Adjuvant chemotherapy for stage III colon cancer in the oldest old

BACKGROUND:

Randomized trials demonstrating the benefits of chemotherapy in patients with American Joint Committee on Cancer stage III colon cancer underrepresent persons aged ≥ 75 years. The generalizability of these studies to a growing elderly population remains unknown.

METHODS:

Using the California Cancer Registry for 1994 through 2008, the authors conducted a population‐based study of postcolectomy patients aged 50 years to 94 years with stage III (N1M0) colon adenocarcinoma. A 2‐sided chi‐square test and Cochran‐Armitage test for trend were used to compare patient and tumor characteristics associated with receipt of chemotherapy across age groups. Multivariate regression was used to assess the association between older age and receipt of chemotherapy. Kaplan‐Meier methods and Cox proportional hazards modeling were used to evaluate the association between chemotherapy and mortality, with propensity score adjustment.

RESULTS:

Approximately 44% (12,382 patients) of the study cohort was aged ≥ 75 years. Persons aged ≥ 75 years were found to be less likely to have received adjuvant chemotherapy than those aged < 75 years (30% vs 68% in patients aged 50 years‐74 years; P < .0001). On multivariate analysis, patients aged 75 years to 84 years were 13 times less likely, and those aged 85 years to 94 years were 24 times less likely, to have received chemotherapy as patients aged 50 years to 64 years. Nevertheless, age‐stratified multivariate survival analyses indicated that chemotherapy provided comparable mortality reduction across age groups.

CONCLUSIONS:

The percentage of persons aged ≥ 75 years receiving adjuvant chemotherapy remains low despite demonstrated survival benefits. These findings deserve attention within the context of a patient's life expectancy, underlying comorbidities, and performance status, as well as clinician bias. The results of the current study support the call for phase II/III studies assessing the toxicities and benefits of adjuvant chemotherapy for the treatment of stage III colon cancer in the elderly. Cancer 2013. © 2012 American Cancer Society     

The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer

Background:

Inflammation has a critical role in the pathogenesis and progression of cancer. The lymphocyte to monocyte ratio (LMR) could be shown to be prognostic in haematologic neoplasia. In this study, we analysed the LMR with clinical outcome in stage II and III colon cancer patients.

Methods:

Three hundred and seventy-two patients with stage II and III colon cancer were included in this retrospective study. Kaplan–Meier curves and multivariate Cox-regression analyses were calculated for time to recurrence (TTR) and overall survival (OS).

Results:

Including all patients, the elevated preoperative LMR was significantly associated with increased TTR and OS in multivariate analysis (HR: 0.47, 95%CI: 0.29–0.76, P=0.002; HR: 0.51, 95%CI: 0.31–0.83, P=0.007; respectively). In subanalyses, the association was limited to patients with stage III (HR: 0.40, 95%CI: 0.22–0.72, P=0.002), in contrast to patients with stage II (HR: 0.40, 95%CI: 0.28–1.66, P=0.397). When the subgroup of patients with ‘high-risk'' LMR⩽2.83 was analysed, no benefit of adjuvant 5-FU-based chemotherapy could be found (HR: 0.99; 95%CI: 0.60–1.63; P=0.953).

Conclusion:

The LMR might be an independent prognostic marker for TTR in stage III colon cancer patients. Our results further suggest that high-risk patients based on the LMR do not benefit from adjuvant chemotherapy. Independent validation of our findings is warranted.     

Evaluation of the transferability of survival calculators for stage II/III colon cancer across healthcare systems

Adjuvant! Online Inc (A!O), the Memorial Sloan Kettering Cancer Center (MSKCC), MD Anderson (MDA) and Mayo Clinic (MC) provide calculators to predict survival probabilities for patients with resected early-stage colon cancer, trained on data from United States (US) patient cohorts or patients enrolled in international clinical trials. Limited data exist on the transferability of calculators across healthcare systems. Calculator transferability to Australian community practice was evaluated for 1,401 stage II/III patients. Calibration and discrimination were assessed for overall (OS), cancer-specific (CSS) or recurrence-free survival (RFS). The US patient cohort-based calculators, A!O, MSKCC and MDA, significantly overestimated risks of recurrence and death in Australian patients, with 5-year OS, CSS and RFS prediction differences of −6.5% to −9.9%, −9.1% to −14.4% and − 3.8% to −6.8%, respectively (p < 0.001). Significant heterogeneity in calibration was observed for subgroups by tumor stage and treatment, age, gender, tumor location, ECOG and ASA score. Calibration appeared acceptable for the clinical trial patient-based MC calculator, but restricted tool applicability (stage III patients, ≥12 examined lymph nodes, receiving adjuvant treatment) limited the sample size. Compared to AJCC 7th edition tumor staging, calculators showed improved discrimination for OS, but no improvement for CSS and RFS. In conclusion, deficiencies in calibration limited transferability of US patient cohort-based survival calculators for early-stage colon cancer to the setting of Australian community practice. Our results demonstrate the utility for multi-feature survival calculators to improve OS predictions but highlight the importance for performance assessment of tools prior to implementation in an external health care setting.     

A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m(-2) LV+450 mg m(-2) 5-FU weekly, weeks 1-6, in 8 weeks cycles x 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61-1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45-1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS.     

Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial

Background:

The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis.

Methods:

Patients aged 20–80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m⁻² per day as tegafur; LV, 75 mg per day on days 1–28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1–28, every 42 days, 4 courses). Treatment status and safety were evaluated.

Results:

Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of ⩾grade 3 AEs were 16% and 14%, respectively.

Conclusion:

Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.     

Real‐world resource use and costs of adjuvant treatment for stage III colon cancer

Since the generalisability of trial‐based economic evaluations may be limited, there is an increasing focus on real‐world cost‐effectiveness. Real‐world studies involve evaluating the effects and costs of treatments in daily clinical practice. This study reports on the real‐world resource use and costs of adjuvant treatments of stage III colon cancer in a population‐based observational study. Analyses were based on a detailed retrospective medical chart review which was conducted for 206 patients with colon cancer treated in 2005 and 2006 in the Netherlands. Mean total costs per patient were €9681 for 5‐FU/LV, €9736 for capecitabine, €32 793 for FOLFOX and €18 361 for CAPOX. Drug costs and the costs related to hospitalisations for chemotherapy administration were the main cost drivers. We identified a potential for substantial cost‐savings when the 48 h administration of 5FU/LV in the FOLFOX regimen were to take place in an outpatient setting or be replaced by oral capecitabine as in the CAPOX regimen. This analysis based on detailed real‐life data clearly indicates that clinical choices made in oncology based on efficacy of therapy have economic consequences. Considering today's reality of finite healthcare resources, these economic consequences deserve a formal role in clinical decision making, for instance in guideline development.     

Administration of adjuvant chemotherapy for stage II‐III colon cancer patients: An European population‐based study

The advantage of adjuvant chemotherapy (ACT) for treating Stage III colon cancer patients is well established and widely accepted. However, many patients with Stage III colon cancer do not receive ACT. Moreover, there are controversies around the effectiveness of ACT for Stage II patients. We investigated the administration of ACT and its association with overall survival in resected Stage II (overall and stratified by low‐/high‐risk) and Stage III colon cancer patients in three European countries including The Netherlands (2009–2014), Belgium (2009–2013) and Sweden (2009–2014). Hazard ratios (HR) for death were obtained by Cox regression models adjusted for potential confounders. A total of 60244 resected colon cancer patients with pathological Stages II and III were analyzed. A small proportion (range 9–24%) of Stage II and over half (range 55–68%) of Stage III patients received ACT. Administration of ACT in Stages II and III tumors decreased with higher age of patients. Administration of ACT was significantly associated with higher overall survival in high‐risk Stage II patients (in The Netherlands (HR; 95%CI = 0.82 (0.67–0.99), Belgium (0.73; 0.59–0.90) and Sweden (0.58; 0.44–0.75)), and in Stage III patients (in The Netherlands (0.47; 0.43–0.50), Belgium (0.46; 0.41–0.50) and Sweden (0.48; 0.43–0.54)). In Stage III, results were consistent across subgroups including elderly patients. Our results show an association of ACT with higher survival among Stage III and high‐risk Stage II colon cancer patients. Further investigations are needed on the selection criteria of Stages II and III colon cancer patients for ACT.     

Adjuvant treatment for elderly patients with stage III colon cancer in the southern Netherlands is affected by socioeconomic status, gender, and comorbidity.

BACKGROUND: Adjuvant 5-fluorouracil-based chemotherapy significantly decreases mortality among patients with stage III colon cancer, but is less prescribed with rising age. We were interested in the pattern of adjuvant treatment and possible effects on survival among elderly patients. PATIENTS AND METHODS: All resected patients aged 65-79 with stage III colon carcinoma, diagnosed between 1995 and 2001 in the Comprehensive Cancer Centre South registry area in the Netherlands were included (n=577). We examined determinants of receipt of adjuvant chemotherapy and their relation to survival. RESULTS: The proportion of elderly patients receiving adjuvant chemotherapy increased from 19% in 1995 to 50% in 2001, but a large inter-hospital variation remained. In a multivariable analysis, females [odds ratio (OR) 0.5, P=0.006], patients with comorbidity [OR 0.5, P=0.005], and patients with a low socioeconomic status [OR 0.5, P=0.02] received less adjuvant therapy. Between 1995 and 2001 survival of elderly patients improved (hazard ratio 0.8, P=0.04). CONCLUSION: Although an increasing proportion of elderly patients with colon cancer are treated with adjuvant chemotherapy, many elderly patients still do not receive this treatment. As expected, receipt of adjuvant treatment decreased in the presence of comorbidity, but the clinical rationale for undertreatment of women and patients with low socioeconomic status is not clear.     

Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers

Microsatellite instability (MSI) has been associated with favourable survival in early stage colorectal cancer (CRC) compared to microsatellite stable (MSS) CRC. The BRAF V600E mutation has been associated with worse survival in MSS CRC. This mutation occurs in 40% of MSI CRC and it is unclear whether it confers worse survival in this setting. The prognostic value of KRAS mutations in both MSS and MSI CRC remains unclear. We examined the effect of BRAF and KRAS mutations on survival in stage II and III MSI colon cancer patients. BRAF exon 15 and KRAS exon 2–3 mutation status was assessed in 143 stage II (n = 85) and III (n = 58) MSI colon cancers by high resolution melting analysis and sequencing. The relation between mutation status and cancer‐specific (CSS) and overall survival (OS) was analyzed using Kaplan–Meier and Cox regression analysis. BRAF V600E mutations were observed in 51% (n = 73) and KRAS mutations in 16% of cases (n = 23). Patients with double wild‐type cancers (dWT; i.e., BRAF and KRAS wild‐type) had a highly favourable survival with 5‐year CSS of 93% (95% CI 84–100%), while patients with cancers harbouring mutations in either BRAF or KRAS, had 5‐year CSS of 76% (95% CI 67–85%). In the subgroup of stage II patients with dWT cancers no cancer‐specific deaths were observed. On multivariate analysis, mutation in either BRAF or KRAS vs. dWT remained significantly prognostic. Mutations in BRAF as well as KRAS should be analyzed when considering these genes as prognostic markers in MSI colon cancers.     

The impact of molecular profile on the lymphatic spread pattern in stage III colon cancer

The anatomical spread of lymph node (LN) metastasis is of practical importance in the surgical management of colon cancer (CC). We examined the effect of KRAS, BRAF, and microsatellite instability (MSI) on LN count and anatomical spread pattern in stage III CC. We determined KRAS, BRAF, and MSI status from stage III CC patients. Biomarker status was correlated with LN count and anatomical spread pattern, which was classified as sequential or skipped. Relapse-free survival (RFS) was estimated using Kaplan-Meier method, and correlations were assessed using log-rank and Cox regression analyses. We analyzed 369 stage III CC patients. The proportion of KRAS mutant (mt), BRAF mt, and MSI-high (H) were 44.2% (163/344), 6.8% (25/344), and 6.8% (25/344), respectively. The mean number of metastatic LN was higher in microsatellite-stable (MSS) compared with MSI patients (3.5 vs. 2.7, P = .0406), although no differences were observed in accordance with KRAS or BRAF status. Interestingly, patients with BRAF mt and MSI-H were less likely to harbor skipped metastatic LN (9.3% vs 20% and 4% vs 10.5% compared with BRAF wild-type (wt) and MSS, respectively), but KRAS status did not predict anatomical spread pattern. Patients with KRAS wt and MSI-H showed superior RFS compared with KRAS mt and MSS patients, respectively, whereas BRAF status did not affect RFS. Differences exist in the anatomical pattern of invaded LN in accordance with the molecular status of stage III CC. Patients with MSI-H CC have less invaded and skipped LN, suggesting that a tailored surgical approach is possible.     

Cost-effectiveness analysis of oxaliplatin compared with 5-fluorouracil/leucovorin in adjuvant treatment of stage III colon cancer in the US

BACKGROUND: The MOSAIC trial demonstrated that oxaliplatin/5-fluorouracil/leucovorin (FU/LV) (FOLFOX4) as adjuvant treatment of TNM stage II and III colon cancer significantly improves disease-free survival compared with 5-FU/LV alone. For stage III patients the 4-year disease-free survival (DFS) was 69% in the FOLFOX4 arm vs 61% in the LV5FU2 arm, P = .002). The cost-effectiveness of FOLFOX4 in stage III patients was evaluated from a US Medicare perspective. METHODS: By using individual patient-level data from the MOSAIC trial (median follow-up: 44.2 months), DFS and overall survival (OS) were estimated up to 4 years from randomization. DFS was extrapolated from 4 to 5 years by fitting a Weibull model and subsequent survival was estimated from life tables. OS beyond 4 years was predicted from the extrapolated DFS estimates and observed survival after recurrence. Costs were calculated from trial data and external estimates of resources to manage recurrence. RESULTS: Patients on FOLFOX4 were predicted to gain 2.00 (95% confidence interval [CI]: 0.63, 3.37) years of DFS over those on 5-FU/LV. The predicted life expectancy of stage III patients on FOLFOX4 and 5-FU/LV was 17.61 and 16.26 years, respectively. Mean total lifetime disease-related costs were $56,300 with oxaliplatin and $39,300 with 5-FU/LV. Compared with 5-FU/LV, FOLFOX4 was estimated to cost $20,600 per life-year gained and $22,800 per quality-adjusted life-year (QALY) gained, discounting costs and outcomes at 3% per annum. CONCLUSIONS: FOLFOX4 is likely to be cost-effective compared with 5-FU/LV in the adjuvant treatment of stage III colon cancer. The incremental cost-effectiveness ratio compares favorably with other funded interventions in oncology.     

DNA methylation predicts recurrence from resected stage III proximal colon cancer

BACKGROUND:

In colorectal cancer (CRC), DNA methylation anomalies define distinct subgroups termed CpG island methylator phenotype 1 (CIMP1), CIMP2, and CIMP‐negative. The role of this classification in predicting recurrence and disease‐free survival (DFS) in resected stage III CRC was evaluated.

METHODS:

Sporadic cancers from 161 patients were analyzed. Bisulfite pyrosequencing was used to examine the methylation of 2 global DNA methylation markers (LINE‐1, Alu) and 9 loci (MINT1, MINT2, MINT31, P16, hMLH1, P14, SFRP1, SFRP2, and WNT5A). Mutations in BRAF and KRAS were assayed.

RESULTS:

Gene hypermethylation clustered in discrete groups of patients, indicating the presence of CIMP. K‐means clustering analysis identified 3 discrete subgroups: CIMP1 (n = 22, 13.7%), associated with proximal location and BRAF mutations; CIMP2 (n = 40, 24.8%), associated with KRAS mutations; and CIMP‐negative (n = 99, 61.5%), associated with distal location. In proximal CRC, CIMP1 was correlated with a higher recurrence rate (53% for CIMP1, 18% for CIMP2, and 26% for CIMP‐negative) and a worse DFS (P = .015). Also in proximal CRC, LINE‐1 methylation was lower in patients whose cancer recurred compared with those whose cancer did not recur (P = .049). In multivariate analysis, CIMP1 and low LINE1 methylation were independent prognostic factors for DFS in proximal CRC (P = .008 for classification by K‐means clustering analysis; P = .040 for LINE‐1 methylation status).

CONCLUSIONS:

DNA methylation is a useful biomarker of recurrence in resected stage III proximal but not distal CRC. However, as the number of CIMP1 cases was small in distal CRC, further study is required to validate our findings. Cancer 2011. © 2010 American Cancer Society.     

Redefining adjuvant chemotherapy in patients with stage III colon cancer: X-ACT trial

The current standard adjuvant chemotherapy for suitable patients with stage III colon cancer is the combination of oxaliplatin and 5-fluorouracil plus folinic acid (5-FU/LV). However, until recently and for many years prior to this, the accepted standard adjuvant chemotherapy was 6–8 months of bolus 5-FU/LV. However, bolus treatment was associated with significant toxicity, namely stomatitis, diarrhea and neutropenia, in addition to multiple hospital visits for drug administration for patients. The X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) compared traditional bolus 5-FU/LV (as per the Mayo Clinic regimen) with capecitabine, in the adjuvant treatment of 1987 stage III colon cancer patients. The main safety, efficacy and pharmacoeconomic results have all been published, and the updated 5-year efficacy results have also recently been presented. This trial demonstrated that capecitabine was at least as effective as bolus 5-FU/LV in terms of disease-free and overall survival, with trends towards superiority for both. Moreover, there was much less toxicity associated with capecitabine, apart from hand–foot syndrome which was significantly more prevalent. On the basis of the X-ACT trial, capecitabine was approved by the US FDA, the National Institute for Clinical Excellence and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer.     

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 x 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135-1.856, P=0.0028; HR 1.506, 95% CI 1.150-1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially.     

Trends in Adjuvant Chemotherapy Use Among Stage III Colon Cancer in Non-Elderly and Low Comorbidity Patients

BackgroundAdjuvant chemotherapy for stage III colon cancer is underutilized in the United States. The aim of this study was to assess the use of adjuvant chemotherapy in younger and medically fit patients and analyze the socioeconomic factors associated with its utilization.MethodsUsing the National Cancer Database from 2004 to 2015, we selected stage III colon cancer patients between age 18 to 65, Charlson-Deyo Comorbidity Index (CDCI) of 0 or 1, and those that survived at least 12 months after surgery. We then compared patients that underwent surgery only with those that received adjuvant chemotherapy. Multivariable logistic regression analysis was performed to identify variables associated with adjuvant chemotherapy use in the population. Overall survival was estimated by Kaplan-Meier curves.ResultsOf the 48,336 patients that met inclusion criteria, 43,315 (90%) received adjuvant chemotherapy. The utilization of adjuvant chemotherapy increased from 87% in 2004 to 91% in 2015. On multivariable regression analysis, the use of adjuvant chemotherapy was lower among males, Non-Hispanic Blacks and Hispanics, low-grade cancer, left-sided tumors, CDCI 1, those who travel ≥ 50 miles, yearly income < $40,227, and uninsured patients. The most common reason for the omission of adjuvant chemotherapy was the patient or caregiver's choice (40% between 2013 and 2015). The 5-year and 10-year overall survival rates were 76.7% and 63.8% respectively, in those who received adjuvant chemotherapy as compared to 65.1% and 49.3% in those who underwent surgery only (P < .001).ConclusionIn young and medically fit stage III colon cancer patients, most patients received guideline-compliant care in the United States. However, socioeconomic disparities adversely impacted the use of adjuvant chemotherapy. The patient or caregiver's decision was the most common reason for non-adherence to adjuvant chemotherapy and lead to poor survival outcomes. Emphasis should be placed on developing patient-centered strategies to improve adherence to chemotherapy in all patients.