Advanced Squamous Cell Cancer Research Articles

Phase II study of definitive chemoradiation for locally advanced squamous cell cancer of the vulva: An efficacy study

ObjectiveTo evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. MethodsIn a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. Results52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute ≥ grade 3 toxicities were regarding skin/mucosa and pain (54% and 37%). Late ≥grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. ConclusionsDefinitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity.

Contrast-enhanced CT radiomics features to predict recurrence of locally advanced oesophageal squamous cell cancer within 2 years after trimodal therapy: A case-control study.

Radiomics transforms the medical images into high-dimensional quantitative features and provides potential information about tumor phenotypes and heterogeneity. We conducted a retrospective analysis to explore and validate radiomics model based on contrast-enhanced computed tomography (CECT) to predict recurrence of locally advanced oesophageal squamous cell cancer (SCC) within 2 years after trimodal therapy. This study collected CECT and clinical data of consecutive 220 patients with pathology-confirmed locally advanced oesophageal SCC (154 in the training cohort and 66 in the validation cohort). Univariate statistical test and the least absolute shrinkage and selection operator method were performed to select the optimal radiomics features. Logistic regression was conducted to build radiomics model, clinical model, and combined model of both the radiomics and clinical features. Predictive performance was judged by the area under receiver operating characteristics curve (AUC), accuracy, and F1-score in the training and validation cohorts. Ten optimal radiomics features and/or 7 clinical features were selected to build radiomics model, clinical model, and the combined model. The integrated model of radiomics and clinical features was superior to radiomics model or clinical model in predicting recurrence of locally advanced oesophageal SCC within 2 years in the training (AUC: 0.879 vs 0.815 or 0.763; accuracy: 0.844 vs 0.773 or 0.740; and F1-score: 0.886 vs 0.839 or 0.815, respectively) and validation (AUC: 0.857 vs 0.720 or 0.750; accuracy: 0.788 vs 0.700 or 0.697; and F1-score: 0.851 vs 0.800 or 0.787, respectively) cohorts. The combined model of radiomics and clinical features shows better performance than the radiomics or clinical model to predict the recurrence of locally advanced oesophageal SCC within 2 years after trimodal therapy.

Dysphagia progression-free survival in oesophageal cancer patients treated with palliative radiation therapy

Background: In patients with advanced oesophageal carcinoma, palliation of dysphagia is important to maintain a reasonable quality of life.Aim: To determine the dysphagia progression-free survival (DPFS) in patients with advanced oesophageal carcinoma treated with palliative radiotherapy (RT).Setting: Groote Schuur Hospital, Cape Town, between January 2015 and December 2016.Methods: The medical records of all patients with oesophageal carcinoma were reviewed, and patients who were not candidates for curative treatment and received palliative RT were selected. For these patients, the dysphagia score (DS) was recorded prior to RT, six weeks after RT and at each follow-up visit. The DPFS was calculated as the time from completion of RT to worsening of DS by ≥ 1 point or until death. Other outcomes measured were objective change in DS and survival post RT.Results: The study population comprised 84 patients. Squamous cell cancer was the primary histological subtype (93%). The median duration of DPFS after RT was 73 days, with approximately two-thirds of remaining patients able to swallow at least liquids and soft diet until death. The difference in median duration of DPFS was not statistically significant in stented versus non-stented patients (54 days vs 83 days, p = 0.224). The mean change in DS was 0.45 ± 0.89 points following RT and the post-RT survival was significantly shorter in patients with stent insertion (81 days vs 123 days, p = 0.042).Conclusion: Palliative RT can successfully be used to prolong DPFS in patients with locally advanced and metastatic squamous cell cancer of the oesophagus.

The sequence of chemotherapy and anti-PD-1 antibody influence the efficacy of neoadjuvant immunochemotherapy in locally advanced esophageal squamous cell cancer: A phase II study.

4051 Background: PD-1 blockade may result in expansion of tumor-specific T cells. However, traditional immunochemotherapy regimens usually designed to use chemotherapy drugs and anti-PD-1 antibody on the same day, which may make chemotherapy drugs kill activated T cells. The purpose of this study was to investigate the rate of pCR of chemotherapy plus anti-PD-1 therapy and the influence of sequence of chemotherapy and anti-PD-1 therapy on pCR in patients with locally advanced esophageal squamous cell cancer. Methods: Thirty esophageal squamous cell cancer patients with T3, T4, or lymph node positive were assigned into experiment group (anti-PD-1 antibody was administrated two days after chemotherapy) and control group ( anti-PD-1 antibody and chemotherapy were administrated on the same day) according to the order of enrollment. There were fifteen patients in each group. The chemotherapeutic regimen was paclitaxel and cisplatin, paclitaxel was given at the dose of 150-175mg/m2 on day 1 and cisplatin was given at the dose of 70-75mg/m2 on day 1. The anti-PD-1 antibody was toripalimab at the fixed dose of 240mg on day 3 or day 1. Operation was performed four to six weeks after the second cycle of chemotherapy combined with toripalimab. Results: From July 2019 to September 2020, a total of 30 patients completed at least one cycle of immunochemotherapy. 11 in the experimental group received operation after two cycles of neoadjuvant chemotherapy plus toripalimab. Thirteen in control groupreceived operation aftertwo cycles of neoadjuvant chemotherapy plus toripalimab. Four patients in experimental group and one in control group got pCR, the rates of pCR in experimental group and control group were 36.4% and 7.7% individually. Although the difference was not significant in statistics, the experimental group had the trend of higher pCR rate(c2= 3.092, p = 0.079). PD-L1 CPS examination before treatment was performed in fourteen patients, it was found that except one patient with PD-L1 CPS was 10, the left thirteen with PD-L1 CPS were all below one. The patient with PD-L1 CPS 10 was in control group and pCR was got in this patient. Except one patient in the experimental group had grade 3 immune-related enteritis, one patient in the control group died from immune-related myocarditis after operation, there were no more immune-related events more than grade 3. Conclusions: Toripalimab was delayed on day 3 when toripalimab plus chemotherapy was taken as neoadjuvant therapy regimen in locally advanced esophageal squamous cell carcinoma might achieve a higher pathological complete response than toripalimab and chemotherapy used on the same day. Clinical trial information: NCT 03985670.

Efficacy and safety of anti-EGFR monoclonal antibody (SCT200) as third-line or further treatment in advanced lung squamous cell cancer.

e21070 Background: Treatment strategies for advanced lung squamous cell cancer (LSCC) of third-line or further-line are limited. We assessed the efficacy and safety of recombinant anti-EGFR monoclonal antibody SCT200 in patients with advanced LSCC in a phase 1b study. Methods: Advanced LSCC Patients previously treated with at least two chemotherapy regimens were randomly assigned to intravenous injection of SCT200 9 or 12 mg/kg every week (QW) for a maximum of 6 cycles, followed by 12 or 15 mg/kg every two weeks (Q2W). The primary endpoint was objective response rate (ORR). The secondary endpoint was progression free survival (PFS), overall survival (OS) and safety. This study was registered at ClinicalTrials.gov (NCT03808701). Results: Between March 19, 2019 and October 19, 2019, a total of 25 patients were enrolled and 23 were included in the final analysis (10 low dose [9mg/kg] and 13 high dose [12mg/kg]). The median age was 57 years old, and 21 (91.3%) patients were males. 22 patients (95.6%) had ECOG performance status of 1, and 17 (74%) were stage IV. The baseline characteristics were similar between the two dose groups. While no patients were evaluated as complete response or partial response, 5 and 6 patients achieved stable disease in the 9mg/kg and 12mg/kg dose groups respectively. However, the mOS was 5.96m (2.14 ̃ NR) and 9.59m (2.86 ̃ NR) in the low and high dose groups respectively. The mPFS was 2.23 (0.23 ̃ 5.26) and 1.38 (1.25 ̃ 3.02) in each group. The most common grade ≥3 treatment-related AEs were hypomagnesemia (13%), rash (13%) and anemia (4.3%). Conclusions: In this trial, a clinical benefit in OS was observed in the high dose group. SCT200 was shown to be safe and well tolerated in all patients. Our study indicated that SCT200 could serve as a potential single treatment or in combination with other therapy for advanced LSCC. Clinical trial information: NCT03808701. [Table: see text]

Nivolumab and ipilimumab for second-line therapy in elderly patients with advanced esophageal squamous cell cancer: Safety interim analysis of the RAMONA trial.

4029 Background: Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients (pts) with additional comorbidities. Limited treatment options are available. We report the safety interim analysis of a phase II clinical trial evaluating nivolumab and ipilimumab as second-line therapy for advanced ESCC in elderly pts. Methods: RAMONA is a multicenter open-label phase II trial assessing nivolumab/ipilimumab combination therapy in elderly pts (≥65 years). The geriatric status of the pts was assessed using the G8 screening tool and the Deficit Accumulation Frailty Index (DAFI). After a run-in phase of 3 cycles nivolumab (240mg Q2W), cohort assignment was based on a safety assessment. Pts with toxicities grade ≤2 were considered eligible for escalation to nivolumab (240mg Q2W)/ipilimumab (1mg/kg Q6W) combination therapy (cohort B). Other pts remained on nivolumab monotherapy (cohort A). Primary endpoint is overall survival (OS). Key secondary endpoint is time to Quality of Life deterioration defined as a loss of ≥ 10 points in the EORTC QLQ-C30 compared to baseline. Adverse events were assessed according to NCI-CTCAE version 4.03. Results: From February 2018 until February 2020, 69 pts entered the study. 61 pts were eligible for safety interim analysis. Median age of the pts was 71.9 yrs (± 5.4), median KPS score was 80% (50-100%). In 73.8% of the pts, metastases were detected at the time of study inclusion. Most pts received the IO therapy in ≥ 2nd line (91.8%). The mean G8-score at screening was 11.9 points (46 pts ≤ 14 points, 75.4%) (mean DAFI: 0.19). Based on safety assessment, 42 pts were escalated to nivolumab/ipilimumab, while 9 pts remained on nivolumab monotherapy. 10 pts were not allocated at the time of analysis. Median numbers of cumulative doses were 3.0 [1.0 - 3.0] for the run-in phase (nivolumab), 6.0 [1.0 – 48.0] for nivolumab therapy (cohort A/B) and 2.5 [1.0 – 16.0] for ipilimumab (cohort B). Median treatment duration was 144.5 days (56-781 days) in cohort A and 231 days (85-484 days) in cohort B. Frailty indices remained stable after 3 cycles of nivolumab with limited toxicity at the time of the safety assessment. Drug-related treatment emergent adverse events (AEs) were observed in 42 pts (68.9%); 29/42 in cohort A, 8/9 in cohort B, and 5/10 pts not allocated at the time of analysis. Grade ≥3 AEs were detected in 9 pts of 42 in cohort A and 4 of 9 pts in cohort B. Drug-related treatment emergent serious adverse events (SAEs) were detected in 12 pts (19.7%); 8/42 in cohort A, 2/9 pts in cohort B, and 2/10 pts not yet allocated. Conclusions: Combined nivolumab/ipilimumab is a safe and feasible second-line therapy for elderly pts with advanced ESCC. Most pts could be escalated to nivolumab/ipilimumab. Treatment duration was exceptional long for a subset of pts. Clinical trial information: NCT03416244.

Safety and efficacy of anti-EGFR monoclonal antibody (SCT200) as second-line therapy in advanced esophageal squamous cell cancer.

e16046 Background: The mainstay treatment of esophageal squamous cell carcinoma (ESCC) involves chemotherapy and immunotherapy. However, alternative therapies are required for patients refractory or intolerant to the existing therapies. Methods: In this single-arm, multicenter, open-label phase Ib study, 30 patients received an intravenous infusion of SCT200, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, 6.0 mg/kg once a week for six weeks, followed by 8.0 mg/kg once every two weeks until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty patients were enrolled between July 2018 and May 2019. The ORR was 16.7% (95%CI: 5.6%–34.7%). The median PFS and OS was 3.1 months (95%CI: 1.5–4.3) and 6.8 months (95%CI: 4.7–10.1) respectively. Numerical difference without a statistical significance in ORR was observed in patients with different EGFR expression (≥50%: 25.0% vs. < 50%: 0%, P = 0.140) or TP53 mutation abundance ( < 10%: 23.8% vs. ≥10%: 0%, P = 0.286). Improved median PFS (3.4 vs. 1.4 months, P = 0.006) and OS (8.0 vs. 4.2 months, P = 0.027) were associated with TP53 mutation abundance of < 10%. The most common treatment-related adverse events of grade 3 or 4 (occurring in ≥2 patients) were hypomagnesemia (7 [23.3%]) and rash (2 [6.7%]). No treatment-related death occurred. Conclusions: SCT200 monotherapy as second- or further-line for advanced ESCC showed favorable efficacy, with an acceptable safety profile. TP53 mutation abundance might serve as potential predictive biomarkers. Clinical trial information: NCT03817567. [Table: see text]

Efficacy and safety of vinorelbine and cisplatin regimen of different doses and intensities for neoadjuvant chemotherapy in patients with locally advanced esophageal carcinoma.

BackgroundThere are few studies focused on comparing the toxicity, postoperative complication rate, and survival among patients with locally advanced esophageal squamous cell cancer receiving a different dose and intensity of vinorelbine plus cisplatin for neoadjuvant chemoradiotherapy (nCRT) followed by surgery.MethodsIn total, 78 patients diagnosed with locally advanced esophageal squamous cell cancer that had received a vinorelbine and cisplatin (VP)1 or VP2 regimen for nCRT followed by surgery in Taizhou Hospital of Zhejiang Province between June 2008 and December 2016 were retrospectively analyzed. The VP1 regimen involved cisplatin 75 mg/m2 on day 1, and vinorelbine 25 mg/m2 on days 1 and 8, for two cycles. The VP2 regimen involved cisplatin 25 mg/m2 on days 1 to 4, and vinorelbine 25 mg/m2 on days 1 and 8, for two cycles. The rate of adverse events, postoperative complications, and survival were compared between the two groups.ResultsThe median overall survival (OS) was 97.6 months (85.6–109.7) in the VP2 group, which was not significantly different to that of the VP1 group [hazard ratio (HR), 1.008 (0.999–1.108); P=0.509]. The main toxicity was hematologic adverse events. The VP2 group had significantly higher rates of all grades of anemia, leukopenia, neutropenia, and thrombocytopenia (all P<0.05), as well as grade 3 or 4 of leukopenia and neutropenia (P<0.05) compared to the VP1 group. Regarding postoperative complications, the VP2 group had a significantly higher rate of pulmonary infection than the VP1 group (P<0.05).ConclusionsCompared with VP2, VP1 showed comparable efficacy in terms of survival, with less hematologic toxicity and postoperative pulmonary infection. Therefore, we recommended that VP1 over VP2 to be the optimized VP neoadjuvant chemotherapy regimen for locally advanced esophageal squamous cell cancer.

A validated nomogram integrating hematological indicators to predict response to neoadjuvant therapy in esophageal squamous cell carcinoma patients.

BackgroundThe prognoses for advanced Esophageal squamous cell cancer (ESCC) was very poor. Neoadjuvant therapy was shown to improve overall survival of ESCC patients. However, there is still no effective indicator to predict the efficacy of neoadjuvant therapy. The present study intended to investigate the correlation between hematological parameters and the efficacy of neoadjuvant therapy so as to provide a reference for the prediction of cancer response to neoadjuvant therapy.MethodsThis study included 197 ESCC patients in our center from January 2010 to December 2018. Response evaluation criteria in solid tumors (RECIST) criteria were used for the treatment evaluation. The results of univariate and multivariate logistic regression analysis were used to select independent factors for construction of the prediction model. The concordance index (C-index), receiver operating characteristic (ROC) curve, and calibration curve were used to evaluate the robustness of the model, while the bootstrap method was used for internal validation.ResultsAmong the 197 included ESCC patients, 94 patients achieved partial remission, 80 patients were in stable condition, and 23 patients had disease progression, 123 of whom underwent surgery. The comparisons of the dynamic hematological test results before and after treatment show that pre-PLT, pre-MONO%, post-Hb, △WBC, and the option of undergoing neoadjuvant chemoradiation were the potential predictors for the effectiveness of neoadjuvant therapy. The model in which the C-index was 0.803 (95% confidence interval: 0.742–0.864) showed good prediction performance, and still reach a C-index of 0.764 when internally validated.ConclusionsFor the neoadjuvant treatment of ESCC, hematological indexes are closely related to the efficacy of neoadjuvant therapy. The nomogram can be used to easily predict the efficacy of neoadjuvant therapy in patients.

Application of a radiation pneumonitis prediction model in patients with locally advanced lung squamous cell cancer.

The aim of the present study was to establish a new prediction model for radiation pneumonitis (RP) in locally advanced non-small cell lung cancer (LA-NSCLC) patients before and after radiotherapy. The study involved 153 patients. Age, arterial partial oxygen pressure (PO2), forced vital capacity, pulmonary emphysema (PE), subclinical interstitial lung disease (sILD), and dosimetric parameters, such as mean lung dose and percentage of lung volume, and a dose >5/20 Gy (V5/V20), were considered candidate RP predictors. Of the 153 eligible patients, 33 (21.6%) developed RP, 68 had PE (43.8%), and 24 (15.7%) had sILD. Grades 2, 3, and 5 RP were scored in 17 (11.1%), 15 (9.8%), and 1 (0.7%) patient/s, Grade 4 RP was not observed. Grades 1, 2, and 3 PE were scored in 45 (29.4%), 22 (14.4%), and 1 (0.7%) patient/s. Grades 0 and 1 sILD were observed in 129 (84.3%) and 24 (15.7%) patients. Univariate analysis found age, PE, and sILD to be significantly correlated with grade ≥2 RP. Multivariate analysis revealed age >68 years, PE grade >1, and sILD grade ≥1 as independent risk factor for grade ≥2 RP in LA-NSCLC with squamous cell carcinoma (SCC). Finally, a new predictive risk score (PRS) comprised of these factors was developed. The PRS score was 0, 3-5, and 6-11 when the cumulative incidence of grade ≥2 RP was 8.8% (5 patients), 13% (3 patients), and 84.6% (13 patients) (P=<0.001). Age, PE, and sILD could independently and significantly predict RP in LA-NSCLC with SCC.

Dose-escalated radiotherapy with PET/CT based treatment planning in combination with induction and concurrent chemotherapy in locally advanced (uT3/T4) squamous cell cancer of the esophagus: mature results of a phase I/II trial

BackgroundThis prospective phase I/II trial assessed feasibility and efficacy of dose-escalated definitive chemoradiation after induction chemotherapy in locally advanced esophageal cancer. Primary study endpoint was loco-regional progression-free survival at 1 year.MethodsEligible patients received 2 cycles of induction chemotherapy with irinotecan, folinic acid and 5-fluorouracil weekly and cisplatin every 2 weeks (weeks 1–6, 8–13) followed by concurrent chemoradiation with cisplatin and irinotecan (weeks 14, 15, 17, 18, 20). Radiotherapy dose escalation was performed in three steps (60 Gy, 66 Gy, 72 Gy) using conventional fractionation, planning target volumes were delineated with the aid of 18F-FDG-PET/CT scans. During follow-up, endoscopic examinations were performed at regular intervals.ResultsBetween 09/2006 and 02/2010, 17 patients were enrolled (male/female:13/4, median age: 59 [range 48–66] years, stage uT3N0/T3N1/T4N1: 4/12/1). One patient progressed during induction chemotherapy and underwent surgery. Of 16 patients treated with definitive chemoradiotherapy, 9 (56%) achieved complete response after completion of chemoradiation. One-, 2-, 3- and 5-year overall survival rates (OS) were 77% [95%CI: 59–100], 53% [34–83], 41% [23–73], and 29% [14–61], respectively. Loco-regional progression-free survival at 1, 3, and 5 years was 59% [40–88], 35% [19–67], and 29% [14–61], corresponding cumulative incidences of loco-regional progressions were 18% [4–39%], 35% [14–58%], and 41% [17–64%]. No treatment related deaths occurred. Grade 3 toxicities during induction therapy were: neutropenia (41%), diarrhoea (41%), during combined treatment: neutropenia (62%) and thrombocytopenia (25%).ConclusionsDose-escalated radiotherapy and concurrent cisplatin/irinotecan after cisplatin/irinotecan/5FU induction chemotherapy was tolerable. The hypothesized phase II one-year loco-regional progression free survival rate of 74% was not achieved. Long-term survival compares well with other studies on definitive radiotherapy using irinotecan and cisplatin but is not better than recent trials using conventionally fractionated radiotherapy ad 50 Gy with concurrent paclitaxel or 5FU and platinum compound.Trial registration The present trial was registered as a phase I/II trial at the EudraCT database: Nr. 2005-006097-10 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-006097-10/DE) and authorized to proceed on 2006-09-25.

Radiomics Signature Facilitates Organ-Saving Strategy in Patients With Esophageal Squamous Cell Cancer Receiving Neoadjuvant Chemoradiotherapy.

After neoadjuvant chemoradiotherapy (NCRT) in locally advanced esophageal squamous cell cancer (ESCC), roughly 40% of the patients may achieve pathologic complete response (pCR). Those patients may benefit from organ-saving strategy if the probability of pCR could be correctly identified before esophagectomy. A reliable approach to predict pathological response allows future studies to investigate individualized treatment plans.MethodAll eligible patients treated in our center from June 2012 to June 2019 were retrospectively collected. Radiomics features extracted from pre-/post-NCRT CT images were selected by univariate logistic and LASSO regression. A radiomics signature (RS) developed with selected features was combined with clinical variables to construct RS+clinical model with multivariate logistic regression, which was internally validated by bootstrapping. Performance and clinical usefulness of RS+clinical model were assessed by receiver operating characteristic (ROC) curves and decision curve analysis, respectively.ResultsAmong the 121 eligible patients, 51 achieved pCR (42.1%) after NCRT. Eighteen radiomics features were selected and incorporated into RS. The RS+clinical model has improved prediction performance for pCR compared with the clinical model (corrected area under the ROC curve, 0.84 vs. 0.70). At the 60% probability threshold cutoff (i.e., the patient would opt for observation if his probability of pCR was >60%), net 13% surgeries could be avoided by RS+clinical model, equivalent to implementing organ-saving strategy in 31.37% of the 51 true-pCR cases.ConclusionThe model built with CT radiomics features and clinical variables shows the potential of predicting pCR after NCRT; it provides significant clinical benefit in identifying qualified patients to receive individualized organ-saving treatment plans.

FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF therapy for locally advanced esophageal carcinoma (JCOG1804E)—The short-term results of cohort A and B.

202 Background: The standard neoadjuvant chemotherapy (NAC) in Japan for locally advanced esophageal squamous cell cancer (ESCC) is CDDP + 5-FU (CF). Immune checkpoint inhibitors (ICI) such as nivolumab provide a survival benefit in ESCC, and have potential as NAC agents in lung, skin, and breast cancers, amongst others. However, whether ICI are efficacious in combination with cytotoxic agents, and whether ICI impact the safety of subsequent surgery after they are used as NAC for ESCC patients (pts) is currently unclear. Methods: FRONTiER is a multi-cohort phase I study designed to evaluate the safety and efficacy of ICI combined with NAC in ESCC. Histologically proven ESCC pts with cT1N1-3M0 or cT2-3N0-3M0 (8th-UICC TNM classification), 20–75 years old, PS ≤ 1, no prior therapies against any cancer were eligible. The primary endpoint was the incidence of dose-limiting toxicities (DLT) from the initial dose to the 30th postoperative day. This study contained 4 experimental cohorts, the NAC regimen of cohort A consisted of 2 courses of CDDP at 80 mg/m2, nivolumab at 360 mg/body on day 1 and 5-FU at 800 mg/m2 on days 1–5, q3wks. The regimen of cohort B consisted of one administration of nivolumab at 240 mg/body 2 weeks before chemotherapy, followed by the same treatments as cohort A. Results: Thirteen pts were enrolled to cohort A (n = 6) and B (n = 7). Characteristics were follows; median age: 62 (range: 34–75), PS 0/1: 9/4 pts, clinical stage I/II/III: 2/1/10 pts. One pt in cohort B was excluded from safety evaluation due to R2 resection, no DLTs were observed in 12 pts. The most frequent adverse events (≥ grade 3) were neutropenia in 6 pts during NAC, lung infection in 1, hyperglycemia in 1, pleural effusion in 1, infection (right neck) in 1, anemia in 1, abdominal pain in 1, and anatomic leakage in 1 during the postoperative period. Within 30 days post-operation, grade 2 adrenal insufficiency was observed in 1 pt of cohort B. No grade 4 adverse events or treatment-related deaths were seen. All pts received two courses of NAC + nivolumab and R0 resection was achieved in 12 pts (92.3%) without interruption of treatment. A pathological complete response was achieved in 2 pts (33.3%) in cohort A. Conclusions: Neoadjuvant CF + nivolumab with/without prior administration of nivolumab followed by surgery for locally advanced ESCC was well tolerated and showed promising efficacy. Clinical trial information: NCT03914443.

Prospective practice survey of management of cetuximab-related skin reactions

PurposeEvidence-based guidelines on how to prevent or treat cetuximab-related skin reactions are lacking and multiple care and management strategies are used. The main purpose of the present study is to gain information about the different skincare products being used against skin reactions in metastatic colorectal cancer (mCRC) and recurrent/metastatic (R/M) or locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) patients treated with cetuximab.MethodsAn open-label, prospective observational study conducted in the Netherlands. The occurrence of skin reactions and the care and management options taken were documented for 16 weeks, starting from the first administration of cetuximab.ResultsA total of 103 patients were included in 7 hospitals. 38 patients (37%) developed a grade ≥ 2 skin reaction. Eighty-six patients could be analysed for the primary endpoint (73.3% males, mean age 62.4 years, n = 44 LA SCCHN, n = 16 R/M SCCHN, n = 26 mCRC). The most frequently used skin products at some point during the observation period were moisturizing products (70%), systemic antibiotics (64%), topical antibiotics (58%), lipid-regenerating (28%) and other topical products (28%). The overall use of products gradually increased from baseline to week 6–10, reducing by week 16. Hospital protocols were the primary reason (> 50%) for choice of the skincare products and medications.ConclusionA variety of skin care products and antibiotics were commonly used. Only few patients developed severe cutaneous reactions. For patients, the occurrence of skin reactions did not influence their willingness to continue cetuximab therapy.

"Christie Regimen" palliative radiotherapy in advanced head-and-neck cancer: A single-center experience.

Relevance of aggressive treatment in advanced head neck squamous cell cancers(HNSCC) is debatable in view of expected poor outcome. Long treatment duration only adds up to the cost of treatment without any improvements in outcomes. To assess the outcomes of hypofractionated "Christie" palliative radiotherapy regimen in advanced HNSCC. Patients of advanced HNSCC registered from June 2015 to June 2019 were treated by parallel pair field technique on Cobalt60 machine (Theatron 780E) to total dose of 50 Gray/16 fractions over 3.2 weeks. Toxicity was scored using Radiation Therapy Oncology Group (RTOG) criteria and response was evaluated as per WHO criteria. Records of 110 patients of HNSCC with mean age of 56.19 years were analysed. Evaluation at 4-8 weeks after radiotherapy resulted in a complete response (CR) in 19.1%, partial response (PR) in 32.7%, stable disease (SD) in 29.1% and progressive disease (PD) in 3.6%, while 15.5% patients did not report for post treatment evaluation. Median progression free survival was 9.52 months (95% CI 5.9 - 13.1 months). The median overall survival was 12.7 ± 2.2 months (95% CI 8.2 - 17.2). Median time to progression after completion of radiotherapy was 84 days. Grade IV dermatitis and mucositis was encountered in 2.7% and 1.8% cases respectively, requiring hospitalization. Christie regimen for advanced HNSCC is a clinically viable option with acceptable outcomes in a resource constrained setting.

Impact Of Adding Induction Chemotherapy To Chemoradiotherapy In The Management Of Locally Advanced Squamous Cell Cancers Of The Head And Neck Presenting With Radiographic Extranodal Extension

In patients with locally advanced squamous cell cancers of the head and neck (LAHNC), the presence of radiographic extranodal extension (rENE) is known to predict for worse local control (LC), distant control (DC), and overall survival (OS). We investigated whether the addition of induction chemotherapy (IC-CRT) to standard chemoradiation (CRT) improved outcomes among this population. From our IRB approved database, we conducted a single-institution retrospective study of patients with LAHNC who were determined to have rENE by an expert head and neck radiologist and underwent definitive therapy with either IC-CRT or CRT. Kaplan-Meier analyses were performed to evaluate impact of treatment regimen (IC-CRT vs CRT) on locoregional control (LRC), distant control (DC), and OS. Survival was calculated from time of pathologic diagnosis. Cox regression multivariate analyses evaluated for independent predictors of survival. Toxicity was evaluated using CTCAE v4.0 and acute toxicity was defined as occurring within 3 months of starting treatment. The association between IC and acute toxicity was evaluated using Chi-Square analysis. Of 141 LAHNC patients who were identified with rENE, 68 received IC-CRT and 73 received CRT. Radiation dose was generally 70Gy and 68% of IC was TPF regimen, of whom 98% completed 2-3 cycles. Median follow up was 4.8 years, and among survivors was 7.1 years. At time of analysis, 52 patients (37%) had died. AJCC 8th edition stage was not significantly different between treatment groups (p = 0.14). Comparing IC-CRT vs. CRT, patients achieved similar 5-year LRC (79.8% vs 68.5%, p = 0.33), DC (73.1% vs 71.9%, p = 0.64), and OS (64.6% vs 59.0%, p = 0.62). Among patients with p16 negative disease (n = 52; 29 IC-CRT vs. 23 CRT, similar stages p = 0.27), use of IC-CRT vs. CRT yielded improved 5-year LRC (78.3% vs 38.4%, p = 0.02), while DC (65.1% vs 63.6%, p = 0.15) and OS (54.8% vs 38.3%, p = 0.23) was similar. MVA showed a trend toward improved LRC for p16 negative cancer with use of IC-CRT (HR 0.33, 95% CI: 0.14-1.10, p = 0.07). Acute grade 3-5 toxicity was significantly more prevalent with IC-CRT than CRT (71% vs 51%, p = 0.01), driven by higher hematologic toxicity (56% vs 33%, p = 0.006). In these long-term results of a retrospective series of patients with LAHNC and rENE, patients who received IC-CRT demonstrated similar LRC, DC, and OS vs. standard CRT. For patients with p16-negative disease, IC-CRT yielded significantly improved LRC. Nevertheless, IC-CRT was associated with worse toxicity, and additional studies are needed to examine ideal treatment strategies among this poorly performing population.

Chemoradiotherapy with extended nodal irradiation and/or erlotinib in locally advanced oesophageal squamous cell cancer: long-term update of a randomised phase 3 trial

BackgroundTo report the long-term outcomes of a phase III trial designed to test two hypotheses: (1) elective nodal irradiation (ENI) is superior to conventional field irradiation (CFI), and (2) chemoradiotherapy plus erlotinib is superior to chemoradiotherapy in locally advanced oesophageal squamous cell cancer (ESCC).MethodsPatients with locally advanced ESCC were randomly assigned (1:1:1:1 ratio) to one of the four groups: A: radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel and cisplatin) plus erlotinib; B: radiotherapy adoption of ENI with two cycles of concurrent TP; C: radiotherapy adoption of CFI with two cycles of concurrent TP plus erlotinib and D: radiotherapy adoption of CFI with two cycles of concurrent TP. A total of 60 Gy of radiation doses was delivered over 30 fractions. We explored the impact of epidermal growth factor receptor (EGFR) expression on the efficacy of erlotinib plus chemoradiotherapy.ResultsA total of 352 patients (88 assigned to each treatment group) were enrolled. The 5-year survival rates were 44.9%, 34.8%, 33.8% and 19.6% in groups A, B, C and D, respectively (P = 0.013). ENI significantly improved OS compared with standard CFI (median, 38.5 vs 22.6 months; HR, 0.74; P = 0.018). The addition of erlotinib significantly improved OS (median, 39.4 vs 27.4 months; HR, 0.75; P = 0.025). Patients with overexpressing EGFR treated with erlotinib had a better OS and PFS than those without erlotinib.ConclusionsConcurrent chemoradiotherapy with ENI and/or erlotinib improved long-term survival in locally advanced ESCC.Clinical trial registrationTrial registration: NCT00686114.

1458P Real-world treatment patterns of unresectable advanced or synchronous metastatic esophageal squamous cell cancer in a Western population

1458P Real-world treatment patterns of unresectable advanced or synchronous metastatic esophageal squamous cell cancer in a Western population

Adjuvant management of locally advanced oral squamous cell carcinoma – real-world challenges and opportunities

Patients with locally advanced oral squamous cell cancer (LAOSCC) are treated with adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) following surgical ablation. This depends on the pathological risk factors and aims to reduce the risk of local recurrence and improve survival. Delivery of these aggressive treatments is, however, challenging particularly following major surgery. To inform the adaptations necessary to deliver gold-standard therapy, we aimed to describe real-world delivery of multimodality treatment in LAOSCC, in a UK population with high levels of disease incidence and low socioeconomic status. Patients with LAOSCC (T1-4 N1-3/T3-4 N0) who were treated between October 2014 and October 2016 and had a minimum follow up of 24 months were included. They were identified using the Somerset Cancer Register and data were collected through retrospective case note review. Approval was obtained from the audit departments at the relevant NHS institutions, and data were analysed using IBM SPSS Statistics for Windows version 24 (IBM Corp). The analysis included 129 patients with 82% having an initial performance status (PS) of 0-1. The most frequent change in PS was a one point drop (46%). Twenty of the 93 eligible patients (22%) underwent adjuvant CRT. A total of 37 (40%) began adjuvant CRT/RT within 42 days, and 79 (85%) within 56 days. A delay in initiating adjuvant therapy was associated with higher rates of complications and a longer postoperative hospital stay. Concordance between imaging and pathological nodal staging was poor (cK 0.223). PS frequently declines after complex surgical procedures and long postoperative recovery periods, leading to difficulties providing adjuvant treatments within the national guidance of 42 days. Frequent deviation from planned adjuvant therapies highlights the need for improved treatment strategies.

Abstract IA25: Radiation as a way to flip the switch: Resistance to responder in HNSCC

Abstract The de novo response to checkpoint inhibitors in advanced head and neck squamous cell cancer (HNSCC) remains at ~20%. Responders in this small cohort of patients also tend to eventually develop resistance. Efforts at simply combining more checkpoint inhibitors in the recurrent setting to overcome such resistance have also proven inadequate. Mounting evidence suggests that radiation may act as an in situ vaccine, boosting and stimulating antigen presentation, altering the tumor microenvironment (TME), enhancing interferon release, and upregulating PD-L1 expression that leads to enhanced response to checkpoint inhibitors. In patients where resistance has developed, radiation may hit the reset button and reconvert cancers to sensitivity again. The genomic landscape of HNSCC may play a role in looking to rationally combine novel agents already approved in breast and ovarian cancers with DNA damage repair defects, and the tumor mutational burden (TMB) may lend itself to predicting improved response to checkpoint inhibition. However, there is evidence that a high TMB might exist in HNSCC, similar to NSCLC, yet lack a proinflammatory TME that theoretically leads to reduced response to immune-modulating agents. In preclinical animal models of HNSCCs, radiation has been shown to enhance tumor responsiveness to checkpoint inhibitors by fueling the TME. Radiation initiates cell death and the production and release of cytokines and chemokines, such as CXCL9 and CXCL10, into the TME, which leads to infiltration of dendritic cells, macrophages, promotion of antigen-specific T-cell priming and cytotoxic T-cell infiltration and effector function. RT, however, can also modulate the infiltration of an immunosuppressive cell population in a dose-dependent manner. Critical to overcoming resistance or initiating a strong response to immune-enabling drugs may be how and when we deliver the radiation and the type of radiation utilized—hypofractionated or conventionally fractionated doses. High infiltration of Tregs and MDSCCs may contribute to radiation resistance along with resistance to immune-enabling drugs, so altering or depleting this population may lend itself to reversing or preventing resistance from developing. Preclinical evidence suggests that combining radiation with Treg depletion is far more effective than Treg depletion alone for improving response to anti-PD1 or PD-L1 therapy. This is just the beginning of our exploration of radiation’s ability to “flip the switch” and improve response to HNSCC that otherwise would be “cold” to checkpoint inhibition. Breaking down HNSCCs that utilize additional immunosuppressive options such as TGFb may also allow for combinatorial approaches to improve response. This lends itself to paradigm shifts in how we utilize radiation in locally advanced and the metastatic settings. Citation Format: David Raben. Radiation as a way to flip the switch: Resistance to responder in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA25.