Purpose: Host immune response to tumor may be an important prognostic factor for colon cancer patients. However, little is known on
prognostic significance of histopathologic lymphoid reaction to ...tumor, independent of the number of lymph nodes examined and
tumoral molecular alterations, including microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP),
both of which are associated with lymphocytic reaction and clinical outcome.
Experimental Design: Using 843 colorectal cancer patients in two independent prospective cohorts, we examined patient prognosis in relation to
four components of lymphocytic reaction (i.e., Crohn's-like reaction, peritumoral reaction, intratumoral periglandular reaction,
and tumor-infiltrating lymphocytes) and overall lymphocytic score (0-12). CIMP was determined using eight markers including
CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 , and SOCS1 . Cox proportional hazard models computed hazard ratio for mortality, adjusted for covariates including tumor stage, body
mass index, lymph node count, KRAS, BRAF , p53, cyclooxygenase-2 ( PTGS2 ), MSI, CIMP, and LINE-1 methylation.
Results: Increasing overall lymphocytic reaction score including tumor-infiltrating lymphocytes was associated with a significant
improvement in colorectal cancerâspecific and overall survival (log-rank P < 0.003). These findings remained significant (adjusted hazard ratio estimates, 0.49-0.71; P trend < 0.009) in multivariate models that adjusted for covariates, including body mass index, MSI, CIMP, LINE-1 hypomethylation,
and cyclooxygenase-2. The beneficial effect of tumoral lymphocytic reaction was consistent across strata of clinical, pathologic,
and molecular characteristics.
Conclusions: Lymphocytic reactions to tumor were associated with improved prognosis among colorectal cancer patients, independent of lymph
node count and other clinical, pathologic, and molecular characteristics. (Clin Cancer Res 2009;15(20):6412â20)
Physically active individuals have a lower risk of developing colorectal cancer but the influence of exercise on cancer survival is unknown.
By a prospective, observational study of 573 women with ...stage I to III colorectal cancer, we studied colorectal cancer-specific and overall mortality according to predefined physical activity categories before and after diagnosis and by change in activity after diagnosis. To minimize bias by occult recurrences, we excluded women who died within 6 months of their postdiagnosis physical activity assessment.
Increasing levels of exercise after diagnosis of nonmetastatic colorectal cancer reduced cancer-specific mortality (P for trend = .008) and overall mortality (P for trend = .003). Compared with women who engaged in less than 3 metabolic equivalent task MET -hours per week of physical activity, those engaging in at least 18 MET-hours per week had an adjusted hazard ratio for colorectal cancer-specific mortality of 0.39 (95% CI, 0.18 to 0.82) and an adjusted hazard ratio for overall mortality of 0.43 (95% CI, 0.25 to 0.74). These results remained unchanged even after excluding women who died within 12 and 24 months of activity assessment. Prediagnosis physical activity was not predictive of mortality. Women who increased their activity (when comparing prediagnosis to postdiagnosis values) had a hazard ratio of 0.48 (95% CI, 0.24 to 0.97) for colorectal cancer deaths and a hazard ratio of 0.51 (95% CI, 0.30 to 0.85) for any-cause death, compared with those with no change in activity.
Recreational physical activity after the diagnosis of stages I to III colorectal cancer may reduce the risk of colorectal cancer-specific and overall mortality.
Macrophages are among the most common cells in the colorectal cancer microenvironment, but their prognostic significance is incompletely understood. Using multiplexed immunofluorescence for CD68, ...CD86, IRF5, MAF, MRC1 (CD206), and KRT (cytokeratins) combined with digital image analysis and machine learning, we assessed the polarization spectrum of tumor-associated macrophages in 931 colorectal carcinomas. We then applied Cox proportional hazards regression to assess prognostic survival associations of intraepithelial and stromal densities of M1-like and M2-like macrophages while controlling for potential confounders, including stage and microsatellite instability status. We found that high tumor stromal density of M2-like macrophages was associated with worse cancer-specific survival, whereas tumor stromal density of M1-like macrophages was not significantly associated with better cancer-specific survival. High M1:M2 density ratio in tumor stroma was associated with better cancer-specific survival. Overall macrophage densities in tumor intraepithelial or stromal regions were not prognostic. These findings suggested that macrophage polarization state, rather than their overall density, was associated with cancer-specific survival, with M1- and M2-like macrophage phenotypes exhibiting distinct prognostic roles. These results highlight the utility of a multimarker strategy to assess the macrophage polarization at single-cell resolution within the tumor microenvironment.
Few patients 75 years of age and older participate in clinical trials, thus whether adjuvant chemotherapy for stage III colon cancer (CC) benefits this group is unknown.
A total of 5,489 patients ≥ ...75 years of age with resected stage III CC, diagnosed between 2004 and 2007, were selected from four data sets containing demographic, stage, treatment, and survival information. These data sets included SEER-Medicare, a linkage between the New York State Cancer Registry (NYSCR) and its Medicare programs, and prospective cohort studies Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) and the National Comprehensive Cancer Network. Data sets were analyzed in parallel using covariate adjusted and propensity score (PS) matched proportional hazards models to evaluate the effect of treatment on survival. PS trimming was used to mitigate the effects of selection bias.
Use of adjuvant therapy declined with age and comorbidity. Chemotherapy receipt was associated with a survival benefit of comparable magnitude to clinical trials results (SEER-Medicare PS-matched mortality, hazard ratio HR, 0.60; 95% CI, 0.53 to 0.68). The incremental benefit of oxaliplatin over non-oxaliplatin-containing regimens was also of similar magnitude to clinical trial results (SEER-Medicare, HR, 0.84; 95% CI, 0.69 to 1.04; NYSCR-Medicare, HR, 0.82, 95% CI, 0.51 to 1.33) in two of three examined data sources. However, statistical significance was inconsistent. The beneficial effect of chemotherapy and oxaliplatin did not seem solely attributable to confounding.
The noninvestigational experience suggests patients with stage III CC ≥ 75 years of age may anticipate a survival benefit from adjuvant chemotherapy. Oxaliplatin offers no more than a small incremental benefit. Use of adjuvant chemotherapy after the age of 75 years merits consideration in discussions that weigh individual risks and preferences.
Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk ...features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability MSI, mismatch repair MMR deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results. All participants underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene. Results One hundred five (9.9%; 95% CI, 8.2% to 11.9%) of 1,058 participants carried one or more pathogenic mutations, including 33 (3.1%) with Lynch syndrome (LS). Twenty-eight (96.6%) of 29 available LS CRCs demonstrated abnormal MSI/MMR results. Seventy-four (7.0%) of 1,058 participants carried non-LS gene mutations, including 23 (2.2%) with mutations in high-penetrance genes (five APC, three biallelic MUTYH, 11 BRCA1/2, two PALB2, one CDKN2A, and one TP53), 15 of whom lacked clinical histories suggestive of their underlying mutation. Thirty-eight (3.6%) participants had moderate-penetrance CRC risk gene mutations (19 monoallelic MUTYH, 17 APC*I1307K, two CHEK2). Neither proband age at CRC diagnosis, family history of CRC, nor personal history of other cancers significantly predicted the presence of pathogenic mutations in non-LS genes. Conclusion Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC. MSI/MMR testing reliably identifies LS probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.
Purpose: The homeodomain transcription factor CDX2 is a relatively specific immunohistochemical marker for gastrointestinal carcinoma.
However, no study has comprehensively examined the relationship ...between CDX2 expression in colon cancer and clinical, pathologic,
prognostic, and molecular features, including microsatellite instability and CpG island methylator phenotype (CIMP).
Experimental Design : Utilizing 621 colorectal cancers with clinical outcome and molecular data, CDX2 loss was detected in 183 (29%) tumors by
immunohistochemistry.
Results : In multivariate logistic regression analysis, CDX2 loss was associated with female gender odds ratio (OR), 3.32; P < 0.0001, CIMP-high (OR, 4.42; P = 0.0003), high tumor grade (OR, 2.69; P = 0.0085), stage IV disease (OR, 2.03; P = 0.019), and inversely with LINE-1 hypomethylation (for a 30% decline; OR, 0.33; P = 0.0031), p53 expression (OR, 0.55; P = 0.011), and β-catenin activation (OR, 0.60; P = 0.037), but not with body mass index, tumor location, microsatellite instability, BRAF, KRAS, PIK3CA, p21, or cyclooxygenase-2.
CDX2 loss was not independently associated with patient survival. However, the prognostic effect of CDX2 loss seemed to differ
according to family history of colorectal cancer ( P interaction = 0.0094). CDX2 loss was associated with high overall mortality (multivariate hazard ratio, 2.40; 95% CI, 1.28-4.51) among
patients with a family history of colorectal cancer; no such association was present (multivariate hazard ratio, 0.97; 95%
CI, 0.66-1.41) among patients without a family history of colorectal cancer.
Conclusions : CDX2 loss in colorectal cancer is independently associated with female gender, CIMP-high, high-level LINE-1 methylation,
high tumor grade, and advanced stage. CDX2 loss may be associated with poor prognosis among patients with a family history
of colorectal cancer.
Several prospective cohort studies have examined the association between prediagnosis and/or postdiagnosis physical activity (PA) on colorectal cancer outcomes and reported conflicting results. To ...quantitatively assess this association, we have conducted a meta‐analysis of prospective studies. Databases and reference lists of relevant studies were searched using MEDLINE and EMBASE up to January 2013. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using random‐effects models. For this meta‐analysis, a total of seven prospective cohort studies were included. The analysis included 5,299 patients for prediagnosis PA and 6,348 patients for postdiagnosis PA, followed up over a period ranging from 3.8 to 11.9 years. The analyses showed that patients who participated in any amount of PA before diagnosis had a RR of 0.75 (95% CI: 0.65–0.87, p < 0.001) for colorectal cancer‐specific mortality compared to patients who did not participate in any PA. Those who participated in high PA before diagnosis (vs. low PA) had a RR of 0.70 (95% CI: 0.56–0.87, p = 0.002). Similarly, patients who participated in any PA after diagnosis had a RR of 0.74 (95% CI: 0.58–0.95, p = 0.02) for colorectal cancer‐specific mortality compared to patients who did not participate in any PA. Those who participated in high PA after diagnosis (vs. low PA) had a RR of 0.65 (95% CI: 0.47–0.92, p = 0.01). Similar inverse associations of prediagnosis or postdiagnosis PA were found for all‐cause mortality. In conclusion, both prediagnosis and postdiagnosis PA were associated with reduced colorectal cancer‐specific mortality and all‐cause mortality.
What's new?
Everyone knows exercise is good for you, and it's been shown that physical activity reduces the risk of developing colorectal cancer. A new study investigated what impact exercise has on colorectal cancer outcomes. The authors included a large sample size from seven prospective cohort studies and compared levels of physical activity before and after diagnosis with mortality from all causes after diagnosis with colorectal cancer. They found that physical activity, undertaken either before or after diagnosis, reduces colon cancer mortality.
To identify and characterize potentially avoidable hospitalizations in patients with GI malignancies.
We compiled a retrospective series of sequential hospital admissions in patients with GI cancer. ...Patients were admitted to an inpatient medical oncology or palliative care service between December 2011 and July 2012. Practicing oncology clinicians used a consensus-driven medical record review process to categorize each hospitalization as "potentially avoidable" or "not avoidable." Patient demographic and clinical data were abstracted, and quantitative and qualitative analyses were performed to identify patient characteristics and outcomes associated with potentially avoidable hospitalizations.
We evaluated 201 hospitalizations in 154 unique patients. The median age was 62 years, and colorectal cancer was the most common diagnosis (32%). The majority of hospitalized patients had metastatic cancer (81%). In all, 53% of hospitalizations were attributable to cancer symptoms, and 28% were attributable to complications of cancer treatment. Medical oncologists identified 39 hospitalizations (19%) as potentially avoidable. Hospitalizations were more likely to be categorized as potentially avoidable for patients with the following characteristics: age ≥ 70 years (odds ratio OR, 2.63; 95% CI, 1.15 to 6.02), receipt of an oncologist's advice to consider hospice (OR, 6.09; 95% CI, 2.54 to 14.58), or receipt of three or more lines of chemotherapy (OR, 2.68; 95% CI, 1.01 to 7.08). Ninety-day mortality was higher after avoidable hospitalizations compared with hospitalizations that were not avoidable (OR, 6.4; 95% CI, 1.8 to 22.3).
Potentially avoidable hospitalizations are common in patients with advanced GI cancer. The majority of potentially avoidable hospitalizations occurred in patients with advanced treatment-refractory cancers near the end of life.
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