Dose Escalated Adaptive RadioTherapy in Definitive Chemo-radiotherapy for Esophageal Cancer

In Denmark, there are almost 900 new cases of oesphageal and gastro-esophageal junction (GEJ) cancer per year, with a 5-year survival rate below 20% for the entire group and a 5-year survival rate of approximately 40% for the curatively treated patients.

Surgery is the primary treatment for patients with localized disease who are considered medically and technically operable. For patients deemed non-resectable, definitive chemoradiotherapy is the treatment of choice, but despite treatment with curative intent, these patients have a poor prognosis, with a median survival of less than 20 months and a 5-year survival at 15-25% in clinical studies.

Survival is affected by several factors like stage, gender and comorbidity, but also by lack of local and regional tumour control. Several studies examined pattern of failure in patients with oesophageal cancer treated with definitive chemoradiotherapy. Most patients experience local failure, and most local failures were located in the Gross Tumor volume (GTV). These findings imply that future therapeutic strategies should focus on improving local control in order to increase successful treatment outcome, although care should be taken to ensure that this does not come at the cost of excess treatment related toxicity.

Strategies to overcome in-GTV failures include radiotherapy-sensitizing agents and dose escalation, the latter has been evaluated in several studies with heterogeneous results.

The role of Positron Emissions Tomografi/ComputerTomografi (PET/CT) in radiotherapy planning has been examined and the diagnostic value of PET/CT in oesophageal cancer is widely accepted, whereas the role in assessing tumour response to treatment is less well established. Flour-Deoxy-Glucose (FDG)-PET scans allow for measurement of changes in tumour cell metabolism that precede changes in tumour size, and reduction in FDG uptake during neoadjuvant therapy has been correlated with favourable outcomes in patients with oesophageal cancer.

PET-positive areas have been suggested as suitable targets for dose-escalation strategies, since studies suggested that high FDG uptake on pre-treatment PET/CT identifies tumour sub-volumes that are at greater risk of recurrence after chemoradiotherapy in patients with locally advanced oesophageal cancer.

The major concern in a dose escalation study is severe and potentially lethal normal tissue complications. Oesophageal cancer irradiation usually results in irradiation of the oesophagus, lungs and heart due to the anatomical tumour location, which may result in acute toxicities dominated by radiation pneumonitis and esophagitis (leading to inappropriate nutricial intake). Late toxicities include oesophageal fistula/ulcers, cardiac events, pulmonary fibrosis, or even deaths related to radiation exposure. Dose gradients between the target and normal tissue may be sharp, in order to limit the norml tissue dose and hence the risk of unacceptable toxicity, while maintaining high doses to the tumour.

Current study Previous studies have suggested that escalating the radiation dose to the GTV may provide improved local control, but requires great caution in relation to normal tissue irradiation to avoid unacceptable side effects. The investigators propose a study approach where both requirements will be met. FDG-PET scans will be used to identify and delineate the tumour sub-volumes with the highest tracer uptake to guide the dose-escalation. The dose to the GTV will be escalated to a high dose (63Gray (Gy) in the FDG-PET avid areas in the primary tumour and 60 Gy in the lymph nodes) while Clinical target volume (CTV) and Planning target volume (PTV) will be treated with standard dose. The patients will be randomized between this dose-escalated arm and a standard arm with 50Gy in 25 fractions. The total number of fractions will be 25 in both arms. Dose escalation will be limited by normal tissues constraints.

The study will be conducted with modern state-of-the-art radiotherapy techniques, including advanced dose calculation algorithms, daily image guidance, and adaptation of the treatment plan during treatment if needed. The participating centres must implement and comply with a quality assurance program in order to maintain high treatment quality in the study.