Development and validation of a risk score (Delay-7) to predict the occurrence of a treatment delay following cycle 1 chemotherapy.

BACKGROUND: The risk of toxicity-related dose delays, with cancer treatment, should be included as part of pretreatment education and be considered by clinicians upon prescribing chemotherapy. An objective measure of individual risk could influence clinical decisions, such as escalation of standard supportive care and stratification of some patients, to receive proactive toxicity monitoring. PATIENTS AND METHODS: We developed a logistic regression prediction model (Delay-7) to assess the overall risk of a chemotherapy dose delay of 7 days for patients receiving first-line treatments for breast, colorectal and diffuse large B-cell lymphoma. Delay-7 included hospital treated, age at the start of chemotherapy, gender, ethnicity, body mass index, cancer diagnosis, chemotherapy regimen, colony stimulating factor use, first cycle dose modifications and baseline blood values. Baseline blood values included neutrophils, platelets, haemoglobin, creatinine and bilirubin. Shrinkage was used to adjust for overoptimism of predictor effects. For internal validation (of the full models in the development data) we computed the ability of the models to discriminate between those with and without poor outcomes (c-statistic), and the agreement between predicted and observed risk (calibration slope). Net benefit was used to understand the risk thresholds where the model would perform better than the 'treat all' or 'treat none' strategies. RESULTS: A total of 4604 patients were included in our study of whom 628 (13.6%) incurred a 7-day delay to the second cycle of chemotherapy. Delay-7 showed good discrimination and calibration, with c-statistic of 0.68 (95% confidence interval 0.66-0.7), following internal validation and calibration-in-the-large of -0.006. CONCLUSIONS: Delay-7 predicts a patient's individualised risk of a treatment-related delay at cycle two of treatment. The score can be used to stratify interventions to reduce the occurrence of treatment-related toxicity.

A multicenter, randomized trial of flat dosing versus intrapatient dose escalation of single-agent carboplatin as first-line chemotherapy for advanced ovarian cancer: an SGCTG (SCOTROC 4) and ANZGOG study on behalf of GCIG.

BACKGROUND: The aim of the study is to demonstrate that intrapatient dose escalation of carboplatin would improve the outcome in ovarian cancer compared with flat dosing. PATIENTS AND METHODS: Patients with untreated stage IC-IV ovarian cancer received six cycles of carboplatin area under the curve 6 (AUC 6) 3 weekly either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2-6 based on nadir neutrophil and platelet counts (Arm B). The primary end-point was progression-free survival (PFS). RESULTS: Nine hundred and sixty-four patients were recruited from 71 centers. Dose escalation was achieved in 77% of patients who had ≥1 cycle. The median AUCs (cycle 2-6) received were 6.0 (Arm A) and 7.2 (Arm B) (P < 0.001). Grade 3/4 non-hematological toxicity was higher in Arm B (31% versus 22% P = 0.001). The median PFS was 12.1 months in Arm A and B [hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.85-1.15; P = 0.93]. The median overall survival (OS) was 34.1 and 30.7 months in Arms A and B, respectively (HR 0.98; 95% CI 0.81-1.18, P = 0.82). In multivariate analysis, baseline neutrophil (P < 0.001), baseline platelet counts (P < 0.001) and the difference between white blood cell (WBC) and neutrophil count (P = 0.009) had a significant adverse prognostic value. CONCLUSIONS: Intrapatient dose escalation of carboplatin based on nadir blood counts is feasible and safe. However, it provided no improvement in PFS or OS compared with flat dosing. Baseline neutrophils over-ride nadir counts in prognostic significance. These data may have wider implications particularly in respect of the management of chemotherapy-induced neutropenia.