Late Endocrine and Metabolic Sequelae and Long-Term Monitoring of Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma Survivors: A Systematic Review by the Fondazione Italiana Linfomi
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Identification
2.2. Eligibility Criteria
2.3. Study Selection and Data Extraction
2.4. Risk of Bias and Quality of Evidence Assessment
2.5. Data Synthesis
3. Results
3.1. Thyroid Diseases
3.1.1. Incidence and Prevalence
3.1.2. Treatment Comparison
3.1.3. Efficacy of Planned Follow-Up Schemes to Early Diagnosis of Thyroid Diseases in Long-Term cHL or DLBCL Survivors Treated with First- and/or Second-Line CT/RT and ASCT?
3.2. Gonadal Dysfunctions
3.2.1. What Is the Incidence or Prevalence of Testicular Dysfunction in Long-Term cHL or DLBCL Survivors Treated with First- and Second-Line CT/RT and ASCT? What Is the Incidence or Prevalence of Ovarian Dysfunction in Long-Term cHL or DLBCL Survivors Treated with First- and/or Second-Line CT/RT and ASCT?
3.2.2. Treatment Comparison
3.2.3. Efficacy of Planned Follow-Up Schemes in the Diagnosis of Testicular Dysfunction in Long-Term cHL or DLBCL Survivors Treated with First- and/or Second-Line CT/RT and ASCT. Efficacy of Planned Follow-Up Schemes in the Diagnosis of Ovarian Dysfunction Long-Term cHL or DLBCL Survivors Treated with First- and/or Second-Line CT/RT and ASCT?
3.3. Bone Diseases
3.3.1. Incidence or Prevalence
3.3.2. Treatment Comparison: Has the Incidence or Prevalence of Changes in Bone Quality and Mineral Density in Long-Term cHL or DLBCL Survivors Treated with First- and/or Second-Line CT/RT and ASCT Changed with the Introduction of Modern Radiotherapy?
3.3.3. Efficacy of Planned Follow-Up Schemes in Diagnosing Changes in Bone Mineral Density and Quality in Long-Term cHL or DLBCL Survivors Treated with First- and/or Second-Line CT/RT and ASCT?
3.4. Metabolic Syndrome
3.4.1. What Is the Incidence of Metabolic Syndrome in Long-Term cHL or DLBCL Survivors Treated with First- and/or Second-Line CT/RT and ASCT?
3.4.2. Efficacy of Planned Follow-Up Schemes to Diagnose Metabolic Syndrome and Related Sarcopenia in Long-Term cHL or DLBCL Survivors Treated with First- and/or Second-Line CT/RT and ASCT?
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Clinical Question | PICOs |
---|---|
What is the incidence or prevalence of thyroid diseases in long-term cHL or DLBCL survivors treated with first- and/or second-line CT/RT and ASCT? | P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis I: chemotherapy (e.g., ABVD for cHL; RCHOP for DLBCL), radiotherapy (neck and/or mediastinum) C1: none C2: general population matched for age and sex C3: other CT/RT regimens O1: incidence or prevalence of abnormal thyroid function tests (overt or subclinical hypothyroidism, hyperthyroidism) O2: autoimmune thyroid disease (Hashimoto’s thyroiditis, Graves’ disease) O3: thyroid nodules (single nodule, multiple nodules, thyroid cancer) |
Treatment comparisons | |
Has the incidence or prevalence of thyroid diseases in in long-term cHL or DLBCL survivors treated with first- and/or second-line CT/RT and ASCT changed with the introduction of modern radiotherapy? | P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis I: new RT approaches (3DCRT, IMRT, dose/volume reduction) C: previous RT regimens (2DRT, Extended Field RT) O: number of cases of abnormal thyroid function test, autoimmune thyroid disease, nodular pathology of the thyroid, thyroid cancer |
Optimal follow-up | |
Efficacy of planned follow-up schemes to early diagnose thyroid diseases in long-term cHL or DLBCL survivors treated with first and/or second line CT/RT and ASCT | P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years, particularly patients at risk (e.g., neck and/or mediastinum RT) I: scheduled follow-up/monitoring planned (e.g., annual thyroid function test, antithyroid autoantibody assay, ultrasound, ultrasound-guided fine needle aspiration, etc.) C1: no follow-up/monitoring planned C2: follow-up/monitoring planned with different intensity (with respect to I, including different components, timing and frequencies) O: incidence or prevalence of abnormal thyroid function test, autoimmune thyroid disease, nodular thyroid disease, thyroid cancer, problems related to overdiagnosis, quality of life, mortality |
Clinical Question | PICOs |
---|---|
What is the incidence or prevalence of late gonadal sequalae in long-term cHL or DLBCL survivors treated with first- and/or second-line CT/RT and ASCT? | (a). P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis I: chemotherapy (e.g., ABVD for HL; RCHOP for DLBCL), pelvic radiotherapy C1: none C2: general population matched for age and sex C3: other CT/RT treatment regimens O: incidence or prevalence of abnormal testosterone secretion (low serum testosterone and/or elevated LH levels) (b). P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis I: chemotherapy (e.g., A BVD for cHL; RCHOP for DLBCL), pelvic radiotherapy C1: none C2: general population matched for age and sex C3: other CT/RT treatment regimens O: incidence or prevalence of symptoms of estrogen deprivation (e.g.,hot flashes, vaginal dryness, dyspareunia) |
Treatment comparisons | |
Has the incidence or prevalence of late gonadal sequalae in long-term cHL or DLBCL survivors treated with first- and/or second-line CT/RT and ASCT changed with the introduction of modern radiotherapy? | (a). P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis I1: new radiotherapy approaches (3DCRT, IMRT, dose/volume reduction,) C: previous radiotherapy regimens 2DRT, Extended Field RT) O: number of cases of abnormal testosterone secretion (low serum testosterone and/or elevated LH levels) (b). P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis I1: new radiotherapy approaches (3DCRT, IMRT, dose/volume reduction,) C: previous radiotherapy regimens (2DRT, Extended Field RT) O: number of cases of secondary (transient, permanent) amenorrhea, number of patients reporting symptoms of estrogen deprivation |
Optimal follow up | |
Efficacy of planned follow-up schemes in the diagnosis of late gonadal dysfunction in long-term cHL or DLBCL survivors treated with first and/or second line CT/RT and ASCT | (a) P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis, particularly patients at risk (e.g., pelvic RT) I: scheduled follow-up/monitoring (e.g., annual total testosterone dosage, LH, annual spermiogram run, etc.) C1: no follow-up/monitoring planned C2: follow-up/monitoring planned with different intensity (with respect to I, including different components, times and frequencies) O: alterations in testosterone secretion, problems related to overdiagnosis, quality of life, mortality (b) P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis, particularly patients at risk (e.g., pelvic RT) I: scheduled follow-up/monitoring (e.g., annual hormone test dosage—FSH, LH, estradiol, inhibin B, AMH, progesterone—and annual transvaginal pelvic ultrasound) C1: no follow-up/monitoring planned C2: follow-up/monitoring planned with different intensity (with respect to I, including different components, times and frequencies) O: secondary amenorrhea, problems related to overdiagnosis, quality of life, mortality |
Clinical Question | PICOs |
---|---|
What is the incidence or prevalence of changes in bone quality and bone mineral density in long-term cHL or DLBCL survivors treated with first and/or second line CT/RT and ASCT | P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis I: CT (e.g., ABVD for cHL; R-CHOP for DLBCL), RT C1: none C2: general population matched for age and sex C3: other CT/RT treatment regimens O: prevalence and/or incidence of osteopenia, osteoporosis, fractures |
Treatment comparisons | |
(3) Has the incidence or prevalence of changes in bone quality and mineral density in long-term cHL or DLBCL survivors treated with first- and/or second-line CT/RT and ASCT changed with the introduction of modern radiotherapy? | P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis I: new RT approaches (3DCRT, IMRT, dose/volume reduction,) C: previous RT regimens (2DRT, extended field RT) O: number of cases of osteopenia, osteoporosis, fractures |
Optimal follow up | |
Efficacy of planned follow-up schemes in diagnosing changes in bone mineral density and quality in long-term cHL or DLBCL survivors treated with first and second line CT/RT and ASCT | P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis, particularly patients at risk (e.g., RT) I: Scheduled follow-up/monitoring planned (e.g., annual calcium and vitamin D dosage, annual bone densitometry) C1: no follow-up/monitoring planned C2: follow-up/monitoring planned with different intensity (with respect to I, including different components, timing and frequencies) O: osteoporosis, osteopenia, fracture, quality of life, mortality |
Clinical Question | PICOs |
---|---|
What is the incidence of metabolic syndrome in long-term cHL or DLBCL survivors treated with first- and/or second-line CT/RT and ASCT? | P: population of long-term cHL or DLBCL survivors (≥5 years disease-/treatment-free) aged ≥ 18 years at diagnosis I: chemotherapy (e.g., ABVD for cHL; RCHOP for DLBCL), radiotherapy C1: none C2: general population matched for age and sex C3: other CT/RT treatment regimens O: incidence of metabolic syndrome |
Optimal follow up | |
What is the efficacy of planned follow-up schemes to diagnose metabolic syndrome and related sarcopenia in in long-term cHL or DLBCL survivors treated with first- or second-line CT/RT and ASCT? | P: population of long-term (≥5 years disease- or/treatment-free) cHL or NHL (DLBCL in particular) aged ≥ 18 years at diagnosis I: chemotherapy (e.g., ABVD for cHL; RCHOP for NHL/DLBCL), radiotherapy C1: general population matched for age and sex C2: autologous stem cell transplant (ASCT), high dose steroids O1: follow-up of metabolic syndrome or metabolic risk O2: long-term nutritional effects such as change of body composition, visceral obesity and weight, sarcopenia and/or dysplipidemia |
Thyroid Diseases | |||
---|---|---|---|
PICO A: Thyroid Diseases Incidence and Prevalence | |||
Study | Study Design and Sample Size | Intervention & Comparison | Outcomes |
Enrici RM, 1999 [26] | Prospective RCT (73 pts) | RT/CT 36 pts RT 37 pts | Prevalence of hypothyroidism 2/73 = 2.7%, hypothyroidism in the CT/RT subgroup (2/36 = 5.5%) |
Illes, 2003 [28] | Retrospective cohort study (151 cHL patients) | RT, CT or both | Prevalence of hypothyroidism, 26.5% prevalence of hyperthyroidism 0.01%, prevalence of antibodies 18% |
Bethge W, 2000 [27] | Retrospective cohort study (177 cHL patients) | RT, CT or both | prevalence of hypothyroidism, 27% prevalence of subclinical hypothyroidism, 20% prevalence of overt hypothyroidism 7% |
PICO B: treatment comparison | |||
Pinnix, 2018 [29] | Retrospective cohort study (140 cHL patients) | RT IMRT (ISRT, mediastinum with-without neck) (90 pts) RT 3DCRT (ISRT, mediastinum with-without neck) (50 pts) | three-year rates of freedom from hypothyroidism of 56.1% for the 3D-CRT group and 40% for the IMRT group (p = 0.057) |
GONADAL DYSFUNCTIONS | |||
PICO A: Gonadal dysfunctions incidence and prevalence | |||
Study | Study design and sample size | Intervention & Comparison | Primary outcomes |
King, 1985 [30] | Retrospective (N° not reported cHL) | CT ± RT | prevalence of azoospermia 100% |
Meissner, 2015 [31] | Retrospective (46 NHL pts) | CT | no/few menopausal symptoms 25.7% mild menopausal symptoms 17.1% moderate menopausal symptoms 37.1% severe menopausal symptoms 20% |
BONE DISEASES | |||
PICO A: Bone diseases incidence and prevalence | |||
Study | Study design and sample size | Intervention & Comparison | Primary outcomes |
Svendsen, 2017 [32] | Retrospective (111, NHL pts) | R-CHOP (-like) | prevalence of fractures 14% |
METABOLIC SYNDROME | |||
PICO A: Metabolic Syndrome incidence and prevalence | |||
Study | Study design and sample size | Intervention & Comparison | Primary outcomes |
Daniele, 2021 [16] | Prospective cohort (60 NHL pts) | CT | presence of metabolic syndrome in 60% of patients |
Risk Category | Suggested Follow-Up |
---|---|
All patients receiving RT on the neck and surrounding structures are at high risk of hypothyroidism |
|
Patients with reproductive intentions and symptoms related to gonadal dysfunction due to CT or RT |
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Patients aged > 60 years treated with high-dose steroids, second-line treatments, ASCT and hypogonadal patients of all ages are at high risk of osteoporosis and bone fractures | DXA ± tomography scan to detect bone alterations are recommended in early follow-up, although optimal timing is unknown |
DLBCL survivors treated with chemotherapy including high-dose steroids are at increased risk of metabolic syndrome and associated sarcopenic obesity |
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Di Molfetta, S.; Daniele, A.; Gerardi, C.; Allocati, E.; Minoia, C.; Loseto, G.; Giorgino, F.; Guarini, A.; De Sanctis, V. Late Endocrine and Metabolic Sequelae and Long-Term Monitoring of Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma Survivors: A Systematic Review by the Fondazione Italiana Linfomi. Cancers 2022, 14, 1439. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061439
Di Molfetta S, Daniele A, Gerardi C, Allocati E, Minoia C, Loseto G, Giorgino F, Guarini A, De Sanctis V. Late Endocrine and Metabolic Sequelae and Long-Term Monitoring of Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma Survivors: A Systematic Review by the Fondazione Italiana Linfomi. Cancers. 2022; 14(6):1439. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061439
Chicago/Turabian StyleDi Molfetta, Sergio, Antonella Daniele, Chiara Gerardi, Eleonora Allocati, Carla Minoia, Giacomo Loseto, Francesco Giorgino, Attilio Guarini, and Vitaliana De Sanctis. 2022. "Late Endocrine and Metabolic Sequelae and Long-Term Monitoring of Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma Survivors: A Systematic Review by the Fondazione Italiana Linfomi" Cancers 14, no. 6: 1439. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061439