Overview of care for adult survivors of non-Hodgkin lymphoma

INTRODUCTION — Non-Hodgkin lymphoma (NHL) consists of a diverse group of malignant neoplasms of the lymphoid tissues variously derived from B cell progenitors, T cell progenitors, mature B cells, or mature T cells. In the United States, NHL is the fifth most common malignancy and the sixth most common cause of cancer death [1]. There are a growing number of long-term survivors of NHL. This is predominantly due to an increasing incidence and improved survival after initial treatment:

●Approximately 80,550 people are diagnosed with NHL in the United States each year, and the incidence of the disease is on the rise, doubling since the 1970s, with a continued 1 to 2 percent increase per year this century [1]. These increases have been seen predominantly in high-grade, potentially curable subtypes [2].

●NHL is often a disease of middle-age and older adults, a demographic that continues to increase in size as the life expectancy of the general population increases.

●Improvements in initial therapy have increased survival rates for some NHL histologies, such as diffuse large B cell lymphoma. NHL survivors now commonly live for many years after completing curative therapy.

Despite improvements in treatment, NHL survivors are at risk of developing long-term complications of intensive therapy, including second malignancies, cardiovascular disease, endocrine dysfunction, and cognitive sequelae.

This topic will provide an overview to the care of the NHL survivor, focusing on issues that require attention at approximately five years from the completion of therapy onwards. Specific care of the early complications of treatment and the long-term care of the hematopoietic cell transplantation survivor are presented separately as is the subclassification of NHL. (See "Long-term care of the adult hematopoietic cell transplantation survivor" and "Classification of hematopoietic neoplasms", section on 'Lymphoid neoplasms'.)

PROGNOSIS AND NATURAL HISTORY — The prognosis and natural history of NHL varies widely depending on the specific histologic subtype in addition to clinical and pathologic prognostic factors, including the general health of the patient. This is discussed in more detail separately. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Prognosis'.)

OVERVIEW OF TREATMENT COMPLICATIONS — The initial treatment of NHL depends upon the histologic subtype and disease stage. Treatment options include chemotherapy, immunotherapy (eg, antibodies targeted against tumor antigens), radiation therapy, or a combination of these. A subset of patients is treated with high-dose chemotherapy followed by stem cell support (ie, autologous hematopoietic cell transplantation). These therapies place NHL survivors at risk for the development of a diverse array of long-term sequelae, with the potential to negatively impact both their quality of life and ultimately, their survival [3-5].

The following sections describe the most common long-term complications associated with treatment. Specific details regarding the long-term complications of autologous hematopoietic cell transplantation are presented separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor".)

Fatigue — Long-term fatigue is a common symptom that may be present in two-thirds of survivors of NHL [6]. Fatigue typically improves in the year after treatment completion, but a significant proportion of patients continue to experience fatigue for months or years after treatment.

●Using a survey mailed in 2015 to 1671 adult NHL survivors (median age 64 years; range 24 to 95 years) enrolled onto 12 successive French clinical studies (1993 to 2010), 37 percent of respondents reported severe fatigue and 27 percent reported moderate fatigue at a median of 11 years after treatment for NHL; rates of fatigue were significantly higher than those in a European general population [7]. Two-thirds had diffuse large B cell lymphoma (DLBCL), and most others had follicular lymphoma. Trial regimens included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and CHOP-like chemotherapy, and one-fifth had upfront autologous hematopoietic cell transplantation. Increased levels of fatigue were associated with increased age, obesity, and the presence of self-reported health disorders that occurred at least six months after the end of lymphoma treatment (eg, second cancer; oral, cardiovascular, pulmonary, digestive, and musculoskeletal disorders; severe infections; anxiety, depression) but not with disease characteristics (including histologic type), initial treatment, or use of rituximab.

●In another study, 136 patients with indolent NHL in two clinical trials of chemotherapy-free first-line therapy were given health-related quality-of-life (HRQoL) questionnaires [8]. Compared with normative data, the mean total fatigue score was higher in NHL patients, with HRQoL lower in four of eight domains [8]. Reduced physical HRQoL in survivors was associated with somatic comorbidities, not being in paid work, and chronic fatigue.

●Another study mailed surveys to 555 NHL survivors to assess quality-of-life, including fatigue (SF-36) at baseline and at five years [9]. Clinically meaningful fatigue was reported at baseline by 28 percent, 19 percent reported persistent fatigue at five years, and 34 percent reported worsening fatigue over time. Independent associations with persistent fatigue included post-traumatic stress symptoms, increased comorbidities, prior chemotherapy, lower education, and female sex.

Second malignancies — A number of studies have shown that the risk of developing a second malignancy is increased in long-term survivors of NHL [10-13]. Risk factors depend on the type of secondary malignancy being considered and include the use of radiation therapy, chemotherapy (eg, alkylating agents, topoisomerase II inhibitors, antimetabolites), and younger age (eg, <25 years) at the time of treatment. Screening for secondary malignancies is discussed below. (See 'Monitoring for complications' below.)

Most studies express the risk of developing a second malignancy as a standardized incidence ratio (SIR) that reflects the ratio of observed cases to those expected in the population. As examples:

●An American study of 5638 patients who developed secondary malignancies (among 77,876 patients who were treated for NHL) reported an SIR of 1.14, compared with the endemic rate [11]. Patients who received radiotherapy as part of their treatment were at particularly high risk of developing sarcomas, breast cancers, and mesothelioma. Of interest, women who did not receive radiation therapy had a decreased risk of breast cancer across all age cohorts (SIR 0.79), and the risk of prostate cancer risk for men who had not undergone radiation therapy was also lower than that expected (SIR 0.89).

●A Swedish study of 28,131 patients treated for NHL (3 percent <20 years old) reported that 2290 patients developed solid tumors (8 percent; SIR 1.65; 95% CI, 1.59-1.72) and 369 developed a second lymphohematopoietic tumor (1 percent; SIR 5.36, 95% CI 4.84-5.94) [14]. Patients treated at a younger age had a higher relative risk of a solid tumor, and the SIR for solid tumors increased up to 30 years after NHL diagnosis, with a peak between years 21 to 30 after diagnosis.

●A British study of 2456 patients <60 years of age with NHL reported 123 second malignancies (5 percent), including leukemia, lung cancer, and all types of cancer [15]. The relative risk of developing a second malignancy was greater in males than females, as well as for those who were younger at the time of first treatment.

The risk of developing a second malignancy differs depending upon the subtype of NHL and the treatment received. As an example, a retrospective analysis of 43,145 patients reported that, compared with the general population, the risk of developing lung cancer was increased among survivors of chronic lymphocytic leukemia (CLL; SIR 1.42) and follicular lymphoma (FL; SIR 1.28), but not DLBCL (SIR 1.00) [16]. Likewise, the risk of developing cutaneous melanoma was increased after CLL (1.92) and FL (1.60), but not after DLBCL (1.06). By contrast, the risk of developing acute myeloid leukemia was increased after FL (5.96) and DLBCL (4.96), but not after CLL (1.13).

The increased risk of secondary malignancy is seen with both early-stage NHL and advanced-stage NHL. In a small retrospective study, four patients were found to have developed squamous cell carcinoma of the head and neck after receiving radiotherapy to this area as part of definitive therapy for localized, early-stage NHL [17].

There are few data regarding the outcomes of patients who develop a second malignancy after the treatment of NHL. Women who develop breast cancer after being cured of NHL may have a poorer prognosis than patients without prior NHL. In a study of 53 women who developed breast cancer following lymphoma, 18 (34 percent) of whom had NHL, women with a prior diagnosis of lymphoma had significantly inferior rates of five-year disease free survival (55 versus 91 percent) and overall survival (87 versus 99 percent) when compared with matched controls with de novo breast cancer [18]. These inferior outcomes may be related to suboptimal radiation therapy for the subsequent breast cancer among women with a prior diagnosis of lymphoma.  

Cardiovascular — Survivors of NHL are at risk for long-term cardiovascular complications related to the chemotherapy they have received (eg, anthracyclines) and/or radiation. Chemotherapy can lead to delayed nonischemic heart failure, and chest radiation has been associated with accelerated atherosclerosis and other cardiotoxicity. Monitoring for cardiovascular disease is discussed below. Acute and chronic cardiotoxicity associated with chemotherapy agents and radiation is discussed in more detail separately. (See 'Monitoring for complications' below 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" and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Initial studies likely underestimated the incidence of cardiovascular disease as a serious late adverse treatment effect among NHL survivors. For example, in a study looking at 141 survivors of both NHL and Hodgkin lymphoma followed for more than five years, only one patient developed long-term clinically significant congestive heart failure, though evidence of subclinical cardiomyopathy was detected on echocardiogram in 39 patients [19]. Subsequent studies suggest that the long-term clinically significant cardiovascular risks of undergoing chemotherapy and/or radiotherapy for NHL may be more substantial than was previously appreciated [19-21].

A Dutch-Belgian study calculated the risks of development of cardiovascular disease in 476 patients with aggressive NHL treated with at least six cycles of doxorubicin-containing chemotherapy in the 1980s and 1990s [20]. Relative risk was expressed as an SIR calculated as the observed incidence divided by the expected incidence. At a median follow-up of 8.4 years, the 5- and 10-year cumulative incidences of cardiovascular disease were 12 and 22 percent, respectively. The following relative risks were observed:

●The risk of chronic heart failure (CHF) was markedly increased (SIR 5.4, 95% CI 4.1-6.9). Most of the cases of CHF observed were found to be due to nonischemic cardiomyopathy, with rhythm disturbances identified much more frequently than coronary artery disease.

●The risk of coronary artery disease matched that of the general population (SIR 1.2, 95% CI 0.8-1.8) and appeared to be more related to age than to treatment.

●The risk of stroke was increased (SIR 1.8, 95% CI 1.1-2.4), especially after radiation therapy in doses >40 Gy.

This study also identified key risk factors for the development of cardiovascular events in NHL survivors. Preexisting hypertension, young age at NHL diagnosis, need for salvage treatment, and amount of radiotherapy all correlated with an increased risk of the subsequent development of cardiac disease. Those patients receiving lower amounts of radiation (<40 Gy) and those not receiving mediastinal radiation appeared to be at the lowest risk of future cardiotoxicity. (See 'Monitoring for complications' below.)

Additionally, a Danish case control study compared 2508 NHL survivors (92 percent of whom received anthracycline, mean cumulative dose 300 mg/m²) to 7399 controls. At a median follow-up of 2.5 years, 115 survivors developed heart failure; risk of heart failure significantly associated with male gender, older age, cumulative anthracycline, presence of cardiovascular risk factors, and pre-existing intrinsic heart disease [22].

Efforts have been made to identify molecular predictors of cardiotoxicity in children who received anthracycline-based chemotherapy and had cardiac sequelae later in life. As examples:

●In one study, 170 survivors with cardiomyopathy were compared with 317 survivors with no cardiomyopathy [23]. Polymorphisms in carbonyl reductases (CBRs) were found to affect the likelihood of developing cardiomyopathy. For example, individuals with CBR3 V244M homozygous G genotypes (CBR3:GG) exposed to low- to moderate-dose anthracyclines had an increased risk of cardiomyopathy compared with individuals with CBR3:GA/AA genotypes (odds ratio 5.48). Patients treated with high-dose anthracyclines (>250 mg/m²) had higher risks of cardiomyopathy regardless of CBR genotype.

●In a different study, 156 anthracycline-treated children from British Columbia were studied for 2977 single-nucleotide polymorphisms in 220 key drug biotransformation genes [24]. A significant association was found between a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene and anthracycline-induced cardiomyopathy. Using this association along with additional associations with SLC28A1 and several ATP-binding cassette transporter genes, the authors developed a single-prediction model to divide patients into high- and low-risk groups. This model was validated in a second cohort of 188 children from across Canada, with further replication of the rs7853758 association in a third cohort of 96 patients from Amsterdam.

Neither of these studies has yet to directly translate into a prospectively validated model that can be utilized in clinical practice; however, the promising results provide hope that we may someday be able to more precisely risk-stratify patients and reduce the risk of cardiotoxicity by selecting alternative chemotherapy regimens in those at highest risk.

Infertility and endocrine dysfunction — NHL survivors are at risk for developing endocrine abnormalities such as gonadal dysfunction and hypothyroidism. Screening for endocrine dysfunction is discussed below. (See 'Monitoring for complications' below.)

Gonadal dysfunction — Cytotoxic agents and radiation therapy can produce gonadal dysfunction in both male and female survivors of NHL. NHL is generally diagnosed in middle- or older-aged individuals who have completed their childbearing. As such, the effects of treatment on fertility are not problematic for many survivors. However, for younger patients treated for NHL, decreased fertility following treatment is a major concern, and the risk increases with age at the time of treatment. Patients at the highest risk for infertility are those who received multiple chemotherapy regimens and those treated with high-dose chemotherapy followed by hematopoietic cell transplantation. A more detailed discussion of reproductive and sexual issues in hematopoietic cell transplantation survivors and an overview of fertility and pregnancy in cancer survivors, in general, are presented separately. (See "Overview of infertility and pregnancy outcome in cancer survivors" and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

In contrast to patients who have received multiple chemotherapy regimens for relapsed or refractory NHL, patients cured after initial chemotherapy for NHL can generally be reassured that their risk for infertility is low. A study of 36 Israeli women treated for clinically aggressive subtypes of NHL found that, although half of the patients had amenorrhea during treatment, all but two patients recovered menses in first remission, typically in the first three months after completing chemotherapy [25]. Eighteen patients (50 percent) became pregnant while in first remission. Medical fertility-preserving measures (ie, contraceptive pills, gonadotropin-releasing hormone analogs) were not associated with improvements in recovery of regular menstruation or increased rates of pregnancy.

Another study looked at the effects of an intensified chemotherapy regimen with high-dose cyclophosphamide (Mega-CHOP) in 13 consecutive younger women (<40 years) with clinically aggressive subtypes of NHL [26]. Similarly, they found no significant effect of this regimen on fertility, with only one case of premature ovarian failure. Eight patients conceived spontaneously and delivered healthy babies.

Male NHL survivors may also be concerned about the effects of chemotherapy and radiation on their fertility. A study from Norway of approximately 300 men under the age of 50 who were survivors of either NHL or Hodgkin lymphoma were treated with a variety of chemotherapy regimens [27]. Patients with NHL treated with CHOP-based chemotherapy were not at significantly increased risk of endocrine hypogonadism, as determined by serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels. Approximately 20 percent of these patients did have abnormal hormonal levels, but this was not significantly different than a group of patients receiving either no chemotherapy or receiving ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy for Hodgkin lymphoma (which is not typically associated with infertility). Endocrine hypogonadism was more common in men over age 50 years and in patients with NHL requiring more intensive regimens such as autologous hematopoietic cell transplantation. Spermatic function and fertility were not specifically assessed in this study.

NHL survivors should be referred to a clinician with expertise in reproductive endocrinology as needed for the evaluation and management of infertility.

Other endocrinopathies — Less is known about other endocrinopathies resulting from treatment of NHL. Radiation to the neck and mediastinum can lead to hypothyroidism, and a small subgroup of NHL patients undergoing hematopoietic cell transplantation with total body irradiation (TBI) conditioning were reported to suffer from growth hormone deficiency, hypogonadism, insulin resistance, and dyslipidemia [28]. The incidence of these endocrine abnormalities in NHL survivors after initial therapy alone is not well described.

NHL survivors whose treatment included radiation to the neck or mediastinum should have an assay of thyroid-stimulating hormone (TSH) measured one year after the completion of therapy and then annually; free T4 should also be tested if the patient received cranial radiation or TBI. If the serum TSH concentration is elevated, the TSH measurement should be repeated along with a serum free T4 to make the diagnosis of hypothyroidism. Assays can be performed earlier if clinical suspicion exists, but the clinician must be aware of the possibility of acquired transient central hypothyroidism (the sick-euthyroid syndrome) early after radiation treatment. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Thyroid function in nonthyroidal illness".)

Neurologic and psychiatric complications — Neurologic complications due to treatment of NHL are rare but potentially serious. Risk factors for neurocognitive impairment include central nervous system (CNS) involvement, cranial irradiation, a history of intrathecal chemotherapy, older age at the time of treatment, and hematopoietic cell transplantation [29,30]. Although it is rare, patients treated with an anti-CD20 monoclonal antibody (eg, rituximab) are at risk for the development of progressive multifocal leukoencephalopathy (PML). NHL survivors are also at risk for psychiatric complications following the completion of treatment, including post-traumatic stress disorder (PTSD) and depression. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis" and "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical features, assessment, and diagnosis".)

The following studies addressed neurologic and psychiatric complications in NHL survivors:

●A retrospective study of 52 patients with lymphoproliferative disorders who developed PML following rituximab-based therapies reported that this condition typically develops soon after completing therapy, with a median time from last rituximab dose to PML diagnosis of 5.5 months [31]. The case-fatality rate was 90 percent, and median time to death was two months after PML diagnosis. The approach to the management of PML is presented separately. (See "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis".)

●In a study of 28 patients with primary CNS lymphoma (PCNSL) who had completed treatment with whole-brain radiotherapy and/or high-dose methotrexate, mild to moderate impairments were found in multiple cognitive domains [29]. Deficits in memory, attention, and executive domains were particularly prominent. Patients who underwent whole-brain radiation therapy (WBRT) had more pronounced deficits than those who had chemotherapy alone. In a subsequent prospective study, a similar group of patients were found to have some recovery of executive domain function at two years, but they continued to have persistent difficulties with verbal memory and motor speed [32]. In contrast, in a series of 30 PCNSL patients treated with R-MVP plus reduced dose WBRT of 23.4 Gy, longitudinal neuropsychiatric testing at baseline, 6 months, and 12 months, showed no neurocognitive decline with this approach [33]. (See "Primary central nervous system lymphoma: Treatment and prognosis", section on 'Whole brain radiation therapy'.)

●In a survey of 886 NHL survivors who were on average 10 years postdiagnosis, 39 percent reported symptoms of PTSD, and 8 percent met diagnostic criteria for PTSD [34]. Younger patients with less education who were not from a White population were more likely to experience these symptoms.

●A prospective matched cohort study compared the use of psychotropic drugs in 8750 NHL survivors with 43,750 sex- and age-matched controls in a nationwide population-based registry [35]. Compared with controls, more NHL survivors used psychotropic drugs (16 versus 5 percent). The usage rate was particularly high in patients within five years of a diagnosis of aggressive NHL but decreased over time. By contrast, patients with indolent NHL continued high usage even beyond five years. Compared with controls, NHL survivors also had higher rates of suicide/intentional self-harm at two years (0.2 versus 0.3 percent).

All patients at increased risk should undergo screening for neurocognitive impairment so that appropriate occupational therapy and social services referrals may be made, if necessary [36]. Oncologists and primary care clinicians should be aware of the high prevalence of mental health issues faced by NHL survivors. As an example, the early identification of patients with symptoms of PTSD can facilitate referral to mental health professionals to initiate treatment [34]. Such interventions can aid greatly in patients' ability to return as closely as possible to the quality of life they enjoyed before their NHL diagnosis and treatment. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Physical and psychosocial well-being'.)

POST-TREATMENT SURVEILLANCE

Monitoring for relapse — Following the completion of therapy, restaging, and documentation of complete remission, patients are seen at periodic intervals to be monitored and assessed for possible relapse. The frequency and extent of these visits depends upon the histologic subtype and comfort of both the patient and clinician. There have been no prospective, randomized trials comparing various schedules of follow-up. Our approach to monitoring for recurrent disease is discussed separately for the individual NHL histologies. Relapsed disease can be suggested by changes on imaging studies but can only be confirmed by biopsy. As such, a biopsy should be obtained to document relapsed disease before proceeding to salvage therapy. (See "Initial treatment of stage I follicular lymphoma", section on 'Surveillance for relapse' and "Treatment of Burkitt leukemia/lymphoma in adults", section on 'Surveillance for relapse' and "Initial treatment of peripheral T cell lymphoma".)

Relapse is much less likely to occur greater than five years after the completion of treatment. From this point forward, it is even less clear how intensively patients need to be followed. A growing trend has been for patients to transition back to their primary care clinician, who often oversees this portion of the care. Given the increasing prevalence of NHL, it is therefore imperative that internists be aware of the potential late complications of NHL treatment. (See 'Coordination of care' below.)

Monitoring for complications — No uniform guidelines exist for how to monitor NHL survivors for long-term complications. Our approach is based upon our experience and extrapolation of data from patients with other primary malignancies (table 1).

●Cancer screening – While NHL survivors are at increased risk of developing secondary malignancies, the ideal screening program has not been defined for malignancies other than breast cancer. No prospective analyses have evaluated the benefit of screening in this population. However, extrapolation of data from other settings suggests that the ability to prevent and detect solid organ malignancies in the NHL survivor relies upon periodic screening examinations and strict adherence to prophylactic measures:

•Risk awareness counseling annually – NHL survivors should be advised of their increased risk of developing a malignancy following treatment and encouraged to report any concerning symptoms to their clinician. Smoking cessation should be recommended, and patients should be counseled to limit unprotected sun exposure. (See "Overview of smoking cessation management in adults".)

•Screening clinical assessment annually – In addition to a routine physical examination, NHL survivors should undergo an at least annual complete skin examination to monitor for the development of skin cancers, particularly focusing on areas within radiation fields.

•NHL survivors should be encouraged to participate in routine age-appropriate cancer surveillance with the following notable exceptions (see "Overview of preventive care in adults", section on 'Cancer screening'):

-Female NHL survivors should undergo screening for breast cancer beginning no later than age 40 years. For patients who have received total body or chest irradiation, breast cancer screening should begin eight years after radiation or at age 25 years, whichever occurs later. The ideal test to use for breast cancer screening has not been determined, and clinical practice varies. The American Cancer Society suggests the use of mammography to screen most women for breast cancers, but also proposes that woman who received radiation to the chest between the ages of 10 and 35 years undergo screening with both annual breast magnetic resonance imaging (MRI) and mammography [37,38].

•Other studies – There are little data to support additional screening measures such as periodic complete blood counts to screen for leukemia or myelodysplastic syndrome, chest radiographs to screen for lung cancer or mesothelioma, or an increase in the frequency of colonoscopy to screen for colorectal cancer.

●Cardiovascular health – Screening and counseling techniques similar to those used for other high-risk populations are applied to NHL survivors with the goal of decreasing mortality from cardiovascular disease. Cardiac risk factors should be minimized (eg, smoking, obesity, hyperlipidemia, hypertension). Routine care should incorporate regular measurement and control of blood pressure, auscultation of the carotids for bruits, nutritional counseling and obesity control, counseling for smoking cessation, and control of diabetes. In addition, we commonly refer NHL survivors to a cardiologist for baseline evaluation after the completion of treatment and determination of the necessity and frequency of additional screening or diagnostic studies (eg, resting and stress echocardiogram). Cardiac evaluation is especially important for patients who have received radiation therapy to the chest wall and those who received cardiotoxic chemotherapy (ie, doxorubicin), particularly once 10 years have passed since the radiation therapy. At a minimum, patients should be instructed not to ignore persistent troubling symptoms and to bring them to the attention of their clinician without delay. Clinicians must be aware of NHL survivors’ treatment history; additional testing should be pursued if suspicion of a late complication arises. (See 'Cardiovascular' above.)

●Endocrine assessment – NHL survivors whose treatment included radiation to the neck or mediastinum should have an assay of thyroid-stimulating hormone (TSH) measured one year after the completion of therapy and then annually; free T4 should also be tested if the patient received cranial radiation or total body irradiation. If the serum TSH concentration is elevated, the TSH measurement should be repeated along with a serum free T4 to make the diagnosis of hypothyroidism. (See 'Infertility and endocrine dysfunction' above.)

●Neurologic and psychiatric evaluation – Annual evaluation should include a discussion of psychiatric health, including an assessment of symptoms of depression and post-traumatic stress disorder (PTSD). All patients at increased risk (eg, history of cranial irradiation, intrathecal therapy) should undergo screening for neurocognitive impairment so that appropriate occupational therapy and social services referrals may be made, if necessary. (See 'Neurologic and psychiatric complications' above.)

LIFESTYLE MODIFICATIONS — At each visit, NHL survivors should be encouraged to incorporate healthy practices into their lifestyle in order to decrease the risk of developing complications.

The cardiovascular sequelae of NHL treatment can be mitigated through active lifestyle modifications. Reducing or eliminating comorbid conditions, such as diabetes, hypertension, hyperlipidemia, and obesity, is important. Smokers should be encouraged to quit to reduce the risk of both cardiac disease and lung cancer. Resources should be provided to NHL 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".)

Engaging in regular physical activity appears to be particularly critical in helping NHL survivors to be healthy. As an example, two studies demonstrated that those NHL survivors who met the public health guidelines of 150 minutes or more of moderately vigorous exercise per week had significantly better health-related quality of life than those who were sedentary [39,40]. Health-related quality of life was also found to have a positive correlation with getting at least some exercise. Therefore, all NHL survivors should be encouraged to participate in at least some exercise, with patients informed that the more exercise they get, the better chance they have of improving their quality of life. Consultation with exercise physiologists and nutritionists may be appropriate in select patients.

COORDINATION OF CARE — During treatment, NHL patients become accustomed to working closely with a multidisciplinary team that often includes medical oncologists, radiation oncologists, mid-level practitioners, nurses, and others. Ideally, involvement of the patient’s primary care physician (PCP) continues during treatment, as the PCP often has a longstanding relationship with the patient that predates the patient's lymphoma diagnosis. Maintaining this relationship becomes particularly important after the patient completes treatment. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Coordination of care'.)

Typically, the medical oncologist follows the patient closely for several years after finishing therapy, and subsequently, the patient transitions back to the PCP as his or her main provider. This transition period can be fraught with miscommunication between even the most well-meaning providers. Establishing a survivorship care plan is one way to facilitate communication and allocation of responsibility during this time period [41]. The patient’s attendance of a survivorship clinic, where available, can also aid in promoting well-coordinated care.

Through a deepened understanding of late treatment effects, we can begin to more effectively counsel our patients on the risks they face and the lifestyle modifications and other interventions that can reduce the ill effects of these complications. Effectively managing these consequences of therapy may improve the quality of life of NHL survivors and has the potential to prolong their survival.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Follicular lymphoma (The Basics)" and "Patient education: Diffuse large B cell lymphoma (The Basics)")

●Beyond the Basics topics (see "Patient education: Follicular lymphoma in adults (Beyond the Basics)" and "Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics)")

SUMMARY

●Description – Growing numbers of patients are long-term survivors of non-Hodgkin lymphoma (NHL). Survivors of NHL should be monitored regularly for disease recurrence and long-term complications, including second cancers, heart disease, endocrine dysfunction, and neurocognitive sequelae.  

●Treatment complications – The most long-term adverse effects (AEs) of treatment include:

•Fatigue – Long-term fatigue is reported by two-thirds of survivors. (See 'Fatigue' above.)

•Second cancers – Solid tumors, leukemia, and other hematologic malignancies are all increased in survivors. Elevated risk continues for at least 25 years. Cancer risk for an individual is influenced by the underlying NHL subtype, treatment, and personal history. (See 'Second malignancies' above.)

•Cardiovascular complications – Include coronary artery disease, heart failure, valvular disease, arrythmias, and stroke. Risk factors include treatment with chemotherapy and/or radiation therapy (RT) and personal history (eg, hypertension, smoking). (See 'Cardiovascular' above.)  

•Endocrine disorders

-Gonadal dysfunction – Cytotoxic chemotherapy and RT can cause gonadal dysfunction in both male and female survivors. Infertility is more common in older patients, those receiving hematopoietic cell transplantation (HCT), and patients treated for relapse or refractory disease. (See 'Gonadal dysfunction' above.)

-Other endocrinopathies – Growth hormone deficiency, hypogonadism, insulin resistance, and other endocrinopathies can occur, especially in patients treated with RT. (See 'Other endocrinopathies' above.)

•Neurologic. (See 'Neurologic and psychiatric complications' above.)

-Risk factors for neurocognitive impairment are central nervous system involvement, cranial RT, intrathecal chemotherapy, older age at treatment, and HCT. Progressive multifocal leukoencephalopathy is a rare but severe AE associated with the rituximab or other anti-CD20 monoclonal antibodies.

-Psychiatric – Survivors may experience post-traumatic stress disorder (PTSD) and depression.

●Monitoring – There are no consensus guidelines for monitoring NHL survivors for relapse and long-term complications of the disease and its treatment.

•Relapse – Monitoring for disease relapse is guided by the subtype of NHL and patient and clinician judgment, as discussed in disease-specific topics. (See 'Monitoring for relapse' above.)

•Late complications – Our approach to monitoring for late AEs is based upon our experience and extrapolation of data from patients with cancers (table 1). (See 'Monitoring for complications' above.)

●Lifestyle – Survivors should be encouraged to incorporate healthy lifestyle practices, including smoking cessation, weight control, healthy diet, and regular exercise. (See 'Lifestyle modifications' above.)

●Coordination of care – Establishing a survivorship care plan and communication/coordination between the treating team and primary care providers can improve monitoring and health maintenance for NHL survivors. (See 'Coordination of care' above.)