Prior Chemoradiation Research Articles

Evaluating the efficacy of chemoradiotherapy combined with immunotherapy for local-regional recurrent esophageal cancer patients after esophagectomy: A retrospective analysis.

e16085 Background: Chemoradiotherapy has been the standard-of-care for esophageal cancer patients with local-regional recurrent disease after esophagectomy without prior chemoradiation. Recent studies have demonstrated that immune checkpoint inhibitors confer survival benefits to patients with esophageal cancer. However, the effectiveness of chemoradiotherapy combined with immunotherapy remains undetermined in patients experiencing local-regional recurrence. Methods: Esophageal cancer patients treated at our institution were screened retrospectively for the following inclusion criteria: histological confirmation of squamous cell carcinoma; loco-regional recurrence after surgery-based first-line treatment; received chemoradiotherapy combined with immunotherapy regimen after loco-regional recurrence. Patients with prior radiotherapy were excluded. The endpoints of the study were overall survival (OS) and progression-free survival (PFS). Loco-regional recurrence was defined as recurrences from below the hyoid to the lower margin of the first lumbar vertebra, including supraclavicular, mediastinal, abdominal lymph nodes, and the tumor bed. PFS was defined as the time from the date of postoperative recurrence until disease progression, recurrence, death, or the last follow-up day; OS was determined as the duration from postoperative recurrence to the date of death from any cause or the last follow-up date. Results: Between January 2020 and July 2023, 685 patients were screened and 61 patients were finally enrolled in this study. The median follow-up period was 14 months (2.9~45.5 months). Regarding the regions of recurrence, 31 patients experienced exclusive mediastinal recurrence, and 30 patients had recurrence beyond the mediastinum (supraclavicular lymph node [n = 21], abdominal lymph node [n = 8], both supraclavicular and abdominal lymph node [n = 1]). In these cases, 26 patients (43%) experienced recurrence after receiving chemoradiotherapy combined with immunotherapy (loco-regional failure [n = 15], distant metastasis [n = 3], and both loco-regional failure and distant metastasis [n = 8]). Fourteen (23%) patients died from disease progression. The median PFS was 18 months (95%CI, 9.6-26.4) and the median OS was not reached. The 2-year OS rate was 65%. In univariate analysis, patients with recurrence in supraclavicular/abdominal lymph nodes had a worse prognosis (P = 0.014, HR = 2.765). Conclusions: Chemoradiotherapy combined with immunotherapy showed a favorable efficacy in radiotherapy-free esophageal cancer patients experiencing loco-regional recurrence post-surgery. Additionally, the regions of recurrence may influence patient outcomes.

Phase II Clinical Trial of Intravenous Levothyroxine to Mitigate Pharyngocutaneous Fistula in Euthyroid Patients Undergoing Salvage Laryngectomy.

Patients undergoing head and neck cancer surgery after prior radiation or chemoradiation are at high risk for wound complications. Hypothyroidism is a known risk factor for wound complications, especially fistulae after salvage total laryngectomy. The purpose of this phase II clinical trial is to investigate the effect of perioperative intravenous levothyroxine supplementation on wound complications in patients undergoing salvage total laryngectomy. Euthyroid patients previously treated with radiation/chemoradiation undergoing total laryngectomy were prospectively recruited (n = 72). Postoperatively, intravenous levothyroxine was administered at a weight-based dose (1.3 mcg/kg/d) and transitioned to enteral dosing on day 7. Free T3, T4, and thyroid-stimulating hormones were collected, and dosing was adjusted accordingly. The primary endpoints were rates of fistula formation and fistula requiring reoperation, compared with matched historic controls. All patients were monitored for adverse effects. The rate of postoperative hypothyroidism was 21% compared with 49% in a matched historic cohort. The rate of fistula formation was 18.1%, whereas the rate of fistula requiring reoperation was 4.2%, significantly lower than rates in our historic cohort (34.6% and 14.8%, respectively; P = 0.02 and 0.01). Postoperative hypothyroidism and recurrent clinical stage predicted fistula requiring reoperation in multivariate analysis; other acute phase reactants were not predictive. There were no observed adverse events related to levothyroxine supplementation. Postoperative intravenous levothyroxine supplementation reduced rates of acute hypothyroidism, fistula formation, and fistula requiring reoperation in patients undergoing salvage total laryngectomy without adverse effects. Intravenous levothyroxine is a viable strategy to reduce wound complications in this high-risk patient population.

The S-REAL study: Spanish real-world data on unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy.

The S-REAL study aimed to assess the effectiveness of durvalumab as consolidation therapy after definitive chemoradiotherapy (CRT) in a real-world cohort of patients with locally advanced, unresectable stage III non-small cell lung cancer (LA-NSCLC) included in a Spanish early access program (EAP). In this multicentre, observational, retrospective study we analysed data from patients treated in 39 Spanish hospitals, who started intravenous durvalumab (10mg/kg every 2weeks) between September 2017 and December 2018. The primary endpoint was progression-free survival (PFS). Secondary endpoints included patient characterization and adverse events of special interest (AESI). A total of 244 patients were followed up for a median of 21.9months [range 1.2-34.7]. Median duration of durvalumab was 45.5weeks (11.4months) [0-145]. Median PFS was 16.7months (95% CI 12.2-25). No remarkable differences in PFS were observed between patients with programmed cell death-ligand 1 (PD-L1) expression ≥ 1% or < 1% (16.7 versus 15.6months, respectively). However, PFS was higher in patients who had received prior concurrent CRT (cCRT) versus sequential CRT (sCRT) (20.6 versus 9.4months). AESIs leading to durvalumab discontinuation were registered in 11.1% of patients. These results are in line with prior published evidence and confirm the benefits of durvalumab in the treatment of LA-NSCLC patients in a real-world setting. We also observed a lower incidence of important treatment-associated toxicities, such as pneumonitis, compared with the pivotal phase III PACIFIC clinical study.

Evaluation of the safety and effectiveness of robot-assisted neck dissections.

Robot-assisted neck dissection (RAND) for the management of the regional lymphatic basin offers the potential for improved cosmesis and reduced lymphedema. While RAND has been previously described, functional outcome and oncologic control rates need further elucidation. A retrospective, matched cohort study of neck dissections completed at UPMC from 2017 to 2021 was conducted. RAND was identified and matched to open neck dissections (open) in a 1:2 ratio. Matching characteristics included primary cancer site, pre-operative clinical N-stage, age at time of surgery, HPV status, and previous chemoradiation treatment (salvage vs. nonsalvage procedure). Additional information was collected on patient demographics, surgery characteristics, and outcomes. Comparisons were made using t-test, chi-square test, Fisher's exact test, and Kaplan-Meier Wilcoxon (KMW) test with p < 0.05 indicating significance. Overall, RAND and open groups had similar distributions of age, gender, BMI, primary site of cancer, HPV status, clinical N-stage, clinical T-stage, known neck disease prior to procedure, prior chemoradiation therapy, and level(s) of neck dissection. Surgically, RAND procedures yielded less drainage on average (124 mL in RAND vs. 220 mL in open approaches; p = 0.01). There was no difference in the rates of complications, estimated blood loss, or number of lymph nodes obtained. There were also no differences in the rates of adjuvant therapy. Long term, there were no differences in the rates of local, locoregional, and distant recurrence of primary disease between RAND and open procedures. There were also no differences in postprocedure disease-free survival time (KMW p-value = 0.32; HR [of RAND compared with open] = 0.62). Similarly, there were no statistical differences in the overall survival of RAND patients when compared with the open group (75 vs. 58.9 months; HR = 0.11, p = 0.87). This study is the first to report the long-term effectiveness of robot-assisted surgery compared with the traditional, open approach. In addition to well-known cosmetic benefits, robot-assisted surgery may also offer patients a reduction in uncomfortable drains and improved effects from lymphedema. Overall, this study provides initial data that the RAND may be considered as an alternative approach to open surgery.

Safety of high-dose rate (HDR) brachytherapy for patients with prostate cancer and history of prior chemoradiation for rectal cancer: A case series

PurposeA history of prior pelvic radiation therapy (RT) for rectal cancer is a relative contraindication for definitive RT for prostate cancer. High-dose-rate (HDR) brachytherapy can significantly limit the dose to surrounding tissues compared to external beam RT. However, there is limited data surrounding its safety in patients with prior pelvic RT. Methods and MaterialsA retrospective chart review was performed at the University of California, San Francisco to identify patients diagnosed with prostate cancer with a history of pelvic RT for rectal cancer who were treated with high-dose-rate brachytherapy (HDR-BT) between 2006 and 2022. Inclusion criteria were biopsy-confirmed prostate cancer with no evidence of distant disease on clinical examination or imaging, and at least one post-treatment clinic appointment. ResultsSeven patients were treated with salvage HDR-BT at a median interval of 17.7 years after RT for rectal cancer. HDR-BT doses included 3600 cGy in six fractions (n = 5), 2700 cGy in 2 fractions (n=1), or 2800 cGy in four fractions (n = 1). There was no acute grade ≥2 gastrointestinal toxicity, and 1 patient developed late grade 2 rectal bleeding. Two patients developed acute grade 2 genitourinary toxicity consisting of urinary frequency and urgency, which persisted through long-term follow up. At a median follow up of 29.5 months after HDR brachytherapy, one patient developed regional and distant failure, and another had seminal vesicle recurrence. ConclusionsHDR-BT is a safe treatment for patients with prostate cancer who previously received RT for rectal cancer. Further studies are needed to better characterize the long-term toxicity of HDR-RT in this population.

Factors associated with successful electrolarynx use after total laryngectomy, a multi-institutional study.

To identify characteristics associated with successful electrolarynx (EL) use after total laryngectomy (TL). Records of 196 adults who underwent TL from 03/15/2012 to 03/15/2022 at the University of Washington and Puget Sound Veterans Affairs were reviewed. Characteristics included age, Charlson Comorbidity Index, social support, pre-operative radiation (RT) and chemoradiation (CRT), and 6-month post-TL swallow status. EL success was evaluated using pre-defined criteria of intelligibility, reliability, and independence with use. Poisson regressions and robust standard error estimates were used to estimate unadjusted risk ratios for each characteristic. Statistically significant characteristics were included in multivariate analysis (MVA) to estimate adjusted risk ratios. Median age was 64, median Charlson Comorbidity Index was 5, 170 (87%) were male, 159 (81%) had high social support, and 159 (81%) attained post-TL full-oral diet. Pre-operatively, 110 (56%) had RT, including 55 (28%) with CRT. Ninety-three (47%) met our criteria for EL success. Characteristics significantly associated with EL success included social support (p = .037) and post-TL full-oral diet (p = .037); both approached significance on MVA. EL success varied by pre-operative treatment on univariate (p = .005) and MVA (p = .014). Compared to no prior RT or CRT, the probability of EL success was 29% higher with prior RT and 29% lower with prior CRT in MVA, although these associations did not reach significance. In this retrospective review, EL success correlated with high social support, post-TL full-oral diet, and pre-operative treatment history. These results warrant validation in a larger prospective study to help guide the choice of voice rehabilitation modalities or intensified speech therapy. 4.

Pembrolizumab or Placebo Plus Chemotherapy With or Without Bevacizumab for Persistent, Recurrent, or Metastatic Cervical Cancer

The KEYNOTE-826 randomized clinical trial showed statistically significant and clinically meaningful survival benefits with the addition of pembrolizumab to chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. Treatment effects in patient subgroups of the study population are unknown. To assess efficacy outcomes in patient subgroups of KEYNOTE-826. Exploratory subgroup analyses were conducted in a global, phase 3, randomized, double-blind, placebo-controlled clinical trial. Participants included women with persistent, recurrent, or metastatic adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma of the cervix that had not been treated with systemic chemotherapy and was not amenable to curative treatment. This subanalysis was conducted from November 20, 2018, to May 3, 2021. Pembrolizumab, 200 mg, every 3 weeks or placebo for up to 35 cycles plus chemotherapy (paclitaxel, 175 mg/m2, plus cisplatin, 50 mg/m2, or carboplatin AUC 5 [area under the free carboplatin plasma concentration vs time curve]) with or without bevacizumab, 15 mg/kg. Overall survival (OS) and progression-free survival (PFS) by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 in subgroups defined by use of bevacizumab (yes or no), choice of platinum (carboplatin or cisplatin), prior chemoradiotherapy (CRT) exposure only (yes or no), and histologic type (squamous or nonsquamous) in patients with programmed cell death ligand 1-positive tumors (defined as a combined positive score [CPS] ≥1) and in the intention-to-treat population. A total of 617 patients (median age, 51 years; range, 22-82 years) were enrolled in the trial. In the CPS greater than or equal to 1 population, hazard ratios (HRs) for OS favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.62; 95% CI, 0.45-0.87) and without bevacizumab (HR, 0.67; 95% CI, 0.47-0.96), use of carboplatin (HR, 0.65; 95% CI, 0.50-0.85) and cisplatin (HR, 0.53; 95% CI, 0.27-1.04), with prior CRT only (HR, 0.56; 95% CI, 0.39-0.81) and without prior CRT only (HR, 0.72; 95% CI, 0.52-1.00), and squamous (HR, 0.60; 95% CI, 0.46-0.79) and nonsquamous (HR, 0.70; 95% CI, 0.41-1.20) histologic type. In the intention-to-treat population, HRs for OS also favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.63; 95% CI, 0.47-0.87) and without bevacizumab (HR, 0.74; 95% CI, 0.53-1.04), use of carboplatin (HR, 0.69; 95% CI, 0.54-0.89) or cisplatin (HR, 0.59; 95% CI, 0.32-1.09), with prior CRT only (HR, 0.64; 95% CI, 0.45-0.91) and without prior CRT only (HR, 0.71; 95% CI, 0.53-0.97), and squamous (HR, 0.61; 95% CI, 0.47-0.80) and nonsquamous (HR, 0.76; 95% CI, 0.47-1.23) histologic type. Similar to OS, the addition of pembrolizumab prolonged PFS across all subgroups in the CPS greater than or equal to 1 and intention-to-treat populations. The findings of this trial suggest that adding pembrolizumab to chemotherapy with or without bevacizumab improved OS across subgroups of patients with persistent, recurrent, or metastatic cervical cancer. ClinicalTrials.gov Identifier: NCT03635567.

Differences in the Course of CD4 and CD8 Cells After Chemoradiotherapy in People Living with HIV with Anal Cancer.

Incidence of anal carcinoma (AC) in people living with HIV (PLWH) is increased compared to the general population. Adverse effects of chemoradiotherapy (CRT) on the immune system are associated with a significant detrimental prognosis on overall survival in patients receiving CRT for solid tumors. The aim of this study was to evaluate immunological factors, in particular the differences in recovery of CD4+ and CD8+ cell counts before and after CRT for AC in PLWH. Retrospective single-center chart review extraction to analyze immunological data collected from PLWH with AC; descriptive statistics were used. Thirty-six PLWH with histologically proven AC were included in the analysis. Absolute CD4 cell count 60 months after CRT was 67.2% of the value at the beginning of CRT, whereas the CD8 cell count reached 82.3%. These differences were statistically significant (p = .048), whereas CD4/CD8-ratio remained stable. The findings of the presented study regarding CD4+ and CD8+ cell recovery after CRT are congruent with results from prior studies in non-HIV infected patients. Although not reaching the level of prior CRT T cell numbers, the ability to generate CD8+ cells seems to be better recovered, while CD4+ regeneration is more impaired. These observations are best explained by faster recovery of CD8+ cells via thymic-independent pathways, which are not available for regeneration of CD4+ cells. Further studies with larger numbers of patients are required to analyze the specific CD4+ and CD8+ cell subsets.

Prognostic Factors and Surgical Impact of Non-metastatic Conventional Chondrosarcoma of the Extremities.

Chondrosarcoma is a common bone malignancy, and the main treatment method is surgery. Different surgeries lead to different survival outcomes. The aim of this study was to construct a new clinical predictive tool to accurately predict the overall survival (OS) and cause specific survival (CSS) of patients with chondrosarcoma receiving different treatments. A total of 620 patients with chondrosarcoma registered between January 1, 2000 and December 31, 2016 were recruited as study targets. The missing values are filled by multiple imputation. Two continuous variables, age and tumor size, were divided into binary variables based on Kaplan-Meier curve. Univariate and multivariate analyses were used to explore predictors and establish nomograms. Propensity score matching (PSM) analysis was used to reduce the impact of potential confounders to determine whether different surgical modalities had any survival benefits in subgroups. In a multivariate cox regression, age, grade, tumor size, radiotherapy, chemotherapy, and surgical methods were identified as independent prognostic factors for chondrosarcoma. To construct 1-, 3-, and 5-year nomogram maps of OS and CSS with prognostic factors and verify the c index internally (OS, 0.807; CSS, 0.847) above American Joint Committee on Cancer (AJCC) (OS, 0.685; CSS, 0.732). This study found that the 5 year overall survival rate of patients with non-metastatic chondrosarcoma of the extremities was about 80%. Age, high malignancy, large tumor, prior chemoradiotherapy, and poor surgical selection were independent risk factors. Therefore, the nomogram established in this study will help to optimize clinicians' personalized decision making for patients.

Prospective Phase II Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy (SBRT) Followed By Concurrent Mediastinal Chemoradiation and Adjuvant Immunotherapy for Locally-Advanced Non-Small Cell Lung Cancer (LA NSCLC)

To report the efficacy and toxicity outcomes of a prospective phase II trial of primary tumor SBRT followed by conventional chemoradiation to the lymph nodes and adjuvant immunotherapy in patients (pts) with unresectable LA NSCLC. Eligible pts included stage II-III LA NSCLC with peripheral primary tumors ≤ 7cm or centrally based tumors that had at least 2 cm separation from involved nodal disease. Pts received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation to 60 Gy in 30 fractions to the involved lymph nodes with concurrent platinum doublet chemotherapy. The trial was amended to allow pts without disease progression after chemoradiation to receive adjuvant durvalumab per the PACIFIC trial. The primary endpoint was 1 year progression free survival (PFS), evaluated as a binary variable. Frequencies and proportions were used for reporting this primary endpoint, in addition to adverse events and patterns of failure. Median PFS and OS were estimated using Kaplan Meier methods. Safety and efficacy is reported on the first 50 pts enrolled in the trial with a median follow-up of 24 months (mos) (range, 1-54 mos). Pts were primarily stage IIIA (60%) or stage IIIB (34%), with 6% of pts stage IIB. Overall grade 3 or higher toxicity related to SBRT and/or mediastinal radiation was 8% with two pts (4%) developing grade 3 pneumonitis and one pt having a grade 5 lung infection possibly related to radiation. Overall grade 2 pneumonitis related to SBRT or mediastinal radiation was 20%. Only one pt (2%) developed grade 3 esophagitis. No late cardiac events have been observed. The one-year PFS for all pts was 62% with a median PFS of 26.3 mos and median overall survival of 40.8 mos. Of the 50 pts enrolled, 37 received at least one dose of adjuvant durvalumab. The one-year PFS for pts who received at least one dose of durvalumab was 70.3% with a median PFS not yet reached in this group (median follow-up 24 mos). Patterns of failure were mostly distant with 26% of pts experiencing distant failure, 6% regional, and 2% distant and regional. There was only one local failure (2%) after SBRT in all 50 pts. SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes and adjuvant immunotherapy was well tolerated and showed improved 1-year PFS compared to prior conventional chemoradiation trials for locally advanced NSCLC. The results of this trial will be further evaluated in a randomized phase III study, NRG LU-008. Pts will receive either conventional chemoradiation vs. SBRT to the primary tumor followed by chemoradiation to the involved lymph nodes followed by consolidative immunotherapy to evaluate the possibility of utilization of SBRT as a new standard of care for LA NSCLC.

Sintilimab Injection Combination with Concurrent Chemoradiotherapy (cCRT) in Patients with Localized Esophageal Squamous Cell Carcinoma: A Prospective, Multi-Center, Single-Arm Trial in Progress

Esophageal cancer had accounted for the sixth highest incidence and the fourth highest death rate in China. The predominant histological subtype is esophageal squamous cell carcinoma (ESCC). At initial diagnosis, more than half of patients with ESCC are unfit for surgery. An accepted alternative to surgery is concurrent chemoradiotherapy (cCRT); however, many patients experience local recurrence or distant metastasis after cCRT. Therefore, innovative therapies are needed. Sintilimab is a fully human IgG4 monoclonal antibody, exhibiting the highest affinity for human PD-1 and a lower off-rate, the PD-1 receptor occupancy of sintilimab on circulating T cells is superior. In previous studies, sintilimab, alone and in combination with chemotherapy, was generally well tolerated and had antitumor activity in patients with advanced ESCC. This prospective, single-arm study (NCT04602013) is designed to explore the efficacy of Sintilimab in combination with cCRT. Eligible patients have histologically confirmed localized ESCC for whom cCRT is suitable and surgery is unsuitable/ declined; patients couldn't have received prior chemoradiotherapy. Approximately 53 Chinese patients from 5 centers will be to receive sintilimab (body weight <60kg: 3mg/kg IV Q3W; body weight ≥60kg: 200mg IV Q3W) in combination with cisplatin (25 mg/m2 IV on Days 1-3 of each 3-week cycle) plus paclitaxel for injection (albumin bound) (180 mg/m2). and radiotherapy at a total dose of 60Gy. Duration of treatment will be up to 12 months for sintilimab, including two cycles for concurrent administration of chemotherapy and radiotherapy. Progression-free survival (PFS), assessed by a Blinded Independent Review Committee per RECIST v1.1, is the primary endpoint of the study. Secondary efficacy endpoints include overall response rate, duration of response, and overall survival. Incidence and severity of adverse events (CTCAE V5.0) and patient-reported outcomes of health-related quality of life are additional secondary endpoints. A total of 17 patients have completed sintilimab injection combination with concurrent chemoradiotherapy,17/53 (32%). Objective response rate (ORR) 62.5% and a median progression free survival (mPFS) 17 months. 1-year overall survival (OS) 88.2%. The most common AEs included granulocytopenia (43.7%), thrombo -cytopenia (56.2%), radiation esophagitis (50%), nausea and vomiting (50%), and immune pneumonia (18.7%). Of these AEs greater than grade 3 granulocytopenia (25.0%), thrombocytopenia (35.0%), radiation esophagitis (12.5%), and nausea and vomiting (31.3%), and one patient developed grade 3 immune pneumonia (6.2%), which recovered with treatment. The treatment of sintilimab with CCRT is safe and effective for localized ESCC patients, even with high-dose radiotherapy (60Gy). This study may help to address the unmet need for new therapeutic options for patients with localized ESCC.

Poor outcome of allogeneic transplantation for therapy-related acute myeloid leukemia induced by prior chemoradiotherapy.

Therapy-related acute myeloid leukemia (t-AML) is a therapeutic challenge as a late complication of chemotherapy (CHT) and/or radiotherapy (RT) for primary malignancy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) presents itself as a curative approach. To establish the optimal allo-HSCT strategy for t-AML, we evaluated the relationship between characteristics of primary malignancy and allo-HSCT outcomes. Patients with t-AML or de novo acute myeloid leukemia (AML) who underwent first allo-HSCT in Japan from 2011 to 2018 were identified using a nationwide database. The detailed background of t-AML was obtained by additional questionnaires. Multivariate analysis and propensity score matching (PSM) analysis were performed to detect the prognostic factors associated with t-AML and compare outcomes with de novo AML. We analyzed 285 t-AML and 6761 de novo AML patients. In patients with t-AML, receiving both CHT and RT for primary malignancy was an independent poor-risk factor for relapse and overall survival (OS) (hazard ratio (HR) 1.62; p = 0.029 and HR 1.65; p = 0.009, reference: CHT alone group), whereas other primary malignancy-related factors had no effect on the outcome. Compared to the CHT alone group, complex karyotypes were significantly increased in the CHT + RT group (86.1% vs. 57.5%, p = 0.007). In the PSM cohort, t-AML patients with prior CHT and RT had significantly worse 3-year OS than those with de novo AML (25.2% and 42.7%; p = 0.009). Our results suggest that prior CHT and RT for primary malignancy may be associated with increased relapse and worse OS of allo-HSCT in t-AML.

SHR-1701 in combination with platinum-based chemotherapy and BP102 (a bevacizumab biosimilar) for persistent, recurrent, or metastatic cervical cancer: Data from a phase 1b/3 study.

5529 Background: Platinum-based chemotherapy (chemo) ± bevacizumab is the standard first-line therapy for cervical cancer, regardless of PD-L1 expression. SHR-1701 is a novel bifunctional fusion protein targeting PD-L1 and TGF-βRII, and shows promising efficacy and controllable safety in pretreated patients (pts) with cervical cancer. This ongoing phase 1b/3 study aims to assess the addition of SHR-1701 to standard first-line therapy. Methods: In the phase 1b part, eligible pts had persistent, recurrent, or metastatic squamous-cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma of the cervix not previously treated with systemic chemo for recurrence or metastasis and not amenable to curative treatment. Prior chemo-radiotherapy was permitted for recurrence, if mono-chemo was used as sensitizer. Pts were given SHR-1701 (30 mg/kg), paclitaxel (175 mg/m2), cisplatin (50 mg/m2) / carboplatin (AUC 5), and BP102 (15 mg/kg) every 3 weeks. The primary endpoints were safety and ORR. Results: From Feb 26 to Aug 12, 2022, 31 pts were enrolled. Median age was 55 years (range, 27-71). 24 (77.4%) had squamous-cell carcinoma, and 7 (22.6%) had adenocarcinoma. 20 (64.5%) had metastatic disease, 7 (22.6%) had recurrent cervical cancer, and 4 (12.9%) had persistent cervical cancer. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 25 (80.6%) pts, with the most common being decreased neutrophil count (n=16, 51.6%), decreased white blood cell count (n=12, 38.7%), and anemia (n=8, 25.8%). TRAEs led to discontinuation of any study agent in 8 (25.8%) pts; of note, only 2 (6.5%) pts discontinued SHR-1701 due to TRAEs (grade 3 infusion reaction and grade 3 immune-mediated rash). No treatment-related deaths occurred. Efficacy outcomes are summarized in Table. ORR was 77.4%, with 4 CRs and 20 PRs; responses were ongoing in all 24 responders. DCR was 93.5%. Shrinkage in target lesions was observed in 30 (96.8%) pts. PFS rate at 6 months reached 93.5%. Conclusions: SHR-1701 plus platinum-based doublet chemo and BP102 provided a manageable safety profile and potent antitumor activity in pts with persistent, recurrent, or metastatic cervical cancer, supporting the subsequent randomized, double-blind, placebo-controlled phase 3 part. Clinical trial information: NCT05179239 . [Table: see text]

Final analysis of a randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311)

ObjectiveTo assess the efficacy of dose-dense weekly paclitaxel plus carboplatin in metastatic or recurrent cervical carcinoma, we conducted a phase II/III randomized controlled study comparing dose-dense paclitaxel and carboplatin with...

DNA methylation biomarkers accurately detect esophageal cancer prior and post neoadjuvant chemoradiation.

Esophageal cancer (ECa) is associated with high mortality, mostly due to late diagnosis, precluding curativeintent surgery. Hence, neoadjuvant chemoradiation (ChRT) is recommended in most patients regardless of histological subtype. A proportion of these patients, however, achieve complete disease remission and might be spared of radical surgery. The lack of reliable, minimally invasive biomarkers able to detect post-ChRT disease persistence is, nonetheless, a major drawback. We have previously shown that miRNA promotor methylation enables accurate cancer detection in tissues and liquid biopsies but has been seldom explored in ECa patients. Herein, we sought to unveil and validate novel candidate biomarkers able to detect ECa prior and post ChRT. Promoter methylation of miR129-2, miR124-3 and ZNF569 was assessed, using quantitative methylation-specific PCR (qMSP), in tissue samples from normal esophagus, treatment-naïve and post-ChRT ECa, as well as in liquid biopsies from ECa patients. All genes disclosed significantly different promoter methylation levels between ECa and normal esophagus, accurately detecting post-ChRT disease, especially for adenocarcinoma. Remarkably, miR129-2me /ZNF569me methylation panel identified ECa in liquid samples with 53% sensitivity and 87% specificity. MiR129-2me , miR124-3me and ZNF569me accurately discriminate ECa, either pre- or post-ChRT, from normal tissue, enabling ECa detection. Furthermore, circulalting methylation-based biomarkers are promising minimally invasive tools to detect post-ChRT residual ECa. Overall, our results encourage the use of miRNA methylation biomarkers as accurate ECa detection tools as a novel approach for ChRT response monitoring.

Prognostic Impact of Secondary Versus De Novo Ontogeny in Acute Myeloid Leukemia (AML) Is Predominantly Accounted for By the European Leukemianet (ELN) 2022 Risk Classification

Background: Compared to de novo AML (dnAML), secondary AML (sAML) is recognized to have worse prognosis regardless of whether it stems from antecedent hematologic disease (AHD) or prior chemoradiation exposure (therapy-related, tAML). This classification is frequently used in determining eligibility for clinical trials or therapies. Additionally, clinicians may consider patients as sAML based on history of antecedent blood count abnormalities in the absence of a pathologically proven AHD. However, the poor prognosis of sAML may reflect the adverse risk genetics that often accompany this label as opposed to the historical features themselves: the European LeukemiaNet (ELN) 2022 risk classification newly incorporates secondary-like genetic features in its adverse risk group, and TP53 mutation underlies the adverse prognosis of many tAML cases. Herein, we evaluated whether AHD, therapy-relatedness, or antecedent blood count abnormalities were independently prognostic after accounting for ELN 2022 risk category and TP53 mutation at time of AML presentation. Methods: Clinical, histopathologic, cytogenetic, and molecular genetic data were collected on 735 adults with newly diagnosed AML from Johns Hopkins Hospital (JHH; Baltimore, MD) and Massachusetts General Hospital (MGH; Boston, MA). Per WHO criteria, post-AHD sAML cases were identified by prior pathologic diagnosis of AHD (e.g., myelodysplastic syndrome or myeloproliferative neoplasm). tAML cases were identified by history of prior chemoradiation exposure. dnAML cases were evaluated for previous abnormal blood counts at least 28 days and up to 2 years prior to AML diagnosis. AML therapies were categorized as either with curative intent (intense therapies, e.g., 7+3) or not (less intense therapies, e.g., hypomethylating agent/venetoclax therapy or supportive care). Wilcoxon rank-sum and Fisher's exact tests were used to compare groups. Uni- and multivariable Cox models evaluated associations between overall survival (OS) and covariates: age, performance status (PS; ECOG 0-1 as good vs 2-4 as poor), therapy type, ELN 2022 risk group, TP53 mutation, prior abnormal counts, and hematopoietic stem cell transplant status (time-dependent). Results: Of the 735 patients in the cohort (388 from JHH, 347 from MGH), 410 (56%) had dnAML, 202 (27%) had sAML from AHD, and 123 (17%) had tAML. Of the dnAML patients, 86 previously had normal and 154 had abnormal prior blood counts documented; antecedent blood counts were not available in the remaining patients. AHD and tAML patients were older than dnAML patients (median age 68 and 67 versus 62 years respectively, P<0.001) and more often ELN adverse compared to dnAML (83% and 69% versus 44% respectively, P <0.001). Fewer AHD and tAML patients received curative intent treatment versus dnAML (36% and 43% versus 71% respectively, P<0.001). On univariate analysis, dnAML patients had longer OS than AHD and tAML patients; OS of dnAML with abnormal prior counts fell between dnAML with normal prior counts, AHD, and tAML patients (Figure 1). On multivariable analysis controlling for age, PS, ELN risk, TP53, therapy class, and transplant, dnAML with abnormal prior counts lost prognostic significance (hazard ratio [HR] = 1.17 [reference = dnAML with normal prior counts]; 95% confidence interval [CI] 0.79-1.73, P=0.44). In a subsequent multivariable analysis, AHD and tAML were associated with a poorer prognosis compared to dnAML (regardless of prior counts) after controlling for the other model covariates including ELN risk, although the HRs were attenuated from the univariate model (Table 1; univariate vs multivariable: AHD HR=2.63, 95% CI 1.84-3.76 vs 1.33, 95% CI 1.06-1.67; tAML HR= 2.67, 95% CI 1.83-3.90 vs 1.29, 95% CI 1.00-1.66). Conclusions: In this multicenter cohort, antecedent blood counts did not provide independent prognostic information for de novo AML patients after accounting for ELN 2022 genetic risk and TP53 mutation status. Nonetheless, AHD/tAML maintained prognostic association with shorter OS in the multivariable model, though with reduced effect size by hazard ratio. These findings suggest there remains a role for using secondary vs de novo ontogeny to clinically risk stratify patients, but also emphasizes the greater role genetics (i.e., ELN) should have in risk assessment and clinical trial eligibility in newly diagnosed AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

481. QUANTITATIVE ESTIMATION OF GASTRIC CONDUIT PERFUSION TO SELECT ESOPHAGECTOMY PATIENTS AT HIGH RISK OF IMPAIRED PERFUSION

Abstract Impaired gastric conduit perfusion is considered the most important factor of anastomotic leaks following esophagectomy. Gastric ischemic preconditioning (GIP) can improve conduit perfusion and may reduce anastomotic leaks; however, it remains unclear which patients could benefit from preconditioning. The aim of this study is to create a paradigm to select patients at high risk of impaired perfusion who may benefit from GIP. Patients undergoing an esophagectomy with gastric conduit reconstruction and indocyanine green fluorescence angiography from July 2015 to December 2021 (Cohort 1), as well as all patients receiving an esophagectomy from 2003 to 2021 (Cohort 2) were reviewed. Analyzed variables for Cohort 1 included patient pre-operative demographics and ingress index (quantitative assessment of blood perfusion). Multiple linear regression model for conduit perfusion was used to select significant preoperative factors and to build a formula to estimate conduit perfusion. The formula was applied to Cohort 2 to estimate the percentage of patients who could receive GIP prior to esophagectomy. 349 patients were in Cohort 1, and 1965 in Cohort 2. There was a significant correlation with older age and low body mass index (BMI) and impaired conduit perfusion. Other factors, such as heart disease, diabetes, and prior chemoradiation did not correlate (Table). Using only two variables “age” and “BMI”, we determined how many could have poor conduit perfusion, defined as a low ingress index of &amp;lt;40 (the median value from the Cohort 1). When applying the formula to Cohort 2, we estimated that 26.7% (525) of patients would be at risk for low perfusion and for anastomotic leaks. Using BMI and age, we are able to risk stratify patients who are likely to have low perfusion in their gastric conduits (Figure, higher risk in red). We feel that this group will be the most likely to benefit from pre-esophagectomy gastric ischemic conditioning.

Assessing the Association Between Endoscopic Tattooing and Lymph Node Yield in Rectal Cancer

IntroductionPreoperative endoscopic tattooing is an effective tool for intraoperative tumor localization in colon cancer. Endoscopic tattooing in rectal cancer may have unidentified benefits on lymph node yield, making it easier for pathologists to identify nodes during histopathologic assessment. There remains concern that tattoo ink may alter anatomical planes, increasing surgical difficulty. MethodsRetrospective chart reviews from 2016 to 2021 of n = 170 patients presenting with rectal cancer were divided into two groups: with (n = 79) and without (n = 91) endoscopic tattoos. Demographics, operative details, tumor characteristics, prior chemoradiation, and pathologic details were collected. Primary outcome was total lymph node yield. Secondary outcomes were rates of adequate (> 12) nodes, margin status, and operative variables including operative time. ResultsNo differences between pathologic stage, tumor height, high inferior mesenteric artery ligation, operative times, conversion rate, or surgical approach (open versus minimally invasive) were noted between groups. Receipt of neoadjuvant chemoradiation was less frequent in the endoscopic tattooing group (53.2% versus 76.9%, P ≤ 0.001). Total node number and rate of adequate lymph node yield were higher with endoscopic tattooing (20.5 ± 7.6 versus 16.8 ± 6.6 lymph nodes and 100.0% versus 83.5% adequate lymph node harvest, both P ≤ 0.001). Rates of positive circumferential and distal margins and complete total mesorectal excision were also similar. Regression analysis identified endoscopic tattooing (Incidence Risk Ratio 1.17, 95% confidence interval 1.04-1.31) and operative time more than 300 min (Incidence Risk Ratio 0.88, 95% confidence interval 0.77-0.99) had significant effects on lymph node harvest. Removal of patients with inadequate lymph node yield resulted in similar rates of total and positive lymph nodes. ConclusionsEndoscopic rectal tattooing is associated with increased lymph node yield (including after neoadjuvant chemoradiotherapy) without sacrificing oncologic or perioperative outcomes, although this effect is inconsistent when only considering patients with an adequate lymph node yield.

Thyroid Gland Flap for Prevention of Pharyngocutaneous Fistula After Total Laryngectomy.

Pharyngocutaneous fistula (PCF) is the one of the major complications after total laryngectomy (TL), which can result in saliva leakage, rupture of major vessels, and increased hospitalization. Several flaps have been tried to prevent PCF during TL, and they are usually associated with donor site morbidity and uncertain viability in case of previously irradiated patients. This study aimed to report a novel bilateral pedicled thyroid gland flap (TGF) technique for delicate and effective reinforcement of neopharynx suture line after TL. Bilateral pedicled TGF was performed for the reinforcement of neopharynx T-shape suture sites after TL in this case series. A total of five cases of the TGF were performed during TL, with four of them being salvage setting following previous chemoradiation therapy (CRT). The well-adapted and viable TGF status was confirmed by post-operative computed tomography scan and normally preserved thyroid hormone levels in all patients. No post-operative infections, hemorrhage, hypothyroidism, hypoparathyroidism, or PCF were reported. The TGF is an effective and reliable flap in TL patents and should be considered as a method in neopharynx reconstruction, even in salvage TL following prior CRT.

Pembrolizumab + chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer: Subgroup analysis of KEYNOTE-826.

5506 Background: In KEYNOTE-826 (NCT03635567),pembrolizumab (pembro) + chemotherapy (chemo) ± bevacizumab (bev) provided statistically significant, clinically meaningful PFS and OS improvements in patients with persistent, recurrent, or metastatic cervical cancer. In the present analysis of KEYNOTE-826, we assessed outcomes in several key patient subgroups. Methods: Eligible adult patients had persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix not previously treated with chemo and not amenable to curative treatment; measurable disease per RECIST v1.1; ECOG PS 0–1; and a tumor sample to determine PD-L1 status. Patients were randomized 1:1 to pembro 200 mg Q3W or placebo (pbo) for up to 35 cycles + chemo (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) ± bev 15 mg/kg. Dual primary endpoints are PFS by investigator assessment per RECIST v1.1 and OS in patients with PD-L1 CPS ≥1, all comers, and CPS ≥10. Treatment effects on PFS and OS were examined in patient subgroups defined by bev use (yes or no), histology (squamous or non-squamous [including adenocarcinoma and adenosquamous]), platinum use (carboplatin or cisplatin), and prior chemoradiation therapy (CRT). Hazard ratios (HR) and 95% CIs were based on a stratified Cox regression model. Results: 617 patients were randomized (pembro + chemo ± bev, n=308; pbo + chemo ± bev, n=309). At the May 3, 2021 data cutoff, median follow-up was 22 months. Pembro + chemo prolonged PFS and OS vs pbo + chemo in all subgroups evaluated in the all-comer population (Table). Similar benefits of pembro + chemo on PFS and OS were also seen in the protocol-specified CPS ≥1 and CPS ≥10 populations. Conclusions: Pembro + chemo ± bev prolonged PFS and OS vs pbo + chemo ± bev among the subgroups defined by bev use, histology, platinum use, and prior CRT and provided clinically meaningful benefits similar to the broader population of patients with persistent, recurrent, or metastatic cervical cancer. Clinical trial information: NCT03635567. [Table: see text]