ESTRO 2021 Abstract Book
The randomized DAHANCA 5 trial demonstrated the benefit of the hypoxic cell sensitizer nimorazole (NIM) in Head & Neck Squamous Cell Carcinoma (HNSCC) treated with conventional fractionated radiotherapy alone. Subsequently a hypoxic gene signature indicated which patients (pts) with hypoxic tumors may benefit from NIM. The objectives of the present trial were to demonstrate the benefit of NIM with accelerated concomitant chemo-radiotherapy (CRT), and the predictive value of the hypoxic gene signature. Materials and Methods Pts with stage III-IV laryngeal, hypopharyngeal or p16-negative oropharyngeal SCC were randomized between NIM and placebo, given concomitantly with CRT. Pts were stratified using the hypoxic gene signature. Quality controlled accelerated radiotherapy was delivered using IMRT up to a total dose of 70 Gy in 6 weeks. Cisplatin (CDDP) was delivered either weekly (40 mg/m 2 on week 1 to 6) or 3-weekly (100 mg/ m 2 on weeks 1 & 4). NIM or placebo were delivered orally with a daily dose of 1.2 mg/m 2 . The 2 co-primary endpoints were the locoregional control rate 1) for the entire population and 2) for the hypoxic-gene-positive pts. Secondary endpoints included overall survival, disease-free survival, disease-specific survival, and acute and late morbidity. Results After two safety reviews, IDMC recommended to only use the weekly CDDP regimen based on the nephrotoxicity of the 3-weekly regimen. At last review, IDMC recommended the early closure of the trial based on the weak conditional power for the hypothesized treatment effect. Thus 194 pts (92 oro, 59 hypo and 43 lar) were randomized out of the 640 originally planned. The majority of pts had T3-T4 (76%) and N2-3 (66%) tumors. Thirty-three % of tumors were hypoxic-gene positive. One hundred and two pts were treated with weekly CDDP (60 with NIM and 62 with placebo), and 72 pts with 3-weekly CDDP (37 with NIM and 35 with placebo). Using the 3-weekly CDDP, 90% of pts developed ≥ grade 3 adverse events (AE) with more nephrotoxicity in the NIM arm (27% compared to 11.4%), and 2 pts had grade 5 AE, 1 with NIM and 1 with placebo. In the weekly CDDP, 94% of pts developed ≥ grade 3 AE, and 7 had grade 5 AE, 3 with NIM and 4 with placebo. A possible relationship to NIM was only described in 1 pt. At 2 years, the locoregional control probability was not clinically different between the 2 arms neither in the entire population (63.8% for NIM and 72.1% for placebo), nor in the hypoxic-gene positive pts. No clinical difference was observed according to the CDDP regimen. For the secondary endpoints, no clinical difference was either observed between the 2 arms. Conclusion The low precision of the estimates precludes any firm conclusion on the effect of NIM versus placebo. However, the data does not show any beneficial effect of NIM in the full pts population, or in the sub-group with hypoxic gene signature. Prohibitive toxicity was observed with the 100 mg/m 2 CDDP regimen. OC-0279 Hypoxic gene expression is a prognostic factor for survival in locally advanced SCC cervical cancer J. Alsner 1 , J. Overgaard 2 , T. Tramm 3 , J.C. Lindegaard 4 1 Aarhus University Hospital, Experimental Clinical Oncology, Aarhus, Denmark; 2 Aarhus Universiy Hospital, Experimental Clinical Oncology, Aarhus, Denmark; 3 Aarhus University Hospital, Department of Pathology, Aarhus, Denmark; 4 Aarhus University Hospital, Department of Oncology, Aarhus, Denmark Purpose or Objective Loco-regional control in locally advanced cervical cancer (LACC) has improved considerably following employment of chemoradiation (CRT) and image guided adaptive brachytherapy (BT). As systemic relapse now is the dominant problem, adjuvant therapy is currently being investigated for high-risk patients. The aim of the present study was to investigate if hypoxia measured by gene expression could be of prognostic value in this context. Materials and Methods Paraffin embedded biopsies were obtained from 230/334 consecutive patients with LACC treated 2005-2016 with CRT and BT. Analysis of hypoxia gene expression was successful in 223 of which 183 (82%) patients had squamous cell carcinoma and is included in the current analysis. Hypoxic gene classification of tumors into ’more’ or ’less’ hypoxic was based on expression levels of 15 hypoxia induced genes and was done using the same method¹ as currently used to classify head and neck cancer patients in an ongoing prospective clinical trial (NCT02661152). HPV was genotyped using INNO-LiPA. The FIGO2009 stage distribution among the 183 patients was IB-IIA 9%, IIB 64% and III-IVA 27%. Local tumour burden was evaluated by the T-score² with a mean of 7.2 and a patient distribution of 41/57/43/42 for T- scores 0-4/5-6/7-9/≥10, respectively. Pathological pelvic nodes (N1) were found in 73 (40%) and para-aortic nodes (N2) in 24 (13%) patients. All patients received pelvic external beam radiotherapy of 45-50 Gy/25-30 fx including also the para-aortic region in 39 (21%). Concomitant weekly cisplatin was given to 142 (78%). All patients were treated with BT with mean CTV HR volume of 35 cm³ and a D90 of 92 Gy EQD2 . Endpoint was disease free survival (DFS) calculated from start of CRT. Events were death of any cause, persistent disease or recurrence. DFS was analysed by Kaplan-Meier and Cox regression. Results Median observation time was 4 years. Local control was obtained in 176/183 (96%) and pelvic control (local and nodal) in 166/183 (91%) patients. In total, 65/183 patients (36%) were classified as ’more’ hypoxic. There was a significant increase in the hypoxic ratio as a function of local tumour burden increasing from 32% for T- score <5 to 55% for T-score ≥10 (p<0.011). Hypoxic gene classification was significantly associated with decreased DFS with a hazard ratio of 2.00 (95% CI: 1.29-3.11) (Figure 1). In multivariate analysis including HPV 16/18, age, T-score, N-stage, and concomitant chemotherapy, hypoxia status remained a significant prognostic factor (Table 1). HPV 16/18 was found in 128/183 (70%) and was associated with improved DFS in univariate but not in multivariate analysis.
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