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Impact of Time to Start Systemic Therapy on the Outcomes of Patients with Metastatic Colorectal Cancer Treated with First Line FOLFOX Chemotherapy; a Patient-Level Pooled Analysis of Two Clinical Trials
Abstract
Background:
Impact of time to start first-line systemic chemotherapy following diagnosis of metastatic colorectal cancer (mCRC) needs to be studied.
Methods:
This is a pooled analysis of the raw data of the comparator arms of two randomized studies (NCT00272051; NCT00305188). Univariate and multivariate analyses of predictors of overall and progression-free survival were conducted through Cox regression analysis. Factors with statistically significant P value (P < 0.05) in the univariate part of the analysis were included in the multivariate analysis.
Results:
In univariate analysis, time to start systemic therapy did not affect overall or progression-free survival (P=0.694; P= 0.891 respectively). In multivariate analysis for overall survival, the following factors were predictive of worse overall survival: older age (P = 0.019), higher ECOG performance score (P = 0.001), more than one site of metastatic disease (P = 0.002), colon site of the primary tumor (P = 0.004), and no oncologic surgery to the primary tumor (P < 0.001). Likewise, in multivariate analysis for progression-free survival, the following factors were predictive of worse progression-free survival: no oncologic surgery to the primary (P < 0.001), more than one organ of metastatic disease (P < 0.001), and no concurrent bevacizumab administration (P = 0.015).
Conclusion:
Time to start systemic chemotherapy does not appear to impact overall or progression-free survival among mCRC patients.
Objective: To assess real-world patterns of arterial and venous thromboembolism among patients with colorectal carcinoma. Methods: The Alberta provincial cancer registry and other provincial medical records were used to identify patients with colorectal cancer (2004-2018) with no preceding or succeeding cancer diagnosis. The incidence of both arterial and venous thromboembolism in this patient population as well as factors associated with these thromboembolic events were examined through logistic regression analysis. Results: A total of 17,296 patients were found eligible and were included into the current study. We observed that 1564 patients (9%) experienced a thromboembolic event and 15,732 patients (91%) did not. The following factors were associated with any thromboembolic event: male sex (odds ratio [OR]: 1.20; 95% CI: 1.08-1.34), higher comorbidity (OR: 1.36; 95% CI: 1.31-1.41), metastatic disease (OR for nonmetastatic vs metastatic disease: 0.53; 95% CI: 0.47-0.60), living within North zone (OR for Edmonton zone vs North zone: 0.70; 95% CI: 0.59-0.84), treatment with fluoropyrimidines (OR for no fluoropyrimidines vs fluoropyrimidines: 0.53; 95% CI: 0.47-0.60) and treatment with bevacizumab (OR: for no bevacizumab vs bevacizumab: 0.53; 95% CI: 0.47-0.60). Factors associated with venous thromboembolism include, younger age (continuous OR with increasing age: 0.99; 95% CI: 0.98-0.99), higher comorbidity (OR: 1.10; 95% CI: 1.04-1.17), metastatic disease (OR for nonmetastatic disease vs metastatic disease: 0.40; 95% CI: 0.35-0.47), North zone (OR for Edmonton zone vs North zone: 0.70; 95% CI: 0.56-0.86), treatment with fluoropyrimidines (OR for no fluoropyrimidines vs fluoropyrimidines: 0.45; 95% CI: 0.39-0.53) and treatment with bevacizumab (OR for no bevacizumab vs bevacizumab: 0.73; 95% CI: 0.58-0.93). Conclusion: Thromboembolic events are not uncommon among colorectal cancer patients, and the risk is increased with male sex, higher comorbidity, presence of metastatic disease, living within the North zone of the province (where there is limited access to tertiary care centers) and treatment with fluoropyrimidines or bevacizumab.
Background: The aim of this study is to assess the impact of baseline quality of life status (as assessed by the EQ-5D-3L questionnaire) on the prognosis of patients with advanced gastric cancer.
Methods: This study represents a pooled analysis from the control arms of two clinical trials (NCT00290966; NCT00678535). Both control arms evaluated fluoropyrimidine/cisplatin combination in the first line treatment of advanced gastric cancer. Univariate and multivariate Cox regression analyses were performed to assess factors affecting overall and progression-free survival. Factors with P < 0.05 in univariate analysis were included in the multivariate analysis.
Results: A total of 654 patients with advanced gastric cancer were evaluated in the current study. Cox regression analyses were conducted to determine factors which might affect overall and progression-free survival. The following factors were predictive of better overall survival in a multivariate Cox regression model: lower ECOG score (P = 0.031) and higher EQ-5D score (P = 0.001). Likewise, the following factors were predictive of better progression-free survival in a multivariate Cox regression model: lower ECOG score (P = 0.005) and higher EQ-5D score (P = 0.041).
Conclusion: Advanced gastric cancer patients with better baseline quality of life status have better overall and progression-free survival. Given the EQ-5D easy-to-use model, extending its use in routine clinical practice settings should be considered.
Background
The current analysis aims to provide an evaluation of the impact of diabetes mellitus (DM) on the efficacy and safety of first-line FOLFOX chemotherapy for patients with metastatic colorectal cancer (mCRC).
Methods
This is a pooled analysis of the comparator arms of two clinical trials (NCT00272051; NCT00305188) which evaluated first-line FOLFOX chemotherapy for patients with mCRC. The overall survival and progression-free survival according to patient subsets (non-diabetic and diabetic patients) were assessed through Kaplan–Meier analysis and log-rank testing. Propensity score matching was additionally conducted to account for heterogeneity in baseline characteristics of different subsets of patients.
Results
A total of 756 patients were enrolled in the current analysis; of which 64 patients have pre-existing DM while 692 patients were non-diabetic. Through Kaplan–Meier analysis, no evidence for overall or progression-free survival difference was found among the two patient subsets (P = 0.501; P = 0.960, respectively). Moreover, metformin treatment does not affect overall or progression-free survival among diabetic patients (P = 0.598; P = 0.748, respectively). Repetition of overall and progression-free survival assessment following propensity score matching does not reveal any differences. Comparing diabetic to non-diabetic patients, there were no differences between the two groups in terms of acute oxaliplatin-induced neurological symptoms including cold-induced dysthesia (P = 0.600), laryngeal dysthesia (P = 0.707), jaw pain (P = 0.743) or muscle pain (P = 0.506). Moreover, no difference was seen between the two groups in terms of the incidence of long-term oxaliplatin-induced paresthesia (P = 0.107), highest grade of paresthesia (P = 0.498) or rates of recovery from paresthesia (P = 0.268). Diabetic patients have, however, a shorter time to develop oxaliplatin-induced paresthesia (P = 0.024).
Conclusion
DM does not seem to affect overall or progression-free survival of mCRC patients treated with first-line FOLFOX chemotherapy. Moreover, DM does not influence the incidence or severity of oxaliplatin-induced paresthesia in those patients while it might lead to a shorter time to develop oxaliplatin-induced paresthesia compared to non-diabetic patients.
Background/aims:
Colorectal cancer is associated with different anatomical, biological, and clinical characteristics. We determined the impact of the primary tumor location in patients with metastatic colorectal cancer (mCRC).
Methods:
Demographic data and clinical information were collected from 1,115 patients from the Republic of Korea, who presented with mCRC between January 2009 and December 2011, using web-based electronic case report forms. Associations between the primary tumor location and the patient's clinical characteristics were assessed, and factors inf luencing overall survival were analyzed using Cox proportional hazards regression models.
Results:
Of the 1,115 patients recruited to the study, 244 (21.9%) had right colon cancer, 483 (43.3%) had left colon cancer, and 388 (34.8%) had rectal cancer. Liver and lung metastases occurred more frequently in patients with left colon and rectal cancer (p = 0.005 and p = 0.006, respectively), while peritoneal and ovarian metastases occurred more frequently in patients with right and left colon cancer (p < 0.001 and p = 0.031, respectively). The median overall survival of patients with tumors originating in the right colon was significantly shorter than that of patients whose tumors had originated in the left colon or rectum (13.7 months [95% confidence interval (CI), 12.0 to 15.5] vs. 18.0 months [95% CI, 16.3 to 19.7] or 19.9 months [95% CI, 18.5 to 21.3], respectively; p = 0.003). Tumor resection, the number of metastatic sites, and primary tumor location correlated with overall survival in the univariate and multivariate analyses.
Conclusions:
Primary tumor location influences the metastatic sites and prognosis of patients with mCRC.
Background: The current study tried to evaluate the factors affecting 10- to 20- years’ survival among long term survivors (>5 years) of colorectal cancer (CRC) and to examine if risk of death from CRC beyond five years varies based on baseline characteristics.
Patients and methods: Surveillance, Epidemiology and End Results (SEER) database (1988-2008) was queried through SEER*Stat program. Univariate probability of overall and cancer-specific survival was determined by the life tables’ option of the SPSS and the difference between groups was examined through Wilcoxon (Gehan) Statistic. Multivariate analysis for factors affecting overall and cancer-specific survival was conducted through Cox regression analysis.
Results: Among node positive patients (Dukes C), 34% of the deaths beyond 5 years can be attributed to CRC; while among M1 patients, 63% of the deaths beyond 5 years can be attributed to CRC. The following factors were predictors of better overall survival in multivariate analysis: younger age, white race (versus black race), female gender, right colon location (versus rectal location), earlier stage and surgery (P <0.0001 for all parameters). Similarly, the following factors were predictors of better cancer-specific survival in multivariate analysis: younger age, white race (versus black race), female gender, right colon location (versus left colon and rectal locations), earlier stage and surgery (P <0.0001 for all parameters).
Conclusion: Among node positive CRC survivors, more than one third of all deaths can be attributed to CRC. Tailored follow up strategies based on baseline risk of each patient need to be established.
Background: The effect of primary tumour resection (PTR) among metastatic colorectal cancer (mCRC) patients remains controversial. Combination chemotherapy with bevacizumab could improve the clinical outcomes of these patients, which might change the importance of PTR in the multi-disciplinary treatment pattern. Methods: We performed a non-randomized prospective controlled study of mCRC pts whose performance status (PS) scored ≤2 and who received bevacizumab combination chemotherapy (FOLFOX/XELOX/FOLFIRI) as a first-line therapy. These patients were classified into the PTR group and the IPT (intact primary tumour) group according to whether they underwent PTR before receiving the systemic therapy. The progression free survival (PFS) time and overall survival (OS) time, which were recorded from the start of the primary diagnosis until disease progression and death or last follow-up, were analysed. We also compared severe clinical events (such as emergency surgery, radiation therapy, and stent plantation) between the two groups. Results: One hundred and nighty-one mCRC pts (108 male patients and 93 female patients) were entered in this prospective observational study. The median age was 57.5 years old. The clinical characteristics (age, gender, performance status, primary tumour site, RAS status, and the number of metastatic organs) did not significantly differ between the two groups. The median PFS and OS times of the PTR group were superior than those of the IPT group (10.0 vs 7.8 months, p Conclusions: The mCRC patients who received PTR and bevacizumab combination chemotherapy had better clinical outcomes than patients who did not receive PTR. PTR also decreased the incidence of severe clinical events and improved quality of life.
Background:
Currently available data suggest that delaying the start of adjuvant chemotherapy in colon cancer patients has a detrimental effect on survival. We analysed which factors impact on the timing of adjuvant chemotherapy and evaluated the influence on overall survival (OS).
Patients and methods:
Stage III colon cancer patients who underwent resection and received adjuvant chemotherapy between 2008 and 2013 were selected from the Netherlands Cancer Registry. Timing of adjuvant chemotherapy was subdivided into: ⩽4, 5-6, 7-8, 9-10, 11-12 and 13-16weeks post-surgery. Multivariable regressions were performed to assess the influence of several factors on the probability of starting treatment within 8weeks post-surgery and to evaluate the association of timing of adjuvant chemotherapy with 5-year OS.
Results:
6620 patients received adjuvant chemotherapy, 14% commenced after 8weeks. Factors associated with starting treatment after 8weeks were older age (Odds ratio (OR) 65-74 versus <65years 1.3 (95% confidence interval (CI): 1.14-1.58); OR ⩾75 versus <65years 1.6 (1.25-1.94)), emergency resection (OR 1.8 (1.41-2.32)), anastomotic leakage (OR 8.1 (6.14-10.62)), referral to another hospital for adjuvant chemotherapy (OR 1.9 (1.36-2.57)) and prolonged postoperative hospital admission (OR 4.7 (3.30-6.68)). Starting 5-8weeks post-surgery showed no decrease in OS compared to initiation within 4weeks (Hazard ratio (HR) 5-6weeks 0.9 (0.79-1.11); HR 7-8weeks 1.1 (0.91-1.30)). However, commencing beyond 8weeks was associated with decreased OS compared to initiation within 8weeks (HR 9-10weeks 1.4 (1.21-1.68); HR 11-12weeks 1.3 (1.06-1.59); HR 13-16weeks 1.7 (1.23-2.23)).
Conclusion:
Our data support initiating adjuvant chemotherapy in stage III colon cancer patients within 8weeks post-surgery.
There is growing evidence that cancer of the ascending (right-side) colon is different from cancer of the descending (left-side) colon at the molecular level. Using microarray data from 102 right-side colon carcinomas and 95 left-side colon carcinomas we show that different pathways dominate progression to relapse in right-side and left-side colon cancer. Right-side tumors at a high risk for relapse exhibit elevated expression of cell cycle control genes and elevated Wnt signaling. On the other hand, relapse-prone left-side tumors show elevated expression of genes that promote stromal expansion and reduced expression of tumor suppressor genes that initiate Wnt signaling. Single gene prognostic biomarkers are found separately for right-side and left-side disease. In left-side tumors with low expression levels of NADPH oxidase 4 (NOX4) the 5-yr relapse-free survival probability is 0.89 95% CI (0.80-0.99), and in tumors with elevated NOX4 expression the probability is 0.51 95% CI (0.37-0.70). Right-side tumors with elevated expression levels of caudal type homeobox 2 (CDX2) have a 5-yr relapse-free survival probability of 0.88 95% CI (0.80-0.96), and those with low CDX2 expression have a corresponding probability of 0.39 95% CI (0.15-0.78). Both NOX4 and CDX2 are much less prognostic on the opposite sides. This newly identified role of NOX4 in colon cancer is further investigated using the SW620 lymph node metastasis colon adenocarcinoma cell line and RNA interference. We show that NOX4 is expressed in the SW620 cell line and that application of NOX4 siRNA causes a significant reduction in reactive oxidative species production.
To assess the clinical effectiveness and cost-effectiveness of bevacizumab and cetuximab in the treatment of individuals with metastatic colorectal cancer (CRC).
Searches of main electronic databases were conducted in April and May 2005.
For the assessment of bevacizumab, trials were included if they recruited participants with untreated metastatic CRC for first-line treatment. Only trials comparing bevacizumab in combination with irinotecan and/or established fluorouracil (5-FU)-containing or releasing regimens given as first-line therapy were included. For the assessment of cetuximab, trials were included if they recruited participants with epidermal growth-factor receptor-expressing metastatic CRC who had previously failed irinotecan-including therapy. Independent cost-effectiveness models of bevacizumab and cetuximab were developed using survival modelling methods.
Adding bevacizumab to irinotecan in combination with 5-FU/folic acid (FA) plus irinotecan resulted in a statistically significant increase in median overall survival (OS) of 4.7 months. Adding bevacizumab to 5-FU/FA resulted in a non-significant increase in median OS of 3.7 months within one study and 7.7 months in another. Adding bevacizumab to irinotecan, fluorouracil and leucovorin (IFL) resulted in a statistically significant increase in median progression-free survival (PFS) of 4.4 months. Adding bevacizumab to 5-FU/FA resulted in a statistically significant increase in median PFS of 3.7 months, and a statistically significant increase in time to disease progression of 3.8 months compared to FU/FA alone. An overall tumour response rate of 44.8% was reported for bevacizumab plus IFL compared to 34.8% for IFL plus placebo. This addition was statistically significant. The addition of bevacizumab to 5-FU/FA resulted in a significant difference in tumour response rate within one study, but not another. Bevacizumab in combination with IFL or 5-FU/FA was observed to result in an increase of grade 3/4 adverse events. The independent health economic assessment suggests that the cost-effectiveness of bevacizumab plus IFL is unlikely to be better than pound 46,853 per life-year gained (LYG); the cost-utility of bevacizumab plus IFL is unlikely to be better than pound 62,857 per quality-adjusted life-year (QALY) gained. The cost-effectiveness of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 84,607 per LYG; the cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. A Phase II trial reported a median OS duration of 8.6 months for patients receiving cetuximab plus irinotecan, plus a median time to progression of 4.1 months, a tumour response rate of 22.9% and suggested that treatment with cetuximab in combination with irinotecan is associated with significantly more adverse events (any grade 3 or grade 4 adverse event) than cetuximab monotherapy. The single arm study of cetuximab plus irinotecan reported a median OS duration of 8.4 months, a median time to progression of 2.9 months and a tumour response rate of 15.2%. The cost-effectiveness model suggested that the expected survival duration of patients receiving cetuximab plus irinotecan is 0.79 years (9.5 months) when the proposed continuation rule is applied. In order for cetuximab plus irinotecan to achieve a cost-utility ratio of pound 30,000 per QALY gained, treatment with cetuximab plus irinotecan must provide an additional 0.65 life years (7.8 months) over treatment with active/best supportive care, implying that survival in the active/best supportive care group must be 0.14 life years (1.7 months) or less.
The trials indicate that bevacizumab in combination with 5-FU/FA, and bevacizumab in combination with IFL, is clinically effective in comparison to standard chemotherapy options for the first-line treatment of metastatic CRC. The health economic analysis suggests that the marginal cost-utility of bevacizumab plus IFL versus IFL is unlikely to be better than pound 62,857 per QALY gained, and the marginal cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. There is no direct evidence to demonstrate whether cetuximab in combination with irinotecan improves health-related quality of life or OS in comparison to active/best supportive care or oxaliplatin plus 5-FU/FA, although the evidence on tumour response rates suggests that cetuximab plus irinotecan has some clinical activity. While it is difficult to suggest whether cetuximab represents value for money, indirect comparisons suggest that the incremental cost-utility of cetuximab plus irinotecan is unlikely to be better than pound 30,000 per QALY gained. This review highlights a number of areas for further research, including clarifying the true impact of first-line bevacizumab in combination with irinotecan and/or infusional 5-FU/FA, without subsequent bevacizumab treatment following disease progression, on OS in patients with metastatic CRC who are representative of the typical population of CRC patients in England and Wales. Further research concerning the impact of therapies on health-related quality of life is essential.
Background:
The current study tried to evaluate the prognostic value of a modified staging system compared to the American Joint Committee on Cancer (AJCC) staging system for patients with colon cancer.
Patients and methods:
Surveillance, epidemiology and end results (SEER) database (2004-2014) was queried through SEER*Stat program and AJCC 7th stages were constructed. Through recursive partitioning analysis and subsequent decision tree formation, suggested new stages were formulated based on T and N descriptors. Overall survival analyses were performed through Kaplan-Meier analysis. The cancer-specific Cox regression hazard (adjusted for age, gender, sub-site, grade, race and surgery) was calculated and pair wise comparisons of hazard ratios were conducted.
Results:
A total of 159,683 non-metastatic patients with colon cancer were recruited in the analysis. Pair wise hazard ratio comparisons among different AJCC 7th stages were conducted and all comparisons were significant (P < 0.0001). However, it should be noted that the adjusted risk of death among stage IIC patients was higher than stage IIIA and IIIB. Pair wise hazard ratio comparisons among different modified system stages were also conducted and all comparisons were significant (P < 0.0001). The outcomes of survival analysis were the same regardless of the number of examined lymph nodes (< 12 vs. ≥ 12). Concordance index (using death from colon cancer as the dependent variable) for AJCC 6th staging system was 0.704 (SE 0.002; 95% CI 0.701-0.708); for AJCC 7th staging system was 0.708 (SE 0.002; 95% CI 0.704-0.711); for Dukes staging system was 0.670 (SE 0.002; 95% CI 0.666-0.674); and for modified staging system was 0.712 (SE 0.002; 95% CI 0.709-0.716).
Conclusion:
The proposed modified staging system provided an improved prognostication for colon cancer patients (particularly for stage II/III disease) compared to AJCC staging system. Further external validation of the proposed staging system is needed before adoption into routine practice.
Importance
Recent data have suggested that disease biology and outcome of colon cancer may differ between right-sided and left-sided tumors. However, the literature on the prognostic value of tumor laterality is conflicting.
Objective
To explore differences in laterality based on disease characteristics and outcomes in a population-based cohort of early-stage colon cancer.
Design, Setting, and Participants
This investigation was a population-based retrospective cohort study of patients with early-stage colon cancer from the province of Ontario, Canada. Electronic records of treatment were linked to the Ontario Cancer Registry to identify all patients with colon cancer who underwent resection between January 1, 2002, and December 31, 2008. The date of the final analysis was October 20, 2016. The study population included a 25% random sample of all patients with resected stage I to III disease. Right-sided colon cancer was defined as any tumor arising in the cecum, ascending colon, hepatic flexure, or transverse colon. Left-sided colon cancer was defined as any tumor arising in the splenic flexure, descending colon, sigmoid colon, or rectosigmoid colon.
Main Outcomes and Measures
Overall survival (OS) and cancer-specific survival (CSS) measured from the time of resection.
Results
This study identified 6365 patients with early-stage colon cancer (48.7% [3098 of 6365] female). Their median age was 72 years, and 51.7% (3291 of 6365) had right-sided disease. Stage distribution was 18.3% (1163 of 6365) stage I, 38.4% (2446 of 6365) stage II, and 43.3% (2756 of 6365) stage III. Patients with right-sided colon cancer were more likely to be older (median age, 73 vs 70 years; P < .001) and female (54.4% [1790 of 3291] vs 42.6% [1308 of 3074], P < .001) and have greater comorbidity. Right-sided cancers were more likely to be T4 (19.2% [631 of 3291] vs 15.9% [490 of 3074], P < .001) and poorly differentiated (21.1% [695 of 3291] vs 9.6% [295 of 3074], P < .001) but less likely to be node positive (42.0% [1383 of 3291] vs 44.7% [1373 of 3074], P = .03) compared with left-sided disease. In adjusted analyses, there was no difference in long-term survival for right-sided compared with left-sided colon cancer: the hazard ratios were 1.00 (95% CI, 0.92-1.08) for OS and 1.00 (95% CI, 0.91-1.10) for CSS. These results were consistent when the survival analyses were restricted to stage III disease: the hazard ratios were 1.03 (95% CI, 0.93-1.14) for OS and 1.10 (95% CI, 0.97-1.24) for CSS.
Conclusions and Relevance
In this population-based cohort of early-stage resected colon cancer, disease laterality was not associated with long-term OS or CSS.
Purpose:
In recent retrospective analyses of early-stage colorectal cancer (CRC), low and high body mass index (BMI) scores were associated with worsened outcomes. Whether BMI is a prognostic or predictive factor in metastatic CRC (mCRC) is unclear.
Patients and methods:
Individual data from 21,149 patients enrolled onto 25 first-line mCRC trials during 1997 to 2012 were pooled. We assessed both prognostic and predictive effects of BMI on overall survival and progression-free survival, and we accounted for patient and tumor characteristics and therapy type (targeted v nontargeted).
Results:
BMI was prognostic for overall survival (P < .001) and progression-free survival (P < .001), with an L-shaped pattern. That is, risk of progression and/or death was greatest for low BMI; risk decreased as BMI increased to approximately 28 kg/m(2), and then it plateaued. Relative to obese patients, patients with a BMI of 18.5 kg/m(2) had a 27% increased risk of having a PFS event (95% CI, 20% to 34%) and a 50% increased risk of death (95% CI, 43% to 56%). Low BMI was associated with poorer survival for men than women (interaction P < .001). BMI was not predictive of treatment effect.
Conclusion:
Low BMI is associated with an increased risk of progression and death among the patients enrolled on the mCRC trials, with no increased risk for elevated BMI, in contrast to the adjuvant setting. Possible explanations include negative effects related to cancer cachexia in patients with low BMI, increased drug delivery or selection bias in patients with high BMI, and potential for an interaction between BMI and molecular signaling pathways.
Previous studies have evaluated the impact of time to adjuvant chemotherapy (AC) on survival in early-stage colon cancer. However, the optimal time to adjuvant chemotherapy (TTAC) in rectal cancer remains unclear. The objective of this study was to identify an optimal TTAC and determine its prognostic effect in stage 2 to 3 rectal cancer.
Patients with stage 2 to 3 rectal cancer treated with preoperative chemoradiation and postoperative AC between 1999 and 2008 were included. Predetermined time points of 4, 6, 8, and 12 weeks from date of surgery were analyzed. Cut-point analysis was then used to determine an optimal TTAC, and overall survival at the identified cut-point was evaluated.
A total of 328 eligible patients were identified with a median age of 61 years (range 22-85 years), 70% male, and 75% stage 3 disease. The median TTAC was 7.0 weeks. Initiation of AC at 6 weeks from date of surgery was associated with a significant survival benefit (hazard ratio 0.52, 95% confidence interval 0.31-0.90, P = .017), while no significant association was seen at 4, 8 or 12 weeks (P > .05). The cut-point analysis identified an optimal TTAC of 5.6 weeks association with improved survival compared to those with a TTAC greater than 5.6 weeks (hazard ratio 0.42, 95% confidence interval 0.22-0.82, P = .0087). This cut-point was also found to be a significant prognostic factor in multivariable analysis (P = .04) adjusted for Eastern Cooperative Oncology Group performance status, age, gender, stage, margin status, and grade.
This study suggests that initiation of AC within an earlier time frame is associated with improved overall survival.
Copyright © 2014 Elsevier Inc. All rights reserved.
The NCCN Guidelines for Colon Cancer address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease,and survivorship. This portion of the guidelines focuses on the use of systemic therapy in metastatic disease. The management of metastatic colorectal cancer involves a continuum of care in which patients are exposed sequentially to a variety of active agents, either in combinations or as single agents. Choice of therapy is based on the goals of treatment, the type and timing of prior therapy, the different efficacy and toxicity profiles of the drugs, the mutational status of the tumor, and patient preference.
The aim of this study was to compare the outcomes in colorectal cancer (CRC) patients with synchronous unresectable metastases who received either primary tumor resection (PTR) or chemotherapy as the first treatment and to investigate the clinical course of asymptomatic patients who received chemotherapy as the first treatment.
We retrospectively analyzed 324 CRC patients with synchronous unresectable metastases. Overall survival (OS) was analyzed for the two groups (upfront PTR group [n = 72] vs. upfront chemotherapy group [n = 252]). Surgical morbidity and mortality were recorded. In the asymptomatic patients who received upfront chemotherapy, the incidences of primary tumor-related complications were analyzed.
In patients who underwent PTR as the first treatment, the median OS period was superior to those who received upfront chemotherapy (17.2 vs. 13.6 months, P = 0.002). In the PTR group, surgical morbidity and mortality were 11.6% and 1.9%, respectively. Of the 252 asymptomatic patients, the incidence of primary tumor-related complications was 35%. Emergent surgery was ultimately done in 14% of the 252 patients.
CRC patients with synchronous unresectable metastases who underwent PTR followed by chemotherapy had significantly longer survival times compared to patients who received chemotherapy as the first treatment. J. Surg. Oncol. © 2014 Wiley Periodicals, Inc.
Colorectal carcinoma (CRC) is the second most common cause of cancer death in the United States, and the rate of CRC is nearly 1.5 times higher in African-Americans (AA) than in Caucasians. Microsatellite instability (MSI) is observed in sporadic CRC reflecting promoter hypermethylation of the DNA mismatch repair gene hMLH1, and anecdotal evidence suggests an increased incidence of MSI among AAs. Additionally, p16 can be inactivated by hypermethylation of the promoter region, abrogating its ability to regulate cell proliferation. The objective of this study is to determine the frequency of MSI and p16 gene methylation in CRC from AA patients.
Experiments were conducted on serially collected archival samples of colon cancer and adjacent normal tissue (n = 22). Five microsatellite markers were used to measure MSI in tumors with direct comparison to normal tissue from the same patient. p16 promoter methylation status was determined by methylation-specific PCR.
Ten cancers (45%) demonstrated high MSI (MSI-H), 1 demonstrated low MSI, and the remaining 11 tumors were microsatellite stable. Most of the MSI-H tumors were proximal, well differentiated, and showed high levels of mucin production. Most patients in the MSI-H group were female (70%), whereas most of the microsatellite-stable group (81%) were male. Five of the 22 tumors (22%) had methylation of the p16 promoter.
Data provided here demonstrated that the incidence of MSI-H tumors was 3-fold higher in our study group of AA patients compared with data reported in nonracially selected but serially collected studies. Odds ratio analysis indicates that the chance of female patients having MSI-H was 11.7 times more than male patients (P < 0.03). The reason for this gender difference is unknown. These findings might reflect dietary differences or genetic polymorphisms that may be common in the AA population. Additional investigation in a larger patient population is needed before strong conclusion can be drawn.
African Americans (AAs) have a 1.5 times higher risk of colorectal carcinoma (CRC) than Caucasians. Gene silencing through CpG island hypermethylation has been associated with the genesis or progression of microsatellite instability (MSI) largely due to 1 target for hypermethylation being the DNA mismatch repair gene hMLH1; there is anecdotal evidence of an increased incidence of MSI among AAs. P16 and hMLH1 can be inactivated by hypermethylation of their respective promoter regions, abrogating the ability to regulate cell proliferation and repair processes. We studied such methylation, as well as hMHS2 expression in colorectal cancers from AA patients to determine if MSI is associated with epigenetic silencing. Experiments were conducted on matched normal and colon cancer tissues from AA patients (n = 51). A total of 5 microsatellite markers (D2S123, D5S346, D17S250, BAT25 and BAT26) were used to evaluate MSI status. P16 and hMLH1 promoter methylation status was determined following bisulfite modification of DNA and using methylation specific PCR, while immunohistochemistry (IHC) was used to examine expression of hMLH1 and hMSH2. A total of 22 (43%) cancers demonstrated microsatellite instability-high (MSI-H), while 27 were microsatellite stable (MSS) and 2 were microsatellite instability-low (MSH-L). Most of the MSI-H tumors were proximal, well differentiated and highly mucinous. Most patients in the MSI-H group were females (68%). The p16 promoter was methylated in 19 of 47 (40%) tumors. A total of 7 of these CRCs demonstrated MSI-H (33%). The hMLH1 promoter was methylated in 29 of 34 (85%) tumors, of which 13 CRCs demonstrated MSI-H (87%). hMLH1 and hMSH2 staining was observed in 66% and 38% of MSI-H tumors, respectively. Overall, the prevalence of MSI-H colorectal tumor was 2-3-fold higher, while the defect in the percentage expression of mismatch repair (MMR) genes (hMLH1 and hMSH2) was similar in AA patients compared to the U.S. Caucasian population. Similar numbers of AA MSS tumors with p16 and hMLH1 methylation likely indicate hemimethylation of genes that might reflect environmental or genetic influences that might be more common in the AA population.
Chemotherapy for colorectal cancer is currently offered to patients based on the stage of their cancer, and there is evidence to show an overall survival benefit with 5-fluorouracil-based (5-FU) therapy for patients with lymph node metastasis who receive it. The pathogenesis of colorectal cancer involves genomic instability, with about 15% of tumors demonstrating a form of genomic instability called high-frequency microsatellite instability (MSI-H) and due to loss of DNA mismatch repair function, and the remainder of colorectal tumors lacking MSI-H with retained DNA mismatch repair function and called microsatellite stable (MSS), with a large proportion of these tumors demonstrating another form of genomic instability called chromosomal instability. There is now evidence to show that the form of genomic instability that is present in a patient's colorectal cancer may predict a survival benefit from 5-FU. In particular, patients whose colorectal tumors have MSI-H do not gain a survival benefit with 5-FU as compared to patients with MSS tumors. In vitro evidence supports these findings, as MSI-H colon cancer cell lines are more resistant to 5-FU compared to MSS cell lines. More specifically, components of the DNA mismatch repair system have been shown to recognize and bind to 5-FU that becomes incorporated into DNA and which could be a trigger to induce cell death. The binding and subsequent cell death events would be absent in colorectal tumors with MSI-H, which have lost intact DNA mismatch repair function. These findings suggest that: (a) tumor cytotoxicity of 5-FU is mediated by DNA mechanisms in addition to well-known RNA mechanisms, and (b) patients whose tumors demonstrate MSI-H may not benefit from 5-FU therapy. Future studies should include a better understanding of the cellular mechanisms of the DNA recognition of 5-FU, multi-centered prospective trials investigating the survival benefit of 5-FU based on genomic instability, and the investigation of alternative chemotherapeutic regimens for patients with MSI-H tumors to improve survival.