Outcomes of induction chemotherapy and concurrent chemoradiation for nasopharyngeal carcinoma D.W. Golden 1 , M.E. Witt 1 , S. Rudra 1 , T. Nwizu 2 , E.E.W. Cohen 2,3 , E. Blair 3,4 , K.M. Stenson 3,4 , E.E. Vokes 1,2,3 , D.J. Haraf 1,3 1 Department of Radiation and Cellular Oncology, 2 Department of Medicine, Section of Hematology/Oncology, 3 Comprehensive Cancer Center, 4 Department of Surgery, Section of Otolaryngology/Head and Neck Surgery, University of Chicago, Chicago, Illinois PURPOSE Current standard therapy for nasopharyngeal carcinoma (NPC) is concurrent chemoradiation (CRT) based on randomized data (1,2). However, limited randomized data exist to support the addition of induction chemotherapy (ICT). Two randomized studies have conflicting results regarding the benefit of induction chemotherapy before CRT (3,4). Here we report updated outcomes of patients with nasopharyngeal carcinoma treated at our institution with induction chemotherapy followed by CRT. Patient and treatment related parameters are evaluated in relation to outcome. MATERIALS 58 patients with NPC were treated from 1990-2010. Treatment, patient, and tumor characteristics are summarized in Table 1, 2, and 3 respectively. All patients received platinum-based ICT. All 58 patients were treated with CRT, 57 in a week-on/week-off (WOWO) fashion. Concurrent chemotherapy included hydroxyurea/5-fluorouracil for all patients. Median radiation dose was 70 Gy. No patient received adjuvant chemotherapy. CONCLUSIONS RESULTS ICT followed by concurrent CRT demonstrates excellent FFLF, FFDF, CSS, and OS with tolerable toxicity. Induction chemotherapy followed by concurrent CRT for patients with NPC should be explored further in a randomized setting. Current randomized studies are ongoing in France (GORTEC NPC2006,) Hong Kong (NCT00379262), Singapore (NCT009979906), Taiwan (NCT00201396), and China (NCT01245959). Figure 1. (a) Freedom from local failure (FFLF) and freedom from distant failure (FFDF), and (b) overall survival (OS) and cause-specific survival (CSS) in patients with nasopharyngeal carcinoma treated with induction chemotherapy followed by CRT. Figure 2. (a) Freedom from local failure (FFLF) and freedom from distant failure (FFDF), and (b) cause-specific survival (CSS) in pediatric patients with nasopharyngeal carcinoma treated with induction chemotherapy followed by concurrent CRT. Note: Overall survival is not shown because it is identical to CSS. AJCC 2009 stage was II=13, III=21, IVa=13, and IVb=11. Median follow- up for surviving patients was 66 months. Response to ICT was complete response (CR) 17% and partial response (PR) 64%. The CR rate after CRT was 96%. 5-year actuarial freedom from local failure (FFLF), freedom from distant failure (FFDF), cause-specific survival (CSS), and overall survival (OS) was 98%, 90%, 90%, and 76%, respectively (Figure 1). Analysis of pediatric patients (n=9) demonstrated 5-year actuarial FFLF, FFDF, CSS, and OS of 100%, 88%, 80%, and 80%, respectively (Figure 2). On univariate analysis of all 58 patients (Table 4), FFDF was favorably associated with T3 or less tumors and a complete response to CRT. There was a trend towards worse distant failure with AJCC Stage 4 disease. Improved CSS was favorably associated with a complete response to CRT with a trend for treatment on protocol and not currently smoking. Improved OS was favorably associated with age <45, WHO grade 3 histology (Figure 3), BID treatment, no treatment delay, complete response to induction chemotherapy, and complete response to CRT. A trend was noted for treatment off protocol. Due to the small number of events, univariate analysis for FFLF and multivariable analysis for FFDF and CSS was not attempted. On multivariable analysis including all factors significant for overall survival on univariate analysis, only a complete response to induction chemotherapy or CRT remained significant for overall survival (data not shown). During CRT the most common acute toxicities (grade ≥3) were mucositis n = 31 (54%), leukopenia n = 39 (67%), and neutropenia n = 31 (55%). Hematologic toxicity is summarized in Table 5. Placement of a gastrostomy tube during treatment was required in n = 29 (50%). Treatment delay due to toxicity or exacerbation of medical comorbidities was required in two patients. No patient required placement of a tracheostomy during or after treatment. Late toxicities included 43% xerostomia, 10% hearing loss, 7% long-term G-tube dependence, 13% dysphagia, and 9% required long-term dietary modifications (Table 6). Figure 3. Overall survival stratified by WHO histology subtype (type 1 and 2 versus type 3/lymphoepithelioma). Table 1. Treatment details (n = 58) Treatment Total treatment time days (median, range) 139 (86 – 175) Surgery Surgery on primary 0 Surgery on neck None 28 Biopsy only 24 Excision of node 6 Neck dissection 0 Chemotherapy Induction chemotherapy regimen Carboplatin/Paclitaxel 32 IFN/CDDP/5FU/leucovorin 19 Carboplatin/Taxotere 1 TPF 4 Cetuximab/Carboplatin/Paclitaxel 1 CDDP 1 Concurrent chemo regimen TFH 23 FH 25 GFH 8 Taxotere-FH 1 CFH 1 Radiation RT treatment time, days (median, range) 87 (52 – 112) RT prescribed dose, Gy (median, range) 70 (66 – 75) RT delivered dose, Gy (median, range) 70 (64 – 75) WOWO Yes 57 No 1 BID Yes 24 No 33 Converted to QD 1 IMRT Yes 38 No 20 5FU = 5-fluorouracil; CDDP = cisplatin; CFH = cetuximab, 5-fluorouracil, hydroxyurea; FH = 5-fluorouracil, hydroxyurea; GFH = gefitinib, 5-fluorouracil, hydroxyurea; IFN = interferon-α2b; TFH = paclitaxel, 5-fluorouracil, hydroxyurea; TPF = docetaxel, cisplatin, 5-fluorouracil Table 2. Patient characteristics (n = 58) Patient characteristics Age at treatment start (years; median, range) 44 (10 – 83) Pediatric (age <18) 9 BMI at treatment start, kg/m 2 (median, range) 23.8 (15.2 – 48.6) BMI at completion of therapy, kg/m 2 (median, range) 21.9 (14.5 – 37.7) BMI change kg/m 2 (median, range) -2.7 (-13.1 – 1.8) Gender Male 34 Female 24 Ethnicity White 31 Black 11 Asian 10 Hispanic 5 Other/unknown 1 Presenting symptom Neck mass 30 Congestion (nasal, sinus, ear) 18 Ear symptoms (hearing loss, pain, tinnitus, congestion) 14 Epistaxis 7 Headache 5 Cranial nerve symptom (excluding hearing loss) 3 Sore throat 2 Table 3. Tumor characteristics Histology WHO I (keratinizing SCC) 6 WHO II (nonkeratinizing SCC) 5 WHO III (lymphoepithelioma) 47 EBV status Positive 19 Negative 1 Not reported 38 T classification (AJCC 2009) T1 15 T2 22 T3 8 T4 13 N classification (AJCC 2009) N0 7 N1 19 N2 21 N3a 5 N3b 6 Stage (AJCC 2009) 1 0 2 13 3 21 4a 13 4b 11 (AJCC = American Joint Committee on Cancer; EBV = Epstein-Barr virus; SCC = squamous cell carcinoma; WHO = World Health Organization) Table 4. Univariate Analysis – reported as Log rank p value Distant Failure Cause specific survival Overall Survival Age >45 0.600 0.755 0.006 Treated on protocol 0.242 0.076 0.060 Smoker (any history) 0.188 0.268 0.107 Current smoker (current or within past month) 0.157 0.080 0.208 Tumor histology WHO 1/2 0.125 0.466 <0.001 T4 0.026 0.275 0.220 N3 0.913 0.859 0.785 Stage 4 (AJCC 2009) 0.054 0.155 0.153 Total treatment time >140 days 0.717 0.981 0.684 Concurrent chemotherapy regimen 0.956 0.946 0.433 BID 0.995 0.962 <0.001 IMRT 0.424 0.601 0.741 Treatment delay 0.850 0.894 <0.001 Response to induction chemotherapy <CR 0.263 0.287 0.047 Response to chemoradiation <CR <0.001 <0.001 <0.001 *local failure is not included due to the low number of events (BID = twice daily; BMI = body mass index; CR = complete response; IMRT = intensity modulated radiation therapy; WHO = World Health Organization) Table 5. Acute hematologic toxicity during concurrent chemoradiation (n = 58) Hematologic (CTCAE v3.0) Hemoglobin Platelets White blood Cell Absolute neutrophi l count Grade 0 0 29 0 1 Grade 1 9 20 3 10 Grade 2 45 3 12 11 Grade 3 0 1 34 21 Grade 4 0 0 5 11 Unknown 4 5 4 4 (CTCAE = common terminology criteria for adverse events) Table 6. Late toxicity (Total number of patients assessed for individual complications is variable) Complications assessed Yes 48 No 10 (>6 months after completion of therapy) a Yes No Xerostomia 13 17 Hearing loss 4 38 Gastrostomy tube 3 42 Dysphagia 6 39 Dietary modifications 3 29 Second primary malignancy 4 19 a Total number of patients assessed for each complication is variable, therefore total does not = 48. REFERENCES 1. Al-Sarraf M, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 16:1310-7, 1998 2. Wee J, et al: Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 23:6730-8, 2005 3. Fountzilas G, et al: Induction chemotherapy followed by concomitant radiotherapy and weekly cisplatin versus the same concomitant chemoradiotherapy in patients with nasopharyngeal carcinoma: a randomized phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation. Ann Oncol 23:427-35, 2012 4. Hui EP, et al: Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol 27:242-9, 2009