|Ahead of print publication
Body composition changes following chemotherapy for testicular germ cell tumor: obesity is the long-term problem
Yuki Takai, Sei Naito, Hidenori Kanno, Atsushi Yamagishi, Mayu Yagi, Toshihiko Sakurai, Hayato Nishida, Takuya Yamanobe, Tomoyuki Kato, Norihiko Tsuchiya
Department of Urology, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan
|Date of Submission||02-Jun-2021|
|Date of Acceptance||15-Oct-2021|
|Date of Web Publication||03-Dec-2021|
Department of Urology, Yamagata University Faculty of Medicine, Yamagata 990-9585
Source of Support: None, Conflict of Interest: None
Metabolic syndrome is a long-term complication of systemic chemotherapy for testicular germ cell tumor (TGCT). It is believed to be caused by secondary hypogonadism or toxic medicines because of orchidectomy followed by systemic chemotherapy. In this study, changes in the body composition of patients over time were quantitatively analyzed up to 24 months after chemotherapy. This study retrospectively analyzed 44 patients with TGCT who underwent chemotherapy at our institution from January 2008 to December 2016. Subcutaneous and visceral fat areas and psoas and skeletal muscle areas were measured by computed tomography before and immediately after chemotherapy as well as 3 months, 6 months, 12 months, and 24 months after chemotherapy. The subcutaneous and visceral fat indices and psoas and skeletal muscle indices were calculated as each area divided by body height squared. The total fat area had already significantly increased 3 months after the initiation of chemotherapy (P = 0.004). However, it did not return to prechemotherapeutic levels even at 24 months after chemotherapy. The skeletal muscle area was significantly decreased at the end of chemotherapy (P < 0.001); however, the value returned to baseline within 12 months. In multivariable analysis, the prechemotherapeutic skeletal muscle index and number of chemotherapy cycles were independently associated with the reduction of skeletal muscle at the end of chemotherapy (P = 0.001 and P = 0.027, respectively). In patients with TGCT, skeletal muscle mass decreased during chemotherapy and recovered within 12 months, whereas fat mass progressively increased from the initiation of chemotherapy until 24 months after chemotherapy.
Keywords: body composition; chemotherapy; obesity; sarcopenia; secondary hypogonadism; testicular cancer
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|How to cite this URL:|
Takai Y, Naito S, Kanno H, Yamagishi A, Yagi M, Sakurai T, Nishida H, Yamanobe T, Kato T, Tsuchiya N. Body composition changes following chemotherapy for testicular germ cell tumor: obesity is the long-term problem. Asian J Androl [Epub ahead of print] [cited 2022 Jun 29]. Available from: https://www.ajandrology.com/preprintarticle.asp?id=331765
| Introduction|| |
Testicular germ cell tumor (TGCT) is the most common malignant disease among young men, and it carries a favorable outcome as indicated by 10-year survival rates as high as 90%. The improvement in survival was greatly influenced by the development of curative chemotherapeutic regimens. As survivors of TGCT treated with chemotherapy increase in number, long-term unfavorable health conditions, including cardiovascular disease, neurotoxicity, nephrotoxicity, cognitive impairment, and second malignancy, have become prominent problems.,,,
A large number of cancer survivors also encounter unfavorable changes in their body composition, including an increase in fat mass (obesity) and a decrease in skeletal muscle mass (sarcopenia). The changes of body composition in cancer survivors are caused by various factors. Cancer treatments (surgery, chemotherapy, and radiotherapy) induce changes in hormonal homeostasis (growth hormone, thyroid hormone, and testosterone), metabolism, and sympathetic nervous activity, and these disorders may cause obesity or sarcopenia. Lifestyle factors such as physical inactivity and dietary intake also cause body composition changes. It is known that most cancer survivors focus on the management of cancer itself, but they have low awareness of healthy lifestyles. These changes in body composition are suggested to be one of the indicators of metabolic syndrome., Recent studies revealed that metabolic syndrome is a common morbidity in cancer survivors., Metabolic syndrome is associated with mortality from cardiovascular disease, diabetes mellitus, and chronic kidney disease and increased cancer risk. Thus, obesity and sarcopenia can possibly lead to a decline in quality of life, a shortened survival, and a second malignancy resulting from metabolic syndrome, even after the successful treatment of primary cancer.
Among patients with advanced TGCT, several studies demonstrated that an increase in fat mass and a decrease in skeletal muscle mass occur along with androgen deficiency after chemotherapy, and these changes are associated with the development of metabolic syndrome over the long term.,,, However, regarding changes in body composition, only short-term data obtained within 12 months from the initiation of chemotherapy are available. This retrospective study assessed changes in body composition up to 24 months after the end of chemotherapy in patients with TGCT who underwent chemotherapy.
| Patients and Methods|| |
Forty-four consecutive patients with TGCT treated with chemotherapy from January 2008 to December 2016 at Yamagata University Hospital (Yamagata, Japan) were enrolled in this study. This retrospective observational study was approved by the Institutional Review Board of the Yamagata University Faculty of Medicine, Yamagata, Japan (Approval No. 2018-43). The opt-out method was used to obtain informed consent. The need for individual consent to participate in this study was waived by the same institutional review board, and the patients were given the opportunity to reject the usage of their data.
Measurement of fat and muscle components
The fat component was automatically analyzed, whereas the muscle component was manually analyzed using SYNAPSE VINCENT version 4 volume analyzer software (Fujifilm, Tokyo, Japan). The subcutaneous fat area, visceral fat area, and total fat area (the sum of the subcutaneous and visceral fat areas), were measured at the level of the umbilicus on axial computed tomography (CT) images. The muscle area was measured at the L3 spine level, and the psoas muscle area and skeletal muscle area which included the psoas muscle area, were also measured. These analyses were performed using CT images taken before and immediately after chemotherapy and 3 months, 6 months, 12 months, and 24 months after chemotherapy. The subcutaneous fat index (SFI), visceral fat index (VFI), and total fat index (TFI) were defined as subcutaneous fat area, visceral fat area, and total fat area divided by body height squared, respectively. Similarly, the psoas muscle index (PMI) and skeletal muscle index (SMI) were defined as the psoas muscle area and skeletal muscle area divided by body height squared, respectively.
All statistical analyses were performed using SPSS version 19 software (IBM Japan, Tokyo, Japan). Statistical analyses of sequential changes of all indices were conducted by analysis of variance (ANOVA). Post hoc analysis was conducted using Tukey's test. The Chi-squared test was used to compare the distribution of the patients stratified by TFI and SMI immediately and 12 months after the chemotherapy. Univariable and multivariable regression analyses were used to investigate the relative contribution of each variable to sarcopenia at the end of chemotherapy and to obesity at 12 months after chemotherapy. The following were included in the analyses as independent variables: pretreatment age, body mass index (BMI), SFI, VFI, TFI, SMI, PMI, retroperitoneal lymph node dissection, and the number of chemotherapy cycles. P < 0.05 indicated statistical significance.
| Results|| |
The demographic and clinical data of the patients were obtained from medical records, and they are summarized in [Table 1]. For adjuvant chemotherapy, three cycles of etoposide plus cisplatin (EP), two cycles of bleomycin, etoposide, and cisplatin (BEP), and one or two cycles of carboplatin (AUC 7) were used in three, one, and six patients, respectively. The other 34 patients were treated with three or four cycles of EP, three or four cycles of BEP, and four or five cycles of vincristine, ifosfamide, and cisplatin as induction chemotherapy. Among these patients, 11 received subsequent salvage chemotherapy. The regimens are described in detail in [Table 1].
Changes in fat components
Pretreatment physical constitution and changes in fat and muscle components after chemotherapy are summarized in [Supplementary Table 1 [Additional file 1]]. The total fat mass was significantly increased at 3 months after the initiation of chemotherapy (P = 0.004), and 34 patients (80.9%) displayed elevated fat mass at the end of chemotherapy. Fat mass progressively increased over time without returning to the baseline level between 6 months and 24 months after the completion of chemotherapy [Figure 1]a. We also evaluated the changes in fat components among the 17 patients who underwent assessments at all time points from the initiation of chemotherapy to 24 months after the completion of chemotherapy. A similar continuous increase of fat mass was observed in this subgroup [Supplementary Figure 1 [Additional file 2]]a. The median total fat area was increased by 27.1% from 184.8 cm2 at baseline to 234.9 cm2 at 24 months after chemotherapy. There was no difference in the contribution of subcutaneous fat and visceral fat to the increase of the total fat area [Supplementary Table 1]. The distribution of the TFI at the end of and 12 months after chemotherapy are presented in [Figure 2]a. The TFI (×10–4) had increased by more than 10 and by 0–10 in 61.9% (26/42) and 19.0% (8/42) of patients, respectively, and decreased in 19.0% (8/42) of patients at the end of the chemotherapy. The distribution did not change even 12 months after chemotherapy (P = 0.604).
|Figure 1: Changes in (a) fat and (b) muscle indices after the initiation of chemotherapy. Each value is presented as the mean change from baseline (mean Δindex). *P < 0.05 (the indicated item vs prechemotherapy), **P < 0.001 (the indicated item vs prechemotherapy). NS: not significant.|
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|Figure 2: Changes in the (a) total fat index and (b) skeletal muscle index immediately and 12 months after the completion of chemotherapy. Each value is presented as the change from baseline (Δindex).|
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Changes in muscle components
The skeletal muscle area decreased within 3 months from the initiation of chemotherapy, reaching its lowest level at the end of chemotherapy (P < 0.001). Unlike fat mass, skeletal muscle mass recovered within 12 months after the end of chemotherapy [Figure 1]b. In the 17 patients who underwent assessments at all time points, the course of the skeletal muscle mass change was similar to that among all patients [Supplementary Figure 1]b. The median skeletal muscle area was decreased by 11.7% from 152.8 cm2 at baseline to 134.9 cm2 at the end of chemotherapy [Supplementary Table 1]. The distributions of the SMI at the end of chemotherapy and 12 months after chemotherapy are presented in [Figure 2]b. The SMI (×10−4) had decreased by more than 5 and by 0–5 in 45.2% (19/42) and 42.9% (18/42) of patients, respectively, and increased in 11.9% (5/42) of patients at the end of the chemotherapy. At 12 months after the completion of chemotherapy, the proportion of patients with a decrease of the SMI of more than 5 (4/27, 14.8%) was significantly reduced compared with the findings at the end of chemotherapy (45.2%; P = 0.009).
Factors affecting changes in body composition
Univariable regression analysis was performed to assess whether clinical factors affected the increase in the TFI at 12 months after the end of chemotherapy. Only the number of chemotherapy cycles was positively associated with the fat component (P = 0.041; [Table 2]). Next, we investigated factors affecting the decrease in the SMI at the end of chemotherapy, which reached its nadir during the follow-up period. In univariable analysis, BMI, the prechemotherapeutic TFI, the prechemotherapeutic SMI, and the number of chemotherapy cycles were negatively associated with the muscle component. Stepwise multivariable regression analysis illustrated that the prechemotherapeutic SMI and the number of chemotherapy cycles independently affected the reduction in skeletal muscle at the end of chemotherapy (P = 0.001 and P = 0.027, respectively; [Table 3]). The change of the SMI in patients who completed more than four cycles of chemotherapy was significantly larger than that in patients who received four or fewer cycles (−17.6% vs −2.6%, P = 0.001).
|Table 2: Factors affecting the increase of the total fat index at 12 months after chemotherapy|
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|Table 3: Factors affecting the decrease of the skeletal muscle index at the end of chemotherapy|
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| Discussion|| |
In this study, we retrospectively analyzed the long-term changes in body composition during and after chemotherapy in patients with TGCT, and found that dynamic body composition changes occur even in relatively young patients. Although the loss of skeletal muscle was reversed within 12 months, the increase in body fat mass did not improve over time in the majority of patients. Previous studies demonstrated that visceral and subcutaneous fat and BMI were significantly increased within 1–12 months after the initiation of chemotherapy., Our long-term observational data illustrated that once gained, the fat component was retained until at least 24 months after the completion of chemotherapy. Meanwhile, lean body mass reportedly continues to decrease until 1 year after the initiation of chemotherapy. The detailed natural course of changes in muscle components after chemotherapy had not been previously reported. The present study first demonstrated that the muscle component, which was most strongly reduced at the time of chemotherapy completion, gradually recovered to baseline within 12 months after systemic chemotherapy.
There is cumulative evidence regarding the association of changes in the sex hormone milieu with obesity or metabolic syndrome following treatment for TGCT. In comparison with their siblings, TGCT survivors exhibited significantly higher levels of follicle-stimulating hormone and luteinizing hormone and significantly lower free and total testosterone levels during a median follow-up period of 12 years. Similar hormonal changes were prominently observed in patients with TGCT treated with systemic chemotherapy compared with the findings in patients who underwent orchiectomy alone., One study demonstrated that the total dose of cisplatin (>850 mg) is associated with a decline in serum testosterone levels during a 10-year follow-up period. These results suggested that orchiectomy and subsequent chemotherapy affect sex hormone levels and that secondary hypogonadism appears to lead to the development of obesity and metabolic syndrome.,,,,
It was revealed that reduced muscle mass is also associated with a decline in serum testosterone levels after chemotherapy. However, our result that muscle mass was lowest at the end of chemotherapy and gradually recovered to baseline within 12 months suggests that factors other than serum testosterone may affect skeletal muscle mass. The direct effects of chemotherapeutic agents and reduced physical activity during treatment may cause the loss of skeletal mass. A previous study demonstrated that three cycles of BEP significantly attenuated muscle fiber size and strength when no planned physical training was prescribed. Our data identified the number of chemotherapy cycles as an independent predictor of the loss of skeletal mass. However, it is unclear whether the toxicity of chemotherapeutic agents or duration of treatment predominantly influences muscle loss.
Regarding the preventative effect of physical training on the loss of skeletal muscle during chemotherapy, several intervention trials have been conducted., Unfortunately, these trials did not demonstrate a sufficient effect of physical training during chemotherapy on lean body mass and muscle fiber size compared with the effects of standard care. The reason for this finding is that the adverse effects of chemotherapy, such as nausea and general malaise, likely lead to the discontinuation of exercise or reduction of its intensity. Our result demonstrated that patients with greater skeletal mass who completed more cycles of chemotherapy had a higher risk of muscle loss after chemotherapy, which suggests that men with higher pretreatment testosterone levels and physical activity are more susceptible to orchiectomy and subsequent chemotherapy. Meanwhile, in patients with advanced cancer undergoing standard care including chemotherapy, a 7-week testosterone injection course significantly improved lean mass as well as quality of life. Testosterone replacement therapy may be an optional treatment for preventing these unfavorable health conditions in patients with TGCT and hypogonadism.,
This study had several limitations. First, because it was not designed as a prospective study, there were substantial amounts of missing or unavailable data. The loss of patients to follow-up could have created some selection bias. Second, this study included patients of various backgrounds who received different treatments. Differences in chemotherapy regimens and the number of cycles might have affected the results. Third, only changes in fat and muscle mass were analyzed, and the association of changes in body composition with biochemical and hormonal data was not assessed because these data were not systematically measured. Finally, this study lacked a control group. Even if patients with stage I TGCT served as a control group, it is unclear whether the direct effect of chemotherapy or reduction of physical activity is the primary component affecting body composition.
| Conclusions|| |
In patients with TGCT treated with systemic chemotherapy, skeletal muscle mass decreased during chemotherapy and recovered within 12 months, whereas fat mass progressively increased from the initiation of chemotherapy without returning to baseline over 24 months after the completion of chemotherapy. These data suggest that interventions targeting obesity rather than skeletal muscle loss are required in the long-term follow-up of patients with TGCT.
| Author Contributions|| |
YT, NT, TK, and SN were involved in study design and data interpretation. HK and MY helped collect data. YT, NT, and SN were involved in the data analysis. AY, TS, HN, and TY critically revised the report, commented on drafts of the manuscript. All authors read and approved the final manuscript.
| Competing Interests|| |
All authors declare no competing interests.
Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.
| References|| |
Sui W, Morrow DC, Bermejo CE, Hellenthal NJ. Trends in testicular cancer survival: a large population-based analysis. Urology
2015; 85: 1394–8.
Travis LB, Fossa SD, Schonfeld SJ, McMaster ML, Lynch CF, et al
. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst
2005; 97: 1354–65.
van den Belt-Dusebout AW, Nuver J, de Wit R, Gietema JA, ten Bokkel Huinink WW, et al
. Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol
2006; 24: 467–75.
Brydoy M, Oldenburg J, Klepp O, Bremnes RM, Wist EA, et al
. Observational study of prevalence of long-term Raynaud-like phenomena and neurological side effects in testicular cancer survivors. J Natl Cancer Inst
2009; 101: 1682–95.
Fossa SD, Aass N, Winderen M, Bormer OP, Olsen DR. Long-term renal function after treatment for malignant germ-cell tumours. Ann Oncol
2002; 13: 222–8.
IJpma I, Renken RJ, Gietema JA, Slart RH, Mensink MG, et al
. Changes in taste and smell function, dietary intake, food preference, and body composition in testicular cancer patients treated with cisplatin-based chemotherapy. Clin Nutr
2017; 36: 1642–8.
De Haas EC, Oosting SF, Lefrandt JD, Wolffenbuttel BH, Sleijfer DT, et al
. The metabolic syndrome in cancer survivors. Lancet Oncol
2010; 11: 193–203.
Seo Y, Kim JS, Park ES, Ryu E. Assessment of the awareness and knowledge of cancer survivors regarding the components of metabolic syndrome. PLoS One
2018; 13: e0199142.
Zhang H, Lin S, Gao T, Zhong F, Cai J, et al
. Association between sarcopenia and metabolic syndrome in middle-aged and older non-obese adults: a systematic review and meta-analysis. Nutrients
2018; 10: 364–76.
Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM, et al
. Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. Diabetes
2004; 53: 2087–94.
Smith WA, Li C, Nottage KA, Mulrooney DA, Armstrong GT, et al
. Lifestyle and metabolic syndrome in adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study. Cancer
2014; 120: 2742–50.
Lee SJ, Kim NC. Association between sarcopenia and metabolic syndrome in cancer survivors. Cancer Nurs
2017; 40: 479–87.
Pothiwala P, Jain SK, Yaturu S. Metabolic syndrome and cancer. Metab Syndr Relat Disord
2009; 7: 279–88.
Willemse PM, van der Meer RW, Burggraaf J, van Elderen SG, de Kam ML, et al
. Abdominal visceral and subcutaneous fat increase, insulin resistance and hyperlipidemia in testicular cancer patients treated with cisplatin-based chemotherapy. Acta Oncol
2014; 53: 351–60.
Nuver J, Smit AJ, Wolffenbuttel BH, Sluiter WJ, Hoekstra HJ, et al
. The metabolic syndrome and disturbances in hormone levels in long-term survivors of disseminated testicular cancer. J Clin Oncol
2005; 23: 3718–25.
Willemse PM, Burggraaf J, Hamdy NA, Weijl NI, Vossen CY, et al
. Prevalence of the metabolic syndrome and cardiovascular disease risk in chemotherapy-treated testicular germ cell tumour survivors. Br J Cancer
2013; 109: 60–7.
IJpma I, Renken RJ, Gietema JA, Slart RH, Mensink MG, et al
. Taste and smell function in testicular cancer survivors treated with cisplatin-based chemotherapy in relation to dietary intake, food preference, and body composition. Appetite
2016; 105: 392–9.
Bandak M, Jorgensen N, Juul A, Lauritsen J, Kier MG, et al
. Reproductive hormones and metabolic syndrome in 24 testicular cancer survivors and their biological brothers. Andrology
2017; 5: 718–24.
Haugnes HS, Aass N, Fossa SD, Dahl O, Klepp O, et al
. Components of the metabolic syndrome in long-term survivors of testicular cancer. Ann Oncol
2007; 18: 241–8.
Zaid MA, Gathirua-Mwangi WG, Fung C, Monahan PO, El-Charif O, et al
. Clinical and genetic risk factors for adverse metabolic outcomes in North American testicular cancer survivors. J Natl Compr Canc Netw
2018; 16: 257–65.
Thorsen L, Kirkegaard C, Loge JH, Kiserud CE, Johansen ML, et al
. Feasibility of a physical activity intervention during and shortly after chemotherapy for testicular cancer. BMC Res Notes
2017; 10: 214–22.
Christensen JF, Jones LW, Tolver A, Jorgensen LW, Andersen JL, et al
. Safety and efficacy of resistance training in germ cell cancer patients undergoing chemotherapy: a randomized controlled trial. Br J Cancer
2014; 111: 8–16.
Wright TJ, Dillon EL, Durham WJ, Chamberlain A, Randolph KM, et al
. A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women. J Cachexia Sarcopenia Muscle
2018; 9: 482–96.
Saad F, Yassin A, Doros G, Haider A. Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies. Int J Obes (Lond)
2016; 40: 162–70.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]