Cisplatin-based Radiochemotherapy Research Articles

707TiP Postoperative adjuvant radiochemotherapy (aRCH) with cisplatin versus aRCH with cisplatin and pembrolizumab in locally advanced head and neck squamous cell carcinoma: The ADRISK trial

PD-1 immune checkpoint inhibitors have been approved for treatment of head and neck squamous cell carcinoma (HNSCC) in recurrent/metastatic settings as they significantly improve patients’ overall survival (OS). The next step is to explore the efficacy of immune checkpoint inhibitors in the curative setting, especially in patients with locoregional, pathologically intermediate and high-risk HNSCC which recur frequently despite adjuvant cisplatin-based radiochemotherapy (aRCH). Based on this rationale, we have developed the ADRISK trial to investigate the addition of pembrolizumab to standard aRCH in the treatment of patients with locally advanced intermediate- and high-risk HNSCC. Given the unmet need for reducing high rates of relapse in this patient group by improved adjuvant treatment, we expect that ADRISK will provide new insights into treatment and might demonstrate the ability of pembrolizumab to improve survival. ADRISK is a prospective, multicenter, randomized controlled phase II trial within the German Interdisciplinary Study Group of German Cancer Society. Patients with primary resectable stage III and IV HNSCC of the oral cavity, oropharynx, hypopharynx and larynx with pathologic high (R1, extracapsular nodal extension) or intermediate risk (R0 <5 mm; N≥2) after surgery who are eligible for cisplatin-based aRCH after surgery will receive either standard aRCH with cisplatin versus the same treatment + pembrolizumab (200 mg iv, in 3-week cycle, max. 12 months). The objectives are to show that addition of pembrolizumab to postoperative adjuvant cisplatin-based RCH improves event-free survival and OS compared with aRCH alone in locally advanced intermediate and high-risk HNSCC. To our knowledge, this is the only multicenter, randomized trial analyzing the addition of pembrolizumab to aRCH in this patient group without prior neoadjuvant treatment. Recruitment started in August 2018 and is ongoing. Until April 2022, 163 patients were registered for the trial and 157 patients were randomized. The planned sample size is 240 patients, the recruitment is estimated to be completed by July 2024 at the latest. NCT03480672. University of Leipzig.

Radio(chemo)therapy in anaplastic thyroid cancer—high locoregional but low distant control rates—a monocentric analysis of a tertiary referral center

BackgroundAnaplastic thyroid cancer (ATC) is a lethal disease with highly aggressive disease progression. This study analyses the influence of radio(chemo)therapy, R(C)T, on disease control, survival rates and predictors for survival.Patients and methodsA total of 33 patients with ATC, treated at a tertiary referral center between May 2001 and April 2020 were included. Univariate and multivariate analysis were used to investigate correlates of R(C)T and predictors on disease control and survival rates.ResultsMedian follow-up was 4 months. In UICC stage IVA and IVB median overall survival (OS) was 8 months, median progression-free survival (PFS) was 6 months. Patients with UICC stage IVA and IVB and patients being irradiated with a radiation dose of more than 60 Gy showed increased OS. Of these patients, 3 were alive and free from disease. All of them receiving cisplatin-based radiochemotherapy and a minimum radiation dose of 66 Gy. UICC stage IVC showed a median OS of 2.5 months and a median PFS of 1 month. Only 2 of 16 patients had local failure.ConclusionDepending on UICC stage, RT with high radiation dose can lead to improved OS or at least higher locoregional control. A limiting factor is the high incidence of distant metastases; therefore modern systemic treatment options should be integrated into multimodal therapy concepts.

Pretreatment [18F]FDG PET/CT Prognostic Factors in Patients with Squamous Cell Cervical Carcinoma FIGO IIIC1.

Purpose: This study aims to determine whether semiquantitative parameters obtained from both the primary tumor and metastatic pelvic lymph nodes (PLN) diagnosed in fluoro-18-deoxy-glucose positron emission tomography (FDG-PET-CT) are associated with disease-free survival (DFS), local control (LC), distant metastasis-free survival (DMFS) and overall survival (OS) in patients with locally advanced squamous cervical cancer (LACC) and metastatic pelvic lymph nodes. Materials: Retrospective analysis was performed on 93 female patients with FIGO IIIC1. The median age was 53 years (27–75). The PET parameters both in the primary tumor and metastatic pelvic lymph nodes, including SUVmax, SUVmean, TLG, MTV, heterogeneity, along with clinical variables, before radical cisplatin-based radiochemotherapy (RCT) were analyzed. The p-values < 0.05 were considered statistically significant. Results: Median follow-up was 38 months (4.5–92.6). Three years and five years OS were 75% and 70% respectively. Patients with SUVmax above 12.6, SUVmean above 7.6 and with TLG in tumors >245.7 lived longer (p < 0.05). The higher SUVmax or SUVmean reduced increased DMFS (HR 0.3 95%CI 0.56–0.96 and 0.59 95%CI 0.37–0.93). The clinical factors and other FDG PET CT parameters were not found to be statistically relevant in terms of OS, DFS, DM and LC. Conclusions: This study is the first report showing that in LACC patient population with PLN involvement treated with definitive RCT, high SUVmean, SUVmax and TLG of the primary tumor in FDG-PET-CT were linked with longer OS. Lower SUVmean and SUVmax were linked with shorter DMFS. None of the clinical factors and the nodal FDG-PET-CT parameters influenced the outcome.

Accelerated Fractionation With Concomitant Boost vs. Conventional Radio-chemotherapy for Definitive Treatment of Locally Advanced Squamous Cell Carcinoma of the Head-and-Neck (SCCHN).

Patients with unresectable head-and-neck cancer (SCCHN) unable to tolerate radiochemotherapy may receive unconventionally fractionated radiotherapy. This retrospective study compared both treatments. Eight patients unsuitable for chemotherapy were assigned to accelerated fractionation with concomitant boost (AF-CB, 69.6 Gy/39 fractions) over 5.5 weeks (group A) and 72 patients to cisplatin-based radiochemotherapy (70 Gy/35 fractions) over 7 weeks (group B). Groups were matched (cancer site, gender, age, performance score, T-/N-stage, histologic grade) and compared for loco-regional control (LRC), metastases-free survival (MFS), overall survival (OS) and toxicities. LRC, MFS, OS and radiation-related toxicities were not significantly different between groups A and B. Improved outcomes were associated with favorable cancer site, better performance score and T3-stage. In group B, toxicity led to reduction/discontinuation of chemotherapy in 38.9% and interruptions of radiotherapy >7 days in 19.3% of patients. AF-CB appeared a reasonable alternative for patients who cannot safely receive radio-chemotherapy for unresectable SCCHN.

ERCC2 gene single-nucleotide polymorphism as a prognostic factor for locally advanced head and neck carcinomas after definitive cisplatin-based radiochemotherapy

Identifying patients with locally advanced head and neck carcinoma on high risk of recurrence after definitive concurrent radiochemotherapy is of key importance for the selection for consolidation therapy and for individualized treatment intensification. In this multicenter study we analyzed recurrence-associated single-nucleotide polymorphisms (SNPs) in DNA repair genes in tumor DNA from 132 patients with locally advanced head and neck carcinoma (LadHnSCC). Patients were treated with definitive radiotherapy and simultaneous cisplatin-based chemotherapy at six partner sites of the German Cancer Consortium (DKTK) Radiation Oncology Group from 2005 to 2011. For validation, a group of 20 patients was available. Score selection method using proportional hazard analysis and leave-one-out cross-validation were performed to identify markers associated with outcome. The SNPs rs1799793 and rs13181 were associated with survival and the same SNPs and in addition rs17655 with freedom from loco-regional relapse (ffLRR) in the trainings datasets from all patients. The homozygote major rs1799793 genotype at the ERCC2 gene was associated with better (Hazard ratio (HR): 0.418 (0.234–0.744), p = 0.003) and the homozygote minor rs13181 genotype at ERCC2 with worse survival (HR: 2.074, 95% CI (1.177–3.658), p = 0.017) in comparison to the other genotypes. At the ffLRR endpoint, rs1799793 and rs13181 had comparable prognostic value. The rs1799793 and rs13181 genotypes passed the leave-one-out cross-validation procedure and associated with survival and ffLRR in patients with LadHnSCC treated with definitive radiochemotherapy. While findings were confirmed in a small validation dataset, further validation is underway within a prospective biomarker study of the DKTK.

Connective tissue growth factor (CTGF) methylation status is associated with prognosis of patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy (RCHT): A multicenter study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).

6050 Background: CTGF plays a central role in tissue remodeling and has emerged as an attractive novel therapeutic target. We sought to investigate the impact of CTGF methylation status (CTGF-M) in predicting outcome of HNSCC patients undergoing RCHT. Methods: CTGF-M was discovered by applying Illumina 450K/850K arrays to DNA extracted from FFPE material of patients homogeneously treated with surgery followed by adjuvant cisplatin-based RCHT in frame of the DKTK-ROG multicenter retrospective trial (n = 194, training cohort). Methylation probes correlating with overall survival (OS) and progression were identified using random forest. Validation was done in 4 cohorts including DKTK-ROG definitive RCHT (n = 110) and 3 RCHT cohorts from Heidelberg, Dresden and Munich (n = 222). CTGF-M and RNAseq data from The Cancer Genome Atlas (TCGA) (n = 206) were analyzed to identify differentially expressed genes (DEG) as a function of CTGF-M. Results: Increased methylation of 2 probes (mapping to CTGF 3’UTR and gene body) was associated with significantly improved OS in the training cohort (HR = 0.51, p = 0.044) and the validation cohort (HR = 0.67, p = 0.016), in multivariate cox regressions adjusting for HPV status, age, T and N stages, location and treatment (adjuvant vs definitive RCHT). In the TCGA, probes’ methylation was significantly inversely correlated with CTGF gene expression (r = -0.18 and -0.51, p &lt; 0.05). 1843 DEGs were found at FDR &lt; 0.05 as a function of CTGF-M. Pathways mapping to tissue remodeling were significantly enriched for among downregulated genes in CTGF hypermethylated tumors. Increased CTGF methylation was inversely correlated with the mesenchymal subtype mRNA gene signature (r = -0.21, p = 0.0026) and correlated with the atypical subtype (r = 0.32, p = 0.000002). Conclusions: Implementation of CTGF-M in routine diagnostic is feasible and correlates well with CTGF gene-expression levels and activation of tissue remodeling pathways. Therefore, CTGF-M might be instructive for stratifying HNSCC patients for CTGF targeting therapies. CTGF emerges as a promising prognostic marker independently of HPV status.

Unilateral cochlea sparing in locoregionally advanced head and neck cancer: aplanning study.

Cochlea sparing can reduce late ototoxicity in head and neck cancer patients treated with cisplatin-based radiochemotherapy. In this situation, amean cochlear dose (MCD) constraint of 10 Gy has been suggested by others based on the dose-effect relationship of clinical data. We aimed to investigate whether this is feasible for primary and postoperative radiochemotherapy in locoregionally advanced tumors without compromising target coverage. Ten patients treated with definitive and ten patients treated with adjuvant intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy were investigated. The cochleae and aplanning risk volume (PRV) with a3 mm margin were newly delineated, whereas target volumes and other organs at risk were not changed. The initial plan was recalculated with aconstraint of 10 Gy (MCD) on the low-risk side. The quality of the resulting plan was evaluated using the difference in the equivalent uniform dose (EUD). Aunilateral MCD of below 10 Gy could be achieved in every patient. The mean MCD was 6.8 Gy in the adjuvant cohort and 7.6 Gy in the definitive cohort, while the non-spared side showed amean MCD of 18.7 and 30.3 Gy, respectively. The mean PRV doses were 7.8 and 8.4 Gy for the spared side and 18.5 and 29.8 Gy for the non-spared side, respectively. The mean EUD values of the initial and recalculated plans were identical. Target volume was not compromised. Unilateral cochlea sparing with anMCD of less than 10 Gy is feasible without compromising the target volume or dose coverage in locoregionally advanced head and neck cancer patients treated with IMRT. Aprospective evaluation of the clinical benefit of this approach as well as further investigation of the dose-response relationship for future treatment modification appears promising.

Prognostic significance of Ki67 expression and the derived neutrophil-lymphocyte ratio in nasopharyngeal carcinoma.

PurposeTo investigate the association of pretreatment Ki67 expression and the derived neutrophil–lymphocyte ratio (dNLR) with clinical outcomes in nasopharyngeal carcinoma (NPC).Patients and methodsFor the study, 46 patients diagnosed with NPC at our hospital were recruited between April 2013 and December 2015. All patients were histologically confirmed to have non-keratinizing undifferentiated NPC. The expression of Ki67 proteins in NPC tissue was analyzed immunohistochemically, and the dNLR was assessed in the peripheral blood, both before treatment. Stage I and II disease was treated with radiotherapy with or without concurrent chemotherapy, and stage III and IV disease was treated with cisplatin-based radiochemotherapy and neoadjuvant chemotherapy regimens.ResultsForty-five of the 46 patients met the criteria, and the median follow-up period was 41 months (15–56 months). The cutoff values for Ki67 and dNLR were 77.5% and 2.01%, respectively. The 3-year overall survival (OS) and progression-free survival rates in the high versus low Ki67 expression groups were 62.5% vs. 93.1% (P = 0.009) and 56.3% vs. 93.1% (P = 0.003), respectively. The 3-year OS rate of patients with high dNLR vs. low dNLR was 64.3% vs. 90.3% (P = 0.023). In the Cox risk ratio model, Ki67 expression and dNLR were independent prognostic factors for OS. Patients were then divided into three groups based on Ki67 expression and dNLR (high risk, both factors were high; intermediate risk, one factor was high; and low risk, neither factor was high). The 3-year OS rates were 20%, 85%, and 95% for the high, intermediate, and low risk groups, respectively (P < 0.001).ConclusionPretreatment Ki67 and dNLR levels can be used as independent prognostic markers in NPC, and elevated values are associated with poor prognosis. Concurrently, high Ki67 expression and dNLR predict a significantly adverse outcome.

Addition of bevacizumab to systemic therapy for locally advanced and metastatic nasopharyngeal carcinoma.

Radiotherapy is a vital treatment option for patients with nasopharyngeal carcinoma (NPC). Concurrent cisplatin-based radiochemotherapy with or without adjuvant chemotherapy had acquired good clinical effects with good local control rates. However, a number of patients present with metastasis following systemic regimens or initial diagnosis of locally advanced NPC, which cause difficulty for subsequent therapy. Therefore, there is an urgent requirement to discover novel targeted therapies. The present report describes one case of a patient with NPC and multiple metastases. The patient was treated with systemic therapy in combination with bevacizumab, palliative radiotherapy and chemotherapy following treatment with cetuximab and concurrent chemoradiotherapy in 2015. Following the addition of bevacizumab, metastases were reduced or disappeared after >2 months, and the duration of progression-free survival was 7 months. Bevacizumab is a monoclonal antibody that targets VEGF, and it is associated with angiogenesis, which causes the growth, invasion and progression of tumors. In previous studies, bevacizumab has been approved for the treatment of several types of malignant cancer and it has been able to effectively improve prognosis. In the present review, the effect of adding bevacizumab to systemic therapy for the treatment of NPC was analyzed, with a particular focus on advanced and metastatic diseases. A growing number of phase I/II clinical trials involving bevacizumab for NPC have been conducted with clinical outcomes showing improved rates of overall survival and progression-free survival as well as improvements in the quality of life of patients. However, severe or deadly toxicities can also result from combination treatment with bevacizumab. In the future, bevacizumab may become a common addition to systemic therapy for the treatment of locally advanced and metastatic NPC.

Radiochemotherapy for locally advanced squamous cell carcinoma ofthe head and neck: Higher-dose cisplatin every 3 weeks versus cisplatin/5-fluorouracil every 4 weeks.

Many patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) receive cisplatin-based radiochemotherapy. The optimal regimen is still unclear when considering both efficacy and feasibility. This study compared two regimens for locoregional control (LRC), overall survival (OS), and adverse events. Data of 329 patients with LASCCHN receiving definitive or postoperative radiochemotherapy were retrospectively analyzed. A total of 131 patients received 100mg/m(2) cisplatin on days 1, 22, and 43 (group A), and 198 patients received 20mg/m(2) cisplatin plus 600/1000mg/m(2) 5-FU on days 1-5 and days 29-33 (group B). Radiochemotherapy regimens plus nine factors were compared for LRC and OS, and radiochemotherapy regimens additionally for adverse events. On univariate analysis, chemotherapy type was not associated with LRC (p=0.36). On multivariate analysis, performance score (p=0.039), N-category (p=0.007), histologic grade (p=0.007), upfront surgery (p=0.030), and pre-radiochemotherapy hemoglobin levels (p<0.001) were associated with LRC. On univariate analysis, chemotherapy type had no impact on OS (p=0.64). On multivariate analysis, performance score (p<0.001), T-category (p=0.025), N-category (p<0.001), histologic grade, and hemoglobin levels (p<0.001) were associated with OS. Renal failure occurred significantly more often in group A (p=0.008). Otherwise, adverse events were not significantly different. Thus, both radiochemotherapy regimens appeared similarly effective for LASCCHN. Patients receiving 100mg/m(2) of cisplatin require close monitoring of their renal function.

Low Cancer Stem Cell Marker Expression and Low Hypoxia Identify Good Prognosis Subgroups in HPV(-) HNSCC after Postoperative Radiochemotherapy: A Multicenter Study of the DKTK-ROG.

To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Expression of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint was locoregional tumor control. Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15-gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA-negative but not with HPV16 DNA-positive tumors the effect of hypoxia-induced genes on locoregional control was apparent (15-gene signature: HR 4.54, P = 0.006; 26-gene signature: HR 10.27, P = 0.024). Furthermore, MET, SLC3A2, CD44, and CD44 protein showed an association with locoregional tumor control in multivariate analyses (MET: HR 3.71, P = 0.016; SLC3A2: HR 8.54, P = 0.037; CD44: HR 3.36, P = 0.054; CD44 protein n/a because of no event in the CD44-negative group) in the HPV16 DNA-negative subgroup. We have shown for the first time that high hypoxia-induced gene expression and high CSC marker expression levels correlate with tumor recurrence after PORT-C in patients with HPV16 DNA-negative HNSCC. After validation in a currently ongoing prospective trial, these parameters may help to further stratify patients for individualized treatment de-escalation or intensification strategies. Clin Cancer Res; 22(11); 2639-49. ©2016 AACR.

HPV16 DNA status is a strong prognosticator of loco-regional control after postoperative radiochemotherapy of locally advanced oropharyngeal carcinoma: Results from a multicentre explorative study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG)

ObjectiveTo investigate the impact of HPV status in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received surgery and cisplatin-based postoperative radiochemotherapy. Materials and methodsFor 221 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity treated at the 8 partner sites of the German Cancer Consortium, the impact of HPV DNA, p16 overexpression and p53 expression on outcome were retrospectively analysed. The primary endpoint was loco-regional tumour control; secondary endpoints were distant metastases and overall survival. ResultsIn the total patient population, univariate analyses revealed a significant impact of HPV16 DNA positivity, p16 overexpression, p53 positivity and tumour site on loco-regional tumour control. Multivariate analysis stratified for tumour site showed that positive HPV 16 DNA status correlated with loco-regional tumour control in patients with oropharyngeal carcinoma (p=0.02) but not in the oral cavity carcinoma group. Multivariate evaluation of the secondary endpoints in the total population revealed a significant association of HPV16 DNA positivity with overall survival (p<0.01) but not with distant metastases. ConclusionsHPV16 DNA status appears to be a strong prognosticator of loco-regional tumour control after postoperative cisplatin-based radiochemotherapy of locally advanced oropharyngeal carcinoma and is now being explored in a prospective validation trial.

Epidermal growth factor receptor targeting and its role for individualisation in radiation oncology

*Dept. of Radiation Oncology and OncoRay National Center for Radiation Research in Oncology,Medical Faculty and University Hospital C.G. Carus, Technische Universita¨t, Dresden, GermanyGerman Cancer Consortium (DKTK), Dresden, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyHelmholtz Center Dresden-Rossendorf, GermanyBecause of its over-expression in many human tumoursand its association with a poor prognosis, the epidermalgrowth factor receptor (EGFR) is used as a therapeutic targetin clinical routine and in clinical trials. Two major classes ofinhibitors are used: anti-EGFR antibodies and EGFR tyrosinekinase inhibitors (TKIs). On simultaneous application of theanti-EGFR antibody cetuximab with radiotherapy in headand neck squamous-cell carcinoma (HNSCC) patients, animprovement in locoregional tumour control and survivalhas been shown as compared with radiotherapy alone, lead-ing to the approval of this drug as the first molecular targetedagent in a curative radio-oncological setting. However, so farthere is no hint of a superiority of this combination oversimultaneous cisplatin-based radiochemotherapy; thus, bothtreatments are used today as alternative schedules.While it is evident from preclinical as well as from clinicaldata that a major heterogeneity exists among the responsesof individual patients to the combined treatment, apart fromskin reactions under cetuximab treatment, there is so far novalidated biomarker predicting response to cetuximab-basedcombined treatment, nor to cisplatin-based radiochemother-apy. Establishing predictive biomarkers would highly increaseefficacy of the treatment due to the positive selection of pa-tients. Some conclusions can currently be drawn from trans-lationally oriented studies: at least for HNSCCs (others havenot been well investigated), cetuximab application duringradiotherapy improves locoregional tumour control in manybut not all individual tumours, with individually impressiveresponses. For EGFR–TKI all local tumour control studies havebeen negative so far, whereas palliative effects have beenshown in most HNSCCs. A promising candidate biomarkerfor the effect of combined radiotherapy and cetuximab inHNSCC is genetic EGFR over-expression measured by the fluo-rescence in situ hybridization (FISH) test. This marker has tobe further validated in clinical settings, aswell as for other tu-mour entities or combination schedules. Because of interac-tions between the treatment modalities, such biomarkerscan be different between single-modality and combined-modality treatments.

Role of serum concentration of VEGFR1 and TIMP2 on clinical outcome in primary cervical cancer: Results of a companion protocol of the randomized, NOGGO–AGO phase III adjuvant trial of simultaneous cisplatin-based radiochemotherapy vs. carboplatin and paclitaxel containing sequential radiotherapy

ObjectiveAim of the present study was to analyze the expression-profile of IGF1, IGFBP3, sICAM1, sVCAM1, MMP2, MMP9, TIMP2, VEGFA, VEGFD, VEGFC and VEGFR1 in patients with high-risk FIGO-stage Ib-IIb cervical cancer. MethodsSerum from 68 cervical cancer patients treated within a phase-III-trial with either simultaneous cisplatin radiochemotherapy or sequential systemic carboplatin and paclitaxel followed by percutaneous irradiation was analyzed by ELISA. Both target expression and correlation with important clinicopathological factors were analyzed following standard statistic procedures. ResultsAll 68 patients underwent a primary radical hysterectomy with pelvic and/or paraaortic lymphadenectomy. 85.3% of the extirpated tumors had clear surgical margins (R0). Increased levels of VEGFR1, TIMP2 and MMP2 were significantly associated with positive surgical margins (p=0.004, p=0.018 and p=0.004, respectively). High concentration of MMP2 and TIMP2 correlated additionally with an advanced age at time of diagnosis (p=0.001 and p=0.007, respectively). For the cut-off value of 100pg/ml, an increased VEGFR1 was significantly associated with poor overall (OS) and progression-free (PFS) survival (p=0.017 and p=0.015, respectively). A TIMP2 concentration of lower than 90ng/ml was significantly associated with poorer OS and PFS (p=0.009 and p=0.043, respectively). In the multivariate analysis, TIMP2 expression in serum was the only independent prognostic factor for OS (p=0.032, HR=6.51, 95% CI=1.17–36.01). ConclusionsExpression-profile of specific biomarkers associated with tumor invasion, cell migration and angiogenesis seems to be of prognostic value for both OS and PFS in patients undergoing surgery due to primary cervical cancer. Further analyses are warranted to allow an implementation of such markers into clinical practice.

Current strategies in radiotherapy of head and neck cancer.

The Intensity Modulated Radiation Therapy (IMRT) together with Image Guided Radiation Therapy (IGRT) improves radiation therapy for head and neck cancer. On the one hand tumors can be better covered with radiation dose and on the other hand normal tissue can be better preserved. Carefully applied this leads to the same tumor control rate with reduced toxicity compared with conventional radiation therapy. Respective to the addition of systemic therapy to irradiation therapy, platinum based radiochemotherapy remains the standard of care and there are first indications, that at least in the primary treatment of head and neck cancer the addition of Cetuximab to a cisplatin-based radiochemotherapy did not improve outcome.

Abstract 3621: Polymorphisms in genes related to DNA repair and to apoptosis: Link with the outcome after radiochemotherapy in head and neck cancer patients

Abstract Background For patients with locally-advanced head and neck cancer (LAHNC), treatment with irradiation (RT), associated or not with chemotherapy (CT), remains a valuable alternative to surgery and is currently being actively investigated. Identification of individual factors able to discriminate good candidates for radiochemotherapy (RCT) would allow optimal handling of RCT (doses, associated drugs). We examined whether functional single nucleotide polymorphisms (SNPs) in genes related to DNA repair and to apoptosis could be related to the outcome of patients with LAHNC treated with RCT. Methods A homogeneous group of 90 patients with LAHNC were treated by either RT (29%) or cisplatin-based RCT (71%). For all study patients, we used DNA extracted from tumor samples stored in liquid nitrogen from 1992 to 2006. The following SNPs (rs) were analysed by PCR-RFLP: ERCC2 (XPD) 751Lys≫Gln (rs13181), XRCC1 399Arg≫Gln (rs25487), TP53 72Arg≫Pro (rs1042522) and MDM2 309T&amp;gt;G (rs2279744). The SNPs ERCC1 259Lys≫Thr (rs735482) and ERCC5 46His C&amp;gt;T (rs1047768) were investigated by Single Base Extension. Results Univariate analyses showed no link between the studied SNPs and overall response rate evaluated at 3 months or 6 months from the end of the treatment. In contrast, there was a significant association between the polymorphism MDM2 309T&amp;gt;G and the occurrence of cutaneous toxicity, since G/G subjects had a higher risk of severe radiation dermatitis (p=0.047). Similarly, the Gln allele of ERCC2 751Lys≫Gln was specifically related to a risk of acute radiation dermatitis following exclusive RT (p=0.009). Also, homozygous patients for XRCC1 399Arg≫Gln (Arg/Arg or Gln/Gln) had an increased risk of developing early osteoradionecrosis, particularly for patients receiving RCT (p=0.032). The occurrence of late toxicities (cervical fibrosis, p=0.011 or xerostomia, p=0.043) was associated with the genotype T/T of ERCC5 46His C&amp;gt;T. Conclusion Individually-based decision criteria are eagerly needed in the context of concurrent chemoradiation in LAHNC, especially with the introduction of anti-EGFR targeted therapies, which increase both anti-tumor efficacy and side-effects (radiation dermatitis). We believe that analyses of gene polymorphisms such as MDM2 and ERCC2 could be of clinical value in establishing the necessary guidelines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3621. doi:1538-7445.AM2012-3621

Adjuvant Low Single Dose Cisplatin-based Concurrent Radiochemotherapy of Oral Cavity and Oropharynx Carcinoma

The aim of this study was to analyze the prognostic importance of extracapsular nodal spread (ECS) in patients with locally advanced squamous cell carcinoma (SCC) of the oral cavity or oropharynx, and the impact of adjuvant low single dose cisplatin-based radiochemotherapy on distant metastases-free survival (DMFS). The study population was selected from 195 patients with high-risk oral cavity or oropharyngeal cancer, who had either adjuvant radiotherapy (RT) or radiochemotherapy (RCT) between January 1, 1997 and December 31, 2006, at the University Clinic of Radiation Oncology of the Martin-Luther-University Halle-Wittenberg. A total of 42 matched pairs of patients with UICC stage III-IVa,b disease were analyzed. The patients were matched (one to one) according to tumor site, sex, T stage, N stage, ECS, resection margin status, and Karnofsky performance status. To analyze the correlation between the treatment modality (RT vs. RCT) and the impact of ECS on DMFS, the Cox proportional hazard model was used. Survival rates were calculated using the Kaplan-Meier method. There was a strong correlation between the degree of nodal involvement and ECS (pN1: 33%; pN2b: 45%; pN2c: 71%). Moreover, the 5-year locoregional control rates (LC) in patients with ECS were 76% vs. 63% (n.s.) for RT and RCT, respectively. However, for patients without ECS, the LC was more favorable after RCT (RT vs. RCT: 62% vs. 88%, p < 0.05). DMFS again was better after RT, and this observation was independent of the presence or absence of ECS. Finally, in multivariate analyses, the presence of ECS significantly decreased the DMFS (p = 0.04, hazard ratio (HR) 2.64). Patients with ECS have an increased risk of distant metastases. Adjuvant low single dose cisplatin-based concurrent chemotherapy seems to have no influence on occult microscopic systemic disease.

Comparison of Four Cisplatin-Based Radiochemotherapy Regimens for Nonmetastatic Stage III/IV Squamous Cell Carcinoma of the Head and Neck

To compare the outcomes of four cisplatin-based radiochemotherapy regimens in 311 patients with Stage III/IV squamous cell carcinoma of the head and neck. Concurrent chemotherapy consisted of three courses of cisplatin 100 mg/m(2) on Day 1 (Group A, n = 74), two courses of cisplatin 20 mg/m(2) on Days 1-5 plus 5-fluorouracil 1,000 mg/m(2) on Days 1-5 (Group B, n = 49), two courses of cisplatin 20 mg/m(2) on Days 1-5 plus 5-fluorouracil 600 mg/m(2) on Days 1-5 (Group C, n = 102), or two courses of cisplatin 20 mg/m(2) on Days 1-5 (Group D, n = 86). The groups were retrospectively compared for toxicity and outcomes, and 11 additional factors were evaluated for outcomes. No significant difference was observed among the groups regarding radiation-related acute oral mucositis and radiation-related late toxicities. Acute Grade 3 skin toxicity was significantly more frequent in Group B than in the patients of the other three groups (p = .013). The chemotherapy-related Grade 3 nausea/vomiting rate was 24% for Group A, 8% for Group B, 9% for Group C, and 6% for Group D (p = .003). The corresponding Grade 3 nephrotoxicity rates were 8%, 1%, 2%, and 1% (p = .019). The corresponding Grade 3-4 hematologic toxicity rates were 35%, 41%, 19%, and 21% (p = .027). Chemotherapy could be completed in 50%, 59%, 74%, and 83% of the Group A, B, C, and D patients, respectively (p = .002). Toxicity-related radiotherapy breaks occurred in 39%, 43%, 21%, and 15% of Groups A, B, C, and D, respectively (p = .005). The 3-year locoregional control rate was 67%, 72%, 60%, and 59% for Groups A, B, C, and D, respectively (p = .48). The corresponding 3-year metastasis-free survival rates were 67%, 74%, 63%, and 79% (p = .31), and the corresponding 3-year survival rates were 60%, 63%, 50%, and 71% (p = .056). On multivariate analysis, Karnofsky performance status, histologic grade, T/N category, preradiotherapy hemoglobin level, completion of chemotherapy, and radiotherapy breaks were associated with the outcome. The four compared radiochemotherapy regimens were not significantly different regarding treatment outcomes. Two courses of cisplatin 20 mg/m(2) on Days 1-5 were better tolerated than the other three regimens.

Cisplatin-based radiochemotherapy in elderly patients with cervical cancer.

e15550 Background: Cervical cancer is a major health problem in Romania because it has advanced stages at diagnose. Older female is a sensible patient category, but their number is in constant increase. We intended to evaluate the efficacy and tolerability of combined conservative treatment for elderly patients with cervical cancer. Methods: Between Jan 2004 and Nov 2007 we treated 63 older patients (median age 75.5 years; range 70 – 86 years) with locally advanced cervical cancer. There were 28 FIGO stage IIB and 35 FIGO stage III patients. All patients had good performance status (ECOG 0-2). 39.7% of patients have concomitant cardiovascular diseases. The treatment consisted in external radiation therapy (total dose 45-50 Gy), HDR brachytherapy (total dose 15-22.5 Gy at point A) and concomitant chemotherapy. The chemotherapy was only platinum salt cisplatin, administered on a weekly schedule (40 mg/sqm on a 30 minutes infusion, weekly during the radiation therapy). The patients received four chemotherapy cycles with 5-FU and cisplatin after irradiation. The response rates were assessed at the end of radiochemotherapy. The follow up period was two years, to determine survival rate and late toxicities. Results: The treatment related acute toxicities were grade 2-3 digestive (55.5%), grade 3-4 hematology (30.1%), and febrile neutropenia (12.7%). Late toxicities were rectitis (14.3%), cystitis (15.9%), grade 2-3 neurological (19%), grade 2 renal function impairment (11.1%), and pelvic fibrosis (14.3%). Some of the complications caused treatment delay but only 3 patients did not finish the intended therapy. Overall treatment was prolonged in 27 cases. No patient died from acute toxicity. Response rates were complete response in 10 patients, partial response in 41 patients, stable disease in 8 patients and progressive disease in 4 patients. Two-year survival rate was 68.25% for stage II and 33.33% for stage III. Conclusions: Elderly patients with locally advanced cervical cancer but good performance status tolerated the curative intended concomitant radiochemotherapy. The toxicities were acceptable and the two-year survival rates were encouraging. This combined therapy may be a good alternative to surgery in elderly patients. No significant financial relationships to disclose.

Acute toxicity of three versus two courses of cisplatin for radiochemotherapy of locally advanced squamous cell carcinoma of the head and neck (SCCHN): A matched pair analysis

This matched pair analysis compared the toxicity of two cisplatin-based radiochemotherapy regimens in patients with locally advanced (stages III or IV) squamous cell carcinoma of the head and neck (SCCHN). Two courses of fractionated cisplatin (20mg/m(2)/d1-5) given concurrently with radiotherapy are better tolerated than other common cisplatin-based regimens. However, in several countries, three courses of unfractionated cisplatin (100mg/m(2)/d1) is standard therapy. Three courses of fractionated cisplatin (20mg/m(2)/d1-5) is another option. In this prospective study, 10 consecutive patients with stage III/IV SCCHN received three courses of fractionated cisplatin (group A). These patients were matched (1:3) to 30 patients who received two courses of fractionated cisplatin (group B). The patients were matched for age, gender, performance status, tumor site, T-category, N-category, tumor stage, and surgery. At least seven factors should match between the matched patients. Because of severe acute toxicity, the planned chemotherapy could not be completed in 90% of group A and 13% of group B patients, respectively (p=0.001). At least one grade >or= 3 toxicity occurred in 90% of group A and 20% of group B patients, respectively (p=0.005). Two courses of fractionated cisplatin appeared much better tolerated than three courses of fractionated cisplatin.