Cynthia S. Johnson

Phase III Study of Cisplatin, Etoposide, and Concurrent Chest Radiation With or Without Consolidation Docetaxel in Patients With Inoperable Stage III Non–Small-Cell Lung Cancer: The Hoosier Oncology Group and U.S. Oncology

PURPOSE Concurrent chemoradiotherapy is standard treatment for patients with inoperable stage III non-small-cell lung cancer (NSCLC). A phase II study by the Southwest Oncology Group using consolidation docetaxel after cisplatin (P), etoposide (E), and radiation (XRT) resulted in a median survival time (MST) of 26 months. This randomized phase III trial evaluated whether consolidation docetaxel was responsible for this improved survival. PATIENTS AND METHODS Eligible patients had stage IIIA or IIIB NSCLC, baseline performance status of 0 to 1, forced expiratory volume in 1 second >or= 1 L, and less than 5% weight loss. Patients received P 50 mg/m(2) intravenously (IV) on days 1, 8, 29, and 36 and E 50 mg/m(2) IV on days 1-5 and 29-33 concurrently with chest XRT to 59.40 Gy. Patients who did not experience progression were randomly assigned to docetaxel 75 mg/m(2) IV every 21 days for three cycles versus observation. The primary end point was to compare overall survival (Kaplan-Meier analysis). RESULTS On the basis of evidence of futility, a data and safety monitoring board recommended early termination after an analysis of the initial 203 patients. Patient characteristics (n = 203) were as follows: 34% female; median age, 63 years; 39.4% stage IIIA; and 60.6% stage IIIB. One hundred forty-seven (72.4%) of 203 patients were randomly assigned to docetaxel (n = 73) or observation (n = 74). Grade 3 to 5 toxicities during docetaxel included febrile neutropenia (10.9%) and pneumonitis (9.6%); 28.8% of patients were hospitalized during docetaxel (v 8.1% in observation arm), and 5.5% died as a result of docetaxel. The MST for all patients (n = 203) was 21.7 months; MST was 21.2 months for docetaxel arm compared with 23.2 months for observation arm (P = .883). CONCLUSION Consolidation docetaxel after PE/XRT results in increased toxicities but does not further improve survival compared with PE/XRT alone in patients with stage III inoperable NSCLC.

Stereotactic body radiotherapy for primary hepatocellular carcinoma.

PURPOSE To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for the treatment of primary hepatocellular carcinoma (HCC). METHODS AND MATERIALS From 2005 to 2009, 60 patients with liver-confined HCC were treated with SBRT at the Indiana University Simon Cancer Center: 36 Child-Turcotte-Pugh (CTP) Class A and 24 CTP Class B. The median number of fractions, dose per fraction, and total dose, was 3, 14 Gy, and 44 Gy, respectively, for those with CTP Class A cirrhosis and 5, 8 Gy, and 40 Gy, respectively, for those with CTP Class B. Treatment was delivered via 6 to 12 beams and in nearly all cases was prescribed to the 80% isodose line. The records of all patients were reviewed, and treatment response was scored according to Response Evaluation Criteria in Solid Tumors v1.1. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Local control (LC), time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were calculated according to the method of Kaplan and Meier. RESULTS The median follow-up time was 27 months, and the median tumor diameter was 3.2 cm. The 2-year LC, PFS, and OS were 90%, 48%, and 67%, respectively, with median TTP of 47.8 months. Subsequently, 23 patients underwent transplant, with a median time to transplant of 7 months. There were no ≥Grade 3 nonhematologic toxicities. Thirteen percent of patients experienced an increase in hematologic/hepatic dysfunction greater than 1 grade, and 20% experienced progression in CTP class within 3 months of treatment. CONCLUSIONS SBRT is a safe, effective, noninvasive option for patients with HCC ≤6 cm. As such, SBRT should be considered when bridging to transplant or as definitive therapy for those ineligible for transplant.

Neuropsychological status at seizure onset in children Risk factors for early cognitive deficits

Objective: This large, prospective, community-based study characterized neuropsychological functioning and academic achievement at the time of the first recognized seizure and identified risk factors for cognitive deficits. Methods: We compared 282 children (ages 6–14 years, IQ ≥70) with a first recognized seizure to 147 healthy siblings on a battery of well-standardized and widely used neuropsychological and academic achievement tests and examined relationships with demographic and clinical variables. Results: In this intellectually normal cohort, 27% with just one seizure and up to 40% of those with risk factors exhibited neuropsychological deficits at or near onset. Risk factors associated with neuropsychological deficits included multiple seizures (i.e., second unprovoked seizure; odds ratio [OR] = 1.96), use of antiepileptic drugs (OR = 2.27), symptomatic/cryptogenic etiology (OR = 2.15), and epileptiform activity on the initial EEG (OR = 1.90); a child with all 4 risks is 3.00 times more likely than healthy siblings to experience neuropsychological deficits by the first clinic visit. Absence epilepsy carried increased odds for neuropsychological impairment (OR = 2.00). Conclusions: A subgroup of intellectually normal children with seizures showed neuropsychological deficits at onset. Academic achievement was unaffected, suggesting that there is a window early in the disorder for intervention to ameliorate the impact on school performance. Therefore, the risk factors identified here (especially if multiple risks are present) warrant swift referral for neuropsychological evaluation early in the course of the condition.

Phase II Trial of Cisplatin, Gemcitabine, and Bevacizumab As First-Line Therapy for Metastatic Urothelial Carcinoma: Hoosier Oncology Group GU 04-75

PURPOSE Novel approaches are needed for patients with metastatic urothelial cancer (UC). This trial assessed the efficacy and toxicity of bevacizumab in combination with cisplatin and gemcitabine (CGB) as first-line treatment for patients with metastatic UC. PATIENTS AND METHODS Chemotherapy-naive patients with metastatic or unresectable UC received cisplatin 70 mg/m(2) on day 1, gemcitabine 1,000 to 1,250 mg/m(2) on days 1 and 8, and bevacizumab 15 mg/kg on day 1, every 21 days. RESULTS Forty-three patients with performance status of 0 (n = 26) or 1 (n = 17) and median age of 66 years were evaluable for toxicity and response. Grade 3 to 4 hematologic toxicity included neutropenia (35%), thrombocytopenia (12%), anemia (12%), and neutropenic fever (2%). Grade 3 to 5 nonhematologic toxicity included deep vein thrombosis/pulmonary embolism (21%), hemorrhage (7%), cardiac (7%), hypertension (5%), and proteinuria (2%). Three treatment-related deaths (CNS hemorrhage, sudden cardiac death, and aortic dissection) were observed. Best response by Response Evaluation Criteria in Solid Tumors was complete response in eight patients (19%) and partial response in 23 patients (53%), for an overall response rate of 72%. Stable disease lasting ≥ 12 weeks occurred in four patients (9%), and progressive disease occurred in six patients (14%). With a median follow-up of 27.2 months (range, 3.5 to 40.9 months), median progression-free survival (PFS) was 8.2 months (95% CI, 6.8 to 10.3 months) with a median overall survival (OS) time of 19.1 months (95% CI, 12.4 to 22.7 months). The study-defined goal of 50% improvement in PFS was not met. CONCLUSION CGB demonstrates promising OS and antiangiogenic treatment-related toxicities in the phase II setting of metastatic UC. The full risk/benefit profile of CGB in patients with metastatic UC will be determined by an ongoing phase III intergroup trial.

Correlation of CT Enteroclysis With Surgical Pathology in Crohn's Disease

BACKGROUND:The response to therapy in Crohns disease (CD) depends on the inflammatory or fibrostenotic nature of the underlying pathological process. Standard diagnostic tests cannot reliably distinguish between these two entities. Although CT enteroclysis (CTE) has shown promise in the evaluation of small bowel disorders, its accuracy for the differentiation of CD phenotypes is unknown.AIMS:To determine the accuracy of CTE compared with surgical pathology in patients with CD and to assess the association of CTE variables with inflammatory or fibrostenotic pathological lesions.METHODS:CTE studies from patients who underwent resective bowel surgery for CD were reviewed and compared with the pathological specimens using a standardized scoring system. Patients were excluded if they had incomplete studies, nonresective surgeries, or a diagnosis of malignancy. CTE variables, such as mucosal and mural enhancement, wall thickness, engorgement of vasa recta (comb sign), adenopathy, and the presence and severity of strictures were compared with the pathology results using Mantel-Haenszel χ2, Spearmans rank coefficient, and logistic regression analyses.RESULTS:Of the 54 patients enrolled, 10 were excluded. The remaining patients (61% female, 84% white) underwent 44 surgical interventions generating 47 bowel segments that were included in the analysis. The indications for surgery were: bowel obstruction in 21; perforating disease in 13; and refractory, nonobstructive disease in 15. The accuracy of CTE for inflammatory and fibrostenotic lesions was 76.6% and 78.7% using a four- and three-point grading system, respectively. There was good correlation between CTE and pathology in regards to inflammation (Spearmans r = 0.7, P < 0.0001) and fibrostenosis (Spearmans r = 0.6, P < 0.0001) scores. The pathological inflammation score was significantly associated with the CTE variables mucosal enhancement, wall thickness, comb sign, and adenopathy (Mantel-Haenszel χ2 P values 0.04, 0.04, <0.0001, and 0.016, respectively). The pathological fibrostenosis score was significantly associated with the presence and severity of stenosis on CTE (P = 0.001 and 0.007, respectively). By logistic regression analysis, the strongest association was seen with the comb sign (OR 5.52, P < 0.001) for inflammation and the presence of stenosis (OR 5.87, P = 0.006) for fibrostenosis. There was no interaction between the time interval from CTE to surgery and the strength of these associations.CONCLUSIONS:CTE may reliably differentiate between inflammatory and fibrostenotic lesions and may have an important role in the management of CD. Specific CTE variables correlate with each of these phenotypes and deserve further investigations in prospective studies.

Behavioral issues involving children and adolescents with epilepsy and the impact of their families: recent research data

OBJECTIVE Using data from a larger study on new-onset seizures, we reported preliminary findings concerning relationships between family factors and child behavioral problems at baseline and 24 months. We also explored which baseline and changes in family factors were associated with changes in child behavioral problems over the 24-month period. METHODS Subjects were 224 children and their primary caregivers. Data were collected using structured telephone interviews and analyzed using multiple regression. RESULTS Deficient family mastery and parent confidence in managing their childs discipline were associated with behavior problems at baseline and at 24 months; they also predicted child behavior problems over time. Decreasing parent confidence in disciplining their child was associated with increasing child behavior problems. Decreases in parent emotional support of the child were associated with increases in child internalizing problems. CONCLUSION Child behavior problems, family environment, and parenting behaviors should be assessed when children present to the clinical setting with new-onset seizures.

The Prognostic Importance of Sentinel Lymph Node Biopsy in Thin Melanoma

BackgroundSentinel lymph node biopsy (SLNB) is prognostically useful in patients with cutaneous melanoma with Breslow thickness >1 mm. The objective of this study was to determine whether sentinel node histology has similar prognostic importance in patients with thin melanomas (≤1 mm).MethodsThis was a retrospective study of patients who underwent SLNB for clinically localized melanoma at Indiana University Medical Center between 1994 and 2003. SLNB results and traditional melanoma prognostic indicators were studied in univariate log-rank tests.ResultsOne hundred eighty-four patients with melanomas ≤1 mm thick underwent SLNB. SLNB was tumor positive in 12 patients (6.5%). Univariate analysis of SLNB results revealed that Breslow thickness, Clark level of invasion, and mitotic index were associated with SLNB status. Tumor positivity was observed at different rates in tumor thickness subsets: <.75 mm, 2.3%; and .75 to 1.0 mm, 10.2% (P = .0372). Disease-free survival and overall survival were significantly associated with SLNB results in melanomas ≤1 mm (log-rank test: P < .0001 and P = .0125, respectively) at a median follow-up of 26.3 months.ConclusionsSLNB histology in melanomas ≤1.0 mm deep is a significant predictor of outcome. SLNB should be considered for selected patients with melanomas .75 to 1.0 mm.

Patterns of initial recurrence and prognosis after sentinel lymph node biopsy and selective lymphadenectomy for melanoma.

&NA; The histologic status of the sentinel lymph node is a highly significant prognostic factor for patients with clinically localized cutaneous melanoma. The patterns of initial treatment failure of patients with positive sentinel lymph node biopsy versus those with negative results have not been well described. The purpose of this study was to determine the relative prognostic importance of sentinel lymph node status and to compare patterns of initial treatment failure and prognosis of node‐positive versus nodenegative cutaneous melanoma patients staged by sentinel lymph node biopsy and selective lymphadenectomy. The authors reviewed the pertinent demographic and surgical data in a consecutive series of patients with cutaneous melanoma who underwent sentinel lymph node staging of nonpalpable regional nodes. Sentinel lymph node biopsy was performed using a combination of blue dye and radiolocalization. Patients with positive biopsy results underwent selective lymphadenectomy, whereas those with negative results were observed. Site(s) and date(s) of initial recurrence and death were determined, and diseasefree and overall survival probabilities were compared between positive and negative groups using the log‐rank test and multivariable Cox regression analysis. Between February of 1994 and August of 2000, 408 patients with melanoma underwent sentinel lymph node biopsy to stage 518 regional lymph node basins. Mean Breslow tumor thickness was 2.27 mm (range, 0.2 to 14.0 mm). Eighty‐five patients (20.8 percent) had at least one histologically positive sentinel lymph node, and selective lymphadenectomy yielded additional positive lymph nodes in 18 of 84 patients (21.4 percent). Recurrences were noted in 70 patients (17 percent) at a median follow‐up period of 31.4 months. Recurrences were more frequent in patients with positive biopsy results (36.5 percent) than in those with negative results (12.1 percent, p < 0.0001). Distant sites of initial recurrence were more likely in the positive group than in the negative group (71 percent versus 49 percent of recurrences, respectively; p = 0.06). The false‐negative rate for sentinel lymph node staging was 4.5 percent and overall accuracy was 99 percent compared with clinical follow‐up. Disease‐free and overall survival correlated significantly with tumor thickness, ulceration, sentinel lymph node status, and the number of tumor‐positive lymph nodes (two‐sided p < 0.0001 for all comparisons). Multivariable analysis revealed that sentinel lymph node status (p = 0.003), tumor thickness (p = 0.016), ulceration (p = 0.006), and age (p = 0.003) were significant independent predictors of survival for the entire group. Tumor thickness and ulceration were significant predictors of recurrence and survival in sentinel node‐negative patients but not in sentinel node‐positive patients. Sentinel lymph node histology is possibly the most important negative predictor of early recurrence and survival in patients with American Joint Committee on Cancer stage I and II melanoma. The number of positive lymph nodes provides additional prognostic information. Although sentinel node‐negative patients are a prognostically favorable group, various combinations of local and regional recurrences comprise the most common pattern of initial relapse after a negative sentinel lymph node biopsy result. (Plast. Reconstr. Surg. 112: 486, 2003.)

Randomized, Double-Blind, Placebo-Controlled, Phase III Cross-Over Study Evaluating the Oral Neurokinin-1 Antagonist Aprepitant in Combination With a 5HT3 Receptor Antagonist and Dexamethasone in Patients With Germ Cell Tumors Receiving 5-Day Cisplatin Combination Chemotherapy Regimens: A Hoosier Oncology Group Study

PURPOSE Aprepitant, a 5-HT3 receptor antagonist (5HT3-RA), and dexamethasone are standard antiemetic therapy for prevention of single-day, cisplatin-induced nausea and vomiting. We conducted a double-blind, placebo-controlled phase III cross-over study that compared aprepitant to placebo combined with standard antiemetic prophylaxis (a 5HT3-RA and dexamethasone) in patients receiving 5 days of cisplatin combination chemotherapy for testicular cancer. PATIENTS AND METHODS Patients receiving two consecutive identical courses of a 5-day cisplatin-based chemotherapy were randomly assigned to aprepitant 125 mg on day 3 and 80 mg per day on days 4 through 7 or to placebo with the initial course and crossover to the opposite treatment with the second course. The primary objective was complete response (CR). Secondary end points were emetic episodes (acute and delayed), nausea measurement based on a visual analog scale (VAS), and patient-stated preference after the second study cycle. RESULTS In all, 71 patients were screened for the study and 69 were evaluable. Thirty-five patients were randomly assigned to receive aprepitant and 34 to receive placebo for the first course. Forty-two percent achieved CR with aprepitant compared with 13% with placebo (P < .001). Eleven patients (16.2%) had at least one emetic episode during the aprepitant cycle versus 32 patients (47.1%) with placebo. Thirty-eight patients preferred the aprepitant cycle whereas 11 preferred placebo (P < .001). There was no statistical difference in VAS for nausea, but it was numerically superior with aprepitant. There was no toxicity with aprepitant compared with placebo. CONCLUSION There was a significant improvement in CR rate with aprepitant combined with a 5HT3-RA and dexamethasone. Patient preference strongly favored the aprepitant cycle.

The Malone antegrade continence enema: single institutional review.

PURPOSE We report the long-term outcome of the Malone antegrade continence enema procedure in the treatment of chronic constipation and fecal incontinence in children with neuropathic bowel. MATERIALS AND METHODS We performed a retrospective chart review of 256 Malone antegrade continence enema procedures. Patient age at surgery, bowel segment used, location of stoma, number and type of revisions required, and fecal continence were documented and a database was created. RESULTS A total of 236 patients with at least 6 months of followup are included in this report. There were 172 in situ appendicocecostomies, 23 split appendix channels, 9 appendicocecostomies with cecal extension, 22 Yang-Monti ileocecostomies and 10 colon flap channels performed. A total of 112 males (47%) and 124 females (53%) were included in the study. Median patient age at surgery was 9 years (range 2 to 36) and median followup for the entire cohort was 50 months (6 to 115). A total of 56 surgical revisions were performed in 39 patients (17%). Median time to first revision was 9.5 months (range 1 to 105). Stomal stenosis occurred in 32 patients (14%). Overall, surgical revisions were required in 14% of in situ appendix channels (24 of 172), 22% of split appendix channels (5 of 23), 33% of appendix channels with cecal extension (3 of 9), 18% of Yang-Monti Malone antegrade continence enema channels (4 of 22) and 30% of colon flap channels (3 of 10). Independent of channel technique, surgical revisions were required in 15% of umbilical stomas and 18% of lower quadrant stomas (p = 0.516). Two patients had minimal stomal leakage, and 94% (221 of 236) achieved fecal continence with irrigations. CONCLUSIONS The long-term results of the Malone antegrade continence enema channel in a large cohort of patients with neuropathic bowel and chronic constipation are encouraging. Of the patients 17% will require revision surgery, and patients/parents should be counseled accordingly. In our series in situ appendicocecostomy had the lowest revision rate on long-term followup, although the difference was not statistically significant (p = 0.226).