Editors: Skeel, Roland T.
Title: Handbook of Cancer Chemotherapy, 7th Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 22 - Hodgkin's Lymphoma
Richard S. Stein
David S. Morgan
Hodgkin's lymphoma ([HL], Hodgkin's disease, HD) is a lymphoproliferative malignancy that accounts for approximately 1% of cancers in the United States. HL almost always presents as solitary or generalized lymphadenopathy, and as documented by clinical observation and by data collected during staging laparotomy, HL generally spreads in a contiguous manner. Most patients present with disease limited to lymph nodes or to lymph nodes and the spleen. The average age at presentation is 32 years with a bimodal incidence curve: one peak occurs at age 25, the other at age 55.
Patients with limited disease can be cured by radiation therapy; patients with advanced disease can be cured by combination chemotherapy. One of the major issues in HL therapy over the last two decades is where to draw the line between limited and advanced disease. Over time, the trend has been to consider chemotherapy for lesser stages of disease.
While HL is highly curable at presentation, patients with relapse following initial treatment may be cured by salvage therapy. Salvage chemotherapy may produce cures in patients initially treated with radiation therapy. 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 HL is a malignancy and that approximately 20% to 25% of patients initially diagnosed with HL eventually die of the disease.
The success in the salvage therapy of HL makes it difficult to offer definitive recommendations regarding initial treatment. For most malignancies, disease-free survival is a valuable surrogate marker for overall survival. However, for HL, the success of salvage therapy means that the treatment options that are associated with superior disease-free survival may not necessarily produce superior overall survival when the results of salvage therapy are considered. Additionally, when therapies have significant long-term consequences such as secondary malignancies associated with larger radiation therapy fields or acute leukemia associated with combined-modality therapy, disease free survival may overestimate the value of a specific therapy. Nevertheless, for each stage of HL, a number of rational therapeutic options exist.
I. Diagnosis and pathology
Diagnosis of HL requires 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. HL and other types of lymphoma may
HL has generally been subclassified into one of four subtypes: lymphocyte-predominant subtype (~5% of cases), nodular sclerosis subtype (~70% of cases), mixed cellularity subtype (~20% of cases), and lymphocyte-depleted subtype (<5% of cases). With the demonstration that lymphocyte-predominant HL is a B-cell neoplasm that is positive for CD20 and negative for CD30, the recent World Health Organization (WHO) classification of HL divides HL into two groups. The first group is nodular lymphocyte-predominant HL; the second group is classical Hodgkin's lymphoma, which includes nodular sclerosis HL, lymphocyte-rich classical HL, mixed cellularity HL, and lymphocyte depletion HL. Stage covaries with histology as patients with lymphocyte-depleted HL usually present with stage III or IV disease (retroperitoneal disease and/or bone marrow involvement). The average patient with mixed cellularity HL usually presents at a more advanced stage than the average patient with the nodular sclerosis subtype of HL. The presentation with cervical, supraclavicular, and mediastinal adenopathy in a young adult is classical for the nodular sclerosis type of HL. Because of this association of stage with histologic subtype, it is generally true that patients with the nodular sclerosis subtype of HL do better than patients with mixed cellularity HL, who, in turn, do better than patients with lymphocytedepleted HL. However, whenever one stratifies patients by stage of disease, the impact of histopathology on prognosis is minimal.
In determining therapy for the patient with HL, the critical variable is the stage of the patient. Accurate staging also provides a baseline so that the completeness of a response can be determined when therapy has been completed.
A. Cotswold staging system
The Cotswold modification of the Ann Arbor Staging System (Table 22.1) is used for patients with HL. Clinically, patients are placed in one of four stages and are further classified as to the absence A or presence B of symptoms. In addition, the subscript E (e.g., IIE) may be used to denote involvement of an extralymphatic site primarily or, more commonly, by direct extension, such as a large mediastinal mass extending into the lung. Stage III HL is often subdivided into stages III1 and III2 based on the extent of intra-abdominal disease.
B. Staging tests
Staging must be performed with consideration of therapeutic options, and not just to complete a checklist. When performing staging tests, one should remember that HL tends to spread in a contiguous manner. Considering that the thoracic duct makes the left supraclavicular area and the abdomen contiguous sites, it is not surprising that abdominal disease is found in 40% of patients with left supraclavicular presentations and in only 8% of patients with right
Table 22.1. Cotswold modification of the ann arbor staging system for hodgkin's lymphoma
History taking. As with any patient, the staging of the patient with HL begins with history and physical examination. 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. The 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 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 the visceral sites of involvement.
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.
Laboratory tests. Complete blood counts, erythrocyte sedimentation rate, serum alkaline phosphatase, and tests of liver and kidney function should be obtained. Hepatic
Chest x-ray and computed tomography (CT) scans. A chest x-ray and CT scans of the chest, abdomen, and pelvis are routinely obtained in patients with HL.
Positron emission tomography (PET) scan. PET scans have been shown to be highly reliable in detecting relapse and persistent disease and therefore should be obtained at baseline to document that tumor is PET positive. The PET scan is especially helpful when the post-treatment CT scan shows a residual mass that could be either scar or tumor.
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.
Staging laparotomy. Staging laparotomy is the most accurate means of determining the extent of abdominal involvement with HL but is of historical interest only as staging laparotomy is rarely performed. Instead, most clinicians are willing to make clinical decisions on the basis of radiologic staging and to compensate for uncertain clinical staging by administering chemotherapy.
III. Therapy of Hodgkin's 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 22.2, which also presents an estimated cure rate for each stage. Historically, limited stages of HL (stages IA and IIA) have been treated with radiation therapy, while advanced stages (IIIB, IVA, and IVB) are generally treated with combination chemotherapy. For intermediate stages (IIB, IIIA), the tendency of most oncologists is to treat these patients with combination chemotherapy. Despite the success in the treatment of HL, decisions regarding the optimal choice of therapy for all stages of HL have become more complex.
Late complications of radiation therapy for HL include breast cancer, lung cancer, hypothyroidism, thyroid cancer, coronary artery disease, and valvular heart disease. While the incidence of each of these complications is fairly low, the cumulative risk of all of these complications may be as much as 15% at 15 years following treatment. It is therefore reasonable to consider chemotherapy or chemotherapy plus involved field radiation therapy as an approach to limited-stage HL. Unfortunately, there are no data showing that the overall survival of patients with limited-stage HL can be improved with this alteration of therapy and studies designed to illustrate the superiority of this approach may require 15 to 20 years of observation to prove the point. Thus, after decades of knowing that radiation therapy was the optimal approach
Table 22.2. Hodgkin's lymphoma: incidence of stages and results of therapy
While chemotherapy has clearly been established as the optimal therapy for advanced-stage disease, clinical trials have not resolved the question as to which regimen represents optimal treatment. Regardless of which chemotherapy regimen is chosen, standard regimens should not be altered arbitrarily as dose reductions may decrease the possibility of cure. Although most patients receive six cycles of chemotherapy, the data actually support the policy of 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. While the tumor lysis syndrome has not been reported in HL, it is prudent to administer allopurinol during the first cycle of chemotherapy or during the first 2 weeks of radiation therapy.
B. Radiation therapy
Studies conducted in the 1960s established that the optimal dose for local control is 36 to 40 Gy given over 3.5 to 4.0 weeks. Standard radiation therapy ports are illustrated in Fig. 22.1.
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 radiation therapy. Patients with elevated levels of TSH, even if clinically euthyroid, should be placed on thyroid hormone replacement to limit stimulation of the irradiated thyroid gland by elevated levels of TSH. While radiation therapy alone has not been associated with an increased risk of acute leukemia, the use of radiation therapy in conjunction with combination chemotherapy has been associated with a risk of acute nonlymphocytic leukemia as high as 7% to 10% in the decade following therapy.
Women receiving radiation therapy for HL are at higher risk of developing breast cancer, and the younger the woman
Figure 22.1. Standard radiation ports used for the treatment of Hodgkin's lymphoma. For disease presenting above the diaphragm, the mantle plus para-aortic and splenic ports would be regarded as extended-field radiation therapy. The use of all three ports would be considered total nodal irradiation. (Reprinted by permission from Salzman JR, Kaplan HS. Effect of prior splenectomy on hematologic tolerance during total lymphoid radiotherapy of patients with Hodgkin's disease. Cancer 1972;27:472.)
C. Treatment by stage of disease
Stages IA and IIA. Patients with stage IA disease are most commonly treated with mantle irradiation when the disease occurs above the diaphragm (as it does in 90% of cases) or with pelvic radiation therapy when the disease presents in an inguinal node. Patients with stage IIA disease presenting above the diaphragm are most commonly treated with mantle plus para-aortic splenic radiation therapy. While the use of more extensive radiation fields has been associated with a significantly lower
Alternatively, clinicians may treat patients with stage IA or IIA disease with chemotherapy such as ABVD plus involved field radiation therapy. While the addition of chemotherapy to radiotherapy in limited-stage disease has been shown to decrease the rate of relapse, as with the use of more extensive radiation therapy fields, this approach has not been associated with superior overall survival. This is due in large part to the fact that patients who relapse after radiation therapy alone may be salvaged by chemotherapy.
In attempts to limit long-term toxicity, investigators at Stanford have studied the use of involved field radiation in conjunction with a combination chemotherapy regimen that is less toxic than usually employed, specifically, vinblastine, bleomycin, and methotrexate (VBM). Early results have been encouraging, but long-term follow-up will be needed to determine if late complications are significantly decreased by this approach. At this time, the following treatment options can be justified for patients with stage IA or IIA disease:
Involved field radiation therapy (for stage IA only),
Extended field radiation therapy,
Involved field radiation therapy with combination chemotherapy, and even
Combination chemotherapy alone.
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 radiotherapy alone, the risk of relapse approaches 50%. Combination chemotherapy with radiation therapy is most commonly employed in these patients. However, it is not clear that radiation therapy is necessary for all patients. Clearly, disease-free survival is superior when combinedmodality therapy is given. However, as stated previously, disease-free survival is not a surrogate for long-term cure in Hodgkin's lymphoma. Combined-modality therapy is associated with an increased risk of acute leukemia, as high as 7% to 10% in the decade following therapy, and the addition of radiation therapy to chemotherapy creates a long-term risk of lung cancer and breast cancer. Therefore, the necessity of a combined-modality approach for all Stage IIX patients is not established.
One approach is to treat the stage IIX patients with combination chemotherapy and to give low-dose radiation therapy (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. Unfortunately, whereas
Stages IB and IIB. In view of the limited number of patients with these stages of disease, available data do not allow firm treatment recommendations to be made. These patients are most commonly treated with extended field radiation therapy or radiation therapy in conjunction with combination chemotherapy such as MOPP, ABVD, or MOPP/ABV (Table 22.3). A discussion of the relative merits of the chemotherapy options for advanced-stage HL is found in the discussion of stage IIIB, IVA, and IVB disease.
Stage IIIA. Therapy for stage IIIA disease has become less controversial in the last 10 to 15 years, although consensus regarding the optimal therapy for these patients has not been achieved. Therapeutic options include total nodal radiation therapy alone, combination chemotherapy alone, or combined-modality therapy, that is, radiation therapy plus chemotherapy.
With the demonstration that combined-modality therapy was associated with a high risk of acute leukemia, this therapy fell out of favor. Additionally, studies in the early 1980s established that total nodal radiation therapy without chemotherapy was adequate only for patients with limited-stage III disease, that is, III1 disease. For patients with III2 disease, the use of radiation therapy alone was associated with a significant increase in mortality due to unacceptably high relapse rates and the inability of these patients to tolerate salvage chemotherapy at the time of relapse. If one decides to use different approaches to stage III1 and stage III2 disease, a staging laparotomy is necessary to definitively stage these patients. Since staging laparotomy is, essentially, never performed, the simplest approach to clinical stage III disease is to treat all stage III patients with combination chemotherapy.
Stages IIIB, IVA, and IVB. Combination chemotherapy is the standard approach to these stages of HL, although there remains some controversy as to which chemotherapy approach is optimal.
In 1970, the demonstration by investigators at the National Cancer Institute (NCI) that MOPP (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone) 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 disease could be cured by combination chemotherapy. This 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 probably not the optimal regimen for patients with advanced HL.
Dose and duration of therapy. Arguments regarding selection of the best regimen should not obscure the following principles:
Drugs should be administered in accordance with prescribed doses and schedules and not modified for toxicities
Table 22.3. Chemotherapy regimens used in the treatment of Hodgkin's lymphoma
Full doses should be given when cytopenias are due to bone marrow involvement with HL.
Vincristine should be decreased only in the presence of ileus, motor weakness, or numbness involving the whole fingers, not just the fingertips.
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.
Classical MOPP therapy. When MOPP was initially administered, 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. Thus, while late relapses have been seen on occasion, 5-year disease-free survival probably represents cure for most patients. Since 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.
Alternatives to MOPP induction therapy. Many efforts have been made to develop combination regimens that are more effective and less toxic than the standard MOPP regimen. Some regimens represent minimal modifications of MOPP, but the regimen that has attracted the most interest is ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine), a regimen composed of agents 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.
Chemotherapy regimens have been created with alternate cycles of MOPP and ABVD or to use a hybrid of MOPP/ABV, in which all drugs are given during each cycle. With use of the MOPP/ABV hybrid, a CR rate of 84% has been achieved. This CR rate was elevated to 97% by administration of radiation therapy to areas of residual adenopathy. At a median follow-up approaching 4 years, 90% of complete responders remained free of disease for a projected disease-free survival of 88%.
In a randomized trial that compared hybrid MOPP/ABV with sequential MOPP and ABVD, the hybrid regimen was found to be superior to the sequential regimen. The MOPP/ABV hybrid produced CRs in 83% of patients with a failure-free survival rate of 64%. However, because of the increased incidence of myelodysplasia associated with MOPP/ABV, ABVD has become the regimen of choice among MOPP, MOPP/ABV, and ABVD.
Although some investigators have combined chemotherapy with radiation therapy for the treatment of advanced disease, there is no evidence that the standard use of this approach can improve results enough to compensate for the leukemogenic risk of that practice. In selected patients with bulky disease, however, it is reasonable to consider
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 inHL. Favorable results have been reported by German investigators using BEACOPP and by investigators at Stanford using Stanford V. Doses of the latter regimen are included in Table 22.3. However, it has not been established that long-term results using these regimens are superior to those achieved with ABVD.
Salvage therapy. Salvage therapy may produce cures in patients with HL who have a 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 patients with limited nodal relapses following radiation therapy, additional radiation therapy 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 radiotherapy alone, this option is rarely clinically relevant.
For patients who have a relapse following chemotherapy, the variable that best predicts the chance of cure is the disease-free interval. 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. Thus, for patients treated with MOPP, the ABVD combination is the most commonly used salvage therapy. As ABVD has become a standard therapy, the regimens generally considered as salvage are MOPP, ICE, and ESHAP (Table 22.4).
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
Table 22.4. Salvage regimens in the treatment of Hodgkin's lymphoma
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 in supportive care, such as the use of granulocyte colony-stimulating factor ([G-CSF]; filgrastim) or granulocyte macrophage colony-stimulating factor ([GM-CSF]; sargramostim), have lowered treatment-related mortality to approximately 5%, it appears that long-term disease-free survival 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 disease-free survival and some studies have suggested that good performance status and persistent sensitivity to standard chemotherapy may predict an excellent response to autologous transplantation.
Table 22.5. Regimens used preparatory to autologous transplantation in Hodgkin's lymphoma
E. Treatment of symptoms
Fever, and occasionally pruritus, 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 over simplification. Indomethacin 25 to 50 mg PO t.i.d. may be helpful in these patients. Anecdotal experience also supports the use of other nonsteroidal anti-inflammatory agents in these patients.
HL patients 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 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 for patients who have received combination chemotherapy. Monitoring for hypothyroidism was discussed in Section III.B. While elevated sedimentation rates and lactic dehydrogenase (LDH) levels may provide hints of relapse, we have not routinely used these tests for follow-up monitoring in our practice. Since women who receive radiation therapy above the diaphragm are at increased risk of breast cancer, we recommend yearly mammograms in these
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