OBJECTIVES Some patients and oncologists choose to treat localized esophageal cancer with definitive chemotherapy and radiation therapy rather than surgery. A subset of these patients have local relapse without distant metastases and therefore have no other curative intent treatment option but salvage esophagectomy. METHODS We reviewed our experience with salvage esophagectomy from 1987 to 2000 at M.D. Anderson Cancer Center (n = 13, salvage after chemotherapy and radiotherapy group) and compared the data with those of patients receiving esophagectomy in a planned fashion 4 to 6 weeks after preoperative chemotherapy and radiation therapy (n = 99, preoperative chemotherapy and radiotherapy group). RESULTS Increases in morbidity were seen after resection in the salvage after chemotherapy and radiotherapy group relative to the preoperative chemotherapy and radiotherapy group: mechanical ventilation (9.0 days vs 3.3 days, P =.08), intensive care unit stay (11.2 days vs 5.1 days, P =.07), hospital stay (29.4 days vs 18.4 days, P =.03), and anastomotic leak rates (5/13 [39%] vs 7/99 [7%], P =.005). Operative mortality (within 30 days) also tended to be increased statistically nonsignificantly (2/13 [15%] vs 6/99 [6%], P =.2). Salvage esophagectomy resulted in long-term survival (25% 5-year survival) in a subset of patients. Improved survival after salvage esophagectomy was associated with early pathologic stage (T1 N0, T2 N0), prolonged time to relapse, and R0 surgical resection. CONCLUSION Patients who undergo salvage esophagectomy for relapse of tumor after definitive chemoradiation therapy have increased morbidity, mortality, and hospital use relative to patients undergoing planned esophagectomy after preoperative chemoradiation. Nevertheless, long-term survival can be achieved in this group, and such treatment should be considered for carefully selected patients at an experienced center.

The present study applied a receiver operating characteristic (ROC) analysis to assess the role of intraindividual variability of cyclosporin A (CsA) drug exposure in predisposing renal transplant recipients to the occurrence of chronic rejection, as well as to increased health care costs using a resource-based economic analysis. Two hundred and four adult renal transplant recipients were treated with tapering doses of prednisone (Pred) and with a concentration-controlled strategy that selected doses of the olive oil-based formulations of CsA (Sandimmune(R)) that achieved target concentrations based on serial pharmacokinetic profiles. The ROC analysis revealed an inflection point of plots of the coefficient of variation (%CV) of CsA exposure versus the risk of chronic rejection at >/=28.4% for the average concentration (C(av)), i.e., the dosing interval-corrected area under the concentration-time curves, and >/=36% for the trough concentration (C(0)). The incidence of chronic rejection over a period of 5 yr was 24% among the less variable (LV) versus 40% among the variable (V) cohort. The economic analysis revealed that the total mean facility and physician costs per patient were $48,789 versus $60,998, respectively (P < 0.01). The degree of variability displayed by any individual could only be predicted by serial measurements of CsA concentrations, and not by demographic features, laboratory determinations, clinical characteristics, individual or mean values of any observed CsA concentration, or other pharmacokinetic parameters calculated following a single drug exposure. Thus, strategies that reduce intrapatient variability of CsA exposure over time may lead to reductions in chronic allograft loss and in treatment costs.

788 Purpose: Pharmacokinetic (PK) parameters or trough concentrations (C0) of cyclosporine (CsA) and of sirolimus (RAPA, Wyeth-Ayerst) were measured serially for 120 renal transplant patients treated de novo with a combination regimen of CsA-RAPA-prednisone and correlated with pharmacodynamic (PD) changes. Methods: The database included demographic features as well as efficacy and adverse events, laboratory tests, and CsA and RAPA concentrations using a validated high-performance liquid chromatography method. A mean of 19 C0 and 5 PK profiles per patient were collected over 24-36 months. Logistic regression and proportional hazards statistical methods were used to analyze individual patient PD associations of PK parameters and percent coefficient of variation (%CV). Results: Among the 120 patients, 7 (6%) experienced acute allograft rejection episodes (ARE), and 17 (14%), chronic rejection (CR). Due to the low incidence of ARE, no RAPA PK parameter was found to show a useful correlation. However, the incidence of CR was inversely proportional to RAPA dose (p=0.01) and correlated with lower RAPA absorption-as assessed by the dose-corrected area under the concentration-time curve (AUC/mg; p=0.04). The occurrence of CR in this cohort also correlated with the %CV of the dose-corrected average CsA concentration (Cav/mg; p=0.006), as it had in the previously reported group of 204 CsA-prednisone-treated patients. There was a significant inverse correlation between C0 (−0.07, p=0.05) or dose (−0.13, p=0.01) and platelet (but not white cell) count. RAPA concentrations did not correlate with the occurrence of nephrotoxicity. PK values were similar between patients treated with the liquid (n=104) versus the solid tablet (n=45). However, among the 30 patients converted from one formulation to the other, the C0/mg showed significantly higher (p=0.01) and the intra-individual %CV, significantly lower (p=0.002) values for the tablet compared to the liquid formulation. Each patient showed an excellent correlation between PK parameters and %CV values of CsA and of RAPA. A comparison of intra-individual %CV Cav/mg values showed Neoral®=18.25% (lower than the mean of 33.17% for Sandimmune®, n=204), RAPA tablets=21.65% (p=NS), and RAPA liquid=24.97%. Compared with spaced administration, simultaneous administration of both drugs produced greater C0 values of RAPA but not CsA. Conclusion: RAPA PK parameters proffer useful indices to forecast the occurrence of CR and show similar degrees of intra-individual variability and direct correlations of observed values with CsA, suggesting the predominant impact of cytochrome P450 3A4 phenotypes.

166 Purpose: African-American renal transplant recipients experience a higher degree of graft loss than other races due to mismatched racially-associated antigens, hypertension, noncompliance, and pharmacokinetic and pharmacodynamic resistance to immunosuppressants. Comparison of our outcomes under a cyclosporine (CsA)-prednisone (Pred) regimen for Caucasian versus African-American patients confirms this difference: namely, 81% (n=556) versus 70% (n=272) one-year graft survival (p<0.01) with equal patient survival (94.5% versus 93.6%, p=NS). Because the benefits of CsA are less evident in African-Americans, the present study sought to evaluate the impact of addition of sirolimus (RAPA) to the CsA-Pred regimen. Methods: The 147 patients in the two overlapping cohorts were treated with CsA-Pred (n=117) or RAPA-CsA-Pred (n=30). Patient and graft survival rates, as well as the incidence of acute rejection episodes, were examined at 1 year using Kaplan-Meier and log-rank statistic tests. All patients have passed the one-year endpoint. Results: The 97% graft survival rate of patients treated with RAPA-CsA-Pred was significantly higher than the 70% for CsA-Pred-treated African-American patients (p=0.01). This benefit may be attributed in part to the reduced occurrence of acute rejection episodes: namely, 3.4% for the RAPA-CsA-Pred versus 49.8% for the CsA-Pred regimen (p<0.0001). Despite the augmented immunosuppression, there was no penalty in patient survival rates, namely, 100% for the RAPA-CsA-Pred group compared with 94% for the CsA-Pred cohort. (Table)TableConclusion: Addition of RAPA to a CsA-based regimen overcomes the higher rates of acute rejection episodes and graft loss among African-American renal transplant recipients. Thus, RAPA represents a significant new addition to the immunosuppressive armamentarium for this group of high-immunologic-risk recipients.