Platinum-based Chemoradiation Therapy Research Articles

Clinical and genomic characterization of chemoradiation-resistant HPV-positive oropharyngeal squamous cell carcinoma.

Most patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) have an excellent response to chemoradiation, and trials are now investigating de-escalated treatment. However, up to 25% of patients with HPV-positive OPSCC will experience recurrence, and up to 5% will even progress through primary treatment. Currently, there are no molecular markers to identify patients with poor prognosis who would be harmed by de-escalation. Herein we report the clinical and genomic characteristics of persistent HPV-positive OPSCC after definitive platinum-based chemoradiation therapy. Patients with HPV-positive OPSCC treated with curative intent platinum-based chemoradiation between 2007 and 2017 at two institutions and with a persistent locoregional disease were included. We evaluated clinical characteristics, including smoking status, age, stage, treatment, and overall survival. A subset of five patients had tissue available for targeted exome DNA sequencing and RNA sequencing. Genomic analysis was compared to a previously published cohort of 47 treatment-responsive HPV+ OPSCC tumors after batch correction. Mutational landscape, pathway activation, and OncoGPS tumor states were employed to characterize these tumors. Ten patients met the inclusion criteria. The tumor and nodal stages ranged from T1 to T4 and N1 to N2 by AJCC 8th edition staging. All patients were p16-positive by immunohistochemistry, and eight with available in situ hybridization were confirmed to be HPV-positive. The 1-year overall survival from the time of diagnosis was 57%, and the 2-year overall survival was 17%. TP53 mutations were present in three of five (60%) persistent tumors compared to 2% (one of 47) of treatment-responsive HPV-positive tumors (p = 0.008). Other genes with recurrent mutations in persistent HPV-positive OPSCC tumors were NF1, KMT2D, PIK3C2B, and TFGBR2. Compared to treatment-responsive HPV-positive tumors, persistent tumors demonstrated activation of DNA Repair and p53, EMT, MYC, SRC, and TGF-beta signaling pathways, with post-treatment samples demonstrating significant activation of the PI3K-EMT-Stem pathways compared to pretreatment samples. Chemoradiation-resistant HPV-positive OPSCC occurs infrequently but portends a poor prognosis. These tumors demonstrate higher rates of p53 mutation and activation of MYC, SRC, and TGF-beta pathways. A comparison of tumors before and after treatment demonstrates PI3K-EMT-Stem pathways post-treatment in HPV-positive tumors with persistent disease after platinum-based chemoradiation.

EE91 Economic Evaluation of Durvalumab for the Treatment of Patients With Stage III Unresectable Locally Advanced Non-Small Cell Lung Cancer Whose Disease Has Not Progressed After Platinum-Based Chemoradiation Therapy

To perform an economic evaluation of durvalumab for the treatment of patients with stage III unresectable locally advanced non-small cell lung cancer whose disease has not progressed after platinum-based chemoradiation therapy from the perspective of public health institutions in Mexico.

Can laparoscopic nerve-sparing ultra-radical hysterectomy play a role in locally advanced cervical cancer? A single-center retrospective study.

The objective of this study is to investigate the outcomes of concurrent platinum-based chemoradiation therapy (CCRT), laparoscopic nerve-sparing ultra-radical hysterectomy (LNSURH), and open radical hysterectomy (ORH) on patients with locally advanced cervical carcinoma (LACC). A single-center retrospective study was conducted on LACC patients who received CCRT, ORH, or LNSURH from January 2011 to December 2019. Data on age, tumor size, overall survival (OS), disease-free survival (DFS), and early and late morbidities were collected. After 24 months of treatment, patients were asked a series of questions about their urinary, bowel, and sexual activities. Early morbidities were defined as those occurring during or within a month of treatment, whereas late morbidities and complications were defined as those occurring a month after treatment. The postoperative complications were classified with reference to the Clavien-Dindo classification (CD) system. The Kaplan-Meier curves revealed no significant differences in OS and DFS among the three groups (P = 0.106 for DFS and P = 0.190 for OS). The rates of early complications in the CCRT group were comparable with those in the operated groups (P = 0.46). However, late complications were significantly lower in the ORH and LNSURH groups relative to those in the CCRT group. The scores of urinary and bowel functions were restored to the pretreatment state, although the sexualfunction scores were not satisfactory. The treatments of CCRT, ORH, and LNSURH can be considered options for patients with LACC, as their OS and DFS showed no significant difference. In addition, LNSURH exhibited a lower incidence of late complications and high sexual function scores.

EP05.01-002 Real World Treatment Patterns and Outcomes among Unresectable Stage III Non-Small Cell Lung Cancer Patients Initiating Chemoradiotherapy

Concurrent platinum-based chemoradiation therapy (cCRT) with or without durvalumab consolidation for 12 months is the current standard of care for patients with unresectable stage III Non-Small Cell Lung Cancer (NSCLC). This study characterized the real-world treatment utilization patterns and associated outcomes after approval of durvalumab for this indication.

Cost-effectiveness analysis of durvalumab as a maintenance treatment for patients with locally advanced, unresectable, stage Ⅲ nsclc in china.

The aim of this study was to evaluate the cost-effectiveness of durvalumab compared with Best supportive care (BSC) after chemoradiotherapy in patients with stage III non-small cell lung cancer from healthcare system perspective in China. A dynamic state transition model was adopted to simulate life time, direct medical costs and QALYs. In the base case scenario, for patients with unresectable, stage Ⅲ non-small cell lung cancer whose disease has not progressed after platinum-based chemoradiation therapy, the treatment group would use durvalumab whereas the control group would use BSC. Clinical data and health utility were derived from the patient-level data of Asian ethnicity in the PACIFIC trial. Cost of drug acquisition, follow-up, medical service, inspection, terminal care and adverse event treatment were considered in this model. The cost of durvalumab was calculated based on retail prices and Patient Assistance Program. In the base case, the durvalumab group yielded an additional 2.60 LYs and 2.37QALYs (discounted), causing an additional cost of 0.459 million RMB and 0.109 million RMB without and with PAP, so the ICER was 193,898 RMB/QALY and 46,093.12 RMB/QALY respectively. This study demonstrated that durvalumab can improve the survival of patients with unresectable, stage Ⅲ non-small cell lung cancer whose disease has not progressed after platinum-based chemoradiation therapy and would be a cost-effective option compared with BSC at a willingness to pay (WTP) threshold of 212676 RMB (three times GDP per capita of China in 2019).

A single-nucleotide-polymorphism in the 5'-flanking region of MSX1 gene as a predictive marker candidate for platinum-based therapy of esophageal carcinoma.

Background:Platinum derivatives are important treatment options for patients with esophageal carcinoma (EC), and a predictive marker for platinum-based therapy is needed for precision medicine.Patients and methods:This study contained two cohorts consisting of EC patients treated using platinum-based chemoradiation therapy (CRT) as the first-line and another external cohort of nationwide clinicogenomic data from the BioBank Japan (BBJ).Results:Genome-wide association study (GWAS) of therapeutic outcomes, refractory disease or not, following platinum-based CRT as first-line in 94 patients in the first cohort suggested the association of 89 SNPs using p < 0.0001. The top 10 SNPs selected from each chromosomal region by odds ratio were evaluated for progression-free survival (PFS) and overall survival (OS) hazard ratios in the first cohort, resulting in four candidates (p < 0.0025). The four selected candidates were re-evaluated in another cohort of 24 EC patients, which included patients prospectively enrolled in this study to fulfill the sample size statistically suggested by the results of the first cohort, and of the four, only rs3815544 was replicated (p < 0.0125). Furthermore, this candidate genotype of rs3815544 proceeded to the re-evaluation study in an external cohort consisting of EC patients treated with platinum derivatives and/or by radiation therapy as the first-line treatment in BBJ, which confirmed that the alternative allele (G) of rs3815544 was statistically associated with non-response (SD or PD) to platinum-based therapy in EC patients (odds ratio = 1.801, p = 0.048). The methylation QTL database as well as online clinicogenomic databases suggested that the region including rs3815544 may regulate MSX1 expression through CpG methylation, and this down-regulation was statistically associated with poor prognosis after platinum-based therapies for EC.Conclusion:rs3815544 is a novel candidate predictive marker for platinum-based EC therapy.

Osimertinib Maintenance After Definitive Chemoradiation in Patients With Unresectable EGFR Mutation Positive Stage III Non–small-cell Lung Cancer: LAURA Trial in Progress

The LAURA trial (NCT03521154) will evaluate the efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable, epidermal growth factor receptor mutation-positive (EGFRm), stage III non–small-cell lung cancer (NSCLC) without disease progression during/following definitive platinum-based chemoradiation therapy (CRT). Eligible patients include adults aged ≥ 18 years (≥ 20 years in Japan) with locally advanced, unresectable, stage III NSCLC with local/central confirmation of an EGFR exon 19 deletion/L858R mutation. Patients must have received ≥ 2 cycles of concurrent/sequential platinum-based CRT, have no investigator-assessed progression, and have creatinine < 1.5 × upper limit of normal and creatinine clearance ≥ 30 mL/min. In this phase III trial, patients will be randomized 2:1 to once-daily osimertinib 80 mg or placebo, until objective radiological disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, confirmed by blinded independent central review (BICR). The primary objective is to assess the efficacy of osimertinib per BICR-confirmed progression-free survival (PFS). Secondary objectives include central nervous system PFS, overall survival, PFS by mutation status and safety. Patients with BICR-confirmed disease progression (or investigator-confirmed progression if after primary PFS analysis) may be unblinded and receive open-label osimertinib; all will have post-progression follow-up. Serious adverse events and adverse events of special interest will be collected throughout the trial and survival follow-up. The first patient was enrolled in July 2018, with results expected in late 2022.

Durvalumab for the Treatment of Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (AstraZeneca) of durvalumab (IMFINZITM) to submit evidence for the clinical and cost effectiveness of durvalumab for the treatment of patients with locally advanced, unresectable, stage III non-small cell lung cancer whose tumours express programmed death-ligand 1 (PD-L1) on ≥ 1% of tumour cells and whose disease has not progressed after platinum-based chemoradiation therapy. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG’s critical review on the clinical- and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The CS included a systematic review that identified one randomised controlled trial, comparing durvalumab with SoC. Participants with tumours expressing PD-L1 on ≥ 1% of tumour cells accounted for approximately 40% of the total participants. In this subgroup, a benefit in progression-free survival (PFS) [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.31–0.63] and overall survival (HR 0.54, 95% CI 0.35–0.81) was reported. Adverse events were comparable between both treatments, but more serious adverse events were reported for durvalumab (64/213 [30%] vs. 18/90 [20%]). The ERG’s concerns regarding the economic analysis included a likely overestimation of PFS for the durvalumab arm, the choice of timepoint for treatment waning, as well as the way treatment waning was incorporated in the model, and potential overestimation of utility values without applying an age- or treatment-related decrement. The revised ERG base-case resulted in a deterministic incremental cost-effectiveness ratio of £50,238 per quality-adjusted life-year gained, with substantial remaining uncertainty. NICE recommended durvalumab as an option for use within the Cancer Drugs Fund only in a subpopulation (concurrent platinum-based chemoradiation therapy) with a commercially managed access agreement in place.

ES02.03 Management of Other Non EGFR Oncogene Addicted Tumors

Stage III non-small cell lung cancer accounts for heterogeneous group of diseases, due to differences in tumor size, location number of nodes involved, and lymph node station involved. Stage III non-small cell lung cancer comprises 2 distinct stages, stage IIIA and IIIB disease that have different prognosis, and are usually treated differently. Approximately 15% of all patients with newly diagnosed non-small cell lung cancer present with stage III disease. Options for stage III non-small cell lung cancer include surgery, with lobectomy or pneumonectomy depending on the tumor stage, and lymph node involvement. Chemotherapy may be administered in the neoadjuvant, concurrent or adjuvant setting. Radiation therapy can be given in a concurrent, sequential approach, or may be administered in the postoperative fashion. Combination approaches are often used, and due to the significant need of multi-modality therapy, treatment decisions are usually made in a multidisciplinary setting. The optimal therapeutic approach for patients with stage IIIA non-small cell lung cancer remains controversial. For subset of patients with T3 to T4 N0-1 disease, and superior sulcus location, surgery remains a viable and preferred option. However, the optimal treatment for patients with stage III A, with bulky lymph node involvement, or multi station lymph node involvement including N2 disease, remains an area of ongoing controversy. Tri-modality approaches using preoperative chemotherapy, or upfront chemoradiation therapy followed by surgery have been evaluated (1). For patients with surgically unresectable, or medically inoperable disease, concurrent chemoradiation therapy has been established as the standard of care for patients spanning the spectrum of stage IIIA and IIIB disease. Recently, the PACIFIC trial demonstrated an improvement in progression free survival and overall survival with the administration of durvalumab as consolidation therapy (regardless of PDL-1 status) for patients who had not progressed after 2 or more cycles of definitive concurrent platinum-based chemoradiation therapy (2, 3). This approach represents a new paradigm in the management of unresectable NSCLC, and has now been adopted as standard of care. Management of Stage III patients with non EGFR oncogene addicted tumors is an area of active research. ALK or ROS directed oral tyrosine kinase inhibitors (TKIs) are not typically administered in the adjuvant setting outside of a clinical trial. There are several trials evaluating the use of targeted therapies. ALINA, is one such trial, that is a phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive ALK positive NSCLC (4). Another study is comparing adjuvant alectinib versus adjuvant platinum-based chemotherapy in patients with ALK positive NSCLC, here the alectinib is administered for 2 years (NCT 03456076). The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing (ALCHEMIST) trial is actively enrolling patients with operable NSCLC and will perform genetic screening of their tumors. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively (NCT02194738). We await the results of these trials prior to routine incorporation of molecularly directed therapy in the management of locally advanced disease. 1. Albain KS, Swann RS, Rusch VW, Turrisi AT, 3rd, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374(9687):379-86. Epub 2009/07/28. https://doi.org/10.1016/S0140-6736(0960737-6). PubMed PMID: 19632716; PubMed Central PMCID: PMC4407808. 2. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. The New England journal of medicine. 2017;377(20):1919-29. 3. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. 2018; 379:2342-2350 4. Solomon BJ, Ahn JS, Barlesi F et al. ALINA: A phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC). J Clin Oncol 37, 2019 (suppl; abstr TPS8569)

Safety Evaluation of Nivolumab Concomitant With Platinum-Based Chemoradiation therapy for Intermediate and High-Risk Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma: RTOG Foundation 3504

Nivolumab (Nivo), which inhibits the programmed death-1 (PD-1) receptor, improved survival for patients (pts) with platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) compared with standard therapy. A clinical trial was designed to evaluate the safety of adding nivo to four standard radiation therapy (RT) regimens for pts with newly diagnosed intermediate (IR) and high-risk (HR) HNSCC (Table 1). Early safety data for cohort 1 (weekly cisplatin) and accrual for cohort 2 (high-dose cisplatin) are reported. Eligibility includes IR (p16+, oropharynx T1-2N2b-N3/T3-4N0-3, >10 pack-years (pys) or T4N0-N3, T1-3N3 ≤10 pys) and HR HNSCC (oral cavity, larynx, hypopharynx, or p16(-) oropharynx, stage T1-2N2a-N3 or T3-4N0-3). Ten pts are enrolled to obtain 8 evaluable pts in each cohort. The feasibility of adjuvant nivo at 3-12 months post-RT is also evaluated. Primary endpoints are safety and feasibility, with dose-limiting toxicity (DLT) defined as nivo-related: ≥grade 3 adverse event unresolved to ≤grade 1 in ≤28 days; RT delay >2 wks; incomplete RT; or inability to receive ≥70% of prescribed systemic therapy due to nivo-related toxicity. DLT window was from first nivo dose (day -14) to 28 days post RT. Characteristics of 10 enrolled pts for cohort 1(weekly cisplatin): median age 56, 80% male, 90% caucasian, 40% PS 0, 80% >10 pys, 50% larynx and 50% p16(+) oropharynx cancer, 80% T3-4 and 80% N2-3 disease. Two of 10 pts were unevaluable due to withdrawal of consent. All 8 evaluable pts completed RT. 3 of 8 pts received 10 doses of concurrent nivo: 1 pt received 9 doses, 3 pts are ongoing after 8 doses, and nivo was discontinued due to blurred vision in 1 pt after 8 doses. Seven of 8 pts received >70% of prescribed cisplatin, which was discontinued early in 3 pts due to AEs unrelated to nivo. No DLT was observed. SAEs included anaphylaxis to cisplatin (cis) (n=1), cholecystitis (1), but none attributable to nivo. Grade ≥3 toxicities attributable to nivo included fatigue (n=1), anorexia (1), WBC decrease (2), neutrophil count decrease (1), mucositis (1), lipase (1) elevation. Seven of 8 pts continued on to maintenance nivo. Toxicity data for cohort 2 (high-dose cisplatin), 10 patients accrued, will also be available at the time of the meeting. Nivo is safe and feasible to administer concurrently with a weekly cisplatin-RT regimen for patients with newly diagnosed IR/HR HNSCC (NCT02764593).

Increased expression of long non-coding RNA XIST predicts favorable prognosis of cervical squamous cell carcinoma subsequent to definitive chemoradiation therapy.

The present retrospective study aimed to examine the association between the expression of long non-protein-coding RNAs (lncRNAs) and clinical prognosis in the pretreatment formalin-fixed, paraffin-embedded (FFPE) tissue samples of cervical squamous cell carcinoma patients that underwent platinum-based chemoradiation therapy. Between 2001 and 2013, 49 consecutive patients with squamous cell cervical carcinoma were selected for the present study (median follow-up period, 44.1 months). The patients possessed an International Federation of Gynecology and Obstetrics stage of IB1/IIA1 (with pelvic lymph node metastasis), IB2 or IIA2-IVA, and had been treated with definitive chemoradiation therapy. The pretreatment FFPE tumor biopsies of the patients obtained diagnosis were used for analysis. Total RNAs were extracted from the FFPE tumor tissues and reverse transcription-quantitative polymerase chain reaction was performed to examine the expression level of lncRNAs. The expression level of X inactive-specific transcript (XIST) demonstrated a significant association with the overall survival rate (P=0.014). The 4-year overall survival rates were 87.1 and 54.4% in the high and low XIST expression groups, respectively. Since the expression of XIST is associated with the overall survival rate, this lncRNA has the potential to become a predictor for the prognosis of cervical squamous cell carcinoma patients that are treated with chemoradiation therapy. Additional studies are required to investigate the underlying mechanisms of XIST that are associated with prognosis.

Dose De-escalation in Human Papillomavirus-Associated Oropharyngeal Cancer: First Tracks on Powder.

Current radiation therapy (RT) treatment schedules for head and neck squamous cell carcinoma (HNSCC) are derived from a combination of rigorous radiobiology and data from prospective clinical trials. Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is now appreciated to be biologically distinct from the traditional type of HNSCC resulting from tobacco and alcohol use. Remarkably high 5-year survival rates, not previously observed in the head and neck cancer patient population, are observed among patients with HPV-positive OPSCC when treated with platinum-based chemoradiation therapy (CRT). Additionally, the patient population afflicted with HPV-positive OPSCC is younger, healthier, and far more likely to be alive to deal with the long-term consequences of therapy. Clinicians who treat HPV-positive OPSCC are now faced with the problem that current treatment paradigms were developed in an era when the traditional HNSCC patient (tobaccoand alcohol-related) predominated. This has led to an appropriate re-examination of treatment paradigms as applied to the HPV-positive OPSCC patient, as well as a new appreciation for the problem of chronic toxicity. We note that it is provocative (and frightening) to “mess with success.” For this reason, the proposition of dose deescalation (of chemotherapy and/or RT) or substitution with

Cetuximab-based Bioradiation Therapy Is Associated With Higher Rates of Distant Metastases Than Platinum-based Chemoradiation Therapy in Human Papillomavirus–Positive Oropharyngeal Cancer

Cetuximab-based Bioradiation Therapy Is Associated With Higher Rates of Distant Metastases Than Platinum-based Chemoradiation Therapy in Human Papillomavirus–Positive Oropharyngeal Cancer

Integration of Targeted Therapy in the Management of Locally Advanced, Unresectable Non-Small-Cell Lung Cancer

SUMMARY The standard of care for unresectable, locally advanced non-small-cell lung cancer (NSCLC; stage IIIA and IIIB) in the past decade has been concomitant platinum-based chemoradiation therapy. Unfortunately, a plateau has been reached in terms of response and survival rates with the present chemotherapeutic paradigm. Targeted biological agents have significantly altered the treatment landscape for stage IV NSCLC and offer an opportunity to do the same for locally advanced NSCLC. While some early trials using unselected patients have shown modest promise for several biologic agents, the overall data remain mixed. One limitation of these trials has been the lack of patient enrichment based on molecular phenotype most likely to benefit from a particular targeted therapy. This review summarizes the most recent data for select classes of targeted agents being tested in the locally advanced NSCLC setting, and gives insights into future developments in this clinical area.

DNA hypermethylation biomarkers to predict response to cisplatin treatment, radiotherapy or chemoradiation: the present state of art

Concurrent platinum-based chemoradiation significantly improved survival of advanced stage cervical patients over radiotherapy alone. However, the 5-year overall survival is still only 66%. Presently, no biomarkers are available to select those cervical cancer patients that might benefit from concurrent platinum-based chemoradiation therapy. DNA methylation is a well-established contributor to the regulation of gene transcription, predominantly causing transcriptional silencing. Differences in promoter hypermethylation patterns and subsequent silencing, could contribute to the variety of responses observed in clinical practice. Several clinical trials on various malignancies reported a better response when Decitabine was administered prior to or in combination with standard therapy. This sensitization is thought to be due to re-expression of tumor suppressor genes. However, not all patients might benefit from demethylating agents, since re-expression of oncogenes could render patients more resistant. In this review, we summarized the present state of art regarding hypermethylated genes and their affected signaling pathways that are associated with outcome after cisplatin treatment, radiotherapy or chemoradiation. Since only few studies were reported in cervical cancer, other malignancies were reviewed as well. From the data presented in this review, we conclude that, in order to select patients that benefit most optimally from demethylating strategies, a comprehensive screening of a large panel of methylation markers, associated with both good as well as poor clinical outcome have to be investigated. Since such panels are not available at this moment, global methylation screening approaches are required to profile such methylated genes. Such methylated gene profiles might be very useful to optimize personalized treatment planning not only in cervical cancer but also in other malignancies.

Acupuncture for dysphagia after chemoradiation in head and neck cancer: Rationale and design of a randomized, sham-controlled trial

IntroductionDysphagia is a common side effect following chemoradiation therapy (CRT) in head and neck cancer (HNC) patients. Current dysphagia management includes swallowing therapy and dilation procedures, but these treatments have limitations. While acupuncture has been reported to positively impact swallowing function and quality of life (QOL) in patients with dysphagia, current evidence is inconclusive. Material and methodsIn an ongoing trial, 42 squamous cell carcinoma HNC patients, who are receiving platinum-based CRT with curative intent, are being recruited from a comprehensive cancer center. They are randomized to 12 sessions of either active acupuncture or to sham acupuncture during and following CRT over a 24-week period. Blinded research staff assesses outcomes at baseline, 20weeks post-CRT (end of acupuncture), and 12months after baseline (6-month follow-up). The primary outcome is change in M.D. Anderson Dysphagia Inventory score from baseline to 12months. Secondary outcomes include QOL measures pertaining to HNC patients. In addition, a subset of study patients are tested for salivary flow rates and cytokines, including plasma transforming growth factor-β1 and interleukin 6 (n=10 per arm), to preliminarily explore the biological mechanisms of acupuncture for dysphagia. DiscussionThis paper addresses unique challenges related to study design in nonpharmacological, sham-controlled acupuncture trials including development of evidence-based credible verum and sham treatment protocols, blinding, and assuring fidelity of treatment. Results of this study will inform the feasibility of conducting a large scale trial and will provide preliminary evidence regarding the value of acupuncture for dysphagia in HNC patients.

HPV prevalence and prognostic value in a prospective cohort of 255 patients with locally advanced squamous cell carcinoma of the head and neck treated with chemoradiation therapy at Centre Hospitalier de l'Université de Montréal: A single-center experience.

5574 Background: HPV has recently been recognised as a good prognostic factor in head and neck (H&N) cancer. However, most of the data is derived from randomised trials with different treatment options or small heterogeneous cohorts. This trial aims to determine the prevalence and prognostic impact of HPV on overall survival (OS), disease-free survival (DFS), local regional control (LRC) and treatment toxicity, in a large cohort of patients with locally advanced SCCHN from one centre, treated with concomitant platinum-based chemoradiation therapy (CRT), followed prospectively. Methods: Prospective data on efficacy and toxicity was available for 560 patients treated with concomitant CRT. Of these, 270 fixed and paraffin embedded specimens were collected. DNA was extracted from specimens and HPV detection was performed as previously described (Coutlée, J Clin Microbiol, 2006). Analysis was performed using Kaplan-Meier survival curves, Fisher's test for categorical data and log-rank statistics for failure times. Results: Median follow-up was 4.7y. DNA extraction was successful in 255 cases. HPV prevalence was 68.6%, and 53.3% for HPV-16 specifically. For HPV+ and HPV- respectively, median LRC were 8.9 and 2.2 years (log-rank p = 0.0002), median DFS were 8.9 and 2.1 years (log-rank p=0.0014) and median OS were 8.9 and 3.1 years (log-rank p=0.0002). Survival was statistically significantly different based on HPV-genotype, stage, treatment period and chemotherapy regimen. COX adjusted analysis for T, N, age, and treatment remained significant (HR 0.45, p=0.004). Subgroup analysis for genotype, TNM, primary site and chemotherapy regimen will be presented at the meeting. Conclusions: An increasing proportion of oropharyngeal cancer is linked to HPV. This large study with a cohort from one centre confirms that HPV status is strongly associated with improved prognosis among H&N cancer patients receiving CRT, and should be a stratification factor for clinical trials including H&N cases. Toxicity of CRT is not modified for the HPV population.

ERCC1 polymorphism in patients with locally advanced head and neck squamous cell carcinoma treated with concomitant chemoradiation: Prevalence and impact on treatment efficacy

6032 Background: Excision repair cross-complementation group 1 (ERCC1) is a gene coding for the nucleotide excision repair complex. Its increased expression and polymorphism at codon 118 have been linked to poor response to chemotherapy or chemoradiation in several types of cancer. ERCC1 removes the cisplatin adducts on the DNA of cells and its polymorphism appears to be a marker of chemotherapeutic resistance to platinum-based therapy. Objectives: To determine the prevalence of the polymorphism of ERCC1 (codon 118) in patients with locally advanced HNSCC treated with concomitant platinum-based chemoradiation therapy with or without prior surgery, and its effect on eficacy evaluated by locoregional control, disease-free survival and overall survival. Methods: Prospective data on efficacy was available on 460 consecutive patients treated with concomitant chemoradiation in our institution with a minimal follow-up of 2 years. Of these, 230 fixed and paraffin embedded biopsies or surgical specimens were collected. DNA was extracted from specimens and polymorphism of codon 118 was determined using a PCR technique. All analysis were performed using Kaplan-Meier survival curves, Fisher's test for categorical data and log-rank statistics for failure times. Results: DNA extraction was successful in 222 patients. Polymorphism mapping was possible in 178 specimens. Genotypic distribution in the population was the following : AAT/AAT:40% (Gr1), AAC/AAT: 48%(Gr2), AAC/AAC: 12% (Gr3). At 3 years, evaluation of efficacy for Gr1, Gr2, and Gr3 was determined. Locoregional control was respectively 77%, 83%, and 67% (p = NS), DFS was 58%, 68% and 55% (p=NS), and OS was 70%, 69%, and 70% (p = NS). Conclusions: ERCC1 polymorphism did not have an impact in our population on response to chemoradiation therapy. It can be postulated that ERCC1 does not seem to discriminate patients for whom another treatment option should be sought for patients with locally advanced SCCHN. Further data will be presented at the meeting including a multivariate analysis using different markers tested in our laboratory (KRAS, MGMT methylation, etc). No significant financial relationships to disclose.

Bcl-2 Blocks Cisplatin-Induced Apoptosis and Predicts Poor Outcome Following Chemoradiation Treatment in Advanced Oropharyngeal Squamous Cell Carcinoma

This study aimed to test the hypothesis that elevated expression of antiapoptotic Bcl-2 family proteins predicts a poor therapeutic response of oropharyngeal squamous cell carcinoma (OPSCC) to concurrent platinum-based chemoradiation therapy. Levels of Bcl-2, Bcl-XL, and Bcl-w were determined and correlated with resistance to cisplatin in a large panel of cell lines derived from squamous cell carcinoma of the head and neck (HNSCC). Univariate and multivariate analyses were used to evaluate the relationship between Bcl-2 and Bcl-XL expression and disease-free survival following chemoradiation therapy in a uniformly treated cohort of patients with OPSCC. In HNSCC cell lines, high endogenous Bcl-2 expression was associated with increased cisplatin resistance, and experimental overexpression of Bcl-2 promoted cisplatin resistance. In patients, tumors positive for Bcl-2 before treatment had greater risk of treatment failure (hazard ratio, 5.99; 95% confidence interval, 1.73-20.8; P=0.0014). In contrast, endogenous Bcl-XL showed no correlation either with cisplatin sensitivity in the cell line panel in vitro, or with risk of recurrence in vivo (hazard ratio, 1.28; 95% confidence interval, 0.39-4.19; P=0.68). Associations between Bcl-2 expression and other clinical characteristics did not account for the predictive value of Bcl-2. Immunohistochemical assessment of Bcl-2 in pretreatment biopsy specimens can predict response of advanced OPSCC to concurrent platinum-based chemoradiation. As treatments targeting Bcl-2 and its family members become available, this immunohistochemical assessment could help personalize therapy by identifying a subpopulation of patients with a poor prognosis who might benefit from such treatments.

Decreased hearing after combined modality therapy for head and neck cancer

Purpose Combined platinum-based chemoradiation therapy is frequently being used as therapy for head and neck cancer at multiple sites. These therapies are individually ototoxic, but little has been reported on their combined toxicity. Materials and methods A retrospective investigation of 37 patients known to have undergone therapy with both agents, in combination, for head and neck malignancy was performed. Sixty percent of the patients had complaints of hearing loss subjectively. Reliable pretreatment and posttreatment audiograms were obtained on 15 of these patients. Audiograms were analyzed for sensorineural changes at 0.5, 1, 2, 4, and 8 kHz. Results By paired t test analysis, there were significant changes in the patients with pretreatment and posttreatment audiograms at all frequencies. More than 50% of the patients had a change of 10 dB or greater in their pure-tone average. More than 85% of the patients experienced changes in their hearing at 4 and 8 kHz. Conclusions We conclude that patients undergoing combined modality therapy for head and neck cancer experience hearing loss. We recommend that hearing assessment, including pretreatment and posttreatment audiometry, be performed in all patients undergoing combined platinum-based chemotherapy and radiation for the treatment of head and neck cancer.