Tumor growth rate is an early indicator of antitumor drug activity in phase I clinical trials.
OBJECTIVE
Response Evaluation Criteria in Solid Tumors (RECIST) evaluation does not take into account the pretreatment tumor kinetics and may provide incomplete information about experimental drug activity. Tumor growth rate (TGR) allows for a dynamic and quantitative assessment of the tumor kinetics. How TGR varies along the introduction of experimental therapeutics and is associated with outcome in phase I patients remains unknown.


METHODS
Medical records from all patients (N = 253) prospectively treated in 20 phase I trials were analyzed. TGR was computed during the pretreatment period (reference) and the experimental period. Associations between TGR, standard prognostic scores [Royal Marsden Hospital (RMH) score], and outcome [progression-free survival (PFS) and overall survival (OS)] were computed (multivariate analysis).


RESULTS
We observed a reduction of TGR between the reference versus experimental periods (38% vs. 4.4%; P < 0.00001). Although most patients were classified as stable disease (65%) or progressive disease (25%) by RECIST at the first evaluation, 82% and 65% of them exhibited a decrease in TGR, respectively. In a multivariate analysis, only the decrease of TGR was associated with PFS (P = 0.004), whereas the RMH score was the only variable associated with OS (P = 0.0008). Only the investigated regimens delivered were associated with a decrease of TGR (P < 0.00001, multivariate analysis). Computing TGR profiles across different clinical trials reveals specific patterns of antitumor activity.


CONCLUSIONS
Exploring TGR in phase I patients is simple and provides clinically relevant information: (i) an early and subtle assessment of signs of antitumor activity; (ii) independent association with PFS; and (iii) it reveals drug-specific profiles, suggesting potential utility for guiding the further development of the investigational drugs.
Authors' Affiliations: Departments of Medical Oncology, Biostatistics and Epidemiology, Innovative Therapeutics and Early Drug Development, Radiology, and Radiotherapy; INSERM U981, University Paris Sud, Gustave Roussy, Villejuif, France; and Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Charles
C
Ferté
Marianna
M
Fernandez
Antoine
A
Hollebecque
Serge
S
Koscielny
Antonin
A
Levy
Christophe
C
Massard
Rastislav
R
Balheda
Brian
B
Bot
Carlos
C
Gomez-Roca
Clarisse
C
Dromain
Samy
S
Ammari
Jean-Charles
JC
Soria
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D055815:Young Adult
D000970:Antineoplastic Agents