Risk Of Recurrence In Stage Research Articles

Reproducibility of colon tumor grade and relationship to recurrence in the context of clinical, pathologic, and genomic tumor features in 504 patients with stage II colon cancer treated with surgery alone at the Cleveland Clinic.

526 Background: High tumor grade is included in practice guidelines as a marker of higher recurrence risk in stage II colon cancer. Multiple systems for tumor grading exist, without a standardized approach. We characterize agreement of 2 methods for tumor grading and association with recurrence in the context of clinical, pathologic, and genomic tumor features including mismatch repair (MMR) and the 12-gene recurrence score (RS). Methods: Colon tumors were graded independently by 2 academic GI pathologists (P1, P2). Grade was defined by % tumor with gland-like structures: well (> 95%), moderately (50-95%) and poorly (< 50%) differentiated. P1 used this 3-tier system while P2 used 2-tier scheme with well and moderately differentiated tumors defined as low grade and poorly differentiated as high grade. All mucinous tumors were high-grade by P2 but not P1. Relationship to recurrence-free interval (RFI) was assessed by Cox regression. Results: Primary tumors from 504 stage II colon cancer treated with surgery alone were included. 18% (P1) and 31% (P2) were high grade. High grade tumors were more likely right-sided (≥ 60%) and MMR deficient (≥ 35%) for P1 and P2 (all p < 0.001). Proportion of mucinous tumors was similar for high and low grade by P1 (25% vs. 21%, p = 0.39). P2 high grade trended to lower recurrence (HR = 0.63, p = 0.10) while P1 grade was not associated w/ RFI (p = 0.46). In multivariate analyses including grade and RS, P2 high grade was associated with lower recurrence (p = 0.007) but P1 grade was not associated w/ RFI (p = 0.30). Neither grade was associated w/ RFI (p > 0.30) after controlling for RS, MMR, tumor location and mucinous histology. Using the two-tier scheme, agreement b/w the 2 pathologists was low (kappa = 0.30, 95% CI 0.21-0.39) in all pts and moderate if mucinous tumors were excluded (kappa = 0.52, 95% CI 0.40-0.64). Conclusions: High tumor grade was not found to be a marker of higher recurrence risk in stage II colon cancer. Other markers validated in stage II colon cancer, such as MMR and RS, should be considered. Interpathologist agreement on colon tumor grade is modest, even with central expert review. [Table: see text]

The PARSC trial: A prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint.

602 Background: Clinical trials have not yet shown convincingly if adjuvant chemotherapy is justified for stage II CC patients of whom 25% are at risk of recurrence. An 18-gene expression profile, ColoPrint, has been developed for identifying CC cancer patients more likely to develop recurrent disease and who would be candidates for adjuvant chemotherapy. The gene signature has been validated in independent cohorts of 206 CC patients and in in-silico datasets (Salazar et al, JCO in press). The profile classified 63.2% of the stage II patients (n=134) as low risk. The HR for relapse free survival (RFS) was 3.34 (p=0.017) with a 5-year RFS rate of 90.9% (95%CI, 84.0 -97.8%) for low risk patients and 73.9% (95%CI, 59.2-88.6%) for high risk patients. Moreover, the profile stratified patients independent of ASCO clinical risk factors. Methods: A prospective trial, PARSC (Prospective Study for the Assessment of Recurrence Risk in Stage II CC Patients Using ColoPrint) has been initiated. The main objectives are: (1) determine risk assessment by ColoPrint profile versus clinical parameters based on local protocol and ASCO high-risk recommendations in stage II patients; (2) establish proportion of ′good prognosis′ and ′poor prognosis profile′ in various countries; and (3) validate the power of risk assessment and compare performance of ColoPrint and clinical risk assessment in estimating 3 year relapse rate. Inclusion criteria: age ≥ 18 years, adenocarcinoma of the colon, stage II,no neoadjuvant systemic therapy, no synchronous tumors, fresh tumor sample, and written informed consent. The treatment of the patient is at the discretion of the physician. Results: The trial started in Sept. 2008 with currently 26 participating sites in 11 countries. So far, 223 stage II patients have been enrolled of whom 183 are eligible. 11 patients were rejected because of prior malignancies; 24 patients were rejected based on low tumor content of the sample (< 30% tumor cells), 3 patients had rectal cancer and 2 synchronous tumor. Conclusions: The aim is to enroll 600 stage II patients to differentiate between 3 year relapse- free survival predicted by ColoPrint versus clinical factors. [Table: see text]

GCC expression in lymph nodes (LNs) as a significant determinant of recurrence in stage II colon cancer (CC) patients (pts).

369 Background: A multi-center prospectively specified retrospective study Validating Indicators to Associate Recurrence (VITAR) is assessing the relationship between guanylyl cyclase C (GCC) gene expression in formalin fixed LNs and recurrence risk in stage II CC pts not treated with adjuvant chemotherapy. Here we report the preplanned initial analysis performed with 241 pts. Methods: GCC mRNA was quantified by RT-qPCR using FFPE LNs tissues from untreated stage II CC pts diagnosed from 1999-2006 with at least 10 LN examined blinded to clinical outcomes. Cox regression models examined the relationship between GCC nodal status and the prespecified primary endpoint of recurrence risk. Results: Twenty-ninepts (12%) had a disease recurrence or cancer death, median follow-up was 60 months and median LNs examined was 15. The ratio of the number of GCC+ LNs over the total number of informative LNs (LNR) significantly predicted higher recurrence risk for 84 pts classified as high risk (HR, 2.38; p=0.02). The estimated 5-yr recurrence rates were 10% and 27% for the low and high risk group, respectively. After adjusting for age, T stage, number of LNs assessed, and MMR status, the significant association remained (HR, 2.61; 95% CI, 1.17-5.83; p=0.02). In a subset of 181 pts with negative margin, T3 tumor only and ≥12 LN examined, the GCC LNR had a HR for recurrence of 5.06 (95% CI 1.61-15.91, p=0.003), translating into 5-yr recurrence rates of 4% among low risk pts and 27% for the high-risk group. Conclusions: Our results suggest that GCC expression in LNs is a significant determinant of recurrence in appropriately staged CC pts not treated with adjuvant chemotherapy. The validation component of the study is ongoing. [Table: see text] [Table: see text]

Specific activity of cyclin dependent kinase 1 as a novel predictor of recurrence risk in stage II colon cancer.

402 Background: Altered cell cycle dynamics and check points are typical features of solid tumors, and cyclin dependent kinases (CDKs) play pivotal roles in these processes. Previously we have demonstrated that CDK-based analysis, composed of CDK1 and CDK2, is useful in the prediction of outcomes in early breast cancer patients (Ann Oncol. 19(1):68-72, 2008, Br J Cancer. 100(3):494-500, 2009). Clinically, there is a need for risk stratification in patients with stage II colon cancer who have a recurrence risk of 20 to 30%. Therefore we investigated the use of CDK-based analysis for recurrence prediction of stage II colon cancer patients. Methods: Fresh frozen tissue samples of 254 patients with histologically confirmed adenocarcinoma of the colon, UICC stage II, who received primary tumor resection in Munich (217 cases), and Leiden (37 cases) were used. Protein expression and activity of CDK1 and CDK2 were determined by in vitro assays as previously described. Specific activity (SA) of CDKs was calculated as kinase activity in relation to its corresponding mass concentration. Results: Development of distant metastasis was observed in 27 patients (10.6%) after a median follow up of 86 months. We found that predictive performance of CDK1SA, but not CDK2SA, for the metastasis was substantial and almost constant for long-term event prediction (average area under the curve (AUC) = 0.69). Tumor recurrence risk analysis in association with CDK1SA identified a low- (41% of population) and high- risk group (59%). Cox proportional hazard model analysis retained the CDK-based patient classification as an independent prognostic factor for distant metastases-free survival (low vs. high-risk group: Hazard ratio = 6.2, 95% CI: 1.45 to 26.9, p=0.0049). Clinical parameters such as grading, T-categories, age, and sex were excluded as confounding factors for CDK1SA-risk. Conclusions: CDK1SA allows stratification of different risk subgroups of stage II colon cancer patients. CDK1SA-based analysis is useful for predicting patients with high risk of distant recurrence, who should be treated with chemotherapy. No significant financial relationships to disclose.

The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint.

The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint.

Abstract 846: Clinical relevance of lymph node evaluation in Stage II and III colon cancers

Abstract Background: Although evaluation of at least 12 lymph nodes is recommended for accurate staging of colon cancer patients, there is still inconsistency in what constitutes adequate lymph node harvest. Methods: We studied 521 colon cancer patients to assess the impact of the current guidelines of collecting at least 12 lymph nodes on cancer-specific survival and recurrence within 2 years after surgery, after adjustment for chemotherapy status, age, race, and tumor size and grade. In addition, patients were placed into categories of 1-6, 7-11, 12-19 and ≥ 20 lymph nodes harvested to evaluate the minimum number required for adequate staging of Stage II and III colon cancer patients. Also, in Stage III patients, the probability of finding lymph node metastases with respect to these quartiles was analyzed. Results: Extraction of 12 lymph nodes as the cut-off point was not significantly associated with colon cancer mortality either in Stage II (HR = 0.66; 95% CI, 0.43-1.02) or Stage III (HR = 0.77; 95% CI, 0.53-1.11) patients. In Stage II and III patients, compared with category 1-6 lymph nodes harvested, collection of ≥20 lymph nodes had a 57% (Stage II, HR = 0.43; 95% CI, 0.23-0.83) and a 43% (Stage III, HR = 0.57; 95% CI, 0.32-1.00) decreased risk of mortality. Although statistically not significant, increased harvest of lymph nodes, especially ≥20 lymph nodes, was associated with reduced risk of recurrence in Stage II (HR = 0.41; 95% CI, 0.16-1.06) but not in Stage III patients (HR = 1.19; 95% CI, 0.47-3.02). For Stage III patients, linear regression analysis demonstrated, for every 8 additional lymph nodes collected, a 13% increased probability of finding a positive lymph node (parameter estimate=0.12601, p< 0.0001). Logistic regression was utilized to obtain the probability of obtaining ≥4 positive lymph nodes (pN2). Patients with 1-6 lymph nodes extracted had a 31% (predictive probability (PP) =0.309) chance of having a tumor with pN2 stage. Patients with 7-11 and 12-19 nodes extracted had similar probabilities, at 35% (PP=0.352) and 37% (PP=0.367), respectively. Patients with ≥ 20 lymph nodes extracted had a 45% chance (PP=0.454) of having a pN2 tumor. Conclusions: These findings suggest that extraction of a minimum of twelve lymph nodes has not provided a useful cut-off point in determining accurate pathologic staging. For Stage III patients, harvest of every eight additional lymph nodes resulted in identification of a single positive node and the probability of finding a pN2 patient also increased with increasing numbers of lymph nodes harvested. Thus, to minimize stage misclassification, and to improve patient survival, emphasis should be on collection of as many lymph nodes as possible. These studies were supported by NCI/NIH grants, R03-CA139629, U54-CA118948, and R01-CA098932-01. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 846.

Phase II Clinical Trial of Postoperative S‐1 Monotherapy for Gastric Cancer Patients with Free Intraperitoneal Cancer Cells Detected by Real‐Time RT‐PCR

We have previously reported the molecular detection of peritoneal micrometastases in patients with gastric cancer by quantifying carcinoembryonic antigen (CEA) mRNA in the peritoneal washes. Patients with CEA mRNA exceeding a cutoff value have a significant risk for developing peritoneal carcinomatosis, but optimal treatment for this population remains unknown. CEA mRNA (+) patients with gastric cancer were treated postoperatively with S-1 monotherapy. Overall survival, the primary endpoint of this phase II trial, was compared with the historical control, which is comprised of CEA mRNA (+) patients who were not given postoperative chemotherapy. A total of 32 patients with CEA mRNA (+) gastric cancer were enrolled. Twelve patients (37.5%) relapsed; ten showed peritoneal relapse. Three-year survival was similar between the study population and the historical control (67.3% vs. 67.1%, respectively). S-1 monotherapy, which significantly reduced risk for recurrence in stage II/III gastric carcinoma in another phase III trial, seems not to be as effective in eradicating free cancer cells in the abdominal cavity.

Uterine papillary serous carcinoma: State of the state

Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer that is likely to present with deep myometrial invasion and lymph vascular involvement. By the time most affected women are diagnosed, the UPSC has spread outside the uterus. Because many reports include patients who are not completely staged, the risk of recurrence in stage I patients has likely been overestimated. Recently, several large series of well-staged patients have demonstrated that survival in stage I patients is similar to that of poorly differentiated endometrioid tumors. Because of the high risk of extrauterine spread, all patients with UPSC should have an extended surgical staging procedure, including lymphadenectomy and omentectomy. Chemotherapy with or without local or regional radiation is probably the most effective adjuvant therapy in both early and advanced disease. Because patients with stage I UPSC are still at significant risk of recurrence, adjuvant therapy is often recommended for all patients. It has been difficult to conduct prospective randomized trials for patients with UPSC because of the rare nature of these cancers.

Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer

BackgroundIdentifying molecular markers for tumor recurrence is critical in successfully selecting patients with stage III colon cancer who are more likely to benefit from adjuvant chemotherapy. The present study analyzed a subset of 10 polymorphisms within eight genes involved in the tumor angiogenesis pathway and their impact on prognosis in stage III colon cancer patients treated with adjuvant chemotherapy. Patients and methodsBlood samples were obtained from 125 patients with locally advanced colon cancer at University of Southern California medical facilities. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR–restriction fragment length polymorphism and 5′-end [γ-33P] ATP-labeled PCR protocols. ResultsPolymorphisms in vascular endothelial growth factor (VEGF) (C+936T; P = 0.003, log-rank test) and interleukin-8 (IL-8) (T-251A; P = 0.04, log-rank test) were independently associated with risk of recurrence in stage III colon cancer patients. In combined analysis, grouping alleles into favorable versus nonfavorable alleles, high expression variants of VEGF C+936T and IL-8 T-251A were associated with a higher likelihood of developing tumor recurrence (P < 0.001). ConclusionHigh expression variants of VEGF C+936T and IL-8 T-251A were associated with shorter time to tumor recurrence, indicating that the analysis of angiogenesis-related gene polymorphisms may help to identify patient subgroups at high risk for tumor recurrence.

Serous Tubal Intraepithelial Carcinoma: Its Potential Role in Primary Peritoneal Serous Carcinoma and Serous Cancer Prevention

A diagnosis of primary peritoneal serous carcinoma (PPSC) requires exclusion of a source in other reproductive organs. Serous tubal intraepithelial carcinoma (STIC; stage 0) has been described in asymptomatic women with BRCA mutations and linked to a serous cancer precursor in the fimbria. This study examined the frequency of STIC in PPSC and its clinical outcome in BRCA-positive women. Presence or absence of STIC was recorded in consecutive cases meeting the 2001 WHO criteria for PPSC, including 26 patients with nonuniform sampling of the fallopian tubes (group 1) and 19 patients with complete tubal examination (group 2; sectioning and extensively examining the fimbriated end, or SEE-FIM protocol). In selected cases, STIC or its putative precursor and the peritoneal tumor were analyzed for p53 mutations (exons 1 to 11). Outcome of STIC was ascertained by literature review. Thirteen (50%) of 26 PPSCs in group 1 involved the endosalpinx, with nine STICs (35%). Fifteen (79%) of 19 cases in group 2 contained endosalpingeal involvement, with nine STICs (47%). STIC was typically fimbrial and unifocal, with variable invasion of the tubal wall. In five of five cases, the peritoneal and tubal lesion shared an identical p53 mutation. Of 10 reported STICs in BRCA-positive women, all patients were without disease on follow-up. The fimbria is the source of nearly one half of PPSCs, suggesting serous malignancy originates in the tubal mucosa but grows preferentially at a remote peritoneal site. The generally low risk of recurrence in stage 0 (STIC) disease further underscores STIC as a possible target for early serous cancer detection and prevention.

Use of polymorphisms in interleukin-1β (IL-1β) and IL-1 receptor antagonist (IL-1Ra) to predict tumor recurrence in stage II colon cancer

4138 Background: Identifying molecular markers for tumor recurrence is critical in successfully selecting patients with stage II colon cancer who are more likely to benefit from adjuvant chemotherapy. IL-1β and IL1-receptor antagonist (IL-1Ra) have been shown to play a critical role in the early initiation of tumor associated angiogenesis. In vitro and in vivo studies have shown that inhibition of the IL-1 receptor in IL-1β overexpressing tumors limits tumor angiogenesis and invasiveness. In this retrospective study, we tested whether 7 functionally significant polymorphisms within 5 genes (IL-1β, IL-1Ra, IL-8, CXCR1, CXCR2) in the chemokine family will predict the risk of tumor recurrence in stage II colon cancer patients treated with adjuvant chemotherapy. Methods: Between 1986 and 2007 blood specimens from 106 patients (median age of 60 years; range: 22–86) were obtained at the University of Southern California medical facilities. All patients were diagnosed with high-risk stage II colon cancer and wer...

A Clinical Model to Estimate Recurrence Risk in Resected Stage I Non-Small Cell Lung Cancer

There are no reliable markers to predict recurrence in resected Stage I non-small cell lung cancer (NSCLC). A validated clinical model to estimate the risk of recurrence would help select patients for adjuvant therapy. We reviewed the medical records of 715 patients who had a potentially curative resection for Stage I NSCLC at our institution from 1990 to 2000. Recurrence rates were estimated by the Kaplan-Meier method. A model to estimate risk of recurrence was developed by combining independent risk factors. With a median follow-up of 4.7 years, the 5-year survival rates for Stages IA and IB were 66% and 55% respectively, and 5-year recurrence rates were 19% and 30%, respectively. Four factors were independently associated with tumor recurrence: tumor size >3 cm (hazard ratio [HR] = 2.4), surgery other than lobectomy (HR = 2.0), nonsquamous histology (HR = 1.4), and high-grade cellular differentiation (HR = 1.4). A scoring system for recurrence was developed by assigning 2 points for each major risk factor (tumor size and surgery) and 1 point for each minor risk factor (histologic subtype and cellular grade). Scores were grouped as low (0-1), intermediate (2-3), and high (>3), yielding 5-year estimates of risk of recurrence of 14%, 27%, and 43%, respectively. This model, based upon readily available clinicopathologic characteristics, can estimate the risk of recurrence in Stage I NSCLC, independent of T classification. This model could be used to select patients for adjuvant therapy if validated in independent data sets.

VEGF and VEGF receptor-2 (VEGFR2) gene polymorphisms predict tumor recurrence in stage II and III colon cancer

4004 Background: Despite recent advances in the treatment of metastatic colorectal cancer, tailoring adjuvant treatment of stage II and III colon cancer patients remains controversial. Identifying a reliable panel of prognostic and predictive markers for tumor recurrence is critical in selecting an individualized and tailored chemotherapy. Tumor angiogenesis plays an important role in tumor development, progression and metastasis. In this retrospective study, we tested whether a specific pattern of 40 functionally significant polymorphisms in 37 genes involved in angiogenesis and tumor microenvironment will predict the risk of tumor recurrence in stage II and III colon cancer patients treated with adjuvant chemotherapy. Methods: Between 1999 and 2006 blood specimens from 140 patients (69 females and 71 males with a median age of 59 years; range=28–86) were obtained at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC). Sixty-three patients had stage II and 77 had stage III colon cancer. The median follow-up was 5.4 years (range=2.0–16.8). 51 of 140 patients (36.4%) developed tumor recurrence with a 5-year probability of 0.28 ± 0.06 for stage II and 0.40 ± 0.06 for stage III colon cancer patients. Genomic DNA was extracted from peripheral blood and genotypes were determined using PCR based RFLP. Results: Polymorphisms in VEGF (C936T; p=0.009, log-rank) and VEGFR2 (+4422 AC- repeat; p=0.04, log-rank and +1416 T/A; p=0.0009, log-rank) were associated with risk of tumor recurrence in stage III colon cancer patients (n=77). VEGFR2 AC-repeat polymorphisms were additionally associated with risk of recurrence in Stage II colon cancer patients (n=63, p=0.02, log-rank). Conclusion: VEGF C936T and VEGFR2 (+4422 AC-repeat and +1416 T/A) polymorphisms may help to identify Stage II and III colon cancer patients who are at increased risk for developing tumor recurrence. Angiogenesis seems to play a crucial role in tumor recurrence, thus targeting VEGF and VEGFR2 may be of clinical benefit for stage II and stage III colon cancer patients. Large prospective trials are needed to validate these preliminary data. No significant financial relationships to disclose.

Prognostic role of VEGF, EGFR, COX-2, cERB-b2 and ER-alpha in stage 1 non-small cell lung cancers

7696 Introduction: Five-year survival rates for pathologic stage one NSCLC are between 57–67%. We looked at VEGF, EGFR, COX-2, cERB-b2 and ER-a in relationship to predicting recurrence. Methods: Tumors from 65 consecutive patients with stage I NSCLC were included. After marking representative areas on the slides, tissue microarrays were prepared and stained immunohistochemically using commercially available antibodies. The scoring was done by the pathologist and the principal investigator and is calculated as the product of staining intensity, the percentage of positively stained tumor cells and extent of membrane involvement. Results: 27 (42%) males/38 (58%) females. 75% stage IA/25% stage IB. Median smoking history was 40 pack-years (range 0–160pyr). 77% adenocarcinomas/23% squamous cell carcinomas. 19 (29%) patients had a recurrence of which 14 (74%) recurred locally and 5 (26.%) recurred at distant sites. The most common site of recurrence was the lung. Median time to recurrence was 30 months (range 4–97 mos). Scores for the molecular markers are reported in table 1 . Logistic regression of all the variables on multivariate analysis showed that VEGF scores predicted recurrence (p=0.021, Odds Ratio of 1.021). Scores of &gt;200 for VEGF were even more discriminatory. (p =0.034, Odds Ratio of 7.22). The rate of recurrence in this subgroup of patients was 39.5% as opposed to a rate of 14.8% among those with scores of less than 200. EGFR, COX-2, cERB-B2 and ER alpha were not found to be significant predictors of recurrence. Table 1 . Univariate analysis: Conclusion: VEGF scores predict risk of recurrence in stage I Non Small Cell Lung Cancers. We propose the use of high scores of VEGF, in Stage I Non Small Cell Carcinoma using immunohistochemistry to select those patients who are likely to recur. No significant financial relationships to disclose. [Table: see text]

Adherence to surveillance guidelines following curative resection for stage II and III colorectal cancer

4051 Background: The risk of disease recurrence in stage II and III colorectal cancer (CRC) patients (pts) following curative resection underscores the need for post-operative surveillance. However, there is continual controversy as to whether an intensive or conservative strategy is more appropriate. Our aims were to determine adherence in the ‘real world‘ to ASCO guidelines on CRC surveillance and to evaluate differences in practice patterns and outcomes between an academic instituation, Princess Margaret Hospital (PMH), and a community cancer center, Credit Valley Hospital (CVH). Methods: Stage II and III CRC pts diagnosed between 1999 and 2001 were identified from hospital cancer registries. Surveillance practices and outcomes in the first 5 years of follow-up were retrospectively reviewed. Results: A total of 244 and 97 pts were identified at PMH and CVH, respectively: 80 stage II and 119 stage III colon cancers (CC), and 66 stage II and 76 stage III rectal cancers (RC). Median age at diagnosis was 61.8 years. Surveillance patterns over a 5-year period, adherence to ASCO guidelines and comparisons between hospitals were tabulated (see table ). There were a total of 70 CRC recurrences: 53/244 (22%) at PMH and 17/97 (18%) at CVH. Among them, 53 (76%) were detected by surveillance (44 PMH, 9 CVH) and 17 (24%) by symptoms (9 PMH, 8 CVH). For recurrences detected by surveillance, 20/53 (38%) were resectable, whereas only 3/17 (18%) of those detected by symptoms were resectable. Of the 20 resectable recurrences detected by surveillance, 40% were CC and 60% were RC; CT scan was the method of detection in 55% of cases, and sites of recurrence included liver (7), lung (6), local (5), and nodes (2). Conclusions: CRC surveillance revealed significant departures from ASCO guidelines with a large academic institution employing a more intensive surveillance strategy with imaging than a community cancer center. Surveillance was associated with a higher proportion of resectable tumor recurrences than detection by symptoms. [Table: see text] No significant financial relationships to disclose.

5‐aminolaevulinic acid‐induced fluorescence cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1 bladder cancer

To assess the influence of 5-aminolaevulinic acid-induced fluorescence cystoscopy (FC) during transurethral resection (TUR) on the recurrence rate and the length of tumour-free interval in stage Ta/T1 transitional cell carcinoma (TCC) of the urinary bladder. In all, 122 patients with primary or recurrent stage Ta/T1 bladder TCC treated with TUR were enrolled in a prospective randomized study. In group A the TUR was performed with standard white-light endoscopy, and in group B with FC. The patients were followed using standard cystoscopy and urinary cytology. The recurrence-free interval was evaluated in whole groups, for single and multiple, and for primary and recurrent tumours separately. At the time of the first cystoscopy (10-15 weeks after TUR) tumour recurrence was detected in 23 of 62 patients (37%) in group A, but only in five of 60 patients (8%) in group B. The recurrence-free survival rates in group A were 39% and 28% after 12 and 24 months, compared to 66% and 40% respectively in group B (P = 0.008, log-rank test). In separate analyses, the recurrence-free survival rates were significantly higher using FC in multiple (P = 0.001) and in recurrent (P = 0.02) tumours. In solitary and primary tumours the median time to recurrence was also longer in group B, but the difference was not statistically significant. 5-aminolaevulinic acid-induced FC during TUR reduces the recurrence rate in stage Ta/T1 bladder TCC. The most significant benefit is in patients with multiple and recurrent tumours.

Wilms’ tumor management

The management of Wilms' tumor continues to evolve with two different approaches being taken by the National Wilms Tumor Study in North America and the International Society of Pediatric Oncology in Europe in regards to preoperative chemotherapy. Limiting the duration, dosage, and number of chemotherapeutic agents and the dosage of radiotherapy are common goals in both trials. Contralateral exploration of unilateral tumors will no longer be recommended in future National Wilms Tumor Studies. Percutaneous biopsy for tissue diagnosis is quite accurate, but there are concerning complications with its use. Partial nephrectomy is successful for low risk unilateral Wilms tumor, but its indications remain controversial. The surgical complication rate was similar between the National Wilms Tumor Study and the International Society of Pediatric Oncology, but intraoperative tumor spill was higher in the North American trials. Doxorubicin decreased the risk of recurrence in stage III tumors by 50%, and its current dose is not associated with late congestive heart failure. For selected patients, shorter courses of vincristine/dactinomycin or vincristine alone show equivalent results compared to current regimens. A longer course of chemotherapy (including doxorubicin) for clear cell sarcoma improves recurrence-free survival. Patients with Wilms' tumor, aniridia, major genitourinary malformations, and mental retardation, the WAGR syndrome, have a 50% chance of unexplained end-stage renal disease 20 years after treatment. Less aggressive means of diagnosis and treatment for Wilms' tumor are continuing to achieve very good cure rates while lowering long term morbidity for low risk patients. High-risk patients with unfavorable histology or the WAGR syndrome benefit from more intensive treatment and long-term follow-up.

From gene expression patterns to IHC diagnostics: Discovery and validation of novel biomarkers for prediction of recurrence in non-small cell carcinoma of the lung (NSCLC)

9509 Background: Gene expression data has revealed that lung cancer cases can be divided into biologically distinct groups with differing outcomes. We generated novel antibodies targeted by gene expression data to develop an IHC-based diagnostic test stratifying early stage lung cancer. Methods: Several hundred novel affinity-purified rabbit anti-peptide antisera were screened by IHC for robust differential staining of NSCLC cases. A selected panel of 43 were tested on tissue arrays which contained 329 paraffin block cores from NSCLC patients diagnosed at CCIH from 1989 to 2002 (mean follow-up of 3.3 years). Univariate analysis was used to identify reagents with an association with outcome. This subset of reagents was then used in Cox proportional hazard and regression tree analysis to build models for prediction of early recurrence. These predictor algorithms were validated by 10-fold cross-validation and on tested on an independent set of 84 Stage III/IV NSCLC patients. Results: 15 individual reagents showed an association with early or delayed recurrence (p<0.1). Algorithms using a panel of eight antibodies identified patients at high risk of recurrence in Stage I/II NSCLC (p<0.01). This algorithm was dependent upon first classifying patients as adenocarcinoma or squamous cell carcinoma which could be performed either by morphology assessment or antibody staining pattern. The predictive power of these models was confirmed on a cohort of Stage III/IV NSCLC patients at the UAB Comprehensive Cancer Center (p<0.05). Conclusions: Novel subtypes of lung cancer associated with poor outcome are distinguished by a panel of IHC antisera. These reagents should prove useful for patient stratification in care of early stage lung cancer patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Applied Genomics Applied Genomics

Variación del valor pronóstico de la proteína p53 en relación con el estadio tumoral en pacientes con adenocarcinoma colorrectal

To analyze the prognostic value of p53 protein as a marker of recurrence risk in each tumoral stage. A prospective study of a cohort of 288 patients who underwent surgery for colorectal adenocarcinoma was performed. Stage 1 of the tumor-node-metastasis (TNM) classification was found in 42 patients (14.6%), stage II in 144 (50%) and stage III in 102 (35.4%). Histopathological variables were examined in tumor samples fixed in formol and embedded in paraffin and p53 (DO7 antibody) and proliferative cell nuclear antigen (PC-10 antibody) proteins were determined using immunohistochemistry. The results of p53 were analyzed in each of the categories of clinical and histopathological variables. Recurrence-free survival was calculated using the Kaplan-Meier method. The value of each variable as a predictive marker for tumoral recurrence was analyzed using Cox regression analysis. Hazard ratios and 95% confidence intervals were calculated as indicators of relative risk. The analysis was applied to the whole cohort and was subsequently repeated in each TNM tumoral stage separately. Tumors with p53 protein overexpression more frequently recurred and showed lower recurrence-free survival at 5 years. However, the association between p53 expression and postoperative outcome was statistically significant in stage III tumors only. In this subgroup of patients, recurrence-free survival at 60 months was 60% in p53-negative tumors and was 26% in p53-positive tumors (p=0.010). In the multivariate analysis, p53 was an independent prognostic factor associated with a high risk of recurrence in stage III tumors (hazard ratio=2.76; 95% CI, 1.29-5.9; p=0.009). Overexpression of p53 showed prognostic value as a marker of high risk of recurrence in the form of metastases (hazard ratio=2.23; 95% CI, 1.04-4.75), but not as a prognostic marker of locoregional recurrence. No relationship was found between the state of p53 protein and the effect of postoperative adjuvant therapy. The p53 protein does not have the same prognostic value in all tumoral stages. This protein is only predictive of high recurrence risk in the subgroup of patients with stage III tumors.

Adjuvant Intraperitoneal 5-Fluorouracil in High-Risk Colon Cancer

To evaluate the results of a prospective multicenter randomized study of adjuvant intraperitoneal 5-fluorouracil (5-FU) administered during 6 days shortly after resection of stages II and III colon cancers. Systemic adjuvant chemotherapy improves the survival of patients with stage III colon cancer receiving treatment for 6 months. Intraperitoneal chemotherapy theoretically combines peritoneal and hepatic effects. After resection, 267 patients were randomized into two groups. Patients in group 1 (n = 133) underwent resection followed by intraperitoneal administration of 5-FU (0.6 g/m2/day) for 6 days (day 4 to day 10). These patients also received intravenous 5-FU (1 g) during surgery. Patients in group 2 underwent resection alone (n = 134). In group 1, 103 patients received the total dose, 18 received a partial dose as a result of technical or tolerance problems, and 12 did not receive the chemotherapy. Rates of surgical death and complications were similar in both groups. Tolerance to treatment was excellent or fair in 97% of the patients and poor in 3%. After a median follow-up of 58 months, 5-year overall survival rates were 74% in group 1 and 69% in group 2; disease-free survival rates were 68% and 62%, respectively. Survival curves were superimposed until 3 years after treatment and began diverging thereafter. Among patients receiving the full treatment, the 5-year disease-free survival rate was improved in the treatment group in patients with stage II cancers but was unchanged in patients with stage III cancers. Chemotherapy with intraperitoneal 5-FU administered during a short period after surgery was well tolerated but was not sufficient to reduce the risk of death significantly. However, it reduced the risk of recurrence in stage II cancers. These results suggest that it should be associated with systemic chemotherapy to reduce both local and distant recurrences.