This study aims to evaluate the efficacy of chemoradiotherapy for advanced cervical cancer using heat shock protein 70 (HSP70) combined with multimodal MRI. The protein expressions of HSP70 in biopsy specimens obtained from 101 patients with cervical cancer were detected by immunohistochemistry. Plain MRI scan, DWI, DCE-MR, and MRS were performed before and after a period of 6 months of chemoradiotherapy. All patients were assigned into the complete response (CR) and partial response (PR) groups. HSP70 protein expression, tumor diameter, and tumor volume were lower in the CR group than in the PR group. The rate of tumor shrinkage, relative positive enhancement integral (rPEI), relative maximum slope of decrease (rMSD), relative signal enhancement ratio at 60 s (rSER ) and maximum SER (rSER ), mean apparent diffusion coefficient (ADC ) and minimum ADC value (ADC ) values in the CR group were higher than those in the PR group. Tumor diameter and volume, rSER and rSER were reduced after chemoradiotherapy, while rMSD, rSER , time to peak (TTP), ADC and ADC were higher after the treatment. The receiver operating characteristic (ROC) curves indicated that HSP70 expression, tumor diameter, rPEI, ADC and Cho peak showed the better chemoradiotherapy efficacy. Our data demonstrates that HSP70 protein combined with multimodal MRI may accurately evaluate the chemoradiotherapy efficacy of patients with advanced cervical cancer. The recurrence of cervical cancer significantly decreased in patients with negative expression of HSP70 and HSP70 protein detection provides potential therapy for the prevention, diagnosis, and prognosis of cervical cancer.
The phosphorylation of EGFR Thr654 is required for nuclear EGFR importing, and our previous study has shown that pEGFR Thr654 is an independent prognostic factor for the low survival rate of patients with cervical squamous carcinoma. Now, we aim to examine the role of pEGFR Thr654 in the activation of DNA-PK and radio resistance. Either CaSki or HeLa cells were exposed to a dose of 4 Gy with a 6 MV Xray in the presence or absence of Cetuximab or Gefitinib, then EGFR, pEGFR Thr654 , DNA-PKcs and pDNA-PK Thr2609 levels were determined using a western blot. DNA damage was quantified with gH2AX foci analysis and the response of CaSki and HeLa cells to irradiation was determined using a colony formation assay. In CaSki and HeLa cells, irradiation induced nuclear EGFR accumulation, and pEGFR Thr654 and pDNA-PK Thr2609 levels were both significantly increased. Cetuximab pre-treatment significantly reduced the expression of pEGFR Thr654 and pDNA-PK Thr2609 and enhanced the gH2AX foci per cell and sensitivity enhancement ratio in CaSki cells. Gefitinib pre-treatment had a similar but weaker effect. In HeLa cells, similar effects of Cetuximab and Gefitinib on pEGFR Thr654 and pDNA-PK Thr2609 were observed, and no significant difference was found. We found that Cetuximab had a better effect than Gefitinib on attenuating the radio resistance in cervical squamous carcinoma cells via inhibiting pEGFR Thr654 -mediated nuclear EGFR transport and related DNA-PK T2609 -mediated DNA repair. However, in adenocarcinoma cells, both EGFR-targeted drugs had no remarkable effects on the radio sensitivity.Taken together, radiotherapy combined with Cetuximab may be a promising strategy to improve the therapeutic gain for cervical squamous carcinoma patients.
8085 Background: Historically, tumor response has been the primary endpoint in phase II (P2) trials in ED-SCLC. We investigated the suitability of alternate PFS based endpoints to predict OS as early evidence of efficacy in the P2 setting. Methods: Individual patient (pt) data from 942 pts from 11 previously untreated ED-SCLC P2 and phase III (P3) platinum- or paclitaxel-based treatment trials were pooled. Best response (BR), response confirmed (RC), objective status at 16 weeks (RR16), and PFS rate at 5 and 6 months were considered. Percent agreement (PA) and kappa (k) for PFS5, PFS6, BR, RC, and RR16 with OS at 12 months (OS12) was calculated on a per-pt basis and predictive utility was assessed using the area under the receiver operating characteristic (A- ROC) curve in logistic models. Cox models were used to assess the prognostic impact of the endpoints on subsequent survival, using landmark analysis. Results: The median OS and PFS were 9.6 m and 5.5 m, respectively. PFS5 and PFS6 had the highest PA, k, and A-ROC values, and were predictive of subsequent survival in the landmark analysis (p <0.0001; c-statistics ≥ 0.60). While RR16 and BR were significantly associated with subsequent survival (p<0.0001, c-statistics of 0.61 and 0.57, respectively) the PA, k, and A-ROC values were lower. Conclusions: PFS rate at 5 and 6 months is more predictive of 12-month OS and subsequent survival than tumor response in untreated ED-SCLC. PFS based endpoints should be routinely used as primary endpoints in P2 trials within ED-SCLC. [Table: see text] No significant financial relationships to disclose.
e18022 Background: The main failure model of locally advanced nasopharyngeal carcinoma (LA-NPC) is local failure and distant metastasis. N stage is a prognostic factor for NPC. Some characteristics of lymph nodes, such as the size, number, laterality, extra-nodal neoplastic spread and central necrosis, were the high-risk factors for treatment failure. Nowadays, neoadjuvant chemotherapy followed with CCRT was recommended for LA-NPC patients. Low-dose radiotherapy (LDRT), which is < 100cGy, induces enhanced cell killing in vitro and in vivo by the hyper-radiation sensitivity phenomenon and potentiates effects of chemotherapy. Few studies reported about it. Recently, a single arm study showed it could improve the ORR to 82% for head and neck squamous carcinoma when combined with neoadjuvant chemotherapy. So, we aimed to investigate the efficacy of LDRT combined with neoadjuvant chemotherapy for high-risk LANPC. Methods: Squamous III-IVA NPC patients (UICC/AJCC 8th) with high-risk factors of lymph nodes were prospectively enrolled in the study. The high-risk factors should include one of these followings: lymph node with central necrosis, extranodal neoplastic spread, contrast-enhancing rim or the shortest diameter of lymph nodes ≥3cm. 3 cycles of neoadjuvant chemotherapy were given, the regimen was docetaxel (75mg/m2 D1) and cisplatin (75mg/m2 D1). LDRT was delivered as 50cGy per fraction twice a day for gross nodal disease on D1 and D2 of neoadjuvant chemotherapy. All the patients received MRI scan before and after the neoadjuvant chemotherapy. Propensity score matching was used to select the patients as control group. RECIST criteria was used to evaluate the ORR. Results: From Jun 2020 to Jan 2021, a total of 27 patients were enrolled in the study. Another 27 patients were matched for control group. For the whole patients, the median age were 43 years. III and IVA Clinical stage were 25.9%, 74.1% and 29.6%, 70.4% respectively for LDRT and control group (p = 0.761). As for the lymph nodes, the ORR of LDRT group was significantly higher than control group (100% vs 85.2%, p = 0.038). The average regression rate of lymph nodes was 89.4% in LDRT group, CR and PR was 7.4% and 92.6%. However, the average regression rate of it was only 56.24% in control group. There was no CR, PR and SD were 88.9% and 11.1%. For the primary tumor, there was no significant difference. But we found the ORR of it was higher in LDRT group (96.3% vs 81.5%, p = 0.083). And the average regression rate was 57.5% and 38.3% respectively in LDRT and control group. Conclusions: LDRT combined with neoadjuvant chemotherapy could improve the ORR for primary tumor and lymph nodes in high-risk LANPC patients, especially for lymph nodes. This new treatment model could be a promising strategy to improve LC, and needed to be confirmed in the future practice.
e17011 Background: The commonly used treatment for cervical cancer is radiotherapy. However, the resistance to irradiation and metastasis at the advanced stage is a common reason for the poor prognosis and high mortality. This study was designed to elucidate the role of epidermal growth factor receptor (EGFR) nuclear translocation in radioresistance, and its correlation with DNA damage repair pathway in the cervical cancer cells. Methods: The dynamic expression of EGFR, DNA-dependent protein kinase (DNA-PK), PDK-1, PKN1 and their phosphorylation level in irradiated cervical cancer cell line CaSki at 0 10 20 40 minutes was determined by western blotting. Besides, nuclear localization signal (NLS) peptide inhibitor and control peptides was synthesized and treated cells before irradiation to elucidate the correlation between EGFR nuclear translocation and DNA damage repair after irradiation. Results: Expression of EGFR, protein kinase N1 (PKN1), and DNA-PK in nucleus was increased after irradiation in CaSki cells. Irradiation also enhanced the phosphorylation level of EGFR at Thr654, PKN1 at T774 and DNA-PK at T2609. Inhibition of EGFR nuclear translocation by NLS peptide decreased the expression level of EGFR and DNA-PK in the nucleus, and attenuated their phosphorylation process. Conclusions: EGFR nuclear translocation riggered by irradiation promoted DNA damage repair in irradiated cervical cancer cells. This work facilitated us to understand the possible molecular mechanism of the resistance to irradiation in the treatment of cervical cancer, providing a potentially potent clinical method to cancer therapy.
6030 Background: Neoadjuvant is a promising chemotherapy modality for recurrent nasopharyngeal carcinoma (NPC). However, there is still controversy for locally advanced NPC. We study the survival results of locally advanced NPC treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (NACT) retrospectively, and to explore the potential beneficiaries. Methods: 147 stage III-IVa+b NPC treated with IMRT were included and divided into two groups. NACT group (76) received 2-3 cycles of neoadjuvant chemotherapy with TP or TPF, and then 2-3 cycles of platinum-based chemoradiotherapy (CCRT). CCRT group (71) received 3 cycles of platinum-based chemoradiotherapy. TNM stage, age and whole blood count before treatment were all collected. The stratified analysis was used for distinguishing the potential beneficiaries. Results: median follow-up time was 30 months. For all patients, the 3-year LRRFS, DMFS and OS in NACT and CCRT were 94.5%, 96.8%; 85.8%, 82.8% and 81.6%, 83.4% respectively ( p> 0.05). For stage III patients, the 3-year LRRFS, DMFS and OS were 95.2%, 97.3%; 91.4%, 84.6% and 86.3%, 82.1% respectively ( p= 0.38, p= 0.15, p= 0.58). Though there was no statistical significance, DMFS in NACT was better than it in CCRT. However, for stage IV, the survival rate had no significant difference. The incidence of grade 3-4 bone marrow suppression was higher in NACT ( p= 0.007), and the other toxicities were similar. Univariate analysis showed the percentages of neutrophil and neutrophil-to-lymphocyte ratio (NLR) were significantly correlated with OS ( p= 0.031, p= 0.049). N and clinical stage were the adverse prognostic factors for OS ( p= 0.025, p= 0.007) and DMFS ( p= 0.018, p= 0.001). Clinical stage was the prognostic factors for OS and DMFS in multivariate analyses ( p= 0.019, p= 0.01). Conclusions: NACT had a comparable survival results and tolerable toxicity with CCRT for locally advanced NPC. Stage III might be the potential beneficiaries from NACT, especially for DMFS. Percentages of neutrophil and NLR might be the new adverse prognostic factor for OS. Clinical stage was still the prognostic factor for OS and DMFS.
Purpose/Objective(s): DW-MRI becomes more and more important, recent study find it help to discriminate the metastatic lymph node and distinguish recurrent tumor. However, we still poorly understand the dynamic changes of it during treatment, especially for 3D-apparent diffusion coefficient (ADC). It is urgent to observe the dynamic changes of 3D-ADC for head and neck cancer during radiotherapy, and to investigate the correlation between the changes of ADC, radiation dose and volume reduction. Materials/Methods: Sixty patients with head and neck cancer treated with image-guided IMRT were enrolled. DW-MRI were performed on 3.0T MRI scanner (b Z 0, 500, 800 s/mm 2 ) at pre-radiation, the 15th, the 25th and post-radiation. Region of interest was the primary tumor (GTV-T) and cervical lymph nodes (GTV-N). The volumes and the maximum, mean and minimum of 3D-ADC value were automatically measured by MIM software. Pearson analysis was used to assess the correlation between 3D-ADC values, delivered radiation dose and tumor volume reduction. Results: All the patients exhibited the mean 3D-ADC increase in GTV-T (0.64AE0.24 x10 -3 mm 2 /s) and GTV-N (0.35AE0.09 x10 -3 mm 2 /s), with the mean increased ratios of 0.50AE0.20 and 0.44AE0.08 between pre-and postradiation. The mean 3D-ADC for GTV-T and GTV-N both changed mostly at the 25 th radiation. However, the changes of the maximum and minimum 3D-ADC values for GTV-T and GTV-N had no correlation with delivered dose and volume reduction. The maximum, mean, and minimum 3D-ADC changes in spinal cord were almost invisible ( 0.04 x10 -3 mm 2 /s). The increased mean ADC had a strong positive correlation with the increased radiation delivered dose for GTV-T and GTV-N respectively (r Z 0.977, P Z 0.023; r Z 0.974, P Z 0.026), and a significantly negative correlation with the volume reduction (r Z -0.989,P Z 0.011; r Z -0.969, P Z 0.031). Conclusion: The mean 3D-ADC value of primary tumor and cervical lymph node can be increased greatly for head and neck cancer during radiotherapy. It had a strong negative correlation with the volume reduction, and a positive correlation with the increased delivered dose. Dynamic 3D-ADC changes during radiotherapy might be an early indicator to assess the treatment response and helps to make treatment strategy for head and neck cancer.
e23029 Background: With the aging society was coming, more elderly nasopharyngeal carcinoma NPC patients should be pay attention. However, no guideline is proposed for them due to lack of prospective clinical trials. We aimed to use propensity score matching method to evaluate the survival outcome and toxicity of the different treatment modalities for them. Methods: II-IV(UICC 8th) elderly NPC patients (≥65 years) were retrospectively enrolled between 2004 to 2016 in our center. All the patients received definitive IMRT, and were allocated into radiotherapy only (RT), concurrent chemoradiotherapy (CCRT) and neoadjuvant chemotherapy followed with CCRT (NACT). Cisplatin-based chemotherapy was used. Survival outcomes and toxicity were analyzed using propensity score-matching method. Results: There were 142 patients included, and the median age was 68 years. The median follow-up time was 47 months. 23 patients received RT only, 61 patients received CCRT and 58 patients received NACT. After matching for gender, age, T and N stage, chemotherapy and non-chemotherapy patients (22 pairs) were analyzed and shown the chemotherapy group had a better OS (86% vs 68%, p= 0.031). The 3-years LRFS, DMFS and DFS of chemotherapy and non-chemotherapy was 95% and 85% ( p= 0.251), 95% and 86% ( p= 0.307), 86% and 73% ( p= 0.309). Furthermore, 41 pairs who underwent chemotherapy were sub-analyzed according to different modalities. CCRT group showed a comparable 3-years LRFS (100% vs 94%, p= 0.143), DMFS (87% vs 89%, p= 0.608), DFS (81% vs 84%, p= 0.892) and OS (79% vs 66%, p= 0.080) with NACT. For acute toxicity, the incidence of G3-5 bone marrow suppression in non-chemotherapy was significantly lower than chemotherapy group (8.7% vs 36.4%, p= 0.31), and the incidence of G3-5 mucositis was similar ( p= 0.517). Besides that, there was no significant difference in the incidence of G3-5 bone marrow suppression and mucositis between CCRT and NACT group ( p= 0.824, p= 0.618). Conclusions: Chemoradiotherapy could improve the survival rate of the elderly NPC patients compared with radiotherapy only. The acute toxicity of CCRT and NACT was similar and acceptable. CCRT was still the standard treatment modality for them. As for the elderly NPC patients who are in good performance status and comorbidity conditions, NACT might be also worthy of recommendation.
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