Advanced Squamous Cell Cancer Research Articles

Preliminary phase 1/1b dose expansion results of the bifunctional EGFR/TGFβ inhibitor ficerafusp alfa (BCA101) with pembrolizumab in patients with squamous cell carcinoma of the anal canal.

4 Background: Anti-PD-1 monotherapy has limited efficacy in patients (pts) with advanced squamous cell cancer of the anal canal (SCAC). In KN-158, pembrolizumab (P) was reported to have an ORR of 10%, DCR of 25%, and a 12-month PFS rate of 15% in patients with incurable SCAC. TGFβ promotes immunosuppression within the tumor microenvironment, and inhibition of this pathway may improve tumor susceptibility to immune checkpoint blockade.Ficerafusp alfa (F)is a bifunctional EGFR/TGFβ inhibitor with manageable safety and favorable preliminary anti-tumor efficacy in advanced solid tumors (ESMO 2022 731MO). We evaluated the combination of F+P in pts with chemotherapy-refractory locally advanced/unresectable or metastatic SCAC. Methods: This single-arm, multicenter dose expansion from an ongoing phase I/Ib trial enrolled pts with ICI-naïve SCAC that was locally advanced/unresectable or metastatic, who had received 1-2 prior lines of chemotherapy. Pts received ficerafusp alfa (1500 mg IV on days 1, 8, 15) and pembrolizumab (200 mg IV on day 1) every 21-day cycle. The primary endpoint was safety (CTCAE v5), and secondary endpoints were radiographic response (RECIST 1.1), duration of response, progression-free survival, and overall survival. Results: Among 26 pts treated, 21 (81%) were female, and median age was 61 (range: 43-82). As of 7/2024, 22 pts are evaluable for efficacy. ORR was 32% (95% CI 13.9-54.9%). Six of the seven responses were confirmed, including one pt with a radiographic PR with pathologic CR to F+P. Seven pts (32%) achieved SD as best response, resulting in DCR of 64%. Median PFS was 2.8 months (95% CI 1.4-14.8) and the PFS rate at 12 months was 36%. G3 treatment-related adverse events were observed in 10/26 pts (38%, most common: Anemia (19%) and acneiform rash (12%)). TRAEs led to permanent discontinuation of study treatment in 2 pts (8%). The most common TRAEs of any grade were acneiform rash (13/26, 50%), epistaxis (46%) and headache (38%). Conclusions: The addition of ficerafusp alfa demonstrated encouraging efficacy, with increased ORR, DCR, and 12-month PFS relative to historical precedent with pembrolizumab alone. Safety and tolerability were acceptable. Further investigation of this combination in pts with advanced SCAC is warranted. Updated data will be presented. Study funded by Bicara Therapeutics Inc. with access to pembrolizumab in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (NCT04429542). Clinical trial information: NCT04429542 .

The Clinical Utility of a Next-Generation Sequencing-Based Approach to Detecting Circulating HPV DNA in Patients with Advanced Anal Cancer.

To extend the practicality of liquid biopsy beyond the historical HPV circulating tumor DNA (ctDNA) assays, we evaluated the clinical relevance of a novel next-generation sequencing HPV ctDNA assay in patients with locally advanced and metastatic squamous cell cancer of the anal canal (mSCCA). ctDNA isolated from the plasma of patients with mSCCA was sequenced using a 1.4 Mb hybrid-capture target-enrichment panel covering the whole genome sequences of all 193 HPV types. The HPV type, copy number (CN), and integration sites were determined using a bioinformatic pipeline. A total of 77 plasma samples from 28 patients with HPV-related SCCA were retrospectively analyzed. HPV ctDNA was detected in 26 cases (93%) (including uncommon subtypes). The median HPV CN was higher in metastatic versus locally recurrent/unresectable SCCA (p = 0.043). Changes in the HPV CN were concordant with the radiographic response (p = 0.027). An integration event was detected in 23 patients (82%), with presumed episomal HPV DNA present in the remaining patients. Higher HPV integration (a mean of ≥1 integration across samples) was associated with a worse overall survival from the start of immunotherapy (13.6 months versus 36.0 months; p = 0.003). Using HPV-informed next-generation sequencing of the ctDNA, we found changes in the HPV CN correlated with the treatment response and that HPV integration detected in the ctDNA is an unfavorable prognostic biomarker.

Camrelizumab combined with neoadjuvant docetaxel, oxaliplatin, and S1 as induction therapy for locally advanced esophageal squamous cell cancer: a real-world single-center cohort study

Camrelizumab combined with neoadjuvant docetaxel, oxaliplatin, and S1 as induction therapy for locally advanced esophageal squamous cell cancer: a real-world single-center cohort study

Integrating tumour and lymph node radiomics features for predicting disease-free survival in locally advanced esophageal squamous cell cancer after neoadjuvant chemotherapy and complete resection.

To investigate the utility of combined tumour and lymph node (LN) radiomics features in predicting disease-free survival (DFS) among patients with locally advanced esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemotherapy and resection. We retrospectively enrolled 176 ESCC patients from January 2013 to December 2016. Tumour and targeted LN segmentation were performed on venous phase CT images. Models were constructed using LASSO Cox regression: a clinical model, a clinical-tumour radiomics model, and a clinical-tumour-LN radiomics model. Model fitting was evaluated using Akaike information criterion and likelihood ratio (LR), while performance was assessed using Harrell's concordance index (C-index) and time-dependent receiver operating characteristic analysis. The clinical model included clinical stage and neutrophil-to-lymphocyte ratio (NLR). Integration of tumour features significantly improved prognostic accuracy (clinical-tumour model vs. clinical model, LR: 17.84 vs. 11.84, P=0.049). Subsequent integration of LN features further augmented model performance (clinical-tumour-LN model vs. clinical-tumour model, LR: 24.48 vs. 17.84, P=0.009). The final model included clinical stage, NLR, two tumour features (Conventional_mean and GLZLM_HGZE), and one LN feature (GLCM_entropy). The C-index was 0.68 for the training set and 0.70 for the test set. The nomogram based on these features effectively stratified patients into high- and low-risk groups (P<0.001). The clinical-tumour-LN model, integrating clinical stage, NLR, and radiomics features, outperformed simpler models in predicting DFS among ESCC patients after neoadjuvant chemotherapy and resection. This underscores the potential of radiomics data to enhance prognostic models, offering clinicians a more robust tool for assessment.

Comparison of neoadjuvant chemoimmunotherapy and neoadjuvant chemotherapy for resectable esophageal squamous cell carcinoma: a retrospective study with 3-year survival analysis

BackgroundNeoadjuvant chemoimmunotherapy (nCIT) for locally advanced esophageal squamous cell cancer (ESCC) has shown short-term benefits, but long-term survival outcomes are unclear. This study compares nCIT and neoadjuvant chemotherapy (nCT) in resectable ESCC.Patients and methodsA retrospective analysis was conducted on ESCC patients who underwent nCT or nCIT followed by esophagectomy. Propensity score matching (PSM) with a caliper of 0.02 was employed to minimize bias. The primary endpoints included disease-free survival (DFS) and overall survival (OS).ResultsA total of 131 comparable pairs of ESCC patients receiving nCT and nCIT were selected for the final analysis. The nCIT had higher rates of pathological complete response (pCR) and major pathological response (mPR) compared to nCT. Additionally, nCIT led to significant tumor down-staging, higher rates of R0 resection, and increased lymph node clearance during surgery. Patients who received nCIT exhibited improved disease-free survival (DFS) and overall survival (OS) at the 3-year follow-up. The incidence of distant and mixed relapses was lower in the nCIT group compared to the nCT group. However, the risk of locoregional relapse was comparable between the two groups. Subgroup analyses showed that the benefits of nCIT were generally observed across most patient subgroups. Interestingly, in patients without pCR or mPR, nCIT still demonstrated better survival benefits than nCT.ConclusionnCIT demonstrated superior pathological response rates and improved 3-year DFS and OS compared to nCT alone in locally advanced ESCC, but long-term survival validation is needed.

The addition of pembrolizumab to neoadjuvant chemoradiotherapy did not increase the risk of developing postoperative anastomotic leakage for ESCC: an analysis from a prospective cohort

BackgroundTo compare the difference of postoperative anastomotic leakage (AL) rate between neoadjuvant chemoradiotherapy (NCRT) with pembrolizumab and NCRT group, and investigate the risk factors of developing AL for locally advanced esophageal squamous cell cancer (ESCC).Materials and methodsThe GF was contoured on the pretreatment planning computed tomography and dosimetric parameters were retrospectively calculated. Univariate and multivariate logistic regression analysis was performed to determine the independent risk predictors for the entire cohort. A nomogram risk prediction model for postoperative AL was established.ResultsA total of 160 ESCC patients were included for analysis. Of them, 112 were treated with NCRT with pembrolizumab and 44 patients with NCRT. Seventeen (10.6%) patients experienced postoperative AL with a rate of 10.7% (12/112) in NCRT with pembrolizumab and 11.4% (5/44) in NCRT group. For the entire cohort, mean, D50, Dmax, V5, V10 and V20 GF dose were statistically higher in those with AL (all p < 0.05). Multivariate logistic regression analysis indicated that tumor length (p = 0.012), volume of GF (p = 0.003) and mean dose of GF (p = 0.007) were independently predictors for postoperative AL. Using receiver operating characteristics analysis, the mean dose limit on the GF was defined as 14 Gy.ConclusionBased on our prospective database, no significant difference of developing AL were observed between NCRT with pembrolizumab and NCRT group. We established an individualized nomograms based on mean GF dose combined with clinical indicators to predict AL in the early postoperative period.

Comparison of immunochemotherapy followed by surgery or chemoradiotherapy in locally advanced esophageal squamous cell cancer

BackgroundSeveral studies have shown that the survival outcomes of chemoradiotherapy (CRT) are not inferior to surgery alone in patients with esophageal squamous cell carcinoma (ESCC). This study aimed to compare survival outcomes of ESCC treated with immunochemotherapy (ICT) followed by surgery or definitive CRT and to explore subgroups of patients who could benefit from one treatment strategy. MethodsPooled data were obtained from two prospectively registered clinical trials of patients with ESCC at the Affiliated Cancer Hospital of Nanjing Medical University. One trial involved treatment with neoadjuvant ICT followed by surgery, while the other involved induction ICT followed by definitive CRT. To balance potential biases, we conducted an overlap weighting (OW) analysis to compare the rates of 2-year progression-free survival (PFS), locoregional relapse-free survival (LRRFS), distant relapse-free survival (DRFS), and overall survival (OS). Additionally, propensity score matching (PSM) was performed to analyze failure pattern. ResultsThe median follow-up time of the survivors was 39.3 months. After overlap weighting, the rates of 2-year PFS, LRRFS, DRFS, and OS for patients undergoing surgery and CRT were 61.5 % and 59.7 %, 67.2 % and 69.9 %, 81.3 % and 90.7 %, 84.6 % and 79.1 %, respectively (P>.05 for all). A trend for improved 2-year OS was observed in the surgery group in patients who did not respond to ICT (P=.07). ConclusionThe differences in the rates of 2-year PFS, LRRFS, DRFS, and OS between the surgery group and the chemoradiotherapy group did not reach statistical significance.

Circulating tumor DNA analysis in patients with esophageal cancer treated with neoadjuvant chemoradiotherapy followed by surgery.

69 Background: The aim of this prospectively study is to investigate circulating tumor DNA (ctDNA) as a prognostic marker for survival in locally advanced esophageal squamous cell cancer (ESCC) patients treated with neoadjuvant chemoradiotherapy (nCRT) and surgery. Methods: Serial plasma samples were collected from 68 ESCC patients treated with neoadjuvant chemoradiotherapy before surgery. ctDNA was detected before treatment, after neoadjuvant chemoradiotherapy and after surgery by personalized, next-generation sequencing assay. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for recurrence-free survival (RFS) and overall survival (OS). Results: ctDNA was detectable in 89.7%, 17.2%, and 6.9% of pretreatment, post-neoadjuvant chemoradiotherapy and post-surgery plasma samples, respectively. The conversion of ctDNA status from positive at baseline to negative at 4-6 weeks after neoadjuvant chemoradiotherapy was significantly associated with pathological complete response (pCR) ( P = 0.02). Significant worse RFS was related to detectable ctDNA after neoadjuvant chemoradiotherapy ( P = 0.008) or after surgery ( P = 0.001). Detectable ctDNA at baseline ( P = 0.01) and after surgery ( P = 0.008) were associated with worse OS. In multivariate analysis, detectable postoperative ctDNA was significantly associated with RFS ( P = 0.012) and OS ( P = 0.025) after adjusting for other clinicopathological risk factors. Conclusions: ctDNA status is a strong prognostic factor of recurrence in locally advanced ESCC patients. Consequently, ctDNA could potentially improve pre- and post-treatment risk assessment and facilitate individual therapy for ESCC patients.

Comparison of the treatment outcomes of different neoadjuvant chemoradiotherapy regimens for resectable locally advanced esophageal cancer

BackgroundNeoadjuvant chemoradiotherapy (nCRT) followed by radical esophagectomy is the standard treatment for locally advanced esophageal squamous cell cancer (LA-ESCC). However, various nCRT regimens have been used, and their comparative efficacy and safety remain unclear. MethodsPatients with histologically confirmed LA-ESCC who underwent nCRT followed by radical esophagectomy between January 2016 and February 2022 were enrolled in this study. Of note, 3 different nCRT regimens were retrospectively compared: conventional radiotherapy (RT) + cisplatin/5-fluorouracil (FP) (Conv-FP), hypofractionated RT + FP (Hypo-FP), and regimens from the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial (CROSS). The overall survival (OS), pathologic complete response (pCR), toxicity, and treatment compliance rates were analyzed. ResultsAmong the 600 patients, 225 received Conv-FP, 255 received Hypo-FP, and 120 received the CROSS regimen. The OS rates at 1 year were 78.7%, 83.9%, and 88.1% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P < .001). The pCR rates were 30.6%, 33.9%, and 35.0%, respectively (P = .653). The overall incidence of grade 3 toxicities was 10.2%. Hematologic and nonhematologic toxicities of grade ≥ 3 were observed in 8.4% and 11.4%, 0% and 7.6%, and 5.5% and 0.8% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P = .002 and P = .030). Weight loss of > 5% was observed in 44.0%, 51.4%, and 32.5% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P < .001). In the multivariate analysis, clinical T stage (P = .004), N stage (P = .012), FP chemotherapy regimen (P = .013), surgical resection (P < .001), hematologic toxicity (P = .001), and weight loss (P = .004) were significantly associated with poor OS. ConclusionThe choice of nCRT regimen did not significantly affect the pCR rates in patients with LA-ESCC. However, the CROSS regimen demonstrated better OS and lower toxicity, suggesting that it may be the optimal treatment option among the groups.

Functional status and quality of life in older patients with advanced esophageal squamous cell cancer receiving second-line nivolumab ± ipilimumab therapy: A post hoc analysis of the phase 2, multicenter RAMONA study

IntroductionThe phase 2 RAMONA study demonstrated that second-line nivolumab ± ipilimumab immunotherapy was feasible and effective in older patients with advanced esophageal squamous cell cancer (ESCC). Here, we presented results from functional status (FS) and quality-of-life (QoL) analyses. Materials and MethodsPatients aged ≥65 years with advanced ESCC and disease progression following first-line therapy were enrolled for study treatment with nivolumab ± ipilimumab. Geriatric assessments (GA) consisting of G8 and GoGo/SlowGo evaluation, and quality of life (QoL) assessments with EORTC QLQ-C30 questionnaires were conducted at baseline and during the treatment. A post hoc analysis was performed to compare therapy efficacy, toxicity, and QoL between age groups (≥70 years vs. <70 years) and functionality groups (G8 > 14 vs. ≤14 and GoGo vs. SlowGo). ResultsIn 66 treated patients with a median age of 70.5 years, older patients had non-inferior overall survival and tumor response compared to younger patients, with no increased treatment-related adverse events. Fitter patients (G8 > 14, GoGo) had a clinically, yet not statistically significant, survival advantage than less fit patients (G8 ≤ 14, SlowGo) patients. Moreover, FS by G8 and GoGo/SlowGo significantly correlated with QoL. Overall, QoL was impaired at baseline but remained stable in all scales over the course of immunotherapy. DiscussionThe administration of nivolumab ± ipilimumab second-line immunotherapy in older patients with ESCC did not show age-dependent effects and maintained QoL. GA could identify functional deficits and limitations of QoL and should be implemented in the context of immunotherapy.ClinicalTrials.gov: NCT03416244.

Safety and short-term outcomes of esophagectomy after neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy for locally advanced esophageal squamous cell cancer: analysis of two phase-II clinical trials.

Preoperative chemotherapy (CT) or chemoradiotherapy (CRT) show survival benefits in patients with locally advanced esophageal squamous cell carcinoma (ESCC); however, ESCC patients still have a dismal prognosis. We conducted two phase-II, single-armed clinical trials to assess the potential benefits, efficacy, feasibility, and safety of esophagectomy after combining preoperative CT or CRT and neoadjuvant programmed cell death protein 1 (PD-1) inhibitors in the treatment of ESCC. Patients were included with histologically confirmed ESCC (clinical stage II-IVA according to the American Joint Committee on Cancer 8th staging system) from two phase-II, single-arm trials (NCT04506138 and NCT03940001). Patients underwent two doses of intravenous PD-1 inhibitor (either camrelizumab or sintilimab) every 3 weeks, combined with two cycles of either CT or CRT. The primary endpoint of the study was the safety and short-term outcomes of esophagectomy as measured by the risk of developing complications within 30 days, after the combination of preoperative PD-1 inhibitor and CT or CRT Secondary endpoint was to evaluate the pCR rates (pT0N0), primary tumor pCR rates (pT0), operation time, postoperative stay, and 30-day mortality rate between both groups. Results between both groups were compared using a multivariable log-binomial regression model to obtain the adjusted relative risk ratios (RRs). Between May 2019 and June 2022, 55 patients were included. All patients completed neoadjuvant therapy. Age, sex, performance status, clinical stage, histologic subtype, procedure type, operative time, and blood loss volume were similar between the two groups. The primary tumor pCR rates were 52.9% in the nICRT group and 21.6% in the nICT group (P=0.03), while the postoperative pCR rates were 41.2% in the nICRT group and 21.6% in the nICT group (P=0.19). The minimally invasive surgery rates were 89.2% (33/37) in the nICT group and 94.1% (16/17) in the nICRT group. The risk of developing pulmonary, anastomotic, or other complications were similar between the two groups. Esophagectomy was safe after the addition of the PD-1 inhibitor to preoperative CT or CRT in ESCC neoadjuvant therapies. Follow-up and the exploratory endpoints, including biomarkers analyses, are ongoing.

Simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with nimotuzumab for locally advanced esophageal squamous cell carcinoma (ESCC): A phase II clinical trial

ObjectiveTo evaluate the feasibility, safety and efficacy of concurrent simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with nimotuzumab in the treatment of locally advanced esophageal squamous cell cancer (ESCC).MethodsEligible patients were histologically proven to have locally advanced ESCC, and were unable to tolerate or refuse concurrent chemoradiotherapy (CCRT). Enrolled patients underwent concurrent SIB-IMRT in combination with nimotuzumab. SIB-IMRT: For the planning target volume of clinical target volume (PTV-C), the prescription dose was 50.4 Gy/28fractions, 1.8 Gy/fraction, 5fractions/week, concurrently, the planning target volume of gross tumor (PTV-G) undergone an integrated boost therapy, with a prescription dose of 63 Gy/28fractions, 2.25 Gy/fraction, 5 fractions/week. Nimotuzumab was administered concurrently with radiotherapy, 200 mg/time, on D1, 8, 15, 22, 29, and 36, with a total accumulation of 1200 mg through intravenous infusion. The primary endpoint of the study was the safety and efficacy of the combined treatment regimen, and the secondary endpoints were 1-year, 2-year, and 3-year local control and survival outcomes.Results(1) From December 2018 to August 2021, 35 patients with stage II-IVA ESCC were enrolled and 34 patients completed the full course of radiotherapy and the intravenous infusion of full-dose nimotuzumab. The overall completion rate of the protocol was 97.1%. (2) No grade 4–5 adverse events occurred in the entire group. The most common treatment-related toxicity was acute radiation esophagitis, with a total incidence of 68.6% (24/35). The incidence of grade 2 and 3 acute esophagitis was 25.7% (9/35) and 17.1% (6/35), respectively. The incidence of acute radiation pneumonitis was 8.6% (3/35), including one case each of Grades 1, 2, and 3 pneumonitis. Adverse events in other systems included decreased blood cells, hypoalbuminemia, electrolyte disturbances, and skin rash. Among these patients, five experienced grade 3 electrolyte disturbances during the treatment period (three with grade 3 hyponatremia and two with grade 3 hypokalemia). (3) Efficacy: The overall CR rate was 22.8%, PR rate was 71.4%, ORR rate was 94.2%, and DCR rate was 97.1%.(4) Local control and survival: The 1-, 2-, and 3-year local control (LC) rate, progression-free survival(PFS) rate, and overall survival(OS) rate for the entire group were 85.5%, 75.4%, and 64.9%; 65.7%, 54.1%, and 49.6%; and 77.1%, 62.9%, and 54.5%, respectively.ConclusionsThe combination of SIB-IMRT and nimotuzumab for locally advanced esophageal cancer demonstrated good feasibility, safety and efficacy. It offered potential benefits in local control and survival. Acute radiation esophagitis was the primary treatment-related toxicity, which is clinically manageable. This comprehensive treatment approach is worthy of further clinical exploration (ChiCTR1900027936).

A phase III trial comparing 5-FU plus cisplatin (CF) versus CF plus docetaxel or radiotherapy as neoadjuvant treatment for locally advanced esophageal cancer: 5-year follow-up from JCOG1109.

4082 Background: Triplet chemotherapy with CF plus docetaxel (DCF) improved survival compared to CF as a neoadjuvant treatment for locally advanced esophageal squamous cell cancer (ESCC) based on the result from JCOG1109 (jRCTs031180202). Here we report results with 5 years minimum follow-up. Methods: Eligible patients (pts) with ESCC of clinical stage IB, II, III (excluding T4) (UICC 7th) from 44 institutions were randomized 1:1:1 to neoadjuvant CF (cisplatin 80 mg/m2 on day1 plus 5-FU 800 mg/m2 on days 1-5 Q3W/2 course), DCF (docetaxel 70 mg/m2 on day 1, cisplatin 70 mg/m2 on day1, plus 5-FU 750 mg/m2 on days 1-5 Q3W/3 course), or CF-RT (cisplatin 75 mg/m2 on day 1 plus 5-FU 1000 mg/m2 on days 1-4 Q4W/2 course, radiation 41.4 Gy/23 fr). Primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), and safety. Differences in OS was assessed in the ITT using the stratified log-rank test. The data cutoff date for the analysis was July 20, 2023. Results: Of 601 pts 199 CF, 202 DCF, and 200 CF-RT were enrolled from December 5, 2012 to July 20, 2018. Among 601 pts, 88.2% were male, median (range) age was 65 (30-75), clinical stage III (nonT4) pts were 62.6%. Median follow-up time (range) was 5.5 years (y) (0-10.6). Median OS in CF, DCF, and CF-RT arm were 5.8 y, 10.2 y, and 8.2 y, and 5-year OS was 51.9%, 65.1%, and 60.2%, respectively (stratified log-rank test: one-sided p = 0.004 for CF vs. DCF and one-sided p = 0.15 for CF vs. CF-RT). By the stratified Cox regression analysis for OS, hazard ratios (HR) [95% CI] with DCF vs. CF was 0.68 [0.51–0.91] and that with CF-RT vs. CF was 0.86 [0.66–1.13]. The HR for OS in exploratory comparison between DCF vs. CF-RT was 0.78 [0.59-1.05]. Median PFS in CF, DCF, and CF-RT arm were 2.7 y, 9.5 y, and 5.8 y, and 5-year PFS was 42.6%, 55.7%, and 53.5%, respectively. In the CF arm, there were initially 4 treatment-related and 15 other deaths, with 1 additional treatment-related and 2 other deaths over two more years. The DCF arm reported 4 and 10 deaths respectively, with 3 additional deaths from other causes. In the CF-RT arm, there were 4 treatment-related and 27 other deaths, followed by 2 more treatment-related and 4 other deaths in the extended period. Conclusions: After 5 years follow-up, neoadjuvant DCF continued to demonstrate clinically meaningful improvements in OS and PFS compared to CF in patients with locally advanced ESCC. Clinical trial information: jRCTs031180202 .

Interplay of cachexia progression on the efficacy and toxicity of immune checkpoint inhibitors in patients with esophageal squamous cell cancer (ESCC): A longitudinal perspective.

e14629 Background: Immune checkpoint inhibitors (ICIs) have significantly improved the survival of patients with advanced esophageal squamous cell cancer (ESCC), however, the benefit of ICIs was limited to a few patients. It is vital to comprehend the factors influencing the response in order to identify patients who might benefit from ICIs. Cachexia, an intricate multifaceted syndrome characterized by the loss of skeletal muscle and substantial weight reduction, might impact on the immune response and efficacy of ICIs in cancer patients. The purpose of this study is to explore the impact of longitudinal dynamics of cachexia on the efficacy and adverse effect of ICIs for advanced ESCC patients. Methods: Advanced ESCC patients received at least two cycles of ICIs were enrolled from 2017 to 2021. The baseline and longitudinal changes of cachexia during ICI treatment were collected. Based on the longitudinal weight changes during ICI treatment, patients exhibiting cachexia at baseline were categorized into "reversible cachexia" and "irreversible cachexia" group, and patients without cachexia at baseline were also divided into "latent cachexia" and "cachexia-free" group. Kaplan-Meier curves and Cox regression analysis were performed to explore the impact of cachexia on the efficacy ICIs for ESCC patients. And chi-square test was used to evaluate the correlation between cachexia and immune-related adverse effects (irAEs). Results: A total of 278 individuals who had either received or were presently undergoing ICI treatment were enrolled, with the median progression free survival (PFS) of 5.8 months and overall survival (OS) of 8.3 months. Patients with cachexia before treatment had notably poorer outcomes, with median PFS of 7.9 vs 5.3 months (P=0.001), median time to progression (TTP) of 10.9 vs 6.1 months (P&lt;0.001), and median OS of 14.3 vs 9.2 months (P=0.001). In terms of the longitudinal dynamics of cachexia, significantly inferior outcomes were observed for patients in irreversible cachexia compared to reversible cachexia, with the PFS of 4.4 months and 9 months (P&lt;0.001), the TTP of 4.9 months and 9 months (P=0.006), and the OS of 7.8 months and 15 months, respectively (P=0.003). Although patients in latent cachexia group had inferior survival compared to cachexia-free group, no statistical difference was observed, with the PFS of 10.0 and 7.9 months and OS of 13.9 and 16.2 months. Besides, neither baseline nor longitudinal changes of cachexia was associated with irAEs for ESCC patients. Conclusions: This study indicated the impact of baseline and longitudinal cachexia on the efficacy of ICIs for advanced ESCC patients with ICIs. Dynamic monitoring and management of cachexia was recommended during the ICI treatment of ESCC patients.

The use of a thoracodorsal flap in the surgical treatment of squamous cell skin cancer (case report)

We report a case of successful surgical treatment of a patient with locally advanced cutaneous squamous cell cancer (cSCC) originating from a burn scar. The burn scar cSCC tends to be more aggressive in nature than conventional skin SCC. treatment of patients with cSCC arising from a burn scar is complicated by the fact that the extensive defects formed after tumor removal are almost impossible to close with local tissues. Purpose: to demonstrate the feasibility of performing surgery for locally advanced cSCC using a thoracodorsal flap. Clinical case description. A 70-year old man presented with cSCC of the right shoulder. The patient had experienced a severe burn covering 70 % of his body surface area at a young age. To repair a large skin defect after tumor resection in the right shoulder, a thoracodorsal artery perforator flap was used. there were no complications in the postoperative period. At a follow-up of 7 months, no evidence of tumor recurrence was observed. Conclusion. The thoracodorsal artery perforator flap has contributed to the efficient reconstruction of extensive soft tissue defects in patients with locally advanced cSCC originating from a burn scar.

Effect of longitudinal changes of cachexia on the efficacy and toxicity of immune checkpoint inhibitors in esophageal squamous cell cancer (ESCC) patients

PurposeImmune checkpoint inhibitors (ICIs) have enhanced survival in advanced esophageal squamous cell cancer (ESCC) patients, but their efficacy varies. Cachexia, characterized by muscle loss and significant weight loss, might influence ICI response. This study examines the relationship between cachexia's longitudinal changes and ICI outcomes in ESCC patients. MethodsESCC patients undergoing at least two ICI cycles from 2017 to 2021 were studied. Cachexia's baseline and evolving patterns during ICI treatment were observed. Kaplan-Meier and Cox regression analyses were used to assess cachexia's effect on ICI efficacy. Chi-square tests were used to determine cachexia's link to immune-related adverse effects (irAEs). ResultsTwo hundred seventy-eight ICI-treated patients had a median progression-free survival (PFS) of 5.78 months and overall survival (OS) of 8.3 months. Pretreatment cachexia led to worse outcomes: PFS 7.87 versus 5.3 months, time to progression (TTP) 10.9 versus 6.1 months, and OS 14.3 versus 9.2 months. Irreversible cachexia showed the poorest results. Cachexia's changes weren't associated with irAEs. ConclusionBaseline and evolving cachexia significantly impact ICI efficacy in ESCC patients. Continuous cachexia monitoring during ICI therapy is crucial for optimal ESCC management.

Abstract 3741: Helper/killer hybrid epitope long peptide (H/K-HELP) cancer vaccine augments Th1-dependent CTL induction at tumor-draining lymph node to eradicate solid tumor: its application to develop an innovative combination cancer immunotherapy(iCCI)

Abstract We have initially demonstrated the pivotal role of IFN-γ-producing tumor-antigen-specific Th1 cells for the complete eradication of established tumor mass by CTL. The accumulated evidence has clearly demonstrated that induction of Th1-dependent full activation of CTL at tumor-draining lymph nodes (TDLN) are crucial for inducing complete rejection of solid tumor by CTL. To induce Th1 immunity efficiently at TDLN in tumor-bearing host, we developed an artificially synthesized helper/killer-hybrid epitope long peptide (H/K-HELP), which conjugated killer and helper epitope peptides of cancer antigen by a glycine-linker. In mouse model, OVA-H/K-HELP was selectively presented in vivo by professional DC in vaccinated TDLN and sustained antigen presentation capability of DC to stimulate both CTL and Th1 cells. Thus, in contrast to short peptide, vaccination of OVA-expressing EG7-bearing mice with OVA-H/K-HELP caused a complete eradication of EG7 tumor mass. To apply these basic findings to clinical treatment of cancer patients, we then developed Survivin-H/K-HELP. Treatment of a patient with a triple-negative breast cancer patient with Survivin-H/K-HELP induced a complete response in a triple-negative breast cancer patient concomitantly with the induction of Th1-dependent cellular and humoral immune responses. In this clinical study, the patients showed Th1-dependent C’-fixing IgG antibody production and exhibited IFN-γ-producing Th1 cellular responses. Finally, we also applied H/K-HELP-pulsing DC-vaccine to develop an innovative combination cancer immunotherapy (iCCI). The iCCI consisting of radiation, low dose of immune check point inhibitors (ICIs:Nibolumab, Ipilimumab) and H/K-HELP-pulsed DC, all of which have been shown to initially modulate antitumor immunity at TDLN. Here, we described a successful outcome of a case of the stage IVA inoperable advanced hypopharyngeal squamous cell cancer patient with lymph node-metastasis. The iCCI treatment of the patient caused a complete disappearance of all cancers and the patient has been cancer free for over 15 months so far. Although the destruction mechanism of cancer is not determined, we image this iCCI might improve patient’s antitumor immune capability in immune microenvironment around tumor (IMAT) including TDLN and TME. Our developed iCCI will become a promising strategy to overcome inoperable advanced cancers in future. Citation Format: Takanori Iwasaki, Yuichiro Yazaki, Takashi Masuko, Takashi Nishimura. Helper/killer hybrid epitope long peptide (H/K-HELP) cancer vaccine augments Th1-dependent CTL induction at tumor-draining lymph node to eradicate solid tumor: its application to develop an innovative combination cancer immunotherapy(iCCI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3741.

Neoadjuvant chemoradiotherapy combined with sequential perioperative toripalimab in locally advanced esophageal squamous cell cancer

BackgroundProgrammed death 1 (PD-1) inhibitor demonstrated durable antitumor activity in advanced esophageal squamous cell carcinoma (ESCC), but the clinical benefit of perioperative immunotherapy in ESCC remains unclear. This study evaluated...

Impact of Skeletal Muscle Loss and Sarcopenia on Outcomes of Locally Advanced Esophageal Cancer during Neoadjuvant Chemoradiation.

The impact of changes in skeletal muscle and sarcopenia on outcomes during neoadjuvant chemoradiotherapy (NACR) for patients with esophageal cancer remains controversial. We retrospectively analyzed the data of patients with locally advanced esophageal squamous cell cancer who received NACR followed by esophagectomy between June 2013 and December 2021. The images at third lumbar vertebra were analyzed to measure the cross-sectional area and calculate skeletal muscle index (SMI) before and after NACR. SMI less than 52.4 cm2/m2 for men and less than 38.5 cm2/m2 for women were defined as sarcopenia. The nonlinearity of the effect of percent changes in SMI (ΔSMI%) to survival outcomes was assessed by restricted cubic splines. Overall, data of 367 patients were analyzed. The survival outcomes between sarcopenia and non-sarcopenia groups had no significant differences before NACR. However, patients in post-NACR sarcopenia group showed poor overall survival (OS) benefit (P = 0.016) and poor disease-free survival (DFS) (P = 0.043). Severe postoperative complication rates were 11.9% in post-NACR sarcopenia group and 5.0% in post-NACR non-sarcopenia group (P = 0.019). There was a significant non-linear relationship between ΔSMI% and survival outcomes (P < 0.05 for non-linear). On the multivariable analysis of OS, ΔSMI% > 12% was the independent prognostic factor (HR 1.76, 95% CI 1.03-2.99, P = 0.039) and significant difference was also found on DFS analysis (P = 0.025). Patients with post-neoadjuvant chemoradiotherapy sarcopenia have worse survival and adverse short-term outcomes. Moreover, greater loss in SMI is associated with increased risks of death and disease progression during neoadjuvant chemoradiotherapy, with maximum impact noted with SMI loss greater than 12%.

Definitive Chemoradiotherapy versus Upfront Surgery in Locoregional Esophageal Squamous Cell Cancer

BACKGROUND Previous studies have indicated that definitive chemoradiotherapy and upfront surgery have comparable survival rates, and definitive chemoradiotherapy is a more applicable treatment option in resectable locally advanced esophageal squamous cell cancer (ESCC). We compared definitive chemoradiotherapy to upfront surgery for survival in locally advanced ESCC patients who denied the standard treatment approach, receiving definitive chemoradiotherapy or upfront surgery. MATERIALS AND METHODS One hundred eighty eight locoregional ESCC patients with thoracic and distal involvement who had upfront surgery were compared with those who received chemoradiotherapy but declined surgery, although their tumor was resectable at presentation. Patients who underwent upfront surgery with negative surgical margins were included. The upfront surgery group received no adjuvant treatment (chemotherapy or radiotherapy). The definitive chemoradiotherapy group received standard therapy with 50.4 Gray/28 fractions/6 weeks concomitantly with weekly Paclitaxel 50 mg/m2 and Carboplatin AUC 2 combination regimen. RESULTS A total of 102 patients (54.3%) underwent surgery up front, whereas 86 patients (45.7%) had definitive chemoradiotherapy.The median follow-up of the study was 31 months. Definitive chemoradiotherapy had a median disease-free survival (DFS) of 39 months compared to 16 months for upfront surgery (p:0.005). Median overall survival (OS) was 29 months in upfront surgery and 47 months in definitive chemoradiotherapy (p=0.01). Although the multivariate Cox regression analysis found no difference in DFS between upfront surgery and definitive chemoradiotherapy groups, OS was greater with the latter (HR, 0.69; 95% CI, 0.47 to 1.00; p=0.05). CONCLUSIONS In this non-randomized retrospective analysis, definitive chemoradiotherapy improved overall survival compared to upfront surgery in locally advanced ESCC patients.