Hodgkin Lymphoma Treatment & Management

Treatment of Hodgkin lymphoma is tailored to disease type, disease stage, and an assessment of the risk of resistant disease. Hodgkin lymphoma is considered to be a curable malignancy, but therapies for this disease can have significant long-term toxicity. Therefore, advances in treatment protocols have sought to (1) minimize the treatment given to patients with early-stage, low-risk disease and (2) safely maximize the treatment given to patients with disease that is likely to be refractory to standard therapies.

This is particularly important in the elderly. As noted above, the elderly are at increased risk of not only developing Hodgkin lymphoma but also of developing toxicity from Hodgkin lymphoma treatment.^[14] Interest in decreasing the toxicity of therapy in the elderly is leading to newer regimens being developed, which have shown some early promising results but have not been directly compared with the existing standard regimens. One such regimen is procarbazine, vinblastine, doxorubicin, and gentamicin (PVAG), which showed excellent response rates and good tolerability in a phase 2 trial.^[15]

Because of the limited number of patients with Hodgkin lymphoma and the importance of the clinical questions that remain about optimal disease management, patient involvement in clinical trials is strongly encouraged.

Published guidelines from the National Comprehensive Cancer Network (NCCN),^[16] the European Society of Medical Oncology (ESMO),^[17] and the International Harmonization Project^[18] provide consensus opinions from leading experts on evidence-based approaches to the diagnosis and treatment of Hodgkin lymphoma.

Combined-modality therapy (radiation therapy [XRT] and chemotherapy) is frequently the preferred approach in for most patients. In early-stage disease, combined-modality therapy provides a synergistic effect while limiting the total exposure to any particular agent.^[19] However, some randomized trials have suggested that radiation may not be necessary in early stage disease and adds considerable toxicity. A study by Meyer et al that was performed before the use of limited field radiation, causing some problems with its interpretation provides the first evidence that radiation can safely be omitted in early stage Hodgkin lymphoma.^[20]

In patients with advanced Hodgkin lymphoma, involved-field XRT can be used for sites of persistent disease following chemotherapy. XRT to sites of disease that were bulky at diagnosis is a standard feature of the Stanford V regimen.

Despite the high rate of cure for this disease, many cases Hodgkin lymphoma do relapse. In most of these cases, salvage chemotherapy followed by high-dose chemotherapy (HDC) with autologous hematopoietic stem cell support is indicated.^[21] The role of allogeneic hematopoietic stem cell transplantation for Hodgkin lymphoma is being explored.^[22] This form of treatment should ideally be pursued only in the context of a clinical trial.

Nodular lymphocyte predominant Hodgkin disease (NLPHD) is clinically distinct from classic Hodgkin lymphoma in that it generally presents as early- stage disease that can be treated with local measures (surgery, radiation) or followed expectantly. However, some cases of NLPHD can transform to aggressive non-Hodgkin lymphomas that are treated using standard protocols.

The following consultations should be sought in cases of Hodgkin lymphoma:

• Hematologist/oncologist
• Radiation oncologist
• Social worker
• Tertiary care center for consideration of clinical trial enrollment

Two sets of consensus guidelines, written by the NCCN and the ESMO, currently help guide the standard of care for Hodgkin lymphoma. The guidelines are very similar, but the NCCN guidelines have more specific recommendations for response evaluation and follow-up.

In addition, a set of revised response criteria for malignant lymphoma, including Hodgkin lymphoma, and recommendations for using positron-emission tomography (PET) scanning to monitor Hodgkin lymphoma were published by the International Harmonization Project. Together, these 3 guidelines provide specific guidance for evaluating the response of disease therapy.

The primary goal of therapy is to induce a complete remission (CR), which is defined as the disappearance of all evidence of disease, as evaluated by PET/CT scanning, physical examination, and bone marrow examination (if appropriate).^[18] PET/CT scanning should be obtained at least 3 weeks and preferably 6-8 weeks following the last therapy in order to lessen the risk of false-positive scans resulting from nonmalignant inflammatory responses.

A partial remission (PR) is defined as "regression of measurable disease and no new sites" of disease. A failure to achieve a CR with initial therapy or a relapse after having attained a CR is an indication for additional HDC and/or XRT, often with autologous hematopoietic stem cell support.

The high sensitivity of positron emission tomography (PET) scanning for classic Hodgkin lymphoma has won this imaging modality a prominent role in the assessment of treatment response in affected patients. A positive PET scan following therapy correlates strongly with a high risk of relapse. An early attainment of a negative PET scan during therapy is a positive prognostic indicator, but studies have not yet provided information on whether a course of therapy can be safely shortened in this situation.^{[23, 24]}

PET/CT scans should be obtained at least 3 weeks, and preferably 6-8 weeks following the last therapy in order to lessen the risk of false-positive scans resulting from nonmalignant inflammatory responses.^[25] Biopsies of PET-positive lesions are typically done in order to test for persistent Hodgkin lymphoma.

For treatment of classic Hodgkin lymphoma, radiation therapy is generally administered in combination with chemotherapy. Radiation fields and doses are selected to minimizing the potential side effects of therapy, while maximizing the potential for long-term disease-free survival. Involved-field therapy encompasses only the areas of observed disease. Regional-field therapy extends the involved field to include adjacent lymph regions.

Other fields that have been used historically and may be used in exceptional clinical circumstances include the mantle field, covering the mediastinal, cervical, and axillary nodes; and the inverted Y field, covering the para-aortic, pelvic, and inguinal nodes. Subtotal nodal irradiation involves the mantle field plus the para-aortic nodes.

The mantle field is shaped in order to reduce radiation exposure to the heart and lungs. Careful avoidance of the spinal cord can reduce the risk of myelitis. Shielding the testes and oophoropexy (temporary surgical suspension of the ovaries [eg, outside of a radiation field]) are important during the reproductive years.

The dose of radiation to be administered is tailored to the specific clinical scenario. Doses used in combined modality therapy are 30-36 Gy for bulky disease sites and 20-30 Gy for nonbulky disease sites. When radiation therapy is used alone, doses may range from 30-44 Gy.

In the NLPHD subtype of Hodgkin lymphoma, involved-field radiation therapy may be recommended for stage IA and IIA disease.

The following induction regimens are given as initial treatment for Hodgkin lymphoma:

• MOPP (mechlorethamine, vincristine, procarbazine, prednisone)
• ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine)
• Stanford V (doxorubicin, vinblastine, mustard, bleomycin, vincristine, etoposide, prednisone)
• BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)

All the medications in these regimens are given intravenously, except for prednisone and procarbazine, which are given orally.

The MOPP regimen was the first effective combination chemotherapy for Hodgkin lymphoma. It is a 4-drug regimen developed by Vincent DeVita and colleagues at the National Cancer Institute in the mid 1960s and is primarily of historical importance.

The ABVD regimen was designed in Italy by Gianni Bonadonna and his colleagues in the early 1970s. This combination has now become the standard chemotherapy regimen for Hodgkin lymphoma. ABVD is superior to MOPP in terms of DFS and has a lower incidence of sterility and secondary leukemia.^[26]

The Stanford V regimen is a multidrug regimen created at Stanford University by Sandra Horning and colleagues.^[27] The drugs are administered weekly, alternating myelosuppressive and nonmyelosuppressive agents, for 12 weeks. Involved-field XRT at the conclusion of the 12-week regimen is an important part of this regimen. A potential advantage of the Stanford V regimen is that its use of a broad spectrum of chemotherapy drugs can limit the exposure (and potential side-effects) of any single drug.

The BEACOPP regimen was developed in Germany by Volker Diehl and colleagues.^[28] A dose-intensified version of BEACOPP (escalated BEACOPP), with higher doses of etoposide, doxorubicin, and cyclophosphamide and the addition of granulocyte colony-stimulating factor (G-CSF) for neutrophil support, has also been developed and may be useful for unfavorable, advanced-stage Hodgkin lymphoma. However, escalated BEACOPP is associated with greater hematologic toxicity and a higher incidence of secondary malignancies, including acute myelogenous leukemia (AML).

In a 10-year follow-up of the German Hodgkin Study Group HD9 trial, Engert et al reported that escalated BEACOPP significantly improved freedom from treatment failure (82% vs 70%) and overall survival (86% vs 80%) compared with baseline BEACOPP.^[29] The study compared the 2 doses of BEACOPP with COPP alternating with ABVD; COPP/ABVD has been the standard of care for this patient population, but freedom from treatment failure was only 64% and overall survival was only 75% in this group.

A study by Viviani et al demonstrated that BEACOPP produced better initial outcomes in patients with advanced Hodgkin disease than treatment with ABVD but found no significant long-term differences between the regimens.^[30]

Ongoing clinical trials will directly compare the ABVD regimen to the Stanford V and escalated BEACOPP regimens.

A study by Bauer et al found that patients aged 16-60 years with early unfavorable or advanced stage disease benefitted from escalated BEACOPP in terms of progression-free survival; however, no significant difference was noted in overall survival.^[31]

While in general, Hodgkin lymphoma is curable for most patients, continued interest in the use of novel agents has led to the development of newer treatment regimens using newer targeted agents. For example, the monoclonal antibody rituximab, directed at the B-cell marker CD20, has been combined with standard ABVD in 2 early-phase-II trials, with interesting results.^{[32, 33]} While CD20 is most often not expressed on the malignant cell (ie, the HRS cell), anti-CD20 therapy appears to improve on the efficacy of ABVD in this disease. This may occur through changes in the tumor microenvironment by affecting associated nonmalignant lymphocytes. These data, while intriguing, require confirmation in phase III studies before they can become part of routine clinical practice. These studies are ongoing.

Induction chemotherapy schedules

The MOPP regimen is given every 28 days for 6 or more cycles, as follows:

• Mechlorethamine: 6 mg/m², days 1 and 8
• Vincristine: 1.4 mg/m², days 1 and 8
• Procarbazine: 100 mg/m², days 1-14
• Prednisone: 40 mg/m², days 1-14, cycles 1 and 4 only

The ABVD regimen is given every 28 days for 6 or more cycles, as follows:

• Adriamycin: 25 mg/m², days 1, 15
• Bleomycin: 10 mg/m², days 1, 15
• Vinblastine: 6 mg/m², days 1, 15
• Dacarbazine: 375 mg/m², days 1, 15

The Stanford V regimen is given as follows^[34] :

• Vinblastine: 6 mg/m², weeks 1, 3, 5, 7, 9, 11
• Doxorubicin: 25 mg/m², weeks 1, 3, 5, 9, 11
• Vincristine: 1.4 mg/m², weeks 2, 4, 6, 8, 10, 12
• Bleomycin: 5 units/m², weeks 2, 4, 8, 10, 12
• Mechlorethamine: 6 mg/m², weeks 1, 5, 9
• Etoposide: 60 mg/m² twice daily, weeks 3, 7, 11
• Prednisone: 40 mg/m², every other day, weeks 1-10, tapered weeks 11, 12
• XRT to bulky sites 2-4 weeks following the end of chemotherapy

The escalated BEACOPP regimen is given every 3 weeks for 8 cycles, as follows:

• Bleomycin: 10 mg/m², day 8
• Etoposide: 200 mg/m², days 1-3
• Doxorubicin: 35 mg/m², day 1
• Cyclophosphamide: 1,250 mg/m², day 1
• Vincristine: 1.4 mg/m², day 8
• Procarbazine: 100 mg/m², days 1-7
• Prednisone: 40 mg/m², days 1-14

When induction chemotherapy fails, or patients experience relapse, salvage chemotherapy is generally given. Salvage regimens incorporate drugs that are complementary to those that failed during induction therapy. Commonly used salvage regimens include the following:

• ICE (ifosfamide, carboplatin, etoposide)
• DHAP (cisplatin, cytarabine, prednisone)
• ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin)

Salvage chemotherapy schedules

The ICE regimen is given as follows:

• Ifosfamide: 5 g/m², day 2
• Mesna: g/m², day 2
• Carboplatin: AUC 5, day 2
• Etoposide: 100 mg/m², days 1-3

The DHAP regimen is given as follows:

• Cisplatin: 100 mg/m², day 1
• Cytarabine: 2 g/m², given twice on day 2
• Dexamethasone: 40 mg, days 1-4

In the EPOCH regimen, etoposide, vincristine, and doxorubicin are given together over a total of 96 hours in a continuous intravenous infusion, as follows:

• Etoposide: 50 mg/m², days 1-4
• Vincristine: 0.4 mg/m², days 1-4
• Doxorubicin: 10 mg/m², days 1-4
• Cyclophosphamide: 750 mg/m², day 5
• Prednisone: 60 mg/m², days 1-6

High-dose chemotherapy (HDC) at doses that ablate the bone marrow is feasible with reinfusion of the patient's previously collected hematopoietic stem cells (autologous transplantation) or infusion of stem cells from a donor source (allogeneic transplantation). Patients with refractory or relapsed Hodgkin lymphoma should be promptly referred to centers capable of HDC with hematopoietic stem cell support.

Historically, hematopoietic stem cells have been obtained from bone marrow, but they are now typically obtained by pheresis of peripheral blood lymphocytes. A validated and relatively safe conditioning regimen for autologous transplantation is the BEAM regimen (carmustine [BCNU], etoposide, cytarabine, melphalan).^[21]

Myeloablative chemotherapy

High-dose therapy, which requires hematopoietic stem cell support for recovery, is given according to the BEAM regimen. Different schedules for BEAM exist that vary primarily in the dose of etoposide administered. The following is the version used by Schmitz et al in a key randomized, prospective clinical trial^[21] :

• BCNU 300 mg/m², day –7
• Etoposide 150 mg/m², every 12 hours, total of 8 doses, days –7 to –4
• Cytarabine 200 mg/m², every 12 hours, total of 8 doses, days –7 to –4
• Melphalan 140 mg/m², day –3

Following this chemotherapy regimen, autologous hematopoietic stem cells are administered on day 0.

Patients with clinical stages IA or IIA classic Hodgkin lymphoma who do not have unfavorable factors (ie, bulky disease, elevated ESR, >3 sites of involvement, B symptoms, extranodal disease) are categorized as having early-stage, low-risk disease.^{[19, 35]} These patients generally should receive 2-4 cycles of the ABVD regimen or 8 weeks of the Stanford V regimen, followed by involved-field XRT.

Radiation alone has been shown to be inferior to the combined modality approach in early stage, low-risk disease. If XRT is contraindicated or not possible, then chemotherapy should continue for 2 additional cycles following the attainment of a CR.

In a multicenter, randomized trial, Engert et al determined that 2 cycles of ABVD followed by 20 Gy of involved-field radiation therapy (IFRT) is as effective as 4 cycles of ABVD followed by 30 Gy of involved-field radiation in patients with early-stage Hodgkin lymphoma who had a favorable prognosis. Toxic effects and adverse events were more common in the group who received the 4 cycles of ABVD and higher dose level of radiation.^[36] This study has led most investigators to recommend 2 cycles of ABVD and 20 Gy of IFRT for patients with early-stage, low-risk disease; however, some studies looking at chemotherapy alone have been published, showing no difference in outcomes when chemotherapy with ABVD was compared with ABVD without radiation in early stage Hodgkin lymphoma.^[20] A study by Barbaro et al is limited by the use of outdated expanded fields, but taken together, the data suggest that either 2 cycles of ABVD with 20 Gy IFRT or 4-6 cycles of ABVD alone are appropriate for early stageHodgkin lymphoma.

Patients with clinical stages I or II with bulky disease, with or without unfavorable factors (ie, elevated ESR, >3 sites of involvement, B symptoms, extranodal disease), are classified as having early-stage disease with unfavorable factors. Chemotherapy plus involved-field XRT is indicated for these patients. The German Hodgkin Study Group HD11 trial demonstrated that ABVD was equivalent to BEACOPP in this setting, so the lower-toxicity regimen (ABVD) is preferred.^[37] Stanford V with involved-field XRT is another reasonable option.

In general, these patients would be treated with 2 cycles of ABVD and have an interim PET scan, the results of which will dictate further therapy. In general, 2 cycles beyond best response (or maximum of 6 cycles of ABVD) is used. Patients with residual disease should always have repeat biopsies to determine therapy. Those with initial bulky disease should have IFRT.

Patients are considered to have advanced disease if they are stage III or IV. Chemotherapy is the mainstay of therapy, with radiation reserved for initial bulky sites or residual PET activity. The NCCN recommends either 4 cycles of the ABVD regimen or 12 weeks of the Stanford V regimen, followed by restaging with PET/CT scanning. If a patient has positive results on PET scans following the ABVD regimen, an additional 2 cycles are administered.

Once a CR has been achieved, involved-field XRT is given to sites of intial bulky disease. If, after 12 weeks of the Stanford V regimen, a patient is in a CR or PR has been attained, then involved-field XRT is standard.

EMSO recommends that patients with this category of disease receive either 8 cycles of the ABVD regimen or the standard-dose BEACOPP regimen, with involved-field XRT applied only to tumors initially more than 7.5 cm or to sites of residual disease following chemotherapy. For patients with advanced-stage disease, the use of the escalated BEACOPP regimen has support in the literature.

However, a recent study by Viviani et al calls the use of escalated BEACOPP into question. In this study, while initial disease control was better with BEACOPP than with ABVD, long-term survival was no different because nonresponding patients were effectively salvaged with high-dose chemotherapy and stem cell transplantation. These data suggest that ABVD should be the initial treatment of choice for the majority of advanced stage patients.^[38]

Early-stage NLPHD can be treated with local excision, involved-field XRT, or expectant management (close observation).^[39] Advanced-stage disease may represent histologic transformation to T-cell rich B-cell lymphoma (TCR-BCL) or diffuse large cell B-cell lymphoma (DLCBL). These are types of non-Hodgkin lymphoma that should be treated with a typical non-Hodgkin regimen, such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).

Rituximab is a humanized monoclonal antibody that is specific for CD20, a cell-surface antigen expressed by the malignant lymphocytic and histiocytic (L&H) cells in NLPHD. It has shown activity as a single agent in NLPHD. On long-term follow-up, the German Hodgkin Lymphoma Study Group observed a 94% overall response rate, with 8 complete remissions, from their population of 15 patients treated with rituximab for relapsed/refractory NLPHD.^[40]

Therefore, rituximab is a promising agent for advanced NLPHD. Nevertheless, the use of rituximab in NLPHD, especially in early-stage disease, should ideally be pursued in the context of a clinical trial.

A phase 2 study by Eichenauer et al found that results with rituximab appear inferior when compared with radiotherapy and combined-modality treatment in patients with early stage NLPHD. However, the authors concluded that investigation of anti-CD20 antibody–based combinations in patients with NLPHD is indicated.^[41]

An era-to-era comparison between ABVD treatment and radiotherapy alone found that treating limited-stage NLPHD similar to classical Hodgkin lymphoma may improve outcome compared with the use of radiation alone.^[42]

In patients with advanced Hodgkin lymphoma and HIV infection, the results with standard chemotherapy (eg, ABVD, BEACOPP) can be dramatically improved by simultaneous treatment with highly active antiretroviral therapy (HAART). Such therapy generally involves 3 drugs: 2 nucleoside reverse transcriptase inhibitors combined with a protease inhibitor, a nonnucleoside reverse transcriptase inhibitor, or a viral fusion inhibitor.

Patients with Hodgkin lymphoma who have never entered a CR, or whose disease has relapsed after the attainment of a CR, have a very poor prognosis when treated with standard chemotherapy and radiation. Therefore, high-dose chemotherapy with autologous stem cell transplantation is recommended for these patients.^[43]

In this procedure, salvage chemotherapy is first administered to help reduce the size of the persistent disease and obtain a CR, if possible. The number of cycles to be administered depends on how well the disease is responding to therapy. An optimal situation is one in which the disease enters a CR with negative PET scan findings, although one study demonstrated that patients may achieve long-term disease-free survival even if their condition has little or no response.^[44]

Following one of the cycles of salvage chemotherapy, hematopoietic stem cells are collected from the peripheral blood by leukapheresis and are stored frozen. Following the administration of myeloablative chemotherapy (eg, BEAM), the stored hematopoietic stem cells are thawed and reinfused into the patient to facilitate hematopoietic recovery. HDC with autologous stem cell transplantation can provide better than 50% long-term, progression-free survival for patients with relapses, although specific predicted outcomes vary widely depending on patient-specific risk factors.

Many questions relating to salvage and HDC therapy for patients with Hodgkin lymphoma need to be addressed and are the subject of ongoing clinical trials. These include the following:

• The optimal salvage regimen or regimens
• The ideal conditioning regimen or regimens
• The potential benefits of twin transplants compared with single transplants
• How to prospectively identify those patients who are unlikely to benefit from HDC and how to best manage their disease

In some cases in which HDC fails, allogeneic stem cell transplantation may be a viable option. In this method, myeloablative therapy (chemotherapy and sometimes XRT) is followed by the infusion of hematopoietic stem cells from a genetically matched donor.^[22] This offers the potential for an immunologic antitumor effect from T cells provided by the hematopoietic stem cell donor, which may improve the chances for cure of the disease.

Historically, allogeneic stem cell transplantation for Hodgkin lymphoma has been considered too high-risk for most patients, due high transplant-related mortality. However, new transplant protocols use less toxic conditioning regimens and may be safer and more effective for patients with refractory Hodgkin lymphoma.^[45]

Brentuximab vedotin was approved by the US Food and Drug Administration (FDA) in August 2011. It is a CD30-directed antibody-drug conjugate consisting of IgG1 antibody cAC10, specific for human CD30, and the microtubule disrupting agent, monomethyl auristatin E (MMAE, or vedotin).^[46] Results from a study of patients with Hodgkin lymphoma in whom autologous stem cell transplantation and a median of 4 chemotherapy regimens had failed (n = 102) showed that 73% (95% confidence interval [CI], 65-83%) achieved an objective response to brentuximab vedotin therapy, including 32% with complete remission (95% CI, 23-42%) and 40% with partial remission (95% CI, 32-49%). Response duration averaged 6.7 months (range, 1.3-21.9 mo).^[47]

A phase 2 study by Witzig et al found that the oral farnesyltransferase inhibitor tipifarnib has activity in refractory or relapsed lymphoma, particularly in heavily pretreated T-cel and Hodgkin lymphoma groups, with little activity in non-Hodgkin lymphoma. Further studies are warranted.^[48]

Targeted immunotherapeutic agents are currently being evaluated for potential use in Hodgkin lymphoma.^[23] The CD30 cell surface antigen, which is expressed at high levels on Reed-Sternberg cells, is a target of 2 monoclonal antibodies, SGN-30 and MDX-60.^{[49, 50, 51]} In August 2011, the US Food and Drug Adminisration (FDA) granted fast-track approval to brentuximab, a CD30 antibody–drug condjugate, for the treatment of relapsed/refractory Hodgkin lymphoma that has progressed on 2 other lines of multiagent chemotherapy. This agent was approved based on early clinical trials suggesting a complete response rate of 34% and an objective response rate of 74%.^[52]

Cardiac disease

Mantle radiotherapy increases the risk the risk of coronary artery disease, chronic pericarditis, pancarditis, valvular heart disease, and defects in the conduction system.^{[53, 54]} Patients with history of mediastinal radiation have a 3-fold increase in their risk of cardiac death.

A study of patients who had previously undergone mediastinal irradiation for Hodgkin lymphoma but who had no clinical evidence of heart disease demonstrated a significant incidence of silent coronary artery obstruction and previous ventricular damage.^[55] Based on these results, it is reasonable to initiate functional screening 5 years after XRT in patients with Hodgkin lymphoma.

Pulmonary disease

The ABVD regimen contains bleomycin, a drug associated with dose-related pulmonary toxicity, mainly interstitial pneumonitis, which may lead to fibrosis. The addition of mantle irradiation enhances lung injury. Pulmonary symptoms, such as cough or dyspnea on exertion, are observed in 50% of patients, and declining pulmonary function is observed in approximately one third of patients during ABVD chemotherapy, with or without radiation therapy. This may necessitate dose reductions or even discontinuation of bleomycin.

Although acute toxicity is common, the incidence of severe long-term pulmonary toxicity is low. Fatal pulmonary toxicity has been reported in up to 2-3% of patients treated with the ABVD regimen.

Secondary cancers

Secondary leukemias and solid tumors are significant causes of morbidity and mortality for patients who have received early therapies, including the MOPP regimen and mantle radiation therapy. With modern therapies that emphasize the widespread use of the ABVD and Stanford V regimens and the application of radiation to involved fields only, the incidence of secondary cancers is expected to be much lower.

The most common secondary malignancy following treatment for Hodgkin lymphoma is lung cancer. Both chemotherapy with alkylating agents and irradiation are associated with a 10-fold increased relative risk of lung cancer. Smoking can further increase the risk.

In addition, retrospective data have suggested that survival is worse in Hodgkin lymphoma survivors who develop lung cancer compared with matched cohorts with de novo lung cancer.^[56]

Myelodysplastic syndromes/acute myelogenous leukemia (MDS/AML) is a particular concern. In the Stanford case series, the projected risk for developing MDS/AML over a follow-up period of 35 years was 2%, and the relative risk compared with matched controls was 38%. The MOPP regimen is associated with an approximately 5% incidence of MDS/AML. With the ABVD regimen the risk is lower, less than 1%.

MDS/AML is usually seen in the first 3-8 years following treatment for Hodgkin lymphoma; subsequently, the risk appears to decline. These findings are consistent with the biology of secondary leukemias following alkylator therapy. MDS/AML usually develops in the context of an MDS with cytogenetic abnormalities in chromosomes 5 and/or 7. Exposure to alkylating agents (eg, the mechlorethamine used in the MOPP regimen) has been implicated.

Exposure to epipodophyllotoxins (etoposide and teniposide) may also result in AML, which generally develops within 3 years and is associated with chromosomal abnormalities at band 11q23.

Breast cancer is 19 times more likely to occur in patients treated with mantle radiation therapy when they are younger than 30 years. If female patients are exposed to chest radiation therapy when they are younger than 15 years, this relative risk increases to 136. MOPP chemotherapy also produces an increased risk for breast cancer when combined with XRT.

Patients in the Stanford case series were also found to have increased risks of developing a variety of other cancers. These include melanoma, non-Hodgkin lymphoma, soft-tissue sarcoma, salivary gland cancers, pancreatic cancers, and thyroid cancers.

A study by Swerdlow et al found that the risk of second malignancy from chemotherapy alone is lower and affects fewer anatomic sites than combined treatment modalities. The authors concluded the risk of second malignancy was slight after 15 years.^[57]

Taken in aggregate, these trial results suggest that altering the treatment paradigms of Hodgkin lymphoma to maximize curability while preventing long-term complications should be a focus of ongoing research. Using the least amount of therapy required to cure the disease and minimize complications should be the goal. Early results have suggested that modification of treatment is feasible and have shown some decreased rates of secondary cancers.^[58]

Infertility

MOPP chemotherapy causes permanent infertility in at least 80% of males and approximately 50% of females. Young females may maintain their ovarian function, and some studies suggest that this may be improved by the use of oral contraceptives.^[59] The escalated BEACOPP regimen is also likely to impair fertility.^[60]

The ABVD and Stanford V regimens pose a lower risk of permanent sterility than regimens that contain an alkylating agent (eg, MOPP chemotherapy).^[61] The EORTC Lymphoma Group reported an 82% rate of recovery of fertility in male patients who were treated without alkylating agents.

Infectious complications

Patients who have undergone splenectomy are predisposed to bacterial sepsis secondary to encapsulated microorganisms (especially Streptococcus pneumoniae). Empiric antibiotic therapy should be instituted promptly in patients who have undergone splenectomy and present with fever. Pneumococcal vaccination before splenectomy and every 5-7 years thereafter is also recommended.

Influenza vaccination annually may help to reduce the incidence and/or complications of influenza in patients who have received bleomycin or chest radiation therapy.

Herpes zoster usually appears in previously irradiated dermatomes, but this condition may also occur in patients who have not been irradiated.

Other complications

Lhermitte syndrome(an electric-shock sensation that radiates along the back and legs upon flexion of the neck) can occur in approximately 15% of patients after mantle irradiation. Lhermitte syndrome is not associated with the development of radiation myelitis, and it does not require treatment. This syndrome may last for many months, but it will eventually resolve without long-term sequelae.

Elevation of thyroid stimulating hormone (TSH) occurs in one third of adult patients after neck/mediastinal radiation therapy.

Survivors of Hodgkin lymphoma have an increased incidence of fatigue, psychiatric distress (anxiety, depression), employment problems, family issues, and sexual functioning problems, as compared with individuals without this disease or relative to survivors of acute leukemia.^{[62, 63]}

Both the NCCN and the ESMO guidelines provide recommendations for the long-term follow-up of treated patients with Hodgkin lymphoma who are in complete remission.^{[16, 17]} Most relapses occur in the first 3 years after therapy. Follow-up visits are recommended every 2-4 months for the first 1-2 years and every 3-6 months for the next 3-5 years.

Follow-up examinations include the following:

• History and physical examination
• Complete blood cell count and chemistry panel, including lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), glucose, and lipid levels
• Thyroid-stimulating hormone (TSH) levels (at least annually if the patient has had neck XRT)
• Chest x-ray or CT scans of the chest every 6-12 months in the first 2-5 years
• Abdominal and pelvic CT scans may be added every 6-12 months in the first 2-3 years, especially if the disease originally occurred below the diaphragm
• Spiral chest CT scans may be appropriate annually, starting 5 years after therapy, to screen patients at increased risk for lung cancer
• Female patients who have received chest irradiation should be screened annually with mammography, starting at age 40 years or 5-8 years following the XRT

Use of PET scans for surveillance in patients with complete remission is specifically not encouraged by the NCCN, due to the possibility of false-positive results.

Vaccinations against pneumococcus (especially in patients who have had splenectomy), Haemophilus influenzae, meningococcus, and influenza (annually, especially in patients who have received bleomycin or chest XRT), should be maintained.

Lung injury may result from mantle irradiation or ABVD chemotherapy. Baseline tests and follow-up evaluation with pulmonary function tests are recommended. The best parameter to follow is the carbon monoxide diffusion capacity.

Prominent goals in the follow-up of survivors of Hodgkin lymphoma include the following:

• Identify secondary cancers in a timely manner
• Consider sepsis as a possible cause for fever in a splenectomized patient
• Diagnose and treat predictable complications of Hodgkin lymphoma treatment, such as coronary artery, pulmonary, or thyroid disease