高雄榮民總醫院耳鼻喉頭頸部 林陞樵 林曜祥 康柏皇 張庭碩 The Impact of Cumulative Cisplatin Dose on Outcomes of N3 Nasopharyngeal Carcinoma Patients in the Era of IMRT 高雄榮民總醫院耳鼻喉頭頸部 林陞樵 林曜祥 康柏皇 張庭碩

Introduction

Treatment Effect of Nasopharyngeal Carcinoma (NPC) Radiotherapy (RT) with chemotherapy (CT) Better Survival advantage Locoregional control Distant control Acute toxicity Dyspepsia Nephrotoxicity Neutropenia Late toxicity Xerostomia Hearing impairment Subcutaneous fibrosis Balanced cumulative dose? Beneficial group? Al-Sarraf, M., et al. (1998). J Clin Oncol 16(4): 1310-1317. Lee, A. W., et al. (2011). Eur J Cancer 47(5): 656-666. Wang, J., et al. (2015). Transl Oncol 8(6): 456-462. Zeng, L., et al. (2014). Br J Cancer 110(1): 49-54.

Cumulative Cisplatin Dose (CCD) Head and Neck SCC NPC CCD ≥ 200mg/m2 in concurrent CT  Better survival CCD ≥ 200mg/m2 ? CCD ≥ 240mg/m2 ? CCD ≥ 300mg/m2 ? No difference?  Still controversial in NPC!!! Heterogeneous RT modalities without focused group. Al-Mamgani, A., et al. (2017). Eur Arch Otorhinolaryngol 274(10): 3757-3765. Ou, X., et al. (2017). J Cancer 8(14): 2836-2845. Peng, H., et al. (2016). Sci Rep 6: 24332.

Materials and Methods

Inclusion and Exclusion Criteria 161 patients NPC undergoing primary IMRT with concurrent CT and/or adjuvant chemotherapy (AC) From February 2006 to September 2015 Exclusion Prior RT or CT Aborting the RT Without complete dosage records of CT With concurrent or adjuvant regimens injected other than cisplatin

Parameter and Outcome Distant-metastasis free survival (DMFS) Disease-specific survival (DSS) Overall survival (OS) CCD during CCRT Clinical T and N staging according to AJCC 7th edition

Results

Table 1 Patient characteristics   Treatment Modalities Variable All Cisplatin dose <200 Cisplatin dose ≧200 P Age 49.21±10.98 49.64±9.76 0.794 Male gender (%) 116(72.0) 56(65.1) 60(80.0) 0.036 Smoking (%)  52(32.3)  23(26.7) 29(38.7)  0.107 CCIS (%) ≧1 30(18.6) 16(18.6) 14(18.7) 0.992 NUC type 143(88.8) 74(86.0) 69(92.0) 0.232 T stage (%) 0.527 T1 43(26.7) 24(27.9) 19(25.3) T2 21(13.0) 10(11.6) 11(14.7) T3 67(41.6) 39(45.3) 28(37.3) T4 13(15.1) 17(22.7) N stage (%) 0.032 N0 8(5.0) 5(5.8) 3(4.0) N1 19(11.8) 11(12.8) 8(10.7) N2 113(70.2) 65(75.6) 48(64.0) N3 16(21.3) Stage 4 (%) 48(29.8) 19(22.1) 29(38.7) 0.022 Adjuvant CT 54(33.5)   21(24.4)  33(44.0) 0.009 RT duration 7.10±0.77 7.07±0.84 0.765 Hemoglobin 13.95±1.83 14.09±1.31 0.570

Table 2　Univariate analyses of risk factors for 3-year LRFS, DMFS, DSS, and OS rates Variable DMFS (%) p DSS (%) OS (%) Age (y) <50  92.2 0.428 0.098  87.7 0.151 Male gender 93.5 0.036 89.6 0.213 83.4 0.917 Smoking 91.7 0.662 87.4 0.913 83.9 0.940 CCIS ≧1 96.2 0.229 92.1 0.358 89.7 0.389 T3/4 94.5 0.035 0.249 84.7 0.659 N3 63.2 <0.001 0.006 AJCC Stage 4  79.6 0.004 74.9 0.002 72.0 0.018 CCD ≧200 91.3 0.639 85.7 0.590 81.4 0.557 Adjuvant CT 0.560 89.9 0.461 85.9 0.506

Table 3　Multivariate analysis for 3-year DMFS, DSS and OS for all patients   DMFS DSS OS Variable Comparison p HR (95% CI) Sex Female vs. Male 0.043 2.898 (1.034-8.121) T stage T3/T4 vs. T1/T2 0.080 0.385 (0.132-1.122) N stage N3 vs. N0/N1/N2 <0.001 11.555 (3.693-36.156) 0.001 4.78 (1.881-12.151) 0.009 3.195 (1.333-7.659) CCD ≧200 vs. <200 Adjuvant CT Yes vs. No 0.067 0.285 (0.074-1.093)

Table 4　Univariate analyses of concurrent cisplatin dose on N3 patients (n=21) for 3-year LRFS, DMFS, DSS, and OS rates Variable DMFS (%) p (one-tailed) DSS (%) OS (%) CCD   0.101 0.06 <200 40.0 ≧200 71.4 CCD<200 n=5; CCD>=200 n=16 柱狀圖

Discussion

Advantaged Cut-off Value of CCD Total group CCD ≥ 200mg/m2 NOT beneficial N3 group CCD ≥ 200mg/m2 MIGHT BE beneficial Low case number

Potential Survival Benefit in N3 group CCD ≥ 200 mg/m2  Lower OS, DSS, and DMFS in N3 group Corelated results with previous studies IC + CCRT in advanced NPC  better OS, DSS, and DMFS CCRT + AC in advanced NPC  better OS, PFS, LRFS IC: stage T1-4/N2-3/ M0 AC: stage III–IVB (except T3-4N0) Sun, Y., et al. (2016). Lancet Oncol 17(11): 1509-1520. Lee, A. W. M., et al. (2017). Cancer 123(21): 4147-4157.

Effect of IMRT Heterogeneous RT modalities in previous studies IMRT  better survival than 2D-RT IMRT with concurrent CT  reduced DMFS Peng  LRFS Zhang, B., et al. (2015). Oral Oncol 51(11): 1041-1046. Peng, G., et al. (2012). Radiother Oncol 104(3): 286-293.

Conclusion N3 status Lower OS, DSS, and DMFS CCD ≥ 200 mg/m2  Survival benefit? NO statistical significance in total group BETTER survival outcomes in patients staged N3 Higher CCD May be exclusively applied on N3 disease Avoid rigorous toxicity Conclusion

Thank you for your attention !