The targeted therapy cetuximab does not improve progression-free survival (PFS) or overall survival (OS) when added to standard chemotherapy as a first-line treatment for advanced colorectal cancer, according to the largest trial to date in advanced bowel cancer. The unexpected results of the COIN trial, published Online First in The Lancet, show that even patients without KRAS mutations in their tumour (the sub-group that showed a benefit from this therapy in other trials) did not benefit from the addition of cetuximab.
In a second part of the COIN study, published Online First in The Lancet Oncology, Tim Maughan and colleagues on behalf of the Medical Research Council Clinical Trials Unit, London, UK report that for the majority of patients with a normal platelet* count before starting treatment, taking breaks from standard chemotherapy might improve quality of life (less time on chemotherapy, fewer hospital visits, and reduced side-effects) without compromising survival.
The COIN study enrolled nearly 2500 previously untreated patients with advanced colorectal cancer from 111 hospitals across the UK and Ireland to investigate whether the addition of a monoclonal antibody (cetuximab) to standard chemotherapy might improve survival, and to establish whether taking treatment holidays from standard chemotherapy might improve quality of life without compromising survival.
Patients were randomly assigned to a continuous combination of oxaliplatin and fluoropyrimidine, the same continuous combination plus cetuximab, or the same combination chemotherapy in an intermittent schedule.
Apart from a modest increase in the rate of tumour shrinkage, cetuximab had no significant benefit on PFS or OS.
Interestingly, even patients with a KRAS wild-type (normal) gene in their tumour (who in theory should have benefited from the addition of cetuximab) did not differ in their OS or PFS.
The authors say: "The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended. However, the trial showed the powerful effect of the presence of specific mutations in the tumour on prognosis and this should influence future clinical trials in bowel cancer.''**
The COIN trial also assessed whether it might be possible to shorten the duration of initial chemotherapy to 12 weeks and then restart on disease progression by comparing standard continuous chemotherapy with the same chemotherapy given with planned treatment holidays (intermittent chemotherapy).
Findings showed that intermittent chemotherapy did not increase or significantly decrease survival. However, platelet count before starting intermittent chemotherapy was identified as a potentially valuable predictor of survival and quality of life. A raised platelet count resulted in a 5-month reduction in survival and impaired quality of life, whereas for the three-quarters of patients with normal platelet counts, time off chemotherapy was associated with improved quality of life (less time on chemotherapy, fewer hospital visits, and reduced neuropathy and hand-foot syndrome [redness, swelling, tenderness, and peeling of palms and soles]) with similar survival.
The authors remark: "There seems to be a large subpopulation of patients for whom intermittent therapy provides similar survival benefit and the results of this trial provide a basis for discussion of options between patients and clinicians."**
In a Comment, Madeleine Hewish and David Cunningham from the Royal Marsden Hospital, Surrey, UK say: "These new data should prompt a review of present guidance from the UK National Institute of Health and Clinical Excellence (NICE), which recommends that patients with liver-only metastatic disease should receive an oxaliplatin-based chemotherapy doublet with cetuximab, and that irinotecan should be reserved for patients for whom oxaliplatin is deemed to be contraindicated."
Professor Tim Maughan, Cardiff University, Cardiff, UK. T) +44 (0) 1865 617413 E) tim.maughan@rob.ox.ac.uk
Professor David Cunningham, Royal Marsden Hospital, Surrey, UK. Via Royal Marsden Hospital Press Office T) +44 (0) 020 7808 2107 E) david.cunningham@rmh.nhs.uk
Journal
The Lancet Oncology