Benefit Of Chemotherapy In Stage Research Articles

Overuse and Limited Benefit of Chemotherapy for Stage II Colon Cancer in Young Patients

BackgroundFew studies have confirmed a benefit for adjuvant chemotherapy (aCTX) in stage II colon cancer. We used the National Cancer Database to explore the use and efficacy of aCTX in patients with both normal-risk (NR) and high-risk (HR) young stage II colon cancer. Patients and MethodsWe identified patients with stage II colon cancer who underwent colectomy between 2010 and 2015. HR patients included at least: lymphovascular or perineural invasion, < 12 lymph nodes, poor/un-differentiation, T4, or positive margins. Rates of aCTX by age and risk were calculated, and adjusted factors associated with aCTX were identified. Overall survival was estimated using the Kaplan-Meier method and Cox multivariable analyses for patients < 50 years. ResultsAmong the 81,066 stage II patients who underwent colectomy, 6093 (7.5%) were < 50 years old. Of these, 2669 patients were HR. Thirty percent of NR and almost 60% of HR patients < 50 years received aCTX, compared with 8% and 23% of patients > 50 years (P < .001). In NR patients < 50 years, 35.3% with microsatellite-stable tumors and 18% with microsatellite unstable tumors received aCTX (P < .001), whereas 63.6% and 43.2%, respectively, of HR patients did (P < .001). The most significant multivariable predictors of aCTX were risk status and age. On univariate analysis, there was no survival benefit associated with aCTX in patients < 50 years. Multivariate analysis failed to demonstrate a survival benefit for aCTX for either group (HR, 0.97; P = .84; NR, 0.1.03; P = .90). ConclusionYoung patients with HR and NR colon cancer received aCXT more frequently than older patients with no demonstrable survival benefit. This bears further evaluation to avoid the real risks of over-treatment in this increasing population.

Distribution of lymph node metastases and impact on survival benefit of oxaliplatin-containing chemotherapy in stage III colon cancer.

e15683Background: This study investigated the effect of oxaliplatin-containing adjuvant chemotherapy according to the distribution of lymph node (LN) metastases for patients with stage III colon ca...

A network-based predictive gene-expression signature for adjuvant chemotherapy benefit in stage II colorectal cancer

BackgroundThe clinical benefit of adjuvant chemotherapy for stage II colorectal cancer (CRC) is controversial. This study aimed to explore novel gene signature to predict outcome benefit of postoperative 5-Fu-based therapy in stage II CRC.MethodsGene-expression profiles of stage II CRCs from two datasets with 5-Fu-based adjuvant chemotherapy (training dataset, n = 212; validation dataset, n = 85) were analyzed to identify the indicator. A systemic approach by integrating gene-expression and protein-protein interaction (PPI) network was implemented to develop the predictive signature. Kaplan-Meier curves and Cox proportional hazards model were used to determine the survival benefit of adjuvant chemotherapy. Experiments with shRNA knock-down were carried out to confirm the signature identified in this study.ResultsIn the training dataset, we identified 44 PPI sub-modules, by which we separate patients into two clusters (1 and 2) having different chemotherapeutic benefit. A predictor of 11 PPI sub-modules (11-PPI-Mod) was established to discriminate the two sub-groups, with an overall accuracy of 90.1%. This signature was independently validated in an external validation dataset. Kaplan-Meier curves showed an improved outcome for patients who received adjuvant chemotherapy in Cluster 1 sub-group, but even worse survival for those in Cluster 2 sub-group. Similar results were found in both the training and the validation dataset. Multivariate Cox regression revealed an interaction effect between 11-PPI-Mod signature and adjuvant therapy treatment in the training dataset (RFS, p = 0.007; OS, p = 0.006) and the validation dataset (RFS, p = 0.002). From the signature, we found that PTGES gene was up-regulated in CRC cells which were more resistant to 5-Fu. Knock-down of PTGES indicated a growth inhibition and up-regulation of apoptotic markers induced by 5-Fu in CRC cells.ConclusionsOnly a small proportion of stage II CRC patients could benefit from adjuvant therapy. The 11-PPI-Mod as a potential predictor could be helpful to distinguish this sub-group with favorable outcome.

Prevalence and survival benefit of adjuvant chemotherapy in stage III colon cancer patients: Comparison of overall and age-stratified results by multivariable modeling and propensity score methodology in a population-based cohort.

649 Background: Few population-based studies have assessed the effectiveness of adjuvant chemotherapy (ACT) in stage III colon cancer patients according to age. We sought to quantify the prevalence of ACT use and the absolute and relative survival benefit of ACT overall and by age in a population-based cohort. Methods: Stage III patients with adenocarcinoma of the colon identified by the Georgia Comprehensive Cancer Registry for the years 2000–07 were eligible (final N = 3057). We utilized Poisson regression to obtain adjusted mortality rates (MR) and Cox proportional hazards models to obtain adjusted hazard ratios (HRs) for 5-year overall survival. We evaluated control of confounding by comparing HRs obtained via multivariable modeling (MM), propensity score weighting (PSW), and propensity score matching (PSM). Results: Just over one-third of colon cancer patients did not receive ACT, and the proportion increased with age. Overall, receipt of ACT conferred an absolute (MR difference [No ACT rate - ACT rate] 25.4 deaths/ 1000 person-years [py], 95% confidence interval [CI]: 19.1–32.7 deaths/1000 py) and relative (MM HR = 0.67, 95% CI: 0.59–0.76) survival benefit. The survival benefit was demonstrated across age groups. mm and propensity score methods yielded highly similar HRs. Conclusions: Unless contraindicated, efforts to ensure receipt of ACT for stage III colon cancer patients up to 84 years of age are needed to improve the prognosis of patients with node-positive disease.

Identification and Construction of Combinatory Cancer Hallmark-Based Gene Signature Sets to Predict Recurrence and Chemotherapy Benefit in Stage II Colorectal Cancer.

Decisions regarding adjuvant therapy in patients with stage II colorectal cancer (CRC) have been among the most challenging and controversial in oncology over the past 20 years. To develop robust combinatory cancer hallmark-based gene signature sets (CSS sets) that more accurately predict prognosis and identify a subset of patients with stage II CRC who could gain survival benefits from adjuvant chemotherapy. Thirteen retrospective studies of patients with stage II CRC who had clinical follow-up and adjuvant chemotherapy were analyzed. Respective totals of 162 and 843 patients from 2 and 11 independent cohorts were used as the discovery and validation cohorts, respectively. A total of 1005 patients with stage II CRC were included in the 13 cohorts. Among them, 84 of 416 patients in 3 independent cohorts received fluorouracil-based adjuvant chemotherapy. Identification of CSS sets to predict relapse-free survival and identify a subset of patients with stage II CRC who could gain substantial survival benefits from fluorouracil-based adjuvant chemotherapy. Eight cancer hallmark-based gene signatures (30 genes each) were identified and used to construct CSS sets for determining prognosis. The CSS sets were validated in 11 independent cohorts of 767 patients with stage II CRC who did not receive adjuvant chemotherapy. The CSS sets accurately stratified patients into low-, intermediate-, and high-risk groups. Five-year relapse-free survival rates were 94%, 78%, and 45%, respectively, representing 60%, 28%, and 12% of patients with stage II disease. The 416 patients with CSS set-defined high-risk stage II CRC who received fluorouracil-based adjuvant chemotherapy showed a substantial gain in survival benefits from the treatment (ie, recurrence reduced by 30%-40% in 5 years). The CSS sets substantially outperformed other prognostic predictors of stage 2 CRC. They are more accurate and robust for prognostic predictions and facilitate the identification of patients with stage II disease who could gain survival benefit from fluorouracil-based adjuvant chemotherapy.

Abstract A27: Discovery of predictive biomarker of adjuvant chemotherapy in stage III colorectal cancer related to KRAS/NRAS mutation status using proteomic approach: results from the two randomized phase 3 trials (NSAS-CC/RC)

Abstract Ras is a well-known oncogene, and patients with metastatic colorectal cancer that harbored activating mutations in KRAS and NRAS did not benefit from anti-epidermal growth factor receptor antibodies in previous clinical trials. However, the value of RAS mutations in stage III colorectal cancer has been controversial. NSAS-CC/RC studies consisting of two multicenter phase 3 randomized trials showed that postoperative adjuvant chemotherapy with uracil-tegafur (UFT) significantly improved relapse-free survival (RFS) and overall survival (OS) in patients with stage III colorectal cancer. Here, we performed an integrated analysis of two trials in order to evaluate the association of RAS (KRAS exons 2, 3, 4 and NRAS exons 2, 3) mutations with effectiveness of adjuvant UFT therapy. The analysis included 178 patients with colon cancer and 146 with rectal cancer. RAS mutations were detected by direct-sequencing with a polymerase chain reaction method and observed in 134/304 (44.0%) patients. In patients with RAS mutations, a significant survival benefit was associated with adjuvant UFT chemotherapy in terms of both RFS (HR = 0.49; p = 0.02) and OS (HR = 0.51; p = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS (HR = 0.89; p = 0.67) and OS (HR = 0.94; p = 0.83) between the surgery-alone group and surgery plus adjuvant UFT group. Therefore, we propose that KRAS/NRAS mutations are predictive indicators of the efficacy of adjuvant UFT chemotherapy. Thereafter, we performed a proteomic analysis of 73 tumors of the patients participating in this study by the system of 2-dimensional image-converted analysis of liquid chromatography and mass spectrometry (2DICAL). The quantity of detected 2652 proteins was compared between RAS mutation group and RAS wild-type groups. Significant differences were observed in the expression of 36/2652 proteins. Moreover, we divided the patients treated with adjuvant UFT chemotherapy into an early-recurrence group (recurrence within 12 months after surgery) and a late recurrence/ no recurrence group. Among the 36 proteins, the quantities of 4 proteins (KRT3, CLU, C6orf70 and FBXW8) were significantly different between these groups. In conclusion, our study suggested that the KRAS/NRAS mutation is a biomarker to predict the benefit of adjuvant chemotherapy in stage III colorectal cancer. The benefit may be caused by differences in the expression of several proteins. Citation Format: Yusuke Sasaki, Yasuhide Yamada, Masahiro Kamita, Masaya Ono. Discovery of predictive biomarker of adjuvant chemotherapy in stage III colorectal cancer related to KRAS/NRAS mutation status using proteomic approach: results from the two randomized phase 3 trials (NSAS-CC/RC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A27.

Oncotype DX scores in BRCA1 and BRCA2 associated breast cancer.

541 Background: The Oncotype DX score is widely used to evaluate recurrence risk and potential benefit of chemotherapy in stage 1, estrogen receptor (ER) positive, Her2 negative tumors. Oncotype DX...

Genomic classifier (ColoPrint) to predict outcome and chemotherapy benefit in stage II and III colon cancer patients.

3612 Background: Although benefit of chemotherapy in stage II and III colorectal cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and validated in independent validation studies (JCO 2011, Ann Surg 2013). Methods: In this study, ColoPrint was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center. Frozen tissue specimen, clinical parameters and follow-up data (median follow-up 64 months) were available. Stage II patients from this study were pooled with patients from previous studies (n=416) and ColoPrint performance was compared to clinical risk factors described in the NCCN Guidelines 2013. Results: In the MDACC patient cohort, ColoPrint classified 56% of stage II and III patients as being at Low Risk. The 3-year Relapse-Free-Survival (RFS) was 90.5% for Low Risk and 78.1% for High Risk patients with a HR of 2.42 (p=0.025). In uni-and multivariate analysis, ColoPrint and stage were the only significant factors to predict outcome. Low Risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (91% 3-year RFS for treated patients, 90% for untreated patients) while ColoPrint High Risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70% 3-year RFS in untreated patients (p=0.037). In the pooled stage II dataset, ColoPrint identified 63% of patients as Low Risk with a 3-year RFS of 93% while High Risk patients had a 3-year RFS of 82.3% with a HR of 2.7 (p=0.001). In the univariate analysis, no clinical factor reached statistical significance. Using clinical high risk factors as described in the NCCN guidelines as classification, 56% of patients were classified as low risk with a 3-year RFS of 90.3% while high risk patients had a 3-year RFS of 87.7% with a HR of 0.6 (p=0.63). Conclusions: ColoPrint significantly improves prognostic accuracy, thereby facilitating the identification of patients at higher risk who might be considered for additional treatment.

Benefit of adjuvant chemotherapy for stage I epithelial ovarian cancer according to the histologic type.

5552 Background: The benefit of adjuvant chemotherapy in stage I epithelial ovarian cancer (EOC) remains controversial. We retrospectively examined stage I EOC patients to clarify the benefits of adjuvant chemotherapy according to the histological type. Methods: The outcomes of 131 patients with stage I EOC that was diagnosed by exact staging laparotomy at the Jichi Medical University Hospital over a 22-year period from 1988 to 2009 were evaluated. Eighty-seven of the patients had received adjuvant chemotherapy (stage: IA 17, IC(intraoperative rupture;R) 27, IC(other) 43; histological type: clear cell adenocarcinoma(CCC) 38, mucinous adenocarcinoma(MC) 18, endometrioid adenocarcinoma(EC) 18, serous adenocarcinoma(SAC) 13), while 44 had undergone observation alone (stage: IA 31, IC(R) 12, IC(other) 1; histological type: CCC 11, MC 17, EC 11 and SAC 5). Outcomes for patients were compared between the two groups. Results: The overall recurrence rate in the adjuvant chemotherapy group was 18.4% (16/87). The rates of recurrence according to stage were IA 5.9% (1/17), IC(R) 14.8% (4/27), and IC (other) 25.6% (11/43). Recurrence by histological type were CCC 12, SAC 2(G1and G2), and one each for EC and MC. Recurrence was seen in all stages in CCC patients; however, there was no recurrence in stage IA in patients with non-CCC. The overall recurrence rate in the observation group was 11.4% (5/44). All five recurrences occurred in CCC patients, and no recurrence was observed in the 33 non-CCC patients (IA 26, IC(R) 7). In patients with IC(R) CCC, the recurrence rate was significantly higher in the observation group (80%;4/5) than in the adjuvant chemotherapy group (18.8%; 3/16) (p = 0.025). Conclusions: This retrospective study showed that the CCC is associated with recurrence in stage I EOC and adjuvant chemotherapy for these patients may improve outcomes. The recommended states for adjuvant chemotherapy in stage I EOC are as follow: 1) all subtype of stage I for CCC, and 2) IC(other) for non-CCC. Although further prospective studies are required, these results afford useful information with which to determine the adjuvant chemotherapy in stage I EOC.

Genomic classifiers (ColoPrint/MSI-Print) predict outcome and chemotherapy benefit in stage II and III colon cancer patients.

378 Background: Although the benefit of chemotherapy in stage II and III colon cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and has been validated in public datasets, independent European patient cohorts and technical studies (Salazar 2011 JCO, Maak 2012 Ann Surg). Methods: In this study, the commercial ColoPrint test was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center from 2003 to 2009. Frozen tissue specimen, clinical parameters, MSI-status and follow-up data (median follow-up 64 months) were available. The 64-gene MSI-signature developed to identify patients with deficient mismatch repair system (Tian 2012 J Path) was evaluated for its accuracy to identify MSI patients and also for prognosis. Results: In this cohort, ColoPrint classified 56% of stage II and III patients as being at low risk. The 3-year Relapse-Free-Survival (RFS) was 90.6% for Low Risk and 78.4% for High Risk patients with a HR of 2.33 (p=0.025). In uni-and multivariate analysis ColoPrint and stage were the only significant factors to predict outcome. The MSI-signature classified 47 patients (24.6%) as MSI-H and most MSI-H patients were ColoPrint low risk (81%). Patients who were ColoPrint low risk and MSI-H by signature had the best outcome with a 3-year RFS of 95% while patients with ColoPrint high risk had a worse outcome independently of the MSI-status. Low risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (90.1% 3-year RFS for treated patients, 91.4% for untreated patients) while ColoPrint high risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70.1% 3-year RFS in untreated patients (p=0.026). Conclusions: The combination of ColoPrint and MSI-Print improves the prognostic accuracy in stage II and stage III patients and may help the identification of patients at higher risk who are more likely to benefit from additional treatment

Abstract 1404: L1CAM in non-small-cell lung carcinoma

Abstract Background: Non-small-cell lung carcinoma (NSCLC) is the predominant type of lung cancer, accounting for 85% of all malignant lung tumors. Early stage (I-II) NSCLC is primarily treated by surgical resection with curative intent, but at least 50% of these patients will experience tumor recurrence and die from it. Recent clinical trials have demonstrated the survival benefit of post-surgery adjuvant chemotherapy in stage II and III patients, but its benefit in stage I remains controversial. Our group has previously reported a 15-gene mRNA expression profile that is predictive of patient prognosis and predictive of benefit from adjuvant chemotherapy by cisplatin and vinorelbine. We hypothesize that these genes may play important roles in malignant progression. One of these prognostic genes is L1CAM, a transmembrane protein. The role of L1CAM in the biology of NSCLC cells has not been clearly defined. Methods: The expression of L1CAM was modified at both the RNA and protein levels in H460, H1264, H125, and H460SM cell lines using the lentiviral cDNA/shRNA system. Matrigel assay was used to assess invasion and cell migration by time-lapse wound-healing assay. Tumorigenicity was assessed by injection of modified cell lines into subcutaneous flank of immunodeficient mice. Results: In vitro studies show that L1CAM expression promotes invasiveness and motility of NSCLC cell lines. In vivo studies demonstrate that knock-down of L1CAM expression reduces tumor growth in immunodeficient mice. Mechanistic studies on L1CAM function are ongoing and the results will be presented. Conclusion: Considering the importance of migratory phenotype during metastasis, the results suggest that L1CAM contribute to malignant progression in NSCLC and may be a novel therapeutic target to treat this disease. (Supported by Canadian Cancer Society Research Institute grant #020527) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1404. doi:10.1158/1538-7445.AM2011-1404

Beliefs among Physicians in the Diagnostic and Therapeutic Approach to Non-small Cell Lung Cancer

The American College of Chest Physicians (ACCP) has established evidence-based guidelines for the evaluation and treatment of patients with lung cancer. Physicians' beliefs and practice patterns may differ significantly from established guidelines. We conducted a survey to assess and compare physician beliefs against the evidence-based guidelines. A survey was sent by electronic mail (e-mail) in March 2006 to 2100 randomly selected physicians who were members of the ACCP practicing in the United States, followed by two reminder e-mails. Three hundred forty-seven surveys were completed and evaluable. The majority (84%) of the respondents reported having read, consulted, or used the guidelines to set practice policies, and 75% found the guidelines helpful. The respondents' practice beliefs were in agreement with the guidelines on the evaluation of operable patients with enlarged mediastinal lymph nodes, the role of chemotherapy in the treatment of stage III disease, and the evaluation of a solitary pulmonary nodule. Nevertheless, a significant percentage of respondents' practice beliefs differed from the guidelines on issues such as screening for lung cancer, the survival benefit of chemotherapy in stage IV disease, and postoperative radiation therapy. Only a minority of respondents believed that chemotherapy improved quality of life in stage IV disease. The survey results indicate that there has been acceptance of the adjuvant chemotherapy and increasing integration of positron emission tomography in the evaluation of a solitary pulmonary nodule and in staging the mediastinum. The majority of physicians found the evidence-based guidelines beneficial; nevertheless, practice beliefs differ from the guidelines in select areas.

Perspectives in adjuvant chemotherapy in NSCLC

In 2007 the long-term outcome of lung cancer is still disappointing, with a 5-year survival rate not exceeding 15%. However, small but significant improvements in survival times have been achieved in the last decade. This progress has been achieved through the improvement of surgical techniques and following the introduction of more effective anticancer agents, mainly cisplatin in combination with newer agents (vinorelbine, taxanes, gemcitabine). The benefit of adjuvant chemotherapy in stage II–IIIA disease has been clearly demonstrated. Hints of some efficacy have also emerged for stage IB, while data on active adjuvant chemotherapy in stage IA, mostly from Japanese studies with oral uracil–tegafur, need to be confirmed in non-Asian patients. Optimal chemotherapy regimens and the role of targeted agents in the adjuvant setting are currently unknown. Increasing numbers of patients must be enrolled in adjuvant trials with a design based on pharmacogenomics profiles. Therefore, efforts should be directed toward the collection of surgical specimens to define biomolecular markers to select patients who will benefit from adjuvant treatments on an individual basis.

Tumor microsatellite-instability status to predict benefit of adjuvant chemotherapy for stage III colon cancer

4046 Background: Microsatellite instability (MSI) is an alternative pathway to colon cancer pathogenesis and may be categorized by the degree of MSI exhibited as MSI-high (MSI-H), MSI-low (MSI-L) or microsatellite stable (MSS). The aim of this study was to determine the prognostic impact MSI status on survival in stage III colon cancer. Methods: A total of 197 patients who received curative resection of stage III colon cancer from 1991 through 2002 were identified. Records of these patients were retrospectively evaluated to determine chemotherapy (CTx) use and vital status. DNA extracted from paraffin embedded tumor specimens was amplified by polymerase chain reaction using a panel of 7 markers. MSI-H was defined as instability in &gt;40% of markers and low as instability in &gt;0% but &lt;40% of markers. Overall survival based on MSI and CTx status was compared using Kaplan-Meier analysis and the log-rank test and Cox multiple regression to adjust for covariates. Results: Median follow-up was 5.4 years. There were 25 (13%) MSI-H, 38 (19%) MSI-L and 134 (68%) MSS patients. Median age was 56 years (MSI-H), 65 years (MSI-L) and 62 years (MSS). 5-fluorouracil adjuvant CTx was completed in 135 (69%), not completed in 36 (18%) and unknown in 26 (13%) patients. Tumors were left sided in 56% of the cohort, 72% among MSI-H, 60% among MSI-L, 51% among MSS. 5-year overall survival after adjuvant CTx ranged 71–82% and was not significantly different among the groups. Completion of CTx improved survival among MSS, HR 0.18 (95% confidence [CI] 0.07–0.42, p&lt;0.0001), but not among MSI- H, HR 0.83 (95% CI 0.19–3.60, p=0.79), with an intermediate effect among MSI-L, HR 0.36 (95% CI 0.09–1.47, p=0.0562). The effect of completing adjuvant CTx persisted after adjustment for age, sex, stage (IIIA, B, C), and histology, RR 0.19 (95% CI 0.089–0.41, p&lt;0.0001), RR 0.059 (95% CI 0.009–0.39, p=0.003), RR 0.26 (95% CI 0.01–13.3, p=0.31) for MSS, MSI-L, and MSI-H, respectively. Conclusions: 5-fluorouracil based adjuvant chemotherapy did not affect overall survival in patients with stage III colon cancer who are MSI-H due to a high baseline survival rate without adjuvant therapy. Adjuvant chemotherapy did improve survival in patients who are MSS and an intermediate effect was seen in paitents who are MSI-L. No significant financial relationships to disclose.