Laryngoesophageal Dysfunction-free Survival Research Articles

Laryngo-Esophageal Dysfunction Free Survival of Chemoradiation for Cervical Esophageal Cancer

Chemoradiotherapy is often the treatment of choice for cervical esophageal cancer due to the invasiveness of surgery. However, toxicity after chemoradiotherapy often affects the quality of life related to swallowing and speech. This study evaluated laryngoesophageal dysfunction-free survival (LEDFS) in patients with cervical esophageal cancer, which has recently been used in head and neck cancer. We analyzed 59 patients with cervical esophageal cancer without distant metastases other than supraclavicular lymph node metastases who received radical chemoradiotherapy with 5-fluorouracilplus platinum between 2002 and 2018. Loco-regional control (LRC), overall survival (OS), LEDFS, metachronous esophageal cancer incidence rates, and late toxicities were evaluated. LEDFS events were defined as death, local recurrence, total or partial laryngectomy, tracheostomy for more than 2 years, and feeding tube use for more than 2 years, as recommended by the Larynx Preservation Consensus Panel. The Kaplan-Meier method was used to calculate survival rates. The generalized Wilcoxon test was used to compare the two groups. The Common Terminology Criteria for Adverse Events v5.0 was used to assess toxicities. The median age was 66 years (range, 38-83). There were 13 women and 46 men. Stage I, II, III, IVA, and IVB disease according to UICC 8th staging were 15, 9, 9, 10, and 16 patients, respectively. 22 received conventional radiotherapy and 37 received volumetric modulated arc therapy. The median total irradiation dose was 66 Gy. Platinum plus 5-fluorouracil chemotherapy was administered to all patients. The median follow-up for survivors was 87.5 months. The 5-year LRC, OS, and LEDFS rates were 54.2%, 48.9%, and 41.9%, respectively. The prognostic factors for OS were performance status (PS), hypopharyngeal extension, and clinical stage in univariate analysis and only clinical stage (hazard ratio [HR] 3.87, 95% Confidence interval [CI]: 1.52-9.87, p<0.01) in multivariate analysis; the prognostic factors for LEDFS were PS, hypopharyngeal extension and clinical stage in univariate analysis and hypopharyngeal extension (HR 2.38, 95% CI: 1.12-5.03, p = 0.02) and clinical stage (HR 4.07, 95% CI: 1.48-11.06, p<0.02) in multivariate analysis. Metachronous esophageal cancer was observed in 28.6% of patients at 5 years. As severe late toxicities, grade 3 pneumonitis, esophageal stricture, esophageal fistula, laryngeal stricture, and laryngeal edema were observed in 1 (2%), 1 (2%) and 4 (7%), 1 (2%) and 1 (2%), respectively. Grade 2 hypothyroidism was observed in 31 (53%) patients. Chemoradiation for cervical esophageal cancer showed good results. The prognostic factors for LEDFS were pharyngeal extension and clinical stage. Late esophageal and laryngeal toxicity, hypothyroidism, and metachronous esophageal cancer should be noted.

Partial Laryngectomy for pT4a Laryngeal Cancer: Outcomes and Limits in Selected Cases.

A large multi-institutional case series of laryngeal cancer (LC) T4a was carried out, including 134 cases treated with open partial horizontal laryngectomies (OPHL) +/- post-operative radiation therapy (PORT). The goal was to understand better whether OPHL can be included among the viable options in selected pT4a LC patients who refuse a standard approach, represented by total laryngectomy (TL) + PORT. All 134 patients underwent OPHL type I (supraglottic), II (supracricoid), or III (supratracheal), according to the European Laryngological Society Classification. Comparing clinical and pathological stages showed pT up-staging in 105 cases (78.4%) and pN up-staging in 19 patients (11.4%). Five-year data on overall survival, disease-specific survival, disease-free survival, freedom from laryngectomy, and laryngo-esophageal dysfunction-free survival (rate of patients surviving without a local recurrence or requiring total laryngectomy and without a feeding tube or a tracheostomy) were, respectively, 82.1%, 89.8%, 75.7%, 89.7%, and 78.3%. Overall, complications were observed in 22 cases (16.4%). Sequelae were observed in 28 patients (20.9%). No patients died during the postoperative period. This large series highlights the good onco-functional results of low-volume pT4a laryngeal tumors, with minimal or absent cartilage destruction, treated with OPHLs. The level of standardization of the indication for OPHL should allow consideration of OPHL as a valid therapeutic option in cases where the patient refuses total laryngectomy or non-surgical protocols with concomitant chemo-radiotherapy.

Upfront surgical organ-preservation strategy in advanced-stage laryngeal cancer

PurposeAdvanced-stage laryngeal cancer is a challenging disease that needs multimodal treatment. Medical and surgical organ-preservation strategies have been developing in the last decades to spare these functions while granting cancer cure. The current work presents the experience of a tertiary-care center in conservative surgery for advanced-stage laryngeal cancer. Materials and methodsWe collected clinical data of patients submitted to open partial horizontal laryngectomies (OPHLs) and any possible adjuvant treatment from 2005 to 2018. Outcomes were also compared to the most recent studies reporting on both medical and surgical organ-preservation strategies. ResultsOne hundred ten patients were included in the analysis. Adjuvant therapy was employed in 51% of cases. The local control rate was 96.4%, while overall survival (OS) was 67%, and laryngo-esophageal dysfunction free survival (LEDFS) was 66%. Stage IV and vascular invasion were associated with a statistically-significant worse survival. ConclusionsOPHLs are valid as upfront treatment in fit patients affected by advanced-stage laryngeal cancer. Disease control and function preservation are granted in a significant percentage of cases, even when followed by adjuvant therapy.

Comparative Treatment Outcome in T3N0 Glottic Cancer With and Without Vocal Fold Fixation Receiving Radiation Therapy and Concurrent Low-Dose Intra-Arterial Cisplatin Infusion.

Selective radiotherapy and concomitant intra-arterial cisplatin infusion (m-RADPLAT) with a lower cisplatin dosage have been performed for organ and function preservation in patients with locally advanced squamous cell carcinoma of the larynx (SCC-L), and results showing a lower rate of adverse events have been reported. This study evaluated the treatment outcomes of patients with T3N0 glottic SCC-L with or without vocal fold fixation (VFF) who were treated with m-RADPLAT. We retrospectively reviewed the data of 33 patients with T3N0 SCC-L who received m-RADPLAT. The vocal fold in patients with VFF 3 months after completing m-RADPLAT resumed normal movement in 15 patients (83%) and persisted fixation in 3 (17%). The 3-year local control, laryngeal cancer-specific survival, and overall survival rates of patients with or without VFF were 88.9% and 86.7%, 94.1% and 93.3%, and 88.9% and 86.7%, respectively. Additionally, the 3-year freedom from laryngectomy, laryngectomy-free survival, and laryngo-esophageal dysfunction-free survival rates of patients with or without VFF were 94.4% and 86.7%, 88.9% and 73.3%, and 83.3% and 73.3%, respectively. Grade 3 or higher toxicities were observed in all patients: leukopenia in 4 patients (12%), neutropenia in 5 (15%), anemia in 2 (6%), thrombocytopenia in 3 (9%), and mucositis in 2 (6%). This study demonstrated that m-RADPLAT yielded VFF improvement and a favorable survival while maintaining laryngeal function not only in patients with T3N0 glottic SCC-L without VFF but also in patients with VFF.

Open partial horizontal laryngectomy and adjuvant (chemo)radiotherapy for laryngeal squamous cell carcinoma: results from a multicenter Italian experience.

To evaluate the functional and oncologic outcomes of adjuvant (chemo)radiation [(C)RT] after open partial horizontal laryngectomies (OPHLs). Multicenter retrospective evaluation of 130 patients (116 males, 14 females) submitted between 1995 and 2017 to OPHL Types II and III for laryngeal cancer and receiving adjuvant (C)RT for one or more of the following risk factors at histopathologic examination of the surgical specimen: pT4a and/or > pN2a categories, close/positive resection margins, or presence of both perineural (PNI) and lympho-vascular invasion (LVI). The primary study endpoints were evaluation of the presence of tracheostomy and/or gastrostomy at last follow-up, and calculation of laryngo-esophageal dysfunction-free survival (LEDFS). Mean age of the study cohort was 60.8 ± 8.9years (median, 62; interquartile range [IQR], 13). Mean follow-up was 50.7 ± 39.4months (range 24-188; median, 38; IQR, 51). Adjuvant therapy consisted of CRT in 53 (41%) patients, and RT alone in 77 (59%). Five-year LEDFS was 85%. Overall survival was 71.5%, while 13% of patients remained tracheostomy- and 3% gastrostomy-dependent at the last follow-up. The only significant variable in predicting survival (p = 0.020) was tracheostomy dependence: it was maintained in 7.5% of subjects after OPHL Type II and in 34% of those submitted to OHPL Type III (p < 0.001). In selected patients affected by advanced laryngeal cancer, OPHLs Type II and III have a relatively good laryngeal safety profile and provide favorable oncologic outcomes even in case of need for adjuvant (C)RT.

A Single Institution's Experience of Definitive Radiotherapy Using Volumetric-modulated Arc Therapy for Hypopharyngeal Cancers.

The present study aimed to analyze the treatment outcome after definitive radiotherapy (dRT) using volumetric-modulated arc therapy (VMAT) in patients with hypopharyngeal cancer (HPC), including an examination of late toxicities. A total of 62 patients with HPC, who underwent dRT using VMAT, were analyzed. Overall survival (OS), progression-free survival (PFS), laryngoesophageal dysfunction-free survival (LEDFS), and locoregional control (LRC) were calculated. The median follow-up period was 49 months. The 3- and 5-year OS, PFS, LEDFS, and LRC rates were 77% and 60%, 61% and 56%, 66% and 53%, and both 79%, respectively. Regarding late toxicities, 11 (17.7%) patients developed grade ≥2 late toxicity. Grade 3 dysphagia was observed in 4 (6.5%) patients, and grade 2 xerostomia in 6 (9.7%). VMAT was an effective treatment for HPC, with a low incidence of late toxicities.

Long-term outcomes of induction chemotherapy followed by chemoradiotherapy using volumetric-modulated arc therapy as an organ preservation approach in patients with stage IVA-B oropharyngeal or hypopharyngeal cancers.

The present study aimed to analyze treatment outcomes after induction chemotherapy followed by chemoradiotherapy (CRT) using volumetric-modulated arc therapy (VMAT) in patients with stage IVA-B oropharyngeal cancer (OPC) or hypopharyngeal cancer (HPC), with long-term observation, including examination of larynx preservation. A total of 60 patients with stage IVA-B OPC or HPC, who underwent induction TPF chemotherapy (a combination regimen consisting of docetaxel, cisplatin, and 5-fluorouracil) followed by CRT using VMAT were analyzed. Overall survival (OS), progression-free survival (PFS), laryngoesophageal dysfunction-free survival (LEDFS), and locoregional control (LRC) were calculated and compared. Univariate and multivariate analyses were performed to determine statistical differences in OS and LEDFS. The median follow-up period at the time of evaluation was 61 months. Twenty-six (43%) patients had OPC and 34 (57%) had HPC. The 5-year OS, PFS, LEDFS, and LRC rates were 57%, 52%, 52%, and 68%, respectively. Response to TPF therapy was the only significant predictive factor of OS and LEDFS in multivariate analyses. Regarding long-term toxicities, grade ≥ 2 late toxicities accounted for 15%. No patients experienced grade ≥ 3 xerostomia, and 5% of all patients developed grade 3 dysphagia. With long-term observation, the OS, PFS, and LEDFS rates were relatively good, and the incidence of late toxicities was low. TPF followed by CRT using VMAT was feasible and more effective in those who responded to induction chemotherapy.

Organ preservation following radiation therapy and concurrent intra-arterial low dose cisplatin infusion for advanced T2 and T3 laryngeal cancer: Long-term clinical results from a pilot study.

BackgroundThis pilot study evaluated the long‐term outcomes of patients with advanced T2 or T3 squamous cell carcinoma of the larynx (SCC‐L) who were treated with selective intra‐arterial cisplatin and concomitant radiotherapy (RADPLAT).MethodsWe retrospectively investigated the data of 49 patients with advanced T2 or T3 SCC‐L who received a RADPLAT regimen with low‐dose cisplatin.ResultsThe 5‐year locoregional control, disease‐specific survival, and overall survival rates were 83.3%, 88.1%, and 82.6%, respectively, while the 5‐year freedom from laryngectomy, laryngectomy‐free survival, and laryngo‐esophageal dysfunction‐free survival rates were 89.6%, 79.4%, and 77.1%, respectively. The incidences of grade 3‐4 hematologic and nonhematologic toxicities were 18% and 6%, respectively. Although two patients (4%) developed late toxicities within 5 years following RADPLAT, no other events were noted beyond 5 years.ConclusionThis pilot study demonstrated that RADPLAT is feasible and safe and yielded favorable survival outcomes and functional laryngeal preservation in patients with advanced T2 or T3 SCC‐L.Level of evidence3

A Multidisciplinary Team Guided Approach to the Management of cT3 Laryngeal Cancer: A Retrospective Analysis of 104 Cases.

The optimal treatment for T3 laryngeal carcinoma (LC) is still a matter of debate. Different therapeutic options are available: Transoral laser microsurgery (TLM), open partial horizontal laryngectomies (OPHLs), total laryngectomy (TL), and organ preservation protocols (radiation therapy (RT) or chemo-radiation (CRT)). This study aimed to retrospectively evaluate oncologic outcomes of 104 T3 LCs treated by surgery or non-surgical approaches from January 2011 to December 2016 at a single academic tertiary referral center. Each case was evaluated by a multidisciplinary team (MDT) devoted to the management of head and neck cancers. We divided the cohort into two subgroups: Group A, surgical treatment (TLM, OPHLs, TL) and Group B, non-surgical treatment (RT, CRT). For the entire cohort, two- and five-year overall survival (OS) rates were 83% and 56%, respectively. The two- and five-year disease-free survival (DFS) rates were 75% and 65%, and disease-specific survival rates were 93% and 70%, respectively. The N category was a significant independent prognosticator for OS (p = 0.02), whereas Group B was significantly and independently associated with DFS (HR 4.10, p = 0.006). Analyzing laryngo-esophageal dysfunction-free survival as an outcome, it was found that this was significantly lower in higher N categories (p = 0.04) and in cases that underwent non-surgical treatments (p = 0.002). Optimization of oncologic outcomes in T3 LCs may be obtained only by a comprehensive MDT approach, considering that different treatment options have heterogenous toxicity profiles and indications.

1112P - Nutritional support dependence after curative chemoradiotherapy in head and neck cancer: A supplementary analysis of a phase II trial (JCOG0706S1)

Background: Curative chemoradiotherapy (CRT) for locally advanced head and neck cancer (LA-HNC) causes severe acute and late adverse reactions, including nutritional support dependence. The aim of this supplementary analysis of a previous single-arm phase II study of CRT with S-1 plus cisplatin for unresectable LA-HNC (JCOG0706) which demonstrated promising efficacy (Cancer Sci.2015;106:726) was to explore risk factors of laryngo-esophageal dysfunction-free survival (LEDFS) and nutritional support dependence over 12 months (NSD12M). Methods: The study population comprised 45 patients (pts) in the JCOG0706. Risk factors of LEDFS and NSD12M were analyzed using Cox regression models and logistic regression models, respectively, with consideration to the pts’ laboratory data just before CRT. Radiation fields were reviewed to analyze the relationship between the extent of irradiated fields and functional outcomes. Results: Proportions of alive without nutritional support at registration and 2, 6, 12, and 24 months after registration were 82.2%, 35.6%, 68.9%, 77.8%, and 64.4%. All six pts who required nutritional support at 12 months remained tube feeding-dependent thereafter. With a median follow-up period of 3.5 years of all pts, 3-year LEDFS was 48.9%. For LEDFS, the hazard ratio was 0.42 in pts with nutritional support at registration (vs. without nutritional support; 95% confidence interval [CI] 0.17-1.04). For NSD12M, odds ratio was 6.78 in pts with hemoglobin less than the median value of 13.4 g/dL (vs. higher than or equal to the median; 95% CI 1.24-36.85); and was 6.00 in pts with albumin less than the median value of 3.9 g/dL (vs. higher than or equal to the median; 95% CI 1.11-32.54). Primary sites in disease-free pts with NSD12M were the oropharynx (N = 2) or hypopharynx (N = 1), and all their pharyngeal constriction muscles were irradiated with a curative dose of 70 Gy/35 fr. Conclusions: Functional outcomes were affected by severe dysphasia requiring nutritional support before CRT, and lower pretreatment values of hemoglobin and albumin. These risk factors should therefore be taken into consideration in planning treatment strategy for pts with LA-HNC. Clinical trial identification: UMIN000001272. Legal entity responsible for the study: JCOG. Funding: National Cancer Center Research and Development Fund (23-A-16, 23-A-21, 25-B-2 and 26-A-4); Grants-in-Aid for Cancer Research (18-19, 20S-3,20S-6) from Ministry of Health, Labour and Welfare of Japan. Disclosure: All authors have declared no conflicts of interest.

Organ preservation vs primary surgery in the management of T3 laryngeal and hypopharyngeal cancers.

The main objective is to compare the oncologic outcomes of patients with T3 laryngeal cancers who underwent total laryngectomy or organ preservation protocol (OPP) as the initial plan of management. This is a retrospective study on 120 patients treated for T3 laryngeal and hypopharyngeal cancers. Patients with functional larynx underwent OPP and dysfunctional larynx underwent upfront laryngectomy. Median follow-up of the patients was 4.6years. There was a significant difference in 3year disease-free survival (DFS) between upfront laryngectomy and OPP (73.2 vs. 55.7%; P = 0.028) group but not in 3year overall survival (73.2 vs. 68.7%, P = 0.8). The rate laryngeal preservation was 65% in CCRT and 44% in only radiotherapy group. At 3years, the laryngectomy-free survival was 57.2% and the laryngo-esophageal dysfunction-free survival (LEDS) was 53.0%. T3 laryngeal cancers treated with upfront laryngectomy have an improved DFS when compared to those treated with non-surgical modalities. Primary surgery should be offered as an option for selected patients especially when CCRT is not feasible.

Evaluation of treatment outcomes in patients with supraglottic laryngeal cancer in Ontario, Canada: A population-based study.

Supraglottic laryngeal carcinoma has an entirely different etiology, clinical presentation, and prognosis compared to glottis cancer but the only evidence for the use of concurrent chemotherapy with radiotherapy (CRT) is the 5.4% 5-year improvement in overall survival (OS) for the combined laryngeal site. We conducted a retrospective population-based study using administrative data to compare OS, disease-specific survival (DSS), laryngectomy-free survival, and laryngoesophageal dysfunction-free survival over time and by treatment for all patients with supraglottic laryngeal carcinoma diagnosed between January 1, 1990, and December 31, 2014, in Ontario, Canada. There was no improvement over time in OS (hazard ratio [HR] 1.006; P = .90), DSS (HR 1.031; P = .65), or laryngoesophageal dysfunction-free survival (P = .39). The patients selected for CRT had similar OS (HR 1.04; P = .66), laryngectomy-free survival (HR 0.95; P = .23), and laryngoesophageal dysfunction-free survival (P = .79) compared with patients undergoing radiotherapy. The addition of CRT by head and neck oncologists in Ontario, Canada, did not improve outcomes for the "real world" patients with supraglottic laryngeal carcinoma.

Abstract 15: Utility of chemoradioselection for the optimization of treatment intensity in advanced hypopharyngeal and laryngeal carcinoma

Abstract Background: Definitive concomitant chemoradiotherapy (CRT) with high-dose cis-platinum (CDDP) is a current standard protocol for advanced laryngeal and hypopharyngeal cancer sparing surgery for salvage. However, this modality is associated with limited feasibility and frequent sever toxicities. We have developed a “chemoradioselection” protocol with minimal toxicity using initial response to CRT as a biomarker for patient selection. Materials and Methods: From 2000 to 2012, 123 patients with stage III (44), IV (79) laryngeal (64) and hypopharyngeal carcinoma (59) excluding T4 cases were enrolled to this protocol. Two cycles of split (15 mg/m2 x 5 days, 2000-2008) or bolus (80 mg/m2, 2009-present) CDDP was concurrently administered. Results: Tumor responses were evaluated after 40 Gy of CRT and 64 responders (i.e., chemoradioselected, CRS) received further CRT up to 70 Gy, while radical surgery was recommended for the 59 non-responders (N-CRS), and 34 underwent surgery (N-CRS-ope). The remaining 25 patients who refused surgery (N-CRS-refu) were treated with continuous CRT. The 5-yr overall survival (OS) and disease-specific survival (DSS) were 67% and 77%, respectively. The CRS demonstrated quite favorable 5-yr OS (73%) and 5-yr laryngo-esophageal dysfunction-free survival (LEDFS, 69%). In contrast, the N-CRS-refu showed significantly (P = 0.0193) lower 5-yr OS (47%) than CRS (73%) and N-CRS-ope (70%), and significantly (P &amp;lt; 0.0001) lower 5-yr LEDFS (20%) than the CRS (69%). On multivariate analyses including T, N, primary site, and planned treatment (CRS + N-CRS-ope) or not (N-CRS-refu), unplanned treatment alone showed a significant correlation with poor OS (Hazard ratio [HR]: 2.584, 95% CI: 1.313–4.354, P = 0.007). Conclusions: Chemoradioselection reflects the biological aggressiveness of each tumor, and can segregate patients for functional laryngeal preservation with moderate intensity CRT (150-160 mg/m2 of CDDP) from those who would be better treated with surgery. This strategy may be useful for the optimization of the therapeutic intensity. Citation Format: Muneyuki Masuda, Satoshi Toh, Hidefumi Rikimaru, Naonobu Kunitake, Yuichiro Higaki. Utility of chemoradioselection for the optimization of treatment intensity in advanced hypopharyngeal and laryngeal carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 15.

Utility of chemoradioselection for the optimization of treatment intensity in advanced hypopharyngeal and laryngeal carcinoma.

Definitive concomitant chemoradiotherapy (CRT) with high-dose cis-platinum (CDDP) is a current standard protocol for advanced laryngeal and hypopharyngeal cancer sparing surgery for salvage. However, this modality is associated with limited feasibility and frequent sever toxicities. In the present study, a ‘chemoradioselection’ protocol with minimal toxicity was developed using initial response to CRT as a biomarker for patient selection. Between 2000, March and 2012, September 123 patients with stage III (44), IV (79) laryngeal (64) and hypopharyngeal carcinoma (59) excluding T4 cases were enrolled to this protocol. Two cycles of split (15 mg/m2 ×5 days, 2000–2008) or bolus (80 mg/m2, 2009-present) CDDP was concurrently administered. Tumor responses were evaluated after 40 Gy of CRT and 64 responders (chemoradioselected, CRS) received further CRT up to 70 Gy, while radical surgery was recommended for the 59 non-responders (N-CRS), and 34 underwent surgery (N-CRS-ope). The remaining 25 patients who refused surgery (N-CRS-refu) were treated with continuous CRT. The 5-year overall survival (OS) and disease-specific survival (DSS) were 67, and 77%, respectively. The CRS demonstrated favorable 5-year OS (73%) and laryngo-esophageal dysfunction-free survival (LEDFS, 69%) rates. In contrast, the N-CRS-refu showed significantly lower 5-year OS (47%) compared with CRS (73%) and N-CRS-ope (70%) (P=0.0193), and significantly lower 5-year LEDFS (20%) compared with the CRS (69%) (P<0.0001). On multivariate analyses, including T, N, primary site and planned treatment (CRS + N-CRS-ope) or not (N-CRS-refu), unplanned treatment alone showed a significant correlation with poor OS [hazard ratio (HR), 2.584; 95% confidence interval (CI), 1.313–4.354; P=0.007). Chemoradioselection reflects the biological aggressiveness of each tumor, and is able to segregate patients for functional laryngeal preservation with moderate intensity CRT (150–160 mg/m2 of CDDP) from those who would be better treated with surgery. This strategy may be useful for the optimization of the therapeutic intensity.

Effect of daily fraction size on laryngoesophageal dysfunction after chemoradiation for squamous cell carcinomas of the larynx and hypopharynx

The purpose of this study was to determine the effect of fraction size on laryngoesophageal dysfunction among patients treated by chemoradiotherapy for laryngeal and hypopharyngeal cancer. Forty patients underwent chemoradiotherapy for stage III/IV squamous cell carcinomas of the larynx and hypopharynx. Median radiation dose was 70 Gy (range, 69.3-70.4 Gy) with daily fractionation ranging from 2 Gy to 2.2 Gy. When comparing 2 Gy versus >2 Gy daily fractionation, there was no difference in 2-year overall survival (71% vs 72%; p = .68), locoregional control (79% vs 77%; p = .43), or laryngectomy-free survival (60% vs 61%; p = .72). Use of 2 Gy versus >2 Gy fractionation improved laryngoesophageal dysfunction-free survival (2-year estimates, 49% vs 27%; p = .07). Patient-reported voice and swallowing were improved with the former. As the importance of a functional larynx becomes recognized as an endpoint for patients treated by voice preservation, the results of our study help refine treatment guidelines. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1322-1326, 2017.

Laryngo-esophageal Dysfunction-free Survival in a Preservation Protocol for T3 Laryngeal Squamous-cell Carcinoma.

We reviewed the outcomes of patients with T3 laryngeal neoplasms with a fixed hemilarynx, a large gross tumor volume or a subglottic extension (SGE), treated with a laryngeal-preservation protocol with induction chemotherapy. The study end-points were laryngo-esophageal dysfunction-free survival (LEDFS), laryngectomy-free survival (LFS), overall survival (OS), and disease-free survival (DFS). A total of 104 patients were included. The 2-year and 5-year OS rates were 70.4% and 54.5%, respectively. OS and DFS were independent of the treatment modality in the whole cohort (p=0.6546 and p=0.3006, respectively) and in patients with SGE (p=0.529 and p=0.255, respectively). The 2-year and 5-year LEDFS rates were 44.3% and 28.2%, respectively. LEDFS was not associated with initial hemilaryngeal fixation or SGE (p=0.5772 and p=0.0623, respectively). Chemoselection is feasible without compromised oncological or functional outcomes in patients with an initially fixed hemilarynx or subglottic extension.

Outcomes following laryngectomy refusal after insufficient response to induction chemotherapy.

To review patients who refused a total laryngectomy and were treated with radiotherapy (RT) after insufficient response to induction chemotherapy in a larynx preservation protocol for advanced-stage cancer of the larynx and to compare their outcomes with good responders. Retrospective cohort study. Eighty-six patients treated with induction chemotherapy followed by RT were included in the analysis: 75 good responders and 11 insufficient responders who refused surgery. We compared overall survival (OS), disease-free survival (DFS), and laryngo-esophageal dysfunction-free survival (LEDFS) of the cohort populations in univariate and multivariate analyses. The median follow-up was 44 months. The 2-year and 5-year survival rates were respectively 72.2% and 58.8% for OS, 62.8% and 49.4% for DFS, and 59.5% and 44.3% for LEDFS. No survival endpoint was significantly decreased among insufficient responders, contrary to what we expected. When we focused on patients with an initially fixed larynx, the recovery of larynx mobility after induction chemotherapy was not associated with OS (P = 0.6055), DFS (P = 0.459), or LEDFS (P = 0.7403). To the best of our knowledge, our study is the first patient treatment evaluation focused on subjects who refused a total laryngectomy after insufficient response to induction chemotherapy in a larynx preservation protocol for advanced-stage cancer of the larynx. Surprisingly, these patients treated with RT in our cancer center did not experience decreased functional and oncologic outcomes compared to good responders. Further studies will explore the relevance of response criteria and their evaluation methods. 4. Laryngoscope, 127:1791-1796, 2017.

984P - Utility of algorithm-based chemoradioselection for advanced laryngeal and hypopharyngeal carcinoma

At our institute, a “chemoradioselection” strategy has been used to select patients with head and neck cancer for organ preservation. In brief, tumor responses are evaluated at 40 Gy of concurrent chemoradiotherapy (CRT). Responders (i.e., chemoradioselected, CRS) receive further CRT up to 70 Gy, while non-responders (N-CRS) are recommended to undergo radical surgery (N-CRS-ope). To those who refuse surgery (N-CRS-refu), continuous CRT is administered. In this study, the results of advanced laryngeal and hypopharyngeal carcinomas were examined. From 2000 to 2012, 123 patients with stage III (44), IV (79) laryngeal (64) and hypopharyngeal carcinoma (59) excluding T4 cases were enrolled to this algorithm-based treatment. Split (15mg/m2 x 5 days, 2000-20008) or bolus (80mg/m2, 2009-present) CDDP was administered at the onset of initial 40 Gy and additional 30Gy of CRT, respectively. Based on the algorithm, 64 patients were CRS. The remaining 59 N-CRS patients proceeded to either N-CRS-ope (34) or N-CRS-refu (25) arm. The 5-yr OS and DSS were 67% and 77%, respectively. The 5-yr OS of N-CRS-refu (47%) was significantly (p = 0.0193) lower than that of CRS (73%) or N-CRS-ope (70%). Intriguingly, multivariate analyses including 4 candidate prognostic factors: T (T1, 2 vs T3), N (N1 vs N2, 3), primary site (larynx vs hypopharynx), and planned treatment or not (CRS + N-CRS-ope vs N-CRS-refu) demonstrated that unplanned treatment alone was significantly correlated with poor OS (HR: 2.584, 95% CI: 1.313–4.354, p = 0.007). This result indicates that chemoradioselection, probably reflecting the biological aggressiveness of each tumor, can segregate patients for organ preservation from those who are better treated with surgery. The overall 5-yr laryngo-esophageal dysfunction-free survival (LEDFS) was 41%. The CRS group demonstrated significantly (P < 0.0001) better 5-yr LEDFS (69%) compared to the N-CRS-refu (20%), albeit identical treatment regimen. Algorithm-based chemoradioselection might provide a novel platform for the treatment of advanced head and neck cancer, taking full advantages of CRT and radical surgery, and thereby achieving optimization of the treatment intensity.

Phosphorylation of gH2AX as a novel prognostic biomarker for laryngoesophageal dysfunction-free survival.

Current larynx preservation treatments have achieved an improvement of laryngoesophageal dysfunction-free survival (LDS) but lead to significant toxicities and recurrences. At present, there is no evidence to select the group of patients that may benefit from preservation approaches instead of surgery. Therefore, laryngeal biomarkers could facilitate pretreatment identification of patients who could respond to chemoradiation-based therapy. In this study, we evaluated retrospectively 53 patients with larynx cancer to determine whether gH2AX phosphorylation (pH2AX) alone or in combination with the membrane protein MAP17 (PDZK1IP1) could be used as prognostic biomarkers. We also evaluated whether the completion of cisplatin treatment and radiotherapy could predict survival in combination with pH2AX.We found that the dose of cisplatin received but not the length of the radiotherapy influenced LDS. High-pH2AX expression was associated with prolonged LDS (HR 0.26, p = 0.02) while MAP17 correlated with overall survival (OS) (HR 0.98, p = 0.05). High-MAP17 and high-pH2AX combined analysis showed improved LDS (with 61.35 months vs 32.2 months, p = 0.05) and OS (with 66.6 months vs 39.8 months, p = 0.01). Furthermore, the subgroup of high-pH2AX and optimal dose of cisplatin was also associated with OS (72 months vs 38.6 months, p = 0.03) and LDS (66.9 months vs 27 months, p = 0.017). These findings suggest that pH2AX alone or better in combination with MAP17 may become a novel and valuable prognostic biomarker for patients with laryngeal carcinoma treated with preservation approaches.

T-status and an oral fluoropyrimidine, S-1, adjuvant chemotherapy are prognostic factors in reduced-RADPLAT for resectable hypopharyngeal cancer

Conclusion: Reduced-RADPLAT for HPC achieved comparative survival and locoregional control rates with lower toxicities compared with concurrent chemoradiotherapies including original RADPLAT. S-1 adjuvant chemotherapy showed a survival benefit. Objectives: To evaluate the efficacy and toxicities of targeted intra-arterial (IA) infusion of cisplatin with concurrent radiotherapy with a reduced dose (reduced-RADPLAT) for resectable hypopharyngeal cancer (HPC). Methods: Between 1999–2012, 50 patients with stage II–IVA HPC primarily treated by reduced-RADPLAT were analyzed. They were treated by 2–5 courses of IA cisplatin infusion (100 mg per body) with simultaneous systemic infusion of sodium thiosulfate concurrent with conventional radiotherapy (66–70 Gy). After 2003, S-1, an oral fluoropyrimidine, adjuvant chemotherapy was administered to all eligible patients. Results: During a median follow-up of 48.6 months, the estimated 3- and 5-year overall survival (OS), progression-free survival (PFS), locoregional control, and laryngoesophageal dysfunction-free survival (LEDFS) rates were 76.0% and 62.0%, 58.0% and 50.0%, 66.0% and 62.0%, and 56.0% and 54.0%, respectively. Grade 3 toxicities were observed in 30.0%. No patient had grade 4 or higher toxicities. No patient required tube feeding or tracheotomy at 3 months after treatment. T4-lesions and S-1 administration were significant factors predicting poor and good OS, PFS, and LEDFS, respectively.