Evaluation for Surrogacy of End Points by Using Data from Observational Studies: Tumor Downstaging for Evaluating Neoadjuvant Chemotherapy in Invasive Bladder Cancer

Abstract

Purpose: In clinical cancer trials for evaluating neoadjuvant chemotherapy, tumor downstaging is frequently used as a surrogate end point for overall survival. We evaluated the surrogacy of tumor downstaging using data from a follow-up observational study in bladder cancer. Experimental Design: A total of 586 patients (from 32 Japanese hospitals) who underwent radical cystectomy for invasive bladder cancer (clinical T2 to T4) between 1990 and 2000 were analyzed. We considered changes over time in clinical stage at diagnosis and pathologic stage at cystectomy as a surrogate end point, and survival time after cystectomy as a true end point. First, we developed a new criterion for tumor downstaging. Second, we statistically evaluated surrogacy for the criterion using Prentice's criteria. Results:To develop the criterion of end points based on tumor downstaging, we selected the best classification among all possible classifications in an attempt to separate prognosis for patients. The hazard ratios after adjustment for prognostic factors in the intermediate effect patients and the poor effect patients were 1.9 (95% confidence interval, 1.0-3.7) and 5.0 (95% confidence interval, 2.6-9.8), respectively, compared with that in the good effect patients. The conditions for correlation and conditional independency of Prentice's criteria were satisfied approximately. Neoadjuvant chemotherapy has a statistically significant tumor downstaging effect, whereas there was no difference on survival between treatment groups. Conclusions: The tumor downstaging effect could be an appropriate intermediate end point for screening novel neoadjuvant chemotherapy for invasive bladder cancer. The dataset from follow-up studies were useful for evaluating the surrogacy of end points.Appropriate surrogate end points are critical for developing new therapies through evaluation of biological activity. The surrogate end point is a test, measurement, score, or some other similar variable that is used in place of a clinical event in the design of a trial, or in summarizing results from it. Used because the variable is believed to be correlated with the clinical event of interest and because of its perceived utility in yielding detectable treatment differences (1). In clinical cancer trials, overall survival is considered to be the most reliable and definitive true end point. However, surrogate end points such as tumor burden outcomes including objective tumor effect, disease-free survival, and progression-free survival, or biomarkers including prostate-specific antigen have been widely used because trials with the true clinical outcome are often longer and larger. In a recent analysis for oncologic drugs in the U.S., 68% (39 of 57) of the regular approvals and all of the 14 accelerated approvals were based on end points other than overall survival in the last 13 years (2). To use a valid and reliable surrogate end point in cancer clinical trials, we should evaluate the surrogacy of end points on a case-by-case basis because the adequacy a...

Comparison of Radical Cystectomy and Chemoradiotherapy in Patients with Locally Advanced Bladder Cancer

“…Therefore, direct comparison between RC and CRT was difficult because of the potential for selection bias in retrospective studies and because of confounding resulting from discordance between clinical and pathological staging. Clinical staging errors in patients with invasive bladder cancer have been reported to occur in 30%-50% of patients (Stein et al, 2001;Teramukai et al, 2006). However, we observed no differences between the patient populations in the two groups.…”

Pathological T0 Following Cisplatin-Based Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Network Meta-analysis

“…The ultimate goal of NACH is to improve the survival times of patients. As mentioned earlier, tumor downstaging following NACH closely correlated with survival (11,(13)(14)(15)(16). Although we did not directly assess the association between pCR and survival, it was expected that pCR after NACH would positively affect survival outcomes among patients with MIBC.…”

“…In particular, chemo-induced tumor downstaging is considered to be a useful and potential surrogate marker that has been associated with favorable survival outcomes among patients treated with subsequent RC (11,(13)(14)(15)(16). The impact of various NACH regimens including CM, CMV, MVAC, and GC, on the achievement of pCR and on survival outcomes has been evaluated by many investigators, both retrospectively and prospectively (14,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

“…In contrast, a lack of response to NACH was associated with a significantly higher rate of local and distant recurrence, and with lower OS (12). Therefore, several investigators have suggested that tumor downstaging might be used as a surrogate endpoint for OS (13). In particular, downstaging to pT0 (pCR, pT0N0M0; pCR) is currently the best predictor of favorable outcomes (14,15).…”

Chemoradiatie bij het spierinvasieve blaascarcinoom

“…Het is gebleken dat de uiteindelijke respons op neoadjuvante chemotherapie een belangrijke voorspellende factor is, aangezien patiënten met downstaging tot een niet-spierinvasief stadium (< ypT2N0) en patiënten met complete pathologische respons (ypT0N0) een betere prognose hebben met een vijfjaarsoverleving van 69% vs. een vijfjaarsoverleving van 26 % van patiënten met persisterend spierinvasief blaascarcinoom [15][16][17][18][19]. Desalniettemin is weinig bekend over de prognostische impact van persisterende lymfekliermetastasen na inductiechemotherapie, alhoewel deze situatie zeer waarschijnlijk gepaard gaat met een infauste prognose [20].…”