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Minocycline for symptom reduction during radiation therapy for head and neck cancer: a randomized clinical trial

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Abstract

Purpose

Local/systemic symptoms during cancer therapy may be exacerbated by dysregulated inflammation and its downstream toxic effects. Minocycline can suppress proinflammatory cytokine release; therefore, we investigated its potential to reduce patient-reported symptom severity during radiotherapy (RT) for head and neck cancer (HNC).

Methods

Eligible patients for this blinded, placebo–controlled trial were adults with T0–3, N-any, and M0 HNC receiving single-modality RT. Participants were randomized 1:1 to either minocycline (200 mg/day) or placebo during RT. The primary endpoint was the area under the curve (AUC) of 5 prespecified symptoms (pain, fatigue, disturbed sleep, poor appetite, difficulty swallowing/chewing) during RT, assessed with the MD Anderson Symptom Inventory for HNC (MDASI-HN).

Results

We analyzed data from 20 evaluable patients per arm. Overall, 75% had oropharyngeal cancer and 78% were male. No grade 3+ adverse events potentially related to study medication were observed. Two minocycline patients required a feeding tube during RT vs 5 placebo patients (P = 0.21). The average daily AUC during RT for the 5 MDASI-HN symptoms was 3.1 (SD = 1.0) for minocycline and 3.7 (SD = 1.7) for placebo (P = 0.16); the 0.37 effect size was less than our 0.70 target. AUC comparisons for several individual symptoms and symptom interference favored minocycline but were not statistically significant. The greatest numerical differences occurred for systemic symptoms, larger toward treatment end, and in early post-RT recovery.

Conclusions

Minocycline was feasible, well tolerated, and achieved a positive signal toward reducing patient-reported symptom severity during RT for HNC, particularly for systemic symptoms. This justifies additional study and informs future trial design.

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References

  1. Garden AS, Kies MS, Morrison WH, Weber RS, Frank SJ, Glisson BS, Gunn GB, Beadle BM, Ang KK, Rosenthal DI, Sturgis EM (2013) Outcomes and patterns of care of patients with locally advanced oropharyngeal carcinoma treated in the early 21st century. Radiat Oncol 8(21). https://doi.org/10.1186/1748-717X-8-21

  2. Rosenthal DI, Mendoza TR, Fuller CD, Hutcheson KA, Wang XS, Hanna EY, Lu C, Garden AS, Morrison WH, Cleeland CS, Gunn GB (2014) Patterns of symptom burden during radiotherapy or concurrent chemoradiotherapy for head and neck cancer: a prospective analysis using the University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module. Cancer 120(13):1975–1984. https://doi.org/10.1002/cncr.28672

    Article  PubMed  Google Scholar 

  3. Goepfert RP, Fuller CD, Gunn GB, Hanna EY, Lewin JS, Zaveri JS, Hubbard RM, Barrow MP, Hutcheson KA (2017) Symptom burden as a driver of decisional regret in long-term oropharyngeal carcinoma survivors. Head Neck 39(11):2151–2158. https://doi.org/10.1002/hed.24879

    Article  PubMed  Google Scholar 

  4. Mirghani H, Blanchard P (2018) Treatment de-escalation for HPV-driven oropharyngeal cancer: where do we stand? Clin Transl Radiat Oncol 8:4–11. https://doi.org/10.1016/j.ctro.2017.10.005

    Article  PubMed  Google Scholar 

  5. Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21(2):153–160. https://doi.org/10.1016/j.bbi.2006.09.006

    Article  CAS  PubMed  Google Scholar 

  6. Dantzer R, Meagher MW, Cleeland CS (2012) Translational approaches to treatment-induced symptoms in cancer patients. Nat Rev Clin Oncol 9(7):414–426. https://doi.org/10.1038/nrclinonc.2012.88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Garrido-Mesa N, Zarzuelo A, Galvez J (2013) Minocycline: far beyond an antibiotic. Br J Pharmacol 169(2):337–352. https://doi.org/10.1111/bph.12139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Smith CJ, Sayles H, Mikuls TR, Michaud K (2011) Minocycline and doxycycline therapy in community patients with rheumatoid arthritis: prescribing patterns, patient-level determinants of use, and patient-reported side effects. Arthritis Res Ther 13(5):R168. https://doi.org/10.1186/ar3491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. O’Dell JR, Blakely KW, Mallek JA, Eckhoff PJ, Leff RD, Wees SJ, Sems KM, Fernandez AM, Palmer WR, Klassen LW, Paulsen GA, Haire CE, Moore GF (2001) Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine. Arthritis Rheum 44(10):2235–2241

    Article  PubMed  Google Scholar 

  10. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J (2001) Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci 21(8):2580–2588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Plane JM, Shen Y, Pleasure DE, Deng W (2010) Prospects for minocycline neuroprotection. Arch Neurol 67(12):1442–1448. https://doi.org/10.1001/archneurol.2010.191

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li C, Yuan K, Schluesener H (2013) Impact of minocycline on neurodegenerative diseases in rodents: a meta-analysis. Rev Neurosci 24(5):553–562. https://doi.org/10.1515/revneuro-2013-0040

    Article  CAS  PubMed  Google Scholar 

  13. Bonelli RM, Hodl AK, Hofmann P, Kapfhammer HP (2004) Neuroprotection in Huntington’s disease: a 2-year study on minocycline. Int Clin Psychopharmacol 19(6):337–342

    Article  PubMed  Google Scholar 

  14. Leporini C, Saullo F, Filippelli G, Sorrentino A, Lucia M, Perri G, Gattuta GL, Infusino S, Toscano R, Dima G, Olivito V, Paletta L, Bottoni U, De Sarro G (2013) Management of dermatologic toxicities associated with monoclonal antibody epidermal growth factor receptor inhibitors: a case review. J Pharmacol Pharmacother 4(Suppl 1):S78–S85. https://doi.org/10.4103/0976-500X.120966

    Article  PubMed  PubMed Central  Google Scholar 

  15. Melosky B, Anderson H, Burkes RL, Chu Q, Hao D, Ho V, Ho C, Lam W, Lee CW, Leighl NB, Murray N, Sun S, Winston R, Laskin JJ (2016) Pan Canadian Rash Trial: a randomized phase III trial evaluating the impact of a prophylactic skin treatment regimen on epidermal growth factor receptor-tyrosine kinase inhibitor-induced skin toxicities in patients with metastatic lung cancer. J Clin Oncol 34(8):810–815. https://doi.org/10.1200/JCO.2015.62.3918

    Article  CAS  PubMed  Google Scholar 

  16. Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ (2012) Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain 135(Pt 4):1224–1236. https://doi.org/10.1093/brain/aws072

    Article  PubMed  Google Scholar 

  17. Rosenthal DI, Mendoza TR, Chambers MS, Asper JA, Gning I, Kies MS, Weber RS, Lewin JS, Garden AS, Ang KK, X SW, Cleeland CS (2007) Measuring head and neck cancer symptom burden: the development and validation of the M. D. Anderson symptom inventory, head and neck module. Head Neck 29(10):923–931. https://doi.org/10.1002/hed.20602

    Article  PubMed  Google Scholar 

  18. Shi Q, Wang XS, Li G, Shah ND, Orlowski RZ, Williams LA, Mendoza TR, Cleeland CS (2015) Racial/ethnic disparities in inflammatory gene single-nucleotide polymorphisms as predictors of a high risk for symptom burden in patients with multiple myeloma 1 year after diagnosis. Cancer 121(7):1138–1146. https://doi.org/10.1002/cncr.29154

    Article  CAS  PubMed  Google Scholar 

  19. Wang XS, Shi Q, Shah ND, Heijnen CJ, Cohen EN, Reuben JM, Orlowski RZ, Qazilbash MH, Johnson VE, Williams LA, Mendoza TR, Cleeland CS (2014) Inflammatory markers and development of symptom burden in patients with multiple myeloma during autologous stem cell transplantation. Clin Cancer Res 20(5):1366–1374. https://doi.org/10.1158/1078-0432.CCR-13-2442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang XS, Shi Q, Williams LA, Mao L, Cleeland CS, Komaki RR, Mobley GM, Liao Z (2010) Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy. Brain Behav Immun 24(6):968–974. https://doi.org/10.1016/j.bbi.2010.03.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang XS, Williams LA, Krishnan S, Liao Z, Liu P, Mao L, Shi Q, Mobley GM, Woodruff JF, Cleeland CS (2012) Serum sTNF-R1, IL-6, and the development of fatigue in patients with gastrointestinal cancer undergoing chemoradiation therapy. Brain Behav Immun 26(5):699–705. https://doi.org/10.1016/j.bbi.2011.12.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wood LJ, Weymann K (2013) Inflammation and neural signaling: etiologic mechanisms of the cancer treatment-related symptom cluster. Curr Opin Support Palliat Care 7(1):54–59. https://doi.org/10.1097/SPC.0b013e32835dabe3

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kwekkeboom KL, Tostrud L, Costanzo E, Coe CL, Serlin RC, Ward SE, Zhang Y (2018) The role of inflammation in the pain, fatigue, and sleep disturbance symptom cluster in advanced cancer. J Pain Symptom Manag 55(5):1286–1295. https://doi.org/10.1016/j.jpainsymman.2018.01.008

    Article  Google Scholar 

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Acknowledgments

The authors extend special thanks to Jeanie F. Woodruff, BS, ELS, for editorial comments.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 97, Houston, TX, 77030, USA

    G. Brandon Gunn, Adam S. Garden, William H. Morrison, Steven J. Frank, Jack Phan, Clifton D. Fuller & David I. Rosenthal

  2. Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Tito R. Mendoza, Xin Shelley Wang, Qiuling Shi & Charles S. Cleeland

  3. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Mark S. Chambers & Ehab Y. Hanna

  4. Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Charles Lu

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  1. G. Brandon Gunn
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  2. Tito R. Mendoza
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  3. Adam S. Garden
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  4. Xin Shelley Wang
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  12. Charles Lu
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  14. Charles S. Cleeland
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Corresponding author

Correspondence to G. Brandon Gunn.

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Conflict of interest

The MD Anderson Symptom Inventory is copyrighted and licensed by The University of Texas MD Anderson Cancer Center and Charles S. Cleeland. Xin Shelley Wang is the spouse of Charles S. Cleeland.

Previous presentation

Presented in part at the American Society for Clinical Oncology (ASCO) Annual Meeting; Chicago, Illinois, 06/2014.

Grant or financial support

Supported in part by an Institutional Research Grant from The University of Texas MD Anderson Cancer Center and by grants from the National Cancer Institute of the National Institutes of Health: grants R01 CA026582 and P01 CA124787 (PI: Charles Cleeland); the Paul Calabresi Clinical Trial Program Subaward of NCI grant K12 CA088084 (PI: Robert Bast); and the MD Anderson Cancer Center Support (Core) Grant P30 CA016672 (PI: Peter Pisters).

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The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Gunn, G.B., Mendoza, T.R., Garden, A.S. et al. Minocycline for symptom reduction during radiation therapy for head and neck cancer: a randomized clinical trial. Support Care Cancer 28, 261–269 (2020). https://doi.org/10.1007/s00520-019-04791-4

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  • DOI: https://doi.org/10.1007/s00520-019-04791-4

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