Patient Selection for Oncology Phase I Trials: A Multi-Institutional Study of Prognostic Factors

The Royal Marsden National Health Service Foundation Trust, Sutton, United Kingdom.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2012; 30(9):996-1004. DOI: 10.1200/JCO.2010.34.5074
Source: PubMed


The appropriate selection of patients for early clinical trials presents a major challenge. Previous analyses focusing on this problem were limited by small size and by interpractice heterogeneity. This study aims to define prognostic factors to guide risk-benefit assessments by using a large patient database from multiple phase I trials.
Data were collected from 2,182 eligible patients treated in phase I trials between 2005 and 2007 in 14 European institutions. We derived and validated independent prognostic factors for 90-day mortality by using multivariate logistic regression analysis.
The 90-day mortality was 16.5% with a drug-related death rate of 0.4%. Trial discontinuation within 3 weeks occurred in 14% of patients primarily because of disease progression. Eight different prognostic variables for 90-day mortality were validated: performance status (PS), albumin, lactate dehydrogenase, alkaline phosphatase, number of metastatic sites, clinical tumor growth rate, lymphocytes, and WBC. Two different models of prognostic scores for 90-day mortality were generated by using these factors, including or excluding PS; both achieved specificities of more than 85% and sensitivities of approximately 50% when using a score cutoff of 5 or higher. These models were not superior to the previously published Royal Marsden Hospital score in their ability to predict 90-day mortality.
Patient selection using any of these prognostic scores will reduce non-drug-related 90-day mortality among patients enrolled in phase I trials by 50%. However, this can be achieved only by an overall reduction in recruitment to phase I studies of 20%, more than half of whom would in fact have survived beyond 90 days.

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Available from: Elisa Gallerani, Feb 10, 2014
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    • "The most common tumour primary types were ovarian/peritoneal (n ¼ 22, 24%), colorectal (n ¼ 19, 20%), breast (n ¼ 7, 8%) and bladder (n ¼ 6, 76%); 92% of patients had metastatic disease, most commonly to the lungs (45%) and lymph nodes (41%). Two patients had previously treated stable brain metastases; 98% had ECOG-PS 0–1, and 80% had a favourable Royal Marsden Hospital Prognostic Index (RMH-PI; Olmos et al, 2012). Patients had received a median of 2 prior lines of therapy and 33% had been exposed to 3 or more lines of treatment. "
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    • "In such cases, the treatment decision is based on the individual patient’s clinical context, physician’s experience and clinical judgment, local practice guidelines and the patient’s medical and treatment history. While the overall rate of success for cancer drug treatment has been estimated at 35% (Jackson, 2009), treatment for these patients is less effective, e.g., the response rate to therapy in patients meeting the inclusion criteria for early clinical studies is around 10% (Olmos et al., 2012). "
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    • "The validation set comprised 324 patients treated in EORTC phase I cancer trials between 2000 and 2009. In this database, the same variables were available (Olmos et al, 2012). Eighteen patients were excluded because they were lost to follow-up before the 90 days, and 134 patients were excluded because of missing values for at least one parameter used in the one or other of the models (Table 1). "
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