Other adverse long-term effects

Treatment of HL also affects the endocrine, cardiac, pulmonary, skeletal, and immune systems. Chronic fatigue can be a debilitating symptom for some long-term survivors.[57] A retrospective survey of 20,007 patients with early- and advanced-stage classical HL treated between 2000 and 2016 (i.e., the era in which ABVD became the preferred frontline chemotherapy regimen) showed 1,321 deaths not attributable to lymphoma (39% of total deaths). Heart disease (estimated EAR: 6.6 per 10,000 patient-years, standardized mortality ratio, 1.7 for early-stage disease and 15.1 per 10,000 patient-years, standardized mortality ratio, 2.1 for advanced-stage disease) and infection (estimated EAR: 3.1 per 10,000 patient-years, standardized mortality ratio, 2.2 for early-stage disease and 10.6 per 10,000 patient-years, standardized mortality ratio, 3.9 for advanced-stage disease) were the leading causes of death, especially in patients older than 60 years.[58]

Infertility. A toxic effect that is primarily related to chemotherapy is infertility, usually after regimens containing MOPP or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).[59-61] After six to eight cycles of BEACOPP, most men had testosterone levels within reference range; however, 82% of women younger than 30 years recovered menses (mostly within 12 months), but only 45% of women older than 30 years recovered menses.[62] ABVD appears to spare long-term testicular and ovarian function.[60,63,64] Increasing age and alkylator-based regimens are the two major factors increasing the risk of premature ovarian insufficiency.[62,65,66] A prospective evaluation of gonadal function embedded in the randomized Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL) study for patients with newly diagnosed advanced-stage HL found good recovery of anti-Müllerian hormone concentration and reduction in follicle-stimulating hormone after ABVD or AVD (doxorubicin, vinblastine, dacarbazine), but less recovery after BEACOPP and for women older than 35 years.[65] A PET scan-adapted treatment regimen to reduce the use of BEACOPP also resulted in less infertility and gonadal dysfunction.[67] While cryopreservation of oocytes or sperm remains the first choice for preservation of fertility, luteinizing hormone-releasing hormone agonists can be tried in this setting, although efficacy for patients with HL has not been confirmed as has been confirmed for patients with breast cancer.[68] A national Danish registry of 793 HL survivors showed that patients who did not have a relapse had similar parenthood rates to the general population, but assistive reproduction methods were required more often for HL survivors (male, 21.6% vs. 6.3%; female, 13.6% vs. 5.5%; P ≤ .001 for both comparisons).[69]

Hypothyroidism. Hypothyroidism is a late complication primarily related to radiation therapy.[70-72] Long-term survivors who receive radiation therapy to the neck are followed up with annual thyroid-stimulating hormone testing.

Cardiac disease. A late complication primarily related to radiation therapy is cardiac disease, the risk of which may persist for over 30 years after the first treatment.[70,73-81] The EAR of fatal cardiovascular disease ranges from 11.9 to 48.9 per 10,000 patient-years and is mostly attributable to fatal myocardial infarction (MI).[73-75,77] A retrospective survey of over 6,000 patients with HL treated in trials between 1964 and 2004 found that cardiac exposure to radiation and use of doxorubicin were significant predictors of ischemic heart disease, congestive heart failure, arrhythmias, and vascular disease.[79] In a cohort of 7,033 patients with HL, MI mortality risk persisted for 25 years after first treatment with supradiaphragmatic radiation therapy (dependent on the details of treatment planning), doxorubicin, or vincristine.[77,78] A nested case-control study of 2,617 5-year survivors of HL diagnosed before age 51 years and treated between 1965 and 1995 found that the 25-year risk of moderate to severe heart failure increased for patients receiving anthracyclines. The risk ranged from 11.2% for patients exposed to 0 Gy to 15 Gy radiation up to 32.9% for patients exposed to radiation equal or greater than 21 Gy.[82] The use of subcranial blocking did not reduce the incidence of fatal MI in a retrospective review, perhaps because of the exposure of the proximal coronary arteries to radiation.[74] Compared with a general matched population, HL patients treated with mediastinal radiation were at increased risk of complications, especially during cardiac surgery.[83] Risk prediction models rely on the dose of mediastinal radiation, smoking history, male sex, and anthracycline exposure to define the patients at highest risk.[81] These risk prediction models found that mediastinal radiation therapy combined with doxorubicin exposure conferred the highest risk, followed by mediastinal radiation therapy alone.[81]

In the U.K. RAPID trial, performed between 2003 and 2010, 183 patients with early-stage HL were PET-negative but still received involved-field radiation therapy (IFRT) (20 Gy) after receiving ABVD.[80] The average predicted 30-year cardiovascular mortality was 5.02%, which included 3.52% expected in the general population, 0.94% EAR from the doxorubicin, and 0.56% from the IFRT. Since 2010, radiation therapy techniques have advanced by using smaller target volumes, lower-dose IFRT (20 Gy), deep inspiration breath holding, intensity-modulated radiation therapy, and proton beam therapy.[80] These techniques will need further evaluation to better assess cardiovascular risks from radiation therapy.

Pulmonary impairment. Impairment of pulmonary function may occur as a result of mantle-field radiation therapy; this impairment is not usually clinically evident, and recovery in pulmonary testing often occurs after 2 to 3 years.[84] Pulmonary toxic effects from bleomycin as used in ABVD are seen in patients older than 40 years.[85]

Bone necrosis. Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy.[86]

Bacterial sepsis. Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL;[87] it is much more common in children than in adults.

Fatigue. Fatigue is a commonly reported symptom among patients who have completed chemotherapy and radiation therapy. In a case-control study design, most HL survivors reported significant fatigue lasting for more than 6 months after therapy, compared with age-matched controls. Quality-of-life questionnaires given to 5,306 patients on GHSG trials showed that 20% of patients complained of severe fatigue 5 years after therapy, and those patients had significantly increased problems with employment and financial stability.[88-90] For more information, see Fatigue.

Neurocognitive impairment. After a median of 23 years from diagnosis, 1,760 HL survivors treated in childhood were compared with 3,180 siblings. Significantly higher rates of memory loss (8.1% vs. 5.7%; P < .05), anxiety (7.0% vs. 5.4%; P < .05), unemployment (9.6% vs. 4.4%; P < .05), depression (9.1% vs. 7.0%; P < .05), and impaired physical quality of life (11.2% vs. 3.0%; P < .05) were reported.[91] Lower risks were associated with survivors who adhered to exercise guidelines and did not smoke, but the design of this study did not allow a cause-and-effect conclusion.