Clinical Trials Of Adjuvant Therapy Research Articles

Leveraging the power of pooled data for cancer outcomes research.

BackgroundClinical trials continue to be the gold standard for determining the efficacy of novel cancer treatments, but they may also expose participants to the potential risks of unpredictable or severe toxicities. The development of validated tools that better inform patients of the benefits and risks associated with clinical trial participation can facilitate the informed consent process. The design and validation of such instruments are strengthened when we leverage the power of pooled data analysis for cancer outcomes research.Main bodyIn a recent study published in the Journal of Clinical Oncology entitled “Determinants of early mortality among 37,568 patients with colon cancer who participated in 25 clinical trials from the adjuvant colon cancer endpoints database,” using a large pooled analysis of over 30,000 study participants who were enrolled in clinical trials of adjuvant therapy for early-stage colon cancer, we developed and validated a nomogram depicting the predictors of early cancer mortality. This database of pooled individual-level data allowed for a comprehensive analysis of poor prognostic factors associated with early death; furthermore, it enabled the creation of a nomogram that was able to reliably capture and quantify the benefit-to-risk profile for patients who are considering clinical trial participation. This tool can facilitate treatment decision-making discussions.ConclusionAs China and other Asian countries continue to conduct oncology clinical trials, efforts to collate patient-level information from these studies into a large data repository should be strongly considered since pooled data can increase future capacity for cancer outcomes research, which, in turn, can enhance patient-physician discussions and optimize clinical care.

Validation of a Postoperative Nomogram Predicting Recurrence in Patients with Conventional Clear Cell Renal Cell Carcinoma

BackgroundClear cell renal cell carcinoma (RCC) continues to be the most commonly diagnosed subtype and is associated with more aggressive behavior than papillary and chromophobe RCC. Predicting disease recurrence after surgical extirpation is important for counseling and targeting those at high risk for adjuvant therapy clinical trials. ObjectiveTo validate a postoperative nomogram predicting 5-yr recurrence-free probability (RFP) for clinically localized clear cell RCC. Design, setting, and participantsWe identified all patients who underwent nephrectomy for clinically localized clear cell RCC from 1990 to 2009 at Memorial Sloan Kettering Cancer Center. After excluding patients with bilateral renal masses, familial RCC syndromes, and T3c or T4 tumors due to the limited number, 1642 participants were available for analysis. InterventionsPartial or radical nephrectomy. Outcome measurements and statistical analysisDisease recurrence was defined as any new tumor after nephrectomy or kidney cancer–specific mortality, whichever occurred first. A postoperative nomogram was used to calculate the predicted 5-yr RFP, and these values were compared with the actual 5-yr RFP. Nomogram performance was evaluated by concordance index and calibration plot. Results and limitationsMedian follow-up was 39 mo (interquartile range: 14–79 mo), and disease recurrence was observed in 50 patients. The nomogram concordance index was 0.81. The calibration curve showed that the nomogram underestimated the actual 5-yr RFP. We updated the nomogram by including the entire patient population, which maintained performance and significantly improved calibration. ConclusionsThe updated clear cell RCC postoperative nomogram performed well in the combined cohort. Underestimation of actual 5-yr RFP by the original nomogram may be due to increased surgeon experience and other unknown variables. Patient summaryWe updated a valuable prediction tool used for assessing the disease recurrence probability after nephrectomy for clear cell renal cell carcinoma.

Molecular Biomarkers in the Personalized Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is a disease in which pathogenesis is influenced by genetic and epigenetic events that occur with tumor initiation and progression. Large variation exists in individual patient prognosis and response to chemotherapy, caused by molecular heterogeneity. Certain biomarkers have been identified that can predict clinical outcome beyond tumor staging, and inform treatment selection. Molecular testing is routinely performed in clinical practice for the selection of patients for targeted biological agents or immunotherapy, and is advocated for prognostic stratification. Estimating prognosis can avoid undertreatment or overtreatment and also guide the intensity of patient follow-up. Classifiers of CRC have been developed that integrate genetic and/or epigenetic features. The mutational status of KRAS and BRAF(V600E) oncogenes combined with analysis of the DNA mismatch repair system with/without the CpG island methylator phenotype (CIMP) has been shown to identify colon cancer subtypes with distinct clinical features and prognoses. Gene expression profiling has also been used to subtype CRCs and can overcome the limitations of single/limited gene testing. A recent effort identified 4 consensus molecular subtypes of biological relevance that were associated with different patient outcomes. Efforts to validate and refine these subtypes to include additional genomic features are ongoing. The focus of this article is to highlight molecular markers that can inform clinical decision-making in patients with CRC.

Prognostic factors in melanoma patients with tumor-negative sentinel lymph nodes

Sentinel lymph node (SLN) biopsy for melanoma results in accurate nodal staging, which guides treatment decisions. Patients with a negative SLN biopsy in general have a favorable prognosis, but certain subsets are at increased risk for recurrence and death. This study aimed to identify risk factors predictive of prognosis in patients with a tumor-negative SLN biopsy for cutaneous melanoma. In this post-hoc analysis of data from a multicenter prospective randomized trial, clinicopathologic data of patients with cutaneous melanoma ≥1.0 mm Breslow thickness and tumor-negative SLN were analyzed. Disease-free survival, overall survival (OS), and local and in-transit recurrence-free survival were compared by Kaplan-Meier analysis. Risk factors for worse survival were identified with Cox proportional hazard models. This analysis included 1,998 patients with tumor-negative SLN with a median follow-up of 70 months. Ulceration, Breslow thickness, nonextremity tumor location, and age ≥45 years were independent risk factors for worse disease-free survival and OS. Breslow thickness and ulceration were the only factors on multivariate analysis that predicted local and in-transit recurrence-free survival. Estimated 5-year OS rates ranged from 55.5 to 95.4% on the basis of the defined risk factors. There is a wide range of prognosis among patients with tumor-negative SLN. Breslow thickness, ulceration, age, and anatomic location of the primary melanoma are important independent factors predicting survival and recurrence among such patients. These factors can be used to stratify prognosis among patients with tumor-negative SLN to formulate rational long-term follow-up strategies as well as identify high-risk, SLN-negative patients for clinical trials of adjuvant therapy.

A miRNA-Based Signature Detected in Primary Melanoma Tissue Predicts Development of Brain Metastasis.

Brain metastasis is the major cause of mortality among patients with melanoma. A molecular prognostic test that can reliably stratify patients at initial melanoma diagnosis by risk of developing brain metastasis may inform the clinical management of these patients. We performed a retrospective, cohort-based study analyzing genome-wide and targeted microRNA expression profiling of primary melanoma tumors of three patient cohorts (n = 92, 119, and 45) with extensive clinical follow-up. We used Cox regression analysis to establish a microRNA-based signature that improves the ability of the current clinicopathologic staging system to predict the development of brain metastasis. Our analyses identified a 4-microRNA (miR-150-5p, miR-15b-5p, miR-16-5p, and miR-374b-3p) prognostic signature that, in combination with stage, distinguished primary melanomas that metastasized to the brain from nonrecurrent and non-brain metastatic primary tumors (training cohort: C-index = 81.4%, validation cohort: C-index = 67.4%, independent cohort: C-index = 76.9%). Corresponding Kaplan-Meier curves of high- versus low-risk patients displayed a clear separation in brain metastasis-free and overall survival (training: P < 0.001; P < 0.001, validation: P = 0.033; P = 0.007, independent: P = 0.021; P = 0.022, respectively). Finally, of the microRNA in the prognostic model, we found that the expression of a key lymphocyte miRNA, miR-150-5p, which is less abundant in primary melanomas metastatic to brain, correlated with presence of CD45(+) tumor-infiltrating lymphocytes. A prognostic assay based on the described miRNA expression signature combined with the currently used staging criteria may improve accuracy of primary melanoma patient prognoses and aid clinical management of patients, including selection for adjuvant treatment or clinical trials of adjuvant therapies.

Risk factors for recurrence after surgery in non-metastatic RCC with thrombus: a contemporary multicentre analysis.

To determine the predictors of post-surgical recurrence for patients with non-metastatic renal cell carcinoma (RCC) and venous thrombus. Records from consecutive patients with non-metastatic RCC with tumour thrombus, treated surgically between 2000 and 2012 at one of three centres, were reviewed. Univariable and multivariable analysis were used to evaluate the association of risk factors for post-surgical recurrence. A total of 465 patients with non-metastatic RCC were identified, including patients with thrombus present in the renal vein (257 patients, 55.3%), infrahepatic inferior vena cava (IVC; 144 patients, 31.0%) and suprahepatic IVC (64 patients, 13.8%). The median (interquartile range) follow-up was 28.3 (12.2-56.4) months, with metastatic RCC developing in 188 patients (40.5%). Independent predictors of recurrence included: body mass index ≤20 kg/m(2) (hazard ratio [HR] 2.66; 95% confidence interval [CI] 1.29-5.49), low preoperative haemoglobin (HR 1.54; 95% CI 1.07-2.20), perinephric fat invasion (HR 1.51; 95% CI 1.09-2.10), IVC thrombus height (HR 2.64; 95% CI 1.47-4.74), tumour diameter (HR 1.04 95% CI 1.00-1.09), nuclear grade (HR 1.56 95% CI 1.12-2.15) and non-clear-cell histology (HR 2.13; 95% CI 1.30-3.50). Independently predictive variables were used to create a recurrence model for three risk groups based on 0, 1-2, or >2 risk factors, respectively. The 5-year recurrence-free survival rate was significantly different in patients with favourable-risk (79.1%) compared with intermediate- (55.1%) or high-risk (22.1%) disease (P < 0.001). Seven risk factors for recurrence were identified for patients with non-metastatic RCC with thrombus, which can be used to select patients who may benefit from increased surveillance or adjuvant therapy clinical trials.

MP72-07 NOMOGRAM PREDICTING CANCER SPECIFIC MORTALITY (CSM) AFTER NEOADJUVANT CHEMOTHERAPY AND RADICAL CYSTECTOMY FOR MUSCLE-INVASIVE BLADDER CANCER (BC): RESULTS OF AN INTERNATIONAL CONSORTIUM

You have accessJournal of UrologyBladder Cancer: Invasive V1 Apr 2015MP72-07 NOMOGRAM PREDICTING CANCER SPECIFIC MORTALITY (CSM) AFTER NEOADJUVANT CHEMOTHERAPY AND RADICAL CYSTECTOMY FOR MUSCLE-INVASIVE BLADDER CANCER (BC): RESULTS OF AN INTERNATIONAL CONSORTIUM Maria Carmen Mir, Cesar Ercole, and Andrew Stephenson Maria Carmen MirMaria Carmen Mir More articles by this author , Cesar ErcoleCesar Ercole More articles by this author , and Andrew StephensonAndrew Stephenson More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2641AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Neoadjuvant chemotherapy with multi-agent cisplatin-based regimens for invasive bladder cancer is associated with improved all-cause and cancer-specific mortality from randomized trials. The post-chemotherapy pathological stage has previously been reported to be a major determinant of outcome. We endeavored to develop a postoperative nomogram for survival based on these and other parameters from an international consortium. METHODS Between the years 2000 and 2013, 1130 patients with cT2-4a N0 M0 carcinoma of the bladder were treated at 19 institutions in USA, Canada, and Europe. Standard chemotherapy regimens (MVAC, GC) and non-standard regimens were administered in 1020 (90%) and 110 (10%) patients, respectively. The median number of cycles received was 3 (IQR: 3-4). Using multivariable Cox regression analysis, we constructed a model to predict cancer-specific mortality RESULTS The overall 5-year CSM was 62% (95% CI, 58%-66%). Significant variables in the model were lymph node metastasis (p<0.001), pathological stage (p<0.001), positive surgical margins (p<0.001) and chemotherapy regimen (p=0.0106). The resultant nomogram was internally validated and had a concordance index of 0.76. According to pathological stage, the 5-year CSM was 84.5% (95%CI, 79%-89%) for pT0, 79.3% (95%CI, 72%-86%)for pTIS-T1, 70% (95%CI, 62%-80%) for pT2, 31% (95%CI, 25%-39%)for pT3-4a, and 20.8% (95%CI, 14%-28%)for pN1-3. CONCLUSIONS We have developed and validated a nomogram predicting CSM after neoadjuvant chemotherapy and radical cystectomy for invasive bladder cancer. The nomogram will be useful for patient counseling and in the identification of patients at high-risk for subsequent disease progression suitable for enrollment in clinical trials of adjuvant therapy. Chemo regimen: 1- MVAC; 2-GC; 3- Gem-Carboplatin © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e923 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Maria Carmen Mir More articles by this author Cesar Ercole More articles by this author Andrew Stephenson More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Adjuvant therapies for HIV-associated neurocognitive disorders.

ObjectiveHIV-associated neurocognitive disorder (HAND) is a frequent and heterogeneous complication of HIV, affecting nearly 50% of infected individuals in the combined antiretroviral therapy (cART) era. This is a particularly devastating statistic because the diagnosis of HAND confers an increased risk of HIV-associated morbidity and mortality in affected patients. While cART is helpful in the treatment of the more severe forms of HAND, there is a therapeutic gap in the milder forms of HAND, where cART is less effective. Multiple adjuvant therapies with various mechanisms of action have been studied (N-methyl D-aspartate [NMDA]-receptor antagonists, MAO-B inhibitors, tetracycline-class antibiotics, and others), but none have shown a clear positive effect in HAND. While this lack of efficacy may be because the appropriate therapeutic targets have not yet been determined, we aimed to discuss that study results may also influenced by clinical trial design.MethodsThis report is a systematic review of clinical trials of adjuvant therapies for HAND performed from January 1996 through June 2014.ResultsPossible drawbacks in study design, including lack of standardized case definitions, poorly defined target populations, inappropriate dose selection and measurable outcomes, and brief study durations may have masked true underlying mechanistic effects of previously investigated adjuvant therapies for HAND in specific patient populations.ConclusionsA proposal for streamlining and maximizing the likelihood of success in future clinical studies using a ‘learning and confirming’ investigational paradigm, incorporating stronger adaptive Phase I/II study designs, computerized modeling, and population/goal of treatment-specific Phase III clinical trials is presented.

SY11-2 - Adjuvant Chemotherapy for Resected Pancreatic Cancer: Focusing on the Jsap Study

Although approximately 20% of patients with pancreatic cancer (PC) undergo surgery, their prognosis is relatively poor, as most develop recurrences after resection. Adjuvant therapies have been used in attempts to improve the prognosis of these patients, but a consensus has not been established for many years. However, recently performed large-scale phase III studies, such as ESPAC-1 and CONKO-001, have revealed that adjuvant chemotherapy using 5-FU plus leucovorin or gemcitabine (GEM) improves the prognosis of PC patients after surgery. Furthermore, JASPAC-01, a phase III study conducted in Japan last year, has demonstrated that S-1 is superior to GEM for resected PC with respect to overall survival. Consequently, S-1 has become the standard adjuvant therapy for resected PC in Japan. In this presentation, we will review the latest information on clinical trials for adjuvant therapy and will report the results of studies conducted by our group (Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer: JSAP). We recently performed a phase I/II study (JSAP03) of GEM and S-1 combination (GS) therapy for resected PC and are presently conducting a phase III study (JSAP04) comparing GEM vs. GS therapy. Although GS therapy did not demonstrate a significant survival benefit in a phase III study for unresectable advanced PC (GEST), its application in an adjuvant setting may be more appropriate, as previous studies have demonstrated high response rates against PC.

PD16-04 CURATIVE SURGERY IN RCC WITH THROMBUS; A COMPREHENSIVE RISK MODEL FROM A MODERN MULTICENTER ANALYSIS

You have accessJournal of UrologyKidney Cancer: Localized I1 Apr 2014PD16-04 CURATIVE SURGERY IN RCC WITH THROMBUS; A COMPREHENSIVE RISK MODEL FROM A MODERN MULTICENTER ANALYSIS Tyler M. Bauman, Vitaly Margulis, Christopher G. Wood, William P. Christensen, Vishnukamal Golla, Ramy F. Youssef, Laura-Maria Krabbe, David F. Jarrard, Tracy M. Downs, and E. Jason Abel Tyler M. BaumanTyler M. Bauman More articles by this author , Vitaly MargulisVitaly Margulis More articles by this author , Christopher G. WoodChristopher G. Wood More articles by this author , William P. ChristensenWilliam P. Christensen More articles by this author , Vishnukamal GollaVishnukamal Golla More articles by this author , Ramy F. YoussefRamy F. Youssef More articles by this author , Laura-Maria KrabbeLaura-Maria Krabbe More articles by this author , David F. JarrardDavid F. Jarrard More articles by this author , Tracy M. DownsTracy M. Downs More articles by this author , and E. Jason AbelE. Jason Abel More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1149AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Recurrence is common in N0M0 patients with renal cell carcinoma (RCC) with venous thrombus after surgery. High risk patients may benefit from increased surveillance or enrollment in adjuvant clinical trials, but quality predictive models for recurrence are lacking for this patient population. The purpose of this study is to identify prognostic factors for disease recurrence in N0M0 RCC with venous thrombus using a multicenter contemporary dataset Methods Comprehensive patient data was collected for N0M0 RCC patients undergoing attempted curative surgery from 2000-2012 at the University of Wisconsin, UT Southwestern, and MD Anderson Cancer Center. Univariate and multivariate (MV) analysis was used to identify variables associated with risk of recurrence. Factors considered in analysis included: age, BMI, gender, smoking status, presence of local or systemic symptoms, year of surgery, laterality, preoperative labs (hemoglobin, creatinine, albumin, neutrophil count, lymphocyte count, ABO blood type), OR blood loss, receipt of blood transfusion, thrombus level, pT stage, tumor diameter, perinephric fat invasion, histologic subtype, and sarcomatoid de-differentiation. Results Of 470 patients identified, 191 (40.7%) progressed to metastatic disease during the study period. Thrombus extended into renal vein in 259 (55.1%), IVC below diaphragm 167 (35.5%) and IVC above diaphragm 44 (9.4%). Median CSS was 136.6 months (IQR 43.8-NR) and median follow-up was 28.4 months (IQR 12.2-54.9). After MV analysis, independent predictors of disease recurrence included: BMI ≤(HR 2.64, p=0.009), hemoglobin <LLN (HR 1.60, p=0.01), perinephric fat invasion (1.58, p=0.006), non-clear cell histology (2.02, p=0.008), and grade 4 (1.80; p=0.04). Independent predictors were used to create a risk factor model (figure). 5 year recurrence free survival (RFS) was 77% in patients with 0 risk factors compared to 19% in patients with more than 2 risk factors. Conclusions Independent predictors of disease recurrence in RCC with thrombus include: BMI ≤20, hemoglobin <LLN, perinephric fat invasion, non-clear cell histology, and grade 4. Patients with multiple risk factors should be considered for increased surveillance or adjuvant therapy clinical trials. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e487-e488 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Tyler M. Bauman More articles by this author Vitaly Margulis More articles by this author Christopher G. Wood More articles by this author William P. Christensen More articles by this author Vishnukamal Golla More articles by this author Ramy F. Youssef More articles by this author Laura-Maria Krabbe More articles by this author David F. Jarrard More articles by this author Tracy M. Downs More articles by this author E. Jason Abel More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Semiparametric regression analysis for time-to-event marked endpoints in cancer studies

In cancer studies the disease natural history process is often observed only at a fixed, random point of diagnosis (a survival time), leading to a current status observation (Sun (2006). The statistical analysis of interval-censored failure time data. Berlin: Springer.) representing a surrogate (a mark) (Jacobsen (2006). Point process theory and applications: marked point and piecewise deterministic processes. Basel: Birkhauser.) attached to the observed survival time. Examples include time to recurrence and stage (local vs. metastatic). We study a simple model that provides insights into the relationship between the observed marked endpoint and the latent disease natural history leading to it. A semiparametric regression model is developed to assess the covariate effects on the observed marked endpoint explained by a latent disease process. The proposed semiparametric regression model can be represented as a transformation model in terms of mark-specific hazards, induced by a process-based mixed effect. Large-sample properties of the proposed estimators are established. The methodology is illustrated by Monte Carlo simulation studies, and an application to a randomized clinical trial of adjuvant therapy for breast cancer.

Immunohistochemistry and fluorescence in situ hybridization assessment of HER2 in clinical trials of adjuvant therapy for breast cancer (NCCTG N9831, BCIRG 006, and BCIRG 005)

A comprehensive, blinded, pathology evaluation of HER2 testing in HER2-positive/negative breast cancers was performed among three central laboratories. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses were performed on 389 tumor blocks from three large adjuvant trials: N9831, BCIRG-006, and BCIRG-005. In 123 cases, multiple blocks were examined. HER2 status was defined according to FDA-approved guidelines and was independently re-assessed at each site. Discordant cases were adjudicated at an on-site, face-to-face meeting. Results across three independent pathologists were concordant by IHC in 351/381 (92 %) and FISH in 343/373 (92 %) blocks. Upon adjudication, consensus was reached on 16/30 and 18/30 of discordant IHC and FISH cases, respectively, resulting in overall concordance rates of 96 and 97 %. Among 155 HER2-negative blocks, HER2 status was confirmed in 153 (99 %). In the subset of 102 HER2-positive patients from N9831/BCIRG-006, primary blocks from discordant cases were selected, especially those with discordant test between local and central laboratories. HER2 status was confirmed in 73 (72 %) of these cases. Among 118 and 113 cases with IHC and FISH results and >1 block evaluable, block-to-block variability/heterogeneity in HER2 results was seen in 10 and 5 %, respectively. IHC−/FISH− was confirmed for 57/59 (97 %) primary blocks from N9831 (locally positive, but centrally negative); however, 5/22 (23 %) secondary blocks showed HER2 positivity. Among 53 N9831 patients with HER2-normal disease adjudicated as IHC−/FISH—(although locally positive), there was a non-statistically significant improvement in disease-free survival with concurrent trastuzumab compared to chemotherapy alone (adjusted hazard ratio 0.34; 95 % CI, 0.11–1.05; p = 0.06). There were similar agreements for IHC and FISH among pathologists (92 % each). Agreement was improved at adjudication (96 %). HER2 tumor heterogeneity appears to partially explain discordant results in cases initially tested as positive and subsequently called negative.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-013-2444-y) contains supplementary material, which is available to authorized users.

Update on Ophthalmic Oncology 2012: Advances in Retinoblastoma and Uveal Melanoma.

The purpose of this article was to review the major advances in both translational and clinical research in 2 diseases, retinoblastoma and uveal melanoma, from November 2011 through October 2012. Literature Review. A MEDLINE search was performed using the search terms "retinoblastoma" and "uveal melanoma." All relevant articles were reviewed, and articles with the most clinical relevance were reported. In retinoblastoma, new clinical data are emerging every year regarding the safety and efficacy of intra-arterial chemotherapy as well as other even newer modalities such as intravitreal chemotherapy. Globe salvage rates for eyes without vitreous seeding approach 100% and are increasing to 80% for those with seeds with new methods of treatment. In uveal melanoma, our understanding of the genetic pathways underlying this disease is improving each day and leading to the initiation of clinical trials for adjuvant therapy and metastatic disease. Ocular oncology is a small but dynamic field in which our knowledge is increasing every day. Exciting data emerged in the fields of both retinoblastoma and uveal melanoma this year.

Targeted Therapy; From Advanced Melanoma to the Adjuvant Setting

Targeted Therapy; From Advanced Melanoma to the Adjuvant Setting

Extranodal Extension Is a Powerful Prognostic Factor in Bladder Cancer Patients with Lymph Node Metastasis

BackgroundLymph node metastasis (LNM) is the most powerful pathologic predictor of disease recurrence after radical cystectomy (RC). However, the outcomes of patients with LNM are highly variable. ObjectiveTo assess the prognostic value of extranodal extension (ENE) and other lymph node (LN) parameters. Design, setting, and participantsA retrospective analysis of 748 patients with urothelial carcinoma of the bladder and LNM treated with RC and lymphadenectomy without neoadjuvant therapy at 10 European and North American centers (median follow-up: 27 mo). InterventionAll subjects underwent RC and bilateral pelvic lymphadenectomy. Outcome measurements and statistical analysisEach LNM was microscopically evaluated for the presence of ENE. The number of LNs removed, number of positive LNs, and LN density were recorded and calculated. Univariable and multivariable analyses addressed time to disease recurrence and cancer-specific mortality after RC. Results and limitationsA total of 375 patients (50.1%) had ENE. The median number of LNs removed, number of positive LNs, and LN density were 15, 2, and 15, respectively. The rate of ENE increased with advancing pT stage (p<0.001). In multivariable Cox regression analyses that adjusted for the effects of established clinicopathologic features and LN parameters, ENE was associated with disease recurrence (hazard ratio [HR]: 1.89; 95% confidence interval [CI], 1.55–2.31; p<0.001) and cancer-specific mortality (HR: 1.90; 95% CI, 1.52–2.37; p<0.001). The addition of ENE to a multivariable model that included pT stage, tumor grade, age, gender, lymphovascular invasion, surgical margin status, LN density, number of LNs removed, number of positive LNs, and adjuvant chemotherapy improved predictive accuracy for disease recurrence and cancer-specific mortality from 70.3% to 77.8% (p<0.001) and from 71.8% to 77.8% (p=0.007), respectively. The main limitation of the study is its retrospective nature. ConclusionsENE is an independent predictor of both cancer recurrence and cancer-specific mortality in RC patients with LNM. Knowledge of ENE status could help with patient counseling, clinical decision making regarding inclusion in clinical trials of adjuvant therapy, and tailored follow-up scheduling after RC.

How Do We Know When a Lymph Node Dissection is Adequate?

How do we know when a lymph node dissection is adequate? Like so many questions, the answer depends in part on who is asking. For our melanoma patients, the answer is pragmatic. Their node dissection is adequate if it fulfills the primary goals of the procedure of providing life-long regional disease control and accurate staging information— ideally with the lowest possible morbidity. Of course, this ‘‘answer’’ for an individual patient cannot readily be determined early on after surgery; only time will tell. For melanoma surgeons, as well as for our oncology colleagues evaluating patients for clinical trial eligibility, there are occasions when we must assess whether a lymph node dissection is adequate during the early postoperative period. Some adjuvant therapy clinical trials mandate a minimum number of nodes be removed, although this number is rarely evidence-based. A scenario surgical oncologists confront with some frequency is the need to assess the adequacy of a node dissection that yielded only a relatively small number of pathologically examined lymph nodes. Possible explanations: the node dissection was adequate and there were simply few lymph nodes in that patient; the dissection was adequate but the pathologic evaluation did not identify or enumerate every harvested node (most of which were likely small and tumor-free); or an inadequate node dissection was performed, leaving lymph nodes behind that ought to have been removed and raising the specter of an increased risk of regional recurrence and potentially underestimating the patient’s risk of distant metastasis. Increasingly, others besides the patient and the surgeon or oncologist are asking about the adequacy of surgery: quality assurance evaluations have become a fact of life for most clinicians, and an appropriate goal of these evaluations should be to identify surgeons who consistently fail to perform adequate surgeries and correct this through remedial education and mentoring or, failing that, restricted privileges. Finally, it is increasingly easy to envision a future where reimbursement for individual surgical procedures is tied to fulfillment of specific criteria that demonstrate its ‘‘adequacy.’’ Will we soon see reimbursement for lymph node dissections tied to removal of a minimum number of lymph nodes? In this issue of the Annals of Surgical Oncology, Spil

Adjuvant trials for pancreatic cancer: where are we going and what is needed?

The prognosis for pancreatic cancer remains poor and curative treatment currently involves multimodality therapy including resection. Effective systemic therapy regimens with or without radiation are needed; however, an optimal treatment paradigm is not clearly defined. Adjuvant therapy clinical trials are evaluating the potential benefit of targeted agents and the addition of radiation to systemic chemotherapy. Neoadjuvant treatments are also under investigation for resectable and borderline/potentially resectable tumors. Additional study goals include identification of patients at risk for pancreatic cancer and improvements in prediction and prognostication, which may lead to personalized treatment strategies. This article reviews data for neoadjuvant and adjuvant treatment for localized pancreatic adenocarcinoma and provides insight into the future evolution of treatment for patients with this deadly disease.

The Influence of Prognostic Factors and Adjuvant Chemoradiation on Survival After Pancreaticoduodenectomy for Ampullary Carcinoma

IntroductionThe prognosis after pancreaticoduodenectomy (PD) for ampullary carcinoma (AC) is superior to that of pancreatic cancer. Decisions regarding adjuvant therapy are influenced by factors such as nodal status, stage, and grade, but the influence of these individual variables on survival is unclear. MethodsA prospective tumor registry database was queried to identify patients who underwent PD for AC at Thomas Jefferson University between Jan 1997 and Apr 2009. The study was conducted with the approval of the institutional review board. Data were collected through review of hospital and departmental charts. Overall survival (OS) was analyzed using univariate and multivariate Cox proportional hazard models. The proportional hazard assumption was verified for the overall model and individual covariates. ResultsA total of 61 patients underwent PD for AC at our institution. There were five perioperative deaths (8.2%). Mean age was 70 years (62% male). Median survival time (MST) was 50 months for all patients. Only primary tumor stage, T1/T2 versus T3/T4 (American Joint Committee on Cancer Staging, version 6), was associated with OS in univariate analyses (p = 0.003). The association of nodal status with OS was borderline-significant (p = 0.08), with the MST being 84 months for node-negative and 17 months for node-positive patients. The remaining covariates were not predictors of OS. In the multivariate analysis, only primary tumor stage (HR, 5.1; p < 0.001) and age (HR, 1.04; p = 0.06), but not nodal status or adjuvant therapy, were associated with overall survival. ConclusionsAdvanced primary tumor stage and age were associated with inferior OS after PD for AC. Adjuvant therapy did not impact survival. Patients with advanced tumor stage should be considered for clinical trials of adjuvant therapy after PD with novel compounds and optimized radiation therapy strategies.

An Accurate, Clinically Feasible Multi-Gene Expression Assay for Predicting Metastasis in Uveal Melanoma

Uveal (ocular) melanoma is an aggressive cancer that often forms undetectable micrometastases before diagnosis of the primary tumor. These micrometastases later multiply to generate metastatic tumors that are resistant to therapy and are uniformly fatal. We have previously identified a gene expression profile derived from the primary tumor that is extremely accurate for identifying patients at high risk of metastatic disease. Development of a practical clinically feasible platform for analyzing this expression profile would benefit high-risk patients through intensified metastatic surveillance, earlier intervention for metastasis, and stratification for entry into clinical trials of adjuvant therapy. Here, we migrate the expression profile from a hybridization-based microarray platform to a robust, clinically practical, PCR-based 15-gene assay comprising 12 discriminating genes and three endogenous control genes. We analyze the technical performance of the assay in a prospective study of 609 tumor samples, including 421 samples sent from distant locations. We show that the assay can be performed accurately on fine needle aspirate biopsy samples, even when the quantity of RNA is below detectable limits. Preliminary outcome data from the prospective study affirm the prognostic accuracy of the assay. This prognostic assay provides an important addition to the armamentarium for managing patients with uveal melanoma, and it provides a proof of principle for the development of similar assays for other cancers.

Adjuvant interferon therapy after curative therapy for hepatocellular carcinoma (HCC): A meta-regression approach

Adjuvant anti-viral therapy after curative therapy for HCC has been studied extensively but the true clinical benefit and the predictors of efficacy remain unclear. MEDLINE, PubMed, and the Cochrane library were searched until December 2008, plus the meeting abstracts of the American Association for the Study of Liver Disease 2005-2008. Randomized trials and cohort studies were included if the studies (1) enrolled HCC patients who had underlying chronic viral hepatitis B or C and had undergone curative surgery or ablation therapy; (2) consisted of one or more treatment arms with interferon-based therapy and a control arm of no anti-viral therapy; and (3) included recurrence-free survival of HCC as an endpoint. Meta-analysis and meta-regression were done according to the Cochrane guidelines. Thirteen studies (9 randomized trials and 4 cohort studies, totally 1180 patients) were eligible for meta-analysis. Surgery and ablation therapy were used in 9 and 8 studies, respectively. All studies used conventional interferon (natural or recombinant) as anti-viral therapy. Overall, interferon improved the 1-year, 2-year, and 3-year recurrence-free survival by 7.8% (95% CI 3.7-11.8%), 35.4% (95% CI 30.7-40.0%), and 14.0% (95% CI 8.6-19.4%), respectively (all p<0.01). Lower percentage of patients with multiple tumors and use of ablation therapy were independent predictors for better treatment efficacy. The quantitative estimation of treatment efficacy and the identification of predictive factors in this study will help design future clinical trials of adjuvant therapy for HCC.