Prognostic Role of Circulating Tumor Cells during Induction Chemotherapy Followed by Curative Surgery Combined with Postoperative Radiotherapy in Patients with Locally Advanced Oral and Oropharyngeal Squamous Cell Cancer

Johanna Inhestern, Katrin Oertel, Viola Stemmann, Harald Schmalenberg, Andreas Dietz, Nicole Rotter, Johannes Veit, Martin Görner, Holger Sudhoff, Christian Junghanß, Claus Wittekindt, Katharina Pachmann, Orlando Guntinas-Lichius, Johanna Inhestern, Katrin Oertel, Viola Stemmann, Harald Schmalenberg, Andreas Dietz, Nicole Rotter, Johannes Veit, Martin Görner, Holger Sudhoff, Christian Junghanß, Claus Wittekindt, Katharina Pachmann, Orlando Guntinas-Lichius

Abstract

Background: The prognostic role of circulating tumor cells (CTCs) after induction chemotherapy using docetaxel, cisplatin and fluorouracil (TPF) prior to surgery and adjuvant (chemo)radiation in locally advanced oral squamous cell cancer (OSCC) was evaluated.

Methods: In this prospective study, peripheral blood samples from 40 patients of the phase II study TISOC-1 (NCT01108042) with OSCC before, during, and after treatment were taken. CTCs were quantified using laser scanning cytometry of anti- epithelial cell adhesion molecule-stained epithelial cells. Their detection was correlated with clinical risk factors, recurrence-free (RFS) and overall survival (OS).

Results: Before starting the treatment CTCs were detected in 32 of 40 patients (80%). The median number at baseline was 3295 CTCs/ml. The median maximal number of CTCs during treatment was 5005 CTCs/ml. There was a significant increase of CTCs before postoperative radiotherapy compared to baseline before 1st cycle of IC (p = 0.011), 2nd cycle of IC (p = 0.001), 3rd cycle of IC (p = 0.004), and before surgery (p = 0.002), but not compared to end of therapy (p = 0.118). CTCs at baseline >median was also associated to risk of recurrence (p = 0.014). Maximal CTCs during therapy >median was more frequently observed in tumors of the oral cavity (p=0.022) and related to higher risk of death during follow-up (p = 0.028). Patients with CTCs at baseline >median value had significant lower RFS than patients with CTCs at baseline <median value (p = 0.025). Patients with maximal CTCs values >median during the complete course of therapy had a significantly lower OS than patients with values <median (p = 0.049). Finally, the multivariate analysis revealed that OS was significantly lower in patients with maximal CTCs during treatment higher than the median value (HR=6.151; CI: 1.244-30.420).

Conclusions: Baseline CTCs and maximal CTCs during therapy both seem to be good prognostic markers for OSCC when treated by TPF induction chemotherapy, surgery, and postoperative (chemo)radiation.

Conflict of interest statement

Competing Interests: The authors declare that they received funding from Sanofi-Aventis for this study. This did not alter the authors' adherence to all PLOS ONE policies. Furthermore, Sanofi-Aventis was not involved in the execution or analysis of the study. Sanofi-Aventis did not have any influence on the publication policy or the content of the manuscript or its revision.

Figures

Fig 1. Number of circulating tumor cells…
Fig 1. Number of circulating tumor cells per ml blood (CTCs/ml; mean ± standard deviation) before start of the treatment, during induction chemotherapy (IC), before surgery, before postoperative radiotherapy (PORT; ± chemotherapy or cetuximab), and at the end of treatment.
Significant increase of CTCs before postoperative radiotherapy compared to baseline before 1st cycle of IC (*; p = 0.011), 2nd cycle of IC (**; p = 0.001), 3rd cycle of IC (***; p = 0.004), and before surgery (****; p = 0.002), but not compared to the end of therapy (#; p = 0.118).
Fig 2. Kaplan-Meier curves on recurrence-free survival…
Fig 2. Kaplan-Meier curves on recurrence-free survival (A, B) and overall survival (C, D) according to therapy arm (A, C), circulating tumor cells (CTCs) at baseline (B), and maximal amount of CTCs during the treatment.

References

    1. Forastiere A, Koch W, Trotti A, Sidransky D (2001) Head and neck cancer. N Engl J Med 345: 1890–1900.
    1. Argiris A, Karamouzis MV, Raben D, Ferris RL (2008) Head and neck cancer. Lancet 371: 1695–1709. 10.1016/S0140-6736(08)60728-X
    1. Balasubramanian P, Lang JC, Jatana KR, Miller B, Ozer E, Old M, et al. (2012) Multiparameter analysis, including EMT markers, on negatively enriched blood samples from patients with squamous cell carcinoma of the head and neck. PLoS One 7: e42048 10.1371/journal.pone.0042048
    1. Schlimok G, Funke I, Holzmann B, Göttlinger G, Schmidt G, Häuser H, et al. (1987) Micrometastatic cancer cells in bone marrow: in vitro detection with anti-cytokeratin and in vivo labeling with anti-17-1A monoclonal antibodies. Proc Natl Acad Sci U S A 84: 8672–8676.
    1. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351: 781–791.
    1. Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, et al. (2008) Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 26: 3213–3221. 10.1200/JCO.2007.15.8923
    1. Scher HI, Jia X, de Bono JS, Fleisher M, Pienta KJ, Raghavan D, et al. (2009) Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol 10: 233–239. 10.1016/S1470-2045(08)70340-1
    1. Posner M, Vermorken JB (2008) Induction therapy in the modern era of combined-modality therapy for locally advanced head and neck cancer. Semin Oncol 35: 221–228. 10.1053/j.seminoncol.2008.03.007
    1. Oertel K, Spiegel K, Schmalenberg H, Dietz A, Maschmeyer G, Kuhnt T, et al. (2012) Phase I trial of split-dose induction docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1). BMC Cancer 12: 483 10.1186/1471-2407-12-483
    1. Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr, Sun J, et al. (2013) Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. J Clin Oncol 31: 744–751. 10.1200/JCO.2012.43.8820
    1. Guntinas-Lichius O, Wendt TG, Kornetzky N, Buentzel J, Esser D, Böger D, et al. (2014) Trends in epidemiology and treatment and outcome for head and neck cancer: A population-based long-term analysis from 1996 to 2011 of the Thuringian cancer registry. Oral Oncol 50: 1157–1164. 10.1016/j.oraloncology.2014.09.015
    1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45: 228–247. 10.1016/j.ejca.2008.10.026
    1. Glombitza F, Guntinas-Lichius O, Petersen I (2010) HPV status in head and neck tumors. Pathol Res Pract 206: 229–234. 10.1016/j.prp.2009.11.007
    1. Pachmann K, Camara O, Kavallaris A, Krauspe S, Malarski N, Gajda M, et al. (2008) Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. J Clin Oncol 26: 1208–1215. 10.1200/JCO.2007.13.6523
    1. Pachmann UA, Hekimian K, Carl S, Ruediger N, Rabenstein C, Pachmann K (2011) Comparing Sequential Steps For Detection Of Circulating Tumor Cells: More Specific Or Just Less Sensitive?. WebmedCentral CANCER 2: WMC001490.
    1. Pachmann K, Camara O, Kavallaris A, Schneider U, Schünemann S, Höffken K. Quantification of the response of circulating epithelial cells (CEC) to neodadjuvant treatment of breast cancer: A new tool for therapy monitoring. Breast Cancer Research 7:R975–R979.
    1. Mockelmann N, Laban S, Pantel K, Knecht R (2014) Circulating tumor cells in head and neck cancer: clinical impact in diagnosis and follow-up. Eur Arch Otorhinolaryngol 271: 15–21. 10.1007/s00405-013-2391-6
    1. Hristozova T, Konschak R, Stromberger C, Fusi A, Liu Z, Weichert W et al. (2011) The presence of circulating tumor cells (CTCss) correlates with lymph node metastasis in nonresectable squamous cell carcinoma of the head and neck region (SCCHN). Ann Oncol 22: 1878–1885. 10.1093/annonc/mdr130
    1. Weller P, Nel I, Hassenkamp P, Gauler T, Schlueter A, Lang S et al. (2014) Detection of circulating tumor cell subpopulations in patients with head and neck squamous cell carcinoma (HNSCC). PLoS One 9: e113706 10.1371/journal.pone.0113706
    1. Wikner J, Grobe A, Pantel K, Riethdorf S (2014) Squamous cell carcinoma of the oral cavity and circulating tumour cells. World J Clin Oncol 5: 114–124. 10.5306/wjco.v5.i2.114
    1. Gröbe A, Blessmann M, Hanken H, Friedrich RE, Schön G, Wikner J, et al. (2014) Prognostic relevance of circulating tumor cells in blood and disseminated tumor cells in bone marrow of patients with squamous cell carcinoma of the oral cavity. Clin Cancer Res 20: 425–433. 10.1158/1078-0432.CCR-13-1101
    1. Buglione M, Grisanti S, Almici C, Mangoni M, Polli C, Consoli F, et al. (2012) Circulating tumour cells in locally advanced head and neck cancer: preliminary report about their possible role in predicting response to non-surgical treatment and survival. Eur J Cancer 48: 3019–3026. 10.1016/j.ejca.2012.05.007
    1. Nichols AC, Lowes LE, Szeto CC, Basmaji J, Dhaliwal S, Chapeskie C, et al. (2012) Detection of circulating tumor cells in advanced head and neck cancer using the CellSearch system. Head Neck 34: 1440–1444. 10.1002/hed.21941
    1. Hsieh JC, Lin HC, Huang CY, Hsu HL, Wu TM, et al. (2014) Prognostic value of circulating tumor cells with podoplanin expression in patients with locally advanced or metastatic head and neck squamous cell carcinoma. Head Neck, 10.1002/hed.23779 [Epub ahead of print].
    1. Mirghani H, Amen F, Moreau F, Lacau St Guily J (2015) Do high-risk human papillomaviruses cause oral cavity squamous cell carcinoma? Oral Oncol; 51: 229–236. 10.1016/j.oraloncology.2014.11.011
    1. Hitt R, López-Pousa A, Martínez-Trufero J, Escrig V, Carles J, Rizo A, et al. (2005) Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 23: 8636–8645.
    1. Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, et al. (2011) Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 12: 153–159. 10.1016/S1470-2045(10)70279-5
    1. Jatana KR, Balasubramanian P, Lang JC, Yang L, Jatana CA, White E, et al. (2010) Significance of circulating tumor cells in patients with squamous cell carcinoma of the head and neck: initial results. Arch Otolaryngol Head Neck Surg 136: 1274–1279. 10.1001/archoto.2010.223
    1. Tinhofer I, Konschak R, Stromberger C, Raguse JD, Dreyer JH, Jöhrens K, et al. (2014) Detection of circulating tumor cells for prediction of recurrence after adjuvant chemoradiation in locally advanced squamous cell carcinoma of the head and neck. Ann Oncol 25: 2042–2047. 10.1093/annonc/mdu271
    1. Kusukawa J1, Suefuji Y, Ryu F, Noguchi R, Iwamoto O, Kameyama T (2000) Dissemination of cancer cells into circulation occurs by incisional biopsy of oral squamous cell carcinoma. J Oral Pathol Med 29: 303–307.
    1. Liu Z, Jiang M, Zhao J, Ju H (2007) Circulating tumor cells in perioperative esophageal cancer patients: quantitative assay system and potential clinical utility. Clin Cancer Res 13: 2992–2997.
    1. Hashimoto M, Tanaka F, Yoneda K, Takuwa T, Matsumoto S, Okumura Y, et al. (2014) Significant increase in circulating tumour cells in pulmonary venous blood during surgical manipulation in patients with primary lung cancer. Interact Cardiovasc Thorac Surg 18: 775–783. 10.1093/icvts/ivu048
    1. Nesteruk D, Rutkowski A, Fabisiewicz S, Pawlak J, Siedlecki JA, Fabisiewicz A. (2014) Evaluation of prognostic significance of circulating tumor cells detection in rectal cancer patients treated with preoperative radiotherapy: prospectively collected material data. Biomed Res Int: 712827.
    1. Perrone F, Bossi P, Cortelazzi B, Locati L, Quattrone P, Pierotti MA, et al. (2010) TP53 mutations and pathologic complete response to neoadjuvant cisplatin and fluorouracil chemotherapy in resected oral cavity squamous cell carcinoma. J Clin Oncol 28: 761–766. 10.1200/JCO.2009.22.4170
    1. Feng Z, Guo W, Zhang C, Xu Q, Zhang P, Sun J, et al. (2011) CCND1 as a predictive biomarker of neoadjuvant chemotherapy in patients with locally advanced head and neck squamous cell carcinoma. PLoS One 6(10): e26399 10.1371/journal.pone.0026399
    1. Zhu DW, Liu Y, Yang X, Yang CZ, Ma J, Yang X, et al. (2013) Low Annexin A1 expression predicts benefit from induction chemotherapy in oral cancer patients with moderate or poor pathologic differentiation grade. BMC Cancer 13:301 10.1186/1471-2407-13-301

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit