Christopher George

PURPOSE: To assess magnetic resonance imaging (MRI) and pathologic staging after neoadjuvant therapy for rectal cancer in a prospectively enrolled, multicenter study. METHODS: In a prospective cohort study, 111 patients who had rectal cancer treated by neoadjuvant therapy were assessed for response by MRI and pathology staging by T, N and circumferential resection margin (CRM) status. Tumor regression grade (TRG) was also assessed by MRI. Overall survival (OS) was estimated by using the Kaplan-Meier product-limit method, and Cox proportional hazards models were used to determine associations between staging of good and poor responders on MRI or pathology and survival outcomes after controlling for patient characteristics. RESULTS: On multivariate analysis, the MRI-assessed TRG (mrTRG) hazard ratios (HRs) were independently significant for survival (HR, 4.40; 95% CI, 1.65 to 11.7) and disease-free survival (DFS; HR, 3.28; 95% CI, 1.22 to 8.80). Five-year survival for poor mrTRG was 27% versus 72% (P = .001), and DFS for poor mrTRG was 31% versus 64% (P = .007). Preoperative MRI-predicted CRM independently predicted local recurrence (LR; HR, 4.25; 95% CI, 1.45 to 12.51). Five-year survival for poor post-treatment pathologic T stage (ypT) was 39% versus 76% (P = .001); DFS for the same was 38% versus 84% (P = .001); and LR for the same was 27% versus 6% (P = .018). The 5-year survival for involved pCRM was 30% versus 59% (P = .001); DFS, 28 versus 62% (P = .02); and LR, 56% versus 10% (P = .001). Pathology node status did not predict outcomes. CONCLUSION: MRI assessment of TRG and CRM are imaging markers that predict survival outcomes for good and poor responders and provide an opportunity for the multidisciplinary team to offer additional treatment options before planning definitive surgery. Postoperative histopathology assessment of ypT and CRM but not post-treatment N status were important postsurgical predictors of outcome.

OBJECTIVE: The Magnetic Resonance Imaging and Rectal Cancer European Equivalence (MERCURY) Study validated the use of MRI for posttreatment staging and its correlation with survival outcomes. As a consequence, reassessment of MRI scans after preoperative therapy has implications for surgical planning, the timing of surgery, sphincter preservation, deferral of surgery for good responders, and development of further preoperative treatments for radiologically identified poor responders. CONCLUSION: In this article we report a validated systematic approach to the interpretation of MR images of patients with rectal cancer after chemoradiation.

PURPOSE: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. PATIENTS AND METHODS: PS-341 1.5 mg/m(2) was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m(2) ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. RESULTS: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P =.07 and.11, respectively). CONCLUSION: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.

Chemotherapy can serve as a stimulus for mobilizing hematopoietic progenitor cells to the peripheral blood for harvest via leukapheresis. Mobilized peripheral blood stem cells (PBSC) support rapid hematologic reconstitution after bone marrow aplasia induced by intensive myelosuppressive treatments. Our purpose was to develop effective mobilization regimens allowing collection of large quantities of PBSC. We administered high-dose cyclophosphamide (HDC, 4 gm/m2) or cyclophosphamide (4 gm/m2) plus etoposide (600 mg/m2) (HDCE) in a nonrandomized, sequential fashion to 94 patients with breast cancer, lymphoma, and other malignancies with collection of PBSC via leukapheresis during white blood cell (WBC) recovery from nadir counts. Each apheresis product was analyzed for total nucleated cell number, granulocyte-macrophage colony-forming units (CFU-GM) and CD34+ cells. Twenty-four additional patients with comparable pretreatment characteristics received HDCE plus recombinant human granulocyte colony-stimulating factor (HDCE+G) after chemotherapy through the end of apheresis. Patients receiving HDC were matched for age, sex, and disease but were more heavily pretreated. HDCE was superior to HDC in mean daily CFU-GM and CD34+ yield (p < 0.05), even when groups were adjusted for performance status and amount of prior therapy. HDCE+G led to 3.7 times more CFU-GM and 4.7 times more CD34+ cells than HDCE. Target PBSC yield, defined as > 20 x 10(4) CFU-GM/kg and >4 x 10(8) cells/kg, was achieved by 92% of HDCE+G patients after a median of three aphereses, 56% of HDCE patients after five aphereses, and 16% of HDC patients after six apheresis (p < 0.0001). Prior chemotherapy inversely correlated with the quantity of PBSC harvested regardless of regimen utilized. Our results demonstrate effective chemotherapy regimens for harvesting hematopoietic progenitors in a diverse patient population. HDCE+G produced the highest number of progenitors, suggesting that increasing dose intensity and adding rhG-CSF enhances mobilization. Correlation between cumulative CD34+ and CFU-GM allows real-time flow cytometric analysis of the number of aphereses required to harvest target numbers of PBSC.