By Gary R. Shapiro, MD
Medical Director, Cancer Center of Western Wisconsin, New Richmond, Wisconsin
Dr. Shapiro reports no financial relationships relevant to this field of study.
SYNOPSIS: Patients with progressive advanced esophagogastric adenocarcinoma treated with docetaxel in addition to active symptom control (ASC) survived 44% longer than those who received ASC alone. In addition to a 5.2 vs 3.6 months increase in overall survival, improved symptom control was observed in the patients receiving docetaxel.
SOURCE: Ford HE, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): An open-label, phase 3 randomized controlled trial. Lancet Oncol 2014;15:78-86.
This Phase 3 randomized trial compared salvage chemotherapy with docetaxel (75 mg/m2 every 3 weeks for up to six cycles) plus active symptom control (ASC) with ASC alone in patients with locally advanced (12.5%) or metastatic (87.5%) adenocarcinoma of the esophagus (20%), esophagogastric junction (35%), or stomach (45%) that had progressed on or within 6 months of treatment with a platinum-fluoropyrimidine chemotherapy combination (which could have been given as adjuvant or neoadjuvant therapy, or for advanced disease). This multicenter study (the COUGAR-02 trial) was conducted in the United Kingdom, and included only patients who had an Eastern Cooperative Oncology Group performance score of 0-2 and satisfactory hematological, renal, and hepatic function. Health-related quality of life (HRQoL) was assessed in all participants using standard (QLQ-C30 and EORTC QLQ-STO22) questionnaires at baseline and at periodic intervals throughout the course of therapy.
The COUGAR-02 study showed that second-line docetaxel improved median overall survival compared with ASC alone — 5.2 months vs 3.6 months. Overall survival in the docetaxel group was 82% at 2 months and 39% at 6 months, compared to 84% and 23% in the ASC alone group. Two-thirds of the 84 patients who received docetaxel were assessable for response, with the best response being partial in 4 (7%) and stable diseases in 24 (43%).
A median of three docetaxel treatment cycles was administered, with only 23% of patients in the docetaxel group completing all six cycles and 20% only one cycle. The main reasons for stopping docetaxel early were progression of disease (40%), unacceptable toxicity (31%), and death from cancer (15%). None of these deaths was attributed to chemotherapy. As one would expect, docetaxel was associated with higher incidence of grade 3-4 neutropenia (15% vs 0) and febrile neutropenia (7% vs 0). Patients receiving docetaxel reported less general pain (P = 0.0008), less nausea and vomiting (P = 0.02), and less constipation (P = 0.02) than those who received ASC alone. Disease-specific HRQoL measures also showed benefits for docetaxel in reducing dysphagia (P = 0.02) and abdominal pain (P = 0.01). The mean overall quality-adjusted life weeks was 12.1 weeks for the docetaxel/ASC group and 9.3 weeks for the ASC alone control group.
Previous studies1,2 have suggested that second-line treatment may extend survival in patients with advanced esophagogastric adenocarcinoma, but this is the first well-designed, randomized, controlled trial that includes rigorous quality-of-life assessments, and it is for this that the COUGAR-02 is most noteworthy. Although COUGAR-02 conclusively shows that those treated with docetaxel in addition to ASC survived 44% longer than those who received ASC alone, someone who takes the time to do the math may reasonably question whether an additional "statistically significant" 1.6 months of life is all that meaningful. However, there is no questioning the benefit of improved symptom control and quality of life that those who received docetaxel enjoyed compared to those who did not. Active symptom management is important, but even the best supportive care has its limitations.
Of course, palliative chemotherapy is not for everybody. The COUGAR-02 investigators should be congratulated for including "real world" older (23%) and symptomatic ECOG performance status 2 (15%) patients in their trial, but many esophagogastric cancer patients spend significantly more than half of their waking hours in bed or in a chair (ECOG performance status 3 or 4) and are older than the 65 years median age of the COUGAR-02 patients. Indeed, subgroup analysis showed that performance status (ECOG 0 better than ECOG 1 or 2; P = 0.001) and disease status (locally advanced better than metastatic; P = 0.006) were predictors of overall survival.
Paclitaxel and irinotecan have also shown activity as second-line chemotherapy for advanced esophagogastric adenocarcinoma, and there is certainly ample room for new regimens.3,4 For now, the COUGAR-02 study provides the most compelling reason to date for oncologists and patients to consider docetaxel the standard of care for those who are reasonably fit following first-line treatment with a platinum-fluoropyrimidine chemotherapy combination.