epidemiol- sotgayg,icnlga,spsir$ocgantioosni,s,dtriaegantmoseinst,, and nursing implications of nonHodgkin's lymphoma DATA SOURCES: NON-HODGKIN'S LYMPHOMA Research studies, review articles, and book chapters pertaining to rum-Hodgkin'slymphoma. BARBARAA. BILODEAUAND OUSTENL.FESSELE CONCLUSIONS: Non-Hodgkins'slymphomas are a heterogeneousgroup of lymphoproliferative disorders, increasing infrequenqy,for which therapy rangesjbm supportive to curative. THE non-Hodgkin's lymphomas (NHLs) are a diverse group of malignancies with a common origin in lymphoid cells. They are heterogeneous in clinical behavior, morphologic appearance, cellular origin, etiology, and pathogenesis.' The American Cancer Society estimates that in 1998 there will be 55,400 new cases of NHL and 24,900 related deaths in the United States.2 IMPLICATIONS FOR NURSING PRACTICE: EPIDEMIOJBGY An understanding of the variety Between 1973 and 1991 there was a 73% increase in the incidence of NHL, one of the largest among the major c a n c e r I of presentationsand treatments of nomHodgkin'slymphomas will sites. Part of this increase has been attributed to the acquired immunodeficiency syndrome (AIDS). Non-Hodgkin's lymphoma is enable the oncology nurse to as- approximately 60 times more common in persons with AIDS than sist patients and theirfamilies to the general United States population, but AIDS alone c a n n o t cope with the disease, make treat- explain the increase in NHL that began years before the AIDS ment-related decisions,and opti- epidemic surfaced and that continues in the absence of h u m a n mize the patient'squality of life. immunodeficiency virus infection.3 Non-Hodgkin's lymphoma is the sixth most common cause of cancer-related deaths in the United States. It is more prevalent in From the ClinicalSupport Services Department,Amgm IC, Thousand Oaks, CA. Barbara A. Bilodeau, RN,MSN, AOCN clinical Support Specialist, Amgen IC; Kristen L.Fessele, RN,MSN, AOCN:Clinical S u m Specialist,Amgen Inc, Thousand oaks, a. Address reprint requests to BarbamA. Bilodeau,RN,MSN,A W N , 1666 Midde- LownAve, Nord&rd, CT 06472. males than females, and the incidence is higher in whites t h a n blacks. Survival outcomes are better for women than men, and for persons younger than 65 years of age. There is a steady, age-dependent increase from childhood through the eighth decade of life. Because the average age at diagnosis is the fifth decade, t h e resultant number of years of life lost to these diseases ranks NHL fourth in economic impact among cancers in the United States.475 ETIOLOGY T h e incidence ofNHL has risen inexplicably. Research is needed to determine possible causes. No hereditary pattern has been identified, nor have any ethnic or dietary risk factors been I specifically linked. No common etiologic agent can be associated \ with dl cases ofNHL.6An increased risk is associated with a variety of immunodeficiency states, autoimmune disorders, and infec- tious, physical, and chemical agents; these are identified in Table 1. 274 BILODEAU AND FESSELE I I TABLE 1. Etiologic Agents Associated With Increased Risk of Non-Hodgkin's Lymphoma Genetic Immunologic Infectious Environmental Chromosomaltranslocations7 Oncogenes (c-myc,c-bcC2, mutant p53)7 Congenital and acquired immunodeficiencies4 Autoimmune disorderswith chronic inflammation4: Hashimoto'sthyroiditis, SjOgren's syndrome, rheu- matoidarthritis, systemic lupus erythematosus Hodgkin's disease treated with chemotherapy and radiations Renal allograftss Epstein-Barrvirusm Pesticides (herbicides, fungi- HumanT-cell IeukemiaAym- cides, in~ecticides)~~~J~ phomavirus-l7 Occupationalexposure to Human herpes virus-8 organic solvents3+J (KSHV-8)'s9 Dark, permanent hair Heli~obacterpylori~~~~ dyes3.5.12.13 I CLASSIFIMTION The classification of NHL has evolved steadily throughout the 20th century. Terminology is complex, inconsistent, and ambiguous. As noted by Willis 50 years ago "nowhere in pathology has a chaos of names so clouded clear concepts as in the subject of lymphoid tumors."14 A classification system for NHL should (1)allow the definition of distinct subgroups to establish a proper diagnosis, (2) be clinically useful, (3) enable clinicians to estimate the prognostic relevance, and (4) guide therapeutic decisions.lS Thus, as insight into the pathogenesis of NHL changes, the classification system must be reviewed and updated. The Rappaport classification system, first proposed in 1956, was largely descriptive and based on histologic and cytologic characteristics of the cells. Lymphomas were divided according to architectural pattern: nodular or diffuse. Small cells were termed "lymphocytic," large cells were called "histiocytic," and intermediate-sized cells lacking evidence of lymphoid or histiocytic origin were called "undifferentiated." "Mixed lymphomas" were combinations of small and large cells. Cells similar in size and morphology to normal lymphocytes were "well-differentiated" and those of irregular shape were "poorly differentiated.'' The Rappaport terminology has been widely used in the Surveillance, Epidemiology and End Results program data b a ~ e . ' ? ~ J ~ Based on expanding knowledge of lymphatic system physiology and immunology, six distinct classification systems evolved worldwide in the 1970s. Consequently, it became difficult to com- pare results obtained in different clinical trials. The Lukes and Collins classification and the Kiel classification (KC) are best known. The Lukes and Collins classification system used B- and T-cell phenotypes as its basis, and attempted to relate malignant lymphomas to their normal counter- parts within the lymphatic system. The KC system defined NHL on the basis of morphologic and immunologic criteria; it divided NHL into two main groupings: high-grade (aggressive) and lowgrade (indolent) malignancies based on their cytologic features, not s~rvival.~Js--'~ The National Cancer Institute funded a study to compare the major classifications in the early 1980s. An examination of 1,175 lymphoma cases revealed that all six could identify tumors of lowor high-grade behavior. No one scheme was significantly better than another. The researchers proposed a "working formulation'' based on clinical parameters and morphology. Lymphomas were grouped according to their natural history, response to therapy, and overall survival. The subtypes were identified with alphabetical letters (A to J) and grouped into three clinical prognostic groups (low, intermediate, and high grades). At the time of publication, the Working Formulation (WF) investigators stated that it was "not proposed as a new classification system but as a means of translation among the various systems.'' However, this distinction has not always been appreciated.l v 4 9 l 6 Ultimately, the WF became the main classification system in the United States and the KC achieved prominence in Europe. This situation has complicated transatlantic communication and interpretation of published studies because the WF categories are designed according to cell size and survival, whereas the KC system reflects the physiopathology of the lymphoid tissue and does not always correlate with clinical behavior.17J8 This frustration, and the recognition of several new lymphoma entities in recent decades, raised the question of whether it was time for a new lymphoma classification system. In 1991, 19 hematopathologists from Europe, the United States, and Asia founded the International Lymphoma Study Group. Joint work revealed that despite different terminology, the ILSG members agreed on a large number of distinct lymphoma entities. Some were easily recognized; others were prone to subjective variability. For this reason, the International Lymphoma Study Group concluded that a lymphoma classification system should simply be a list of well-defined "real" disease entities. Cases that do not fit into one of the defined entities should be left unclassified, reflecting the fact that everything about lymphomas and the immune system is not yet understood. This Revised European-AmericanLymphoma (REAL) classification was proposed in 1994. The REAL systeln includes all lymphoma types and the extranodal lymphomas that were not included in the other systems. It corresponds in many aspects to the KC because of its biologically oriented approach. Studies aimed at facilitating the translation of the REAL into clinically useful prognostic groupings are ongoing. The goal is an internationally agreed on approach to lymphoma cla~sification.~4-T*oable 2 compares the WF, the KC, and the REAL classification systerns.l5 DIAGNOSTIC EVALUATION The initial approach to the patient with uncertain lymphadenopathy first involves a high TABLE 2. Summary of NHL Classification Systems WF REALB-Cell Neoplasms* REALT-CellNeoplasms' KC A: Small lymphocytic, plasma- B-cellCLUSLUPU mantle T-cell CLUPLL; LGL; lym- B- andT-cell CLUPLL; lym- cytoid cell; lymphoplacytoid phoplasmacytoid phoplasmacytoid immuno- cytoma 8: Follicular, predominantly small cleavedcell Mantle zone; marginalzone; follicular center, follicular Centroblastidcentrocytic, follicular grade 1 C: Follicular, mixed small cleaved and large cell D: Follicular, large cell Follicularcenter; follicular, grade II; marginal zone/MALT Follicle center; follicular, grade Centroblastidcentrocytic, follicular Centroblastic,follicular E:Diffuse, small cleavedcell 111 Mantle cell; follicle center, dif- fuse small cell; marginal zonelMALT PeripheralT-cell, unspeci- Mycosisfungoidedsezary fied; mycosisfungoided cell syndrome; pleomor- Sezary syndrome; adult phic, smallT-cell; centro- T-cell lymphomaheukemia cytic; centroblastidcentro- cytic, diffuse F Diffuse, mixed small and large cell Marginalzone/MALT mantle cell PeripheralT-cell, unspeci- T-cell angioimmunoblastic; fied; angiocentic; angioim- pleomorphicmedium and munoblastic largeT-cell; lymphoepithe- loid G: Diffuse, large cell H: Large cell immunoblastic Diffuse large B cell Diffuselarge B cell PeripheralT-cell, unspeci- fied PeripheralT-cell, unspeci- f.ie._d:_i,ntestinalT-cell Centroblastic; pleomorphic T-cell 8- and T-cell immunoblastic; B- and T-cell large Cell anaplastic I: Lymphoblastic J: Small noncleaved cell B-precursor lymphoblastic Burkitt's; high-gradeB-cell, PrecursorT-lymphoblastic B and T-cell lymphoblastic Burkitt's lymphoma with WF categories. Adapted and reprintedwith perrnis~ion.'~ 276 BILODEAU A N D FESSELE - -____- index of suspicion combined with a systematic evaluation. While the appearance of an enlarged lymph node in the absence of infection may cause alarm, it is important to note that up to 56%of healthy adults may exhibit cervical adenopathy2`; a study of healthy college students found not only adenopathy, but also splenomegaly.22Certainly, any enlargement of the nodes warrants follow-up evaluations to document regression or further pathology. As with any new complaint, the work-up begins with a thorough history and physical examination. Complete blood cell count, erythrocyte sedimentation rate, and peripheral blood smear are performed to rule out other causes of lymphadenopathy, such as infectious mononucleosis. Blood cultures and other serologic studies for viral and autoimmune disease provide important differential information. Chemistries, especially lactate dehydrogenase, are performed, as elevated lactate dehydrogenase may be seen in advanced NHL, and is considered a poor prognostic factor.23Recent localized infectious processes or other illnesses, as well as home and occupational exposure to carcinogens are evaluated. On examination, lymph nodes involved in infectious processes are generally tender and possibly painful, whereas lymphomatous nodes tend to appear firm and rubbery and are found in generalized patterns. Carcinomatous nodes are often hard and sometimes matted to one another or fixed to underlying structures in contiguous or regional patterns.24Other hallmarks of lymphoma such as systemic B symptoms are seen in approximately 20% to 30% of patients, but also may be found in other disease states, such as certain infections, connective tissue diseases, and angioimmunoblastic lymphadenopathy.25 When used discriminantly, lymph node biopsy specimens are an important part of the diagnostic process. Indications include adenopathy persisting for longer than 3 weeks which progresses in size or spreads to further areas, B symptoms that cannot be attributed to other causes, abnormal blood testing, or radiography indicating possible extranodal presentation. Additionally, due to the aggressive nature of AIDS-related NHL, any symptomatic patient at increased risk for or known to be positive for the human immunodeficiency virus should undergo biopsy to rule out high-eade lymphoma.2.i STAGING 0nce the diagnosis of NHL is made and the histology or cell type causing the disease has been determined, it is necessary to gauge the amount and location of lesions throughout the patient's body, or to stage. Historically, the exploratory laparotomy, with the surgeon responsible for palpation of organs and lymph node chains to uncover disease, was the "gold standard." Later, lymphangiography became important in discerning levels of involvement within the lymph system. However, because of the clarity of results, it has been generally supplanted by the use of computerized tomography, except when structural intranodal changes must be evaluated.26 Since the advent of non-invasive imaging techniques, computed tomography and magnetic resonance imaging studies have been usefully applied to the initial staging of NHL and they represent today's standards. To further determine the presence and extent of extranodal involvement, renal and liver function tests are performed. Bilateral bone marrow biopsies and aspirates are essential as spread to the marrow is common, especially in low-grade disease.27 To organize all these clinical data, the Ann Arbor staging system was initially developed in 1971 to describe the amount and location of disease in Hodgkin's disease patients.2RIt consists of four major stages that elucidate the presence of certain symptoms or sites of presentation. The later adaptation of the system to accommodate the staging of NHL is not precise in that some of the important prognostic implications in the system as illustrated by Hodgkin's disease are lost, and the capacity to describe bulky disease and other factors is not included. Table 3 in the article by Callaghan outlines general staging criteria for lymphomas. TREATMENT PRINCIPLES The treatment of NHL varies widely by histology, or cell type causing the disease, and stage, or amount and location of tumors in the body. The approach to a low-grade lymphoma will be quite different from that of a high-grade tumor, as each will behave quite distinctly, with almost an opposite natural history. Low-grade tumors (WF subsets A to C) tend to progress slowly, and are often asymptomatic for long periods. With or without treatment, the natural course of the disease may fluctuate considerably over 5 to 10 or more years. However, as benign as this course may appear, low-grade lymphoma cells eventually transform into a more aggressive leukemidymphoma-like process and causc the death of the patient soon after. As a result, this chronic, indolent disease is usually felt to be incurable, and many controversies exist related to treatment standards, especially in those patients who present with disseminated disease. The progression of intermediate- and high-grade lymphomas (WF subsets D to J) is similar to that of other cancers. They are diagnosed in the presence of symptomatology, grow and metastasize more consistently, and cause death if left untreated. However, due to their higher growth fraction, these tumors tend to be more chemosensitive and radiosensitive, and therefore demonstratc higher response rates when treated. Typically, combination chemotherapy is offered to produce shrinkage of disease and, hopefully, complete regression. Combinations are chosen from active agents with differing mechanisms of action to provide maximal cell kill even during short infusions. Cyclophosphamide and doxorubicin are very active against lymphoma, as is methotrexate to a slightly lesser extent. These agents usually are used in today's protocols in various schedules and doses. Tablc 3 outlines common regimens used for both primary treatment and salvage in the NHL population. A relationship seems to exist between the growth fraction of the tumor cells and their response to increasing dose intensity, which is defined as the dose of drug per unit of time. In animal models, a nonlinear relationship has been demonstrated wherein doubling the drug dose in a single time period may increase cell kill 10-fold, and a dose reduction of as little as 20% may decrease the cure rate by 50%.'9 In humans, a s t u d y by Kwak et a130 examined the relative dose intensity of each drug in the CHOP, M-BACOD, and MACOP-Bregimens when admiiiistered to 115 previously untreated intermediate-grade NI1L pa- tients. These investigators found a correlation between dose intensity and survival, and when a multivariable analysis of prognostic factors wdS performed, the most important predictor of survival was a relative dose intensitv of doxorubicin MACOP-6 ProMACE-MOpp CVP COPA CHVP Salvage treat ment IMVP-16 MIME ESHAP Transplantation BEAC BEAM DHAP ni<&;/ methotrexate Methotrexate with l0UWvorin res- cue/&xoru bicin/cyCloPhosphamide/vincristine/prednisone/ bleornycin prednisone/methotreXate/dOXOrubicin/cytarabine/ mechloretha- mine/vincristine/procarbazine/ prednisone Cyclophosphamide/etoposide/ cisplatin Cyclophosphamide/vincristine/ doxorubicin/prednisone Cyclophosphamide/doxoru bicin/ teniposide/prednisone Ifosfarnide/rnethotrexate/etoposide Methyl-gag/ifosfamide/methotrexatdetoposide Etoposide/cytosine arabinoside/ CiSplatin/methylprednisolone BCNUletoposidelcytosine arabinoside/cyclophosp hamide BCNUJetoposide/cytosine arabinosidelmel p h a l a n DeXamethasone/high-dose cytarabine/cispiatin 278 BILODEAG' A N D PESSELE follow-up, however, there were no significant differences in disease-free and overall survival, and the incidence of treatment-related mortality in the CHOP group was significantly lower. These findings affirm the practice of using CHOP as first-line therapy in many academic and community settings.31 Treatment ofLow-GradeNm-Hodgkin's Lymphoma For patients with low-grade NHL in stage 1-11, radiation therapy alone may be curative, although reports of recurrence beyond 10 years are seen. These lymphomas tend to recur in sites distant from the original field of therapy, such as extranodally, or in other lymph node regions.32 Depending on whether the site of disease is supradiaphragmatic or subdiaphragmatic, typical fields used as single-modality therapy include mantle and inverted "Y" field irradiation. Total lymphoid irradiation is unlikely to be advocated as a primary intervention in early low-grade lymphoma as its benefit has not been demonstrated clinically and its use has the potential to render a patient ineligible for transplantation later in their disease course due to bone marrow or other organ damage. Management of stage I11 and IV low-grade lymphoma with any modality remains controversial. In asymptomatic patients, a "watch and wait" approach may be offered, as a classic study by Rosenberg and K a ~ l a ns"h~owed that there was no survival advantage for patients treated at the time of initial diagnosis. Despite a lower CR rate than combination chemotherapy might offer, singleagent chemotherapy continues to be used routinely at several centers. It may be offered as an alternative for those patients with minor symptoms or for those who are unwilling to take an expectant approach without some form of treatment.34This can be a successful long-term tactic, as Rosenberg and Kapla~Palso showed that if single-agent therapy is delivered for more than 1 year, overall survival is similar compared with combination therapy, such as CW.33 Combinations such as CHOP, with or without radiotherapy, are another possible modality for disseminated (stage 111-IV) low-grade disease. Concurrent radiotherapy and chemotherapy,especially when using total lymphoid irradiation, may limit the intensity of the chemotherapy able to be provided due to toxicity.35 A National Cancer Institute prospective random- ized study comparing aggressive initial therapy versus watchful waiting helps to further illustrate the frustration found in treating this patient population. Eighty-nine patients were offered either ProMACE/MOPPfollowed by low-dose total lymphoid irradiation or observation. Disease-free survival after 4 years of follow-up was striking a t 51% in the treatment group versus 12% in the observed patients. However, at the study's conclusion, no difference in overall survival was observed.36 This is typical of the current data comparing initial aggressive therapy versus observation or less aggressive therapy in stage 111-IV low-grade NHL patients, and contributes to the confusion related to a standard of care for this group. Treatment ofIntermediate-Grade Non-Hodgkin's Lymphoma Before the evolution of effective combination chemotherapy regimens, radiotherapy alone was the primary intervention for patients with localized (stage 1-11) intermediate-grade NHL. A clear advantage has since been demonstrated by incorporating cytotoxic agents into treatment protocols, and in fact they have probably supplanted radiotherapy in this patient population. Targeted use of radiotherapy to decrease tumor bulk is clinically beneficial and still remains common. Stage 111-IV intermediate-grade lymphoma patients require combination chemotherapy as an immediate intervention, and those patients presenting with high-risk disease according to the International NHL Prognostic Factors Index should be especially offered aggressive regimens that provide higher dose i n t e n s i t i e ~H. ~ig~h-risk factors are age over 60 years, stage 111-IVdisease, elevated lactate dehydrogenase, and poor performance status. Treatment ofHigh-Grade Non-Hodgkin's Lymphoma The diagnosisof a high-grade NHL (WF subtypes H to J) prompts immediate and aggressive action. Depending on cellular histology, these patients present with rapidly growing disease, which has the potential to double in bulk within days or hours. Treatment mandates dose-intense chemotherapy, with or without radiotherapy, and prophylactic central nervous system therapy. It is necessary to prophylax the central nervous system as the blood-brain barrier prevents the perfusion of systemic chemotherapy into this compartment, ~ - 3PY `ate and prevents destruction of micrometastases seeking a sanctuary site. These patients are also monoclonal antibodies spur the body's own mune system to act directly against the im- ent red excellent candidates for transplantation (to be discussed in more detail later) as the high growth cells. Each biotherapeutic agent plays an impor- tant part in successful therapy. )tal fraction of the tumors responds dramatically to Interferons. The antiproliferative effects of ree the super-dose intensity of transplant preparative IFNs have been known since the 1960s, but it was ;at regimens. the availability of human interferons in the 1970~ the that spurred research into their use in a host of !lU- Salvage malignan~iesI.n~t~erferons can induce intracellu- ob- Unfortunately, 30% to 60% of patients will not lar protein activity by enhancing the immune ata achieve CR or will ultimately relapse after receiv- surveillance properties of natural killer cells and -Iv,er- ing standard-dose chemotherapy regimens, and changing the cell surface of the tumor cells.45 will require "salvage" therapy to offer contr01.3~ Interferons are used as monotherapy to induce the his Conventional salvage regimens include IMW-16, MIME, and DHAP. Although none of these offers regression or remission in patients with follicular lymphoma, low-grade T-cell lymphoma, and hairy .on {as !al3ar orto:ed :ed is patients more than a small likelihood of surviving 2 years after treatment,38-40 ESHAP, another salvage regimen, is intended for aggressive control of disease, not palliation. It has been found to be most effective in chemosensitive patients who had no evidence of bulky disease or B symptoms. A controversy exists related to the effectiveness of this regimen after initial reports of a 65% response rate at M.D. Anderson Cancer Center (Houston, TX)?' were not able to replicated by a UK study, which had no re~ponders.~A*later study by King Faisal Specialist Hospital and Research Centre (Riyadh, Saudi Arabia) confirmed the efficacy of cell leukemidymphoma. They have not shown as great a response as single agents in intermediateor high-grade disease.44In one of the first studies using IFN-a-2a for the treatment of NHL, Foon et a14(j reported responses in 13 of 24 low-grade patients, with only two of six intermediate and one of seven high-grade patients responding. Overall, the response rate for those with follicular lymphomas is most impressive, with approximately a 50% response rate in one series.44 Animal models have suggested that IFN-a-2a and chemotherapy agents with activity against ESHAP when used aggressively in patients who low-grade lymphoma may act synergistically, ,a- have previously achieved a CR.43The UK study spurring investigations into combining these mo- an included older patients who were initially resistant dalities. Because of the slow induction of remis- re- to therapy, thereby reinforcing the need to apply sion by IFN-a-2a alone, it is logical to incorporate he therapy to appropriate patients in appropriate an effective chemotherapy regimen to promote the l d situations, and to be clear on the intent of therapy best response, then use IFN-a-2a to prolong iat when formulating the treatment plan. An attempt remission. It also has been questioned whether, )rs to "secretly" palliate, perhaps at the patient or despite the known additive myelosuppression of ed family's request, by using an aggressive salvage concomitant IFN and chemotherapy, they should ce regimen in diluted doses actually may be less be combined from the start due to the Prolonged effective than using a known palliative regimen. time to maximal effect of the IFN therapy. Several studies have sought to illustrate this hypothesis, Biological Response Modifiers including Smalley et al's work4' in an Eastern The prospect of using the body's own innate Cooperative Oncology Group study in which les immune system to act on a malignancy has COPA alone or COPA plus IFN-a-2a was givento In. recently become reproducibly successful in clini- previously untreated patients. Response Its cal practice. The increasing interest in biological were not significantly different,but an Il-month as response modifiers to treat malignancies such as event-free survival benefit and an increase in the or NHL may test in part on the inability of standard &year survival rate from 68% to 76%( p = .o- chemotherapy to sustain a durable remission. were gained. Unfortunately, a 5-year update Of .Y- Biological response modifiers are used in several these data showed no overall survival benefit at is ways to treat lymphoma. Proteins such as hernato- m poietic growth factors support the patient through In the deleterious effects of other treatment modali- It, ties while interferons (IFNs), interleukins, and 280 BILODEAU A N D F E S S E L E to either CHVP alone for 18months versus CHVP plus IFN-a-2b for the same period. The patients who received IFN along with CHVP had signifi- cantly higher response rates, as well as event-free and overall survival rates at 3 years.48 Side effects of IFN therapy, while quite unlike the effects typically associated with traditional chemotherapy regimens, can be dose-limiting. A flu-like syndrome is common among all multilineage cytokines. Due to activation of the cytokine cascade, it includes fever, fatigue, headache, chills, and myalgia. These symptoms may be dose and route dependent, and as the onset of the syndrome usually can be anticipated approximately 2 to 3 hours after administration, acetominophen may be used prophylacticallyto lessen the severity. Some patients find administration before bedtime to be helpful in managing the experience and, in many patients the appearance of symptoms also lessens with subsequent doses. In a subset of patients, these symptoms may become the dose-limiting toxicity. Careful nursing support and persistent symptom management may be the difference between successful completion and discontinuation of therapy, even in a patient who is responding to IFN therapy. When used concomitantly with chemotherapeutic agents, IFN may limit further therapy by leading to myelosuppression throughout the platelet, red blood cell, and neutrophil cell lines. Central nervous system toxicity, especially depression, may occur, but as IFN does not cross the blood-brain barrier, this effect is thought to be due to other cytokines released in response to IFN admini~tration.~~ Monoclonal antibodies. In November 1997, rituximab, a monoclonal antibody specifically targeted to the CD20 B cell, was approved by the Food and Drug Administration to treat patients with relapsed or refractory follicular, CD20positive, B-cell NHL. Rituximab is unconjugated, meaning that it is not bound to another molecule, such as other diagnostic monoclonal antibodies have been. The primary mechanism of action for this molecule consists of fixing complement to the target CD20 receptor, thereby activating the specific immune system (also known as complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity). Cytotoxic T lymphocytes and natural killer cells may then recognize the malignant B cell as tumor and destroy it throughout the body. Another possible mecha- nism of action relates to a proposed function of the CD20 receptor as a cell cycle regulator. By binding rituximab to this receptor site, the antibody may affect propagation of the tumor cells.49 Transplantation The first successfulreport of treating lymphoma with autologous bone marrow transplantation was in 1978 by Appelbaum et also Since that time, the use of cellular supportive techniques such as bone marrow and peripheral stem cell transplantation (collectively referred to here as transplantation) have become widespread, and in many cases, no longer the exclusive domain of clinical research. Transplantation in patients with NHL has become increasingly common in community settings, with the decreased morbidity related to the technique and ability to deliver greater proportions of the therapy on an outpatient basis, thereby rendering it easier to provide outside academic settings. Originally used when even salvage regimens failed,other indications for this type of therapy are being studied. A movement from treatment of last resort to use as a targeted early intervention is under way, and this appeals theoretically in diseases such as lymphoma in which dose intensity is a known key driver of successful therapy. As previously discussed, the behavior and treatment of low-grade NHL differs greatly from intermediate- and high-grade lymphoma. Hesitancy arose regarding the appropriateness of using such an intense regimen in patients whose natural course of disease may leave them asymptomatic for another decade. The lack of progress in preventing the transformation of these cells into a more aggressive tumor type, or in treating them once transformed, has recently shifted consensus toward moving transplantation research forward in low-grade patients. Several studies in low-grade NHL report CR rates that range from 40%to 75%,51-5b4ut follow-up time has been relatively short, and due to the prolonged natural history of this tumor type, further evaluation is needed to assess durability. Most of the mature data have come from studies in which patients with low-grade NHL who are in their second or more relapse or those refractory to standard chemotherapy are treated with high doses of cyclophosphamideand total body irradiation. An advantage in freedom from progression is typically shown, but thus far no survival advantage is evident, possibly due to mortality related to the procedure or to an increase in myelodysplastic -- ____-___ NON-HODGKIN'S LYMPHOMA 281 syndrome years after the high-dose therapy has been givens4 In the arena of intermediate- and high-grade NHL, an important intergroup study evaluating the efficacy of conventional salvage treatment versus transplant showed the advantage of increased dose intensity in these tumor types. One hundred twenty-five patients who relapsed after a previous CR were randomized to receive either four courses of DHAP and radiotherapy, or the preparative regimen BEAC with or without radiotherapy, followed by autologous bone marrow transplantation (ABMT). Response rate in the DHAP group was 44%,compared with 84%after ABMT. After 63 months of follow-up, event-free survival in the DHAP group was 12%versus 46%in the ABMT group ( P = .001). The 5-year overall survival rate was also significantly improved in the ABMT patients, at 53%versus 32%in the DHAP group (P = .038).55 The leading data comparing ABMT with peripheral blood progenitor cell therapy (PBPC or stem cell transplant) came from a study by Schmitz et al,56in which 58patients with Hodglun'sdisease or high-grade NHL received BEAM preparation followed by either granulocyte colony-stimulating factor-mobilized PBPC infusion or ABMT. In the granulocyte colony-stimulating factor-mobilized PBPC group, patients experienced significant reductions in time to platelet and neutrophil recovery and required significantly fewer transfusions of packed red blood cells and platelets than the ABMT group."G In stem cell mobilization, the only significant side effect associated with granulocyte colony-stimulating factor administration is medullary bone pain, which is generally wellcontrolled with nonnarcotic analgesics. These findings, coupled with the significantly shorter hospitalizations needed in the PBPC group, explain the increasing utilization of granulocyte colony-stimulatingfactor-mobilizedstem cell product during transplantation. An interesting and promising area of research demonstrated by several centers is that of marrow manipulation. Altering the natural contents of the harvested product so that malignant clonal cells are removed or neutralized may be a major step toward improving this type of therapy. Contro- versy still exists regarding the effect that reinfusing tumor cells present in marrow product may have on disease recurrence, but the recurrence rate of Patients who received manipulated marrow was significantly better than those patients who received a "contaminated" infusi~n.~' Also intriguing is the potential for the use of biotherapy to augment the immune system after the patient has recovered from the transplantation. In the minimal residual disease state presumed after high-dose chemotherapy, activation of the immune surveillance system to recognize and eradicate remaining or recurring microscopic tumor cells is feasible, and may actually become a standard part of multimodal therapy. NURSING IMPLICATIONS The heterogeneous nature of NHL challenges the oncology nurse to meet a variety of physical and psychosocial needs for both patients and families. An understanding of the varied presentations and treatment options provides the basis for nursing interventions and education. Lewiss observed that while the medical process from diagnosis to cure, or diagnosis to recurrence and death, identifies critical points along the disease trajectory for health care providers, it is not the same trajectory experienced by the patient and family. The family must somehow also manage the demands of the diagnosis, treatment, and impact of the disease on daily routines and patterns. Health care professionals often assume that patients with supportive families will manage well on their own, but growing evidence suggests that family members share the strain of the illness and require support.59 Nurses have a unique opportunity to be advocates for patients with NHL and their families. It is critical that nursing objectives change along with the treatments and goals of therapy. CONCLUSION It is recognized that NHL is not just one disease, but actually a host of diseases that arise from the lymphoid system in the bone marrow and take UP residence in other sites, both in and out of the lymph nodes. Careful evaluation of risk factors and physical signs and symptoms may lead to a diagnosis with one of a variety of diseases, each with its own behavior and treatment principles. Whether watchful waiting is prescribed in the low-grade patient, or granulocyte colony-stimulat- 282 BILODEAU AND FESSELE m ing factor-mobilized PBPC therapy in the person with high-gradeNHL, the nurse'sguidingresponsibilities remain essentially the same. We must guard with equal vigilance against both untoward physical effects and psychosocial distress,and use the nursing process to maintain the patient's greatest possible degree of wellness wherever the disease continuummay lead. REFERENCES 1. Jaffe ES, Raffeld M, Medeiros W,et al: An overview of the classification of Non-Hodgkin's lymphomas: An integration of morphological and phenotypical concepts. Cancer Res 52: 5447~-54521~9,92 (SUPPI) 2. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1998. CA Cancer J Clin 486-29,1998 3. Zahm S: Non-Hodgkin's Lymphoma. Cancer Rates and Risks (ed 4). Bethesda, MD, US Department of Health and Human Services, 1996,pp 170-174 4. Shipp MA, Mauch PM, Harris NL: Non-Hodgkin's lymphoma, in DeVita VT,Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 5). Philadelphia, PA, Lippincott-Raven, 1997,pp 2165-2220 5. Lin AY, Tucker MA: Epidemiology of Hodgkin's disease and non-Hodgkin'slymphoma, in Canellos GP, Lister TA, Sklar JL (eds): The Lymphomas. Philadelphia, PA, Saunders, 1997, pp 43-61 6. Bierman PJ, Vose JM, Armitage JO: Clinical manifestations and staging of and therapy for nomHodgkin's lymphomas, in HolYman R, Benz EJ Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein LE (eds): Hematology: Basic Principles and Practice (ed 2). New York, NY, Churchill Livingstone, 1995, pp 1278-1298 7. Berliner J, Smith BR: Pathobiology of lymphoproliferative disease, in Hoffman R, Benz EJ Jr, Shattil SJ,Furie B, Cohen HJ, Silberstein LE (eds): Hematology:Basic Principles and Practice (ed 2). New York, NY, Churchill Livingstone, 1995, pp 1193-1213 8. Klein G, Klein E: Epstein-Barr virus and human lymphomas, in Canellos GP, Lister TA, Sklar JL (eds): The Lymphomas. Philadelphia, PA, Saunders, 1997, pp 63-73 9. Gaidano G, Dalla-Favera R: Lymphomas, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practices of Oncology (ed 5 ) . Philadelphia, PA, LippincottIiaven, 1997,pp 2131-2145 10. Parsonnet J, Hansen S, Rodriguez I,, et al: Helicobacter pylori infection and gastric non-Hodgkin's lymphoma. N Engl J Med 330:1267-1271,1994 11. Zahm SH, Blair A Pesticides and non-Hodgkin's lymphoma. Cancer Res 52:5485~-5488s1,992 (suppl) 12. Zahm SA, Blair A, Fraumeni JF Jr: Hair coloring products: Safe or suspect?, J Natl Cancer Inst 86:941-943,1994 13. Thun MJ, Altekruse SF, Namboordiri MM, et al: Hair dye use and risk of fatal cancers in U S . women. J Natl Cancer Inst 86:210-215,1994 14. Ioachim IIL: The revised European-American lymphoma classification of lymphoid neoplasms: A belated commentary. Cancer 78:4-9,1996 1.5. Hiddemann W, Long0 DL, Coifier R, et al: Lymphoma classification-The gap between biology and clinical managcment is closing. Blood 88:4085-4089,1996 16. O'Connor N: New classification for lymphomas. Lancet 3451521-1522,1995 17. Pileri SA, Ceccarelli C, Sabattini E, et al: Molecular findings and classification of malignant lymphomas. Acta Haematol95:181-187,1996 18. Pittaluga S, Bijnens L, Teodorovic A, et al: Clinical analysisof 670 cases in two trials of the European Organization for the Research and Treatment of Cancer Lymphoma CooperativeGroup subtyped accordingto the revised European- American classification of lymphoid neoplasms: A comparison with the Working Formulation. Blood 87:4358-4367,1996 19. Hams JL, Jaffe ES, Stein H, et al: A revised EuropeanAmerican classification of lymphoid neoplasms: A proposal from the International LymphomaStudy Group. Blood 8413611392,1994 20. The Non-Hodgkin's Lymphoma Classification Project: A clinical evaluation of the International Lymphoma Study Group classification of Non-Hodgkin's lymphoma. Blood 89: 3909-3918,1997 21. Linet 01, Metzler C: Incidence of palpable nodes in adults. Postgrad Med 62:210,1977 22. Hoagland RJ: Infectious Mononucleosis. New York, NY, Grune & Stratton, 1967 23. Shipp MA: Prognostic factors in aggressive non- Hodgkin's lymphoma: Who has "high-risk" disease? Blood 83:1165-1173,1994 24. Pangalis GA, Vassilakopoulos TP, Boussiotis VA, et al: Clinical approach to lymphadenopathy. Semin Oncol 20570582,1993 25. Skarin AT: Approach to the patient with suspected lymphoma, in Canellos GP, Lister TA, Sklar JL (eds): The Lymphomas. Philadelphia, PA, WB Saunders, 1998,pp 207-211 26. Castellino RA: Diagnostic radiology, in Canellos GP, Lister TA, Sklar JL (eds): The Lymphomas. Philadelphia, PA, Saunders, 1998, pp 187-206 27. Skarin AT, Dorfman DM: Non-Hodgkin's lymphomas: Current classification and management. CA Cancer J Clin 47:351-372,1997 28. Carbone PP, Kaplan HS, Musshoff K, et al: Report of the committee on Hodgkin's disease staging classification. Cancer Res 31:1860-1861,1971 29. DeVita VT Jr: Principles of chemotherapy, in Devita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott, 1988, pp 257-285 30. Kwak LW, Halpern J, Olshen RA, et al: Prognostic significance of actual dose intensity in diffuse large cell lymphoma: Results of a tree-structured survival analysis. J Clin Oncol8:963-977,1990 31. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced nomHodgkin's lymphoma. N Engl J Med 14:1002-1006,1993 32. Paryani S, Hoppe R, Cox R, et al: Analysis of nonHodgkin's lymphomas with nodular and favorable histologies, stages 1and 11. Cancer 52:2300-2307,1983 33. Rosenberg SA, Kaplan HS: The evolution and summary -- NON-HODGKIN'S LYMPHOMA 283 of the Stanford randomized clinical trials of the management of Hodgkin's disease: 1962-1984. Int J Radiat Oncol Bioi Phys 11:5-22, 1% 34. Lister T:The management of follicular lymphoma. Ann oncol2:131-135,1991 (SUPPI 2) 35. Marcus KC,Buck B. blauch PM: Principles of radiation therapy for lymphomas, in Canellos GP, Lister Til, Sklar JL (e&): The Lymphomas. Philadelphia, PA, Saunders, 1998, pp 215-234 36. Young R, Longo D, Glatstein E, et al: The treatment of indolent lymphomas: Watchful waiting versus aggressive combined modality treatment. Semin liematol 25:ll-16, 1988 (SUPPl2) 37. Vose JM, Armitage JO: Bone marrow transplantation for malignant lymphoma, in Canellos GP, Lister TA,Sklar JL (eds): The Lymphomas. Philadelphia, PA, Saunders, 1998, pp 247-260 38. Cabanillas F, Hagermiester FB, Bodey GP, et al: IMVP-16: An effective regimen for patients with lymphomawho have relapsed after initial combination therapy. Blood 60:693- 697,1982 39. Cabanillas F, Hagemeister FB, McLaughlin P, et al: Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol5:407-412.1Y87 40. Velasquez IVS, Cabanillas F, Salvador P, et al: Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Xra-C and dexamethasone (DHXP). Blood 71:117 - 1 2 2 , 1 9 8 8 41. Velasquez U'S, McLaughIin P, Tucker S, et al: ESHAP-An effective chemotherapy regimen in refractory and relapsing lymphoma: h 4-year follo\v-up study. J Clin Oncol 12:1169-1176,1994 42. Johnson P\VM Sweetenham fiV. bIcCallum P, et al: ~ S H A P :Inadequate treatment for poor-prognosis recurrent lymphoma. Ann Oncol4:63-6i, 1993 43. Ezzat Ail, Khalifa F. Berry J, et al: E-Sf LIP: An effective treatment in selected patients with relapsed non-IIodgkin's lymphoma. Ann Oncol5:453--l56.1994 44. Crowther D. Biologic therapy tor lymphomas, in Canel- 10s GP, Lister TX. Sklar JI, (eds). The Lymphomas. Philadelphia, PA, Saunders. 1998. pp 261-284 45. Moldawer SP. Figlin kl The interferons, in Rieger PT (ed): Biotherapy: Comprehensive Overview. Boston, MA, Jones and Bartlett. 1995. pp 69-02 46. Foon U, Sherwin S.1, Abrams PG. et al: Treatment of advanced non-I1odgkin.s Iyniphomn with recombinant leukocyteAinterferon. S Engl J hied311:114S-1152. 1984 47. Smalley RY, Anderson JU',flawkins 11J. et al: Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. N Engl J Med 327:1336-1342,1992 48. Solal-CelignyP, Lepage E, BrousseN, et al: Recombinat interferon alpha-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. N EnglJ Med 329:1608-1614,1993 49. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et d:IDEcC2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol 15:32663274,1997 50. Appelbaum FR, Herzig GP, Ziegler JL, et al: Successful engraftment of cryopreserved autologous bone marrow in patients with malignant lymphoma. Blood 52:85-89,1978 51. Freedman AS, Ritz J, Neuberg D, et al: Autologous bone marrow transplantation in 69 patients with a history of low-grade B-cell non-Hodgkin's lymphoma. Blood 7725242529,1991 52. Bierman P, Vose J, Armitage JO: High dose therapy followed by autologous hematopoietic rescue for follicular low-grade non-Hodgkin's lymphoma (NHL). Proc Am Soc Clin Oncol 11,1992 (abstr 1074a) 53. Molina A, Nademanee A, Schmidt GM, et al: High dose therapy (HDT) followed by autologoushematopoietic stem cell transplantation (AGSCT) for follicular low-grade and transformed lymphoma. Proceedings of the Fifth International Conference on Lymphoma. 1993(abstr 130a) 54. Rohatiner AZS, Johnson PWM, Price CGA, et al: Myeloablativetherapy with autologousbone marrow transplan- tation as consolidation therapy for recurrent follicular lymphoma. J Clin Oncol12:1177-1184,1994 5.5. Philip T, Gugliemi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage therapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl JMed 3331540-1545,1995 56. Schmitz X,Lineh DC, Dreger P, et al: Randomised trialof filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphomapatients. Lancet 347:353-357,1996 57. Gribben JG, Freedman AS, Neuberg D,et ak I m m n o - logic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N En@ J hied 3251525-1533,1991 58. Lewis FW Psychosocial transitions and the family'swork in adjusting to cancer. Semin Oncol Nurs 9:127-129,1993 59. Laizner Alf, Yost LM,Barg FK, et al: Needs of family caregiversof persons with cancer: A review. Semin OncolNurs 9:111-120.1993