Senescence and the Early Ageing Phenotype After Chemotherapy for Testicular Cancer: the SEA-CAT Study

• ClinicalTrials.gov Identifier: NCT04113122
• Recruitment Status: Recruiting
• First Posted: October 2, 2019
• Last Update Posted: February 2, 2021
• Sponsor: University Medical Center Groningen
• Collaborator: Dutch Cancer Society
• Information provided by (Responsible Party): J.A. Gietema, University Medical Center Groningen

Study Description

Brief Summary:

Cisplatin-combination chemotherapy causes inevitably DNA damage by platinum-DNA adduct formation of both tumor cells but also healthy cells. It therefore stands to reason that testicular cancer treatment causes an increased burden of senescent cells, which causes upregulation of the SASP resulting in a pro-inflammatory phenotype. The investigators hypothesize that this may be an important mechanism behind development of late effects and an early ageing phenotype after treatment for testicular cancer.

Condition or disease	Intervention/treatment	Phase
Testicular Cancer	Diagnostic Test: Skin biopsy; Diagnostic Test: Subcutaneous fat biopsy	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 192 participants
• Allocation: Non-Randomized
• Intervention Model: Factorial Assignment

Intervention Model Description

A study will be performed consisting of two cohorts. Cross-sectional study Testicular cancer survivors treated between 2000 and 2005 or between 2006 and 2012 with cisplatin-combination chemotherapy and were extensively phenotypically mapped within two longitudinal trials will be invited to participate in a single cross-sectional follow-up study visit 5-20 years after chemotherapy.

Longitudinal study

Patients with metastasized testicular cancer who are about to start with cisplatin-combination chemotherapy will be invited. Study participation involves four study visits:

Visit 1: before start of chemotherapy Visit 2: before third cycle of chemotherapy Visit 3: one month after completion of chemotherapy Visit 4: one year after start of chemotherapy

Patients with stage I testicular cancer will serve as control group with three study visits:

Visit 1: at time of orchidectomy Visit 2: one month after orchidectomy Visit 3: one year after orchidectomy

• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Senescence and the Early Ageing Phenotype After Chemotherapy for Testicular Cancer: the SEA-CAT Study
• Actual Study Start Date: February 9, 2019
• Estimated Primary Completion Date: September 2022
• Estimated Study Completion Date: September 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cross-sectional study: Testicular cancer survivors who were treated between 2000 and 2005 or between 2006 and 2012 with cisplatin-combination chemotherapy and who were extensively phenotypically mapped within two longitudinal trials (15,16) will be invited to participate in a single cross-sectional follow-up study visit 5-20 years after chemotherapy.	Diagnostic Test: Skin biopsy; A 4 mm skin biopsy will be performed at the upper leg of the patient. Before the skin biopsy local anesthesia is applied subcutaneously. In these skin biopsies senescent cells will be detected by p16, p21 and yH2Ax staining. Furthermore, we will measure platinum levels in the skin biopsies.; Diagnostic Test: Subcutaneous fat biopsy; An abdominal subcutaneous fat biopsy will be performed 7-10 cm on the right side of the umbilicus. Before the fat biopsy local anesthesia is applied subcutaneously. An amount of 30 mg fat tissue will be collected using needle aspiration. In these fat biopsies senescent cells will be detected by p16, p21 and yH2Ax staining. Furthermore, we will measure platinum levels (ICP-MS), adipocytokines (leptin, adiponectin, interleukin-6, PAI-1, TNF-α), p53 activation indirectly by measuring p21 or mdm2 expression using immunohistochemistry, microRNA regulation of insulin signaling in adipose tissue: miR-103, miR-107, miR-29.
Experimental: Longitudinal study - chemotherapy group; Patients with metastasized testicular cancer who are about to start with cisplatin-combination chemotherapy will be invited in the longitudinal part of this study. Study participation involves four study visits: Visit 1: before start of chemotherapy Visit 2:before third cycle of chemotherapy Visit 3: one month after completion of chemotherapy Visit 4: one year after start of chemotherapy	Diagnostic Test: Skin biopsy; A 4 mm skin biopsy will be performed at the upper leg of the patient. Before the skin biopsy local anesthesia is applied subcutaneously. In these skin biopsies senescent cells will be detected by p16, p21 and yH2Ax staining. Furthermore, we will measure platinum levels in the skin biopsies.; Diagnostic Test: Subcutaneous fat biopsy; An abdominal subcutaneous fat biopsy will be performed 7-10 cm on the right side of the umbilicus. Before the fat biopsy local anesthesia is applied subcutaneously. An amount of 30 mg fat tissue will be collected using needle aspiration. In these fat biopsies senescent cells will be detected by p16, p21 and yH2Ax staining. Furthermore, we will measure platinum levels (ICP-MS), adipocytokines (leptin, adiponectin, interleukin-6, PAI-1, TNF-α), p53 activation indirectly by measuring p21 or mdm2 expression using immunohistochemistry, microRNA regulation of insulin signaling in adipose tissue: miR-103, miR-107, miR-29.
Longitudinal study - stage I control group; Patients with stage I testicular cancer will serve as control group with three study visits: Visit 1: at time of orchidectomy Visit 2: one month Visit 3: one year after orchidectomy	Diagnostic Test: Skin biopsy; A 4 mm skin biopsy will be performed at the upper leg of the patient. Before the skin biopsy local anesthesia is applied subcutaneously. In these skin biopsies senescent cells will be detected by p16, p21 and yH2Ax staining. Furthermore, we will measure platinum levels in the skin biopsies.; Diagnostic Test: Subcutaneous fat biopsy; An abdominal subcutaneous fat biopsy will be performed 7-10 cm on the right side of the umbilicus. Before the fat biopsy local anesthesia is applied subcutaneously. An amount of 30 mg fat tissue will be collected using needle aspiration. In these fat biopsies senescent cells will be detected by p16, p21 and yH2Ax staining. Furthermore, we will measure platinum levels (ICP-MS), adipocytokines (leptin, adiponectin, interleukin-6, PAI-1, TNF-α), p53 activation indirectly by measuring p21 or mdm2 expression using immunohistochemistry, microRNA regulation of insulin signaling in adipose tissue: miR-103, miR-107, miR-29.

Outcome Measures

Primary Outcome Measures :

1. Cellular senescence [ Time Frame: 1 year ]
   The change in the amount of senescent cells in skin and fat tissue (defined as % of cells in which nucleus is stained positive for P16, P21 and yH2Ax)

Secondary Outcome Measures :

1. Senescence-associated secretory phenotype (SASP) [ Time Frame: 1 year ]
   Change in levels of the cytokines: IL-6, IL-8, VEGF
2. Pulse-wave velocity [ Time Frame: 1 year ]
   Presence or development of the early ageing phenotype will be assessed measuring vascular damage: change in vascular stiffness (pulse-wave velocity, PWV).
3. Platinum levels [ Time Frame: 1 year ]
   Changes in circulating platinum levels and the amount of platinum depositions in skin and fat tissure will be assessed.
4. Adipocytokines 1 [ Time Frame: 1 year ]
   Changes in levels of leptin and PAI-1 (ug/L)
5. Adipocytokines 2 [ Time Frame: 1 year ]
   Changes in levels of adiponectin (ug/mL)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

In order to be eligible to participate in the cross-sectional part of this study, a subject must meet all of the following criteria:

• Diagnosed with metastatic testicular cancer in 1999-2012 (stage II or higher)
• Received first-line cisplatin-based chemotherapy
• Was younger than 50 years of age at start of chemotherapy

In order to be eligible to participate in the longitudinal part of this study, a subject must meet all of the following criteria:

Chemotherapy-group:

• Diagnosis of metastatic testicular cancer (stage II or higher)
• Is about to start with first-line cisplatin-based chemotherapy
• Younger than 50 years of age at diagnosis of metastatic testicular cancer

Stage I control-group:

• Diagnosis of testicular cancer stage I disease
• Younger than 50 years of age at diagnosis of testicular cancer

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

- Not able to provide informed consent (in example in case of mental or psychiatric disability)

Contacts and Locations

Contacts

Contact: J. A. Gietema, prof.; +31 50 361 2821; j.a.gietema@umcg.nl

Locations

Netherlands

University Medical Center Groningen; Recruiting

Groningen, Netherlands, 9713 GZ

Contact: J. A. Gietema, Prof. +31 50 361 2821 j.a.gietema@umcg.nl

Principal Investigator: J. A. Gietema, Prof.

Sponsors and Collaborators

University Medical Center Groningen

Dutch Cancer Society

Investigators

• Principal Investigator: J. A. Gietema, Prof.; University Medical Center Groningen

More Information

• Responsible Party: J.A. Gietema, Principal Investigator, University Medical Center Groningen
• ClinicalTrials.gov Identifier: NCT04113122
• Other Study ID Numbers: 201700615
• First Posted: October 2, 2019
• Last Update Posted: February 2, 2021
• Last Verified: February 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Testicular Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Endocrine System Diseases; Testicular Diseases; Gonadal Disorders