Research ArticleClinical Studies

Doxorubicin Combined With Ifosfamide for Sarcoma Induces Muscle Atrophy and Sleep Disruption

HIDEYUKI KINOSHITA, YOKO HAGIWARA, TAKESHI ISHII, HIROTO KAMODA, TOSHINORI TSUKANISHI, SEIJI OHTORI and TSUKASA YONEMOTO
Anticancer Research December 2021, 41 (12) 6273-6278; DOI: https://doi.org/10.21873/anticanres.15448

Abstract

Background/Aim: There are no reports evaluating sleep disturbance and skeletal muscle loss in response to the treatment of soft tissue sarcoma (STS) with chemotherapy. This study investigated the effects of combined doxorubicin (DXR) and ifosfamide (IFM) on sleep and skeletal muscle. Patients and Methods: This retrospective cohort study included 14 patients with high-grade STS. Participants underwent five 7-day hospitalizations during which they received chemotherapy for 5 consecutive days. Sleep analysis and muscle-volume evaluation were investigated using a wearable device during hospitalization and by bioelectrical impedance analysis at each chemotherapy course. Results: Chemotherapy significantly impeded sleep, increased wake-time after sleep onset, and aggravated movement index during hospitalization. In long-term body composition assessment, chemotherapy induced muscle-mass loss and fat-mass gain. Conclusion: Combination of DXR and IFM for STS induces skeletal muscle loss and sleep disruption.

Key Words:

Soft tissue sarcomas (STSs) account for only 5/100,000 cases of cancer per year (1, 2). Surgery is the standard treatment for localized, low-grade or small STS. Conversely, deep-seated, high-grade, and large STS are considered high-risk, and adjuvant chemotherapy is necessary (3). The first-line chemotherapy for STS is doxorubicin (DXR), often in combination with ifosfamide (IFM) (4). In most facilities in Japan, the treatment involves daily chemotherapy and intravenous infusion, requiring a week of hospitalization. However, since DXR and IFM are cytotoxic chemotherapies, not molecular-targeted drugs, they have strong side effects and adverse events often occur (5).

Sleep disturbance due to chemotherapy is a problem in many cancers (6). Recently, wearable devices have been developed to assess sleep quality. Thus, evaluations of sleep disturbance in cancer patients receiving chemotherapy have increased (7, 8). Furthermore, the exacerbation of sarcopenia and frailty, i.e., skeletal-muscle loss, during chemotherapy treatment is a problem (9). However, there have been no reports on the evaluation of sleep disturbance and skeletal-muscle loss with chemotherapy for STS. Here, we employed wearable devices and bioelectrical impedance analysis (BIA) to investigate sleep disturbance and skeletal-muscle loss associated with DXR and IFM chemotherapy for STS.

Patients and Methods

Study design and patients. Study approval by the review board of Chiba Cancer Center and written informed consent from each patient were obtained before starting this study (Approval number: R03-177). We retrospectively reviewed our institution’s database to identify patients diagnosed with STS who underwent DXR and IFM therapy between January 2019 and December 2020. Of 86 patients with STS, patients diagnosed with stage I and II who received other chemotherapies, and without body composition or sleep analysis, were excluded. Fourteen patients were finally included the study.

Schedule of chemotherapy and evaluation. At many institutions in Japan and worldwide, the first-line chemotherapy for STS consists of 5-6 perioperative courses of combined DXR and IFM (3, 10). In Japan, these chemotherapies are often administered for 5 consecutive days. Here, the day of admission was defined as day 0, whereas the day of initiation of chemotherapy was day 1. We administered IFM (2 g/m2) from 10 AM to 2 PM on days 1-5, and DXR (30 mg/m2) from 2 PM to 4 PM on days 1 and 2 (Figure 1A). Mesna (1,200 mg/m2/day) was administered during and after the administration of IFM on days 1-5 by continuous infusion. Sleep analysis was performed from day 0 to day 6 of hospitalization. Body composition was evaluated before chemotherapy and after each chemotherapy course (Figure 1B). The sixth evaluation was performed approximately 15 weeks after the initiation of chemotherapy. The iliopsoas muscle was evaluated using computed tomography (CT) before the initiation of chemotherapy and approximately 15 weeks after the initiation of chemotherapy, contingent on the patient’s condition.

Figure 1.
Figure 1.

Schedule for sleep analysis and body composition analysis. (A) In the current study, the day of admission was defined as day 0 and the day of initiation of chemotherapy as day 1. Sleep analysis was performed from day 0 to day 6 after hospitalization. IFM and DXR were administered on days 1-5, and on days 1 and 2, respectively. (B) Chemotherapy was administered once every 3 weeks for a total of five courses. Body composition was evaluated using bioelectrical impedance analysis before chemotherapy and after each course. PMI was assessed at 0 and 15 weeks post-surgery. IFM: Ifosfamide; DXR: doxorubicin; PMI: psoas muscle index.

Sleep analysis. The participants used a wrist-worn ActiGraph GT9X triaxial accelerometer (ActiGraph GT9X Link; ActiGraph, Pensacola, FL, USA) continuously for 24 h during the 7-day hospitalization except when taking a shower. Data were assessed using ActiLife software Version 6.13.4. A sampling rate of 32 Hz, 1-minute epoch setting, and the sleep period scoring option of Cole Kripke were used as previously described (11, 12). The evaluation items were sleep efficiency (%), wake-time after sleep onset (min), average awakening length (min), and movement index. Bedtime and waking times were based on the participants’ self-reports and medical records.

Assessment of body composition and psoas muscle index (PMI). Various parameters of body composition, including skeletal muscle volume, fat volume, and body fat percentage, were measured using an eight-electrode multi-frequency BIA (MC-180; TANITA, Tokyo, Japan). Skeletal-muscle volume from the image was calculated using the PMI based on CT images according to previously described methods (13). The sum of the L3 level cross-sectional area of the right and left psoas muscle was calculated, and the value was divided by height squared (cm2/m2).

Statistical analysis. Patient data are expressed as the mean±standard deviation (SD). Significant differences between mean values were calculated using Student’s t-test, with p<0.05, used as the criterion for statistical significance. In the sleep study, significant differences between day 0 and each subsequent day were examined. Body composition was evaluated for significant differences before and after each course of chemotherapy. Significant differences between pre- and post-chemotherapy PMI were examined.

Results

Patient demographics. Patient and tumor characteristic data are presented in Table I. Eight patients (57%) were male and six patients (43%) were female. The average age at the time of chemotherapy was 51 years (range=15-68 years). The mean follow-up period after the first course of DXR/IFM was 9.8 months (range=8-13 months). The mean body-mass index (BMI) was 23.9 (range=17.1-31.6). Tumors were located in the extremities (57%), trunk (36%), and head and neck (7%). Thirteen patients (92%) underwent wide resection. The rates of adjuvant and palliative chemotherapy were 71% and 29%, respectively. Six participants (43%) used sleep medication. The histological tumor subtypes were myxofibrosarcoma (29%), leiomyosarcoma (14%), undifferentiated pleomorphic sarcoma (14%), and other tumors (43%).

View this table:
Table I.

Patient demographics and disease characteristics.

Chemotherapy induced sleep disorders. Figure 2A shows the actogram sleep analysis of a 33-year-old woman. The gray area in the actigraph shows the approximate duration of sleep. Relative to day 0, body movement increased during and immediately after chemotherapy (days 1-6). Indeed, chemotherapy significantly inhibited the efficiency of sleep from 85.7% to a maximum of 76.7% (Figure 2B). Furthermore, wake-time after sleep onset was increased from 62.7 min to a maximum of 104.9 min, average awakening length increased from 2.8 min to a maximum of 5.4 min (Figure 2C and D) and movement index worsened during chemotherapy (Figure 2E).

Figure 2.
Figure 2.

A combination of doxorubicin (DXR) and ifosfamide (IFM) for sarcoma induced sleep disorders. (A) An example of the actogram sleep analysis in a 33-year-old woman. The gray area in the actigraph shows the approximate duration of sleep. Compared with the time before chemotherapy (day 0), the body movement increased during and immediately after chemotherapy (days 1-6). (B) Chemotherapy significantly inhibited the effectiveness of sleep. (C) Chemotherapy increased wake-time after sleep onset. (D) Chemotherapy increased average awakening length. (E) The movement index worsened during chemotherapy. Significant differences between the means both of each day and day 0 were evaluated. *p<0.05.

Chemotherapy decreased muscle mass and increased fat mass over time. Chemotherapy reduced muscle volume from 43.6 kg to a maximum of 42 kg (Figure 3A). Conversely, chemotherapy increased fat mass over time, from 16.8 kg to 19.1 kg (Figure 3B). Accordingly, chemotherapy increased body-fat percentage over time, from 24.9% to 28.3% (Figure 3C). In men and women, the volume of the iliopsoas muscle significantly decreased after chemotherapy (Figure 3D). Accordingly, the PMI after chemotherapy was significantly decreased; from 6.3 cm2/m2 to 5.2 cm2/m2 in men and from 4 cm2/m2 to 3.2 cm2/m2 in women.

Figure 3.
Figure 3.

Chemotherapy decreased muscle mass and increased fat mass over time. (A) Chemotherapy decreased skeletal muscle volume. (B) Chemotherapy increased fat volume over time. (C) Chemotherapy increased body fat percentage over time. In A-C, significant differences between the means both of each course and before chemotherapy were evaluated. (D) In men and women, the volume of the iliopsoas muscle was significantly decreased before and after chemotherapy. *p<0.05.

Discussion

We used a minimally-intrusive wearable device to show that the combination of DXR and IFM interfered with the sleep efficiency of STS patients during hospitalization. Furthermore, BIA indicated that for STS patients administered DXR/IFM, the skeletal-muscle volume decreased and body-fat percentage increased.

Cancer can lead to insomnia due to anxiety about the future and death (14) and chemotherapy-related sleep disturbance has been reported in various cancers (15). Steur et al. reported that maintenance therapy disturbed sleep-wake rhythms, lowered physical activity levels and heightened cancer-related fatigue levels. Interventions for enhancing sleep-wake rhythms during maintenance therapy could improve cancer-related fatigue. Recently, wearable devices have enabled detailed assessment of parameters of sleep disturbance in patients with cancer (6). Charlotte et al. suggested that many patients with breast cancer experienced sleep disturbance at the beginning of neoadjuvant chemotherapy. However, no detailed sleep analysis using wearable devices during chemotherapy has been reported for STS. In the current study, sleep analysis revealed that chemotherapy reduced sleep efficiency, increased wake-time after sleep onset, and aggravated movement index during hospitalization.

Both cancer and chemotherapy have been reported to induce sarcopenia and frailty (16). Huillard et al. reported that sorafenib in advanced differentiated thyroid cancer induced significant skeletal-muscle loss 6 months after treatment initiation (17). Critically, frailty is associated with mortality in patients with cancer (18). Yan et al. reported that higher degrees of frailty correlated with higher risk of mortality among a cohort of older patients with breast cancer (19). The body composition in patients with STS is thought to represent a marker of risk among patients with trunk and retroperitoneal sarcomas (20). Hamaguchi et al. determined sex-specific cut-off values for low skeletal-muscle mass of PMI as 6.36 cm2/m2 for men and 3.92 cm2/m2 for women (21). Here, we assessed the effect of chemotherapy on STS-induced skeletal-muscle loss, fat-volume increase and body composition imbalance with BIA, and movement index. PMI was decreased from 6.3 cm2/m2 to 5.2 cm2/m2 in men, and from 4 cm2/m2 to 3.2 cm2/m2 in women. Based on Hamaguchi’s criteria, both men and women were considered to have worsened, developing sarcopenia pathology. These results suggest that aggressive rehabilitation is necessary to prevent sarcopenia and frailty during chemotherapy for STS. The prevention of sarcopenia and frailty may improve the prognosis of patients with STS.

DXR is a key drug used not only for sarcoma, but also for breast cancer, lung cancer, and malignant lymphoma (22). Our reports of DXR and IFM on sleep disturbance and skeletal-muscle loss will thereby be useful in many fields. Nevertheless, the current study has a few limitations. This was a retrospective cohort study and the number of cases examined was small, due to the rarity of STS. Moreover, other factors, such as room size, frequency and skillfulness of intravenous drip exchange could not be standardized. Pointedly, other regimens and dosing schedules required by participants could not be standardized.

Conclusion

The current study found that the combination of DXR and IFM for STS decreased skeletal muscle and interfered with sleep quality. In future, the correlation between sleep disorders and parameters, such as nausea, anxiety, and overall quality of life should be examined and intervention studies on the prevention of sleep disorders and skeletal-muscle loss are needed.

Acknowledgements

This work was supported by JSPS KAKENHI grants (19K16760) and the Foundation for Total Health Promotion (Tokyo, Japan) and Cancer Research Funds for Patients and Family (Chiba, Japan).

Footnotes

  • Authors’ Contributions

    H. K. designed and performed experiments, analyzed data, and wrote the article; Y. H., T. I., H. K., T. T., S. O. and T. Y. provided technical support and conceptual advice.

  • Conflicts of Interest

    The Authors have no conflicts of interest directly relevant to the content of this article.

  • Received September 23, 2021.
  • Revision received October 15, 2021.
  • Accepted October 18, 2021.

References

  1. ↵
    1. Kinoshita H,
    2. Yonemoto T,
    3. Kamoda H,
    4. Hagiwara Y,
    5. Tsukanishi T,
    6. Inoue M,
    7. Terakawa F,
    8. Ohtori S and
    9. Ishii T
    : Effectiveness of salvage knee rotationplasty on sarcoma around the knee in adolescents and young adults. Anticancer Res 41(2): 1041–1046, 2021. PMID: 33517313. DOI: 10.21873/anticanres.14860
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Kinoshita H,
    2. Ishii T,
    3. Kamoda H,
    4. Hagiwara Y,
    5. Tsukanishi T,
    6. Inoue M,
    7. Ueta T,
    8. Ohtori S and
    9. Yonemoto T
    : Poor efficacy of postoperative radiotherapy in infiltrative high-grade soft tissue sarcomas. Anticancer Res 41(8): 4027–4032, 2021. PMID: 34281869. DOI: 10.21873/anticanres.15202
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Tanaka K,
    2. Mizusawa J,
    3. Naka N,
    4. Kawai A,
    5. Katagiri H,
    6. Hiruma T,
    7. Matsumoto Y,
    8. Tsuchiya H,
    9. Nakayama R,
    10. Hatano H,
    11. Emori M,
    12. Watanuki M,
    13. Yoshida Y,
    14. Okamoto T,
    15. Abe S,
    16. Asanuma K,
    17. Yokoyama R,
    18. Hiraga H,
    19. Yonemoto T,
    20. Morii T,
    21. Ae K,
    22. Nagano A,
    23. Yoshikawa H,
    24. Fukuda H,
    25. Ozaki T and
    26. Iwamoto Y
    : Ten-year follow-up results of perioperative chemotherapy with doxorubicin and ifosfamide for high-grade soft-tissue sarcoma of the extremities: Japan Clinical Oncology Group study JCOG0304. BMC Cancer 19(1): 890, 2019. PMID: 31492159. DOI: 10.1186/s12885-019-6114-2
    OpenUrlCrossRefPubMed
  4. ↵
    1. Le Cesne A
    : Making the best of available options for optimal sarcoma treatment. Oncology 95(Suppl 1): 11–20, 2018. PMID: 30554197. DOI: 10.1159/000494861
    OpenUrlCrossRefPubMed
  5. ↵
    1. Tanaka K,
    2. Mizusawa J,
    3. Fukuda H,
    4. Araki N,
    5. Chuman H,
    6. Takahashi M,
    7. Ozaki T,
    8. Hiruma T,
    9. Tsuchiya H,
    10. Morioka H,
    11. Hatano H and
    12. Iwamoto Y
    : Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities (JCOG0304). Jpn J Clin Oncol 45(6): 555–561, 2015. PMID: 25838293. DOI: 10.1093/jjco/hyv042
    OpenUrlCrossRefPubMed
  6. ↵
    1. Kreutz C,
    2. Müller J,
    3. Schmidt ME and
    4. Steindorf K
    : Comparison of subjectively and objectively assessed sleep problems in breast cancer patients starting neoadjuvant chemotherapy. Support Care Cancer 29(2): 1015–1023, 2021. PMID: 32556623. DOI: 10.1007/s00520-020-05580-0
    OpenUrlCrossRefPubMed
  7. ↵
    1. Bhave MA,
    2. Speth KA,
    3. Kidwell KM,
    4. Lyden A,
    5. Alsamarraie C,
    6. Murphy SL and
    7. Henry NL
    : Effect of aromatase inhibitor therapy on sleep and activity patterns in early-stage breast cancer. Clin Breast Cancer 18(2): 168–174.e2, 2018. PMID: 29361424. DOI: 10.1016/j.clbc.2017.12.012
    OpenUrlCrossRefPubMed
  8. ↵
    1. Rissling MB,
    2. Liu L,
    3. Natarajan L,
    4. He F and
    5. Ancoli-Israel S
    : Relationship of menopausal status and climacteric symptoms to sleep in women undergoing chemotherapy. Support Care Cancer 19(8): 1107–1115, 2011. PMID: 20508951. DOI: 10.1007/s00520-010-0914-x
    OpenUrlCrossRefPubMed
  9. ↵
    1. Rinninella E,
    2. Cintoni M,
    3. Raoul P,
    4. Pozzo C,
    5. Strippoli A,
    6. Ponziani FR,
    7. Pompili M,
    8. Bria E,
    9. Tortora G,
    10. Gasbarrini A and
    11. Mele MC
    : Skeletal muscle loss during multikinase inhibitors therapy: Molecular pathways, clinical implications, and nutritional challenges. Nutrients 12(10): 3101, 2020. PMID: 33053632. DOI: 10.3390/nu12103101
    OpenUrlCrossRefPubMed
  10. ↵
    1. Sundby Hall K,
    2. Bruland ØS,
    3. Bjerkehagen B,
    4. Zaikova O,
    5. Engellau J,
    6. Hagberg O,
    7. Hansson L,
    8. Hagberg H,
    9. Ahlström M,
    10. Knobel H,
    11. Papworth K,
    12. Zemmler M,
    13. Goplen D,
    14. Bauer HCF and
    15. Eriksson M
    : Adjuvant chemotherapy and postoperative radiotherapy in high-risk soft tissue sarcoma patients defined by biological risk factors-A Scandinavian Sarcoma Group study (SSG XX). Eur J Cancer 99: 78–85, 2018. PMID: 29929092. DOI: 10.1016/j.ejca.2018.05.011
    OpenUrlCrossRefPubMed
  11. ↵
    1. Van Someren EJ,
    2. Swaab DF,
    3. Colenda CC,
    4. Cohen W,
    5. McCall WV and
    6. Rosenquist PB
    : Bright light therapy: improved sensitivity to its effects on rest-activity rhythms in Alzheimer patients by application of nonparametric methods. Chronobiol Int 16(4): 505–518, 1999. PMID: 10442243. DOI: 10.3109/07420529908998724
    OpenUrlCrossRefPubMed
  12. ↵
    1. Mitchell JA,
    2. Quante M,
    3. Godbole S,
    4. James P,
    5. Hipp JA,
    6. Marinac CR,
    7. Mariani S,
    8. Cespedes Feliciano EM,
    9. Glanz K,
    10. Laden F,
    11. Wang R,
    12. Weng J,
    13. Redline S and
    14. Kerr J
    : Variation in actigraphy-estimated rest-activity patterns by demographic factors. Chronobiol Int 34(8): 1042–1056, 2017. PMID: 28650674. DOI: 10.1080/07420528.2017.1337032
    OpenUrlCrossRefPubMed
  13. ↵
    1. Ohara M,
    2. Suda G,
    3. Kimura M,
    4. Maehara O,
    5. Shimazaki T,
    6. Shigesawa T,
    7. Suzuki K,
    8. Nakamura A,
    9. Kawagishi N,
    10. Nakai M,
    11. Sho T,
    12. Natsuizaka M,
    13. Morikawa K,
    14. Ogawa K and
    15. Sakamoto N
    : Computed tomography, not bioelectrical impedance analysis, is the proper method for evaluating changes in skeletal muscle mass in liver disease. JCSM Rapid Communications 3(2): 103–114, 2020. DOI: 10.1002/rco2.20
    OpenUrlCrossRef
  14. ↵
    1. Aggeli P,
    2. Fasoi G,
    3. Zartaloudi A,
    4. Kontzoglou K,
    5. Kontos M,
    6. Konstantinidis T,
    7. Kalemikerakis I and
    8. Govina O
    : Posttreatment anxiety, depression, sleep disorders, and associated factors in women who survive breast cancer. Asia Pac J Oncol Nurs 8(2): 147–155, 2021. PMID: 33688563. DOI: 10.4103/apjon.apjon_65_20
    OpenUrlCrossRefPubMed
  15. ↵
    1. Steur LMH,
    2. Kaspers GJL,
    3. van Someren EJW,
    4. van Eijkelenburg NKA,
    5. van der Sluis IM,
    6. Dors N,
    7. van den Bos C,
    8. Tissing WJE,
    9. Grootenhuis MA and
    10. van Litsenburg RRL
    : The impact of maintenance therapy on sleep-wake rhythms and cancer-related fatigue in pediatric acute lymphoblastic leukemia. Support Care Cancer 28(12): 5983–5993, 2020. PMID: 32285260. DOI: 10.1007/s00520-020-05444-7
    OpenUrlCrossRefPubMed
  16. ↵
    1. Fearon K,
    2. Arends J and
    3. Baracos V
    : Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol 10(2): 90–99, 2013. PMID: 23207794. DOI: 10.1038/nrclinonc.2012.209
    OpenUrlCrossRefPubMed
  17. ↵
    1. Huillard O,
    2. Jouinot A,
    3. Tlemsani C,
    4. Brose MS,
    5. Arrondeau J,
    6. Meinhardt G,
    7. Fellous M,
    8. De Sanctis Y,
    9. Schlumberger M and
    10. Goldwasser F
    : Body composition in patients with radioactive iodine-refractory, advanced differentiated thyroid cancer treated with sorafenib or placebo: A retrospective analysis of the phase III DECISION trial. Thyroid 29(12): 1820–1827, 2019. PMID: 31860408. DOI: 10.1089/thy.2018.0784
    OpenUrlCrossRefPubMed
  18. ↵
    1. Torres-Perez P,
    2. Álvarez-Satta M,
    3. Arrazola M,
    4. Egaña L,
    5. Moreno-Valladares M,
    6. Villanua J,
    7. Ruiz I,
    8. Sampron N and
    9. Matheu A
    : Frailty is associated with mortality in brain tumor patients. Am J Cancer Res 11(6): 3294–3303, 2021. PMID: 34249463.
    OpenUrlPubMed
  19. ↵
    1. Yan CH,
    2. Coleman C,
    3. Nabulsi NA,
    4. Chiu BC,
    5. Ko NY,
    6. Hoskins K and
    7. Calip GS
    : Associations between frailty and cancer-specific mortality among older women with breast cancer. Breast Cancer Res Treat 189(3): 769–779, 2021. PMID: 34241741. DOI: 10.1007/s10549-021-06323-3
    OpenUrlCrossRefPubMed
  20. ↵
    1. Boyle EA,
    2. Elliott JA,
    3. McIntyre TV,
    4. Barnes ME,
    5. Donlon NE,
    6. Umair M,
    7. Gillis AE and
    8. Ridgway PF
    : Body composition is associated with operative and oncologic outcomes in the management of retroperitoneal and trunk soft tissue sarcoma. Am J Surg, 2021. PMID: 34389158. DOI: 10.1016/j.amjsurg.2021.08.005
    OpenUrlCrossRefPubMed
  21. ↵
    1. Hamaguchi Y,
    2. Kaido T,
    3. Okumura S,
    4. Kobayashi A,
    5. Hammad A,
    6. Tamai Y,
    7. Inagaki N and
    8. Uemoto S
    : Proposal for new diagnostic criteria for low skeletal muscle mass based on computed tomography imaging in Asian adults. Nutrition 32(11-12): 1200–1205, 2016. PMID: 27292773. DOI: 10.1016/j.nut.2016.04.003
    OpenUrlCrossRefPubMed
  22. ↵
    1. Ajzashokouhi AH,
    2. Bostan HB,
    3. Jomezadeh V,
    4. Hayes AW and
    5. Karimi G
    : A review on the cardioprotective mechanisms of metformin against doxorubicin. Hum Exp Toxicol 39(3): 237–248, 2020. PMID: 31735071. DOI: 10.1177/0960327119888277
    OpenUrlCrossRefPubMed
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Doxorubicin Combined With Ifosfamide for Sarcoma Induces Muscle Atrophy and Sleep Disruption
HIDEYUKI KINOSHITA, YOKO HAGIWARA, TAKESHI ISHII, HIROTO KAMODA, TOSHINORI TSUKANISHI, SEIJI OHTORI, TSUKASA YONEMOTO
Anticancer Research Dec 2021, 41 (12) 6273-6278; DOI: 10.21873/anticanres.15448
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