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Approach to the adult survivor of classic Hodgkin lymphoma

Approach to the adult survivor of classic Hodgkin lymphoma
Literature review current through: May 2024.
This topic last updated: Feb 15, 2024.

INTRODUCTION — Classic Hodgkin lymphoma (cHL; formerly called Hodgkin's disease) accounts for approximately 10 percent of all lymphomas. More than three-quarters of patients treated for cHL experience long-term survival without disease recurrence, but cardiovascular disease, second cancers, and other therapy-related adverse effects (AEs) cause morbidity and mortality among cHL survivors that may not be apparent until years after treatment.

Risk-reduction strategies and screening for late complications of treatment can lessen the impact of late AEs on cHL survivors.

This topic discusses an overview of management of the adult survivor of cHL beyond one year from completion of treatment, whether treatment was delivered as a child or as an adult.

Related topics include:

Second cancers after cHL therapy (see "Second malignancies after treatment of classic Hodgkin lymphoma")

Late complications of HL therapy in children and adolescents (see "Overview of Hodgkin lymphoma in children and adolescents", section on 'Late complications')

Our suggestions for management are consistent with guidelines published by the International Working Group and the National Comprehensive Cancer Network Clinical 2020 Practice Guidelines in Oncology [1,2].

RISK OF RELAPSE — Outcomes with Hodgkin lymphoma (HL) are influenced by initial disease stage and treatment. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

Most deaths in the first 5 to 10 years after treatment are associated with relapse of HL, while later deaths are more likely to be due to other causes (eg, second malignancy, cardiovascular disease). In a retrospective study of 1541 patients with early-stage HL treated with combined modality treatment (chemotherapy plus radiation therapy) or radiation therapy alone and followed for >15 years, non-HL mortality surpassed death from relapse of HL eight years after diagnosis [3]. In a multicohort study of 4919 patients with HL (treated from 1965 to 2000), with a median follow-up >20 years, HL patients experienced a fivefold higher risk of death due to causes other than HL; the absolute excess mortality (AEM) was estimated to be 123 excess deaths per 10,000 person-years [4]. Solid tumors and cardiovascular disease accounted for two-thirds of the AEM. A study of 20,007 patients treated from 2000 to 2015, which captured patients treated in the era of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and reduced use of radiation, HL remained the most common cause of death through 12 years of follow-up, and cardiovascular disease was the most common non-lymphoma cause of death [5].

Late complications of treatment for HL are described below. (See 'Late complications' below.)

Rates of relapse-free survival (RFS) and overall survival (OS) at five years can be summarized as follows:

Favorable prognosis, early-stage HL – RFS >90 percent, OS >95 percent [6-8] (see "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma")

Unfavorable prognosis, early-stage HL – RFS >85 percent, OS >90 percent [7-9] (see "Classic Hodgkin lymphoma (cHL): Treatment of unfavorable prognosis early (stage I-II) cHL in adults")

Advanced-stage HL – RFS 60 to 85 percent, OS 85 to 90 percent [10-12] (see "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma")

Most relapses of HL occur within the first two years of diagnosis, and the risk of relapse declines thereafter. As an example, in one study of 1402 patients with HL who were followed for a median of eight years, the risk of relapse within five years of diagnosis was 18 percent; for patients who were relapse-free at one, two, and three years, the risk of subsequent relapse was 10, 6, and 4 percent, respectively [13]. Although the risk declines with time, there is no time point after which relapses no longer occur. A retrospective study of nearly 7000 patients observed no plateau for late relapses of HL, and reported 2.5, 4.3, and 6.9 percent cumulative incidence of relapse at 10, 15, and 20 years, respectively [14].

Changes in therapy have led to improved prognosis for patients with HL [3]. Factors that contribute to better outcomes include improved staging, more effective and less toxic chemotherapy, advances in radiation therapy technique and delivery, and stratification of treatment based on prognostic factors. (See 'Evolution of "standard" treatment' below.)

TREATMENTS AND THEIR COMPLICATIONS — Selection of HL therapy influences the likelihood of certain long-term treatment-related complications. (See 'Late complications' below.)

Combination chemotherapy — The predominant modality for treating HL is combination chemotherapy, which generally includes several agents with non-overlapping toxicities. The most common long-term toxicities of chemotherapy for HL and agents associated with them are:

CardiacDoxorubicin

Neuropathy – Vinca alkaloids, brentuximab vedotin

PulmonaryBleomycin

Endocrine/InfertilityCyclophosphamide, nitrogen mustard

HematologicDoxorubicin, etoposide, mechlorethamine, cyclophosphamide

Second cancersProcarbazine, cyclophosphamide

Combination chemotherapy regimens used for treatment of classic HL (table 1) include:

ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) (see "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma")

A+AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine)

Stanford V (doxorubicin, vinblastine, nitrogen mustard, vincristine, bleomycin, etoposide, prednisone)

BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) (see "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma")

MOPP (mechlorethamine, vincristine, procarbazine, prednisone) [15,16]

Note that some of these regimens/agents (eg, Stanford V, MOPP) are no longer routinely used for treatment of HL, but they are included for historical reasons.

Radiation therapy — The major late effects of radiation therapy (RT) for HL include second malignancies and cardiac disease. Other late complications include thyroid dysfunction, pulmonary fibrosis, peripheral vascular disease, and muscle atrophy.

Benefits and complications of RT are influenced by radiation field, dose, and technique (table 2), as discussed separately. (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma".)

The dose-dependent cardiac toxicity of RT is illustrated by a study that included >1100 pediatric HL survivors who were treated on successive clinical studies (from 1975 to 1995) with diminishing doses of mediastinal RT [17]. The 25-year cumulative incidence of cardiac disease was 21, 10, 6, 5, and 3 percent in patients who received mediastinal radiation doses of 30, 25, 20, and 0 Gy, respectively.

Hematopoietic cell transplantation — Some patients with classic HL undergo hematopoietic cell transplantation (HCT), primarily for management of relapsed disease. Long-term complications of HCT are presented separately. (See "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults".)

Antibody-directed therapy — Antibody-directed therapy, including antibody-drug conjugates (eg, brentuximab vedotin) and checkpoint inhibitors (eg, nivolumab, pembrolizumab), may be utilized for consolidation of remission or for relapsed disease. Few data regarding long-term consequences of immunotherapy for HL are available. Immunotherapy for HL is discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma", section on 'Targeted chemotherapy and immunotherapy'.)

Splenectomy — Splenectomy was formerly used as a component of pathologic staging of HL, but this has been supplanted by clinical staging using imaging. Splenectomy increases the risk of certain infections, as discussed separately. (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function" and "Prevention of infection in patients with impaired splenic function".)

EVOLUTION OF "STANDARD" TREATMENT — The standard treatment of HL has evolved to utilize lower doses and smaller radiation fields, less toxic chemotherapy, and reduced radiation exposure from imaging studies. All-cause mortality (ie, deaths from HL relapse plus deaths from late complications of therapy) is significantly lower in patients treated in more recent eras [3].

Long-term complications of HL treatment reflect therapy from the era in which it was treated:

1960s and 1970s – Patients typically underwent pathologic staging with laparotomy and splenectomy. Early-stage HL was treated with extended-field radiation therapy (RT) to doses of 40 to 44 Gy [18]. Advanced-stage HL was treated with MOPP chemotherapy [19,20]. ABVD chemotherapy (table 1) was introduced in the late 1970s as a less toxic alternative to MOPP [15].

1980s – Clinical staging based on imaging studies supplanted pathologic staging. Early-stage HL was treated with extended-field RT. Advanced-stage HL was increasingly treated with ABVD chemotherapy after randomized trials showed significantly superior treatment outcome and lower toxicity compared with MOPP [21,22].

1990s – For early-stage disease, combined modality therapy with ABVD and more limited radiation treatment volumes and doses was shown to improve disease-free and overall survival [21,22]. Advanced-stage HL was treated with ABVD or Stanford V (table 1). High dose chemotherapy followed by stem cell support (ie, autologous hematopoietic cell transplantation) became available for treatment of patients with relapsed disease.

2000s – Most patients were and continue to be treated with ABVD chemotherapy, with or without limited RT (eg, 20 to 36 Gy), as consolidation [23]. BEACOPP was used for treatment of advanced disease, mostly in Europe [24].

The treatment of HL continues to evolve with a focus on improving disease control, while limiting treatment-related complications.

LATE COMPLICATIONS — The major causes of treatment-related morbidity and mortality in HL survivors are second cancers and cardiovascular disease. Other late complications include pulmonary dysfunction, endocrinopathies, infertility, neuromuscular complications, and psychosocial conditions. Deaths from treatment-related complications continue to increase with time after treatment of HL [25]. For HL survivors treated in the more recent era with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)-based chemotherapy and either reduced or no radiation therapy (RT), a significantly increased excess mortality from causes other than HL continued to be observed, especially among advanced-stage patients [5].

Second malignancies — Second cancers are the leading cause of death in long-term survivors of HL. Details of incidence (table 3) and risk factors for specific cancers after treatment for HL are provided separately. (See "Second malignancies after treatment of classic Hodgkin lymphoma".)

Non-Hodgkin lymphomas (NHL) and solid tumors account for most second cancers in HL survivors, with NHL, breast, lung, and colon cancer being the most frequent (table 3) [26-28]. Others include cancers of skin, thyroid, esophagus, colon, and sarcomas, typically in the areas of radiation. An increased risk for solid tumors begins to appear approximately five years after completing therapy, but continues to rise for at least 20 years, and perhaps indefinitely. Compared with the general population, the relative risk for solid tumors in adult survivors of HL is estimated at 1.5- to 4.5-fold; the relative risk is even greater in those treated for HL as children. Risk factors include radiation dose and field; chemotherapy agents and doses; age, sex, history of smoking, and family history of cancer. (See "Second malignancies after treatment of classic Hodgkin lymphoma", section on 'Solid tumors'.)

Acute myeloid leukemia (AML) and other hematologic malignancies are less common than solid tumors, but the relative risk is greater because of their lower incidence in the general population. The risk of AML peaks at five to nine years and is associated with chemotherapy (eg, alkylating agents, doxorubicin, etoposide) and RT; AML is extremely uncommon after treatment with ABVD. (See "Second malignancies after treatment of classic Hodgkin lymphoma", section on 'Acute leukemia'.)

Our approach to cancer screening in HL survivors is described below. (See 'Cancer screening' below.)

Cardiovascular disease — Cardiovascular (CV) disease is the most common non-malignant cause of death in long-term survivors of HL [3,29]. Treatment of HL is associated with coronary artery disease, valvular disease, pericardial disease, arrhythmia, cardiomyopathy, and peripheral artery disease.

Increased CV risk emerges soon after completion of treatment and remains elevated for the survivor's lifetime [29]. Pre-existing heart disease is the most significant predictor for post-HL therapy cardiac complications [30]. Other contributing risk factors are chemotherapy, RT, and traditional cardiac risk factors (eg, hypertension, hypercholesterolemia, smoking) [30-35]. Risk of non-coronary atherosclerotic disease is increased in patients who underwent RT to the neck, and in those with traditional cardiac risk factors. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" and "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

Informative studies of the risk of CV disease in HL survivors treated in the era of 1960s to 1990s include:

A study of >7000 patients with HL reported that, compared with the general population, the standardized mortality ratio for cardiac disease in HL survivors was increased 2.5-fold (95% CI 2.1-2.9) and remained elevated for at least 25 years [36]. Cardiac events were increased 10-fold in patients who received ABVD chemotherapy and 15-fold after supradiaphragmatic RT plus vincristine without anthracyclines.

In another study, when compared with community controls, adult survivors of HL at age 50 experienced twice the number of CV conditions and had fivefold more severe (grade 3 to 5) CV conditions; adult HL survivors had, on average, one severe, life-threatening, or fatal CV condition [37].

A prospective study screened 294 asymptomatic HL survivors with a history of chest irradiation [38]. Echocardiography detected mild or greater aortic regurgitation in 4.5, 22, and 60 percent of patients 2 to 10, 11 to 20, and >20 years after therapy, respectively; only 6 percent of cases were detectable by auscultation. There was a two- to threefold risk of diastolic dysfunction after 10 years, which was significantly associated with subclinical coronary disease, and subsequent cardiac events [39].

The risk of stroke in HL survivors is increased two- to sixfold compared with the general population [40,41].

Further details of cardiac complications of HL treatment are provided separately. (See "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies" and "Overview of Hodgkin lymphoma in children and adolescents", section on 'Late complications'.)

Monitoring for CV disease is discussed below. (See 'Cardiovascular health' below and "Risk and prevention of anthracycline cardiotoxicity".)

Other complications — Other late effects of treatment of HL include endocrine, pulmonary, and psychiatric complications.

Pulmonary dysfunction — Long-term survivors of HL are at risk for late pulmonary complications, including pulmonary fibrosis, bronchiectasis, chronic pleural effusions, and recurrent pneumonia [42-45]. Reduced pulmonary function can affect daily function and quality of life. (See "Radiation-induced lung injury" and "Bleomycin-induced lung injury".)

Factors that contribute to lung injury in HL survivors include bleomycin therapy, radiation pneumonitis, and smoking. In a prospective study of pulmonary function in HL patients who were treated with bleomycin-based chemotherapy, with or without mediastinal irradiation, smoking was associated with a persistently reduced diffusing capacity at one year [46]. Contemporary RT (ie, limited dose and field) and chemotherapy regimens (with reduced pulmonary toxic drugs) are expected to reduce the risk of long-term lung complications in future survivors.

Decreased lung function contributes to fatigue in HL survivors, as described below. (See 'Psychosocial issues' below.)

Endocrine/metabolic dysfunction — Between 30 and 60 percent of HL survivors who received neck irradiation will experience thyroid dysfunction, and most cases occur within the first five years after treatment [47]. Higher doses are associated with an increased risk.

Long-term risk of diabetes mellitus is not known to be increased in association with contemporary chemotherapy and RT. However, a retrospective study of 2264 HL survivors treated between 1965 and 1995 reported an increased incidence of diabetes mellitus among those who received ≥36 Gy para-aortic irradiation (14 percent at 30 years), especially among those treated at age <25 years; there was no increase of diabetes mellitus in patients who received lower doses of para-aortic irradiation [48].

Neuromuscular complications — HL survivors are at risk for neuromuscular complications (eg, neuropathy, muscular atrophy) following the completion of treatment.

Vinblastine and brentuximab vedotin are associated with peripheral neuropathy that usually stabilizes or improves after completion of treatment. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Vinca alkaloids'.)

Muscle atrophy in the neck and upper chest wall, known as "dropped-head syndrome" because of difficulty in keeping the head in an upright position, may occur decades after irradiation [49-51]. The pathogenesis is uncertain, but myogenic, neurogenic, and/or vascular factors may contribute. One study reported that, with a median of 23 years of follow-up, 83 percent of 20 patients experienced neck muscle weakness after mantle field RT [51]. Nearly all patients demonstrated myogenic changes on electromyography of the neck muscles and neurogenic damage in the deltoid, biceps, and/or antebrachial flexor muscles.

Fertility/pregnancy — Gonadal dysfunction can occur after treatment for HL but, in the absence of alkylating chemotherapy and/or pelvic radiation, ovarian function and pregnancy success are comparable to control populations.

One study, with median follow-up of 16 years, reported 3 percent premature ovarian failure (POF) in 460 women with HL who received nonalkylating chemotherapy between ages 15 and 40 years; the rate of POF was 60 percent in those treated with alkylating chemotherapy [52]. The risk of POF increased by 23 percent per year of age at treatment, and fewer women who developed POF bore children after treatment (22 versus 41 percent). In a study that used anti-Müllerian hormone (AMH) as a biomarker of ovarian function, women treated with ABVD showed recovery of AMH levels within 12 months of stopping treatment, while those who received cyclophosphamide showed no recovery [53]. The impact of immunotherapy (eg, PD-1 inhibitors) is uncertain at present.

Informative studies of pregnancy outcomes after treatment for HL include:

A prospective study, with a median follow-up of 20 years, reported that approximately one-half of 467 female survivors of childhood HL had at least one live birth [54]. Factors associated with a decreased likelihood of successful pregnancy included pelvic radiation and age ≥40 years at first conception; for those <40 years old, the likelihood of parenthood was similar to an age-matched population.

A survey of 453 HL survivors, with 15-year median time from last treatment, reported that most who attempted to have children were successful (63 percent of males and 75 percent of females) without infertility therapy [55]. Another study reported similar outcomes in women treated for HL, but lower rates in women who received BEACOPP or six to eight courses of chemotherapy plus RT [56].

A cohort study that included 192 children of female HL survivors reported no increased risk of preterm birth, low birth weight, stillbirth, or congenital anomalies [57].

In male survivors treated without alkylating agents, gonadal function is generally normal [58].

Broader discussions of fertility and pregnancy in childhood cancer survivors are provided separately. (See "Overview of cancer survivorship in adolescents and young adults", section on 'Fertility' and "Cancer survivors: Overview of fertility and pregnancy outcomes" and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Psychosocial issues — Mental health issues, neurocognitive problems, and impaired quality of life (QOL) are prevalent in HL survivors.

Persistent fatigue, anxiety, and depression are common in HL survivors [59-65]. A study of 4215 patients reported fatigue in one-quarter to one-third of patients two and five years after completing treatment for HL; increased age and fatigue at baseline were associated with later fatigue [65]. Some studies reported a correlation between increased fatigue and cardiac disease, pulmonary dysfunction, and other late treatment-related complications in HL survivors [60,63,66,67].

Adult survivors of childhood HL are at increased risk for neurocognitive impairment. One study reported impaired attention span, short- and long-term recall, memory, and cognitive fluency in 62 adults with HL who were treated with either high dose thoracic radiation or lower dose thoracic radiation plus an anthracycline [68]. The underlying pathophysiology is unclear, but neurocognitive impairment may be related to cerebrovascular pathology and/or cardiopulmonary dysfunction.

Many long-term HL survivors have impaired QOL, primarily due to problems with physical health and/or fatigue [69,70]. A longitudinal survey reported reduced motivation, emotional strain, and limitations in all functional domains except cognitive function among 935 patients treated for early-stage HL and followed for a median of 90 months [71]. Inferior QOL was associated with female sex and older age, but not with the type of treatment. Most functional domains of QOL improved within 18 months of the end of treatment.

HL survivors may suffer from job discrimination, difficulty in obtaining health and life insurance, marital problems, and decreased sexual functioning [72,73]. Some of these difficulties may be related to treatment-associated long-term cosmetic changes (eg, scarring and permanent local hair loss). However, a study comparing long-term HL survivors and their siblings found no difference in sexual function and satisfaction between the two groups [74]. A large study reported that patients with early-stage HL achieved a normal level of sexual QOL, while patients with advanced HL reported impaired sexual QOL when compared with healthy controls [75].

One study reported that lower socioeconomic status was associated with poorer adherence to routine health care and a higher likelihood of engaging in unhealthy habits, including physical inactivity, smoking, and moderate/heavy alcohol use [76].

POST-TREATMENT MANAGEMENT — Long-term management (ie, beyond one year from treatment) of the adult survivor of classic HL involves monitoring for disease relapse, surveillance for treatment-related complications, and routine health maintenance.

The time course of possible relapse and late complications of therapy is discussed above. (See 'Risk of relapse' above.)

Schedule — There is no consensus regarding the optimal schedule for follow-up, and clinical practice varies.

We suggest that patients should be seen at three- to six-month intervals during the first two years after completion of therapy, every 6 to 12 months until year 3, and annually thereafter. However, the frequency of visits and the nature of associated testing can be individualized based on clinical circumstances (eg, age, stage at diagnosis, initial treatment modality, social habits) and the comfort of both the patient and clinician. Our approach is consistent with recommendations of the United States National Comprehensive Cancer Network (NCCN) [23].

Our approach to monitoring the HL survivor for long-term complications is summarized in the accompanying table (table 4).

Follow-up visits may be with the treating hematologist/oncologist, a survivor clinic, or the primary care provider (PCP), as discussed below. (See 'Coordination of care' below.)

History and examination — The history and physical examination should seek clinical findings that might suggest disease relapse or treatment-related complications.

The interval history should probe symptoms suggestive of recurrent disease (eg, constitutional symptoms, pruritus, lymphadenopathy, abdominal fullness, dyspnea, wheezing), especially in the first three to five years after treatment. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Clinical presentation'.)

The history should also assess symptoms suggestive of treatment-related toxicity, including second cancers (with attention paid to prior radiation exposure), cardiovascular and musculoskeletal symptoms, and thyroid disease for the life of the HL survivor. (See 'Late complications' above.)

Physical examination should assess findings that might suggest relapse, second cancer, or other treatment-related complications (eg, lymphadenopathy, organomegaly, heart, lungs, peripheral vasculature, neuromuscular).

Laboratory studies — There are limited data and no consensus regarding the value of specific laboratory studies. Our suggestions follow:

Complete blood count (CBC) is performed at each visit for ≥10 years after completing treatment.

Metabolic/Endocrine testing

Lipid testing should be performed annually for all patients. (See "Screening for lipid disorders in adults".)

Fasting glucose or hemoglobin A1c should be tested every two years (or more often) in survivors who received chest or abdominal irradiation.

Serum thyroid stimulating hormone (TSH) should be obtained annually for patients who received radiation to the neck.

Electrolytes, kidney function, and liver function tests may be performed as clinically indicated.

Use of laboratory studies in monitoring the patient for complications of therapy is discussed below. (See 'Monitoring for complications' below.)

Imaging — We suggest not obtaining routine imaging studies for detection of relapse, as described below. (See 'Monitoring for relapse' below.)

Imaging for clinically suspected relapse and screening for second cancers is described below. (See 'Evaluation of potential relapse' below and 'Cancer screening' below.)

Immunization — Immunizations are important for preventing infections in survivors of HL. (See "Standard immunizations for nonpregnant adults" and "Immunizations in adults with cancer".)

Patients should be vaccinated annually against influenza and against Streptococcus pneumoniae. (See "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults".)

Indications for other vaccines depend upon age and/or other aspects of care. (See "Vaccination for the prevention of shingles (herpes zoster)" and "Immunizations in hematopoietic cell transplant candidates, recipients, and donors" and "Prevention of infection in patients with impaired splenic function".)

Risk awareness counseling — The following topics should be discussed with HL survivors at least annually:

Second cancers – Increased risk of a second malignancy and the importance of reporting worrisome symptoms. (See 'Cancer screening' below.)

Lifestyle/Cardiovascular risk and prevention – Smoking cessation, weight control, physical activity, limiting unprotected sun exposure, and other lifestyle changes to reduce risk and/or prevent late complications. (See 'Cardiovascular health' below and 'Lifestyle modifications' below.)

Neuropsychiatric sequelae – Mental health and quality of life should be assessed.

Monitoring for relapse — Monitoring for relapse of HL is an important part of all routine visits, especially in the first three to five years. (See 'Risk of relapse' above.)

There have been no prospective randomized studies of routine follow-up in patients with HL, and the screening value and cost-effectiveness of components of the screening evaluation are not clear. (See 'Schedule' above.)

We suggest not obtaining routine imaging studies (eg, positron emission tomography [PET], computerized tomography [CT], and/or PET/CT scans) in the absence of clinical findings of potential relapse. We seek to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. This approach is consistent with that proposed by the International Working Group and the National Comprehensive Cancer Network Clinical 2017 Practice Guidelines in Oncology – Hodgkin lymphoma [1,77]. However, the role of routine radiologic surveillance for relapse is controversial, and some experts suggest CT scans with contrast of the neck, chest, abdomen, and/or pelvis at 6, 12, and/or 24 months after completion of therapy [77].

Most relapses are detected following evaluation of a patient's symptoms rather than routine examination, blood tests, or imaging studies. A retrospective review of 210 patients who relapsed with HL reported that 81 percent of relapses were diagnosed in patients with symptoms; one-half of these symptomatic relapses resulted in an earlier appointment being scheduled [78]. Only four relapses were detected as a result of routine physical examination in an asymptomatic patient.

Routine imaging (ie, in the absence of symptoms) provides little additional benefit for detection of relapse. A population-based study of 2071 HL survivors reported that among 5352 CT scans performed two to five years after treatment, only 125 were followed within six months by the administration of chemotherapy [79]. A decision-analysis model reported decreased quality-adjusted life expectancy for patients with early-stage HL who were followed with CT for 5 or 10 years, when compared with patients who were followed by history, physical exam, and routine blood work (either with or without chest x-ray) [80].

Evaluation of potential relapse — Appropriate radiologic investigation should accompany any concern about symptoms or signs of possible recurrent disease. However, relapsed disease must be confirmed by biopsy before proceeding to subsequent therapy. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma", section on 'Confirming refractory/relapsed disease'.)

Monitoring for complications — HL survivors are at risk of developing therapy-related complications (eg, second cancers, cardiovascular disease) that cause significant morbidity and mortality and may present years after treatment [81,82]. (See 'Late complications' above.)

Monitoring for potential complications should include cancer screening, cardiovascular evaluation, endocrine assessment, and psychiatric screening (table 4). Early detection and risk-reduction strategies may reduce the adverse impact of late effects on HL survivors.

Cancer screening — Second malignancies are the leading cause of death in long-term survivors of HL. Types of cancer and the time course of development are described above and separately. (See 'Second malignancies' above and "Second malignancies after treatment of classic Hodgkin lymphoma".)

There is no consensus regarding the optimal screening program. Our approach is consistent with those proposed by the American Cancer Society [83,84], the Children's Oncology Group [85], and the National Comprehensive Cancer Network (NCCN) [23].

We suggest the following screening for second cancers (table 4) in patients treated for HL:

Hematologic malignancies – A complete blood count (CBC) should be obtained at each visit (for ≥10 years after completing treatment) to screen for bone marrow dysfunction (eg, myelodysplasia, leukemia), although this may not be necessary after treatment with ABVD.

Lung – For patients with a significant smoking history (eg, ≥20 pack-years), we suggest an annual low dose chest CT scan for lung cancer screening, starting five years after the diagnosis of HL [86]. (See "Screening for lung cancer", section on 'Low-dose chest CT'.)

Breast – For all women beginning at age 40, we suggest an annual screening mammogram.

For women who received chest irradiation, we suggest the following (beginning at age 25 or eight years after radiation, whichever is later):

Annual screening mammogram

Consider annual breast magnetic resonance imaging (MRI; in addition to mammogram) for women who received radiation to the chest between the age of 10 and 30 years [23]

Consider referral to high-risk breast clinic for discussion of chemoprevention

In the updated recommendations from the International Guideline Harmonization Group for female survivors of childhood, adolescent, or young adult cancer, mammography and breast MRI are recommended for survivors who have ≥10 Gy chest radiation at least annually up to age 60 years [87].

Colorectal – Colorectal screening should begin at least 10 years earlier than would be recommended for the general population (ie, beginning at age 35 or 40 in HL survivors), because the absolute risk of colorectal cancer in a 40-year-old HL survivor is at least that of an adult ≥50 years old [88,89]. (See "Screening for colorectal cancer: Strategies in patients at average risk".)

Skin – Complete skin examination should be performed at least once per year to monitor for skin cancers, especially within prior radiation treatment fields, because of the increased risk for developing secondary skin cancers (estimated as ≥20 percent at 30 years) [90].

Other – HL survivors should be encouraged to participate in routine age- and sex-appropriate cancer surveillance (eg, cervix, prostate). (See "Overview of preventive care in adults", section on 'Cancer screening'.)

Lifestyle changes to prevent cancer among adult HL survivors are discussed below. (See 'Lifestyle modifications' below.)

Cardiovascular health — Cardiovascular (CV) sequelae are the major non-malignant long-term complications of treatment of HL. (See 'Cardiovascular disease' above.)

Screening and counseling for CV risk factors in HL survivors are similar to those used for other high-risk populations. Our approach is consistent with those proposed by the NCCN [23] and the Children's Oncology Group [85].

We suggest the following (table 4):

Routine management – Routine care should include auscultation for heart murmurs and carotid bruits, management of blood pressure, smoking cessation, nutritional counseling/obesity control, and evaluation of diabetes and lipids.

Symptom reporting – Patients should be instructed to report troubling symptoms (eg, chest pain, palpitations, dyspnea) without delay. Complaints of fatigue should initiate investigation for potential cardiopulmonary abnormalities in an otherwise healthy HL survivor, as discussed above. (See 'Psychosocial issues' above.)

Testing/referral – We obtain an echocardiogram one year after completing therapy with radiation therapy and/or an anthracycline to establish a new baseline. Cardiology consultation may be helpful to determine if other screening or diagnostic studies should be performed.

We suggest an echocardiogram for pregnant women who received radiation therapy and/or anthracycline and monitoring by an obstetrician with expertise for managing high-risk, complicated pregnancies.

For other HL survivors, a decision to obtain baseline testing (eg, resting and/or stress echocardiogram) is informed by the presence of other cardiac risk factors.

Other caregivers should be made aware of the increased risk for CV complications in HL survivors.

Endocrine/metabolic — Late endocrine and/or metabolic complications are common in HL survivors, especially in patients who received radiation therapy. (See 'Endocrine/metabolic dysfunction' above.)

We suggest testing:

Serum thyroid-stimulating hormone (TSH) on an annual basis in patients who received radiation to the neck or mediastinum. Elevated TSH concentration should be confirmed with repeat testing along with serum free T4 to make the diagnosis of hypothyroidism. (See "Laboratory assessment of thyroid function", section on 'Clinical use of thyroid function tests'.)

Fasting glucose or hemoglobin A1c every two years (or more frequently), especially in HL survivors who received chest or abdominal irradiation. This suggestion is consistent with the Children's Oncology Group recommendations [85].

Bone density, especially for women who undergo premature menopause. (See "Screening for osteoporosis in postmenopausal women and men".)

Counseling regarding infertility risks and early involvement of reproductive endocrinology may be prudent in patients of childbearing age. (See "Cancer survivors: Overview of fertility and pregnancy outcomes".)

Laboratory testing to screen for endocrine/metabolic abnormalities in HL survivors is summarized above. (See 'Laboratory studies' above.)

Pulmonary — There is a lack of data on the value of screening for pulmonary dysfunction following HL therapy.

We suggest baseline pulmonary function tests (PFT) for patients who underwent radiation to the chest wall, with or without bleomycin treatment. For patients with chronic and/or progressive respiratory symptoms (eg, dyspnea, fatigue, wheezing, cough) we suggest imaging, PFTs with diffusing capacity, and/or referral to a pulmonologist, as clinically indicated.

The risk of late pulmonary complications is increased in patients who received bleomycin and/or radiation to the chest. (See 'Pulmonary dysfunction' above.)

Neuropsychiatric — Mental health issues and neurocognitive impairment are prevalent in HL survivors. Early identification of patients with mental health issues can facilitate referral to mental health professionals and aid in a return to the quality of life enjoyed before their HL diagnosis and treatment.

Our suggestions for evaluation are discussed separately. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Physical and psychosocial well-being'.)

Neurologic conditions such as dropped-head syndrome may benefit from early referral to physical therapy, neck strengthening exercises, and braces for support. (See 'Neuromuscular complications' above.)

Lifestyle modifications — At each visit, HL survivors should be encouraged to incorporate healthy practices into their lifestyle in order to decrease the risk of developing complications and enhance the sense of wellbeing.

Managing comorbid conditions (eg, diabetes mellitus, hypertension, hyperlipidemia, obesity) is important for mitigating cardiovascular sequelae of HL treatment. Smokers should be encouraged to quit tobacco to reduce the risk of cardiac disease, improve lung function, and decrease the risk of lung cancer [32,46,91]. Resources should be provided to HL survivors who smoke to educate them about the behavioral and pharmacologic interventions that can assist with smoking cessation efforts. (See "Overview of smoking cessation management in adults".)

Physical activity may help to reduce fatigue and lessen the risk of heart disease [92]. In a pilot study, a home-based exercise intervention reduced fatigue and enhanced physical functioning and maximal aerobic capacity [93]. Lifestyle modification is particularly important for HL survivors of lower socioeconomic status, who are more likely to engage in unhealthy habits, including physical inactivity, smoking, and moderate/heavy alcohol use [76], as discussed above. (See 'Psychosocial issues' above.)

Consultation with an exercise physiologist and/or nutritionist may be appropriate in select patients.

Pregnancy — Fertility may be a concern for HL survivors of childbearing age. (See 'Fertility/pregnancy' above.)

We generally suggest that women delay pregnancy for at least two years after treatment has been completed, as the risk of relapse diminishes greatly beyond that time point. A woman should be evaluated for infertility if she does not become pregnant within one year; for women >35 years of age, fertility work-up is indicated if pregnancy does not occur within six months. (See "Overview of infertility".)

Pregnancy does not appear to increase the risk of recurrence among HL survivors [94] and does not alter suggestions for surveillance. During pregnancy, women should continue to be clinically monitored for relapse and late complications of treatment, but imaging should be avoided unless relapse is suggested by physical findings or symptoms.

Proper thyroid function is important for mother and fetus. Women need more thyroid hormone during pregnancy, and those with treatment-related hypothyroidism are at particular risk. On average, hypothyroid women need 45 percent more T4 during pregnancy to maintain normal TSH secretion [95]. (See "Treatment of primary hypothyroidism in adults", section on 'Pregnancy'.)

We suggest echocardiography for pregnant women who received radiation therapy and/or an anthracycline, as described above. (See 'Cardiovascular health' above.)

A general discussion of fertility and pregnancy issues in cancer survivors is presented separately. (See "Cancer survivors: Overview of fertility and pregnancy outcomes" and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

COORDINATION OF CARE — We suggest development of a survivorship care plan, clear communication between providers, and active participation by the HL survivor in long-term management.

Long-term follow-up care can be delivered by the treating hematologist/oncologist, a survivor clinic, or the primary care provider (PCP). It is important to communicate findings between all providers. Maintaining long-term follow-up for an HL survivor may be a challenge because many are young, highly mobile, asymptomatic, and may be less motivated to maintain contact with their caregivers.

Typically, the medical oncologist follows the patient closely for several years after finishing therapy, but often the patient later transitions to the PCP. The transition period can be fraught with lack of adequate communication between providers. Establishing a survivorship care plan is one way to facilitate communication and allocation of responsibility during this time period [96]. The patient's participation in a survivorship clinic, where available, can also aid in promoting well-coordinated care. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Coordination of care'.)

Survivors can be encouraged to take an active role in their follow-up care, and this can be facilitated by providing information about their treatment history and educating patients regarding the potential late complications and the importance of adherence to screening practice and risk-reducing behavioral modification.

Some reports describe benefits to long-term follow-up care by oncologists, who might be more experienced with late effects of cancer therapy and health issues in cancer survivors. In a study conducted by the Childhood Cancer Survivor Study (CCSS) group, 87 percent of young cancer survivors reported general medical contact, but only 19 percent reported visits to a cancer center [40]. Survivors who received care in a cancer center were more likely than those who received their care elsewhere to obtain an indicated echocardiogram (53 versus 22 percent) or mammogram (62 versus 35 percent) [97]. In another study, HL survivors who had received information from an oncologist were significantly more likely to correctly assess their breast cancer risk than those who received information from other sources [67].

SUMMARY

Description – Treatment of classic Hodgkin lymphoma (cHL) provides excellent long-term survival, but survivors are at risk for disease relapse, cardiovascular (CV) complications, second cancers, and other late adverse effects (AEs) of treatment.

Relapse risk – The risk of relapse is related to the initial stage of disease and the nature of treatment with chemotherapy and/or radiation therapy (RT). Relapses diminish after three to five years following treatment. (See 'Risk of relapse' above.)

Late complications – Risks for second cancers (solid tumors, hematologic malignancies) (table 3), CV complications, and other late AEs remain elevated indefinitely. (See 'Late complications' above.)

Monitoring – Management of the adult survivor more than one year after treatment involves monitoring for disease relapse, surveillance for treatment-related complications, and routine health maintenance.

Follow-up protocol – The schedule of follow-up visits, nature of evaluation (eg, history and examination, laboratory studies) (table 4), and other aspects of long-term management are described above. (See 'Post-treatment management' above.)

Imaging – We suggest not obtaining routine imaging with positron emission tomography (PET), computed tomography (CT), and/or PET/CT in the absence of clinical or laboratory findings that suggest relapse. Routine imaging surveillance in the asymptomatic patient rarely detects recurrence and exposes the patient to excessive radiation. (See 'Imaging' above.)

Surveillance – Monitoring for specific late complications includes:

Second cancers – Surveillance for second cancers (eg, breast, lung, colorectal, hematologic) (table 4) is individualized based on prior cHL treatment, individual risk factors, and lifestyle. (See 'Cancer screening' above.)

CV complications – Survivors of cHL are at risk for long-term CV complications (eg, congestive heart failure, myocardial infarction, stroke) related to chemotherapy (eg, anthracyclines) and/or RT (including technique, dose, and field). Other risk factors include pre-existing hypertension and young age at initial treatment of cHL. (See 'Cardiovascular disease' above.)

Other late effects – Monitoring and counseling for other treatment-related AEs (eg, pulmonary, endocrine, neuropsychiatric) are described above. (See 'Monitoring for complications' above.)

Lifestyle – Survivors are encouraged to modify their lifestyles to include regular exercise, smoking cessation, and a healthy diet. (See 'Lifestyle modifications' above.)

Coordination of care – Coordination of care among the medical oncologist, primary care physician, and other healthcare professionals is critical and can be facilitated by the patient's participation in a survivorship clinic, where available. (See 'Coordination of care' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Jonathan W Friedberg, MD, who contributed to earlier versions of this topic review.

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Topic 14232 Version 37.0

References

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