Abstract
Growth hormone deficiency (GHD) is a common complication in survivors of cancer and patients with tumors of the pituitary region. Growth hormone replacement therapy (GHT) has proven beneficial effects, including increased growth velocity, positive effects on body composition and skeletal integrity, and increased quality of life. However, due to known pro-proliferative, angiogenic, and anti-apoptotic properties of growth hormone, there are still some concerns about the safety of GHT in survivors. This narrative review aims to provide an overview of the long-term sequelae, and subsequently long-term safety, of GHT in survivors of (childhood) cancer and patients with tumors of the pituitary region. We identified predominantly reassuring results regarding the safety of survivors with GHT, although we must take into account the shortcomings of some studies and limited information on adult cancer survivors. Besides the already increased risk for second neoplasms, recurrences, or mortality in survivors due to host-, disease-, and treatment-related factors, we could not identify an increased risk due to GHT in particular. Therefore, we support the consensus that GHT can be considered in survivors after careful individual risk/benefit analysis and in open discussion with the patients and their families, taking into account the known morbidity of untreated GHD in cancer survivors and the positive effects of GHT.
Introduction
There has been a significant improvement in the outcomes of childhood cancer over the past decades, now exceeding a 5-year survival rate of 80% in western countries (Gatta et al. 2014). However, these survivors are already at an increased risk for (late) mortality and morbidity, due to recurrences, secondary neoplasms, and relatively early (cardiovascular) deaths (Armstrong et al. 2009). Moreover, the growing number of adult childhood cancer survivors (CCS) is known to suffer from various long-term side effects due to their early disease and treatment. Of these, endocrine comorbidities, including growth hormone deficiency (GHD), are among the most prevalent sequellae (van Santen et al. 2020). Despite the proven beneficial effects of growth hormone replacement therapy (GHT) in survivors with GHD, there are still concerns about the long-term safety of GHT in survivors due to its mitogenic properties and subsequently possible increased risk of recurrences, second neoplasms (SNs), and mortality.
GHD is a common complication in survivors of cancer and, especially, in patients with tumors of the pituitary region, even when they are rather benign. Brain tumors and their treatment, due to their location, often cause hypothalamic–pituitary axis dysfunction and subsequently GHD. The disease itself and required surgery often lead to early damage, whereas radiation to the sellar region can lead to the occurrence of GHD several months, or many years, after treatment (van Iersel et al. 2019, van Santen et al. 2020). In adults, tumors of the sellar region and pituitary adenomas are the main cause of GHD, being responsible for almost 90% of all cases. In CCS, the prevalence of developing GHD is estimated at 22% and even 40% for all CSS who received radiotherapy to the hypothalamic–pituitary area (van Iersel et al. 2019). The most prominent feature of GHD in children is short stature. In both children and adults, we observed that GHD patients revealed decreased bone mineral density, lean body mass, quality of life, and an increase in fat mass and, possibly, higher incidence of cardiovascular disease (Molitch et al. 2011, Tamhane et al. 2018).
Since 1985, recombinant GHT is used in GHD patients for varying underlying conditions, including after (childhood) cancer treatment. The effects of GHT, however, differ depending on the life phase of the patient. In children, the primary goal and effect of GHT are normalizing height and attaining an adult height within the normal range. Several studies in CCS show significant improvement in final height when treated with GHT compared to those that are not (Sfeir et al. 2018), although some characteristics, such as radiation therapy on the craniospinal axis, can undermine the full growth potential of GHT. Growth impairment can have a strong negative effect on the quality of life of survivors, as it can interfere with self-confidence, self-image, and social development, explaining the increased quality of life reported by growth hormone (GH)-treated patients (Tamhane et al. 2018). Moreover, the metabolic effects of GHT in children, such as a decrease in body fat and an increase in fat-free mass, may have improving effects on health risks later in life (Cutfield et al. 2000). In teenagers and young adults, the goal of linear growth shifts toward the goal of improved bone and muscle development, and in adults, the clinical benefits of GHT are solely based on metabolic changes. Multiple studies have supported these clinical benefits of GHT in all age groups, including in body composition, exercise capacity, skeletal integrity, and several cardiovascular surrogate outcomes (including endothelial function, inflammatory cardiovascular biomarkers, and lipoprotein metabolism), which are therefore included in the guideline of the Endocrine Society (Molitch et al. 2011).
In patients without a history of cancer, such as children born small for gestational age (SGA) or patients with Turner syndrome, studies did not observe associations of GHT with an increased risk of cancer (Sävendahl et al. 2020). However, due to known pro-proliferative, angiogenic, and anti-apoptotic properties of GH and insulin-like growth factor1 (IGF1), there are some concerns about the safety of GHT in survivors with a history of cancer or non-malignant (brain) tumors. This is due to some strong evidence for the role of the GH–IGF1 axis in the development and support of abnormal cell growth in experimental data of cellular and mice models (Chesnokova & Melmed 2020, Qian et al. 2022).
In this narrative review, we aimed to provide an overview of all available knowledge on the long-term sequelae of GHT to get insight into the long-term safety of GHT in survivors of (childhood) cancer and patients with tumors of the pituitary region. We elaborate on the possible influence of GHT on long-term risks in survivors, including cancer recurrences, occurrences of SNs, and mortality.
Methods
For this narrative review, to identify studies that investigated long-term effects of GHT in survivors of cancer, and patients with tumors of the pituitary region, we searched PubMed and EMBASE in November 2022 with the usage of the following search terms (including synonyms and words closely related): ‘growth hormone therapy/treatment’ and ‘cancer survivor’ or ‘pituitary tumor’ or ‘meningioma’ and ‘mortality’ or ‘morbidity’ or ‘neoplasm’ or ‘safety’. The complete search strategy is depicted in (Supplementary Table 2, see section on supplementary materials given at the end of this article). We included papers that (i) described participants with a history of any cancer or tumor of the pituitary region (including malignant and benign tumors) at any age that used GHT and that compared results to comparable participants not using GHT, (ii) described at least one of our outcome measurements (recurrences, SNs, mortality), (iii) were written in English or Dutch language, and (iv) were available in full text. We performed a cross-reference check of included papers to add missing articles. If we had arguments to believe that papers described duplicate participants, we included the most recent paper with the largest cohort. If the most recent paper did not have the largest cohort, we included the study that best fitted our research question (e.g. the participants group with all CCS instead of a particular subgroup). The flowchart of our search is depicted in (Fig. 1). All relevant articles without a sufficient control group for our research question were scanned and, if contributory, used for background information and discussion (Supplementary Table 3).
Flowchart of literature search. The total number of articles included and articles per outcome measure do not add up due to some studies reporting on more than one of our outcomes and are therefore reported twice. For the number of included papers, two numbers are depicted; the first is the number of original articles included, and the second (between brackets) is the number of meta-analyses included.
Citation: Endocrine-Related Cancer 30, 7; 10.1530/ERC-23-0026
Results
We identified 29 articles concerning (or with a subgroup of well-defined) cancer survivors and/or patients with a tumor of the pituitary region that received GHT vs survivors that did not receive GHT, also reporting at least one of our outcome measures (recurrences, SNs, mortality) (Fig. 1). Of these 29 articles, 21 articles reported on recurrences (Table 1), 11 on SNs (Table 2), and 6 on mortality (Table 3). Due to the possible double inclusion of participants (i.e. overlapping cohorts), we excluded some studies as described in the methods (Fig. 1). In addition, we identified six meta-analyses, which were partly overlapping in included studies. Four of these meta-analyses reported on recurrences, four on SNs, and two on mortality (Supplementary Table 4).
Overview of studies on safety of growth hormone replacement therapy in survivors, addressing recurrences / progression.
| Reference | Design* | Participants | Follow-up | Recurrences |
|---|---|---|---|---|
| Losa et al. (2020) | 2 | 74 GH-treated patients with NFPA 120 non-GH-treated patients with NFPA 49 GH-treated patients with craniopharyngioma 40 non-GH-treated patients with craniopharyngioma |
88 months (IQR: 48–128) | 73/283 (25.8%) tumour recurrences (total) Association of recurrence of pituitary tumor and GHT: Unadjusted HR (95% CI): 0.53 (0.32–0.86), P = 0.01 Adjusted HR (95% CI): 0.82 (0.47–1.44), P = 0.50a |
| Child et al. (2019) GeNeSIS | 1 | 1087 GH-treated patients with a tumor of which 622 GH-treated CCS 114 non-GH-treated CCS |
Mean 4.2 y ± 3.2 (∼92,000 person-years) | 74/1087 (6.8%) tumor recurrences (all types) in GHT group 67/823 (8.1%) intracranial tumor recurrences in GHT group 37/271 (13.7%) craniopharyngioma recurrences in GHT group 6/218 (2.8%) medulloblastoma recurrences in GHT group 9/148 (6.1%) recurrences in no GHT group |
| Gasco et al. (2019) | 2 | 90 GH-treated patients 110 non-GH-treated patients with GHD 109 non-GH-treated patients with no GHD. All with tumors of the hypothalamic–pituitary region. |
Mean 9.9 y ± 8.3 | Tumor progression rate in GH-sufficient, not-treated, and treated GH-deficient patients: 16.5, 16.4, and 10.0%. Univariate analysis of GH dose on tumor progression: HR: 0.89 (95% CI: 0.51–1.57), P = 0.69. Multivariate analysis of GHT and no GHT group on tumor progression: HR: 0.58 (95% CI: 0.21–1.66), P = 0.313. |
| Child et al. (2015) HypoCCS | 2 | 3668 GH-treated patients with pituitary adenoma 720 non-GH-treated patients with pituitary adenoma 956 GH-treated patients with craniopharyngioma 102 non-GH-treated patients with craniopharyngioma |
Mean 4.8 y ± 3.9 | 257/3537 (7.3%) pituitary adenoma recurrence, adjusted RR: 0.91 (95% CI: 0.68–1.22) in GHT groupb
64/956 (6.7%) craniopharyngioma recurrence, adjusted RR: 1.32 (95% CI: 0.53–3.31) in GHT groupb |
| Olsson et al. (2012) | 4 | 56 GH-treated patients with craniopharyngioma 70 non-GH-treated patients with craniopharyngioma |
Mean 13.6 y ± 5.0 Mean 13.4 y ± 7.8 |
9/56 (16.1%) tumor progression in GHT group 30/70 (42.9%) tumor progression in no GHT group 10-year progression-free survival: 85% for GHT group and 65% for control group |
| Mackenzie et al. (2011) | 3 | 110 GH-treated previously brain-irradiated patients 110 matched controls, non-GH treated Both groups including pituitary adenoma, craniopharyngioma, and intracranial neoplasms | Median 14.5 y (IQR: 11–22) Median 15.0 y (IQR: 10–20) | 6/110 (5.5%) recurrence in GHT group 8/110 (7.3%) recurrence in no GHT group, P = 0.7835 |
| Rohrer et al. (2010) | 2 | 44 GH-treated CCS (brain tumors) 59 non-GH-treated CCS (brain tumors) |
Median 7.5 y (range: 0.9–20.7) Median 4.5 y (range: 0.3–22.1) |
13/44 (29.5%) recurrence in GHT group 28/59 (47.5%) recurrence in no GHT group Logistic regression for recurrence and GHT: regression coefficient 1.308, s.e.m. 1.061, P = 0.218 |
| Arnold et al. (2009) | 2 | 23 GH-treated patients with NFPA 107 non-GH-treated patients with NFPA |
Mean 6.8 y ± 4.2 | 8/23 (34.8%) tumor regrowth in GHT group 38/107 (35.5%) tumor regrowth in no GHT group R: 0.51 (95% CI: 0.24–1.12), P = 0.09 for GHT as predictor of recurrence |
| Olsson et al. (2009) | 4 | 121 GH-treated patients with NFPA 114 non-GH-treated patients with NFPA (matched controls) |
Mean 9.9 y ± 3.9 Mean 10.1 y ± 4.4 |
31/121 (25.6%) tumor progression in GHT group 37/114 (32.5%) tumor progression in no GHT group. 10-year tumor progression-free survival rate: 74% in GHT group and 70% in no GHT group |
| Buchfelder et al. (2007) | 4 | 55 GH-treated patients with hormonally inactive pituitary adenomas undergoing tumor surgery 55 non-GH-treated controls (matched pairs) |
5 y after initial postoperative MRI | 16/55 (29.1%) tumor progression in GHT group 12/55 (21.8%) tumor progression in no GHT group, P = 0.617 6/29 (20.7%) recurrence in GHT group 4/29 (13.8%) in no GHT group, P = 0.317 |
| Karavitaki et al. (2006) | 2 | 32 GH-treated patients with craniopharyngioma 53 non-GH-treated patients with craniopharyngioma |
Mean 10.8 ± 9.2 y (range: 1.9–40) Mean 8.3 ± 8.8 y (range: 0.5–36) |
4/32 (12.5%) recurrence in GHT group 22/53 (41.5%) recurrence in no GHT group Adjusted HR: 0.309, 95% CI: 0.09–1.04, P = 0.06 for GHT as predictor for recurrenced |
| Leung et al. (2002) | 2 | 43 GH-treated ALL CCS 544 non GH-treated ALL CCS |
Median 15.6 y (range: 7.3–22.1) | 0/43 (0%) leukemia relapse in GHT group 8/544 (1.5%) leukemia relapse in no GHT group |
| Sklar et al. (2002) CCSS | 2 | 297 GH-treated CCS (172 brain tumor survivors) 11,742 non-GH-treated CCS |
Median 6.2 y (range: 0.4–20.6) | RR: 0.75 (95% CI: 0.34–1.68), P = 0.48, for recurrence in GHT group in univariate model RR: 0.83 (95% CI: 0.37–1.86), P = 0.65, for recurrence in GHT group in multivariate modele |
| Packer et al. (2001) | 2 | 170 GH-treated CCS with medulloblastoma 375 non-GH-treated CCS with medulloblastoma |
5y | RR: 0.71 (95% CI: 0.65–4.27) for recurrence in GHT group (infants, <3 y old) RR: 0.65 (95% CI: 0.37–1.15) for recurrence in GHT group (older children, >3 y old) |
| Swerdlow et al. (2000) | 2 | 180 GH-treated CCS with brain tumor 891 non-GH-treated CCS with brain tumor |
Mean 6.4 y Mean 4.5 y |
35/180 (19.4%) recurrence in GHT group 434/891 (48.7%) recurrence in no GHT group Adjusted RR for recurrence in GHT group: 0.6 (95% CI: 0.4–0.9), P < 0.05f |
| Corrias et al. (1997) | 4 | 25 GH-treated CCS with brain tumor 100 non-GH-treated CCS with brain tumor |
Time from primary therapy range 2.1–12.1 y | 4/25 (16%) relapses in GHT group 18/100 (18%) relapses in no GHT group |
| Ogilvy-Stuart et al. (1992) | 2 | 47 GH-treated CCS with brain tumor 160 non-GH-treated CCS with brain tumor 15 GH-treated CCS with ALL 147 non-GH-treated CCS with ALL |
Mean 5.1 y | 5/47 (10.6%) recurrence in GHT group (brain tumor) 42/160 (26.9%) recurrence in no GHT group (brain tumor) Adjusted RR: 0.82 (95% CI: 0.28–2.37)g 1/15 (6.7%) recurrence in GHT group (ALL) 11/147 (7.5%) recurrence in no GHT group (ALL) |
| Clayton et al. (1987) | 2 | 13 GH-treated CCS with brain tumor 21 non-GH-treated CCS with brain tumor |
NR | 4/13 (30.8%) recurrence in GHT group 5/21 (23.8%) recurrence in no GHT group |
| Arslanian et al. (1985) | 2 | 24 GH-treated CCS with brain tumor 10 non-GH-treated CCS with brain tumor |
Mean 5.5 y (range: 0.5–14.3) | 8/24 (33.3%) recurrence in GHT group 3/10 (30.0%) recurrence in no GHT group |
*Design: 1 = prospective observational study, 2 = retrospective cohort study, 3 = retrospective matched pair analysis, 4 = case-control study.
aAdjusted for age, gender, surgery, type of tumor, residual disease, and radiotherapy; badjusted for 27 baseline imbalances; cadjusted for radiotherapy, residual tumor, and gender; dadjusted for sex, age at diagnosis, and type of tumor therapy; emultivariate model including radiation, age at diagnosis, and chemotherapy; fadjusted for age at diagnosis, tumor type, calendar period of diagnosis, time since diagnosis, chemotherapy and hospital of treatment; gadjusted for age, sex, diagnosis, and use of chemotherapy.
ALL, acute lymphoblastic leukemia; CCS, childhood cancer survivor; GH, growth hormone; GHD, growth hormone deficiency; GHT, growth hormone replacement therapy; HR, hazard ratio; IQR, interquartile range; MRI, magnetic resonance imaging; NFPA, nonfunctioning pituitary adenoma; NR, not reported; RR, relative risk; RT, radiotherapy; y, year.
Overview of studies on safety of growth hormone replacement therapy in survivors, addressing second neoplasms
| Reference | Design* | Participants | Follow-up | Second neoplasms |
|---|---|---|---|---|
| Thomas-Teinturier et al. (2020) | 2 + 4 | 196 GH-treated CCS (126 brain tumors) 2656 non-GH-treated CCS |
Median 26 y (range: 5–41) Median 27 y (range: 5–54) |
40/196 (20.4%) SN in GHT group 334/2656 (12.6%) SN in no GHT group RR: 1.3 (95% CI: 0.9–2) for all secondary cancers in GHT group. RR: 0.6 (95% CI: 0.2–1.5), P = 0.3 for non-meningioma brain tumors RR: 0.7 (95% CI: 0.4–1.2), P = 0.2 for non-brain cancer RR: 1.9 (95% CI: 0.9–4), P = 0.09 for meningioma |
| Child et al. (2019) GeNeSIS | 1 | 1087 GH-treated patients with a tumor of which 622 GH-treated CCS 114 non-GH-treated CCS |
Mean 4.2 y ± 3.2 (∼92,000 person-years) | 31/622 (5.0%) SN in GHT group 9/114 (7.9%) SN in no GHT group. Crude incidence/1000 person-years is10.7 (95%CI: 7.5–15.2) for SN inGHT group |
| Hammarstrand et al. (2018) | 2 | 207 GH-treated patients with NFPA 219 non-GH-treated patients with NFPA |
Median 12.2 y (range: 0–24) Median 8.2 y (range: 0–27) |
19/219 (8.7%) malignant neoplasm of brain/prostate/breast/colon in GHT group 20/207 (9.7%) malignant neoplasm of brain/prostate/breast/colon in no GHT group. SIR: 0.98 (95% CI: 0.32–2.28), P = 0.99 for colon/rectum neoplasma SIR: 1.33 (0.71–2.28), P = 0.37 for prostate neoplasma |
| Brignardello et al. (2015) | 2 | 26 GH-treated CCS 23 non-GH-treated CCS |
Median 16.1 y |
8/26 (30.8%) SN in GHT group 6/23 (26.1%) SN in no GHT group (P = 0.331) Both groups included 5 secondary meningiomas Adjusted HR: 3.74 (95% CI: 0.85–16.43) for GHT on SNb |
| Woodmansee et al. (2013) HypoCCS (GeNeSIS not shown) | 2 | 252 GH-treated CCS 28 non-GH-treated CCS |
Median 2.9 y (IQR: 1.5–5.1) | 15/252 (6.0%) SN with GHT 2/28 (7.1%) SN with no GHT Most common SN was meningioma (10/27, 37.0%) |
| Mackenzie et al. (2011) | 3 | 110 GH-treated previously brain-irradiated patients 110 matched controls, non-GH-treated. Both groups including pituitary adenoma, craniopharyngioma, and intracranial neoplasms | Median 14.5 y (IQR: 11–22) Median 15.0 y (IQR: 10–20), respectively |
5/110 (4.5%) SN in GHT group 3/110 (2.7%) SN in no GHT group (P = 0.7215) |
| Rohrer et al. (2010) | 2 | 44 GH-treated CCS (brain tumors) 59 non-GH-treated CCS (brain tumors) |
Median 7.5 y (range: 0.9–20.7) Median 4.5 y (range: 0.3–22.1) |
3/44 (6.8%) SN in GHT group 1/59 (1.7%) SN in no GHT group |
| Ergun-Longmire et al. (2006) CCSS | 2 | 361 GH-treated CCS 13,747 non-GH-treated CCS |
Additional 32 months FU compared to Sklar et al. (2002), which had a median FU of 6.2 y (range 0.4–20.6) | Univariate RR 1.92 (95% CI 1.22–2.99) for an SN in GHT group Adjusted RR 2.15 (95% CI 1.3–3.5) for an SN in GHT groupc Total: 9/20 (45%) meningiomas |
| Leung et al. (2002) | 2 | 43 GH-treated ALL CCS 544 non-GH-treated ALL CCS |
Median 15.6 y (range: 7.3–22.1) | 2/43 (4.7%) SN in GHT group 16/544 (2.9%) SN in no GHT group |
*Design: 1 = prospective observational study, 2 = retrospective cohort study, 3 = retrospective matched pair analysis, 4 = case-control study.
aSIRs for an SN in the GHT group are calculated with the general population as a reference; badjusted for gender, age, and cancer type; cadjusted for age at diagnosis, sex, radiation, alkylating agents
ALL, acute lymphoblastic leukemia; CCS, childhood cancer survivor; CNS, central nervous system; FU, follow-up; GH, growth hormone; GHD, growth hormone deficiency; GHT, growth hormone replacement therapy; HR, hazard ratio; IQR, interquartile range; NFPA, nonfunctioning pituitary adenoma; PNET, primitive neuroectodermal tumor; RR, relative risk; SIR, standardized incidence ratio; SN, second neoplasm; y, year.
Overview of identified studies on safety of growth hormone replacement therapy in survivors of cancer and tumors of the pituitary region, addressingmortality. Only participants used for our outcome measures (i.e. survivors with or without GHT) are shown.
| Reference | Design* | Participants | Follow-up | Mortality |
|---|---|---|---|---|
| Olsson et al. (2017) | 2 | 207 GH-treated adults with NFPA 219 non-GH-treated adults with NFPA |
Median 12.2 y (range: 0–25) Median 8.2 y (range: 0–27) |
29/207 (14.0%) deaths in GHT group 93/219 (42.5%) deaths in no GHT group SMR 0.65 (95% CI 0.44–0.94, P = 0.018) in GHT groupa SMR 1.16 (95% CI 0.94–1.42, P = 0.17) in no GHT groupa |
| Berglund et al. (2015) | 3 | 43 GH-treated children with craniopharyngioma 5 non-GH-treated children with craniopharyngioma 23 GH-treated CCS (malignant) 12 non-GH-treated CCS (malignant) |
Median 19.9 y (95% CI: 9.2–20.9) | HR: 0.83 (95% CI: 0.07–10.20) for mortality in GHT group (craniopharyngioma) HR: 0.41 (95% CI: 0.09–1.88) for mortality in GHT group (CCS) |
| Woodmansee et al. (2013) GeNeSIS and HypoCCS | 2 | GeNeSIS: 394 GH-treated CCS 27 non-GH-treated CCS HypoCCS: 252 GH-treated CCS 28 non-GH-treated CCS |
Median 2.1 y (IQR: 1.1–3.5) Median 2.9 y (IQR:1.5–5.1) |
7/394 (1.8%) deaths in GHT group 1/27 (3.7%) deaths in no GHT group 3/252 (1.2%) deaths in GHT group 1/28 (3.6%) deaths in no GHT group |
| Mackenzie et al. (2011) | 3 | 110 GH-treated previously brain-irradiated patients 110 matched controls, non-GH-treated. Both groups including pituitary adenoma, craniopharyngioma, and intracranial neoplasms | Median 14.5 y (IQR: 11–22) Median 15.0 y (IQR: 10–20), respectively |
7/110 (6.4%) deaths in GHT group 15/110 (13.6%) deaths in no GHT group (P = 0.03) |
| Sklar et al. (2002) CCSS | 2 | 361 GH-treated CCS (172 brain tumor survivors) 12963 non-GH-treated CCS |
Median 6.2 y (range: 0.4–20.6) | RR: 1.21 (95% CI: 0.75–1.94), P = 0.43 in GHT group in multivariate modelb |
| Swerdlow et al. (2000) | 2 | 180 GH-treated CCS with brain tumor 891 non-GH-treated CCS with brain tumor |
Mean 6.4 y Mean 4.5 y |
RR: 0.5 (95% CI: 0.3–0.8) in GHT group |
*Design: 1 = prospective observational study, 2 = retrospective cohort study, 3 = retrospective matched pair analysis.
aGeneral population used as a reference; badjusted for age at diagnosis, sex, radiation, and chemotherapy
CCS, childhood cancer survivor; CNS, central nervous system; GH, growth hormone; GHT, growth hormone replacement therapy; HR, hazard ratio; IQR, interquartile range; NFPA, nonfunctioning pituitary adenoma; RR, relative risk; SMR, standardized mortality ratio; y, year.
GHT and recurrences
We identified 21 articles that reported on recurrences, of which 20 were retrospective cohort studies and 1 was a prospective study (GeNeSIS) (Table 1). We identified four studies having possible duplicate participants of which we excluded two studies. Two studies reported on (subparts of) the HypoCCS cohort, that is, the Hypopituitary Control and Complications Study (Hartman et al. 2013, Child et al. 2015). Since the most recent paper had included the largest number of participants and had the longest median follow-up, we included that paper (Child et al. 2015). Two other studies reported on the same group of patients (n = 47 GH-treated CCS with brain tumors), of which one study extended their participant group with 15 extra CCS with acute lymphoblastic leukemia (ALL), and therefore, we included the latter (Ogilvy-Stuart & Shalet 1992, Ogilvy-Stuart et al. 1992).
Of the remaining 19/21 studies, most reported on recurrences in participants with brain tumors, of which 7 studies (Karavitaki et al. 2006, Buchfelder et al. 2007, Arnold et al. 2009, Olsson et al. 2009, Olsson et al. 2012, Child et al. 2015, Losa et al. 2020) reported on recurrences in participants with benign cranial tumors and 8 studies (Arslanian et al. 1985, Clayton et al. 1987, Corrias et al. 1997, Swerdlow et al. 2000, Packer et al. 2001, Rohrer et al. 2010, Mackenzie et al. 2011, Gasco et al. 2019) on participants with both underlying benign and malignant cranial tumors. Four studies reported on CCS including non-brain tumor types (Ogilvy-Stuart et al. 1992, Leung et al. 2002, Sklar et al. 2002, Child et al. 2019), and there were no studies reporting on adults including other tumor types.
None of the seven (0/19) studies (altogether n = 5034 participants with GHT) reporting on recurrences after benign cranial tumors (mostly nonfunctioning pituitary adenoma (NFPA) or craniopharyngioma) revealed a correlation between GHT and an increased risk for tumor recurrence in these patients (Karavitaki et al. 2006, Buchfelder et al. 2007, Arnold et al. 2009, Olsson et al. 2009, Olsson et al. 2012, Child et al. 2015, Losa et al. 2020). Of these studies, the largest cohort was included in the retrospective HypoCCS study (n = 3668 GH-treated pituitary adenoma participants and n = 956 GH-treated craniopharyngioma participants). They showed in pituitary adenoma survivors an adjusted relative risk (RR) for recurrence of 0.91 (95% CI: 0.68–1.22) and in craniopharyngioma survivors an adjusted RR of 1.32 (95% CI: 0.53–3.31) (Child et al. 2015). However, the mean follow-up time was only 4.8 years, which is a big limitation that applies to many, but not all, of our included studies. Another small, case-control study (n = 56 GH-treated craniopharyngioma participants) with a longer follow-up time (mean: 13.6 years) showed that initial radiotherapy and residual tumor after initial treatment were the most important prognostic factors for tumor progression and found no effect of GHT on the 10-year progression-free survival rate (85% in the GHT group vs 65% in the control group after adjustment for radiotherapy, residual tumor, and gender) (Olsson et al. 2012).
All eight (8/19) studies (altogether n = 656 participants with GHT) reporting on recurrences after malignant cranial tumors (or unspecified malignant/benign) could not show evidence for an increased risk of tumor recurrence with variating follow-up times (Arslanian et al. 1985, Clayton et al. 1987, Corrias et al. 1997, Swerdlow et al. 2000, Packer et al. 2001, Rohrer et al. 2010, Mackenzie et al. 2011, Gasco et al. 2019). Most cohorts included small numbers of participants receiving GHT. The retrospective cohort study from Swerdlow et al. included the largest patient numbers (n = 180 GH-treated CCS) and had a mean follow-up time of 6.4 years. They observed a decreased adjusted RR for relapse (0.6, 95% CI: 0.4–0.9) in GH-treated (brain tumor) survivors, as compared to controls (Swerdlow et al. 2000). The authors, however, mentioned a possible bias in the selection of participants, as patients with a better prognosis might have received GHT more often.
In addition, four (4/19) studies reported on recurrences after non-brain tumors, including two studies having a cohort of ALL survivors (Ogilvy-Stuart et al. 1992, Leung et al. 2002) and two studies on CCS with a history of all possible cancer types (Sklar et al. 2002, Child et al. 2019). Both ALL survivor studies did not show any correlation between GHT and recurrence of ALL (Ogilvy-Stuart et al. 1992, Leung et al. 2002). Concerning CCS with a history of all possible cancer types: Sklar et al. showed in their retrospective cohort study of 13,539 CCS (of which n = 361 with GHT) an RR of 0.83 (95% CI: 0.37–1.86) for a recurrence in GH-treated CCS (Sklar et al. 2002). Child et al. compared the overall recurrence rate between GH-treated vs non-GH-treated survivors and found percentages of 6.8 and 6.1%, respectively (Child et al. 2019).
We visualized abovementioned results through forest plots (Fig. 2), for which only studies are included that reported (sufficient information to calculate) the RR of recurrence (Table 1). Moreover, we identified four meta-analyses (Wang & Chen 2014, Shen et al. 2015, Alotaibi et al. 2018, Tamhane et al. 2018) looking at recurrences in GH-treated survivors. All four meta-analyses had some overlap in studies included, but all had additionally included cohorts as well; therefore, the total number of participants cannot be reported. Two studies included patients with underlying intracranial tumors (both benign and malignant), one study included CCS with variating tumor types and one study included only pediatric patients with a craniopharyngioma (Supplementary Table 4). All four meta-analyses reported no or even a lower recurrence rate of tumor recurrence with GHT.
Visualization of relative risks for recurrences, second neoplasms and mortality in survivors of growth hormone replacement therapy. * Studies that only included participants with an underlying benign tumor. º Studies that reported an adjusted RR, which is therefore shown in the forest plot instead of a non-adjusted relative risk. Visualization of results shown in Tables 1–3, regarding recurrences, second neoplasms and mortality in survivors of cancer and patients with tumors of the pituitary region on growth hormone replacement therapy. We used the (adjusted) RR provided by the study or we calculated the RR if the study provided sufficient data to construct two-by-two contingency tables. When a study reported both the adjusted and non-adjusted RR, we show the adjusted RR in our image (= second row of studies per figure, as shown by º). We only show studies that calculated RR by comparing survivors with GHT to survivors with no GHT. Some studies are shown twice in the forest plot due to different reported RRs corresponding different subgroups of participants. Child (2015) first shown RR is on pituitary adenoma recurrences, the second RR is on craniopharyngioma recurrences. Packer (2001) first shown RR is on recurrences in infants (<3 years) with medulloblastoma, the second shown RR is on recurrences in older children (>3 years) with medulloblastoma. Berglund (2015) first shown RR is on CCS (malignancy) and the second RR is on children with craniopharyngioma. Woodmansee (2013) first shown RR is from the GeNeSIS cohort and the second RR is derived from the HypoCCS cohort. A full color version of this figure is available at https://doi.org/10.1530/ERC-23-0026.
Citation: Endocrine-Related Cancer 30, 7; 10.1530/ERC-23-0026
GHT and second neoplasms
We identified 11 articles reporting on SNs, the majority being retrospective cohort studies with only 1 study (GeNeSIS) being prospective (Table 2). Three consecutive studies reported on the same cohort over time (Childhood Cancer Survivor Study, CCSS); two studies included one and the same cohort and outcomes but had an additional follow-up and one study only focused on CNS-SN instead of all SN (Sklar et al. 2002, Ergun-Longmire et al. 2006, Patterson et al. 2014). We included the largest study focusing on all SN in our review (Ergun-Longmire et al. 2006). Moreover, we identified one study reporting summarizing results of two cohorts (HypoCCS and GeNeSIS cohort) (Woodmansee et al. 2013). Child et al. reported on the GeNeSIS cohort as well, but with a greater number of participants and longer follow-up, and this study was therefore included in our review (Child et al. 2019), instead of the results for the GeNeSIS cohort from the summarized report (Woodmansee et al. 2013). Since we had no studies solely reporting on the HypoCCS cohort with SN as an outcome, we did include the results of the summarized report of Woodmansee et al. for only this cohort (Woodmansee et al. 2013).
Of the remaining nine (9/11) original articles, six studies reported on CCS (Leung et al. 2002, Ergun-Longmire et al. 2006, Woodmansee et al. 2013, Brignardello et al. 2015, Child et al. 2019, Thomas-Teinturier et al. 2020), with various tumour types and three studies reported on patients with underlying brain tumor in particular (including benign and malignant tumors) (Rohrer et al. 2010, Mackenzie et al. 2011, Hammarstrand et al. 2018).
One (1/9) study (n = 361 GH-treated CCS) showed a significant correlation between GHT and an SN in cancer survivors, being the CCS Study (Ergun-Longmire et al. 2006). They identified an increased risk of subsequent neoplasms in GH-treated patients; however, these became less significant when increasing their follow-up time (RR: 2.15 vs RR: 3.21 after an additional 32-month follow-up) (Ergun-Longmire et al. 2006).
Eight (8/9) other studies (n = 1500 in total), with a follow-up time range from median 2.9 years to median 26 years, did not show a significant correlation between GHT and an SN in survivors (Leung et al. 2002, Rohrer et al. 2010, Mackenzie et al. 2011, Woodmansee et al. 2013, Brignardello et al. 2015, Hammarstrand et al. 2018, Child et al. 2019, Thomas-Teinturier et al. 2020). When separating malignant and benign tumors as underlying conditions and the occurrence of SNs, there was only one study reporting solely on benign tumors. They (n = 207 GH-treated participants) did not reveal an increased risk for SN in patients with an NFPA as an underlying condition (Hammarstrand et al. 2018).
A striking group of SN in several papers are the meningiomas. Three studies in our search observed a higher meningioma prevalence in their cohorts compared to what they had expected; however, this was true for both the GH-treated as well as the non-GH-treated group (Ergun-Longmire et al. 2006, Woodmansee et al. 2013, Brignardello et al. 2015). Moreover, two other studies did not observe similar results (Patterson et al. 2014, Thomas-Teinturier et al. 2020). In a French cohort (n = 2852 survivors in total), with multivariate analysis of 374 survivors that developed an SN, they found no increased risk of GHT on secondary non-meningioma brain tumors (RR 0.6, 95% CI 0.2–1.5), secondary non-brain cancer (RR 0.7, 95% CI 0.4–1.2), or meningioma (RR 1.9, 95% 0.9–4). However, they did observe a slight non-significant (P = 0.05) increase (1.6-fold vs 2.3-fold after <4 years vs longer exposure) of the risk of meningioma with GHT duration (Thomas-Teinturier et al. 2020).
We visualized the RRs of identified studies through forest plots (Fig. 2), including only studies with sufficient information on (or to calculate) the RR for SNs in GH-treated survivors. Moreover, we identified four meta-analyses that included SNs as an outcome, of which two studies included both adult and childhood survivors, one study included only CCS and one study included only CCS with brain tumors (benign and malignant) (Supplementary Table 4). All meta-analyses reported on an important number of duplicate articles when being compared to each other. In total, three meta-analyses showed increased risks for an SN, including a mean RR for an SN in GH-treated survivors of 1.77 (95% CI: 1.33–2.35) and 1.99 (95% CI: 1.28–3.08) (Deodati et al. 2014, He et al. 2022). Another study showed a pooled RR of 1.84 (95% CI: 1.05–3.21, P = 0.03) in GH-treated CCS with brain tumors (Wang & Chen 2014). However, the meta-analysis from the Endocrine Society calculated no significant risk for an SN in GH-treated CCS (OR: 1.10, 95% CI: 0.72–1.67) (Tamhane et al. 2018).
GHT and mortality
We identified six articles, including seven (retrospective only) studies (altogether n = 1570 participants treated with GHT), reporting on mortality (Table 3). One study reported on two separate cohorts (HypoCCS and GeNeSIS) which we both included (Woodmansee et al. 2013). Three studies reported on CCS with variating cancer types (Sklar et al. 2002, Woodmansee et al. 2013, Berglund et al. 2015), and three studies reported on only cranial tumor survivor outcomes (including both children and adults) (Swerdlow et al. 2000, Mackenzie et al. 2011, Olsson et al. 2017).
Five (5/7) studies, including CCS and patients with cranial tumors, with a median follow-up time between 2.1 and 14.5 years, showed no difference in mortality between participants with GHT and no GHT (Sklar et al. 2002, Mackenzie et al. 2011, Woodmansee et al. 2013, Berglund et al. 2015). Two (2/7) studies, including CCS with brain tumors and adults with NFPA, with a median follow-up time of 6.4 years and mean follow-up time of 12.2 years respectively, showed an even lower mortality rate in GH-treated survivors, including an RR of 0.5 (95% CI: 0.3–0.8) in the CCS (with brain tumors) treated with GHT (Swerdlow et al. 2000, Olsson et al. 2017). The authors stressed that the lower mortality rates may have been due to bias: patients may have been selected for GHT or not based on their prognosis/disease status.
Again, we visualized the results, that is, RRs for mortality, of identified studies through forest plots (Fig. 2). We identified no meta-analyses that looked at mortality in a subgroup of cancer survivors/patients with tumors of the pituitary region on GHT (Supplementary Table 4). However, two meta-analyses reported the overall mortality of patients that received GHT (including survivors), showing an overall cause standardized mortality rate (SMR) of 1.28 (95% CI: 0.58–2.84) and 1.19 (95% CI: 1.08–1.32). Both meta-analyses consisted of both original as well as some duplicate cohorts (Deodati et al. 2014, He et al. 2022). He et al. showed no significant association between GHT and all-cause mortality or cancer mortality when follow-up time was ≥10 years (SMR: 0.98, 95% CI: 0.75–1.29) and SMR: 2.59, 95% CI: 0.55–12.09, respectively), in contrast to the significant association between GHT and all-cause mortality in studies with follow-up <10 years (SMR: 4.62, 95% CI: 1.19–18.01) (He et al. 2022).
Discussion
We identified predominantly results that support the long-term safety of GHT in both survivors of cancer and patients with benign tumors of the pituitary region (Fig. 2). However, most of the available studies are based on retrospective cohort studies with relatively short follow-up times and still there are conflicting results. Moreover, the vast majority of conducted studies represent CCS and data on the safety of GHT in adult cancer survivors are still very limited. Currently, there is no evidence of an increased risk for recurrences, SNs, or mortality in survivors receiving GHT, besides the already increased risk due to host-, disease-, and treatment-related factors. Hence, individual risk/benefit analysis is needed to balance the risks in certain subgroups of patients to the known morbidity of untreated GHD in cancer survivors. Moreover, the shown positive effects of GHT in survivors corresponding to the life phase they are in, including improved growth velocity, clinical benefits in body composition, exercise capacity, skeletal integrity, and increased quality of life, should be considered when discussing this therapy (Molitch et al. 2011, Sfeir et al. 2018, Tamhane et al. 2018).
The debate on the safety of GHT based on the suggested relationship between cancer and the growth of tumors is supported by results from experimental data of cellular and mice models. Moreover, a genome-wide association study identified GH-induced intracellular signaling pathways to be highly associated with breast cancer susceptibility (Menashe et al. 2010). GH and IGF1 are key players in cell regulation, differentiation, angiogenesis, and apoptosis. Many human types of cancer express GH or IGF1 (and/or their receptors). Therefore, GH can contribute to tumor microenvironment by promoting epithelial–mesenchymal transition and vascularization, both enabling the survival and proliferation of tumor cells (Chesnokova & Melmed 2020). Moreover, (higher levels of) GH are thought to suppress DNA damage repair and to drive cancer resistance by the suppression of apoptosis, upregulation of drug efflux, and the induction of cancer stem cell niches (Basu & Kopchick 2019, Chesnokova & Melmed 2020). GH is also thought to play a role in the homing processes, and hence the development of metastases and relapse as well (Basu & Kopchick 2019). However, most of these effects of GH on the tumor microenvironment have been demonstrated only in vitro and are derived from supra-physiological GH levels. Currently, we have no reason to think that patients on GHT, while mimicking physiological GH levels, would have an increased (cancer) risk compared to patients that have normal GH levels without intervention. However, further studies are needed to confirm or reject the abovementioned relationships in vivo while restoring physiological levels of GH (Chesnokova & Melmed 2020).
Epidemiological studies and mouse models on GH–IGF1 excess/deficiency have supported the existing relationship of GHT with the occurrence of cancer and the development of metastases/relapse as well. Studies on Laron syndrome, in which patients suffer from a decreased endogenous activity of GH and IGF1, showed a lower prevalence of cancer. GH receptor knockout mouse models (Laron mouse) confirmed this intrinsic resistance to tumor development (Kopchick et al. 2014). In contrast, studies on acromegaly, characterized by abnormal growth due to an excess amount of endogenous GH production, have described ambiguous results regarding its relationship to cancer. Some studies have shown a higher colon cancer mortality rate (standardized mortality ratio 2.47, 95% CI 1.31–4.22) in these patients (Orme et al. 1998), but other studies could not confirm this association. Since the purpose of GHT is restoring normal values of IGF1 instead of establishing supra-physiological levels, it is questionable whether this relationship is transferable to our GH-treated population. Recent studies revealed a normalization of the risk for cancer-related deaths in acromegaly patients after achieving biochemical control, suggesting no increased risk of cancer when restoring physiological values of GH, which is the main goal in our GH-treated survivor population.
On the other hand, we have to take into account the recent developments regarding long-term acting GH (LAGH) preparations instead of daily GHT. Several LAGHs are currently at various stages of development, with some already on the market, trying to improve adherence and subsequently efficacy (Lal & Hoffman 2019, Miller et al. 2020). However, the non-pulsatile and possibly higher serum peak GH and IGF1 levels that derive from these LAGH preparations are raising concerns that these agents would lead to overtreatment and subsequently even the development of acromegaly or enhancement of other possible side effects. Although some randomized controlled trials have shown comparable effects of LAGH compared to daily GHT on the IGF–IGFBP axis, bone metabolism, body composition, insulin sensitivity, and lipoprotein metabolism (Laursen et al. 2001), the very long-term effects, and safety, still need to be elucidated. Moreover, the correct timing of monitoring serum IGF1 levels needs to be identified with consideration of the pharmacokinetic and dynamic properties of these new agents.
Despite all associations of GH with increased risk for abnormal growth and therefore (primary) cancer and neoplasms in cellular and epidemiological studies, our review does not reveal strong evidence for an enhanced risk in GH-treated survivors. Clinicians have years of experience with GHT in this population and it has been deemed safe by this experience. Moreover, the mandatory registries of all patients using GHT in some countries have been lifted after reassuring results, supporting its safety. Human studies, in patients without a history of cancer, such as children born SGA or patients with Turner syndrome, have already established lack of an association with GHT and increased risk of cancer in well-designed observational studies. One of the most important studies in that respect is a worldwide observational study (n = 15,809 GH-treated patients) which found the de novo cancer incidence, in both adult-onset as well as childhood-onset GHD, comparable to that in the general population (standardized incidence ratio (SIR): 0.92, 95% CI: 0.83–1.01), although we have to take into account the short follow-up time of 5.3 years in this study (Johannsson et al. 2022). A recent systematic review (2022) showed that GHT in children and adolescence is not associated with all-cause mortality (SMR: 1.28, 95% CI: 0.58–2.84), cancer mortality (SMR: 2.59, 95% CI: 0.55–12.09), and cancer incidence (SIR: 1.54, 95% CI: 0.68–3.47). However, they did find a statistical significance for SNs (RR: 1.77, 95% CI: 1.33–2.35) (He et al. 2022). It is already known that (childhood) cancer survivors are at high risk for recurrences early after their disease, and at high risk for SNs and early mortality later in life (Armstrong et al. 2009). Whether these risks are even more increased in survivors receiving GHT is still under debate in current literature, although our review does not reveal strong evidence for an association between GHT and recurrences, SNs, and mortality in survivors of cancer and patients with tumors of the pituitary region.
Most existing literature supports the safety of GHT in cancer survivors in terms of recurrence risk (Fig. 2), although there are many confounders and limitations in these studies that call for caution. Most of the conducted studies are retrospective cohort studies with a small number of participants. Moreover, very limited data are available on adult malignant cancer survivors, such as breast or colon cancer. Since cellular models have shown that especially these types of cancers can express GH or IGF1 (and/or their receptors), the hypothesis that participants with a history of these types of cancers could be at an increased risk for a recurrence is still not rejected. However, the lack of evidence for an increased risk of these types of malignancy in GH-treated patients without a history of cancer seems to support its safety. More, longitudinal, prospective research on a large scale, on adult malignant cancer survivors, is needed to fully support the safety of GHT in these survivors.
Concerning the risk for developing an SN in life, the results are more inconclusive about the possible increased risk caused by GHT. Literature shows that cancer survivors already have an increased risk of developing an SN in their life, in both CCS (Armstrong et al. 2009) as well as adult cancer survivors (Sung et al. 2020). Not only genetic predisposition is likely to increase this risk in survivors, but treatment-related damage, such as damage done by radiotherapy or chemotherapy, increases this risk as well. In most conducted studies, patient, disease-, and treatment-related factors seem to be the main cause for the increased risk of secondary neoplasms. For example, a higher cranial irradiation dose increases both the risk of subsequent CNS neoplasms as well as the risk of GHD. After adjusting for confounding risk factors, such as cranial radiotherapy (CRT) dose, time from CRT exposure, age, and sex, studies often find no contributed risk from received GHT to subsequent neoplasms (Patterson et al. 2014). KIMS (n = 2972 survivors with GHT) identified an increased SIR of SN in GH-treated CCS (10.4, 95% CI: 5.9–16.9). However, they compared CCS treated with GHT to the general population and not to CCS without GHT, making these results confounded and not transferable to a causative relationship between GHT and an increased risk of SNs in cancer survivors in particular (Krzyzanowska-Mittermayer et al. 2018). In addition, they also observed no increased SIR for an SN in adult-onset cancer patients, NFPA patients, or patients with idiopathic GHD, showing again the highly confounded relationship between GHT, the underlying disease, and received treatment, and the occurrence of subsequent neoplasms.
Interesting results are derived from studies showing an increased meningioma prevalence compared to what was expected. Although not all studies could reproduce these results, these results were one of the main reasons for the safety debate of GHT in cancer survivors. An important note is that meningioma is known to have a high prevalence of subclinical disease. A study from 2007 (n = 2000, aged 45.7–96.7 years), showed 1.6% of their total participant group to have a subclinical benign primary tumor. In the age group 45–59 years (n = 750), they found an asymptomatic meningioma in 0.5%, with an even increasing prevalence corresponding with increasing age groups (Vernooij et al. 2007). Therefore, it is possible there is a screening bias in the survivors population due to more intensive medical contacts and imaging leading to more asymptomatic meningioma diagnoses instead of a legitimate higher prevalence. Moreover, the DCOG-LATER cohort (n = 5843 CCS, median follow-up time: 23.3 years) showed that one in eight survivors had developed a meningioma by the age of 40 years, significantly related to radiation dose and exposure age (Kok et al. 2019), showing the highly confounded relationship between meningiomas and GHT in cancer survivors. Unfortunately, they did not explore GHT as a possible prognostic variable in their models. It is hypothesized that the higher occurence of a second meningioma in specific survivor groups (i.e. leukemia survivors) and the higher occurence of a second meningioma in cerebrum instead of in the spinal canal can (partly) be explained by genetic components as well as by a site effect of radiotherapy being of influence in the development of second meningiomas in survivors. For example, Swerdlow et al. reported an increased SIR for secondary meningioma (SIR: 75.4, 95% CI: 54.9–103.6) in GH-treated CCS, but this effect disappeared when adjusting for administered radiotherapy and could therefore not be linked to GHT (Swerdlow et al. 2019).
When exploring mortality in survivors of cancer and tumors of the pituitary region, we observed no increased mortality rate in GH-treated survivors when they are compared to participants with comparable characteristics (i.e. survivors treated with GHT vs survivors not treated with GHT). There are some studies showing increased mortality rates in GH-treated survivors; however, those all use a general population as a reference group (Mills et al. 2004, van Bunderen et al. 2011, Gaillard et al. 2012, Sävendahl et al. 2021). CCS, even without hypopituitarism or GHD, have a shorter life expectation compared to the normal population (Armstrong et al. 2009) and can therefore not be compared to GH-treated patients without the same baseline risks due to their underlying disease. For example, the Safety and Appropriateness of Growth Hormone Treatments in Europe (SAGhE) study (n = 24,232 GH-treated patients, mean follow-up time: 16.5 years) observed an increased overall mortality (SMR: 17.1, 95% CI: 15.6–18.7) in their risk group 3 (including all cancer survivors with craniopharyngioma and chronic renal failure patients), with higher mortality in patients with tumor diagnosis before treatment start, in particular patients with underlying CNS tumors (SMR: 23.6, 95% CI: 21.0–26.6) (Sävendahl et al. 2020). However, they could not conclude that this higher risk of mortality was due to the GHT since the underlying diagnosis is associated with increased mortality as well. Moreover, they did not show any association between the increased SMRs and daily or cumulative GH dosage, indicating there is no effect of GHT on mortality (Sävendahl et al. 2020). Current literature does not provide evidence that GHT specifically increases the risk of mortality, which is as such therefore stated in the Endocrine Society Guideline (Molitch et al. 2011). Other factors, such as host- (genetic predisposition), disease- (tumor latency period, comorbidities such as hypertension and hyperlipidemia), and treatment-related (damage done by radiotherapy, chemotherapy) factors are all likely to contribute to this increased mortality risk. In addition, in studies separating their participants into groups with malignant and benign tumors as underlying diagnosis, we see increasing SMRs in patients with malignant tumors and no increased SMRs in patients with benign (cranial) tumors (van Bunderen et al. 2011, Gaillard et al. 2012). These differences, again, underline the highly confounded relationship between GHT and mortality in survivors of cancer or tumors of the pituitary region. Although current literature shows no evidence for an increased mortality risk in survivors receiving GHT, besides the already increased risk due to host-, disease-, and treatment-related factors, still the limitations of conducted studies, such as retrospective designs, small cohorts, and often lack of a proper control group, must be taken into account.
Although we focused on recurrences, SNs, and mortality in this narrative review, other side effects following GHT in cancer survivors must also be taken into consideration. In CCS, GHT seems to be associated with exacerbation of scoliosis and increased risk for slipped capital femoral epiphysis (Darendeliler et al. 2007). Rapid growth could be a possible risk factor for both side effects. However, other confounding factors, such as irradiation or the presence of hormone deficiencies (including GHD), may have an influence as well, making the causative relationship between GHT and these side effects difficult to prove. Comparable results are described for increased intracranial pressure in CCS, with again, no proven causative relationship (Darendeliler et al. 2007). For adult cancer survivors, no differences in side effects of GHT are reported in literature.
Overall, the findings of our search are reassuring and confirm the long-term safety of GHT regarding recurrences, SNs, and mortality in cancer survivors and patients with tumors of the pituitary region. The strengths of this review relate to the comprehensive literature search and the wide-ranging participant population that was included (with both malignant and benign underlying tumors). However, there are still limitations in the available studies that need to be considered, such as a lack of information about dosage, primary disease, the (mostly) retrospective designs, and the often short follow-up times. Moreover, several studies lacked a representative control group, introducing bias in the results of highly confounded relationships between GHT and recurrences, SNs, and mortality. Studies on recurrences and secondary malignancies in adult malignant cancer survivors are still too limited and with too short follow-up times, to draw strong conclusions. More, longitudinal, prospective studies with longer follow-up times, bigger cohorts of participants, and adequate controls (i.e. survivors without GHT) are required to confirm, in particular, the long-term safety of GHT in survivors. This seems even more important since the latest findings reveal that some pediatric cancer cases are occurring with overgrowth syndromes in even higher percentages than previously envisaged. More research into particular sub-groups of survivors, such as patients with a strong family history of cancer or with a cancer-predisposing genetic condition, is needed to provide guidelines for these types of patients, as well as research into the appropriate waiting period after cancer to start GHT.
In summary, we identified predominantly reassuring results on the long-term safety of GHT in both survivors of cancer and patients with benign tumors of the pituitary region. However, we need to take into account the shortcomings of several studies, underlining the urgent need for longitudinal case-control studies on adult malignant cancer survivors and on participants with comparable characteristics that did and did not receive GHT. Conclusively, there is no evidence for an increased risk for recurrences, SNs, or mortality in survivors receiving GHT, besides the already increased risk due to host-, disease-, and treatment-related factors. Therefore, we support the consensus that GHT can be considered in survivors after careful individual risk/benefit analysis and in open discussion with the patients and their families, provided that the uncertainties in certain cases (such as overgrowth syndromes or cancer predisposition cases) are discussed as well. We need to balance these uncertainties to the known morbidity of untreated GHD in cancer survivors and shown positive effects of GHT in survivors corresponding to the life phase they are in, including improved growth velocity, clinical benefits in body composition, exercise capacity, skeletal integrity, and increased quality of life, which should be taken into account when discussing this therapy (Molitch et al. 2011, Sfeir et al. 2018, Tamhane et al. 2018).
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ERC-23-0026.
Declaration of interest
All authors declare to have no conflicts of interest.
Funding
The authors did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector for this narrative review.
Author contribution statement
Concept and design: M Bolier, M.M. van den Heuvel-Eibrink, SJCMM Neggers; Data analysis and interpretation: M Bolier, MM van den Heuvel-Eibrink, SJCMM Neggers; Manuscript writing: All authors; Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors.
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