Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis

Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.     

Association of Apatinib and Breast Cancer: A systematic review and meta-analysis

BackgroundBreast cancer (BC) is a common malignant tumor. Apatinib in combination with other treatments has been used for BC; however, its safety and efficacy are not well-known. Therefore, this meta-analysis was performed to assess the efficacy and safety of apatinib in the treatment of BC.MethodsStudies comparing the effects of apatinib-based therapy versus control among BC patients were included. On January 21, 2022, a systematic search was performed in 9 databases. The risk ratio (RR) with 95% confidence interval (CI) was used to estimate efficacy and safety. The I square value (I²) was used to assess heterogeneity. A leave-one-out sensitivity analysis was also conducted. Publication bias was assessed by funnel plots and Egger's and Begg's tests.ResultsA total of 31 studies including 2,258 BC patients were included. The results showed that apatinib group had a significant improvement in disease control rate (DCR, RR = 1.43, 95% CI = 1.35–1.52, I² = 43.8%) and objective response rate (ORR, RR = 1.79, 95% CI = 1.51–2.13, I² = 61.8%) compared to the control group. Except for hemorrhage, hypertension, and hand-foot syndrome, the adverse events were similar between apatinib group and control group. Subgroup analyses found statistically significant differences in DCR in all subgroups except for apatinib combined with radiation therapy and with paclitaxel liposome plus S1. For ORR, there were statistically significant differences in all subgroups except for the radiation therapy, and apatinib monotherapy subgroups.ConclusionsOur study shown apatinib showed good efficacy and acceptable safety in the treatment of BC patients. More high-quality randomized controlled trials from different regions and countries are needed to confirm our findings.     

The Cardioprotective Effect of Vitamin D in Breast Cancer Patients Receiving Adjuvant Doxorubicin Based Chemotherapy

PurposeThe primary objective of this study was to investigate the potential protective effect of Vitamin D (Vit D) on DOX induced cardio toxicity (DIC) in early breast cancer patients receiving adjuvant DOX based chemotherapy (AC). The secondary objective was to investigate the anti–inflammatory effect of Vit D by measuring serum IL-6 and its correlation with cardio toxicity.MethodsThis study was carried out on 150 newly diagnosed women with breast cancer who were planned to receive four cycles of adjuvant AC chemotherapy regimen (60 mg/m² DOX and 600 mg/m² cyclophosphamide) every 21 days. Study patients were randomized 1:1 into a control group treated with AC and a Vit D group treated with AC plus 0.5 µg of Vit D (Bon One 0.5 µg) orally once daily during the whole treatment course. The cardio protective effect of Vit D was assessed by measuring serum levels of Lactate dehydrogenase (LDH), cardiac troponin T (cTnT), and anti–inflammatory Interleukin 6 (IL-6) at baseline, and after 4 cycles of AC in all study patients.ResultsVit D supplementation in Vit D group patients was associated with a significant decrease (P < 0.001) in serum levels of LDH, cTnT, and IL-6 compared to the control group .ConclusionThe present work provides a promising clinical evidence to support the cardio protective effects of Vit D against DIC through attenuating the evoked pro-inflammatory cytokines induced by DOX.     

Vinorelbine After Prior Treatment With Eribulin for Advanced Breast Cancer: A Single-Centre Experience Suggesting Cross-Resistance

IntroductionThe tubulin inhibitor, eribulin, improves survival for previously treated advanced breast cancer (ABC) compared to chemotherapy of physician's choice, including vinorelbine, an older anti-tubulin. Vinorelbine is commonly still used after eribulin, but potentially risks cross-resistance and its efficacy in this setting is unproven.Materials and MethodsA retrospective analysis of all patients who received vinorelbine after prior eribulin (VAE) 2011-2015 and a parallel cohort of consecutive patients who received vinorelbine without prior eribulin (VWE) for previously treated ABC between 2005 and 2011. Patient demographics, histopathological features, treatment duration and responses were recorded. The primary endpoint was progression-free survival from date of first vinorelbine for each cohort. Secondary endpoints included radiological response rate, and overall survival (OS).ResultsThirty-five VAE and 103 VWE patients were identified, all female, 71.4% and 78.6% were ER positive/HER2 negative, 8.6% and 6.8% HER2 positive, and 20.0% and 14.6% triple negative for VAE and VWE cohorts, respectively. The median number of lines of chemotherapy lines prior to vinorelbine was 4 (range 2-6) and 2 (range 0-4), respectively. Fifteen VAE patients (42.9%) received ≥1 line of chemotherapy between eribulin and vinorelbine. VAE and WWE Patients received a median of 3 cycles of vinorelbine (range 1-9 and 1-12, respectively). The median progression-free survival for VAE patients was 2.1 months and 2.0 months for VWE patients. No VAE patients were progression-free at 24 weeks, compared to 15.5% of VWE patients. Median OS from commencing vinorelbine was 4.3 months for VAE and 6.4 months for VWE patients.ConclusionVinorelbine was of limited benefit after prior eribulin in our study, suggesting cross-resistance. Even without prior eribulin, only 15% of patients experienced clinical benefit from vinorelbine monotherapy.     

Margetuximab Versus Trastuzumab in Patients With Advanced Breast Cancer: A Cost-effectiveness Analysis

BackgroundIn the international, randomized, open-label, phase III study SOPHIA trial, margetuximab plus chemotherapy showed improved progression-free survival (PFS), and overall survival (OS) compared with trastuzumab plus chemotherapy. This study aimed to investigate whether margetuximab plus chemotherapy is cost-effective compared with trastuzumab plus chemotherapy in pretreated patients with ERBB2-positive advanced breast cancer.Materials and MethodsThe clinical data for this model was derived from the SOPHIA trial. Costs and utility were either derived from the standard fee database or extracted from previously published literature. A three-state Markov model was developed to simulate the disease process of patients with advanced breast cancer. One-way sensitivity analyses were conducted to investigate the impact of variables in the analysis model. Probabilistic sensitivity analysis was performed based on 10,000 Monte-Carlo simulations. A subgroup analysis was performed to test whether margetuximab is cost-effective in CD16A-158F allele carriers.ResultsMargetuximab plus chemotherapy provided an incremental 0.04 QALYs with an incremental cost of $66,109.78, compared with the trastuzumab plus chemotherapy, resulting in the incremental cost-effectiveness ratio (ICER) of $1,486,442.35/QALY, which exceeded the willingness to pay (WTP) threshold. While in the CD16A-158F allele carriers subgroup, the ICER decreased to $592,669.73/QALY. The variance of the utility of PFS state, costs of margetuximab, and utility of progressive disease state were the most influential factors in the sensitivity analysis.ConclusionUnder current WTP threshold, margetuximab plus chemotherapy is not cost-effective compared with trastuzumab plus chemotherapy in pretreated patients with ERBB2-positive advanced breast cancer. Selecting CD16A-158F allele carriers might be a considerable option to optimize the cost-effectiveness of margetuximab.     

Geriatric Early-Stage Triple-Negative Breast Cancer Patients in Low-risk Population: Omitting Chemotherapy Based on Nomogram

BackgroundConsidering old age and comorbidities, the actual benefit of chemotherapy in older patients with early triple-negative breast cancer (TNBC) remains uncertain. We aimed to select appropriate patients who could avoid chemotherapy in this population.MethodsA total of 6482 patients more than 65 years old with T1-2N0-1M0 TNBC in 2010-2015 were extracted from SEER program. Multivariate logistic regression was performed to identify independent factors associated with chemotherapy usage. Survival analysis was performed using Kaplan-Meier plots and log-rank tests. Independent prognostic factors were identified by multivariate Cox analysis. A nomogram predicting breast cancer-specific survival (BCSS) and a risk stratification model were constructed.ResultsA total of 3379 (52.13%) patients received chemotherapy while 3103 (47.87%) did not. Age, married status, grade, T-stage, N-stage, radiation and breast-conserving surgery (BCS) were significantly associated with chemotherapy usage (all P < .05). Chemotherapy significantly improved OS (HR = 0.606, P < .001) and BCSS (HR = 0.763, P = .006) in the entire population. A nomogram was built by incorporating independent risk factors (age, T-stage, N-stage, grade and radiation). Based on the score of the nomogram, the risk stratification model demonstrated that chemotherapy improved OS (P < .001) and BCSS (P < .001) of patients in the high-risk group (score >180), but not in the low-risk group (score ≤75).ConclusionChemotherapy is beneficial for geriatric patients with T1-2N0-1M0 TNBC in this study, and the risk stratification model indicates the feasibility of sparing chemotherapy in low-risk subgroup without sacrificing survival, providing clinicians tools to weigh the risk–benefit of chemotherapy and customize the individualized treatment accordingly.     

Model-Based Selection for Proton Therapy in Breast Cancer: Development of the National Indication Protocol for Proton Therapy and First Clinical Experiences

AimsProton therapy is a radiation technique that yields less dose in normal tissues than photon therapy. In the Netherlands, proton therapy is reimbursed if the reduced dose to normal tissues is predicted to translate into a prespecified reduction in toxicity, based on nationally approved validated models. The aim of this paper is to present the development of a national indication protocol for proton therapy (NIPP) for model-based selection of breast cancer patients and to report on first clinical experiences.Materials and methodsA national proton therapy working group for breast cancer (PWG-BC) screened the literature for prognostic models able to estimate the individual risk of specific radiation-induced side-effects. After critical appraisal and selection of suitable models, a NIPP for breast cancer was written and subjected to comments by all stakeholders. The approved NIPP was subsequently introduced to select breast cancer patients who would benefit most from proton therapy.ResultsThe model of Darby et al. (N Engl J Med 2013; 368:987–82) was the only model fulfilling the criteria prespecified by the PWG-BC. The model estimates the relative risk of an acute coronary event (ACE) based on the mean heart dose. The absolute lifetime risk of ACE <80 years was calculated by applying this model to the Dutch absolute incidence of ACE for female and male patients, between 40 and 70 years at breast cancer radiotherapy, with/without cardiovascular risk factors. The NIPP was approved for reimbursement in January 2019. Based on a threshold value of a 2% absolute lower risk on ACE for proton therapy compared with photons, 268 breast cancer patients have been treated in the Netherlands with proton therapy between February 2019 and January 2021.ConclusionThe NIPP includes a model that allows the estimation of the absolute risk on ACE <80 years based on mean heart dose. In the first 2 years, 268 breast cancer patients have been treated with proton therapy in The Netherlands.     

Clinical Utility of Genomic Recurrence Risk Stratification in Early,Hormone-Receptor-Positive,Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Real-World Experience

BackgroundRNA-based genomic risk assessment estimates chemotherapy benefit in patients with hormone-receptor positive (HR+)/Human Epidermal Growth Factor 2-negative (ERBB2-) breast cancer (BC). It is virtually used in all patients with early HR+/ERBB2- BC regardless of clinical recurrence risk.Patients and methodsWe conducted a retrospective chart review of adult patients with early-stage (T1-3; N0; M0) HR+/ERBB2- BC who underwent genomic testing using the Oncotype DX (Exact Sciences) 21-genes assay. Clinicopathologic features were collected to assess the clinical recurrence risk, in terms of clinical risk score (CRS) and using a composite risk score of distant recurrence Regan Risk Score (RRS). CRS and RRS were compared to the genomic risk of recurrence (GRS).ResultsBetween January 2015 and December 2020, 517 patients with early-stage disease underwent genomic testing, and clinical data was available for 501 of them. There was statistically significant concordance between the 3 prognostication methods (P < 0.01). Within patients with low CRS (n = 349), 9.17% had a high GRS, compared to 8.93% in patients with low RRS (n = 280). In patients with grade 1 histology (n = 130), 3.85% had a high GRS and 68.46% had tumors > 1 cm, of whom only 4.49% had a high GRS. Tumor size > 1cm did not associate with a high GRS.ConclusionGenomic testing for patients with grade 1 tumors may be safely omitted, irrespective of size. Our finds call for a better understanding of the need for routine genomic testing in patients with low grade/low clinical risk of recurrence.     

Limited Impact of Breast Cancer and Non-breast Malignancies on Survival in Older Patients with Early-Stage Breast Cancer: Results of a Large,Single-Centre,Population-Based Study

AimsTo analyse the disease-free survival and overall survival in older adults with breast cancer after breast-conserving therapy, focusing on the relevance of non-breast malignancy (NBM) with respect to survival rates.Materials and methodsAnalyses were based on 1205 women aged 65 years and older with breast cancer treated with breast-conserving therapy between 1999 and 2015. Patients were divided into three age categories: 65–70, 71–75 and >75 years. Multivariate survival analysis was carried out using Cox regression analysis.ResultsThe two youngest age categories showed excellent results, with a 12-year disease-free survival of 84.6 and 86.3%, respectively. We noted a 17.2% incidence of NBM, particularly for colon cancer and lung cancer. Most (72.9%) occurred after a diagnosis of breast cancer. Of those 72.9%, about 50% died as a result of NBM within 2 years of the diagnosis of NBM. The overall 12-year NBM-specific survival was 92.0%. The 12-year overall survival was 60.0% for all and for the three abovementioned age categories was 73.3, 54.4 and 28.4%, respectively. The cause of death for all was predominantly non-malignancy-related morbidity.ConclusionThe impact of breast cancer on life expectancy was limited, in particularly for women aged 65–75 years. The relevance of NBM on survival was limited.     

Presentation,Diagnosis and Treatment Delays in Breast Cancer Care and Their Associations in Sri Lanka,a Low-resourced Country

AimsDelays in breast cancer care, one important attributable factor for breast cancer being diagnosed at advanced stages, are not systematically studied in many countries. This study assessed the magnitude and factors associated with delays in breast cancer care in Sri Lanka, from symptom detection to treatment initiation.Materials and methodsWe interviewed 800 consecutively sampled female breast cancer patients, diagnosed within the last 12 months, using context-specific questionnaires and medical records. We defined the cut-off times for delays using international guidelines and features of the national health system and care-seeking patterns in the country. Delays were estimated as proportions with 95% confidence intervals and presented for: (i) presentation delay; (ii) diagnosis delay and (iii) treatment delay. We looked at how sociodemographic and healthcare availability and accessibility at the individual level were associated with delays using multivariate logistic regression, with a P value of 0.05 to define statistical significance.ResultsNearly two-thirds of patients reported a presentation delay (63.3%, 95% confidence interval 59.9–66.6%). A diagnosis delay (36.7%, 95% confidence interval 33.4–40.0%) was also seen among one-third, whereas treatment delays (13.2%, 95% confidence interval 10.8–15.5%) were less common. Low family monthly income (odds ratio 6.3; 95% confidence interval 4.2–9.3) and poor knowledge on breast cancer (odds ratio 2.7; 95% confidence interval 1.8–3.8) were associated with presentation delay. Poor health literacy (odds ratio 1.7; 95% confidence interval 1.1–2.7) and the need to make more than two visits to the first contact health provider prior to diagnosis (odds ratio 7.2; 95% confidence interval 4.6–11.1) were associated with diagnosis delays, whereas directly contacting an appropriate specialised health provider once the lump was detected reduced diagnosis delay (odds ratio 0.3; 95% confidence interval 0.2–0.4). Having undergone a core biopsy (odds ratio 0.5; 95% confidence interval 0.3–0.8) and having a mammogram (odds ratio 0.6; 95% confidence interval 4.7–32.7) reduced the likelihood of treatment delays.ConclusionsOur study findings show that delays in breast cancer care in Sri Lanka are much lower than those in other lower-middle income countries. However, there is significant room for improvement, especially in relation to the excellence in quality of care, such as improving access to mammography services. Periodical estimation of breast cancer delays enabling temporal comparisons will probably provide useful information to policy makers in improving care delivery for breast cancer patients and, hence, is recommended. Such future assessments designed for comparisons between different treatment modalities would provide more information to assist policy decisions in care improvement.     

Tumor-Infiltrating Lymphocytes (TIL), Tertiary Lymphoid Structures (TLS), and Expression of PD-1, TIM-3, LAG-3 on TIL in Invasive and In Situ Ductal Breast Carcinomas and Their Relationship with Prognostic Factors

IntroductionImmunotherapy has been determined as an important choice in breast carcinomas, especially in tumors with markedly inflammatory response. About this promising subject, tumor-infiltrating lymphocytes (TIL) and the expression of immune control point receptors on TIL have gained importance.Materials and MethodsIn this study, stromal TIL and tertiary lymphoid structures (TLS) were determined in tumor tissues of 312 invasive and 68 in situ breast cancer patients. Expression rates of PD-1, LAG-3, and TIM-3 on intratumoral and stromal TIL were immunohistochemically evaluated.ResultsIn invasive breast carcinomas, stromal TIL was found to be significantly associated with lymph node metastasis, HR and HER2 expression, and basal-like phenotype, as the presence of TLS with neoadjuvant therapy, recurrence, death, and expression of HR and HER2. PD-1, LAG-3, and TIM-3 expressions were found to be associated with HR and HER2 status, stromal TIL rates, and TLS. In multivariate analysis, high stromal TIL and PD-1 expression in intratumoral TIL were found to be independent prognostic factors in terms of overall survival and disease-free survival.ConclusionEvaluation of TIL and immune control point receptor expressions in breast cancer is particularly important in terms of planning the therapeutic approaches based on immunotherapy protocols.     

Clinical Updates for Colon Cancer Care in 2022

Colon cancer needs better screening and treatment options. Its incidence in the young population is rising. Recent changes in guidelines recommend beginning screening for colon cancer at the age of 45. Circulating tumor DNA presents an opportunity to select patients for administration of adjuvant chemotherapy. Immunotherapy is an option for patients with a deficiency in mismatch repair proteins. However, its efficacy outside of this group of patients remains a challenge. Targeted therapies such as BRAF inhibitors are an option for patients with poor prognosis, for whom cytotoxic chemotherapy is not as effective. This review presents the recently published evidence regarding screening and treating patients with colon cancer.     

Breast reconstruction after therapeutic or prophylactic mastectomy for breast cancer: A comparison of guideline recommendations

BackgroundThe purpose of this article is to illuminate differences in published clinical practice guideline recommendations for breast reconstruction after prophylactic and therapeutic mastectomy.MethodsTen guidelines were identified through a systematic search of websites and databases of reputable oncology guideline developers, and key differences and gaps in recommendations were noted. Quality assessment of the guidelines was conducted by three reviewers using the AGREE II tool, focusing on breast reconstruction specific documents rather than the general breast cancer guidelines.ResultsThe most comprehensive guidelines were published by Alberta Health Services, Cancer Care Ontario, the American Society of Plastic Surgeons, and the Association of Breast Surgery/British Association of Plastic Reconstructive and Aesthetic Surgeons. AGREE II scores in the domains of “Scope and Purpose” and “Clarity and Presentation” were ranked relatively high for all four guidelines while “Applicability” and “Editorial Independence” were ranked relatively low. The Alberta and Ontario guidelines were the overall highest ranked guidelines across all domains.ConclusionOverall, these guidelines provide consistent recommendations on who should receive breast reconstruction education, who is a candidate for postmastectomy breast reconstruction, and the appropriate timing of reconstruction and extent of mastectomy. Future updates from all should focus on expanding to include alloplastic and autologous forms of reconstruction and should include a broad scope of relevant questions.     

BCG Administration after Prior Radiation Treatment for Prostate Cancer

IntroductionProstate radiotherapy is associated with worse oncologic outcomes in patients with bladder cancer. The underlying mechanism is incompletely understood but is thought to be related to an altered microenvironment promoting tumorigenesis. However, there is a gap in the literature regarding how the effect of BCG varies according to prior radiotherapy in patients with non–muscle invasive bladder cancer (NMIBC). In this context, we sought to evaluate oncologic outcomes in NMIBC patients who have previously undergone prostate radiotherapy compared to patients with no prior history of pelvic radiotherapy.MethodsThis is a retrospective cohort study that includes all patients who received intravesical for NMIBC at our institution from 2001 to 2019. Patients were stratified into 3 cohorts: prior radiotherapy (RT), radical prostatectomy (RP), and no prostate cancer (No PCa). The outcomes of interest were recurrence at 1-year, progression to muscle-invasive bladder cancer (MIBC), and progression to metastatic disease. Comparisons were also made between cohorts with respect to elapsed time from radiation therapy. Wilcoxon rank-sum test was used for comparing continuous variables, while χ² and Fischer's exact tests were used to examine categorical variables.ResultsIn 199 total patients who underwent BCG for NMIBC, 23 had a prior history of prostate radiotherapy treatment, while 17 underwent prior radical prostatectomy. Overall, 41.2% of patients had recurrence at 1 year. There was no difference in the number of induction or maintenance BCG administrations received between the cohorts within the first year. There was no significant difference in recurrence at 1 year between the 3 cohorts (P = .56). There was also no difference in progression to MIBC or progression to metastatic disease with P = .50 and 0.89, respectively.ConclusionThe risk of recurrence after induction BCG treatment for high-grade NMIBC does not vary according to prior radiation treatment for prostate cancer.     

The effect of the American Joint Committee on Cancer eighth edition on breast cancer staging and prognostication

IntroductionBreast cancer staging has been developed to quantify prognosis and guide treatment. The American Joint Committee on Cancer eighth edition manual (AJCC8) departed from traditional anatomic staging by incorporating biological factors such as grade, hormone and HER2 receptor status into a novel prognostic staging model. The aim of this study was to externally validate AJCC8 prognostic staging.MethodsThis retrospective cohort investigated patients diagnosed between 2010 and 2013 at the McGill University Health Center. Patients were classified using both anatomic and prognostic staging systems according AJCC8. Overall survival analysis using a multivariate Cox-proportional hazard model was performed and model accuracy was evaluated using the Harrell concordance index (C-index) and Akaike Information Criterion (AIC).ResultsThe cohort included 1703 women. Anatomic and prognostic stage assignments displayed discrepancies for 46.2% of patients, where 38.8% were downstaged and 7.5% were upstaged with prognostic staging. Patients with anatomic stages IB, IIA, IIB, IIIA and IIIC had high rates of downstaging (64.6–96.5%), as opposed to anatomic stages IA and IIIB where 93.1% and 75.0% of patients stage remained unchanged, respectively. The prognostic stage displayed increased prognostic accuracy with respect to overall survival, where the C-index was significantly higher compared to anatomic staging (0.810 vs 0.799, p < 0.05). In addition, prognostic staging displayed an improved model fit with a lower AIC (983.9) compared to anatomic staging (995.2).ConclusionPrognostic and anatomic staging differ in their classification of patients, where prognostic staging displays improved accuracy, supporting its use in informing patient prognosis and guiding treatment decisions.     

Validation of the American Joint Committee on Cancer 8th edition staging system for the pancreatic ductal adenocarcinoma

Background & aimsThe American Joint Commission on Cancer (AJCC) 8th edition staging system for pancreatic ductal adenocarcinoma (PDA) contains several significant changes. This study aimed to validate the AJCC 8th edition staging system of PDA.MethodsWe analyzed patients with resected PDA between 2001 and 2017 using the Korean Pancreatic Cancer (K-PaC) registry. Overall survival (OS) was estimated using the Kaplan-Meier survival curves and compared via the log-rank test.ResultsIn total, 701 resected PDA patients were identified. During a median follow-up of 24.5 months, the median OS was 21.7 months. Meanwhile, the median OS of each stage according to the AJCC 8th edition was 73.5 months (stage IA), 41.9 months (stage IB), 24.2 months (stage IIA), 18.3 months (stage IIB), and 16.8 months (stage III). However, the new N-category (pN1 vs. pN2) did not subdivide prognosis, although the lymph node ratio (i.e., the ratio of the number of LN involved to the number of examined LN) did. Although pT3 and pN2 belong under stage III, pN2 has a significantly longer median OS than pT3 (16.9 months vs 11.2 months; p < 0.01).ConclusionThe AJCC 8th edition staging system appropriately stratifies the prognosis of PDA patients. However, the cutoff of the N-category is not statistically valid, and the new stage III includes a heterogeneous category (pN2 and pT4). Therefore, we propose that stage III be divided into stage IIIA (Tany N2 M0) and stage IIIB (T4 Nany M0).     

Comorbidities,timing of treatments,and chemotherapy use influence outcomes in stage III colon cancer: A population-based European study

IntroductionFor stage III colon cancer (CC), surgery followed by chemotherapy is the main curative approach, although optimum times between diagnosis and surgery, and surgery and chemotherapy, have not been established.Materials and methodsWe analysed a population-based sample of 1912 stage III CC cases diagnosed in eight European countries in 2009–2013 aiming to estimate: (i) odds of receiving postoperative chemotherapy, overall and within eight weeks of surgery; (ii) risks of death/relapse, according to treatment, Charlson Comorbidity Index, time from diagnosis to surgery for emergency and elective cases, and time from surgery to chemotherapy; and (iii) time-trends in chemotherapy use.ResultsOverall, 97% of cases received surgery and 65% postoperative chemotherapy, with 71% of these receiving chemotherapy within eight weeks of surgery. Risks of death and relapse were higher for cases starting chemotherapy with delay, but better than for cases not given chemotherapy. Fewer patients with high comorbidities received chemotherapy than those with low (P < 0.001). Chemotherapy timing did not vary (P = 0.250) between high and low comorbidity cases. Electively-operated cases with low comorbidities received surgery more promptly than high comorbidity cases. Risks of death and relapse were lower for elective cases given surgery after four weeks than cases given surgery within a week. High comorbidities were always independently associated with poorer outcomes. Chemotherapy use increased over time.ConclusionsOur data indicate that promptly-administered postoperative chemotherapy maximizes its benefit, and that careful assessment of comorbidities is important before treatment. The survival benefit associated with slightly delayed elective surgery deserves further investigation.