Randomised phase III study of docetaxel vs active symptom control in patients with relapsed oesophagogastric adenocarcinoma

Research summary

Carcinoma of the Oesophagus and stomach are respectively the 5th and 7th most common causes of death from cancer in the UK, between them accounting for more than 12,500 deaths per annum, more than any other individual cancer site apart from lung and colorectal cancer. Historically these cancers usually presented as distal gastric adenocarcinoma and proximal squamous cell carcinoma of the oesophagus, but the epidemiology of the disease has changed dramatically over the last 30 years, and in the UK today up to 70% of all oesophago-gastric cancers are adenocarcinomas of the distal oesophagus, oesophago-gastric junction or gastric cardia. Gastric cancer remains a major international health problem, and worldwide is the second most common cause of death from cancer. The treatment of advanced oesophago-gastric cancer (AOGC) is unsatisfactory. Although response rates of up to 55% are seen with modern chemotherapy regimens, the median survival is only approximately 9 months.

A number of drugs demonstrate activity in oesophagogastric cancer, but first-line therapy in Europe and the USA normally consists of combination therapy based on fluoropyrimidines and cisplatin or oxiplatin. Following failure of first-line chemotherapy outcomes are poor, and although a number of cytotoxic drugs such as irinotecan, oxaliplatin, paclitaxel and docetaxel have demonstrated activity no study has yet been performed which demonstrates that chemotherapy in this clinical situation is superior to best active symptom control. Notwithstanding this a high proportion of patients with AOGC in Europe and the US go on to receive second line therapy. Cytotoxic chemotherapy with these agents is expensive and potentially toxic. With poor response rates and outcomes overall many UK oncologists do not therefore routinely offer second-line therapy even to patients of good performance status, and practice in the UK and internationally is fragmented in this increasingly common clinical situation.

With the publication of the MRC-OE02 and MRC-ST02 trial (MAGIC) trials an increasing number of patients with operable oesophago-gastric cancer will receive pre- or perioperative chemotherapy with a platinum/fluoropyrimidine combination. Even with this treatment, 65-70% of patients will have recurred within 5 years, and there is no standard therapy which can currently be offered on relapse. There is therefore a need to demonstrate the superiority of systemic chemotherapy over active symptom control since there is no randomised trial data supporting either chemotherapy or active symptom control. A number of agents have shown activity in this setting in small phase II studies, but no single treatment stands out as superior.

It is a widely held opinion in the oncology community that there are patients who benefit from chemotherapy, but no consensus as the appropriate regimen. Additionally the lack of evidence makes it difficult to justify the use of scarce resources. Treatment is therefore often guided by cost rather than evidence. The current study proposes to establish the role of chemotherapy for advanced oesophago-gastric cancer previously treated with a platinum/fluoropyrimidine combination or raltitrexed. This is a A multicentre open-label, randomised controlled phase III trial of docetaxel vs active
symptom control for patients with advanced oesophago-gastric adenocarcinoma who have relapsed within 6 months of previous chemotherapy. The primary objective is to compare overall survival in patients treated with docetaxel + active symptom control to those receiving active symptom control alone.

Main inclusion criteria

  1. Age ≥18 years

  2. Histologically confirmed adenocarcinoma of the oesophagus or stomach (including adenocarcinoma of the oesophago-gastric junction)

  3. Advanced disease not amenable to curative treatment

  4. Documented progressive disease while receiving or within 6 months of completion of chemotherapy with a platinum and fluoropyrimidine or raltitrexed based therapy either for advanced disease or as neoadjuvant/perioperative therapy

  5. Estimated life expectancy of at least 12 weeks

  6. ECOG performance status 0,1 or 2

  7. Satisfactory haematological (Hb ≥10g/dL, WBC ≥3.0 x 109/L, ANC ≥1.5 x 109/L, Plt ≥100 x 109/L), renal (Creatinine ≤Upper Limit of Normal (ULN), or measured/calculated Creatinine clearance ≥ 60 ml/min) and hepatic (T. Bili ≤ULN, ALT ≤ 1.5 x ULN, ALP ≤ 5 x ULN (for patients with liver metastasis) or ALP ≤ 2.5 x ULN (in absence of liver metastasis) function

  8. Written informed consent

  9. Completion of baseline QoL questionnaires (QLQ-C30, STO22 & EQ-5D)

  10. Female patients of childbearing potential must have had a negative pregnancy test 48 hours before entering the trial.

  11. Patients of both sexes with reproductive potential must employ barrier contraception whilst on treatment and for 3 months after completion of treatment.

Main exclusion criteria

Patients with any of the following will not be eligible for entry into the study

  • Cerebral or leptomeningeal metastasis

  • Prior chemotherapy with taxanes

  • Clinically significant peripheral neuropathy (Grade 2 to Grade 4) which in the view of the investigator would be a contraindication to taxane therapy

  • Previous malignancy within the 5 years before study entry except for curatively treated basal cell carcinoma of the skin or cervical intraepithelial neoplasia

  • Pregnant or breast-feeding women

  • Any medical or psychiatric condition which would influence the ability of patients to provide informed consent

  • Any other serious or uncontrolled illness which, in the opinion of the investigator, makes it undesirable for the patient to enter the trial

Chief investigator

Dr Hugo Ford

Contact details

Cancer Theme Email: [email protected]