Anal cancer
Anal cancer is a rare condition, primarily treated with radiotherapy, which is given in three Danish centers. The Danish Anal Cancer Group (DACG) was established in 2017 and is developing a national research strategy, including a study flow for optimized individualized radiotherapy, based on studies of individual risk for substantial side effects and sensitivity for radiotherapy. This part of the overall strategy comprises analysis of detailed information of patients reported outcome regarding acute and late side effects in relation to current and future technical options of the radiotherapy. Furthermore, we will analyze so-called biomarkers in the tumor tissue and collected blood samples for efficacy and side effects. Together these studies will form the basis for identification of patients, who are candidates for clinical trials testing more feasible and less toxic options, and conversely, those with the need for intensified treatments strategies.
Background and Aim
The overall aim of this research proposal is to improve the outcome, provide individualized therapy and increase the awareness for anal cancer patients in Denmark.
Squamous cell carcinomas of the anus is classified as a rare disease, but the incidence is increasing in Denmark and expected to reach approximately 200 new patients per year. Treatment is a complex process centralized in three centers in Denmark, with concomitant chemo-radiotherapy being primary curative modality. The rate of treatment success is high, but therapy often leads to significant acute and late toxicity with a high risk of long-term impaired quality of life.
The multidisciplinary cancer group Danish Anal Cancer Group (DACG), has been established in 2017 and is responsible for revision of treatment guidelines and establishing a national database for treatment outcome, and the close cooperation between the three centers gives a unique opportunity to expand the work to an overall national research strategy, building on local expertise in different fields of anal cancer treatment.
We seek to improve treatment of anal cancer patients in Denmark by addressing the following aspects;
- Individualized radiotherapy
- Optimal systemic therapy
- Prevention and management of treatment failure and recurrences
- Integration of translational research
- Shared decision making, patient involvement and awareness program
The here presented study proposal is a part of an overall national strategy covering broad aspects of anal cancer research. A larger funding application is under development to cover the full program, and the IP 11 will support the WP1 during 2018-2019, with the aim to collect, extend and analyse data from a national cohort of anal cancer patients undergoing curative radiotherapy in DK (PLAN-A). The overall purpose is to design individualised treatment options based on relevant outcome and toxicity data.
PLAN-A preliminary data
The current data-collection has shown feasibility and a high PROM-data collection rate > 90%, indicating a robust data-set for NTCP modelling of acute toxicity data from the first 150 patients, and 1 year toxicity dataset in the first 100 patients within the next 6 months. This will provide us with a platform for toxicity risk assessment for acute and intermediate toxicity parameters comprising bowel, bladder and vaginal morbidity.
An example is our single center observation of high frequent pelvis insufficiency fractures after pelvic irradiation (Kronborg et al. EMCC 2016), which was presented last year, and a separate prospective pilot study is designed to investigate the rate of symptomatic pelvic fractures and potential interventions.
Based on the first PLAN-A dataset comparative planning studies between fixed field IMRT, 3 or 4 arcs VMAT and proton plans have shown a benefit from feasible VMAT planning, and a future role of proton planning in high-risk patients (Hansen et al ESMO WGI 2016, Kronborg et al. ESTRO 36, 2017). Furthermore, plan-modelling studies have shown a feasible plan library strategy as future potential tool for shared decision making (Rønde et al. Acta Oncol. 2017; 56(10):1277-1285).
Methods PLAN-A analysis 2018-2019
Task A: To identify groups of patients with a high risk of failure, by identifying prognostic and predictive factors for local recurrence and distant failure. Clinicopathological parameters and dose-correlation studies will be analysed as pilot study from the first 300 patients. The first translational research study will be initiated on the samples from the first 100 patients, and a separate plan for further translational research studies are then made for validation studies (see below).
Task B: To identify groups of patients with high risk of unnecessary toxicity, by NTCP modelling and correlation to clinical outcome data. Both CTC and PROMs will be included in the models, and supplemented by translational biomarker studies. Advanced delineations and relation to specific toxicity endpoints such as bowel and bladder toxicity as well as pelvic insufficient fractures and vaginal late toxicity are being explored in separate pilot studies with the purpose of inclusion in a future strategy.
Task C: To continuously work on radiotherapy techniques for optimised dose-distribution and reduction of dose to relevant OAR (Fixed field IMRT, VMAT, Proton planning and MR based therapy, Adaptive treatment and brachytherapy).
Translational research
HPV: We will analyze the predictive and prognostic value of HPV/p16 in tumor tissue from 300 patients, including a test cohort of 150 patients retrospectively analyzed and a prospective validation cohort (when the median FU time in PLAN-A reaches 2 years). HPV will also be analyzed in consecutive blood samples from 100 patients. If positive, these results will be validated in a similar cohort of 100 patients with available blood samples. Cooperation within the Nordic Anal Cancer Group will be established upon positive data.
Hypoxia profiling: Retrospective analysis of an established gene expression profile for hypoxia will be performed on 200 primary tumor biopsies. If positive, a potential trial design will be developed.
Circulating DNA: When the biobank reached 100 patients, cell-free DNA quantification will be performed and analyzed in relation to treatment response and outcome. Tumor specific features of the circulating DNA is yet unknown in this disease, but cfDNA will be extracted from baseline and prospective samples for quantification of the total DNA and subsequent future analysis of tumor specific DNA.
Expected outcome
The continuous work of the PLAN-A analysis will allow us to assign Danish anal cancer patients to relevant clinical trials according to their individual risk of severe toxicity and treatment failure and hereby continuously improve the overall outcome and QoL after treatment.
Clinical trials
- PLAN-A/DACG I, ClinicalTrials.gov identifier: NCT05570279
- PC-anal-1, ClinicalTrials.gov identifier: NCT02785263
- DACG-II, ClinicalTrials.gov identifier: NCT05385250
- DACG-III, ClinicalTrials.gov identifier: NCT05233540
- DACG-IV, No ClinicalTrials.gov identifier yet
- DACG-V/RERAD-III, ClinicalTrials.gov identifier: NCT05055635
- ETHOS/ROAR, ClinicalTrials.gov identifier: NCT05438836
