Circulating Biomarkers in Patients With Anal Cancer Treated With Induction Chemotherapy

To investigate the prognostic and predictive value of plasma HPV (pHPV) prior, during and after induction chemotherapy (ICT) in locally advanced squamous cell carcinoma of the anus (SCCA) or synchronous metastatic SCCA patients treated with ICT prior to definitive (chemo)radiotherapy ((C)RT) according to multidisciplinary team (MDT) conferences based decisions. Further to investigate the use of pHPV measurements and other relevant markers for prediction of response and survival after ICT prior to definitive (C)RT.

Study Overview

• Status: Recruiting
• Conditions: Anal Cancer; Circulating Tumor Cell; Oligometastatic Disease; Human Papilloma Virus; Locally Advanced Squamous Cell Carcinoma

Detailed Description

Anal cancer is a rare malignancy with approximately 200 new cases in Denmark per year, and the standard treatment is chemoradiotherapy (CRT). The treatment is centralised at three oncological departments at Aarhus University Hospital, Herlev Hospital and Vejle Hospital. The majority of anal cancers are squamous cell carcinomas (SCCA) and are strongly associated with human papilloma virus (HPV) which can be detected in tumour tissue in more than 80% of cases. Patients with large tumours, tumours invading nearby organs and/or local lymph node metastases could be treated with induction chemotherapy (ICT) in cases where downsizing prior definitive treatment is needed. Selected patients with metastatic (M1) SCCA could also be treated with ICT with the purpose of making definitive treatment possible.

HPV, cell-free DNA, circulating tumour DNA and immune related markers:

HPV is a virus group consisting of more than 130 subtypes, of which a minor part is categorised as oncogenic types. The most common HPV subtypes found in SCCA is HPV-16 and -18, but the total landscape of HPV subtype distribution in SCCA is sparsely investigated. Small fragments of cell-free DNA (cfDNA) can be detected in the circulation with elevated levels in cancer patients, but also in other circumstances. Aberrant methylation of DNA occurs in almost all malignant tumours and is shed into the circulation. The level of tumour specific methylated DNA (meth-ctDNA) can be analysed by modern PCR technology. It seems to hold biological information, which holds promise of clinical utility. The literature has focused on colorectal cancer and meth-ctDNA has been introduced as a prognostic marker. The possible importance in anal cancer has not been elucidated which is one the aims of the present protocol. With a simple blood test (so called "liquid biopsy"), it is possibility to characterise both the level of total cfDNA and meth-ctDNA. HPV associated anal cancer has a viral sequence integrated into the genome of the cancer cells. In HPV associated anal cancer meth-ctDNA is shredded to the blood stream, and can be measured as HPV tumour cell DNA (plasma HPV or pHPV). The observational and translation part of the DACG Plan-A study have shown that levels of pre-treatment pHPV are higher in large tumours compared to small and higher in node positive disease compared to node negative which is in agreement with results on advanced anal cancer where pHPV levels were correlated to tumour burden. The Plan-A study have also shown that pHPV is eliminated during CRT in case of response to treatment.

Immunotherapy has changed the treatment of several malignant tumours, especially malignant melanoma. The checkpoint inhibitors block PD/PD-L1 interaction, which elicits immune response to the malignant tumour. The treatment also seems to have effect in anal cancer. The literature is sparse, but a number of studies are ongoing. It is therefore well motivated to analyse one of the central stakeholders in the immune response. The level of PD-L1 in serum holds potential as a prognostic marker in anal cancer.

Perspective:

In patients treated with ICT prior to definitive CRT it is crucial not to exceed the necessary amount of potentially toxic treatment cycles and the ability of pHPV to address early response or progression is highly relevant. Complete response after ICT have been reported and treatment with ICT consisting of e.g. cisplatin, 5-flourouracil, leuroverin and ifosfamide (CILF) have shown a complete local tumour response rate of 15% and prediction of response is therefore highly relevant. In the metastatic setting taxol and carboplatin has now been introduced as first line option. This combination is also a relevant candidate for ICT. The potential perspective will be development of studies with pHPV guided intensified ICT.

Purpose:

To investigate the prognostic and predictive value of pHPV prior, during and after ICT in patients treated with ICT according to multidisciplinary team (MDT) conferences based decisions. Further to investigate the use of pHPV measurements and other relevant markers for prediction of response and survival after ICT prior to definitive CRT.

• Study Type: Observational
• Enrollment (Anticipated): 60

Contacts and Locations

• Study Contact: Name: Karen L Wind, MD; Phone Number: 20614431; Email: karen.lycke.wind@auh.rm.dk

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Not yet recruiting
    • Department of Oncology Herlev and Gentofte Hospital
    • Contact: Eva Serup-Hansen, PhD
  • Vejle, Denmark, 7100
    • Not yet recruiting
    • Department of Oncology, Vejle hospital, University Hospital of Southern Denmark
    • Contact: Birgitte M Havelund, PhD
  • Aarhus N
    • Aarhus, Aarhus N, Denmark, 8200
      • Recruiting
      • Department of Oncology, Aarhus University Hospital
      • Contact: Karen L Wind, MD; Email: karen.lycke.wind@auh.rm.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with newly diagnosed anal cancer who by standard of care are eligible for ICT prior to definitive CRT or radiotherapy alone (RT) will be screened according to inclusion- and exclusion criteria.

Description

Inclusion Criteria:

• Histological verified squamous cell carcinoma of the anus
• Treatment with ICT prior to definitive CRT or RT due to locally advanced disease or
• Patients with synchronous metastatic disease treated with ICT with the purpose of definitive CRT (potentially in combination with organ directed therapy (surgery, RFA, SBRT) for the metastatic sites)
• Age ≥ 18 years
• Written and orally informed consent

Exclusion Criteria:

• Contraindications for blood sampling
• Other malignancy within the past five years, with exception of basal cell carcinoma

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Locally advanced or synchronous metastatic anal cancer treated with induction chemotherapy; Patients with newly diagnosed anal cancer who by standard of care are eligible for induction chemotherapy prior to definitive CRT or radiotherapy alone (RT) will be screened according to inclusion- and exclusion criteria. Patients eligible for induction chemotherapy will be patients with locally advanced or synchronous metastatic anal cancer.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival according to circulating tumour DNA status	Overall survival: Time from diagnosis to time of dead or date of last follow-up.	2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free survival according to circulating tumour DNA and immune markers.	Time from end of treatment to progression, recurrence or death whatever comes first.	2 year
Recurrence-free survival according to circulating tumour DNA and immune markers.	Time from end of treatment to recurrence (locoregional or distant failure) or death whatever comes first.	2 year
Overall survival according to circulating tumour DNA and immune markers.	Overall survival: Time from diagnosis to time of death or date of last follow-up.	2 year

Collaborators and Investigators

• Sponsor: Aarhus University Hospital
• Investigators: Principal Investigator: Karen L Wind, MD, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: January 25, 2022
• First Submitted That Met QC Criteria: February 9, 2022
• First Posted (Actual): February 10, 2022

Study Record Updates

• Last Update Posted (Actual): February 10, 2022
• Last Update Submitted That Met QC Criteria: February 9, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Neoplasms, Squamous Cell; Rectal Neoplasms; Anus Diseases; Anus Neoplasms; Neoplastic Cells, Circulating; Papilloma
• Other Study ID Numbers: DACG-III

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No