Stage Disease-specific Survival Research Articles

The impact of adjuvant radiation therapy on disease-specific survival in stage I and II Merkel cell carcinoma: A SEER database analysis.

9593 Background: Merkel Cell Carcinoma (MCC) is a rare, cutaneous neuroendocrine tumor associated with poor prognosis. Adjuvant radiation therapy (RT) is commonly used for the treatment of locoregional disease, but the impact on survival remains controversial. Previous studies from the Survival, Epidemiology, and End Results (SEER) database have shown an overall survival benefit to adjuvant RT without controlling for important prognostic differences in comparison groups such as age. To better control for these variables, we examined the impact of postoperative adjuvant radiation therapy on stage I and II disease-specific survival using the SEER database. Methods: SEERStat was used to obtain and analyze the outcomes of 2423 histologically confirmed MCC patients treated with surgery monotherapy or surgery with postoperative radiation therapy between 2004 and 2020 in the 17-registry (November 2021) SEER database. We compared the 5-year disease-specific survival (DSS) between the surgery monotherapy and adjuvant RT groups for stage I (n=1697) and stage II (n=726) MCC patients. Results: Patients treated with surgery and adjuvant RT were younger than those who received surgery monotherapy (median age 72 versus 77, respectively). Adjuvant RT was not associated with an increase in disease-specific survival. In contrast, adjuvant RT was associated with a statistically significant decrease in 5-year DSS among stage I patients (82.8% for those treated with RT versus 87.5% for those treated with surgery monotherapy, p = 0.023). Additionally, RT was not associated with a significant increase in DSS among stage II patients (77.0% versus 74.4% for patients treated with surgery monotherapy, p=0.490). Conclusions: This study demonstrates that there is no statistically significant disease-specific survival benefit from adjuvant radiation therapy for stage I and II MCC in the SEER database. Interestingly, in stage I patients we find a significant negative association between adjuvant RT and DSS. Younger patients are more likely to receive adjuvant RT, which likely contributes to higher overall survival previously reported from the SEER database, but the explanation for decreased DSS in patients who received RT remains unclear. Further studies regarding the effect of radiation therapy on local disease control and tumor microenvironment are needed to establish the appropriate role of RT in stage I-II MCC patients. [Table: see text]

RNA expression-based risk stratification of stage III cutaneous melanoma.

e21551 Background: Prognostication of locally advanced cutaneous melanoma (CM) relies on accurate assessment of primary tumor invasion depth and extent of lymph node involvement. However, precision is often limited by detection limits of positron emission computed tomography and sentinel lymph node biopsy, and the estimated disease-specific survival (DSS) can vary widely. In this study, we explored tumor gene expression-based risk stratification strategies and found that CDH1 (E-cadherin) and BRAF transcript level profiles can predict DSS in stage III CM. Methods: The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) project’s normalized RNA-Seq transcriptome profile (n = 288) was analyzed with MATLAB software. TCGA-SKCM adopted AJCC 7th edition staging. "High” or “low” level of each gene was determined by the median FPKM of the cohort used as cutoff. P-values were obtained from Cox proportional hazards regression model. Results: In stage III (n = 96), 3-year DSS for high- and low-CDH1 groups were 45% and 75%, respectively (p = 1.5x10-5). High-BRAF group was weakly associated with superior 3-year DSS compared to low-BRAF group (75% vs. 55%; p = 0.06), although high-BRAF group was composed of more BRAF hotspot mutants compared to low-BRAF group (56% vs. 30%). The 3-year DSS for high-CDH1/low-BRAF and low-CDH1/high-BRAF groups were 28% and 84%, respectively (p = 4.4x10-5). Composition of stages [IIIA, IIIB, IIIC, IIINOS] in high-CDH1/low-BRAF and low-CDH1/high-BRAF groups were [5%, 18%, 45%, 32%] and [23%, 13%, 37%, 27%], respectively. For high-CDH1/high-BRAF group, 3-year DSS was 54% with stage composition [6%, 33%, 39%, 22%]. DSS was not associated with CDH1/BRAF levels in stage I and II. Stage IV was not analyzed due to the small sample size. Conclusions: We demonstrate CDH1/BRAF transcript level-based prognostication of CM cases with regional metastasis (metastatic node, in-transit or satellite metastasis) defined as stage III. Our findings are contrary to the notion that CDH1 is a tumor/invasion suppressor gene, although we note the emerging evidence that CDH1 expression boosts establishment of cancer at a secondary site once they escape from the primary site1). The association between high BRAF level and superior survival may also seem counterintuitive given the well-accepted oncogenicity of activating BRAF mutations in variety of malignancies. However, we speculate that wild-type and oncogenic BRAF, which RNA-Seq cannot easily differentiate, may play independent roles in tumorigenesis similar to what has been previously reported in wild-type and oncogenic RAS2).

Younger patients with colorectal cancer may have better long-term survival after surgery: a retrospective study based on propensity score matching analysis

BackgroundThe relationship between postoperative long-term prognosis and age in colorectal cancer patients remains controversial. The purpose of this study based on a Chinese CRC cohort is to determine the disparity in long-term survival outcomes between younger and older colorectal cancer (CRC) patients after surgery using a propensity score matching (PSM).MethodsData for this study was derived from the CRC cohort of the Database from Colorectal Cancer (DACCA) at West China Hospital of Sichuan University from January 2007 to September 2022. The long‑term prognoses were compared between younger and older groups.ResultsA total of 2374 CRC patients were evaluated in this study, including 1039 older patients and 1335 younger ones. After 1:1 ratio PSM, each group contained 784 CRC patients. There was no significant difference in baseline information after PSM (p < 0.05). Multivariate analysis showed that younger age was an independent predictor of better overall survival (OS) (p < 0.001, HR = 1.750, 95% CI = 1.407–2.177) and disease-specific survival (DSS) (p < 0.001, HR = 1.718, 95% CI = 1.369–2.157). In terms of different tumor pathological stages after PSM, in comparison to older group, younger group had better OS in stage II (p < 0.001), stage III (p = 0.0085), and stage IV (p = 0.0014) and better DSS in stage II (p = 0.0035), stage III (p = 0.0081), and stage IV (p < 0.001).ConclusionYounger CRC patients have better prognosis than older CRC patients after surgery, especially, and have better OS and DSS in stages II, III, and IV CRC. Younger CRC patient may gain greater benefit from CRC resection and combined therapy. As for the cut-off age, it may be determined by a specific model suitable for local patients.

A prognostic six-gene expression risk-score derived from proteomic profiling of the metastatic colorectal cancer secretome.

The necessity to accurately predict recurrence and clinical outcome in early stage colorectal cancer (CRC) is critical to identify those patients who may benefit from adjuvant chemotherapy. Here, we developed and validated a gene‐based risk‐score algorithm for patient stratification and personalised treatment in early stage disease based on alterations in the secretion of metastasis‐related proteins. A quantitative label‐free proteomic analysis of the secretome of highly and poorly metastatic CRC cell lines with different genetic backgrounds revealed 153 differentially secreted proteins (fold‐change >5). These changes in the secretome were validated at the transcriptomic level. Starting from 119 up‐regulated proteins, a six‐gene/protein‐based prognostic signature composed of IGFBP3, CD109, LTBP1, PSAP, BMP1, and NPC2 was identified after sequential discovery, training, and validation in four different cohorts. This signature was used to develop a risk‐score algorithm, named SEC6, for patient stratification. SEC6 risk‐score components showed higher expression in the poor prognosis CRC subtypes: consensus molecular subtype 4 (CMS4), CRIS‐B, and stem‐like. High expression of the signature was also associated with patients showing dMMR, CIMP+ status, and BRAF mutations. In addition, the SEC6 signature was associated with lower overall survival, progression‐free interval, and disease‐specific survival in stage II and III patients. SEC6‐based risk stratification indicated that 5‐FU treatment was beneficial for low‐risk patients, whereas only aggressive treatments (FOLFOX and FOLFIRI) provided benefits to high‐risk patients in stages II and III. In summary, this novel risk‐score demonstrates the value of the secretome compartment as a reliable source for the retrieval of biomarkers with high prognostic and chemotherapy‐predictive capacity, providing a potential new tool for tailoring decision‐making in patient care.

Abstract 31: Favorable impact of higher environmental temperature on clinical outcomes in breast cancer - Does residence matter? A NCDB and SEER population-based study

Abstract Background: Murine tumor models show that cold stress increases tumor growth rate by norepinephrine release, altering the tumor microenvironment (TME). Tumor-bearing mice when housed at standard temperature of 22°Celsius (°C) exhibited a pro-tumorigenic TME (with fewer CD8+ T Cells and an increase in immunosuppressive cells) than mice housed at 30°C. The incidence of cancer has been shown to be higher in colder climates. Achievement of pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for early stage breast cancer (BC) is associated with improved overall survival (OS) and disease specific survival (DSS). Based on these findings, we hypothesized that pCR would be increased while mortality would be decreased in BC patients (pts) living in warmer climates. Methods: A retrospective, population-based analysis was conducted utilizing the Surveillance, Epidemiology and End Results (SEER) from 1996-2017 and National Cancer Database (NCDB) from 2004-2018, and average annual temperature (AAT) data from the National Centers for Environmental Information. Cut-offs for AAT were obtained using the Youden’s index (for pCR) and maximum log-rank (for OS and DSS) methods. Associations between AAT and both pCR and OS/DSS were evaluated using logistic and Cox regression models, respectively, adjusting for confounders (age, race, education, insurance, BC subtype, treatment). Results: A total of 1,209,332 and 270,496 stage I-III BC pts in the US were analyzed using NCDB and SEER, respectively. In NCDB, 52.1% were hormone receptor (HR)+/HER2-, 8.6% triple negative (TNBC), 7.2% HR+/HER2+ and 3.1% HR-/HER2+ and 29% unknown. 37.7% received chemotherapy, 62.6% radiation and 94.3% surgery. 10.2% pts received NAC and 19.5% (19,021/97,669) achieved pCR. The AAT ranged from 44.7°Fahrenheit (°F) to 62.3°F with median 50.9°F. When adjusting for covariates, pts in regions with AAT &amp;gt; 60.9°F, had a greater chance of achieving pCR compared to AAT &amp;lt; 60.9°F with odds ratio (OR) 1.12 (95% CI 1.07-1.18), p &amp;lt;0.001. This was consistent in the TNBC and HR-/HER2+ subgroups with OR 1.14 (95% CI 1.07-1.23) and 1.15 (95% CI 1.04-1.27), respectively. There was a 2% improvement in OS with every 5°F increment, HR 0.98 (95% CI 0.97-0.99), p &amp;lt; 0.001. In SEER, 22.4% were HR+/HER2-, 4.4% TNBC, 4.0% HR+/HER2+, 1.8% HR-/HER2+ and 68.5% unknown. 43.4% received chemotherapy, 49.7% radiation and 94.2% surgery. The AAT ranged from 33.6°F to 67.3°F with median 57.4°F. There was a 3% improvement in OS [HR 0.97 (95% CI 0.968-0.977), p &amp;lt; 0.001] and 2.5% improvement in DSS [HR 0.98 (95% CI 0.968-0.982), p&amp;lt;0.001] with every 5°F increment. Conclusions: Higher environmental temperatures are associated with significant improvements in rate of pCR, OS and DSS in Stage I-III BC pts. Research focusing on underlying mechanisms and therapeutic strategies to abrogate this disparity is warranted. Citation Format: Ashish Gupta, Kristopher Attwood, Kush Gupta, Asha Gandhi, Stephen Edge, Kazuaki Takabe, Elizabeth Repasky, Shipra Gandhi. Favorable impact of higher environmental temperature on clinical outcomes in breast cancer - Does residence matter? A NCDB and SEER population-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 31.

A novel morphology-based risk stratification model for stage I uterine leiomyosarcoma: an analysis of 203 cases

AbstractUterine leiomyosarcoma is the most common uterine mesenchymal malignancy. The majority present at stage I, and clinical outcomes vary widely. However, no widely accepted risk stratification system for stage I uterine leiomyosarcoma is currently available. We studied 17 routinely evaluated clinicopathologic parameters in 203 stage I uterine leiomyosarcoma from three institutions to generate a novel risk stratification model for these tumors. Mitoses >25 per 2.4 mm2 (10 high-power fields), atypical mitoses, coagulative necrosis, lymphovascular invasion, and serosal abutment were significantly associated with disease-free and disease-specific survival in univariate and multivariate analyses. These prognostic parameters were each scored as binary (“yes” or “no”) variables and fitted to a single optimized algebraic risk model:Risk score = (coagulative necrosis)(1) + (mitoses > 25 per 2.4 mm2)(2) + (atypical mitoses)(2) + (lymphovascular invasion)(3) + (serosal abutment)(5)By logistic regression, the risk model was significantly associated with 5-year disease-free (AUC = 0.9270) and 5-year disease-specific survival (AUC = 0.8517). Internal and external validation substantiated the model. The continuous score (range, 0–13) was optimally divided into 3 risk groups with distinct 5-year disease-free and disease-specific survival: low risk (0–2 points), intermediate risk (3–5 points), and high risk (6–13 points) groups. Our novel risk model performed significantly better than alternative uterine leiomyosarcoma risk stratification systems in predicting 5-year disease-free and disease-specific survival in stage I tumors. A simplified risk model, omitting terms for serosal abutment and lymphovascular invasion, can be accurately applied to myomectomy or morcellated specimens. We advocate routine application of this novel risk model in stage I uterine leiomyosarcoma to facilitate patient counseling and proper risk stratification for clinical trials.

High expression of miR-17-5p and miR-20a-5p predicts favorable disease-specific survival in stage I-III colon cancer

In many types of cancer, microRNAs (miRs) are aberrantly expressed. The aim of this study was to explore the prognostic impact of miR-17-5p and miR-20a-5p in colon cancer. Tumor tissue from 452 stage I-III colon cancer patients was retrospectively collected and tissue microarrays constructed. miR-17-5p and miR-20a-5p expression was evaluated by in situ hybridization and analyzed using digital pathology. Cell line experiments, using HT-29 and CACO-2, were performed to assess the effect of miR-17-5p and miR-20a-5p over expression on viability, invasion and migration. In multivariate analyses, high miR-17-5p expression in tumor (HR = 0.43, CI 0.26–0.71, p < 0.001) and high expression of miR-20a-5p in tumor (HR = 0.60, CI 0.37–0.97, p = 0.037) and stroma (HR = 0.63, CI 0.42–0.95, p = 0.027) remained independent predictors of improved disease-specific survival. In cell lines, over expression of both miRs resulted in mitigated migration without any significant effect on viability or invasion. In conclusion, in stage I-III colon cancer, high expression of both miR-17-5p and miR-20a-5p are independent predictors of favorable prognosis.

CEA-Ki-67- Pathologic Subtype: An Adjunct Factor for Refining Prognosis in Stage I Pulmonary Adenocarcinoma.

ObjectivesThe prognosis for stage I pulmonary adenocarcinoma is generally good. However, some patients with stage I pulmonary adenocarcinoma have an unexpectedly poor outcome. This warrants consideration of adjunct markers. In this study, we analyze carcinoembryonic antigen, Ki-67, and a pathologic subtype in combination for prognostic evaluation of stage I pulmonary adenocarcinoma. These factors were selected for study as they have been shown to be individually associated with prognosis in many studies.MethodsA total of 650 patients with stage I pulmonary adenocarcinoma were investigated retrospectively. Each patient was re-staged using standard TNM criteria. Carcinoembryonic antigen (CEA) values were obtained from preoperative blood samples, and Ki-67 was evaluated with tumor tissue immunohistochemistry. Patient clinicopathologic characteristics, survival status, and date of death were obtained from medical records and telephone follow-up.ResultsCEA > 4.4 ng/ml, Ki-67 > 13%, and a solid-micropapillary tumor growth pattern were each independent adverse prognostic markers for 5-year disease specific survival in stage I pulmonary adenocarcinoma. However, in combination, these 3 factors yielded a prognostic value (designated “CEA-Ki-67-pathologic subtype” value). Stage I pulmonary adenocarcinoma of low-risk CEA-Ki-67-pathologic subtype (CKP) value show biologic behavior similar to TNM stage IA1 tumors, while stage I tumors of high-risk CKP value are similar in prognosis to TNM stage II.ConclusionThe CKP value may be used as an adjunct to the TNM classification, which may yield a more accurately defined prognosis for cases of stage I pulmonary adenocarcinoma. CKP value may identify patients at higher risk who may benefit from adjuvant chemotherapy. Conversely, lower risk CKP values may support avoidance of chemotherapy.

Stage I-IV Colorectal Cancer Prognosis Can Be Predicted by Type and Number of Intratumoral Macrophages and CLEVER-1+ Vessel Density.

Simple SummaryTumor-associated macrophages can either promote or prevent cancer growth depending on factors such as macrophage polarization status, tumor type, and disease stage. Macrophages and vessels interact with each other, and the number of lymphatic vessels also affects cancer survival. CLEVER-1 is a protein expressed both on immunosuppressive M2 macrophages and lymphatic vessels. The aim of this study was to validate our previous results regarding the prognostic role of CLEVER-1+ macrophages, CD68+ macrophages, and CLEVER-1+ lymphatic vessels in stage I–IV colorectal cancer. The results indicate that the prognostic role of tumor-associated macrophages and lymphatic vessels changes during disease progression. The findings resemble our earlier results, but are not completely equal, which may be due to the different types of tumor samples used in the two studies (whole section vs. tissue microarray).Macrophages, which are key players in the tumor microenvironment and affect the prognosis of many cancers, interact with lymphatic vessels in tumor tissue. However, the prognostic role of tumor-associated macrophages (TAM) and lymphatic vessels in human colorectal cancer (CRC) remains controversial. We investigated the prognostic role of CD68+ and CLEVER-1+ (common lymphatic endothelial and vascular endothelial receptor 1) TAMs in addition to CLEVER-1+ lymphatic vessels in 498 stage I–IV CRC patients. The molecular markers were detected by immunohistochemical (IHC) analysis. The results showed that, in early stage I CRC and in young patients (age below median, ≤67.4 years), a high number of CD68+ and CLEVER-1+ TAMs was associated with longer disease-specific survival (DSS). In early stage I CRC, high intratumoral CLEVER-1+ lymphatic vessel density (LVD) predicted a favorable prognosis, whereas the opposite pattern was observed in stage II CRC. The highest density of CLEVER-1+ lymphatic vessels was found in metastatic disease. The combination of intratumoral CLEVER-1+ lymphatic vesselhigh + CD68+ TAMlow was associated with poor DSS in stage I–IV rectal cancer. The present results indicate that the prognostic significance of intratumoral macrophages and CLEVER-1+ lymphatic vessels differs according to disease stage, reflecting the dynamic changes occurring in the tumor microenvironment during disease progression.

Abstract 2096: A deep learning system to predict disease-specific survival in stage II and stage III colorectal cancer

Abstract Accurate prognosis in colorectal cancer can have important implications for clinical management. Here, we develop a deep learning system (DLS) to first identify invasive cancer and then directly predict disease specific survival (DSS) for stage II and stage III colorectal cancer using only digitized histopathology whole-slide images. The DLS was trained using slides from 1173 stage II and 1266 stage III cases (18,304 total slides) and was evaluated on a held-out test set of 601 stage II and 638 stage III cases (9,340 total slides). The area under the receiver operating characteristic curve (AUC) for 5-year DSS prediction was 68.0 for stage II (95% CI 62.2-73.1) and 65.5 for stage III (95% CI 61.1-70.0). For stage II, 5-year DSS was 64% for DLS-predicted high-risk cases versus 89% for DLS-predicted low-risk cases (upper and lower risk quartiles; p&amp;lt;0.001, log rank test). For stage III, 5-year DSS was 35% for DLS-predicted high-risk cases versus 66% for DLS-predicted low-risk cases (upper and lower risk quartiles; p&amp;lt;0.001, log rank test). In a multivariable Cox model, the DLS prediction remained significantly associated with DSS after adjusting for T-category, N-category, age, gender, tumor grade, and lymphovascular invasion (stage II: adjusted hazard ratio 1.55, 95% CI 1.33-1.81, p&amp;lt;0.0001; stage III: adjusted hazard ratio 1.35, 95% CI (1.21-1.51), p&amp;lt;0.0001). Finally, a combined proportional-hazards model using the DLS along with baseline clinicopathologic information provided better risk prediction than the DLS or baseline information alone, increasing 5-year AUC over the baseline-only model by 8.9 points (95% CI 3.9-13.6) and 5.3 points (95% CI 2.3-8.4) for stages II and III, respectively. Taken together, these findings demonstrate that the DLS provides significant prognostic value and risk stratification in both stage II and stage III colorectal cancer, and can be combined with known risk features to further improve prognostic accuracy. This represents novel work to train a DLS to directly predict patient outcomes using whole-slide images and weakly supervised learning. The ability to use non-annotated slides as input has important implications for possible clinical applications and the features learned by the model may also help to identify new prognosis-associated morphologic factors in colorectal cancer. Additional work is ongoing to confirm the utility of these findings, such as validation in additional datasets and interpretability experiments to better understand the features learned by the DLS for these predictions. Citation Format: Ellery Wulczyn, David F. Steiner, Melissa Moran, Markus Plass, Robert Reihs, Heimo Mueller, Apaar Sadhwani, Yuannan Cai, Isabelle Flament, Po-Hsuan Cameron Chen, Yun Liu, Martin C. Stumpe, Zhaoyang Xu, Kurt Zatloukal, Craig H. Mermel. A deep learning system to predict disease-specific survival in stage II and stage III colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2096.

CDX2 Loss With Microsatellite Stable Phenotype Predicts Poor Clinical Outcome in Stage II Colorectal Carcinoma.

Current risk factors in stage II colorectal carcinoma are insufficient to guide treatment decisions. Loss of CDX2 has been shown to associate with poor clinical outcome and predict benefit for adjuvant chemotherapy in stage II and III colorectal carcinoma. The prognostic relevance of CDX2 in stage II disease has not been sufficiently validated, especially in relation to clinical risk factors, such as microsatellite instability (MSI) status, BRAF mutation status, and tumor budding. In this study, we evaluated the protein expression of CDX2 in tumor center and front areas in a tissue microarrays material of stage II colorectal carcinoma patients (n=232). CDX2 expression showed a partial or total loss in respective areas in 8.6% and 10.9% of patient cases. Patients with loss of CDX2 had shorter disease-specific survival when scored independently either in tumor center or tumor front areas (log rank P=0.012; P=0.012). Loss of CDX2 predicted survival independently of other stage II risk factors, such as MSI status and BRAF mutation status, pT class, and tumor budding (hazard ratio=5.96, 95% confidence interval=1.55-22.95; hazard ratio=3.70, 95% confidence interval=1.30-10.56). Importantly, CDX2 loss predicted inferior survival only in patients with microsatellite stable, but not with MSI-high phenotype. Interestingly, CDX2 loss associated with low E-cadherin expression, tight junction disruption, and high expression of ezrin protein. The work demonstrates that loss of CDX2 is an independent risk factor of poor disease-specific survival in stage II colorectal carcinoma. Furthermore, the study suggests that CDX2 loss is linked with epithelial-to-mesenchymal transition independently of tumor budding.

Novel Internationally Verified Method Reports Desmoplastic Reaction as the Most Significant Prognostic Feature For Disease-specific Survival in Stage II Colorectal Cancer.

Multiple histopathologic features have been reported as candidates for predicting aggressive stage II colorectal cancer (CRC). These include tumor budding (TB), poorly differentiated clusters (PDC), Crohn-like lymphoid reaction and desmoplastic reaction (DR) categorization. Although their individual prognostic significance has been established, their association with disease-specific survival (DSS) has not been compared in stage II CRC. This study aimed to evaluate and compare the prognostic value of the above features in a Japanese (n=283) and a Scottish (n=163) cohort, as well as to compare 2 different reporting methodologies: analyzing each feature from across every tissue slide from the whole tumor and a more efficient methodology reporting each feature from a single slide containing the deepest tumor invasion. In the Japanese cohort, there was an excellent agreement between the multi-slide and single-slide methodologies for TB, PDC, and DR (κ=0.798 to 0.898) and a good agreement when assessing Crohn-like lymphoid reaction (κ=0.616). TB (hazard ratio [HR]=1.773; P=0.016), PDC (HR=1.706; P=0.028), and DR (HR=2.982; P<0.001) based on the single-slide method were all significantly associated with DSS. DR was the only candidate feature reported to be a significant independent prognostic factor (HR=2.982; P<0.001) with both multi-slide and single-slide methods. The single-slide result was verified in the Scottish cohort, where multivariate Cox regression analysis reported that DR was the only significant independent feature (HR=1.778; P=0.002) associated with DSS. DR was shown to be the most significant of all the analyzed histopathologic features to predict disease-specific death in stage II CRC. We further show that analyzing the features from a single-slide containing the tumor's deepest invasion is an efficient and quicker method of evaluation.

Association of obesity with survival in patients with endometrial cancer

BackgroundObesity confers an overall increased risk for development of endometrial cancer. However there are conflicting reports regarding the effect of obesity on patients' overall and disease specific survival. The purpose of this study was to evaluate the effect of obesity on survival in women with endometrial cancer. MethodsAfter IRB approval, records of women with diagnosis and treatment of endometrial cancer from 1999 to 2016 were abstracted for histopathological, treatment and demographic data. Death was confirmed by query of the Social Security Death Index. Kaplan Meier survival curves and Cox regression modeling was performed with Stata version 14.0. ResultsOf 1732 evaluable patients, there were significant differences in age at diagnosis, histology (endometrioid versus non-endometrioid), stage, race, grade, hypertension, hyperlipidemia, diabetes, and treatment between normal weight, overweight, obese, and morbidly obese patients (p < 0.01). There was a linear association of younger age at diagnosis with increasing obesity (p < 0.01) R2 = 0.04. Younger age, endometrioid histology, lower stage, and statin use were independently associated with decreased hazard of death (p < 0.01). However, in stratified analysis of non-endometrioid histologies, patients with Stage 3 and 4 disease over the age of 65 showed a survival benefit for women associated with obesity (p = 0.02). ConclusionsObesity is associated with younger age at diagnosis and earlier stage disease. Obesity is associated with improved disease specific survival for stage 3 and 4 non-endometrioid endometrial cancers.

Long-term survival outcome and failure pattern after intensity-modulated radiotherapy for nasopharyngeal carcinoma

Objective To analyze the 10-year survival outcome and failure patterns for patients with nasopharyngeal carcinoma (NPC) after intensity-modulated radiotherapy (IMRT), aiming to provide reference for optimized treatment for NPC. Methods Clinical data of 866 patients with NPC receiving IMRT from January 2001 to December 2008 were retrospectively analyzed. Survival analysis was performed using the Kaplan-Meier estimator. Univariate analysis was carried out by log-rank test and multivariate analysis was performed using Cox proportional hazards model. Results The median follow-up time was 132 months. The 10-year local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS) and disease specific survival (DSS) were 92.0%, 83.4%, 75.7% and 78.6%, respectively. A total of 210 patients died including 124 patients (59.0%) from distant metastasis, which was the primary cause of death, and 47(22.3%) from local regional recurrence. Independent negative factors of DSS included age>50 years (P=0.00), LDH≥245 IU/L (P=0.00), Hb 20 cm3(P=0.00). The 10-year LRFS, DMFS and DSS of stage Ⅱ NPC patients did not significantly differ after IMRT alone and chemoradiotherapy (P=0.83, 0.22, 0.23). For patients with stage Ⅲ NPC, the 10-year LRFS and DSS in the chemoradiotherapy arm were significantly higher than those in the IMRT alone (P=0.01, 0.01), whereas no statistical significance was observed in the DMFS between two groups (P=0.14). The overall survival of stage Ⅳa+ Ⅳb NPC patients is relatively poor. Conclusions IMRT can improve the long-term survival of NPC patients. Distant metastasis is the primary failure pattern. Patients with stage Ⅰ-Ⅱ NPC can obtain satisfactory survival outcomes after IMRT alone. The addition of chemotherapy can further enhance the LRFS and DSS of stage Ⅲ NPC patients. However, the optimal therapeutic strategy remains to be urgently investigated for stage Ⅳa+ Ⅳb NPC patients. Key words: Nasopharyngeal neoplasms/intensity-modulated radiotherapy; Failure pattern; Prognosis

Preoperative Tumor Markers Independently Predict Survival in Stage III Gastric Cancer Patients: Should We Include Tumor Markers in AJCC Staging?

The aim of this study was to determine the prognostic significance of preoperative carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 levels in patients with resectable gastric cancer (GC). Patients who underwent a radical resection for GC at the Fujian Medical University Union Hospital between 2007 and 2014 were included in this study. The estimated area under the curve (AUC) was compared to evaluate the discriminatory ability of tumor makers. Additional external validation was performed using a dataset from Sun Yat-sen University Cancer Center. Preoperative CEA/CA19-9 levels were identified as an independent predictor of overall survival (OS) and disease-specific survival (DSS) (both p < 0.05) in the development group. In a subgroup analysis based on TNM stage, preoperative CEA/CA19-9 levels clearly stratified the survival rates for stage III GC (p < 0.05). A multivariate analysis revealed that preoperative CEA/CA19-9 levels were an independent prognostic factor (p < 0.05) in stage III; the AUC of the preoperative CEA/CA19-9 was equivalent to that of T stage. A prediction model (TNMC) for stage III GC was developed by incorporating preoperative CEA/CA19-9 levels into the American Joint Committee on Cancer (AJCC) staging system. The AUC of the TNMC was significantly higher than that of the TNM staging system at 1, 3, and 5years postoperatively (all p < 0.05), with similar results also being obtained in the external validation set. Preoperative CEA/CA19-9 levels are an independent predictor of OS and DSS in stage III GC patients. The inclusion of preoperative CEA/CA19-9 levels in AJCC TNM staging provided an optimal prognosis in stage III GC.

Tumor mitotic rate is an independent predictor of survival for nonmetastatic melanoma

BackgroundTumor mitotic rate is a known prognostic variable in Stage I melanoma; however, its importance is unclear in Stages II and III. MethodsPatients diagnosed with nonmetastatic cutaneous melanoma from 2010 to 2014 were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry. ResultsOf a total of 71,235 patients, the majority were white (94.7%), male (58.5%), and had a Stage I tumor (79.0%). On univariable analysis, 5-year disease-specific survival decreased with each increasing tumor mitotic rate category of 0–3, 4–10, and >10 mitoses/mm2 (Stage I 98.3%, 90.9%, 79.7%; Stage II 86.1%, 74.2%, 72.9%; and Stage III 72.5%, 58.6%, 49.7%). In multivariable models, tumor mitotic rate as both a continuous and categorical variable was associated with disease-specific survival for Stages I–III melanoma. Each unit increase in tumor mitotic rate increased the risk of death by 23% in Stage I, 5% in Stage II, and 3% in Stage III. Compared with the 0–3 tumor mitotic rate category, the risk of disease-specific mortality increased for tumors in the 4–10 and >10 categories for Stage I (RR 3.07 and 6.74, P < .0001), Stage II (RR 1.37 and 1.62, P = .0002), and Stage III (RR 1.24 and 1.35, P = .0004). ConclusionIn this cohort study, tumor mitotic rate is an independent predictor of survival for localized melanoma.

Radiation therapy improves disease-specific survival in women with Stage II endometrioid endometrial cancer—Brachytherapy may be sufficient

PurposeTo evaluate disease-specific survival (DSS) outcomes in Stage II endometrioid endometrial cancer (EC) patients based on pathology and treatment information including adjuvant radiotherapy and lymph node assessment. Methods and MaterialsUsing the Surveillance, Epidemiology, and End Results database, 2877 patients with Stage II EC diagnosed between 2004 and 2012 treated with radiation were identified. DSS was determined for different modalities of radiation. Kaplan–Meier estimates of survival and Cox regression modeling were used to explore the risk associated with various factors on DSS. ResultsThe 4-year DSS for the study population was 90%. Radiation was associated with improved 4-year DSS when compared to no radiotherapy (p = 0.03). Patients with Grade 2 and 3 tumors had improved 4-year DSS with radiation (94% vs. 90%, p = 0.02 and 81% vs. 73%, p = 0.15), respectively, but no differences in DSS when vaginal brachytherapy alone was compared with external beam alone or both. Patients with Grade 2 (p = 0.002) and Grade 3 (p < 0.001) tumors without a lymph node dissection (LND) had worse DSS compared to patients with any LND. Patients with Grade 3 tumors without an LND who received radiation showed improved DSS (p = 0.008). Multivariable analysis revealed that age >60 years (p < 0.001), Grade 3 (p < 0.001), no radiotherapy (p = 0.05), and no LNDs (p < 0.001) were significant prognostic factors for worse DSS. ConclusionsAdjuvant radiation, whether delivered by brachytherapy or external beam radiation, is associated with improved DSS in Stage II EC patients with high-grade tumors, therefore brachytherapy may be sufficient.

The Patterns of Practice and Outcomes of Penile Cancer in Ontario

AimsPenile cancer is a rare malignancy in Western countries. The management guidelines are mainly derived from retrospective studies as there are no randomised trials. The primary objective of this study was to assess patterns of practice and outcomes of penile squamous cell carcinoma in Ontario. Secondary objectives included examining trends in incidence, pathological characteristics and prognostic factors. Materials and methodsAll patients diagnosed with penile cancer between 2000 and 2010 were identified from the Ontario Cancer Registry and all available pathology reports related to penile cancer during this period were reviewed. ResultsPathology reports of 419 new cases of penile squamous cell carcinoma were reviewed. There was a significant improvement in completeness of the pathology reports in recent years. The age-adjusted incidence was 0.9 per 100 000 person-years. Most patients presented with a pT1 lesion (63%). A partial penectomy (40%) was the most common surgical procedure. Over 38% of patients identified to be eligible for organ-sparing surgery had a total or partial penectomy. Only 23% of the eligible patients identified to require lymph node dissection underwent the procedure. The 5 year disease-specific survival for stage 0, I, II, III were 94%, 93%, 74% and 52%, respectively. ConclusionsThere is a significant variation in the patterns of practice in Ontario. A large proportion of patients in this cohort were probably overtreated for the primary malignancy and undertreated for the regional nodes.

Prognostic Factors for Overall and Disease-specific Survival of Stage I Non-Small-Cell Lung Cancer after Stereotactic Body Radiotherapy: A Retrospective Analysis

Prognostic Factors for Overall and Disease-specific Survival of Stage I Non-Small-Cell Lung Cancer after Stereotactic Body Radiotherapy: A Retrospective Analysis

Variation in Delayed Time to Adjuvant Chemotherapy and Disease-Specific Survival in Stage III Colon Cancer Patients.

There is a paucity of literature quantifying the extent to which time to adjuvant chemotherapy for stage III colon cancer patients varies between individual surgeons, medical oncologists, and hospitals. A retrospective cohort study was conducted by merging the New York State Cancer Registry with the Statewide Planning & Research Cooperative System and Medicare claims to identify stage III colon cancer patients from 2004 to 2009 who underwent resection and received adjuvant chemotherapy. Multilevel logistic regression models characterized variation in delayed time to adjuvant chemotherapy (>8weeks vs.≤8weeks). Multilevel competing-risks Cox proportional hazards models assessed the effect of delayed time to adjuvant chemotherapy on disease-specific survival. The proportion of delayed time to adjuvant chemotherapy was 36% in 1133 patients treated by 516 surgeons and 351 medical oncologists at 163 hospitals. After controlling for case-mix, the majority of the clustering variation (72%) in delayed time to adjuvant chemotherapy is attributed to differences between medical oncologists. Risk-adjusted surgeon-specific, medical oncologist-specific, and hospital-specific probabilities of delayed time to adjuvant chemotherapy ranged from 30 to 38, 17 to 59, and 27 to 43%, respectively. Delayed time to adjuvant chemotherapy was associated with disease-specific survival (hazard ratio [HR]1.24, 95% confidence interval [CI]1.07-1.45). These findings suggest there is substantial variation in time to adjuvant chemotherapy among stage III colon cancer patients. Reasons for delays may be due to system factors that influence individual providers to make varying decisions on the time of initiation. Future research should identify what these factors may be and how to address them to promote better delivery of care.