Surrogate Marker For Long-term Outcome Research Articles

Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials

Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking. In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2×ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n= 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3mg/kg q3w; n= 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n= 26) followed by surgery. The median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response. Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.

Chemotherapy response score: Validation of a three-tier system to quantify histopathologic response to neoadjuvant chemotherapy in ovarian carcinoma.

e17539 Background: Neoadjuvant chemotherapy (NACT) with interval debulking surgery is considered for patients with advanced-stage ovarian carcinoma (OC) who are not ideal candidates for primary debulking surgery due to advanced age, frailty, poor performance status, comorbidities, or who have disease unlikely to be optimally resected. Moreover, response to NACT may be a suitable surrogate end point for long-term clinical outcome in ovarian cancer. The aim of the present study is to evaluate the utility of a three-tier Chemotherapy Response Score (CRS) and validate whether residual disease or evidence of regression following NACT may provide prognostic information in ovarian cancer. Methods: We conducted a retrospective single-institution study of patients who received NACT with carboplatin and paclitaxel for FIGO stage III/IV ovarian cancer. Response to NACT was graded as no or minimal tumor response (CRS1); appreciable tumor response amid readily identifiable viable tumor (CRS2); or complete/near-complete response with no residual tumor or minimal scattered tumor foci (CRS3) as described previously (Böhm S, et al. J Clin Oncol 33:2457-2463). Multivariate progression free survival (PFS) and overall survival (OS) analyses were performed accounting for age, FIGO stage and BRCA status. Results: Of the 86 patients accrued to date, median age was 65 years, 62% had stage IV disease and 16% had a somatic/germline BRCA mutation. CRS scores 1, 2 and 3 were found in 26 (30%), 43 (50%) and 17 (20%) of cases, respectively, and were associated with PFS (log rank p = 0.002). A high CRS score predicted improved PFS and OS (CRS 2/3 vs 1; median PFS 17.3 vs. 11.8 mo, adjusted hazard ratio (HR), 0.33; 95%CI 0.17-0.62; p &lt; 0.001; median OS 47.9 vs. 38.3 mo, adjusted HR 0.36, 95%CI 0.15-0.88, p = 0.026). Similarly, when comparing CRS 3 with 1/2, the high score predicted improved outcome for PFS but not OS (median PFS 17.3 vs. 14.7 mo, adjusted HR, 0.42; 95%CI 0.19-0.95; p = 0.037; median OS 48.6 vs. 46.5 mo, adjusted HR 0.43, 95%CI 0.14-1.35, p = 0.149). Conclusions: In this study, we validate a simple three-tier chemotherapy response scoring system for assessing histopathologic response of OC to NACT. Residual disease and evidence of complete/near complete regression following NACT provides prognostic information in OC. CRS may serve as a potential surrogate marker for long-term outcome and be a useful alternative intermediate end point in future clinical trials.

Differential impact of white matter hyperintensities on long-term outcomes in ischemic stroke patients with large artery atherosclerosis

BackgroundThe presence of white matter hyperintensity (WMH) is related to poor long-term outcomes in stroke patients. However, the long-term outcome is unknown in patients with both large artery atherosclerosis (LAA) and WMH.MethodsWe investigated the impact of WMH on long-term outcome in patients with LAA. Consecutive patients in a prospective stroke registry were included. Patients were followed for a median of 7.7 years (interquartile range, 5.6–9.7). The degree of WMH was assessed by Fazekas grade on fluid-attenuated inversion recovery images. Total WMH burden was calculated by summation of Fazekas scores in periventricular and deep white matter. Severe WMH was defined as total burden score ≥ 3.ResultsAmong 2529 patients, 639 patients (25.3%) were classified with the LAA subtype. After applying exclusion criteria, the data from 538 patients were analyzed. The mean patient age was 65.7 ± 10.3 years. Severe WMHs were found in 243 patients (45.2%). During follow-up, 200 patients (37.2%) died. Cox regression analysis showed that LAA patients with severe WMH had a 1.50-fold (95% CI, 1.12–2.00, p = 0.007) higher death rate compared to those without. In the older age group (≥65 years), Cox regression revealed that patients with severe WMH had a 1.75-fold (95% CI, 1.15–2.65, p = 0.008) higher 5-year death rate, whereas the younger age group did not have this association.ConclusionThe degree of WMH might be a surrogate marker for long-term outcome in patients with LAA. Atherosclerotic burdens in both small and large arteries might impact long-term prognosis in ischemic stroke patients.

No observable difference in operative oncological outcomes between extra-levator versus standard abdominoperineal excision

In recent years, concerns have arisen regarding the poorer outcomes of patients undergoing abdominoperineal excision (APE), compared with those having total mesorectal excision (TME). This was attributed to higher rates of involved circumferential resection margins (CRMs) and tumour perforations after APE, and was thought to have occurred due to adherence of the TME plane to the puborectalis sling. This apparent disparity was addressed by the re-introduction of a more radical approach to APE surgery, which closely mirrored the operation described by Miles [1]. The procedure, extra-levator abdominoperineal excision (ELAPE), entails a more extensive, wider perineal dissection down to the origin of the levators. Several retrospective studies have reported a reduction in rates of CRM positivity and intraoperative perforation with ELAPE, compared with standard APE (SAPE). Each of these histopathological findings is deemed a crucial marker in determining prognosis for low rectal cancer. Thus, pathological assessment of the resected specimen, as a surrogate marker of oncological superiority, can also be used as a surrogate marker for long-term outcome. Although the loco-regional clearance obtained by ELAPE may be superior to SAPE, the substantial perineal defect, which is often too large for primary closure, can result in delayed wound healing and perineal herniation. Asplund [2] compared outcomes for 158 patients with low rectal cancer, half of whom underwent SAPE and half ELAPE. No advantage for ELAPE was shown, in terms of local recurrence, intraoperative perforation and CRM positivity, but higher rates of perineal wound complications were reported. This is in contradiction to other studies demonstrating higher rates of CRM positivity and intraoperative perforations with SAPE. Having adopted the ELAPE technique (performed with the patient in the prone position), we sought to ascertain whether the wider cylindrical dissection offers any oncological advantage over SAPE, through comparing the pathological findings of our resected specimens. We studied 34 consecutive patients who underwent APE: 17 underwent SAPE and 17 ELAPE. The results are outlined in Table 1. There was no difference in patient demographics or tumour T stage between the two groups. Similar proportions of patients in each group had received preoperative radiotherapy, ELAPE: 71 % (12) and SAPE: 88 % (15) (p = 0.40). The mean distance to the CRM did not differ between groups, ELAPE: 6.5 mm and SAPE: 5.8 mm (p = 0.80), nor did the R0 resection rate, ELAPE: 82 % (14) SAPE: 71 % (12) (p = 0.69). There was 1 intraoperative tumour perforation in the ELAPE group (6 %), and 2 (12 %) of the SAPE specimens were perforated (p = 1.00). Comparable mean numbers of lymph nodes were harvested (ELAPE: 8.9 and SAPE: 8.6) (p = 0.90). Throughout the period, that ELAPE was performed tumour perforation, and R1 or 2 resections occurred sporadically and did not correlate with a perceived learning curve. We have not detected any difference in short-term surrogate markers for oncological outcome between ELAPE and SAPE. Our numbers are small; however, the results mirror those of Asplund et al. [2] who reported a specimen perforation rate of 13 % (ELAPE) versus 10 % (SAPE), and CRM positivity of 17 and 20 %, respectively. The Asplund study failed to find any oncological advantage of K. J. Gash (&) L. Cooper N. Smart R. Longman M. Thomas University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8HW, UK e-mail: kat_jg@hotmail.com

10-year outcomes of breast cancer patients with histologically confirmed axillary lymph node metastases and pathologic complete response after primary systemic chemotherapy.

1017 Background: Pathologic complete response (pCR) of tumors in the breast and axillary lymph nodes (ALN) after primary systemic chemotherapy (PST) is associated with an excellent outcome. A previous analysis showed superior 5-year overall survival (OS) and relapse-free survival (RFS) for patients who achieved an ALN pCR after PST compared to those without a pCR in 5 prospective clinical trials. This study is an expanded analysis of all patients treated with PST at our institution examining the impact of ALN pCR on 10-year OS and RFS. Methods: Patients with clinical stage II/III and pathologically confirmed ALN metastases who underwent PST were categorized into 1 of 2 groups: ALN pCR and ALN residual disease. Additional data were collected, including breast cancer subtype, clinical tumor size, and lymph node staging, pathologic tumor (T) stage, and class of PST. RFS and OS were estimated by the Kaplan-Meier product limit method. Subset analyses were performed on patients with HER2-positive cancer. Results: 1,600 women diagnosed between 1989 and 2007 were identified. Median follow-up was 79 months (5-277); 454 (28.4%) achieved an ALN pCR. ALN pCR was associated with triple-negative and higher grade cancers, lower clinical stage, and lower pathologic breast T stage. 5-year OS and RFS estimates were similar to prior analysis. The 10-year OS was 85% and 58% and the 10-year RFS 83% and 55% (p &lt; 0.001), for patients who achieved an ALN pCR and those with residual ALN disease. For HER2-positive breast cancers, 67.3% of patients who received HER2-targeted therapy achieved an ALN pCR vs. 32.3% without HER2-targeted therapy (p &lt; 0.001). For patients receiving HER2-targeted therapy for HER2-positive breast cancer (n = 153), the 10-year OS was 92% and 52% (p = 0.006), and the 10-year RFS was 89% and 59% (p &lt; 0.001) for those with and without an ALN pCR. Conclusions: ALN pCR is an excellent early surrogate marker for long-term outcome, 10-year RFS and OS. In HER2-positive breast cancers, HER2-targeted therapy is associated with high rates of pCR. Despite the aggressive nature of their disease, patients who achieve ALN pCR with PST have an excellent 10-year prognosis.

Biomarkers Predicting Clinical Benefit: Fact or Fiction?

Preoperative therapy is increasingly used in operable disease to improve the chance for breast-conservative surgery. Moreover, this strategy allows for a better definition of patient prognosis. Independently from stage at diagnosis and breast cancer subtype, the achievement of a pathological complete response (pCR) is a surrogate marker for long-term outcome. The likelihood of pCR depends on tumor biology, being poorly differentiated tumors with ductal histology, absence of hormone receptors, and high proliferation rate those with a higher chance of achieving a CR. However, pCR is a late efficacy parameter that can be evaluated at the end of the preoperative treatment; moreover, a pCR is achieved in a minority of patients and is not an appropriate efficacy measure for neoadjuvant endocrine therapy. The predictive role of tumor biomarkers such as p53, microtubule-associated tau protein, and poly (ADP-ribose) polymerase will be reviewed along with potential markers of early treatment effect.

Abstract S3-1: Lapatinib vs Trastuzumab in Combination with Neoadjuvant Anthracycline-Taxane-Based Chemotherapy: Primary Efficacy Endpoint Analysis of the GEPARQUINTO STUDY (GBG 44)

Abstract Background: The tyrosine-kinase inhibitor lapatinib (L) has shown to improve efficacy of cytotoxic and endocrine treatment in HER2-positive metastatic breast cancer (BC). Improved pathological complete response (pCR) rates were demonstrated by adding trastuzumab (T) to neoadjuvant chemotherapy. However, so far no head-to-head comparison of the two anti-HER2-agents is available. One primary aim of the GeparQuinto study was to improve the pCR rate by adding L instead of T to anthracycline-taxane-based neoadjuvant chemotherapy. We previously reported interim safety data of this study showing more diarrhea, skin changes, and hot flushes, but no cardiac events with L compared to T (von Minckwitz G et al, Ann Oncol 2010 in press). Patients and Methods: Patients (P) with untreated HER2-positive BC were eligible if they had cT3/4a-d; or estrogen (ER) and progesterone (PgR) receptor-negative; or ER/PgR-positive tumors with clinically N+ (for cT2) or pNSLN+ (for cT1) disease, and no increased cardiac risks. P were randomized to receive 4 cycles epirubicin/cyclophosphamide (EC) (90/600 mg/m2) q3w followed by 4 cycles docetaxel (D) (100mg/m2) given in combination with either T 6 (loading dose 8) mg/kg every 3 weeks or L 1000-1250 mg/d throughout all cycles. pCR was defined as no invasive or non-invasive tumor residuals in breast and nodes. We assumed a pCR rate of 26% with ECT-DT (based on GeparQuattro) and expected a pCR of 37% for ECL-DL (odds ratio 1.67). A two-sided Pearson's Chi2 with α=0.05 and β=0.20 calculated a sample size of 613 P. Results: Between May ‘07 and June ‘10 597 P were randomized to ECT-DT (N=299) and ECL-DL (N=298). Median tumor size was 40/40 [T/L] mm (clinically) and 28/29 mm (sonographically); 4.7%/4.3% had T4a-c, 14.8%/14.2% T4d, 2.9%/1.8% bilateral, 17.0%/17.7% multifocal, and 9.0%/12.1% multicentric disease, 96.7%/97.9% had non-lobular, 45.6%/48.9% grade 3, 70.0%/67.7% node-positive, and 56.5%/56.0% ER and PgR-negative disease. Baseline characteristics were well balanced between the treatment arms. The last randomized P will have surgery early Dec'10. Final results on histological response and surgical outcome will be reported. Conclusion: The GeparQuinto trial will provide for the first time randomized phase III efficacy data on the comparison of L and H in combination to chemotherapy for patients with early breast cancer. As pCR has been confirmed as being a surrogate marker for long-term outcome after T treatment, this result will give insight on the overall efficacy of L in patients with early breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S3-1.

Superior pathological complete response to neo-adjuvant chemotherapy in breast cancer amongst women with BRCA1/2 mutations.

Abstract Abstract #5104 Background: Germline mutations in BRCA1 and BRCA2 occur in ∼ 11% of Jewish Ashkenazi women with breast cancer. BRCA1 and BRCA2 proteins are key players in the repair mechanisms of double-strand DNA breaks induced by DNA-damaging agents such as anthracyclines. Hence, inactivating mutations in BRCA1/2 genes have been postulated to result in increased chemo-sensitivity in women with breast cancer who carry these germline mutations. Neo-adjuvant therapy provides the opportunity for a rough, in vivo assessment of this notion by assessing chemotherapy (CT) sensitivity via pathological complete response (pCR) rates, in breast cancer patients, both carriers and non-carriers of deleterious BRCA1 BRCA2 mutations. In particular, response in the axillary lymph nodes to neo-adjuvant therapy is significant, as it is a surrogate marker for long-term outcome. This study assessed the pCR amongst women with BRCA1/2 mutations compared to those who are BRCA1/2 mutation negative.&amp;#x2028; Methods: Retrospective evaluation of response to neo-adjuvant CT amongst consecutive women diagnosed with breast cancer who had received neo-adjuvant CT and who have all undergone genetic testing at the Oncogenetics unit, Sheba Medical Centre to define their BRCA1 BRCA2 mutational status. pCR was defined as the absence of residual invasive carcinoma in the breast and axillary lymph nodes. Only women who received anthracycline based therapy were included. Women who had received concurrent trastuzumab in the neo-adjuvant setting were excluded. Statistical analysis included Fisher's exact test for categorical variables, and student t-test for continuous variables.&amp;#x2028; Results: A total of 75 women were identified who had received neo-adjuvant chemotherapy and who had undergone genetic testing. Overall, 61 were BRCA non-carriers and 14 harbored BRCA1/2 mutations (5 BRCA1 mutation carriers and 9 BRCA2 mutation carriers). There were no statistically significant differences between the BRCA1/2 positive and BRCA1/2 negative groups with regard to mean age, grade 3 histology, hormone receptor status or HER2/neu over-expression, and clinical T and N staging. Seven women received anthracycline based CT and 68 received an anthracycline and taxane regimen. No statistically significant differences existed between the two groups with regards to chemotherapy treatment protocol. Amongst women with a BRCA1/2 mutation 50% had a pCR compared with only 21% in BRCA-negative women, p=0.035.&amp;#x2028; Conclusions: Women with BRCA1/2 mutations demonstrated a higher pCR compared with women who were BRCA negative. Further studies that encompass more mutation carriers with a prospective design are needed to optimize choice of chemotherapy agents in BRCA1/2 positive breast cancer patients in order to exploit the putative biological mechanisms underlying the seemingly unique chemo-sensitivity in this subset of patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5104.

Four‐year data after pediatric renal transplantation: A randomized trial of tacrolimus vs. cyclosporin microemulsion

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with cyclosporin microemulsion (CyA) in pediatric renal recipients. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 yr) were randomly assigned (1:1) to receive either Tac (n = 103) or CyA (n = 93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection (intent-to-treat). Baseline characteristics were comparable between treatment groups. Excluding deceased patients (n = 9) and patients lost to follow-up (n = 31, mostly transferred to adult care), 95% of 2-yr data (159 of 167 possible patients), 87% of 3-yr data (142 of 163) and 73% of 4-yr data (114 of 156) were retrieved. At 1 yr Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA (59.1%, p = 0.003). The incidence of corticosteroid-resistant rejection was also significantly lower with Tac (7.8% vs. 25.8%, p = 0.001). At 4 yr, patient survival was similar (94% vs. 92%, p = 0.86) but graft survival significantly favored Tac (86% vs. 69%; p = 0.025, log-rank test), respectively. At 1 yr, the mean glomerular filtration rate (GFR) (Schwartz formula, ml/min/1.73 m(2)) was 64.9 +/- 20.7 (n = 84) vs. 57.8 +/- 21.9 (n = 77, p = 0.0355), at 2 yr 64.9 +/- 19.8 (n = 71) vs. 51.7 +/- 20.3 (n = 66, p = 0.0002), at 3 yr 66.7 +/- 26.4 (n = 81) vs. 53.0 +/- 23.3 (n = 55, p = 0.0022), and at 4 yr 71.5 +/- 22.9 (n = 51) vs. 53.0 +/- 21.6 (n = 44, p = 0.0001) for Tac vs. CyA, respectively. Cholesterol remained significantly higher with CyA throughout follow-up. Three patients in each arm developed post-transplant lymphoproliferative disease. Incidence of insulin-dependent diabetes mellitus was not different. Tac was significantly more effective than CyA in preventing acute rejection in pediatric renal recipients. Renal function and graft survival were also superior with Tac. Glomerular filtration rate appears to be an useful surrogate marker for long-term outcome.

Evaluation of Serum S100B as a Surrogate Marker for Long-term Outcome and Infarct Volume in Acute Middle Cerebral Artery Infarction

An easily accessible and valid surrogate marker for interventional stroke trials is needed. To investigate the usefulness of various S100B serum measures to predict long-term outcome and infarct volume in patients with acute stroke. Inception cohort study. Tertiary care university hospital. Thirty-nine patients (mean +/- SD age, 69.1 +/- 11.5 years) with acute nonlacunar middle cerebral artery infarction presenting less than 6 hours after symptom onset. Functional outcome 6 months after stroke (modified Rankin scale score) and final infarct volume on day 7 by means of standardized volumetry of brain images. Serum S100B level was determined at hospital admission and 24, 48, 72, 96, 120, and 144 hours after symptom onset. Single S100B measures obtained 48 and 72 hours after stroke onset demonstrated the highest Spearman rank correlations with modified Rankin scale scores (rho = 0.68 and rho = 0.67, respectively; P<.001) and infarct volume (rho = 0.95 and rho = 0.94, respectively; P<.001). A 48-hour S100B value of 0.37 microg/L or less revealed a sensitivity of 0.87 and a specificity of 0.78 in predicting an independent functional outcome. In a multivariate model, S100B emerged as an outcome predictor that was independent of age, sex, stroke severity, etiology, lesion side, and risk factors. Single S100B values obtained 48 and 72 hours after stroke onset provide the highest predictive values with respect to functional outcome and infarct volume in nonlacunar middle cerebral artery infarction. More complex measures of the S100B kinetic (ie, area under the curve or peak value) were not superior. Therefore, these single S100B measures appear to be useful surrogate end points in acute interventional stroke trials.

Multicenter Intravascular Ultrasound Validation Study Among Heart Transplant Recipients: Outcomes After Five Years

We sought to assess the validity of first-year intravascular ultrasound (IVUS) data as a surrogate marker for long-term outcome after heart transplantation. Cardiac allograft vasculopathy (CAV) is a major impediment to long-term graft survival. Intravascular ultrasound is more sensitive than coronary angiography and detects intimal thickening (early CAV) in the coronary arteries of the donor heart. Single-center studies have suggested first-year IVUS results might be a surrogate marker for long-term outcome. First-year IVUS results and subsequent five-year clinical follow-up data were reviewed in 125 heart transplant recipients from five institutions. The IVUS tapes (at baseline and one year) were re-analyzed at a core IVUS laboratory. The change in maximal intimal thickness (MIT) from baseline to one year was recorded for several matched sites in the same coronary artery. Patients were classified into two groups: those with ≥0.5 mm in the MIT in any matched site (group 1) and those with MIT <0.5 mm (group 2). Group 1 patients compared with group 2 patients had a higher incidence of death or graft loss (D/GL, 20.8% vs. 5.9%; p = 0.007), had more nonfatal major adverse cardiac events and/or D/GL (45.8% vs. 16.8%; p = 0.003), and had more findings of newly occurring angiographic luminal irregularities (65.2% vs. 32.6%, p = 0.004). This multicenter study suggests that progression of intimal thickening ≥0.5 mm in the first year after transplantation appears to be a reliable surrogate marker for subsequent mortality, nonfatal major adverse cardiac events, and development of angiographic CAV through five years after heart transplantation.

Glomerular filtration rate as a putative 'surrogate end-point' for renal transplant clinical trials in children.

Only with prospective randomized controlled trials is it possible to evaluate the several immunosuppressive regimens available to renal allograft recipients. Commonly used surrogate markers of clinical outcome, such as patient and graft survival, are constantly improving. Current immunosuppressive protocols have improved 1-yr graft survival to over 90%. The small differences in graft survival among the various immunosuppressive regimes require large patient cohorts in order to establish statistical significance. Such studies are often difficult to conduct in a timely manner, particularly in children. This necessitates the search for better surrogate markers sensitive enough to detect differences in smaller cohorts and in a shorter period of time. While the degree of fibrosis in transplant biopsies might well predict long-term graft survival, protocol biopsies are expensive, invasive, and unpopular among clinicians. In native kidneys, glomerular filtration rate (GFR) closely correlates with disease progression and interstitial fibrosis and appears to be well positioned as a less invasive surrogate marker for long-term outcome. Nonetheless, the ideal marker for GFR remains obscure. Serum creatinine has several major drawbacks, making it a poor predictor of GFR. This review discusses the several methods used to estimate or measure GFR with emphasis on 125I-iothalamate clearance and serum cystatin C (cys-C). Of all the serum markers, cys-C is the most reliable and the most promising. However, cys-C and other endogenous markers cannot replace the diagnostic sensitivity and reliability of radiolabeled markers of GFR such as 125I-iothalamate in renal transplant clinical trials. Unfortunately, clearance of most radiolabeled markers of GFR including 125I-iothalamate remain costly and time consuming.