DOCTOR

Protocol Title

A Randomised Phase II Trial of pre-operative cisplatin, 5 fluorouracil and docetaxel, +/-Radiotherapy, based on poor early response to standard chemotherapy for resectable adenocarcinoma of the oesophagus and/or gastro oesophageal junction.

Publication Reference

None to date.

Conference Presentation Reference

Barbour A, Walpole E, Mai GT, Chan H, Barnes E, Watson D, Ackland S, Wills V, Martin J, Burge M, Karapetis C, Shannon J, Nott L, Gebski V, Wilson K, Thomas J, Lampe G, Zalcberg J, Simes J, Smithers M. An AGITG trial: a randomised phase II study of pre-operative cisplatin, fluorouracil and docetaxel ± radiotherapy based on poor early response to cisplatin and fluorouracil for resectable esophageal adenocarcinoma. European Society for Medical Oncology 41st Congress; 7–11 Oct 2016 2016; Copenhagen.

Barbour A, Smithers BM, Burmeister B, Zalcberg JR, Spry N, Smith G, Wilson K, Roff K, Yip S, Walpole ET; Australasian Gastro-Intestinal Trials Groups (AGITG). DOCTOR: a randomized phase II trial of preoperative cisplatin, 5-fluorouracil, and docetaxel with or without radiotherapy based on poor early response to standard chemotherapy for resectable adenocarcinoma of the esophagus and/or OG junction. American Society of Clinical Oncology Annual Meeting; 1–5 Jun 2012; Chicago. Abstract TPS4145.

Aim

The DOCTOR study aims to determine whether the addition of docetaxel, +/- radiotherapy, can significantly improve the histological response rate for early metabolic non-responders compared with historical outcomes if the same chemotherapy has been continued. The molecular sub-study also aims to identify biomarkers of FDG-PET response, response to the regimens and survival.

BACKGROUND

The incidence of oesophageal adenocarcinoma (OAC) is increasing faster than any other adult cancer. The disease affects approximately 1,400 Australians each year and most patients present with advanced cases that cannot be cured. Curative treatment for OAC involves major surgery that aims to completely remove the cancer and usually involves removal of most of the oesophagus and some of the stomach. It typically takes approximately 6 to 9 months for health‐related quality of life to return to normal after the surgery.

Unfortunately, despite improvements in surgical outcomes (death following surgery now occurs in <5% of patients), remission following treatment is often short lived. OAC recurs in the majority of patients, causing death in >60% of patients treated with curative intent. OAC may recur locally at the site of the surgery or at distant sites, the most common of which is the liver.

Preoperative chemotherapy, with or without radiotherapy, has been shown improve outcomes after surgery. Patients who respond to chemotherapy or radiotherapy prior to surgery have consistently demonstrated better survival than non-responders. Recent data suggests that a reduction in the level of tumour activity seen on a PET scan performed 14 days after the start of pre-operative chemotherapy compared with a baseline PET scan is predictive of histological response and improved survival.

Therefore, there is a clinical need to develop treatments that improve outcomes for early metabolic non-responders. One potential approach is by changing patients’ therapy if they do not have a metabolic response after the first cycle of standard pre-operative chemotherapy.

The DOCTOR study is the first study to focus on metabolic non-responders to pre-operative therapy to try to improve response and potentially survival by applying alternative treatment plans. More specifically, this study will investigate the effect of changing therapy after the first cycle of standard pre-operative chemotherapy to include docetaxel, with or without radiotherapy. There will also be a molecular sub-study to investigate possible biomarkers associated with different patient responses to treatment. The study will be conducted on pre-treatment tumour and blood samples.

The DOCTOR study is currently in follow up. It will provide valuable data regarding the potential to individualise therapy based on early treatment response.

Early results have demonstrated that adding docetaxel to chemotherapy and radiotherapy produces promising response rates in patients.

Clinical Trial Design

The DOCTOR study is a randomised Phase II study for patients who are early metabolic non-responders to induction chemotherapy.

Eligible participants will have localised, resectable adenocarcinoma of the oesophagus or gastroesophageal junction. The patients will be randomised equally to two treatment groups. Information about a third group of patients, who respond to induction chemotherapy, will also be collected to help inform future studies.

All patients will receive the standard chemotherapy treatment of a 21-day cycle of Cisplatin and 5-fluorouracil intravenously over 2 hours. Cisplatin will be given on day 1, and 5-fluorouracil will be given on days 1 to 4. Early metabolic response will be assessed on day 14 with a PET scan. If there is an early metabolic response then the standard treatment will be repeated over another 21-day cycle. This will be followed by surgery.

If there is no significant response on PET scan, subjects will be randomised to receive either chemotherapy (cisplatin/5-FU with the addition of docetaxel) followed by surgery, or radiotherapy and chemotherapy (cisplatin/ 5-FU with the addition of docetaxel) followed by surgery. All participants will have surgery in an attempt for complete resection.

The DOCTOR study will last for a period of 48 months with 36-month follow up. In addition, routine pre-treatment tumour and blood banking will provide a unique opportunity to search for OAC biomarkers of FDG-PET response, response to the regimens used and survival.

Study Chairs

Professor Andrew Barbour (Princess Alexandra Hospital, Woolloongabba QLD)
Associate Professor Euan Walpole (Princess Alexandra Hospital, Woolloongabba QLD)

Contact Email

Principal Investigator

Professor Andrew Barbour

More Information

Available online at the Australian New Zealand Clinical Trial Registry (ANZCTR) here.

Funding

National Health and Medical Research Council (NHMRC)