Neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV negative head and neck squamous cell carcinoma (HNSCC).

6012 Background: Pembrolizumab has efficacy in metastatic HNSCC. We hypothesized that treatment intensification in surgically resectable HPV-negative, Stage III/IV HNSCC with neoadjuvant plus post-operative adjuvant (POA) pembrolizumab would be safe and reduce 1-year locoregional recurrence/distant metastases (LRR/DM) from 35% (historical: Cooper and Bernier NEJM 2004) to 15%. Methods: Phase II trial where all eligible patients received 1 dose of pembrolizumab (200 mg) prior to surgery and only those with high-risk pathologic features (HRPF: extracapsular extension/positive margin) were given POA cisplatin and radiation followed by pembrolizumab. PD-L1 staining was assessed by immunohistochemistry (9A11 antibody). Results: The study continues to enroll. Characteristics of 21 enrolled patients (pts) were median age 59 (32-87) yrs, tobacco use 81% (17 pts), clinical T2 (n = 2), T3 (n = 1), T4 (n = 18), and cN0/1 (n = 8), cN2 (n = 13). Preliminary analyses revealed five important findings: 1) No serious study drug-related AEs or unexpected surgical delays/complications, 2) No LRR/DM events in the first 10 patients with > 1-year follow-up after surgery 3) HRPF rate of 38% (95% CI: 18%-62%) (expected: 80%), 4) 43% of pts (95% CI: 22%-66%) with pathologic treatment response to neoadjuvant pembrolizumab (definition: tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris in > 10% of tumor area), and 5) 48% of pts (95% CI:26%-70%) with clinical-to-pathologic downstaging. Pathologic treatment effect (TE) in ≥ 70% of the resected tumor or lymph node tissue area occurred in 6/21 pts (29%). Baseline tumor biopsies were PD-L1 positive ( > 1% of tumor cells) in 11/19 (58%) evaluable samples and in 7/8 (88%) evaluable pathologic responders. A significant correlation existed between baseline PD-L1 expression on tumor cells and pathologic treatment effect in the tumor (correlation coefficient: 0.72 and p = 0.0005). Conclusions: Neoadjuvant and adjuvant pembrolizumab was safe and well tolerated. We observed several lines of evidence supporting an anti-tumor effect in these pts with a single dose of pre-operative pembrolizumab. Further evaluation of this strategy is warranted. Clinical trial information: NCT02296684.

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Optimal timing of post-prostatectomy radiotherapy for prostate cancer with high-risk pathologic features: A multi-institutional analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.24 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 24-24

Author(s):

William L. Hwang ◽

Rahul D. Tendulkar ◽

Andrzej Niemierko ◽

Shree Agrawal ◽

Kevin L. Stephans ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Locally Advanced ◽

Distant Metastases ◽

Recurrence Risk ◽

Optimal Timing ◽

Cancer Specific Survival ◽

Prognostic Features ◽

Kaplan Meier ◽

Pathologic Features

24 Background: The use of radical prostatectomy (RP) as initial treatment of high-risk/locally-advanced prostate cancer is increasing but patients (pts) with adverse pathologic features such as positive surgical margins or T3 disease have up to 70% recurrence risk. These high-risk pts may be managed with adjuvant radiotherapy (ART) or early salvage radiotherapy (ESRT). The optimal timing of post-operative radiotherapy is unclear. Methods: Individual data from 1566 consecutive pts with pT2N0M0/R1 or pT3N0M0/R0-1 disease who underwent post-prostatectomy ART or ESRT (1987-2013) at 10 academic centers were pooled. Post-irradiation freedom from biochemical failure (FFBF), freedom from distant metastases (FFDM), prostate-cancer specific survival (PCSS), and overall survival (OS) were compared using Kaplan-Meier and multivariate competing-risks regression (MVA) analyses. Propensity score (PS) matching was used to account for covariates potentially associated with treatment allocation. All outcomes were measured from the date of surgery to address lead time bias. Results: After PS-matching, median follow-up after surgery was 66 vs. 73 months for the ART and ESRT groups, respectively, and baseline characteristics were well-matched. ART was associated with higher FFBF (12-yr: 69% vs. 43%; log-rank P < 0.0001), FFDM (12-yr: 95% vs. 85%; log-rank P = 0.03), PCSS (12-yr: 99% vs. 94%; log-rank P = 0.048), and OS (12-yr: 91% vs. 79%; log-rank P = 0.01). ART, lower Gleason score, lower T-stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on MVA for BF. Sensitivity analysis demonstrated that the decreased risk of BF associated with ART remained significant unless more than 56% of ART pts were cured by surgery alone. This threshold is greater than the estimated 12-yr FFBF of 46% after RP alone as determined by a contemporary nomogram. Conclusions: To the best of our knowledge, this represents the largest multi-institutional study to date comparing ART to ESRT. ART was associated with reduced biochemical recurrence, distant metastases, and death compared to ESRT for high-risk pts, pending prospective validation.

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Improved Outcome by Adding Concurrent Chemotherapy to Cetuximab and Radiotherapy for Locally Advanced Head and Neck Carcinomas: Results of the GORTEC 2007-01 Phase III Randomized Trial

Journal of Clinical Oncology ◽

10.1200/jco.2017.76.2518 ◽

2018 ◽

Vol 36 (31) ◽

pp. 3084-3090 ◽

Cited By ~ 22

Author(s):

Yungan Tao ◽

Anne Auperin ◽

Christian Sire ◽

Laurent Martin ◽

Cedric Khoury ◽

...

Keyword(s):

Randomized Trial ◽

Head And Neck ◽

Locally Advanced ◽

Progression Free Survival ◽

Distant Metastases ◽

Concurrent Chemotherapy ◽

Phase Iii ◽

Locoregional Control ◽

Treatment Intensification ◽

Significance Level

Purpose To investigate the effect of adding concurrent chemotherapy (CT) to cetuximab plus radiotherapy (RT; CT-cetux-RT) compared with cetuximab plus RT (cetux-RT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Patients and Methods In this phase III randomized trial, patients with N0-2b, nonoperated, stage III or IV (nonmetastatic) LA-SCCHN were enrolled. Patients received once-daily RT up to 70 Gy with weekly cetuximab or with weekly cetuximab and concurrent carboplatin and fluorouracil (three cycles). To detect a hazard ratio (HR) of 0.64 for progression-free survival (PFS) with 85% power at a two-sided significance level of P = .05, 203 patients needed to be included in each arm. Results Four hundred six patients were randomly assigned to either CT-cetux-RT or cetux-RT. Patient and tumor characteristics were well balanced between arms, including p16 status. With a median follow-up of 4.4 years, the HR for PFS favored the CT-cetux-RT arm (HR, 0.73; 95% CI, 0.57 to 0.94; P = .015), with 3-year PFS rates of 52.3% and 40.5% and median PFS times of 37.9 and 22.4 months in the CT-cetux-RT and cetux-RT arms, respectively. The HR for locoregional control was 0.54 (95% CI, 0.38 to 0.76; P < .001) in favor of CT-cetux-RT. These benefits were observed regardless of p16 status for oropharynx carcinomas. Overall survival (HR, 0.80; P = .11) and distant metastases rates (HR, 1.19; P = .50) were not significantly different between the two arms. The CT-cetux-RT arm, compared with cetux-RT, had a higher incidence of grade 3 or 4 mucositis (73% v 61%, respectively; P = .014) and of hospitalizations for toxicity (42% v 22%, respectively; P < .001). Conclusion The addition of concurrent carboplatin and fluorouracil to cetux-RT improved PFS and locoregional control, with a nonsignificant gain in survival. To our knowledge, this is the first evidence of a clinical benefit for treatment intensification using cetux-RT as a backbone in LA-SCCHN.

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Spatial Distribution and Predictive Significance of Dendritic Cells and Macrophages in Esophageal Cancer Treated With Combined Chemoradiotherapy and PD-1 Blockade

Frontiers in Immunology ◽

10.3389/fimmu.2021.786429 ◽

2022 ◽

Vol 12 ◽

Author(s):

Xiaoxue Ma ◽

Zhoubo Guo ◽

Xiaoying Wei ◽

Gang Zhao ◽

Dong Han ◽

...

Keyword(s):

Dendritic Cells ◽

Spatial Distribution ◽

Tumor Cells ◽

Combination Treatment ◽

Locally Advanced ◽

Underlying Mechanism ◽

Stromal Compartment ◽

Mutation Burden ◽

Antigen Presenting ◽

Tumor Biopsies

BackgroundThe first clinical study (NCT03671265) of first-line chemoradiotherapy combined with PD-1 blockade showed promising treatment outcomes in locally advanced esophageal squamous cell carcinoma (ESCC). However, partial patients did not respond to the combination treatment. The roles of dendritic cells (DCs) and macrophages in this combination treatment remain poorly understood.MethodsWe performed multiplexed immunofluorescence method to identify CD11c+ DCs, CD68+ macrophages, and their PD-L1- or PD-L1+ subpopulations in paired tumor biopsies (n = 36) collected at baseline and during the combination treatment (after radiation, 40 Gy) from the phase Ib trial (NCT03671265). We applied whole exome sequencing in the baseline tumor biopsies (n = 14) to estimate tumor mutation burden (TMB). We dynamically investigated the spatial distribution of DCs and macrophages under chemoradiotherapy combined with PD-1 blockade, and evaluated the association between their spatial distribution and combination outcome, and TMB.ResultsThe results showed that high percentages of PD-L1- DCs and macrophages in the baseline tumor compartment, but not in the stromal compartment, predicted improved OS and PFS. Chemoradiotherapy combined with PD-1 blockade promoted DCs and macrophages to migrate closer to tumor cells. During combination treatment, PD-L1- tumor cells were nearest to PD-L1- DCs and macrophages, while PD-L1+ tumor cells were next to PD-L1+ DCs and macrophages. High TMB was closely associated with a shorter distance from tumor cells to DCs and macrophages. Shorter distance between PD-L1+ tumor cells and PD-L1+ DCs or PD-L1- macrophages during the combination was correlated with better OS. Shorter distance between PD-L1- tumor cells and PD-L1- macrophages during combination was associated with both longer OS and PFS.ConclusionsPD-L1- or PD-L1+ DCs and macrophages exhibit distinct spatial distribution in ESCC. The close distance between tumor cells and these antigen-presenting cells (APCs) is critical to the clinical outcome in chemoradiotherapy combined with PD-1 blockade in ESCC patients. Our results highlight the predictive potential of spatial patterns of APCs in chemoradiotherapy combined with immunotherapy and reveal the underlying mechanism of APCs participating in chemoradiotherapy-induced antitumor immune response in ESCC.

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Molecular and Dynamic Evaluation of Proteins Related to Resistance to Neoadjuvant Treatment with Chemoradiotherapy in Circulating Tumor Cells of Patients with Locally Advanced Rectal Cancer

Cells ◽

10.3390/cells10061539 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1539

Author(s):

Virgílio Souza e Silva ◽

Emne Ali Abdallah ◽

Bianca de Cássia Troncarelli Flores ◽

Alexcia Camila Braun ◽

Daniela de Jesus Ferreira Costa ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Transforming Growth Factor ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Disease Free Survival ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer

The heterogeneity of response to neoadjuvant chemoradiotherapy (NCRT) is still a challenge in locally advanced rectal cancer (LARC). The evaluation of thymidylate synthase (TYMS) and RAD23 homolog B (RAD23B) expression in circulating tumor cells (CTCs) provides complementary clinical information. CTCs were prospectively evaluated in 166 blood samples (63 patients) with LARC undergoing NCRT. The primary objective was to verify if the absence of RAD23B/TYMS in CTCs would correlate with pathological complete response (pCR). Secondary objectives were to correlate CTC kinetics before (C1)/after NCRT (C2), in addition to the expression of transforming growth factor-β receptor I (TGF-βRI) with survival rates. CTCs were isolated by ISET and evaluated by immunocytochemistry (protein expression). At C1, RAD23B was detected in 54.1% of patients with no pCR and its absence in 91.7% of patients with pCR (p = 0.014); TYMS− was observed in 90% of patients with pCR and TYMS+ in 51.7% without pCR (p = 0.057). Patients with CTC2 > CTC1 had worse disease-free survival (DFS) (p = 0.00025) and overall survival (OS) (p = 0.0036) compared with those with CTC2 ≤ CTC1. TGF-βRI expression in any time correlated with worse DFS (p = 0.059). To conclude, RAD23B/TYMS and CTC kinetics may facilitate the personalized treatment of LARC.

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Treatment Intensification in Locally Advanced/Unresectable NSCLC Through Combined Modality Treatment and Precision Dose Escalation

Seminars in Radiation Oncology ◽

10.1016/j.semradonc.2020.11.007 ◽

2021 ◽

Vol 31 (2) ◽

pp. 105-111

Author(s):

Jing Zeng ◽

Stephen R. Bowen

Keyword(s):

Dose Escalation ◽

Locally Advanced ◽

Combined Modality Treatment ◽

Treatment Intensification ◽

Combined Modality

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Polymorphisms in the Gene Encoding Caspase 8 May Predict the Response to First-Line Platinum-Based Chemotherapy in Locally Advanced or Advanced Non-Small-Cell Lung Cancer

Journal of Clinical Medicine ◽

10.3390/jcm10051126 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1126

Author(s):

Michał Szczyrek ◽

Radosław Mlak ◽

Aneta Szudy-Szczyrek ◽

Karolina Kędziora ◽

Teresa Małecka-Massalska ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Locally Advanced ◽

Distant Metastases ◽

Small Cell ◽

Caspase 8 ◽

Small Cell Lung ◽

Gene Encoding ◽

Platinum Based Chemotherapy

Caspase 8 is a protein involved in the process of cell apoptosis, which may affect the efficacy of anti-cancer treatment. The aim of our study was to determine the impact of polymorphisms in the CASP-8 gene encoding caspase 8 on the prognosis in non-small-cell lung cancer (NSCLC). The study involved 99 patients with newly diagnosed locally advanced or metastatic NSCLC treated with platinum-based chemotherapy. The presence of the GG genotype was associated with distant metastases, smoking, and a family history of cancer. The higher risk of early progression was associated with weight loss and the CASP-8 genotype (GG vs. AG or AA: 20.51% vs. 2.86%). The higher risk of progression-free survival (PFS) shortening was associated with a higher stage of disease (hazard ratio (HR) = 2.50, 95% CI: 1.61–3.89, p < 0.0001), distant metastases (HR = 2.30, 95% CI: 1.42–3.72, p = 0.0016), and the GG genotype (HR = 1.68, 95% CI: 1.10–2.57, p = 0.0152). The influence of the GG genotype on the PFS was confirmed in a multivariate analysis (HR = 1.80, 95% CI: 1.06–3.05, p = 0.0317). We did not confirm the influence of CASP-8 genotypes on the overall survival (OS).

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Association Between the Cytogenetic Profile of Tumor Cells and Response to Preoperative Radiochemotherapy in Locally Advanced Rectal Cancer

Medicine ◽

10.1097/md.0000000000000153 ◽

2014 ◽

Vol 93 (26) ◽

pp. e153 ◽

Cited By ~ 4

Author(s):

María González-González ◽

Jacinto Garcia ◽

José A. Alcazar ◽

María L. Gutiérrez ◽

Luis M. Gónzalez ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Cells ◽

Locally Advanced ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Preoperative Radiochemotherapy ◽

Cytogenetic Profile

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Primary Angiosarcoma of the Bladder

Archives of Pathology & Laboratory Medicine ◽

10.5858/2006-130-1543-paotb ◽

2006 ◽

Vol 130 (10) ◽

pp. 1543-1547 ◽

Cited By ~ 5

Author(s):

Raja R. Seethala ◽

Jose A. Gomez ◽

Funda Vakar-Lopez

Keyword(s):

Data Extraction ◽

Locally Advanced ◽

Female Ratio ◽

Primary Angiosarcoma ◽

Study Selection ◽

Pathologic Features ◽

Male Female Ratio ◽

Bibliographic Search ◽

Primary Bladder ◽

Microscopic Pathology

Abstract Context.—Primary bladder angiosarcomas are extremely rare, and their clinical and pathologic features are not well described. Objective.—To further refine the clinical features of primary bladder angiosarcomas and define their pathologic spectra. Data Sources.—Relevant sources were identified using MEDLINE and a subsequent bibliographic search of all pertinent reports and reviews. We also searched the M. D. Anderson pathology archives. Study Selection.—After excluding 4 cases that likely secondarily involved the bladder, we identified 9 true primary bladder angiosarcomas. Data Extraction.—Data were extracted on the following: demographics, clinical presentation, predisposing factors, gross pathology, microscopic pathology, immunophenotype, therapy, and outcomes. Data Synthesis.—Primary bladder angiosarcomas were found at a mean age of 64.2 years, with a male-female ratio of 8:1. Two cases arose in a postirradiation setting. Primary bladder angiosarcomas typically presented with hematuria and were grossly hemorrhagic, raised masses (mean size, 6.7 cm) of the trigone and/or dome. Histologically, most showed classic anastomosing channels lined by plump hyperchromatic cells, though many showed variant histology such as solid growth and epithelioid cytology. Three (43%) of 7 patients died within a year, but only 1 patient died with evidence of disease. The remaining patients were alive at the time of publication of their respective cases (mean, 22 months). Conclusions.—Primary angiosarcomas of the bladder are typically rare tumors of middle-aged and elderly men that present with locally advanced disease and show a wide histologic spectrum. However, their prognosis may be better than previously thought.

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Adrenal Cortical Adenoma With Adrenalin-Type Neurosecretory Granules Clinically Mimicking a Pheochromocytoma

Archives of Pathology & Laboratory Medicine ◽

10.5858/2002-126-1530-acawat ◽

2002 ◽

Vol 126 (12) ◽

pp. 1530-1533 ◽

Cited By ~ 2

Author(s):

Tomislav Ivsic ◽

Richard A. Komorowski ◽

Gary S. Sudakoff ◽

Stuart D. Wilson ◽

Milton W. Datta

Keyword(s):

Electron Microscopy ◽

Clinical Outcome ◽

Tumor Cells ◽

Clinical Features ◽

Adrenal Tumor ◽

Histologic Examination ◽

Adrenal Tumors ◽

Neurosecretory Granules ◽

Adrenal Cortical Adenoma ◽

Pathologic Features

Abstract Adrenal tumors often present with clinical features that are specific and unique to their endocrine metabolism. When these features are in conflict with the pathologic appearance of the tumor, there can be great consternation for both the pathologist and the surgeon. In the case reported herein, an adrenalectomy was performed for clinical features of pheochromocytoma that on gross and histologic examination had the pathologic features of an adrenal cortical adenoma. Electron microscopy subsequently revealed that the tumor cells contained adrenalin-type granules, explaining the clinical outcome. It is crucial for both the surgeon and the surgical pathologist to be aware of this possibility when the clinical and pathologic features of an adrenal tumor are not congruent.

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