Palliative treatment for advanced gastrointestinal cancer: is response a suitable end-point?

Abstract

Treatment results of standard chemotherapy in advanced gastrointestinal tract cancer are disappointing. 5-Fluorouracil (FU) is the therapeutic mainstay since its discovery more than 35 years ago. Response rates of single agent FU treatment range between 5 and 20% dependent on dose and schedule. The efforts of the last two decades have been focused on the improvement of objective response rates using several combinations of chemotherapy regimens including doxorubicin, cisplatin, mitomycin and etoposide. Most of the phase l/II studies have reported encouraging treatment results initially with respect to response rates. Subsequent randomized trials, however, revealed a high rate of World Health Organization (WHO) grade III/IV toxicity of these combination regimens, which was not compatible with the palliative treatment intention (1). Another approach to improve the therapeutic effects of standard FU treatment was to combine it with modulating agents such as cl-interferon, folinic acid, Nphosphon-acetyl-L-aspartate (PALA) and methotrexate. Biomodulation of FU with folinic acid has become the standard treatment for advanced colorectal cancer, with response rates being superior to those with single agent FU and low treatment-related toxicity. Double modulation of FU with folinic acid and cl-interferon has achieved respectable response rates in advanced gastric and pancreatic carcinoma. Moderate toxicity and effective control of tumour-related symptoms, notably tumour-related pain, have emerged as the crucial parameters supporting a high palliative quality of this treatment, rather than high objective response rates. Over the past few years, the authors have conducted phase II trials in advanced pancreatic and gastric carcinoma and two randomized multicentre trials in advanced colorectal cancer. End-points of all trials were toxicity profile, objective responses, duration of response, progression-free intervals, median survival time and quality of life under treatment. Evaluation of the randomized trial in colorectal cancer with weekly high dose (A) vs low dose (B) folinic acid/ FU revealed objective response rates of 28% (A) and 23% (B), respectively. Toxicity was mild with a rate of WHO grade III/IV toxicity ~15% in both arms. Median survival was 12.5 months in both arms. Quality of life under treatment was high due to the outpatient treatment setting, low toxicity and effective