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Rh-endostatin combined with chemotherapy in patients with advanced or recurrent mucosal melanoma: retrospective analysis of real-world data

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Summary

Background. Mucosal melanoma is rare and has distinct clinical and genetic features. Even with advances in targeted and immune therapies, the survival of patients with advanced or recurrent mucosal melanomas remains poor. The standard treatment remains controversial and we conducted this real-world study aimed to explore continuous intravenous recombinant human endostatin (Rh-endostatin) infusion plus chemotherapy in this population in the first-line setting. Methods. Overall, 43 patients with advanced or recurrent mucosal melanoma treated at Fudan University Shanghai Cancer Center between April 2017 and August 2020 were retrospectively included. Patients received dacarbazine plus cisplatin or temozolomide plus cisplatin per the investigators’ preference. Rh-endostatin (105 mg/m2) was administered with continuous infusion for 168 h (Civ 168 h). Results. Of the 43 patients, 72.1% had metastatic disease, and the most common primary site was the gastrointestinal tract (51.2%). The most commonly observed mutations were NRAS (23.1%), BRAF (7.7%) and CKIT mutations (5.1%). An objective response was observed in 12 (30.0%) of the 40 evaluable patients, and disease control was achieved in 31 (77.5%) patients. With a median follow-up of 17.6 months, the median progression-free survival (PFS) and overall survival (OS) were 4.9 and 15.3 months, respectively. Additionally, high lymphocyte-to-monocyte ratio (LMR) (p = 0.023, HR 0.29, 95% CI: 0.10–0.84) and BRAF/KIT/RAS mutation (p = 0.028, HR 0.24, 95% CI: 0.07–0.86) were independently correlated with prolonged OS. Toxicity was manageable overall. Conclusion. Continuous Rh-endostatin infusion plus chemotherapy was effective and safe for the treatment of advanced or recurrent mucosal melanoma. High LMR was correlated with favorable PFS and OS in this patient population.

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Data availability

All data of this study are available per the corresponding author’s approval.

Abbreviations

BRAF:

B-raf proto-oncogene

ORR:

Overall response rate

ICIs:

Immune checkpoint inhibitors

NSCLC:

Non-small-cell lung cancer

SCLC:

Small-cell lung cancer

PFS:

Progression-free survival

OS:

Overall survival

ECOG:

Eastern Cooperative Oncology Group

PS:

Performance status

LDH:

Lactate dehydrogenase

NLR:

Neutrophil-to-lymphocyte ratio

LMR:

Lymphocyte-to-monocyte ratio

AEs:

Adverse events

NCI CTCAE:

National Cancer Institute Common Terminology Criteria for Adverse Events

RECIST:

Response Evaluation Criteria in Solid Tumors

CR:

Complete response

PR:

Partial response

HR:

Hazard ratio

CI:

Confidence interval

TKIs:

Tyrosine kinase inhibitors

References

  1. Barth A, Wanek LA, Morton DL (1995) Prognostic factors in 1,521 melanoma patients with distant metastases. J Am Coll Surg 181(3):193–201

    CAS  PubMed  Google Scholar 

  2. Lian B, Cui C-L, Zhou L, Song X, Zhang X-S, Wu D, Si L, Chi Z-H, Sheng X-N, Mao L-L, Wang X, Tang B-X, Yan X-Q, Kong Y, Dai J, Li SM, Bai X, Zheng N, Balch C-M, Guo J (2017) The natural history and patterns of metastases from mucosal melanoma: an analysis of 706 prospectively-followed patients. Annals of oncology: official J European Soc Med Oncol 28(4):868–873. https://doi.org/10.1093/annonc/mdw694

    Article  CAS  Google Scholar 

  3. D’Angelo SP, Larkin J, Sosman JA, Lebbé C, Brady B, Neyns B, Schmidt H, Hassel JC, Hodi FS, Lorigan P, Savage KJ, Miller WH Jr, Mohr P, Marquez-Rodas I, Charles J, Kaatz M, Sznol M, Weber JS, Shoushtari AN, Ruisi M, Wolchok JD (2017) Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis. Journal of clinical oncology: Official J European Soc Med Oncol 35(2):226–235. https://doi.org/10.1200/JCO.2016.67.9258

    Article  CAS  Google Scholar 

  4. Lyu J, Wu Y, Li C, Wang R, Song RG, Guo W (2016) Mutation scanning of BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma: a study of 57 cases. Journal of oral pathology and medicine: official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 45(4):295–301. https://doi.org/10.1111/jop.12358

    Article  CAS  Google Scholar 

  5. Kuk D, Shoushtari AN, Barker CA, Panageas KS, Munhoz RR, Momtaz P, Ariyan CE, Brady MS, Coit DG, Bogatch K, Callahan MK, Wolchok JD, Carvajal RD, Postow MA (2016) Prognosis of Mucosal, Uveal, Acral, Nonacral Cutaneous, and Unknown Primary Melanoma from the Time of First Metastasis. Oncologist 21(7):848–854. https://doi.org/10.1634/theoncologist.2015-0522

    Article  PubMed  PubMed Central  Google Scholar 

  6. McLaughlin CC, Wu XC, Jemal A, Martin HJ, Roche LM, Chen VW (2005) Incidence of noncutaneous melanomas in the U.S. Cancer 103(5):1000–1007. https://doi.org/10.1002/cncr.20866

  7. Chi Z, Li S, Sheng X, Si L, Cui C, Han M, Guo, J (2011) Clinical presentation, histology, and prognoses of malignant melanoma in ethnic Chinese: a study of 522 consecutive cases. BMC cancer 11(85). https://doi.org/10.1186/1471-2407-11-85

  8. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88(2):277–285. https://doi.org/10.1016/s0092-8674(00)81848-6

    Article  CAS  PubMed  Google Scholar 

  9. Yoon SS, Eto H, Lin CM, Nakamura H, Pawlik TM, Song SU, Tanabe KK (1999) Mouse endostatin inhibits the formation of lung and liver metastases. Can Res 59(24):6251–6256

    CAS  Google Scholar 

  10. Kim YM, Jang JW, Lee OH, Yeon J, Choi EY, Kim KW, Lee ST, Kwon YG (2000) Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinase. Can Res 60(19):5410–5413

    CAS  Google Scholar 

  11. Boehm T, Folkman J, Browder T, O’Reilly MS (1997) Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390(6658):404–407. https://doi.org/10.1038/37126

    Article  CAS  PubMed  Google Scholar 

  12. Mendoza L, Valcárcel M, Carrascal T, Egilegor E, Salado C, Sim BK, Vidal-Vanaclocha F (2004) Inhibition of cytokine-induced microvascular arrest of tumor cells by recombinant endostatin prevents experimental hepatic melanoma metastasis. Can Res 64(1):304–310. https://doi.org/10.1158/0008-5472.can-03-1829

    Article  CAS  Google Scholar 

  13. Han B, Xiu Q, Wang H, Shen J, Gu A, Luo Y, Bai C, Guo S, Liu W, Zhuang Z, Zhang Y, Zhao Y, Jiang L, Zhou J, Jin X (2011) A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of paclitaxel-carboplatin alone or with endostar for advanced non-small cell lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer. 6(6):1104–1109.https://doi.org/10.1097/JTO.0b013e3182166b6b

  14. Zhou Z-T, Zhou F-X, Wei Q, Zou L-Y, Qin B-F, Peng X-S (2011) Phase II study of cisplatin/etoposide and endostar for extensive-stage small-cell lung cancer. Cancer Chemother Pharmacol 68(4):1027–1032. https://doi.org/10.1007/s00280-011-1576-1

    Article  CAS  PubMed  Google Scholar 

  15. Lu S, Li L, Luo Y, Zhang L, Wu G, Chen Z, Huang C, Guo S, Zhang Y, Song X, Yu Y, Zhou C, Li W, Liao M, Li B, Xu L, Chen P, Hu C, Hu C (2015) A multicenter, open-label, randomized phase II controlled study of rh-endostatin (Endostar) in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 10(1):206–211. https://doi.org/10.1097/JTO.0000000000000343

    Article  CAS  Google Scholar 

  16. Yang H, Sui Y, Guo X, Tan X, Li Y, Wang M (2018) Endostar continuous intravenous infusion combined with S-1 and oxaliplatin chemotherapy could be effective in treating liver metastasis from gastric cancer. J Cancer Res Ther 14(Supplement):S1148–S1151. https://doi.org/10.4103/0973-1482.204880

    Article  CAS  PubMed  Google Scholar 

  17. Zhou J-F, Bai C-M, Wang Y-Z, Li X-Y, Cheng Y-J, Chen S-C (2011) Endostar combined with chemotherapy for treatment of metastatic colorectal and gastric cancer: a pilot study. Chin Med J 124(24):4299–4303

    CAS  PubMed  Google Scholar 

  18. Jia Y, Liu M, Huang W, Wang Z, He Y, Wu J, Ren S, Ju Y, Geng R, Li Z (2012) Recombinant human endostatin endostar inhibits tumor growth and metastasis in a mouse xenograft model of colon cancer. Pathology oncology research: POR 18(2):315–323. https://doi.org/10.1007/s12253-011-9447-y

    Article  CAS  PubMed  Google Scholar 

  19. Su A, Zhang J, Pan Z-H, Zhou Q-M, Lv X (2013) Salvage therapy of gemcitabine plus endostar significantly improves progression-free survival (PFS) with platinum-resistant recurrent epithelial ovarian cancer. Asian Pacific journal of cancer prevention: APJCP 14(3):1841–1846. https://doi.org/10.7314/apjcp.2013.14.3.1841

    Article  PubMed  Google Scholar 

  20. Jin T, Jiang F, Jin Q-F, Piao Y-F, Chen X-Z (2018) Endostar Combined with Gemcitabine and Cisplatin Chemotherapy for Patients with Metastatic Nasopharyngeal Carcinoma: an Update. Translational oncology 11(2):286–291. https://doi.org/10.1016/j.tranon.2018.01.002

    Article  PubMed  PubMed Central  Google Scholar 

  21. Guan Y, Li A, Xiao W, Liu S, Chen B, Lu T, Zhao C, Han F (2015) The efficacy and safety of Endostar combined with chemoradiotherapy for patients with advanced, locally recurrent nasopharyngeal carcinoma. Oncotarget 6(32):33926–33934. https://doi.org/10.18632/oncotarget.5271

  22. Li Y, Tian Y, Jin F, Wu W, Long J, Ouyang J, Zhou Y (2020) A phase II multicenter randomized controlled trial to compare standard chemoradiation with or without recombinant human endostatin injection (Endostar) therapy for the treatment of locally advanced nasopharyngeal carcinoma: Long-term outcomes update. Curr Probl Cancer 44(1):100492. https://doi.org/10.1016/j.currproblcancer.2019.06.007

    Article  PubMed  Google Scholar 

  23. Cui C, Mao L, Chi Z, Si L, Sheng X, Kong Y, Li S, Lian B, Gu K, Tao M, Song X, Lin T, Ren X, Qin S, Guo J (2013) A phase II, randomized, double-blind, placebo-controlled multicenter trial of Endostar in patients with metastatic melanoma. Molecular therapy: the journal of the American Society of Gene Therapy 21(7):1456–1463. https://doi.org/10.1038/mt.2013.79

    Article  CAS  Google Scholar 

  24. Carvajal RD, Spencer SA, Lydiatt W (2012) Mucosal melanoma: a clinically and biologically unique disease entity. Journal of the National Comprehensive Cancer Network: JNCCN 10(3):345–356. https://doi.org/10.6004/jnccn.2012.0034

    Article  CAS  PubMed  Google Scholar 

  25. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N (2000) Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 18(1):158–166. https://doi.org/10.1200/JCO.2000.18.1.158

    Article  CAS  Google Scholar 

  26. Eggermont AM, Kirkwood JM (2004) Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years. European journal of cancer (Oxford, England:1990) 40(12):1825–1836. https://doi.org/10.1016/j.ejca.2004.04.030

  27. Postow MA, Hamid O, Carvajal RD (2012) Mucosal melanoma: pathogenesis, clinical behavior, and management. Curr Oncol Rep 14(5):441–448. https://doi.org/10.1007/s11912-012-0244-x

    Article  CAS  PubMed  Google Scholar 

  28. Ma H-L, Hui Z-G, Peng F, Zhao LJ, Li D-M, Xu Y-J, Bao Y, Xu L-M, Zhai Y-R, Hu X, Wang J, Kong Y, Wang L-H, Chen M (2020) Different administration routes of recombinant human endostatin combined with concurrent chemoradiotherapy might lead to different efficacy and safety profile in unresectable stage III non-small cell lung cancer: Updated follow-up results from two phase II trials. Thoracic cancer 11(4):898–906. https://doi.org/10.1111/1759-7714.13333

    Article  CAS  Google Scholar 

  29. Cui CL, Lu S, Chi ZH, Sheng XN, Mao LL, Wang X, Lian B, Yan XQ, Guo J (2015) Preliminary results of a phase II trial with continuous intravenous infusion of rh-endostatin in combination with dacarbazine as the first-line therapy for metastatic acral melanoma. Anticancer Res 35(7):4350–4351

    Google Scholar 

  30. Si L, Zhang X-S, Shu Y-Q, Pan H-M, Wu D, Liu JW, Lou F, Mao L-L, Wang X, Wen XZ, Gu YH, Zhu LJ, Lan SJ, Cai X, Diede SJ, Zhou Y, Ge J, Li JF, Wu HY, Guo J (2019) A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151). Translational oncology 12(6):828–835. https://doi.org/10.1016/j.tranon.2019.02.007

    Article  PubMed  PubMed Central  Google Scholar 

  31. Tang B, Chi Z, Chen Y, Liu X, Wu D, Chen J, Song X, Wang W, Dong L, Song H, Wu H, Feng H, Yao S, Qin S, Zhang X, Guo J (2020) Safety, Efficacy, and Biomarker Analysis of Toripalimab in Previously Treated Advanced Melanoma: Results of the POLARIS-01 Multicenter Phase II Trial. Clinical cancer research: an official journal of the American Association for Cancer Research 26(16):4250–4259. https://doi.org/10.1158/1078-0432.CCR-19-3922

    Article  CAS  Google Scholar 

  32. Sheng X, Yan X, Chi Z, Si L, Cui C, Tang B, Li S, Mao L, Lian B, Wang X, Bai X, Zhou L, Kong Y, Dai J, Wang K, Tang X, Zhou H, Wu H, Feng H, Yao S, Guo J (2019) Axitinib in Combination With Toripalimab, a Humanized Immunoglobulin G4 Monoclonal Antibody Against Programmed Cell Death-1, in Patients With Metastatic Mucosal Melanoma: An Open-Label Phase IB Trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 37(32):2987–2999. https://doi.org/10.1200/JCO.19.00210

    Article  CAS  Google Scholar 

  33. Si L, Sheng XN, Mao LL, Li CL, Wang X, Bai X, Qi Z, Chi ZH, Cui CL, Lian B, Tang BX, Yan XQ, Zhou L, Li SM, Duan R (2020) A phase II study of vorolanib (CM082) in combination with toripalimab (JS001) in patients with advanced mucosal melanoma. J Clin Oncol 38(15_suppl):10040–10040

  34. Ma J-Y, Liu Q (2018) Clinicopathological and prognostic significance of lymphocyte to monocyte ratio in patients with gastric cancer: A meta-analysis. International journal of surgery (London, England) 50:67–71. https://doi.org/10.1016/j.ijsu.2018.01.002

    Article  Google Scholar 

  35. Mao Y, Chen D, Duan S, Zhao Y, Wu C, Zhu F, Chen C, Chen Y (2018) Prognostic impact of pretreatment lymphocyte-to-monocyte ratio in advanced epithelial cancers: a meta-analysis. Cancer Cell Int 18:201. https://doi.org/10.1186/s12935-018-0698-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nishijima TF, Muss HB, Shachar SS, Tamura K, Takamatsu Y (2015) Prognostic value of lymphocyte-to-monocyte ratio in patients with solid tumors: A systematic review and meta-analysis. Cancer Treat Rev 41(10):971–978. https://doi.org/10.1016/j.ctrv.2015.10.003

    Article  PubMed  Google Scholar 

  37. Lacono D, Basile D, Gerratana L, Vitale MG, Pelizzari G, Cinausero M, Poletto E, Puglisi F, Fasola G, Minisini AM (2019) Prognostic role of disease extent and lymphocyte-monocyte ratio in advanced melanoma. Melanoma Res 29(5):510–515. https://doi.org/10.1097/CMR.0000000000000584

    Article  CAS  Google Scholar 

  38. Leontovich AA, Dronca RS, Nevala WK, Thompson M, Kottschade LA, Ivanov LV, Markovic SN, Melanoma Study Group of the Mayo Clinic Cancer Center (2017) Effect of the lymphocyte-to-monocyte ratio on the clinical outcome of chemotherapy administration in advanced melanoma patients. Melanoma Res 27(1):32–42. https://doi.org/10.1097/CMR.0000000000000290

    Article  CAS  Google Scholar 

  39. Minowa T, Kato J, Hida T, Horimoto K, Sato S, Sawada M, Uhara H (2018) Prognostic role of platelet to lymphocyte and lymphocyte to monocyte ratios in advanced melanoma treated with anti-programmed death-1. European journal of dermatology: EJD 28(5):705–707. https://doi.org/10.1684/ejd.2018.3381

    Article  PubMed  Google Scholar 

  40. Wang Y, Zhang H, Yang Y, Zhang T, Ma X (2019) Prognostic Value of Peripheral Inflammatory Markers in Preoperative Mucosal Melanoma: A Multicenter Retrospective Study. Front Oncol 9:995. https://doi.org/10.3389/fonc.2019.00995

    Article  PubMed  PubMed Central  Google Scholar 

  41. Amit M, Tam S, Abdelmeguid AS, Roberts DB, Takahashi Y, Raza SM, Su SY, Kupferman ME, DeMonte F, Hanna EY (2017) Mutation status among patients with sinonasal mucosal melanoma and its impact on survival. Br J Cancer 116(12):1564–1571. https://doi.org/10.1038/bjc.2017.125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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Funding

This work was supported by Natural Science Foundation of Xinjiang Uygur Autonomous Region. (Grant No. 2016D01C091).

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Author notes

  1. Xiaowei Zhang, Feng Jin and Shiyu Jiang contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Xiaowei Zhang, Shiyu Jiang, Jun Cao, Yanchun Meng, Xin Liu & Zhiguo Luo

  2. Department of Digestive Disease, 900Th Hospital of Joint Logistics Support Force, Fuzhou, 350002, China

    Feng Jin

  3. Department of Bone and Soft Tissue Sarcomas, Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Yu Xu,  ChunmengWang & Yong Chen

  4. Department of Gynecological Oncology, Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Huijuan Yang

  5. Department of Pathology, Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Yunyi Kong

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  1. Xiaowei Zhang
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SYJ, XWZ and FJ drafted the manuscript. ZGL and XL supervised and revised the manuscript. All authors read and approved the final manuscript.

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Zhang, X., Jin, F., Jiang, S. et al. Rh-endostatin combined with chemotherapy in patients with advanced or recurrent mucosal melanoma: retrospective analysis of real-world data. Invest New Drugs 40, 453–460 (2022). https://doi.org/10.1007/s10637-021-01172-9

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