Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Head and Neck Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Antineoplastic Agents

Hormones

Cisplatin

External beam radiotherapy for prostate cancer

External beam radiotherapy for head and neck cancer

Patients will receive radiotherapy for prostate cancer and possible adjuvant hormone therapies as foreseen by international guidelines. No modification of standard regimens is considered. PCa patients are treated with 78 Gy, 2Gy/fraction, in exclusive setting and with 70 Gy, 2Gr/fraction in the post-prostatectomy setting. Lymph node irradiation is performed (50 Gy, 2Gy/fraction) when indicated by risk class.

Patients will receive radiotherapy for head and neck cancer and possible concomitant chemotherapies as foreseen by international guidelines. No modification of standard regimens is considered. In curative setting, HNCa patients are treated at a total dose of 70 Gy, 59.4 Gy and 56.1 Gy in 33 fractions to high risk Planning Target Volume (PTV), intermediate risk and low risk PTV, respectively. In high risk post-operative setting they are treated with 66 Gy (according to histopathological features), 60 Gy and 56.1 Gy to high, intermediate and low risk PTV, respectively; while, in intermediate risk post-operative case, intermediate and low risk PTV are irradiated with 60 Gy and 54 Gy, respectively. Chemotherapy will be platinum based (weekly or 3-weekly cisplatin).

Riccardo Valdagni, MD, PhD

Tiziana Rancati, MS

Ester Orlandi, MD

Nice Bedini, MD

Loris De Cecco, PhD

Nadia Zaffaroni, PhD

The main idea behind MICRO-LEARNER is to provide new insights about the response of healthy tissues to radiation by using information from the micro-environment obtained by biological measurements and imaging. This new knowledge will be included in current available predictive models of radio-induced toxicity, thus allowing to add unique biological characteristics of patients to dosimetry and treatment/clinical related variables.

MICRO-LEARNER focuses on prostate cancer (PCa) and head-and-neck cancer (HNCa). For both cancers, radiotherapy is effectively used as curative treatment, in single modality or within a multidisciplinary approach including surgery (PCa) and/or chemotherapy (HNCa). Prediction and reduction of radio-induced side effects are becoming a priority: for PCa, high survival rates should be accompanied by a very low rate of moderate/severe toxicities; for HNCa, there is the need to tailor radiation dose according to disease recurrence risk profile. The shared aim of both cancers is to balance the improvement in outcome with a well-tolerated toxicity profile.

Recent research indicates that the intestinal/salivary bacteria are strongly suspected of being very important in mediating the response to inflammation and lesions. Although their balance deeply changes during radiotherapy, studies done so far in the field of the microbiota-host relationship in radiotherapy have not addressed their role in insurgence of radiation toxicity.

In this study, the investigators will assess how microbial populations evolve and how this influences the host and radiation induced toxicity in a significant number of patients. Moreover, the individual response at the tissue microstructure level, through analysis of images with advanced bioengineering techniques, will be determined.

Results from this research, besides suggesting new ways to predict patients at risk of relevant side-effects, may also suggest possible treatments to change the baseline microbiota of patients at high risk or to modify it during therapy, in order to mitigate toxicity. Understanding the microbiota-radiotherapy interaction may thus lead to novel, effective and inexpensive ways of assessing and managing complications of cancer treatment.

\*\*Prospective Clinical Trial: discovery population\*\*

130 PCa and 130 HNCa consecutive patients will be enrolled in 18 months. All patients will receive radiotherapy at radical curative doses at the National Cancer Institute in Milan, and follow-up visits at the same centre.

Detailed pre-treatment evaluation will include: recording of demographic features, clinical history, comorbidities and habits, evaluation of normal tissue functioning by the health practitioner (CTCAE scoring system), evaluation of quality of life and normal tissue functioning through validated patient reported outcome (PROs) questionnaires, evaluation of organ functioning by instrumental measures (i.e. baseline swallowing screening with flexible endoscopic evaluation of swallowing - FEES - and unstimulated salivary flow for HNCa patients), biochemical examinations, gut (PCa)/salivary (HNCa) microbiome measurement, determination of baseline level of plasma/salivary inflammatory markers, baseline multi-parametric magnetic resonance imaging (MRI).

Patients will receive radiotherapy and possible adjuvant (hormone or chemo) therapies as foreseen by international guidelines. In this aspect the here proposed trial is an observational study, no modification to standard regimens is considered. Radiotherapy is performed with 6 MV photon beams delivered with Volumetric Modulated arc Therapy (VMAT) technique at conventional fractionations.

Evaluation during treatment will include weekly assessment of toxicity, as measured by the clinician (according to CTCAE v 4.0) and by PROs and biochemical measurements, and evaluation of inflammatory markers (plasmatic and salivary cytokines) after a dose of 20 Gy. For a subpopulation of 60 oropharyngeal cancer patients treated with definitive radiotherapy +/- chemotherapy an additional MRI study during the second week of treatment is foreseen.

Assessment at the end of radiotherapy will include evaluation of toxicity by the clinician and by PROs, FEES and unstimulated salivary flow for HNCa patients, biochemical examinations, gut/salivary microbiome measurement.

Evaluation at 3, 6 and 12 months will include: evaluation of toxicity by the clinician and by PROs, FEES and unstimulated salivary flow for HNCa patients and biochemical examinations.

Minimum follow-up is set to 12 months for the specific purpose of evaluation of acute and mid-term toxicity, which are the endpoints considered in this project. Nevertheless, follow-up will continue until 3 years after the end of radiotherapy (beyond the end of the project) in order to allow evaluation of incidence, prevalence and patterns of late side-effects, as well as for survival outcome assessment. After 12 months, follow-up will be performed every 6 months and limited to assessment of toxicity by the clinician and by PROs.

Follow-up MRI studies will be performed at 3, 12 and 24 months for HNCa patients and at 12 months for PCa patients.

\*\*Prospective Clinical Trial: validation population\*\*

70 PCa and 70 HNCa consecutive patients will be enrolled in 12 months, starting immediately after the end of enrolment of the discovering population.

The specific aim of this second phase is validation of results on microbiota, specifically on association between selected baseline microbiota profiles and the risk of acute toxicity (for the purpose of this project) and for mid-term/late toxicity (beyond this projects). This result should be the more significant from the clinical point of view, allowing development of a therapeutic algorithm to be used before treatment and permitting introduction ways of changing the make-up of gut/salivary bacteria in patients at high risk of toxicity.

Baseline assessment, treatment and follow-up evaluation of toxicity by the clinician and by PROs will follow the scheme described for the developing population. Microbioma measurement will be only performed at baseline, due to the higher clinical interest in having a test determining patient radiosensitivity before treatment. Imaging and assessment of inflammatory marker levels will not be accomplished in the validation population.

Whole blood samples of all patients, stool samples of prostate cancer patients, salivary samples of head and neck cancer patients

Predictors of Normal Tissue Response From the Microenvironment in Radiotherapy for Prostate and Head-and-neck Cancer

Microbiota, Inflammatory Environment, Clinical and Radiomic Features as Predictors of Normal Tissue Response in Radiotherapy for Prostate and Head-and-neck Cancer

If any, acute (\<within 90 days from radiotherapy completion) Grade 1, Grade 2, Grade 3-4 disorder, according to the Common Terminology Criteria for Adverse Events (CTCAE) grading system, and its association with clinical variables, absorbed dose, microbioma characteristics and radiomic features.

If any, late (\> 90 days after radiotherapy completion) Grade 1, Grade 2, Grade 3-4 disorder, according to the Common Terminology Criteria for Adverse Events (CTCAE) grading system, and its association with clinical variables, absorbed dose, microbioma characteristics and radiomic features.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Gland and Hormone Related Diseases

Symptoms and General Pathology

Rare Diseases

Ovarian Neoplasms

Genital Diseases, Female

Endocrine Gland Neoplasms

Cysts

Ovarian Cysts

Genital Neoplasms, Female

Endocrine System Diseases

Adnexal Diseases

Ovarian Diseases

Gonadal Disorders

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Ovarian Cancer

Standardized transvaginal ultrasound examination

Dirk Timmerman, MD, PhD

Wouter Froyman, MD

Dirk Timmerman, PhD

Tom Bourne, MD, PhD

Ben Van Calster, MSc, PhD

Ignace Vergote, MD, PhD

Lil Valentin, MD, PhD

Antonia C Testa, MD, PhD

Sabine Van Huffel, MSc, PhD

The ability of different methods to discriminate between benign and malignant adnexal masses has been compared in a meta-analysis showing that the IOTA Simple Rules and the IOTA logistic regression model LR2 were superior to RMI and to all other methods for predicting malignancy in an adnexal mass included in the meta-analysis. However, a fair comparison of methods requires them to be applied on the same tumor population.

The general objective of this study is to prospectively validate the Simple Rules, ADNEX, the Simple Rules risk model, LR2, and RMI on a large multicenter dataset to allow direct comparison of these tools.

IOTA7 is an international multicenter prospective observational study including different types of ultrasound centers and examiners with different levels of ultrasound experience. In total, about 1700 adnexal masses with histological outcome will be included in IOTA 7.

Ovarian cancer is a common and lethal disease for which early detection and treatment in high volume centers and by specialized clinicians is known to improve survival. Hence, accurate methods to preoperatively characterize the nature of an ovarian tumor are pivotal.

The best ultrasound method for discrimination between benign and malignant adnexal masses is subjective assessment, i.e. subjective evaluation of ultrasound findings. Subjective assessment, however, requires a very experienced ultrasound examiner. More objective methods may be preferred by less experienced examiners who are not confident with using subjective assessment. The Risk of Malignancy Index (RMI) is one such method. There are also more recently developed methods. The International Ovarian Tumor Analysis (IOTA) group have created logistic regression models (LR1, LR2, and the ADNEX model) including clinical and ultrasound information to calculate the likelihood of malignancy in adnexal masses.

The IOTA group has also suggested simple ultrasound rules that can be used to classify adnexal masses as benign or malignant.

The ability of different methods to discriminate between benign and malignant adnexal masses has been compared in a meta-analysis showing that the IOTA Simple Rules and the IOTA logistic regression model LR2 were superior to RMI and to all other methods for predicting malignancy in an adnexal mass included in the meta-analysis. However, a fair comparison of methods requires them to be applied on the same tumor population.

The general objective of this study is to prospectively validate the Simple Rules, ADNEX, the Simple Rules risk model, LR2, and RMI on a large multicenter dataset to allow direct comparison of these tools. The patients will be examined by operators of varying levels of experience, such that the investigators can study how experience might affect diagnostic performance.

IOTA7 is an international multicenter prospective observational study including different types of ultrasound centers and examiners with different levels of ultrasound experience. In total, about 1700 adnexal masses with histological outcome will be included in IOTA 7.

Patients with a known or suspected adnexal mass examined with transvaginal (or transrectal if vaginal is not possible) ultrasound by an IOTA certified ultrasound examiner and confirmed to have an adnexal mass judged not to be physiological but likely to undergo surgery (primarily planned for surgical management based on subjective assessment by the ultrasound investigator) will be recruited consecutively Upon inclusion in the study, an oral or written (depending on the requirements of the local Ethics Committee) informed consent is obtained from the patient.

Data collection is done through the web-based clinical data miner (CDM) software. Data are stored on a secure server.

First, clinical information about the patient is entered into CDM. Second, the ultrasound examiner provides a diagnosis based on subjective assessment, and notes the suggested management. Third, detailed ultrasound information needed for the different models to be validated is entered. When these data have been frozen (so they can no longer be changed) the examiner gets access to the results of the Simple Rules and ADNEX. The ultrasound examiner then records whether these results make him/her change the management suggested on the basis of subjective assessment. If so the new management is specified.

Gold standard for validation of discriminative ability and calibration is the histology of the adnexal mass within 180 days after the ultrasound examination following surgical removal by laparotomy or laparoscopy as considered appropriate by the surgeon. In case of malignancy, the stage of the malignant tumors using the classification of the International Federation of Gynecology and Obstetrics (FIGO) is noted.

Prospective Validation and Comparison of Different Ultrasound Methods for Discrimination Between Benign and Malignant Ovarian/Tubal Masses Prior to Surgery

Prospective Validation and Comparison of Subjective Assessment, the International Ovarian Tumor Analysis (IOTA) ADNEX Model, Logistic Regression Model LR2, Simple Rules and the Risk of Malignancy Index (RMI) for Discrimination Between Benign and Malignant Adnexal Masses in the Hands of Ultrasound Examiners With Different Levels of Experience

KU Leuven

Prof. Dr.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Predictors of Normal Tissue Response From the Microenvironment in Radiotherapy for Prostate and Head-and-neck Cancer	NCT03294122	Prostate Cancer Head and Neck C...	External beam r... External beam r...	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Prospective Validation and Comparison of Different Ultrasound Methods for Discrimination Between Benign and Malignant Ovarian/Tubal Masses Prior to Surgery	NCT02847832	Patients With A...	Standardized tr...	-	KU Leuven
Predictors of Normal Tissue Response From the Microenvironment in Radiotherapy for Prostate and Head-and-neck Cancer	NCT03294122	Prostate Cancer Head and Neck C...	External beam r... External beam r...	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Predictors of Normal Tissue Response From the Microenvironment in Radiotherapy for Prostate and Head-and-neck Cancer	NCT03294122	Prostate Cancer Head and Neck C...	External beam r... External beam r...	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

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