Upper gastrointestinal cancer

The Danish oesophageal, GEJ and ventricle (DECV) group is based on centralized collaboration between diagnostic and treatment facilities at four Danish centres treating these patients. Within the framework of DECV, a new clinical trial, DART, based on dose escalation to the tumour is proposed. The aim is to increase survival and avoid surgery with no additional RT related toxicity compared to the current RT treatment with lower doses. The national trial will secure uniform diagnosis and treatment, including state of the art RT delivery. Currently, a variety of chemo-RT regimens is used. However, the trial will standardize this. Toxicity scoring will be collected during and after the chemo-RT treatment, and patient reported outcome measurements (PROM) will be employed. In addition, robust proton RT and NTCP is prepared as part of the Heart Check clinical trial in oesophageal and GEJ cancer is initiated focusing on heart disease during chemo-RT.

Aim

1. Investigate the effect of dose escalation for ECV patients treated by definitive chemo-RT

2. Prepare a national trial for ECV patients treated by definitive chemo-RT. This requires:

  • Standardized diagnostic imaging for target definition
  • Standardized RT treatment planning and delivery in all Danish centres
  • Investigation and implementation of up to date respiration including techniques
  • Setup a national research database for collection of recurrence, survival and toxicity data. 

3. Prepare proton treatment (PT) of ECV cancer

  • Develop optimal treatment plans for PT
  • Investigate the effect of intra and interfractional changes for PT
  • Compare proton and photon plans taking into account intra and interfractional changes in preparation for patient selection for an upcoming proton trial

Background

Until recently and still treatment of ECV patients differs among Danish centres. The Danish oesophageal GEJ ventricle group (DECV) formed a RT committee in April 2016. The mandate was to create national recommendations for RT of ECV cancer. First version of the guidelines is established. Based on a national workshop, consensus was reached on recommended treatment regimens, delineation of tumour targets and normal tissues. Two treatment regimens have been used for definitive chemo-RT of ECV cancer; 50Gy/27fx homogeneous delivered to the PTV or 60Gy/50Gy/30fx heterogeneous dose delivery with 60 Gy to the GTV and 50 Gy to the PTV. The proposed clinical trial, DART will investigate these two regimens in a phase 2 study, aiming for proton RT.

The trial requires development of a uniform strategy for treatment delivery (including intra and interfraction changes and planning techniques). This is also important for standardizing the treatment nationwide.

The trial involves routine assessment of normal tissue side effects to RT studied in detail by CTC AE and PRO CTCAE. A national strategy for treatment and side effect monitoring of ECV cancer patients is of utmost importance for patient selection and referral of the patients to PT.  The effect of intra and interfractional changes is more pronounced for PT than for RT and may well be investigated by use of the data obtained from the photon treatments in this trial.

DECV members (B Weber, DCPT) and M Nordsmark (DECV oncology and RT groups, head) have contributed to the EPTEN initiated European collaboration on data registration for oesophageal cancer.

A separate national DECV project with specific focus on heart disease and toxicity (HEARTCHECK) is on-going. This is i) a prospective pilot study on heart disease in ECV patients receiving chemo-RT. NTCP modelling is planned. ii) a retrospective national epidemiological study linking existing data from the Danish ECV QA database (DECV), the National Patient Registry (LPR), Danish Medicines Agency Prescription Registry and the Danish Civil Registration System (CPR). The study sample is patients with EGEJ cancer treated by chemo-RT with curative intent from 2008 until 2018 at AUH, OUH, RH and Aalborg.

Methods

1. This trial will include 60 patients randomized between two dose regimens. The number is based on approximately 40 patients treated per year nationwide, and inclusion of 75% of the patients over two years.

  • Inclusion criteria: biopsy verified malignant histopathology (adenocarcinoma or squamous cell carcinoma) of the oesophagus or GEJ cancer cT2 cN0-3 M0 by gastroscopy, PET CT scan, with the final diagnosis determined at a multidisciplinary team conference and patient considered non-resectable or inoperable.
  • Systemic treatment includes concurrent cisplatin weekly or twice week 1 and 3 and 5 fluouracil continuously during RT.
  • The standard RT regime is 50Gy/25fx and the escalated regime is 60Gy/50Gy/30fx, 5 fx/week with 60Gy to the GTV-T and GTV-N and 50 Gy to the PTV.
  • Treatment delineation is based on planning PET and 4DCT or DIBH-CT.
  • PET follow up at 9 and 18 months, CT follow up every third months
  • CTCAE Toxicity scoring complemented by PROM CTCAE as determined by DECV.
  • Detailed clinical and RT relevant data at diagnosis, during treatment and follow-up will be recorded in a national research data base. Collection of treatment plans in the National CIRRO data base will be established.

2. Protocol preparation:

  • National guidelines including atlas for target delineation is available.
  • National guidelines for treatment planning will be established through planning of selected patients at all centres, followed by data analysis
  • Strategies to account for respiratory effect will be investigated in two patient cohorts: a retrospective cohort with markers implanted treated in FB, and a prospective cohort treated in DIBH.
  • Strategies to account for interfractional changes will be investigated in a cohort of patients with daily CBCT images.

3. For all patients in the trial comparative proton plans will be made.

  • Strategies to account for respiratory effect will be investigated in two patient cohorts treated by FB or DIBH
  • Strategies to account for interfractional changes will be investigated in a cohort of patients with daily CBCT images.
  • Comparison of photon and proton treatment plans will be performed based on dose to normal tissue and dose coverage due to intra and interfractional changes. This comparison will be used for patient selection in a future proton trial

Expected results

Registration of normal tissue toxicity and pattern of failure for patients in the trial. The results will be compared to data from a retrospective group of patients. Standardization of national treatment, including delineation, treatment planning and delivery, follow up and toxicity scoring.

Impact/Relevance/Ethics

National standardization of chemo-RT treatment of ECV patients referred for definitive treatment. Collection of clinical and follow up data for the patients. Preparation for PT treatment. The ultimate hope is to establish an organ preserving strategy for frail and elderly patients using PT.

  • Eva Holtved

    Consultant

    Odense University Hospital
  • Mirjana Josipovic

    Hospitalsfysiker, PhD

    Rigshospitalet, Copenhagen
  • Lone Hoffmann

    PhD

    Aarhus University Hospital
  • Signe Normann Risum

    Overlæge

    Rigshospitalet, Copenhagen
  • Hanna Rahbek Mortensen

    læge

    Aarhus University Hospital
  • Ditte Sloth Møller

    Hospital physicist, PhD

    Aarhus University Hospital
  • Agon Olloni

    Læge, ph.d. studerende

    Odense University Hospital