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1. TNTox – Outcome und Toxizität nach totaler neoadjuvanter Therapie beim Rektumkarzinom: Eine multizentrische Analyse der jDEGRO Trial Group

Author

Wurschi, Georg, Mäurer, Matthias, Aninditha, Kynann Putra, Becker, Jan-Niklas, Bischoff, Martin, Büttner, Marcel, Cieslak, Adrianna, Depardon, Alina, Diefenhardt, Markus, Edelmann, Marcus, Ehret, Felix, Fabian, Alexander, Ferdinandus, Simone, Fiegert, Sean, Frerker, Bernd, Heß, Sebastian, Hlouschek, Julian, Hoffmann, Elgin, Irschfeld, Lisa-Marie, Kaufmann, Justus, Keßler, Christopher, Rühle, Alexander, Salfelder, Maria-Elena, Schepers-von Ohlen, Daphne, Schneider, Melanie, Schöneich, Maren, Schunn, Fabian, Sonnhoff, Mathias, Spohn, Simon, Sprengel, Simon David, Trommer, Maike, Trommer, Simon, and Pietschmann, Klaus

Published
2024
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3. Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: Pooled analysis of the CAO/ARO/AIO-12 and the OPRA randomized phase 2 trials

Author

Fokas, Emmanouil, Williams, Hannah, Diefenhardt, Markus, Lin, Sabrina, Qin, Li-Xuan, Piso, Pompiliu, Dapper, Hendrik, Germer, Christoph-Thomas, Grützmann, Robert, Tim Friede, J., Joshua Smith, J., Saltz, Leonard B., Wu, Abraham J., Weiser, Martin R., Omer, Dana, Ghadimi, Michael, Hofheinz, Ralf-Dieter, Garcia-Aguilar, Julio, and Rödel, Claus

Published
2024
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5. Clinical outcome after total neoadjuvant treatment (CAO/ARO/AIO-12) versus intensified neoadjuvant and adjuvant treatment (CAO/ARO/AIO-04) a comparison between two multicenter randomized phase II/III trials

Author

Diefenhardt, Markus, Fleischmann, Maximillian, Martin, Daniel, Hofheinz, Ralf-Dieter, Piso, Pompiliu, Germer, Christoph-Thomas, Hambsch, Peter, Grützmann, Robert, Kirste, Simon, Schlenska-Lange, Anke, Ghadimi, Michael, Rödel, Claus, and Fokas, Emmanouil

Published
2023
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10. Tumor Response and Its Impact on Treatment Failure in Rectal Cancer: Does Intensity of Neoadjuvant Treatment Matter?

Author

Diefenhardt, Markus, Martin, Daniel, Fleischmann, Maximilian, Hofheinz, Ralf-Dieter, Ghadimi, Michael, Rödel, Claus, and Fokas, Emmanouil

Subjects
*DATA analysis, *RESEARCH funding, *TREATMENT effectiveness, *CANCER patients, *DESCRIPTIVE statistics, *LONGITUDINAL method, *ADJUVANT chemotherapy, *COMBINED modality therapy, *STATISTICS, *TREATMENT failure, *COMPARATIVE studies, *TUMOR classification, *DISEASE incidence, RECTUM tumors
Abstract

Simple Summary: The response to neoadjuvant treatment in rectal cancer varies among patients, while the evidence of benefit from additional adjuvant chemotherapy, especially in patients with persistent tumor and/or lymph node metastases, is unclear. In our cohort study of 1778 patients, we showed that persistent tumor and/or lymph node metastasis after intensified neoadjuvant treatment, e.g., total neoadjuvant treatment (TNT), was not more strongly associated with an extensive risk of treatment failure (TF, local recurrence and/or distant metastasis) than after less intensive neoadjuvant treatment, e.g., 5-flurouracil-based chemoradiotherapy (5-FU CRT). These results may help clinicians to individualize their surveillance strategies, but do not provide an argument for adding additional chemotherapy in non-responders after TNT. Objectives: Additional adjuvant treatment in patients with rectal cancer with limited response to neoadjuvant treatment to mitigate their higher risk of treatment failure remains controversial. Methods: This is a post hoc analysis of a cohort study of 3 randomized phase 2 or 3 trials (CAO/ARO/AIO-94, -04, and -12 trial) that included 1948 patients with locally advanced rectal adenocarcinoma. After excluding patients with missing information, 1788 patients (1254 men and 524 women; median age: 62.6 years, age range: 19–84 years) were eligible. We analyzed the extent of tumor response and its association with the incidence of treatment failure after different neoadjuvant treatment approaches. Results: Tumor response was significantly enhanced with more intensive neoadjuvant treatment. After a median follow-up of 55 months for the entire cohort (IQR: 37 months–62 months), the incidence of treatment failure (TF) stratified by tumor response or post-neoadjuvant pathological outcome was not significantly affected by the intensity of neoadjuvant treatment, whereas the ypTNM stage was significantly associated with the risk of treatment failure. Conclusions: In this cohort study, we provide evidence that limited or no response to intensified neoadjuvant treatment protocols is not likely to be more strongly associated with an extensive risk of TF after 5-FU CRT+/− adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Author

Nicolas, Adele M., Pesic, Marina, Engel, Esther, Ziegler, Paul K., Diefenhardt, Markus, Kennel, Kilian B., Buettner, Florian, Conche, Claire, Petrocelli, Valentina, Elwakeel, Eiman, Weigert, Andreas, Zinoveva, Anna, Fleischmann, Maximilian, Häupl, Björn, Karakütük, Cem, Bohnenberger, Hanibal, Mosa, Mohammed H., Kaderali, Lars, Gaedcke, Jochen, Ghadimi, Michael, Rödel, Franz, Arkan, Melek C., Oellerich, Thomas, Rödel, Claus, Fokas, Emmanouil, and Greten, Florian R.

Published
2022
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16. Progression-free survival is a suboptimal predictor for overall survival among metastatic solid tumour clinical trials

Author

Pasalic, Dario, McGinnis, Gwendolyn J., Fuller, C. David, Grossberg, Aaron J., Verma, Vivek, Mainwaring, Walker, Miller, Austin B., Lin, Timothy A., Jethanandani, Amit, Espinoza, Andres F., Diefenhardt, Markus, Das, Prajnan, Subbiah, Vivek, Subbiah, Ishwaria M., Jagsi, Reshma, Garden, Adam S., Fokas, Emmanouil, Rödel, Claus, Thomas, Charles R., Jr., Minsky, Bruce D., and Ludmir, Ethan B.

Published
2020
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23. 3D‐gedruckte Moulagen für die individualisierte HDR‐Brachytherapie kutaner Malignome im Gesichtsbereich: Erste klinische Erfahrungen

Author

Chatzikonstantinou, Georgios, primary, Diefenhardt, Markus, additional, Fleischmann, Maximilian, additional, Meissner, Markus, additional, Scherf, Christian, additional, Trommel, Martin, additional, Ramm, Ulla, additional, Rödel, Claus, additional, Tselis, Nikolaos, additional, and Licher, Jörg, additional

Published
2023
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24. Prognostic Impact of Caspase-8, CDK9 and Phospho-CDK9 (Thr 186) Expression in Patients with Uterine Cervical Cancer Treated with Definitive Chemoradiation and Brachytherapy

Author

Fleischmann, Maximilian, primary, Mandal, Ranadip, additional, Kostova, Izabela, additional, Raab, Monika, additional, Sanhaji, Mourad, additional, Hehlgans, Stephanie, additional, Diefenhardt, Markus, additional, Rödel, Claus, additional, Fokas, Emmanouil, additional, Strebhardt, Klaus, additional, and Rödel, Franz, additional

Published
2022
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25. Development and Validation of a Predictive Model for Toxicity of Neoadjuvant Chemoradiotherapy in Rectal Cancer in the CAO/ARO/AIO-04 Phase III Trial

Author

Diefenhardt, Markus, primary, Martin, Daniel, additional, Ludmir, Ethan B., additional, Fleischmann, Maximilian, additional, Hofheinz, Ralf-Dieter, additional, Ghadimi, Michael, additional, Kosmala, Rebekka, additional, Polat, Bülent, additional, Friede, Tim, additional, Minsky, Bruce D., additional, Rödel, Claus, additional, and Fokas, Emmanouil, additional

Published
2022
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26. Total Neoadjuvant Therapy for Rectal Cancer in the CAO/ARO/AIO-12 Randomized Phase 2 Trial: Early Surrogate Endpoints Revisited

Author

Diefenhardt, Markus, primary, Schlenska-Lange, Anke, additional, Kuhnt, Thomas, additional, Kirste, Simon, additional, Piso, Pompiliu, additional, Bechstein, Wolf O., additional, Hildebrandt, Guido, additional, Ghadimi, Michael, additional, Hofheinz, Ralf-Dieter, additional, Rödel, Claus, additional, and Fokas, Emmanouil, additional

Published
2022
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27. Total Neoadjuvant Therapy for Rectal Cancer in the CAO/ARO/AIO-12 Randomized Phase 2 Trial: Early Surrogate Endpoints Revisited

Author

Diefenhardt, Markus, Schlenska-Lange, Anke, Kuhnt, Thomas, Kirste, Simon, Piso, Pompiliu, Bechstein, Wolf O., Hildebrandt, Guido, Ghadimi, Michael, Hofheinz, Ralf-Dieter, Rödel, Claus, Fokas, Emmanouil, Diefenhardt, Markus, Schlenska-Lange, Anke, Kuhnt, Thomas, Kirste, Simon, Piso, Pompiliu, Bechstein, Wolf O., Hildebrandt, Guido, Ghadimi, Michael, Hofheinz, Ralf-Dieter, Rödel, Claus, and Fokas, Emmanouil

Abstract

Background: Early efficacy outcome measures in rectal cancer after total neoadjuvant treatment are increasingly investigated. We examined the prognostic role of pathological complete response (pCR), tumor regression grading (TRG) and neoadjuvant rectal (NAR) score for disease-free survival (DFS) in patients with rectal carcinoma treated within the CAO/ARO/AIO-12 randomized phase 2 trial. Methods: Distribution of pCR, TRG and NAR score was analyzed using the Pearson’s chi-squared test. Univariable analyses were performed using the log-rank test, stratified by treatment arm. Discrimination ability of non-pCR for DFS was assessed by analyzing the ROC curve as a function of time. Results: Of the 311 patients enrolled, 306 patients were evaluable (Arm A:156, ArmB:150). After a median follow-up of 43 months, the 3-year DFS was 73% in both groups (HR, 0.95, 95% CI, 0.63–1.45, p = 0.82). pCR tended to be higher in Arm B (17% vs. 25%, p = 0.086). In both treatment arms, pCR, TRG and NAR were significant prognostic factors for DFS, whereas survival in subgroups defined by pCR, TRG or NAR did not significantly differ between the treatment arms. The discrimination ability of non-pCR for DFS remained constant over time (C-Index 0.58) but was slightly better in Arm B (0.61 vs. 0.56). Conclusion: Although pCR, TRG and NAR were strong prognostic factors for DFS in the CAO/ARO/AIO-12 trial, their value in selecting one TNT approach over another could not be confirmed. Hence, the conclusion of a long-term survival benefit of one treatment arm based on early surrogate endpoints should be stated with caution.

Published
2022

32. HDR brachytherapy with individual epithetic molds for facial skin cancer: techniques and first clinical experience

Author

Diefenhardt, Markus, Chatzikonstantinou, Georgios, Meissner, Markus, Köhn, Janett, Scherf, Christian, Trommel, Martin, Licher, Jörg, Ramm, Ulla, Rödel, Claus, and Tselis, Nikolaos

Subjects
ddc:610
Abstract

Background: Facial skin cancer lesions in close proximity to critical organs require further development of radiotherapeutic techniques for highly conformal treatment, especially when treating elderly frail patients. We report on our treatment technique and first clinical experience for patients with perinasal/periorbital skin cancer treated with individualized epithetic mold high-dose-rate brachytherapy (BRT). Methods: From January 2019, patients with complex shaped or unfavorably located skin cancer not eligible for surgery or external beam radiotherapy (RT) were screened for mold-based BRT. Six patients were identified. Toxicity and clinical response were documented during therapy and posttreatment follow-up. Results: Median patient age was 80 years (74–92 years). Median prescription dose was 42 Gy (range, 33–44 Gy) delivered in once-daily fractions of 3 or 4 Gy. Two patients had treatment interruptions caused by acute conjunctivitis grade 2 and a nontreatment-related cardiac event, respectively. At a median follow-up of 335 days (96–628 days), no ≥ grade 2 late toxicity was documented with all patients showing complete clinical response. Conclusions: High-dose-rate BRT with individualized epithetic molds for perinasal/periorbital skin cancer is a well-tolerated and safe treatment option for patients not eligible for primary surgery or definitive external beam RT because of comorbidities or tumor location.

Published
2021

33. Individualized mould-based high-dose-rate brachytherapy for perinasal skin tumors: technique evaluation from a dosimetric point of view

Author

Scherf, Christian, Licher, Jörg, Mletzko, Christina, Trommel, Martin, Tselis, Nikolaos, Chatzikonstantinou, Georgios, Diefenhardt, Markus, Rödel, Claus, Köhn, Janett, Ramm, Ulla, Scherf, Christian, Licher, Jörg, Mletzko, Christina, Trommel, Martin, Tselis, Nikolaos, Chatzikonstantinou, Georgios, Diefenhardt, Markus, Rödel, Claus, Köhn, Janett, and Ramm, Ulla

Abstract

Purpose: Dosimetric treatment planning evaluations concerning patient-adapted moulds for iridium-192 highdose-rate brachytherapy are presented in this report. Material and methods: Six patients with perinasal skin tumors were treated with individual moulds made of biocompatible epithetic materials with embedded plastic applicators. Treatment plans were optimized with regard to clinical requirements, and dose was calculated using standard water-based TG-43 formalism. In addition, retrospective material-dependent collapsed cone calculations according to TG-186 protocol were evaluated to quantify the limitations of TG-43 protocol for this superficial brachytherapy technique. Results: The dose-volume parameters D90, V100, and V150 of the planning target volumes (PTVs) for TG-43 dose calculations yielded 92.2% to 102.5%, 75.1% to 93.1%, and 7.4% to 41.7% of the prescribed dose, respectively. The maximum overall dose to the ipsilateral eyeball as the most affected organ at risk (OAR) varied between 8.9 and 36.4 Gy. TG-186 calculations with Hounsfield unit-based density allocation resulted in down by –6.4%, –16.7%, and –30.0% lower average D90, V100, and V150 of the PTVs, with respect to the TG-43 data. The corresponding calculated OAR doses were also lower. The model-based TG-186 dose calculations have considered reduced backscattering due to environmental air as well as the dose-to-medium influenced by the mould materials and tissue composition. The median PTV dose was robust within 0.5% for simulated variations of mould material densities in the range of 1.0 g/cm³ to 1.26 g/cm³ up to 7 mm total mould thickness. Conclusions: HDR contact BT with individual moulds is a safe modality for routine treatment of perinasal skin tumors. The technique provides good target coverage and OARs’ protection, while being robust against small variances in mould material density. Model-based dose calculations (TG-186) should complement TG-43 dose calculations for verification purpose and q

Published
2021

40. Association of polo-like kinase 3 and PhosphoT273 caspase 8 levels with disease-related outcomes among cervical squamous cell carcinoma patients treated with chemoradiation and brachytherapy

Author

Small, William, Jr., Fleischmann, Maximilian, Martin, Daniel, Peña-Llopis, Samuel, Oppermann, Julius, Müller-von der Grün, Jens, Diefenhardt, Markus, Chatzikonstantinou, Georgios, Fokas, Emmanouil, Rödel, Claus, Strebhardt, Klaus, Becker, Sven, Rödel, Franz, Tselis, Nikolaos, Small, William, Jr., Fleischmann, Maximilian, Martin, Daniel, Peña-Llopis, Samuel, Oppermann, Julius, Müller-von der Grün, Jens, Diefenhardt, Markus, Chatzikonstantinou, Georgios, Fokas, Emmanouil, Rödel, Claus, Strebhardt, Klaus, Becker, Sven, Rödel, Franz, and Tselis, Nikolaos

Abstract

Introduction: Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT. Methods: We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset. Results: PLK3 expression levels were associated with pT273 Caspase 8 levels (p = 0.009), as well as N stage (p = 0.046), M stage (p = 0.026), and FIGO stage (p = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p = 0.009), improved CSS (p = 0.001), and OS (p = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p = 0.021), and increased CSS (p < 0.001) and OS (p < 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p < 0.05), as well as increased propensity for metastasis (p = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p = 0.005), and both improved CSS (p < 0.001) and OS (p < 0.001); this combined score independent

Published
2019

41. Association of Polo-Like Kinase 3 and PhosphoT273 Caspase 8 Levels With Disease-Related Outcomes Among Cervical Squamous Cell Carcinoma Patients Treated With Chemoradiation and Brachytherapy

Author

Fleischmann, Max, primary, Martin, Daniel, additional, Peña-Llopis, Samuel, additional, Oppermann, Julius, additional, von der Grün, Jens, additional, Diefenhardt, Markus, additional, Chatzikonstantinou, Georgios, additional, Fokas, Emmanouil, additional, Rödel, Claus, additional, Strebhardt, Klaus, additional, Becker, Sven, additional, Rödel, Franz, additional, and Tselis, Nikolaos, additional

Published
2019
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42. Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO‐04 randomized phase 3 rectal cancer trial.

Author

Diefenhardt, Markus, Hofheinz, Ralf‐Dieter, Martin, Daniel, Beißbarth, Tim, Arnold, Dirk, Hartmann, Arndt, Grün, Jens, Grützmann, Robert, Liersch, Torsten, Ströbel, Philipp, Grabenbauer, Gerhard G., Rieger, Michael, Fietkau, Rainer, Graeven, Ullrich, Weitz, Jürgen, Folprecht, Gunar, Ghadimi, Michael, Rödel, Franz, Rödel, Claus, and Fokas, Emmanouil

Subjects
RECTAL cancer, LEUCOCYTOSIS, CHEMORADIOTHERAPY, CARCINOEMBRYONIC antigen, LACTATE dehydrogenase, ADJUVANT treatment of cancer, BIOMARKERS
Abstract

Peripheral blood leukocytosis and neutrophilia reflect cancer inflammation and have been proposed as prognostic immunological biomarkers in various malignancies. However, previous studies were limited by their retrospective nature and small patient numbers. Baseline peripheral blood leukocytes, neutrophils, hemoglobin, platelets, lactate dehydrogenase and carcinoembryonic antigen (CEA) were correlated with clinicopathologic characteristics, and clinical outcome in 1236 patients with rectal cancer treated with 5‐FU‐based preoperative chemoradiotherapy (CRT) alone or with oxaliplatin followed by surgery and adjuvant chemotherapy within the CAO/ARO/AIO‐04 randomized phase 3 trial. Multivariable analyses were performed using Cox regression models. After a median follow‐up of 50 months, baseline leukocytosis remained an independent adverse prognostic factor for disease‐free survival (DFS; HR 1.457; 95% CI 1.163–1.825; p = 0.001), distant metastasis (HR 1.696; 95% CI 1.266–2.273; p < 0.001) and overall survival (OS; HR 1.716; 95% CI 1.264–2.329; p = 0.001) in multivariable analysis. Similar significant findings were observed for neutrophilia and high CEA levels. Conversely, treatment‐induced leukopenia correlated with favorable DFS (p = 0.037), distant metastasis (p = 0.028) and OS (p = 0.012). Intriguingly, addition of oxaliplatin to 5‐FU CRT resulted in a significant DFS improvement only in patients with neutrophilia and leukocytosis (p = 0.028 and p = 0.002). Our findings have important clinical implications and provide high‐level evidence on the adverse prognostic role of leukocytes and neutrophils, and the impact of chemotherapy in the context of these biomarkers. These data could help guide patient stratification and should be further validated within prospective studies. What's new? Cancer often causes an inflammatory response, recruiting leukocytes and neutrophils to the tumor site where they hinder anti‐cancer treatments. Here, the authors asked how leukocytosis and neutrophilia affect outcomes in rectal cancer. Unlike previous studies, which have been retrospective, this study examined a large cohort of patients within a phase 3 clinical trial. They found that baseline leukocytosis and neutrophilia independently predicted poor outcomes, including distant metastasis and shorter survival. Treatment‐induced leukopenia, meanwhile, correlated with better outcomes. Adding oxaliplatin to standard chemoradiation improved disease‐free survival only in those patients with leukocytosis & neutrophilia. These findings could lead to improved personalized treatments. [ABSTRACT FROM AUTHOR]

Published
2019
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43. Association of Polo-Like Kinase 3 and PhosphoT273 Caspase 8 Levels With Disease-Related Outcomes Among Cervical Squamous Cell Carcinoma Patients Treated With Chemoradiation and Brachytherapy

Author

Fleischmann, Max, Martin, Daniel, Peña-Llopis, Samuel, Oppermann, Julius, von der Grün, Jens, Diefenhardt, Markus, Chatzikonstantinou, Georgios, Fokas, Emmanouil, Rödel, Claus, Strebhardt, Klaus, Becker, Sven, Rödel, Franz, and Tselis, Nikolaos

Subjects
3. Good health
Abstract

Introduction:Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT. Methods:We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset. Results:PLK3 expression levels were associated with pT273 Caspase 8 levels (p= 0.009), as well as N stage (p= 0.046), M stage (p= 0.026), and FIGO stage (p= 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p= 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p= 0.009), improved CSS (p= 0.001), and OS (p= 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p= 0.021), and increased CSS (p< 0.001) and OS (p< 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p< 0.05), as well as increased propensity for metastasis (p= 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p= 0.005), and both improved CSS (p< 0.001) and OS (p< 0.001); this combined score independently predicted distant failure (p= 0.041) and CSS (p= 0.003) on multivariate analyses. Conclusion:Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context.

44. Association of Polo-Like Kinase 3 and PhosphoT273 Caspase 8 Levels With Disease-Related Outcomes Among Cervical Squamous Cell Carcinoma Patients Treated With Chemoradiation and Brachytherapy

Author

Fleischmann, Max, Martin, Daniel, Peña-Llopis, Samuel, Oppermann, Julius, von der Grün, Jens, Diefenhardt, Markus, Chatzikonstantinou, Georgios, Fokas, Emmanouil, Rödel, Claus, Strebhardt, Klaus, Becker, Sven, Rödel, Franz, and Tselis, Nikolaos

Subjects
3. Good health
Abstract

Introduction: Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT. Methods: We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset. Results: PLK3 expression levels were associated with pT273 Caspase 8 levels (p = 0.009), as well as N stage (p = 0.046), M stage (p = 0.026), and FIGO stage (p = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p = 0.009), improved CSS (p = 0.001), and OS (p = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p = 0.021), and increased CSS (p < 0.001) and OS (p < 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p < 0.05), as well as increased propensity for metastasis (p = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p = 0.005), and both improved CSS (p < 0.001) and OS (p < 0.001); this combined score independently predicted distant failure (p = 0.041) and CSS (p = 0.003) on multivariate analyses. Conclusion: Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context.

45. Association of Polo-Like Kinase 3 and PhosphoT273 Caspase 8 Levels With Disease-Related Outcomes Among Cervical Squamous Cell Carcinoma Patients Treated With Chemoradiation and Brachytherapy

Author

Fleischmann, Max, Martin, Daniel, Peña-Llopis, Samuel, Oppermann, Julius, von der Grün, Jens, Diefenhardt, Markus, Chatzikonstantinou, Georgios, Fokas, Emmanouil, Rödel, Claus, Strebhardt, Klaus, Becker, Sven, Rödel, Franz, Tselis, Nikolaos, and Small, William, Jr.

Subjects
Medizin, ddc:610
Abstract

Introduction: Definitive chemoradiation (CRT) followed by high-dose-rate (HDR) brachytherapy (BT) represents state-of-the-art treatment for locally-advanced cervical cancer. Despite use of this treatment paradigm, disease-related outcomes have stagnated in recent years, indicating the need for biomarker development and improved patient stratification. Here, we report the association of Polo-like kinase (PLK) 3 expression and Caspase 8 T273 phosphorylation levels with survival among patients with cervical squamous cell carcinoma (CSCC) treated with CRT plus BT. Methods: We identified 74 patients with FIGO Stage Ib to IVb cervix squamous cell carcinoma. Baseline immunohistochemical scoring of PLK3 and pT273 Caspase 8 levels was performed on pre-treatment samples. Correlation was then assessed between marker expression and clinical endpoints, including cumulative incidences of local and distant failure, cancer-specific survival (CSS) and overall survival (OS). Data were then validated using The Cancer Genome Atlas (TCGA) dataset. Results: PLK3 expression levels were associated with pT273 Caspase 8 levels (p = 0.009), as well as N stage (p = 0.046), M stage (p = 0.026), and FIGO stage (p = 0.001). By the same token, pT273 Caspase 8 levels were associated with T stage (p = 0.031). Increased PLK3 levels corresponded to a lower risk of distant relapse (p = 0.009), improved CSS (p = 0.001), and OS (p = 0.003). Phospho T273 Caspase 8 similarly corresponded to decreased risk of distant failure (p = 0.021), and increased CSS (p < 0.001) and OS (p < 0.001) and remained a significant predictor for OS on multivariate analysis. TCGA data confirmed the association of low PLK3 expression with resistance to radiotherapy and BT (p < 0.05), as well as increased propensity for metastasis (p = 0.019). Finally, a combined PLK3 and pT273 Caspase 8 score predicted for decreased distant relapse (p = 0.005), and both improved CSS (p < 0.001) and OS (p < 0.001); this combined score independently predicted distant failure (p = 0.041) and CSS (p = 0.003) on multivariate analyses. Conclusion: Increased pre-treatment tumor levels of PLK3 and pT273 Caspase 8 correspond to improved disease-related outcomes among cervical cancer patients treated with CRT plus BT, representing a potential biomarker in this context. CA extern

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47. Customized 3D-printed molds for high dose-rate brachytherapy in facial skin cancer: First clinical experience.

Author

Chatzikonstantinou G, Diefenhardt M, Fleischmann M, Meissner M, Scherf C, Trommel M, Ramm U, Rödel C, Tselis N, and Licher J

Subjects
Humans, Aged, Printing, Three-Dimensional, Radiotherapy Dosage, Melanoma, Cutaneous Malignant, Brachytherapy adverse effects, Skin Neoplasms radiotherapy, Skin Neoplasms etiology, Melanoma radiotherapy, Melanoma etiology
Abstract

Background and Objective: Radiotherapy of elderly, frail patients with facial skin cancer in proximity to critical organs is challenging. This is the first report on clinical experience with facial skin cancer treated by individualized 3D-printer-based mold high-dose-rate (HDR) brachytherapy (BT)., Patients and Methods: Fifteen patients not eligible for radical surgery or definitive external beam radiotherapy (EBRT) were treated with 3D-printer-based mold HDR-BT. Patient selection and treatment were in accordance with multidisciplinary tumor board recommendations. Clinical response, toxicity and cosmesis were analyzed., Results: Median age was 77 years. Histology revealed squamous cell carcinoma in seven, basal cell carcinoma in five, melanoma in situ in one, Lentigo maligna in one, and melanoma in one patient, respectively. Median prescription dose was 39 Gy delivered in once-daily fractions of 3 Gy. After a median follow-up of 12.2 months, local recurrence was observed in one patient with melanoma in situ. Apart from one grade 4 cataract, no other > grade 2 late toxicity was documented., Conclusions: HDR-BT with 3D-printer-based molds for facial skin cancer is a well-tolerated and safe treatment option for elderly, frail patients not eligible for radical surgery or definitive EBRT due to functional inoperability or tumor location., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Published
2023
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