Svetlana Mironov

Phase II Study of Gemcitabine, Carboplatin, and Bevacizumab in Patients With Advanced Unresectable or Metastatic Urothelial Cancer

PURPOSE Although gemcitabine and carboplatin (GCa) is a standard option for patients with advanced urothelial cancer (UC) who are ineligible for cisplatin, outcomes remain poor. This trial evaluated the efficacy and safety of bevacizumab with GCa in advanced UC. PATIENTS AND METHODS Patients with Karnofsky performance status of 60% to 70%, creatinine clearance less than 60 mL/min, visceral metastasis, or solitary kidney were eligible and received a lead-in dose of bevacizumab 10 mg/kg followed 2 weeks later by gemcitabine 1,000 mg/m(2) on days 1 and 8 and carboplatin at area under the [concentration-time] curve (AUC) 5.0 or 4.5 and bevacizumab 15 mg/kg on day 1 every 21 days for six cycles. Patients achieving at least stable disease (SD) continued bevacizumab 15 mg/kg every 21 days for 18 additional cycles. The study was powered to detect a 50% improvement in median progression-free survival (PFS) over a historical control. RESULTS Fifty-one patients, median age 67 years (range, 42 to 83 years), were enrolled onto the study and were evaluable for toxicity. Twenty (39%) experienced grade 3 to 4 toxicity, and 10 (20%) had thromboembolic events (deep venous thrombosis or pulmonary embolism). Four received one or fewer cycles leaving 47 evaluable for outcomes. Twenty-three (49%) achieved response (three complete; 20 partial), and 11 had SD. Median PFS was 6.5 months (95% CI, 4.7 to 7.8 months); PFS was greater in the carboplatin AUC 5.0 group (P = .04). Median overall survival (OS) was 13.9 months. CONCLUSION The 95% one-sided lower confidence bound of 4.77 months for median PFS did not meet the predesignated PFS of more than 4.8 months considered sufficient for further study. Median OS was greater than expected. An ongoing phase III trial in patients who are eligible for therapy with cisplatin will define the role of bevacizumab in UC.

Implementation of Evidence-Based Guidelines for Thyroid Nodule Biopsy: A Model for Establishment of Practice Standards

OBJECTIVE Multiple studies have defined criteria for the selection of thyroid nodules for biopsy. No set of criteria is sufficiently sensitive and specific. The aim of this study is to develop a method for assessing consistency of practice in an ultrasound group and to determine whether a 5-point malignancy rating scale can be used to select patients for biopsy. MATERIALS AND METHODS One hundred one nodules (50 benign and 51 malignant) were selected from a thyroid biopsy database. Seven radiologists were educated on evidence-based criteria used to select nodules for biopsy. Using this information, readers graded the likelihood of malignancy using a 5-point malignancy rating scale, where 1 equals the lowest probability of malignancy and 5 equals the highest probability of malignancy, on the basis of overall impression of sonographic findings. Interobserver agreement on biopsy recommendation, reader sensitivity, specificity, and accuracy were determined. RESULTS The sensitivity and specificity of biopsy recommendation were 96.1% and 52%, respectively. The misclassification rate was 25.7%, and accuracy was 74.3%. Interobserver agreement on biopsy recommendation was fair to substantial (κ, 0.38-0.69). The proportion of agreement was excellent for malignant nodules (0.88-1.0). The risk of malignancy increased with increasing malignancy rating: 4.3% of nodules with a malignancy rating of 1 were malignant versus 93.4% of those assigned a rating of 5. CONCLUSION Our study illustrates a method to evaluate the standard of practice for thyroid nodule assessment among radiologists within an ultrasound group. Application of a 5-point malignancy rating scale to select nodules for biopsy is feasible and shows good diagnostic accuracy.

Significance of non-calcified pulmonary nodules in patients with extrapulmonary cancers

Background: This study sought to determine the rate and patterns of malignancy in patients with extrapulmonary cancers and non-calcified pulmonary nodules, and to develop a statistical model to guide clinicians regarding choice of patients for diagnostic biopsy. Method: The medical records of 151 patients evaluated at the Memorial Sloan-Kettering Cancer Center between January 1999 and December 2001 for non-calcified pulmonary nodules were reviewed. Nodules were considered malignant based on the results of a diagnostic biopsy, and were considered benign if their appearance remained stable 2 years after the initial study, if they resolved, or if a biopsy showed a non-malignant condition. Results: Sixty four of 151 patients (42%) were diagnosed with malignant nodules; 32 had newly diagnosed lung cancers, 28 had metastatic spread of their primary cancers, and four had lesions that were either new cancers or of undetermined aetiology. On univariate analysis the likelihood of malignancy increased with nodule size, tobacco exposure, and the finding of a solitary nodule. On multivariable analysis only nodule size and tobacco exposure were predictive of malignancy. The model had good predictive accuracy (area under the curve 0.751) but had insufficient discrimination for use as a clinical tool to determine which patients should undergo diagnostic biopsy. Conclusion: Nearly half the non-calcified pulmonary nodules identified in this series were malignant. Lung cancer was more common than metastatic disease. These findings support the need for close interval follow up and a low threshold for diagnostic biopsy in patients with extrapulmonary cancers and non-calcified pulmonary nodules. In smokers, such lesions should raise concern for lung cancer.

Phase II trial of dose-dense doxorubicin plus gemcitabine followed by paclitaxel plus carboplatin in patients with advanced urothelial carcinoma and impaired renal function

Cisplatin‐based therapy is standard in patients with advanced urothelial carcinoma but a large proportion are ineligible due to renal impairment. The safety and activity of a dose‐dense carboplatin‐based regimen in this patient population were explored.

Final Results of Sequential Doxorubicin Plus Gemcitabine and Ifosfamide, Paclitaxel, and Cisplatin Chemotherapy in Patients With Metastatic or Locally Advanced Transitional Cell Carcinoma of the Urothelium

PURPOSE Sequential chemotherapy with doxorubicin and gemcitabine (AG) followed by ifosfamide, paclitaxel, and cisplatin (ITP) was previously demonstrated to be well tolerated in patients with advanced transitional cell carcinoma (TCC). This study sought to evaluate the efficacy and to additionally define toxicity. PATIENTS AND METHODS Sixty patients with advanced TCC received AG every 2 weeks for five or six cycles followed by ITP every 21 days for four cycles. Granulocyte colony-stimulating factor was given between cycles. RESULTS Myelosuppression was seen with 68% of patients who experienced grades 3 to 4 neutropenia and with 25% who experienced febrile neutropenia. Grade 3 or greater nonhematologic toxicities were infrequent. Forty (73%) of 55 evaluable patients (95% CI, 59% to 84%) demonstrated a major response (complete, n = 19; partial, n = 21) and had a median response duration of 11.3 months (range, 1.7 to >or= 105.6 months). Twenty-seven (79%) of 34 patients with locally advanced disease (ie, T4, N0, M0) or with regional lymph node involvement (ie, T3-4, N1, M0) and 10 (56%) of 18 patients with distant metastases achieved a major response. The median progression-free survival was 12.1 months (95% CI, 9.0 to 14.8 months), and the median overall survival was 16.4 months (95% CI, 14.0 to 22.5 months). At a median follow-up of 76.4 months, seven (11.7%) patients remain alive, and all were disease free. CONCLUSION AG plus ITP is an active regimen in previously untreated patients with advanced TCC; however, it is associated with toxicity and does not clearly offer a benefit compared with other nonsequential, cisplatin-based regimens.

Pleural effusion detected at CT prior to primary cytoreduction for stage III or IV ovarian carcinoma: effect on survival.

PURPOSE To determine the prognostic importance of pleural effusions on preoperative computed tomographic (CT) images in patients with advanced epithelial ovarian cancer. MATERIALS AND METHODS The institutional review board waived informed consent for this HIPAA-compliant study of 203 patients with International Federation of Obstetrics and Gynecology stage III (n = 172) or IV (n = 31) epithelial ovarian cancer who underwent CT before primary cytoreductive surgery between 1997 and 2004 (mean age, 61 years; range, 37-96 years). Two radiologists retrospectively evaluated chest and/or abdominal CT images for pleural malignancy and the presence, size, and laterality of pleural effusions. To evaluate survival, Kaplan-Meier methods were used, with log-rank P values for comparisons. Multivariate analyses were conducted by using Cox proportional hazards regression. κ Statistics were calculated for interreader agreement. RESULTS Median survival was 50 months (95% confidence interval [CI]: 45, 55 months) for patients with stage III disease and 41 months (95% CI: 27, 58 months) for patients with stage IV disease. Readers 1 and 2 found pleural effusions in 40 and 41 stage III and 20 and 21 stage IV patients, respectively. At multivariate analysis, after controlling for stage, age at surgery, preoperative serum CA-125 level, debulking status, and ascites, moderate-to-large pleural effusion on CT images was significantly associated with worse overall survival (reader 1: hazard ratio = 2.27 [95% CI: 1.31, 3.92], P < .01; reader 2: hazard ratio = 2.25 [95% CI: 1.26, 4.01], P = .02). Preoperative CA-125 level, debulking status, and ascites were also significant survival predictors (P ≤ .03 for all for both readers). Readers agreed substantially in distinguishing small from moderate-to-large effusions (κ = 0.764). CONCLUSION Moderate-to-large pleural effusion on preoperative CT images in patients with stage III or IV epithelial ovarian cancer was independently associated with poorer overall survival after controlling for age, preoperative CA-125 level, surgical stage, ascites, and cytoreductive status.

Prognostic significance of supradiaphragmatic lymphadenopathy identified on preoperative computed tomography scan in patients undergoing primary cytoreduction for advanced epithelial ovarian cancer.

Introduction: It has been hypothesized that the supradiaphragmatic lymph nodes serve as the principal nodes for lymphatic drainage of the entire peritoneal cavity. The purpose of this study was to determine the prognostic significance of enlarged supradiaphragmatic nodes noted on preoperative computed tomographic (CT) scan in patients undergoing primary cytoreduction for advanced epithelial ovarian cancer (EOC). Methods: We performed a retrospective chart review of all patients with stage III and IV EOC according to the International Federation of Gynecology and Obstetrics who had preoperative CT scans, including the supradiaphragmatic region, and had undergone primary cytoreductive surgery at our institution between January 1997 and June 2004. Scans were retrospectively reviewed by a radiologist. We defined supradiaphragmatic adenopathy as nodes measuring greater than 5 mm on the largest of 2 perpendicular measurements on the CT scan. The Fisher exact test was used to compare proportions. Kaplan-Meier curves and log-rank tests were used for the survival analyses. Results: A total of 212 evaluable patients were identified. All underwent attempted primary cytoreduction followed by systemic chemotherapy. None had any supradiaphragmatic nodes removed at primary cytoreduction. With a median follow-up time of 52 months, median overall survival for the entire cohort was 48 months. Of 212 patients, 92 (43%) had supradiaphragmatic adenopathy. Median survival was 50 months for patients without adenopathy and 45 months for patients with adenopathy (P = 0.09). Of the 212 patients, 155 (73%) underwent optimal cytoreduction. In these patients, median survival was 55 months for the 91 without adenopathy and 50 months for the 64 patients with supradiaphragmatic adenopathy (P = 0.09). Conclusions: We observed a trend toward worse survival in patients with enlarged supradiaphragmatic nodes. The prognostic impact of supradiaphragmatic adenopathy remains uncertain and deserves further study.

Antibiotic Use in the Management of Pulmonary Nodules

BACKGROUND Pulmonary nodules are common incidental findings on thoracic imaging examinations. This study sought to determine whether antibiotic use is associated with any improvement in nodule appearance and to identify clinical findings and nodule characteristics potentially influencing the decision to prescribe antibiotics. METHODS Electronic medical records were reviewed of outpatients referred to a metropolitan cancer center for pulmonary nodules seen on chest CT scans who did not undergo biopsy. The primary end point was the appearance of each nodule on the first follow-up scan. A subset analysis was performed for patients manifesting symptoms or radiographic findings suggesting infection. An analysis was performed to determine what clinical and radiographic findings were associated with the decision to prescribe antibiotics. RESULTS Between January 2003 and December 2004, 143 evaluations were performed for 293 nodules. Antibiotics were prescribed to 34 (24%) evaluations. A trend toward improvement was seen with antibiotic use, which was not significant. The percentage of nodules that improved was 33% among those receiving antibiotics and 27% among those who did not (odds ratio 1.33; 95% CI, 0.55-3.27). Among 63 patients with pulmonary symptoms, 41% of nodules improved among those receiving antibiotics and 28% among those who did not (odds ratio 1.78; 95% CI, 0.42-7.78). The decision to prescribe antibiotics was associated only with larger nodule size and bronchiectasis. CONCLUSIONS These data do not support antibiotic use for pulmonary nodules. However, the trend toward improved nodule appearance suggests that larger prospective trials are warranted to clarify the role of antibiotics in managing lung nodules.

Characterization of Adnexal Masses Using Feature Analysis at Contrast-Enhanced Helical Computed Tomography

Objective: To determine the computed tomographic imaging features predictive of adnexal malignancy and evaluate the accuracy of contrast-enhanced helical computed tomography (CT) in the characterization of adnexal masses. Materials and Methods: The institutional review board waived the informed consent requirement for this retrospective study, which was Health Insurance Portability and Accountability Act compliant. For 143 consecutive patients who underwent preoperative contrast-enhanced CT of the abdomen and pelvis and had adnexal masses found at surgical pathology, preoperative contrast-enhanced computed tomographic scans were retrospectively and independently reviewed by 2 radiologists. Receiver operating characteristic analysis was used to assess the value of contrast-enhanced CT in detecting and characterizing adnexal masses. Feature analysis was performed to select the findings with the highest sensitivities and specificities for predicting malignant lesions. Interobserver variability was assessed using κ statistics. Results: At surgical pathology, 234 adnexal masses were found (165 were malignant). Readers 1 and 2 detected 215 and 216 (92%) adnexal masses, respectively. For both readers, the features most predictive of malignancy were heterogeneity for a solid lesion, multilocularity (>3 locules), irregular and thickened cystic septations or walls, and the presence of internal vegetations for a cystic lesion. Irregular lesion contour and ancillary findings, including ascites, peritoneal implants, lymphadenopathy, and pleural effusion, were predictive of malignancy in both solid and cystic lesions. In diagnosing malignancy in all patients and in the subgroup without ancillary findings, areas under the receiver operating characteristic curves were 0.88 (95% confidence interval [CI], 0.84-0.93) and 0.89 (95% CI, 0.83-0.96) for reader 1, respectively, and 0.90 (95% CI, 0.86-0.94) and 0.88 (95% CI, 0.80-0.97) for reader 2, respectively. Interobserver agreement (κ = 0.71) was good. Conclusions: Contrast-enhanced helical CT is highly accurate in characterizing adnexal masses as malignant. Recognition of the computed tomographic features most often associated with adnexal malignancy will assist in more confident use of this modality and may potentially obviate the need for additional imaging studies before treatment selection.

Follow-up study of the correlation between postoperative computed tomographic scan and primary surgeon assessment in patients with advanced ovarian, tubal, or peritoneal carcinoma reported to have undergone primary surgical cytoreduction to residual disease of 1 cm or smaller

Introduction: We previously reported a 52% correlation between the primary surgeons assessment and the postoperative computed tomographic (CT) scan findings of residual disease in patients reported to have undergone cytoreduction to residual disease of 1 cm or smaller. This is a follow-up analysis of survival and prognostic factors for patients who had concordant and discordant postoperative CT scan findings. Methods: Patients scheduled for primary cytoreductive surgery for presumed advanced ovarian carcinoma were offered enrollment in a prospective study evaluating the ability of preoperative CT scan to predict cytoreductive outcome. If cytoreduction to residual disease of 1 cm or smaller was reported, a CT scan was done 7 to 35 days postoperatively. The CT scan findings were graded by protocol radiologists using a qualitative analysis scale from 1 (normal) to 5 (definitely malignant). Results: From January 2001 to September 2006, 285 patients were enrolled; 67 patients were eligible. Postoperative CT scans confirmed the primary surgeons assessment of no residual disease larger than 1 cm in 38 cases (57%). In 29 cases (43%), the radiologist found residual disease larger than 1 cm and reported it as probably or definitely malignant. Comparing concordant versus discordant findings, there was no significant difference in median progression-free survival (21 vs 17 months; P = 0.365) or overall survival (60 vs 43 months; P = 0.146). Age (P = 0.040), stage (P = 0.038), and residual disease of 0.5 mm or smaller versus 0.6 to 1.0 cm (P = 0.018) were significant for overall survival on multivariate analysis. Conclusions: On this follow-up analysis, only age, stage, and residual disease were significant prognostic factors for overall survival. Discordant findings between the primary surgeons assessment and the postoperative CT scan findings of residual disease was not an independent prognostic factor.