Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

21. Hodgkin Lymphoma

Richard S. Stein and David S. Morgan

Hodgkin lymphoma (HL) is a lymphoproliferative malignancy that accounts for approximately 1% of cancers in the United States. Most patients present with disease limited to lymph nodes or to lymph nodes and the spleen. The bone marrow is involved in approximately 5% of cases. HL generally spreads in a contiguous fashion, making the use of radiation therapy (RT) feasible for many patients. The average age at presentation is 32 years with a bimodal incidence curve; one peak occurs before age 25 years and the other at age 55 years.

Most patients with HL are cured with primary therapy. Patients with advanced disease can be cured with combination chemotherapy, while those with limited disease can be cured either with limited combination chemotherapy and limited RT, or with more extensive RT alone. A major focus of HL therapy in the last 40 years has been the recognition of and the attempt to limit long-term side effects of therapy. Thus, the recent trend has been away from extensive RT alone for limited-stage disease.

While HL is highly curable at presentation, a significant minority will not respond or will relapse after initial treatment. Many of these patients can be cured by salvage therapy. Salvage chemotherapy may produce cures in patients initially treated with RT. Readministration of standard-dose chemotherapy or, more commonly, the administration of high-dose chemotherapy in conjunction with autologous stem cell transplantation may produce cures in patients initially treated with combination chemotherapy. Nevertheless, the potential for cure should not lead clinicians and patients to lose sight of the fact that approximately 20% to 25% of patients with HL eventually die of the disease.

For most cancers, disease-free survival (DFS) is a valuable surrogate marker for overall survival and thus evaluating DFS is a useful method for choosing optimal initial therapy. However, for HL, the success of salvage therapy means that the treatment options that are associated with superior DFS may not necessarily produce superior overall survival when the results of salvage therapy are considered, and this makes the selection of initial therapy somewhat subtler. In fact, because radiation and chemotherapy have significant long-term consequences such as secondary malignancies (associated with larger RT fields) or acute leukemia (associated with combined-modality therapy), DFS may overestimate the value of a specific therapy. Therefore, for each stage of HL, more than one rational therapeutic option may exist.

I. DIAGNOSIS AND PATHOLOGY

The diagnosis of HL requires excisional biopsy of an involved node and review of the material by a hematopathologist. Lymph node biopsy is recommended for any patient with lymphadenopathy greater than 1 cm in diameter and persisting for more than 4 weeks. Lymphoma, including HL, may be suspected when the nodes are freely movable and rubbery rather than stony hard. However, these clinical features are not specific for HL or for lymphoma in general. Key features of the histopathology of HL include the presence of Reed-Sternberg (RS) cells (or variants) in a mixed inflammatory background. The RS cells of classical HL (see subsequent discussion) are of B-cell origin, stain for CD15 and CD30, and are negative for CD45 and CD20. Whenever the diagnosis of HL is made in a patient presenting at an extranodal site or at a nodal site below the diaphragm, the diagnosis should be subjected to greater than usual scrutiny.

Tie current World Health Organization classification divides HL into two major groups: classical HL and nodular lymphocyte predominant HL (NLPHL). Classical HL includes the four subtypes: nodular sclerosis HL (approximately 70% of cases), mixed cellular-ity HL (approximately 20%), lymphocyte-rich HL (less than 5%), and lymphocyte depletion HL (less than 5%). NLPHL (5% of all HL) is a B-cell neoplasm characterized by variant RS cells (“L and H cells”or “popcorn cells”) that are positive for CD20 and negative for CD30 and CD15. In immunophenotype and behavior, NLPHL bears similarities to low-grade non-HL.

In the past, much was made of the prognostic significance of the subtypes of classical HL. Most of the difference is explained by the fact that stage covaries with histology. For instance, the average patient with mixed cellularity HL presents at a more advanced stage than the average patient with the nodular sclerosis HL. Tus it is generally true that patients with nodular sclerosis HL do better than patients with mixed cellularity HL. However, when one stratifies patients by stage, the impact of histopathology on prognosis is minimal.

II. STAGING

Accurate staging is critical to determining the optimal therapy for the patient with HL. It also provides a baseline so that the completeness of a response can be determined when therapy has been completed.

A. Cotswold staging system

Tie Cotswold modification of the Ann Arbor Staging System (Table 21.1) is used for patients with HL. Clinically, patients are placed in one of four stages based on anatomic extent of disease and are further classified as to the absence, “A,” or presence, “B,” of systemic symptoms (see subsequent discussion). In addition, the subscript E (e.g., IIE) may be used to denote involvement of an extralymphatic site primarily or, more commonly, to denote direct extension into an organ, such as a large mediastinal mass extending into the lung. Stage III HL is subdivided into two substages, stages IIL and III2, based on the extent of intra-abdominal disease. However, as current treatment recommendations are the same for both substages, this distinction is of little clinical relevance.

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B. Prognostic score for advanced HL (International Prognostic Score [IPS])

In 1998, Hasenclever and Diehl created a prognostic model for advanced HL based on a multivariate analysis of patients. Seven factors were identified as having prognostic value: serum albumin 4 gm/dL, hemoglobin 10.5 gm/dL, male sex, stage IV disease, age &45 years, white cell count &15,000/μL, and lymphocyte count either 600/μL or 8% of the white cell count. In the paper presenting the model, the prognostic score correlated with both freedom from progression and overall survival rate. However, the utility of the IPS is limited by the fact that most patients had a score of 0 to 3, with only 12% of patients having a score of 4 and only 7% of patients having a score of 5 to 7.

C. Staging tests

Before the advent of modern radiographic and nuclear medicine techniques, clinicians made use of the knowledge that HL tends to spread in a contiguous manner, and elegant and detailed descriptions ofpatterns of disease weremade.Forinstance.itwas recognized that because the thoracic duct makes the left supraclavicular area and the abdomen contiguous sites, abdominal disease is found in 40% of patients with left supraclavicular presentations and in only 8% of patients with right supraclavicular presentations. While such fascinating associations were useful before modern imaging was available, today they are largely superseded by computed tomog-raphy (CT) and positron emission tomography (PET) scans. Proce-dures used in the staging of HL are as follows.

1. History taking. As with anypatient, the staging of the patient with HL begins with a history and a physical exam. Special attention should be given to symptoms such as bone pain that might signal a specific extranodal site of disease. The symptoms that are considered “B symptoms” are fever, night sweats, and weight loss greater than 10% of body weight. Fever in HL can have any pattern. Te pattern of days of high fever separated by days without fever, so-called Pel-Ebstein fever, has been associated with HL for over a century but is quite rare in modern times when the diagnosis of HL is usually made early in the course of disease and effective therapy is initiated. Pain at the site of HL in association with alcohol ingestion is a rare finding but may give hints as to visceral sites of involvement.

2. Complete physical examination.Attention must be paid to all lymph node regions and the spleen. Splenomegaly is seen at presentation in approximately 10% of patients with HL and does not necessarily indicate splenic involvement by HL.

3. Laboratory tests. Complete blood counts, erythrocyte sedimentation rate (ESR), serum alkaline phosphatase, and tests of liver and kidney function should be obtained. Hepatic enzymes may be elevated “nonspecifically” in patients with HL and do not necessarily indicate hepatic involvement by HL.

4. Chest radiographs and CT scans of the neck, chest, abdomen, and pelvis are routinely obtained in patients with HL.

5. PET scans, especiallyPET/CT fusion scans, have been shown to be highly sensitive in HL and may “upstage” patients in comparison to CT scans alone. The PET scan is also useful for detecting relapse and persistent disease and therefore should be obtained at baseline for comparison with later scans. Te PET scan is especially helpful when the posttreatment CT scan shows a re-sidual mass, which could be either an inactive residual mass or persistent HL. Te value of PET has been shown in many studies and was most clearly shown in a study by Gallamini and associates in which the PET scan was repeated after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy. Therapy was not changed based on the PET findings (i.e., ABVD was continued). Two-year progression-free survival was 13% for patients who were PET-positive as compared to 95% in patients who had become PET-negative (p 0.0001). Whether or not changing the chemotherapy in patients with a positive PET can alter the poor prognosis of those patients is the subject of ongoing clinical trials.

6. Bone marrow biopsy. The test is rarely positive except in patients who are found to have at least stage III disease by other tests. However, because of the potential use of autologous bone marrow transplantation (ABMT) or stem cell transplantation as salvage therapy, a bone marrow biopsy is a reasonable baseline study in all patients with HL. Alternatively, if chemotherapy is planned and if blood counts are normal, the test may be omitted until the time that stem cell transplantation is considered.

7. Staging laparotomy. With the widespread availability of PET scans, and the tendency to treat even limited disease with che-motherapy, staging laparotomy is of historical interest only.

III. THERAPY OF HODGKIN LYMPHOMA

A. General considerations

Therapy of HL must be considered on a stage-by-stage basis. The incidence of various stages of HL is presented in Table 21.2, which also presents an estimated cure rate for each stage. Historically, potentially curative RT was available before curative chemotherapy was defined, and therefore there has been a traditional bias to use radiation as the sole modality of therapy or as part of combination therapy whenever possible. Thus, RT has been used for limited-stage HL, and even stage Ilia HL in the recent past, even after more effective, and safer, chemotherapy had been advocated for use in HL. Indeed, there are only limited data for the use of chemotherapy alone in stage I and II HL.

Late complications of RT for HL include breast cancer, lung cancer, hypothyroidism, thyroid cancer, musculoskeletal atrophy or growth deficit, coronary artery disease, cardiomyopathy, and valvular heart disease. While the incidence of each of these complications is fairly low, the cumulative risk of death from all of these complications may be as much as 15% at 15 years following treatment. It is therefore reasonable to consider decreasing the field and dose of RT or eliminating it entirely as an approach to limited-stage disease. We now have numerous reports of combined modality therapy for limited-stage HL showing excellent DFS; however, there are no data showing that the overall survival of patients with limited-stage HL can be improved with this alteration of therapy. Studies designed to illustrate the superiority of combined modality therapy with respect to the incidence of late side effects may require 15 to 20 years of follow-up. Thus, after decades of general agreement that RT was the optimal approach to limited-stage HL, there has been a shift to incorporating chemotherapy in the treatment of limited-stage HL.

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Chemotherapy has been established as the optimal therapy for advanced-stage disease. A series of U.S. cooperative group studies in the 1980s and 1990s established ABVD as the most effective and least toxic of the candidate regimens, and most authorities, at least in North America, would agree that this regimen is the standard for use alone in advanced disease and for sequencing with RT in limited-disease stages. Two multidrug regimens, Stanford V from the Stanford group and BEACOPP (Table 21.3) and its variation from the German Hodgkin Study Group, have been proposed as alternatives, but have not been widely adopted in North America. Te standard regimens should not be altered arbitrarily as dose reductions may decrease the possibility of cure. Although most patients receive six cycles of chemotherapy (e.g., ABVD) for advanced-stage disease, the data actually support administering a minimum of six cycles, with therapy being given until a complete remission (CR) has been achieved and then administered for an additional two cycles.

B. Radiotherapy (RT)

Studies conducted in the 1960s established that the optimal dose for local control if RT used as a single modality was 36 to 40 Gy given over 3.5 to 4 weeks.

With modern equipment, adequate radiation can be administered to involved areas while shielding adjacent tissues. As a result, radiation pneumonitis and radiation pericarditis occur only rarely. Because of the common occurrence of hypothyroidism and the less common occurrence of thyroid cancer in patients who receive radiation to the thyroid gland, thyroid-stimulating hormone (TSH) levels should be monitored yearly in these patients starting at 8 to 10 years following administration of RT. Patients with elevated levels of TSH, even if clinically euthyroid, should be placed on thyroid hormone replacement to limit stimulation of the radiated thyroid gland by elevated levels of TSH. While RT alone has not been associated with an increased risk of acute leukemia, the use of RT in conjunction with combination chemotherapy (especially alkylator therapy as in the outdated mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone [MOPP] regimen) has been associated with a risk of acute nonlymphocytic leukemia as high as 7% to 10% in the decade following therapy.

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Women receiving RT for HL are at higher risk of developing breast cancer, and the risk is higher the younger the woman is at the time RT is administered. Women who receive RT for HL should receive yearly mammograms starting 8 years following the completion of therapy.

C. Treatment by stage of disease

1. Stages IA and IIA. Patients with stage IA disease were traditionally treated with mantle irradiation when the disease occurred above the diaphragm (as it does in 90% of cases) or with pelvic RT when the disease presented in an inguinal node. Patients with stage IIA disease presenting above the diaphragm were previously treated with mantle plus para-aortic–splenic RT. In the last decade, however, evidence has accumulated that RT, as traditionally used in Hodgkin disease, is associated with an increase in late malignancies to the point that second malignancies, rather than Hodgkin disease, are the major cause of death in stage IA and IIA patients treated with extended-field RT alone. While certain patients who are not candidates for chemotherapy might still be treated with RT alone, the current standard of care for stage IA and IIA, based on excellent DFS, is an abbreviated course of chemotherapy such as four cycles of ABVD followed by involved-field-only, limited-dose RT.

2. Stage IIX disease with bulky mediastinal mass. Patients with bulky mediastinal masses (disease diameter greater than 10 cm or greater than one-third of the chest diameter) present a special problem. When these patients, who are generally at stage IIX, are treated with RT alone, the risk of relapse approaches 50%. “Full course” combination chemotherapy with RT is most commonly employed in these patients.

However, the value of a combined modality approach for all stage IIX patients is not obvious. As the majority of stage IIx patients have residual disease when evaluated by CT scans following completion of chemotherapy, treating patents with chemotherapy alone was not feasible when CT scans were the best method of evaluating residual disease.

The introduction of PET scans and the documentation that relapse rates are markedly increased in PET-positive patients as compared to patients who are PET-negative following the completion of chemotherapy has simplified this issue. One logical approach is to treat stage IIXpatients with combination chemotherapy and to give low-dose RT (20 Gy) only to patients who have residual disease on the basis of the PET scan obtained on completion of chemotherapy. When this is done, radiation is administered only to the area of residual disease. Long-term followup will be necessary to determine the ultimate value of using the PET scan to select patients who will not receive RT in this clinical situation.

3. Stages IB and IIB and stages I or II with other unfavorable characteristics. Several cooperative groups have identified unfavorable features in limited-stage patients, including elevated ESR, mixed cellularity subtype, and B symptoms. In the RT-only era, these patients were often treated with extended field RT, presumably with the thought that these features were associated with more extensive, occult disease. While the available data do not allow firm treatment recommendations to be made,unfavorable stage I and II patients are most often treated as if they had more advanced-stage disease (i.e., with “full-course chemotherapy”).

4. Stages III and IV. Combination chemotherapy is the standard approach for these stages of HL, and the standard chemotherapy regimen in North America is ABVD. The data support the use of six to eight cycles, using the rule of “two cycles past the best response.” Tis approach does not incorporate PET scanning. A common, though technically unproven, approach is to stop the therapy if the PET is negative after six cycles.

D. Chemotherapy

In 1970, the demonstration by investigators at the National Cancer Institute that MOPP chemotherapy could cure advanced HL was one of the major milestones of the modern chemotherapy era as it was the first demonstration that a previously incurable advanced adult cancer could be cured by combination chemotherapy. Tis has provided the rationale for the use of combination chemotherapy in medical oncology. However, more recent studies have indicated that the classic MOPP regimen is not the optimal regimen for patients with advanced HL.

1. Dose and duration of therapy. Arguments regarding selection of the “best” regimen should not obscure the following principles:

bull Drugs should be administered in accordance with prescribed doses and schedules and not modified for toxicities such as nausea and vomiting (which should be controlled with antiemetics).

bull Full doses should be given when cytopenias are due to bone marrow involvement with HL.

bull Vinca alkaloids should be decreased only in the presence of ileus, motor weakness, or numbness involving the whole fingers, not just the fingertips.

bull Patients should be treated for a minimum of six cycles, but also until a CR is documented, and then for another two cycles. If tests are equivocal, it is better to treat with additional cycles rather than to prematurely discontinue therapy. However, many clinicians would stop therapy if a PET scan were negative after the sixth cycle.

2. Classical MOPP therapy. When MOPP was initially administered in the late 1960s, 81% of patients achieved a CR. Of these patients, 66% (representing 53% of the total series) remained in CR for 5 years, and an identical percentage remained in CR for 10 years. Tus, while late relapses have been seen on occasion, 5-year DFS represents cure for most patients. Because salvage therapy can cure patients who are not cured by initial chemotherapy, the figure of 53% represents a minimal estimate for the cure of advanced HL.

3. ABVD was developed by Bonadonna and colleagues in Milan as a nonleukemogenic, nonsterilizing regimen that was not cross-resistant to MOPP. In a large randomized trial, ABVD was shown to be superior to MOPP with respect to remission rates and survival. In a randomized cooperative group clinical trial, reported in 1992, Canellos and associates reported a freedom from progression rate of 61% in patients receiving ABVD; however, more recent studies have shown failure-free survival rates of 75% to 88% using ABVD.

Chemotherapy regimens that alternate cycles of MOPP with cycles of ABVD or which administer the regimens sequentially have been studied in clinical trials. None was superior in efficacy or in toxicity profile to ABVD.

Although some investigators have combined chemotherapy with RT as treatment of advanced disease, there is no evidence that the routine addition of RT to combination chemotherapy can improve results enough to compensate for the leukemo-genic risk of that practice. Additionally, while one might consider supplementing combination chemotherapy with local RT to sites of previously bulky disease, if the area in question has become negative by repeat PET scan following the completion of chemotherapy, the logic of that approach is minimal.

Also, as high-intensity therapy in conjunction with stem cell transplantation has been shown to be effective salvage therapy of HL, more intense induction regimens have been studied in HL. Favorable results have been reported by German investigators using BEACOPP (and escalated BEACOPP) and by investigators at Stanford using Stanford V. Doses of these regimens are included in Table 21.3. A recently reported randomized trial demonstrated that Stanford V was equivalent to but not superior to ABVD with respect to DFS and overall survival. Te incidence of serious toxicities of the two regimens was similar, though more pulmonary toxicity was seen in patients receiving ABVD and more nonpulmonary toxicity was observed in patients receiving Stanford V. Te results of a U.S. cooperative group trial (Eastern Cooperative Oncology Group 2496) comparing Stanford V and ABVD are still pending.

BEACOPP has never been compared directly with ABVD, although it has been shown to be superior to an alternating regimen of cyclophosphamide, prednisone, procarbazine, and vincristine, and ABVD. However, because ABVD is generally regarded as superior to MOPP alternating with ABVD, it is not clear that the excess toxicity of BEACOPP, including sterility, justifies its use as standard chemotherapy in all patients receiving chemotherapy.

In the absence of definitive data that BEACOPP represents a superior therapeutic choice, it has been suggested that chemotherapy for Hodgkin disease should be stratified based on the basis of either risk (baseline prognostic status) or on the early response to therapy. For example, Dann and associates5 have demonstrated the feasibility of using standard BEACOPP for patients with an IPS of less than 2 and escalated BEACOPP for patients with an IPS of at least 3. Of course this begs the question of whether either BEACOPP regimen is necessary.

A further option is to alter therapy based on the early response to therapy. For example, in the aforementioned BEACOPP/escalated BEACOPP study, patients receiving escalated BEACOPP who became PET-negative after two cycles were switched to standard BEACOPP; patients receiving standard BEACOPP and remaining PET-positive after two cycles were switched to escalated BEACOPP. As yet, there are no data showing the superiority of this approach, but the results of the trial are awaited.

4. Salvage therapy. Salvage therapy may produce cures in patients with HL who relapse following initial therapy. However, the chance of curing a patient with relapsed HL is greater if the relapse is nodal than if the relapse is visceral. Additionally, the chance of cure is greater when the initial stage of disease was limited than when the initial stage was advanced.

For the rare patient treated with RT alone who experiences a limited nodal relapse, additional RT may be considered. If the recurrence represents a marginal miss at the edge of a radiation field, this may be feasible. However, if the recurrence is within a treatment field, further irradiation of the area is usually contraindicated and chemotherapy is needed. Furthermore, as fewer patients are treated with RT alone, this option is rarely clinically relevant.

For patients who relapse following chemotherapy, the variable that best predicts the chance of cure is the disease-free interval. Te data is clearest for patients treated with MOPP. Among patients initially treated with MOPP therapy, patients whose first CR lasted less than 1 year had a second CR rate of 29%, and only 14% of these second remissions lasted more than 4 years. Among patients whose first CR lasted more than 1 year, 93% achieved a second CR, and 45% of second CRs were projected to last more than 20 years. While the drugs used to obtain the first CR may be successful as salvage therapy, the general trend is to use drugs to which the patient has not been exposed. Tus, for patients treated with MOPP, the ABVD combination is the most commonly used salvage therapy. As ABVD has become the standard therapy, the regimens generally considered as salvage are ifosfamide, carboplatin, and etoposide (known as ICE); etoposide, methylprednisone, cytarabine, and cisplatin (known as ESHAP); and gemcitabine, vinorelbine, and doxorubicin (known as GND; Table 21.4).

However, rather than rely on salvage chemotherapy alone, the more common approach to salvage therapy is to follow a few cycles of salvage chemotherapy with high-dose chemotherapy in conjunction with ABMT or peripheral blood stem cell transplantation (PBSCT).

High-dose therapy in conjunction with ABMT or PBSCT is based on the rationale that bone marrow toxicity limits the dosages of the drugs that are most effective in HL. When autologous marrow or stem cells are stored and reinfused following chemotherapy, drug doses can be escalated to levels that would ordinarily be fatal in the absence of stem cell reinfusion. A number of standard preparative regimens exist for use in conjunction with ABMT and PBSCT, and some of these regimens are presented in Table 21.5.

Controlled trials comparing preparative regimens for autologous transplantation have not been conducted, and in view of the heterogeneity of relapsed patients with respect to prior therapy, sensitivity to therapy, site of relapse, and disease-free interval, it is impossible to compare regimens across studies. Nevertheless, as improvements incare, such as the use of granulocyte colony-stimulating factor (filgrastim) or granulocyte-macrophage colony-stimulating factor (sargramostim), have lowered treatment-related mortality to approximately 5%, it appears that long-term DFS may occur in approximately 50% of patients treated with ABMT or PBSCT. Patients who achieved long disease-free intervals with standard treatment seem to have the best chance for long-term DFS, and some studies have suggested that good performance status and persistent sensitivity to standard chemotherapy may predict an excellent response to autologous transplantation.

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E. Treatment of symptoms

Fever, and occasionally pruritis, may be disabling for some patients with HL. The basic approach to these problems is to treat the disease. However, if disease is drug resistant, that approach may be an oversimplification. Indomethacin 25 to 50 mg by mouth twice a day may be helpful in these patients. Anecdotal experience also supports the use of other nonsteroidal anti-inflammatory agents in these patients.

IV. FOLLOW-UP

Patients with HL who achieve a CR and who later relapse usually do so at a site of previous disease. Our policy for follow-up is to see the patient every 2 months for the first year, every 3 months for the second year, every 4 months during the third year, every 6 months during the fourth year, and every year thereafter. There is no standard panel of tests for routine follow-up, but our practice is to obtain CT scans or a whole body PET/CT every 6 months for 1 to 2 years, then every year for the next 3 to 4 years. If such tests suggest that disease has recurred, it is advisable to obtain pathologic confirmation before initiating salvage therapy.

Because of the risk of acute leukemia following therapy, we obtain complete blood counts at the time of each visit in patients who have received combination chemotherapy during the previous 8 years. Monitoring for hypothyroidism was discussed in the section on RT. While elevated sedimentation rates and lactic dehydrogenase levels may provide hints of relapse, we have not routinely used these tests for follow-up monitoring in our practice. Because women who receive RT above the diaphragm are at increased risk of breast cancer, we recommend yearly mammograms in these patients starting at age 40 or at 8 years following the completion of RT.

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