Pharmacogenetic Profiling in High-Risk Soft Tissue Sarcomas Treated with Neoadjuvant Chemotherapy.

Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are substantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chemotherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (ABCB1, ABCC2, NQO1, CBR3, and SLC22A16) and in ifosfamide catabolism (ALDH1A1) in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: ABCC2 and ALDH1A1. In patients treated with anthracyclines, ABCC2 rs3740066 was associated with risk of febrile neutropenia (p = 0.031), and with decreased overall survival (OS) (p = 0.024). ABCC2 rs2273697 was associated with recurrence-free survival (RFS) (p = 0.024). In patients treated with ifosfamide, ALDH1A1 rs3764435 was associated with RFS (p = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to establish their clinical utility.

Quantitative and qualitative application of clinical drawings for image-guided brachytherapy in cervical cancer patients.

PURPOSE: Clinical drawings are integral part of image-guided adaptive brachytherapy (IGABT) of cervical cancer. It was used in EMBRACE study protocol as a useful tool. In our study clinical drawings from EMBRACE study were modified to include scales in all the dimensions for more accurate representation of various tumor related volumes. The aim of the present study was to understand patterns of tumor regression and relationship between gross tumor at diagnosis (GTVD) and high-risk clinical target volume (CTV-THR)/intermediate-risk clinical target volume (CTV-TIR) in brachytherapy (BRT), using modified clinical drawings. MATERIAL AND METHODS: 42 cervical cancer patients, staged as FIGO IIB-IIIB according to EMBRACE study, were enrolled. Advanced schematic 3D mapping diagram (3D-MD) in axial, coronal, and sagittal orientations, with a measurement scale (grid with 10 mm distance) for precise assessment and documentation was applied (through MRI at diagnosis and during brachytherapy). Dimensions, including height, width, and thickness as well as volumes (GTVD, CTV-THR and CTV-TIR) were compared both qualitatively and quantitatively. RESULTS AND CONCLUSIONS: We found qualitative and quantitative correlation of the dimensions of final CTV-THR with initial GTVD. Meticulous mapping of tumor volumes can provide useful insights to CTV-THR volume during brachytherapy.

Predictive capacity of IL-8 expression in head and neck squamous carcinoma patients treated with radiotherapy or chemoradiotherapy.

OBJECTIVE: To analyse the relationship between the transcriptional expression of interleukin-8 (IL-8) and response to treatment with radiotherapy or chemo-radiotherapy in patients with squamous cell carcinoma of the head and neck (SCCHN). MATERIAL AND METHODS: Retrospective study from tumour biopsies obtained before a treatment with radiotherapy or chemo-radiotherapy in 87 patients with SCCHN. We had a sample of healthy mucosa in 35 cases. We determined the transcriptional expression of IL-8 with RT-PCR. The transcriptional expression of IL-8 was categorized according to the local control of the disease with a recursive partitioning analysis. RESULTS: The transcriptional expression of IL-8 in tumour tissue was about 50 times higher than that in the samples of healthy mucosa. Patients with a high transcriptional expression of IL-8 (n = 56) had a 5-year local recurrence-free survival of 65.6%, and for patients with low expression (n = 31) it was 90.2% (P = 0.017). According to the results of a multivariate analysis, patients with high expression of IL-8 had a 4.1 higher risk of local recurrence of the tumour. CONCLUSIONS: SCCHN have a significant increase in transcriptional expression of IL-8 in relation to non-tumour tissue. Tumours with high IL-8 expression have an increased risk of local recurrence after treatment with radiotherapy or chemo-radiotherapy.

Capacidad predictiva de la expresión de IL-8 en pacientes con carcinomas escamosos de cabeza y cuello tratados con radioterapia o quimio-radioterapia / Predictive capacity of IL-8 expression in head and neck squamous carcinoma patients treated with radiotherapy or chemoradiotherapy

Objetivo: Analizar la relación entre la expresión transcripcional de interleucina-8 (IL-8) y la respuesta al tratamiento con radioterapia o quimio-radioterapia en pacientes con carcinoma escamoso de cabeza y cuello (CECC).Material y métodosEstudio retrospectivo realizado a partir de biopsias de tumor obtenidas de forma previa a un tratamiento con radioterapia o quimio-radioterapia en 87 pacientes con CECC. Se dispuso de una muestra de mucosa sana en 35 ocasiones. Se determinó la expresión transcripcional de la IL-8 mediante RT-PCR. Se categorizó el nivel de expresión transcripcional de IL-8 en función del control local de la enfermedad mediante un análisis de partición recursiva.ResultadosLa expresión transcripcional de IL-8 en el tejido tumoral fue unas 50 veces superior al de las muestras de mucosa sana. La supervivencia libre de recidiva local a los 5años para los pacientes con una expresión transcripcional elevada de IL-8 (n=56) fue del 65,6%, y para los pacientes con una expresión baja (n=31) del 90,2% (p=0,017). De acuerdo con los resultados de un análisis multivariante, los pacientes con unos niveles de expresión elevada de IL-8 contaron con un riesgo 4,1 veces superior de recidiva local de la enfermedad.ConclusionesLos CECC cuentan con un incremento significativo en los niveles de expresión transcripcional de la IL-8 en relación con el tejido no tumoral. Los tumores con unos niveles de expresión elevados de IL-8 tienen un incremento en el riesgo de sufrir una recidiva local del tumor tras un tratamiento con radioterapia o quimio-radioterapia. (AU)

Objective: To analyse the relationship between the transcriptional expression of interleukin-8 (IL-8) and response to treatment with radiotherapy or chemo-radiotherapy in patients with squamous cell carcinoma of the head and neck (SCCHN).Material and methodsRetrospective study from tumour biopsies obtained before a treatment with radiotherapy or chemo-radiotherapy in 87 patients with SCCHN. We had a sample of healthy mucosa in 35 cases. We determined the transcriptional expression of IL-8 with RT-PCR. The transcriptional expression of IL-8 was categorized according to the local control of the disease with a recursive partitioning analysis.ResultsThe transcriptional expression of IL-8 in tumour tissue was about 50 times higher than that in the samples of healthy mucosa. Patients with a high transcriptional expression of IL-8 (n=56) had a 5-year local recurrence-free survival of 65.6%, and for patients with low expression (n=31) it was 90.2% (P=.017). According to the results of a multivariate analysis, patients with high expression of IL-8 had a 4.1 higher risk of local recurrence of the tumour.ConclusionsSCCHN have a significant increase in transcriptional expression of IL-8 in relation to non-tumour tissue. Tumours with high IL-8 expression have an increased risk of local recurrence after treatment with radiotherapy or chemo-radiotherapy. (AU)

Preservación de órgano en pacientes con tumores avanzados de laringe. Resultados de la quimioterapia de inducción versus quimio-radioterapia en la práctica clínica real / Organ preservation in patients with advanced laryngeal tumours. Results of induction chemotherapy versus chemoradiotherapy in actual clinical practice

Introducción y objetivos: Un porcentaje elevado de pacientes con carcinomas localmente avanzados de laringe son candidatos a ser incluidos en protocolos de preservación de órgano. El objetivo del presente estudio es comparar los resultados de dos esquemas de preservación, quimioterapia de inducción versus quimio-radioterapia, en pacientes con carcinomas de laringe localmente avanzados en un contexto de práctica clínica real.MétodosEstudio retrospectivo realizado en 157 pacientes con tumores localmente avanzados de laringe (T3-T4) tratados con quimioterapia de inducción (n = 121) o quimio-radioterapia (n = 36).ResultadosDe los 121 pacientes que iniciaron tratamiento con quimioterapia de inducción, seis fallecieron como consecuencia de toxicidad, 37 fueron tratados con cirugía y 78 completaron el esquema de preservación; 36 pacientes recibieron un tratamiento inicial con quimio-radioterapia. No existieron diferencias significativas en la supervivencia específica a los cinco años en función de que los pacientes iniciasen un tratamiento con quimioterapia de inducción o quimio-radioterapia (68,9% versus 75,7%, p = 0,259). Un 45,9% de los pacientes consiguió una preservación de la función laríngea. Los pacientes tratados con quimio-radioterapia tuvieron una tendencia a conseguir una supervivencia libre de pérdida de la función laríngea a los cinco años superior a la de los pacientes tratados con quimioterapia de inducción (55,6% versus 44,8%, p = 0,079).ConclusiónLos pacientes incluidos en un protocolo de preservación consiguieron una supervivencia libre de disfunción laríngea a los cinco años del 45,9%. No se observaron diferencias significativas en la supervivencia específica entre los pacientes tratados con quimioterapia de inducción o quimio-radioterapia. (AU)

Introduction and objectives: A high percentage of patients with locally advanced larynx carcinomas are candidates for inclusion in organ preservation protocols. The objective of this study is to compare the results of two schemes of preservation, induction chemotherapy versus chemoradiotherapy, in patients with locally advanced larynx carcinomas in the context of actual clinical practice.MethodsOur retrospective study included 157 patients with locally advanced tumours of the larynx (T3-T4) treated with induction chemotherapy (n = 121) or chemoradiotherapy (n = 36).ResultsFrom 121 patients who began treatment with induction chemotherapy, 6 died due to toxicity, 37 were treated with surgery, and 78 completed the preservation scheme; 36 patients received treatment with chemoradiotherapy. There were no significant differences in 5-year disease-specific survival between both treatments: 68.9% in induction chemotherapy versus 75.7% in chemoradiotherapy (p = 0.259). In 45.9% of patients the laryngeal function was preserved. Patients treated with chemoradiotherapy had a tendency to have better 5-year laryngeal dysfunction-free survival than patients treated with induction chemotherapy (55.6% versus 44.8%, p = 0.079).ConclusionPatients included in a protocol of organ preservation achieved a 5-year laryngeal dysfunction-free survival of 45.9%. There were no significant differences in disease-specific survival among patients treated with induction chemotherapy or chemoradiotherapy. (AU)

Early morbidity and dose-volume effects in definitive radiochemotherapy for locally advanced cervical cancer: a prospective cohort study covering modern treatment techniques.

PURPOSE: Predicting morbidity for patients with locally advanced cervix cancer after external beam radiotherapy (EBRT) based on dose-volume parameters remains an unresolved issue in definitive radiochemotherapy. The aim of this prospective study was to correlate patient characteristics and dose-volume parameters to various early morbidity endpoints for different EBRT techniques, including volumetric modulated arc therapy (VMAT) and adaptive radiotherapy (ART). METHODS AND MATERIALS: The study population consisted of 48 patients diagnosed with locally advanced cervix cancer, treated with definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT). Multiple questionnaires (CTCAE 4.03, QLQ-C30 and EORTC QLQ-CX24) were assessed prospectively for patients treated with different EBRT techniques, including online adaptive VMAT. Contouring and treatment planning was based on the EMBRACE protocols. Acute toxicity, classified as general, gastrointestinal (GI) or genitourinary (GU) and their corresponding dose-volume histograms (DVHs) were first correlated by applying least absolute shrinkage and selection operator (LASSO) and subsequently evaluated by multiple logistic binomial regression. RESULTS: The treated EBRT volumes varied for the different techniques with ~2500 cm3 for 3D conformal radiotherapy (3D-CRT), ~2000 cm3 for EMBRACE­I VMAT, and ~1800 cm3 for EMBRACE-II VMAT and ART. In general, a worsening of symptoms during the first 5 treatment weeks and recovery afterwards was observed. Dose-volume parameters significantly correlating with stool urgency, rectal and urinary incontinence were as follows: bowel V40Gy < 250 cm3, rectum V40Gy < 80% and bladder V40Gy < 80-90%. CONCLUSION: This prospective study demonstrated the impact of EBRT treatment techniques in combination with chemotherapy on early morbidity. Dose-volume effects for dysuria, urinary incontinence, stool urgency, diarrhea, rectal bleeding, rectal incontinence and weight loss were found.

Preservación de órgano tras un tratamiento con quimioterapia de inducción en pacientes con carcinomas localmente avanzados (T3-T4) de cavidad oral y orofaringe / Organ preservation after treatment with induction chemotherapy in patients with locally advanced carcinomas (T3-T4) of oral cavity and oropharynx

INTRODUCCIÓN Y OBJETIVOS: Con el objetivo de conseguir la preservación funcional, una de las estrategias de tratamiento para los pacientes con carcinomas localmente avanzados de cabeza y cuello consiste en iniciar el tratamiento con quimioterapia (QT) de inducción y decidir la segunda maniobra terapéutica en función de la respuesta. El objetivo del presente estudio es evaluar la capacidad de preservación de órgano basada en esta estrategia terapéutica en pacientes con tumores de cavidad oral y orofaringe. MÉTODOS: Estudio retrospectivo de 246 pacientes con carcinomas de cavidad oral u orofaringe localmente avanzados (cT3-T4) tratados inicialmente con QT de inducción. RESULTADOS: Tras la QT de inducción el 28% de los pacientes consiguieron una respuesta completa de la localización primaria del tumor, el 43,1% una respuesta parcial superior al 50% y el 28,9% una reducción inferior al 50% o persistencia. Tras el tratamiento de QT de inducción 70 pacientes (28,5%) recibieron tratamiento quirúrgico y 176 (71,5%) radioterapia (RT) o quimiorradioterapia (QRT). Considerando a los pacientes tratados de forma no quirúrgica (n = 176), la preservación de órgano para los pacientes con una respuesta completa (n = 66) fue del 65,2%, para los pacientes con una respuesta parcial superior al 50% (n = 75) fue del 30,7% y para los pacientes con una respuesta inferior al 50% o persistencia (n = 35) fue del 14,3%. CONCLUSIÓN: La respuesta al tratamiento con QT de inducción cuenta con capacidad pronóstica en los pacientes con carcinomas localmente avanzados de cavidad oral y orofaringe. Los pacientes candidatos a tratamiento conservador con RT o QRT serían aquellos que consiguen una respuesta completa tras la administración del tratamiento de inducción

INTRODUCTION AND OBJECTIVES: With the goal of achieving functional preservation, one of the treatment strategies for patients with locally advanced squamous cell carcinomas of the head and neck is to initiate treatment with induction chemotherapy (CT) and decide the second therapeutic manoeuvre depending on the response. The objective of this study is to evaluate organ preservation capacity based on this therapeutic approach in patients with tumours of the oral cavity and oropharynx. METHODS: A retrospective study of 246 patients with locally advanced carcinomas of the oral cavity or oropharynx (cT3-T4) initially treated with induction CT. RESULTS: After induction CT 28% of patients achieved a complete response of the primary location of the tumour, 43.1% a partial response greater than 50%, and 28.9% a reduction less than 50% or persistence. After the induction CT treatment 70 patients (28.5%) underwent surgical treatment, and 176 (71.5%) radiotherapy (RT) or chemoradiotherapy (CRT). Considering the patients treated non-surgically (n = 176), organ preservation for patients with a complete response (n = 66) was 65.2%, for those patients with a partial response greater than 50% (n = 75) it was 30.7%, and for patients with a partial response less than 50% or persistence (n = 35) it was 14.3%. CONCLUSION: The response to treatment with induction CT has prognostic value in patients with locally advanced carcinomas of the oral cavity and oropharynx. Patients who are candidates for conservative treatment with RT or CRT would be those who achieve a complete response after induction treatment

Organ preservation after treatment with induction chemotherapy in patients with locally advanced carcinomas (T3-T4) of oral cavity and oropharynx. / Preservación de órgano tras un tratamiento con quimioterapia de inducción en pacientes con carcinomas localmente avanzados (T3-T4) de cavidad oral y orofaringe.

INTRODUCTION AND OBJECTIVES: With the goal of achieving functional preservation, one of the treatment strategies for patients with locally advanced squamous cell carcinomas of the head and neck is to initiate treatment with induction chemotherapy (CT) and decide the second therapeutic manoeuvre depending on the response. The objective of this study is to evaluate organ preservation capacity based on this therapeutic approach in patients with tumours of the oral cavity and oropharynx. METHODS: A retrospective study of 246 patients with locally advanced carcinomas of the oral cavity or oropharynx (cT3-T4) initially treated with induction CT. RESULTS: After induction CT 28% of patients achieved a complete response of the primary location of the tumour, 43.1% a partial response greater than 50%, and 28.9% a reduction less than 50% or persistence. After the induction CT treatment 70 patients (28.5%) underwent surgical treatment, and 176 (71.5%) radiotherapy (RT) or chemoradiotherapy (CRT). Considering the patients treated non-surgically (n=176), organ preservation for patients with a complete response (n=66) was 65.2%, for those patients with a partial response greater than 50% (n=75) it was 30.7%, and for patients with a partial response less than 50% or persistence (n=35) it was 14.3%. CONCLUSION: The response to treatment with induction CT has prognostic value in patients with locally advanced carcinomas of the oral cavity and oropharynx. Patients who are candidates for conservative treatment with RT or CRT would be those who achieve a complete response after induction treatment.

Organ preservation in patients with advanced laryngeal tumours. Results of induction chemotherapy versus chemoradiotherapy in actual clinical practice. / Preservación de órgano en pacientes con tumores avanzados de laringe. Resultados de la quimioterapia de inducción versus quimio-radioterapia en la práctica clínica real.

INTRODUCTION AND OBJECTIVES: A high percentage of patients with locally advanced larynx carcinomas are candidates for inclusion in organ preservation protocols. The objective of this study is to compare the results of two schemes of preservation, induction chemotherapy versus chemoradiotherapy, in patients with locally advanced larynx carcinomas in the context of actual clinical practice. METHODS: Our retrospective study included 157 patients with locally advanced tumours of the larynx (T3-T4) treated with induction chemotherapy (n = 121) or chemoradiotherapy (n = 36). RESULTS: From 121 patients who began treatment with induction chemotherapy, 6 died due to toxicity, 37 were treated with surgery, and 78 completed the preservation scheme; 36 patients received treatment with chemoradiotherapy. There were no significant differences in 5-year disease-specific survival between both treatments: 68.9% in induction chemotherapy versus 75.7% in chemoradiotherapy (p = 0.259). In 45.9% of patients the laryngeal function was preserved. Patients treated with chemoradiotherapy had a tendency to have better 5-year laryngeal dysfunction-free survival than patients treated with induction chemotherapy (55.6% versus 44.8%, p = 0.079). CONCLUSION: Patients included in a protocol of organ preservation achieved a 5-year laryngeal dysfunction-free survival of 45.9%. There were no significant differences in disease-specific survival among patients treated with induction chemotherapy or chemoradiotherapy.

Predictive capacity of IL-8 expression in head and neck squamous carcinoma patients treated with radiotherapy or chemoradiotherapy. / Capacidad predictiva de la expresión de IL-8 en pacientes con carcinomas escamosos de cabeza y cuello tratados con radioterapia o quimio-radioterapia.

OBJECTIVE: To analyse the relationship between the transcriptional expression of interleukin-8 (IL-8) and response to treatment with radiotherapy or chemo-radiotherapy in patients with squamous cell carcinoma of the head and neck (SCCHN). MATERIAL AND METHODS: Retrospective study from tumour biopsies obtained before a treatment with radiotherapy or chemo-radiotherapy in 87 patients with SCCHN. We had a sample of healthy mucosa in 35 cases. We determined the transcriptional expression of IL-8 with RT-PCR. The transcriptional expression of IL-8 was categorized according to the local control of the disease with a recursive partitioning analysis. RESULTS: The transcriptional expression of IL-8 in tumour tissue was about 50 times higher than that in the samples of healthy mucosa. Patients with a high transcriptional expression of IL-8 (n=56) had a 5-year local recurrence-free survival of 65.6%, and for patients with low expression (n=31) it was 90.2% (P=.017). According to the results of a multivariate analysis, patients with high expression of IL-8 had a 4.1 higher risk of local recurrence of the tumour. CONCLUSIONS: SCCHN have a significant increase in transcriptional expression of IL-8 in relation to non-tumour tissue. Tumours with high IL-8 expression have an increased risk of local recurrence after treatment with radiotherapy or chemo-radiotherapy.

Postoperative staging of the neck dissection using extracapsular spread and lymph node ratio as prognostic factors in HPV-negative head and neck squamous cell carcinoma patients.

OBJECTIVES: The presence of nodes with extracapsular spread (ECS) and the lymph node ratio (LNR) have prognostic competence in the pathologic evaluation of patients with a head and neck squamous cell carcinoma (HNSCC) treated with a neck dissection. The purpose of this study is to assess the effect of ECS & LNR on prognosis of HPV negative HNSCC patients treated with neck dissection and to compare to 8th edition TNM/AJCC classification. MATERIALS AND METHODS: We carried out a retrospective study of 1383 patients with HNSCC treated with a neck dissection between 1985 and 2013. We developed a classification of the patients according to the presence of nodes with ECS and the LNR value with a recursive partitioning analysis (RPA) model. RESULTS: We obtained a classification tree with four terminal nodes: for patients without ECS (including patients pN0) the cut-off point for LNR was 1.6%, while for patients with lymph nodes with ECS it was 11.4%. The 5-year disease-specific survival for patients without ECS/LNR < 1.6% was 83.3%; for patients without ECS/LNR ≥ 1.6% it was 61.5%; for patients with ECS/LNR < 11.4% it was 33.7%; and for patients with ECS/LNR ≥ 11.4% it was 18.5%. The classification obtained with RPA had better discrimination between categories than the 8th edition of the TNM/AJCC classification. CONCLUSION: ECS status and LNR value proved high prognostic capacity in the pathological evaluation of the neck dissection. The combination of ECS and LNR improved the predictive capacity of the 8th edition of the TNM/AJCC classification in HPV-negative HNSCC patients.

Image guided adaptive external beam radiation therapy for cervix cancer: Evaluation of a clinically implemented plan-of-the-day technique.

BACKGROUND: Radiotherapy for cervix cancer is challenging in patients exhibiting large daily changes in the pelvic anatomy, therefore adaptive treatments (ART) have been proposed. The aim of this study was the clinical implementation and subsequent evaluation of plan-of-the-day (POTD)-ART for cervix cancer in supine positioning. The described workflow was based on standard commercial equipment and current quality assurance (QA) methods. MATERIALS AND METHODS: A POTD strategy, which employs a VMAT plan library consisting of an empty bladder plan, a full bladder plan and a motion robust backup plan, was developed. Daily adaption was guided by cone beam computed tomography (CBCT) imaging after which the best plan from the library was selected. Sixteen patients were recruited in a clinical study on ART, for nine POTD was applied due to their large organ motion derived from two computed tomography (CT) scans with variable bladder filling. All patients were treated to 45Gy in 25 fractions. Plan selection frequencies over the treatment course were analyzed. Daily doses in the rectum, bladder and cervix-uterus target (CTV-T) were derived and compared to a simulated non-adapted treatment (non-ART), which employed the robust plan for each fraction. Additionally, the adaption consistency was determined by repeating the plan selection procedure one month after treatment by a group of experts. ART-specific QA methods are presented. RESULTS: 225 ART fractions with CBCTs were analyzed. The empty bladder plan was delivered in 49% of the fractions in the first treatment week and this number increased to 78% in the fifth week. The daily coverage of the CTV-T was equivalent between ART and the non-ART simulation, while the daily total irradiated volume V42.75Gy (95% of prescription dose) was reduced by a median of 87cm3. The median delivered V42.75Gy was 1782cm3. Daily delivered doses (V42.75Gy, V40Gy, V30G) to the organs at risk were statistically significantly reduced by ART, with a median difference in daily V42.75Gy in rectum and bladder of 3.2% and 1.1%, respectively. The daily bladder V42.75Gy and V40Gy were decreased by more than 10 percent points in 30% and 24% of all fractions, respectively, through ART. The agreement between delivered plans and retrospective expert-group plan selections was 84%. CONCLUSION: A POTD-ART technique for cervix cancer was successfully and safely implemented in the clinic and evaluated. Improved normal tissue sparing compared to a simulated non-ART treatment could be demonstrated. Future developments should focus on commercial automated software solutions to allow for a more widespread adoption and to keep the increased workload manageable.

Changes in Tumor Biology During Chemoradiation of Cervix Cancer Assessed by Multiparametric MRI and Hypoxia PET.

PURPOSE: Imaging biomarkers assessed with magnetic resonance imaging (MRI) and/or positron emission tomography (PET) enable non-invasive tumor characterization in cervix cancer patients. We investigated the spatio-temporal stability of hypoxia, perfusion, and the cell density of tumors over time by repetitive imaging prior to, during, and after radio-chemotherapy. PROCEDURES: Thirteen patients were included in this prospective study. The imaging protocol included the following: [18F]fluoromisonidazole ([18F]FMISO)-PET/x-ray computed tomography (CT) and multiparametric (mp)-MRI at four time-points (TP): baseline (BL); and weeks 2 (TP1), 5 (TP2), and 19 after treatment start (follow-up FU). Complete datasets for six patients could be assessed for tumor volume, enhancement kinetics, diffusivity, and [18F]FMISO-avidity (P1-P6). In addition, two patients completed all PET/CT examinations (P7-P8) but not all MR scans; however, one of them had no hypoxia (P8). Descriptive statistics, correlations, and voxel-by-voxel analysis were performed. For various, independent reasons, five patients could not complete the study according to the protocol with all imaging sequences. RESULTS: Median tumor ADCs (in ×10-3 mm2/s) were 0.99 ± 0.10 at BL, 1.20 ± 0.12 at TP1, 1.33 ± 0.14 at TP2, and 1.38 ± 0.21 at FU. The median TBRpeak (tumor-to-background) was 2.7 ± 0.8 at BL, 1.6 ± 0.2 at TP1, 1.8 ± 0.3 at TP2, and 1.7 ± 0.3 at FU. The voxel-by-voxel analysis of the [18F]FMISO uptake at BL and TP1 showed no correlation. Between TP2 and TP1 and FU and TP2, weak correlations were found for two patients. CONCLUSIONS: Longitudinal mp-MR and PET imaging enables the in vivo tumor characterization over time. While perfusion and cell density decreased, there was a non-uniform change of hypoxia observed during radiotherapy. To assess the potential impact with regard to more personalized treatment approaches, hypoxia imaging-based dose painting for cervix cancer requires further research.

Impact of hybrid PET/MR technology on multiparametric imaging and treatment response assessment of cervix cancer.

BACKGROUND AND PURPOSE: Multimodal tissue characterization by combined MRI and PET has high clinical potential in the context of sub-target definition for dose painting and response assessment but its clinical exploration is yet limited. The aim of this study was to prove the potential and feasibility of hybrid PET/MRI to non-invasively measure tumor hypoxia, perfusion and microstructure at one stop in tumors of the uterine cervix during chemoradiotherapy. MATERIAL AND METHODS: Ten cervix cancer patients were subjected to simultaneous multiparametric PET/MRI with [18F]fluoromisonidazole ([18F]FMISO). Imaging was scheduled before, twice during and after chemoradiotherapy. Intra- and inter-time point analyses of the extracted parameters (i.e. ADC, Ktrans, ABrix, [18F]FMISO-tumor to background ratio (TBR)) were performed. The [18F]FMISO uptake- and ADC-spatio-temporal changes were assessed. RESULTS: Patient averaged ADC values increased from baseline to follow up (1.03 ±â€¯0.11/1.30 ±â€¯0.13 × 10-3 mm2/s), while the TBR decreased (1.73 ±â€¯0.24/1.36 ±â€¯0.19), Ktrans dropped over time (0.17 ±â€¯0.05/0.05 ±â€¯0.05 min-1); for all above p < 0.05. None of these parameters correlated significantly on a voxel-by-voxel basis. Low-ADC regions spatially varied over time. There was pronounced reduction of the [18F]FMISO-avid volumes during treatment. CONCLUSIONS: The suggested hybrid PET/MRI protocol to non-invasively investigate tumor hypoxia, perfusion and microstructure at one stop was feasible, revealing spatio-temporal response patterns that could be utilized for comprehensive sub-target definition for dose painting and response assessment.

Evaluation of planning aims and dose prescription in image-guided adaptive brachytherapy and radiochemotherapy for cervical cancer: Vienna clinical experience in 225 patients from 1998 to 2008.

BACKGROUND: To assess planning aims (PAs) and dose prescription in image-guided adaptive brachytherapy (IGABT) of cervical cancer and investigate potential impact on clinical outcome. MATERIAL AND METHODS: Our study population consists of 225 consecutive cervical cancer patients (FIGO stages IB-IVA) treated between 1998 and 2008 at the Medical University of Vienna by external beam radiotherapy (EBRT) ± chemotherapy and IGABT. For this retrospective study, patients were stratified into two treatment groups: PA+ group, all dose constraints fulfilled for prescription; PA-, one or more dose constraints not fulfilled for prescription. The following dose constraints (EBRT+ IGABT) were applied: clinical target volume (CTV)HR D90 ≥ 85 Gy, D2cm3 Rectum < 70 Gy, D2cm3 Bladder < 90 Gy. Differences in patient, tumor and treatment characteristics and clinical outcome (event: local failure or grade 3 + 4 toxicity) were compared between Group 1 and 2. Further, the impact of learning period (1998-2000) and protocol period (2001-2008) on the fulfillment of PAs for dose prescription and clinical outcome was analyzed. RESULTS: In the PA+ group there were 77 (34%) and in the PA- group 148 (66%) patients. In the PA- group, CTVHR D90 < 85 Gy was prescribed in 82 patients, D2cm3 bladder > 90 Gy was prescribed in 80 patients and D2cm3 Rectum > 70 Gy in 60 patients. Fulfillment of the PA for dose prescription improved from 4% in the learning period to 48% in the protocol period. The five-year event-free interval was 64% in the learning period and 84% in the protocol period (p = 0.008). CONCLUSION: Fulfillment of all PAs for dose prescription is challenging - especially in patients with more advanced tumors. However, with growing experience fulfillment of PA for dose prescription can be significantly increased (learning and protocol period). Such increase in fulfilling PA for dose prescription is followed by a significant improvement in clinical outcome.