Christopher George

Magnetic Resonance Imaging–Detected Tumor Response for Locally Advanced Rectal Cancer Predicts Survival Outcomes: MERCURY Experience

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.

Phase II Trial of PS-341 in Patients With Renal Cell Cancer: A University of Chicago Phase II Consortium Study

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.

A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer

Purpose: The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy. Experimental Design: Patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m2); regimen 2 was pemetrexed (500 mg/m2) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower). Results: Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m2). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m2; AUC = 6); grade 3/4 leukopenia (4 of 12 patients) was the main hematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed. When systemically active chemotherapy doses were reached, further dose escalation was discontinued, and a phase II dose-range was established (pemetrexed 500 mg/m2 and carboplatin AUC = 5-6). Conclusions: The combination of pemetrexed (500 mg/m2) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.

MRI After Treatment of Locally Advanced Rectal Cancer: How to Report Tumor Response—The MERCURY Experience

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.

Diagnostic Accuracy of Nodal Enhancement Pattern of Rectal Cancer at MRI Enhanced With Ultrasmall Superparamagnetic Iron Oxide: Findings in Pathologically Matched Mesorectal Lymph Nodes

OBJECTIVE The purpose of this study was to evaluate the diagnostic accuracy of the pattern of nodal enhancement at MRI enhanced with ultrasmall superparamagnetic iron oxide (USPIO) in the nodal classification of rectal cancer in pathologically matched mesorectal lymph nodes. SUBJECTS AND METHODS Twenty-five patients with adenocarcinoma of the rectum underwent prospective evaluation with 3-mm axial T2-weighted and USPIO-enhanced T2*-weighted MRI before surgery. Mesorectal nodes visible at in vivo MRI were independently scored by two radiologists as malignant or nonmalignant according to morphologic criteria (irregular nodal contour, heterogeneous signal intensity) on T2-weighted MR images and according to USPIO enhancement pattern on T2*-weighted MR images. The sensitivity, specificity, and positive and negative predictive values of morphologic and USPIO criteria in identification of malignancy in the pathologically matched mesorectal nodes were compared by use of the McNemar test. Interobserver agreement was compared by use of kappa statistics. RESULTS After surgery, radiologic-pathologic comparison of 126 mesorectal nodes (116 benign, 10 malignant) was possible. Use of morphologic criteria resulted in an average sensitivity of 65% (95% CI, 35-88%); specificity, 75% (67-83%); positive predictive value, 19% (8-34%); and negative predictive value, 96% (91-99%). Use of USPIO criteria resulted in an average sensitivity of 65% (95% CI, 35-88%); specificity, 93% (87-96%); positive predictive value, 43% (21-67%); and negative predictive value, 97% (92-99%). Use of USPIO MRI improved diagnostic specificity for both observers (p < 0.01). Interobserver agreement was fair for morphologic criteria (kappa = 0.39) but good for USPIO criteria (kappa = 0.68). CONCLUSION Use of the pattern of USPIO enhancement had higher diagnostic specificity than but the same sensitivity as morphologic findings in pathologically matched mesorectal lymph nodes.

Relevance of magnetic resonance imaging-detected pelvic sidewall lymph node involvement in rectal cancer

The significance of magnetic resonance imaging (MRI)‐suspected pelvic sidewall (PSW) lymph node involvement in rectal cancer is uncertain.

Can a novel MRI staging system for low rectal cancer aid surgical planning

BACKGROUND: Low rectal cancers are associated with worse outcomes in comparison with mid and upper rectal tumors. OBJECTIVE: This study aimed to assess the predictive accuracy of MRI in identifying the correct surgical approach based on the mesorectal and extralevator planes. DESIGN: This study involved the retrospective analysis of MRI and histopathology data of 33 patients with low rectal cancer, with the use of an anatomically based staging system. Three radiologists reported on the available surgical planes of excision based on the predicted relationship of tumor to key anatomical features. MRI-predicted planes of excision were then compared with the histopathological planes actually required, with the use of the same staging criteria. SETTINGS: The study was conducted at 4 English district general hospitals. PATIENTS: Unselected patients with low rectal cancer, all of whom were participants in a multicenter study, were eligible for this study. MAIN OUTCOME MEASURES: The main outcome measured was the accuracy of operative plane prediction on MRI. RESULTS: On pathological analysis, the mesorectal plane would have been sufficient to achieve a clear margin in 28 of 33 (84.9%) of cases. The extralevator plane was required in 5 of 33 (15.1%). Planes were correctly predicted by MRI in 29 of 33 cases by radiologist 1 and 24 of 33 cases by radiologists 2 and 3 with an accuracy of 87.9% and 72.7%. Overstaging (extralevator plane predicted when a mesorectal plane would have sufficed) occurred in 3 of 33 and 7 of 33 cases. Understaging (mesorectal plane predicted when an extralevator plane was required) occurred in 1 of 33 and 2 of 33 cases. The positive and negative predictive values of MRI in determining the histopathological plane of excision required were 57% and 96% for radiologist 1 and 30% and 91% for radiologists 2 and 3. LIMITATIONS: This study was limited by its retrospective nature and its relatively small patient numbers. No account was taken of postoperative function when recommending the surgical plane. CONCLUSIONS: This supports an anatomically based MRI staging system for low rectal cancer to predict the planes of surgical excision. This may help to reduce margin positivity and to improve outcome in patients with low rectal cancer.

A phase I trial of the oral platinum analogue JM216 with concomitant radiotherapy in advanced malignancies of the chest

JM216 is an orally administered platinumanalogue. We undertook this study todetermine the maximally tolerated dose(MTD) of JM216 when administered withconcomitant radiotherapy to the chest(200 cGy daily, 5×/week) in patients withlocoregionally advanced non-small cell lung(NSCLC) or esophageal cancer. Patientswere excluded for inadequate bone marrowreserve, prior radiotherapy to the primarytumor or previous treatment with platinumdrugs. A dose-limiting toxicity (DLT) wasdefined using the National Cancer Institute(NCI) Common Toxicity Criteria (CTC) andconsisted of grade ≥2 renal, hepatic,cardiac, or pulmonary toxicity or grade ≥3hematologic, neurological, orgastrointestinal toxicity. A total of 23patients were registered; two neverreceived treatment and are excluded fromanalyses. Six patients were treated at adose of 30 mg/m2/day for 5 days withtwo grade 2 DLTs: cough (1 pt) andelevated trans-aminases (1 pt). Sevenevaluable patients were treated at60 mg/m2/day and seven experiencedgrade 3 or 4 toxicity, five related tomyelosuppression. The dose was thenreduced to 45 mg/m2/d. Eight patientswere evaluable for toxicity, of which 5experienced DLT: myelosuppression (3 pts),esophagitis (2 pts), dyspnea (1 pt), andelevated creatinine (1 pt). Fourteenpatients were evaluable for efficacy, ofwhich 6 had an objective response,including one complete response. Therecommended phase II dose of JM216 withconcurrent radiation therapy is30 mg/m2/d for 5 days. The major DLTis myelosuppression with only limitedincreased toxicity within the field ofradiation. This conceivably may limit theuse of JM216 as a radiation sensitizer.

The role of systemic chemotherapy in the treatment of kidney cancer.

Traditional cytotoxic chemotherapy has been considered to be ineffective in renal cell carcinoma, likely due to multiple mechanisms of high-level drug resistance proteins such as p-glycoprotein expressed by these cancers. Nonetheless, low level activity of several nucleoside analogues and the elucidation of critical molecular pathways and targets in this disease, such as the angiogenic pathway, provide hope that important advances can and will be made.