Impact of colorectal cancer screening on survival after metachronous metastasis.

BACKGROUND: An increasing proportion of colorectal cancer (CRC) cases in Europe are detected by screening with faecal immunochemical testing (FIT). Previous studies showed that population screening with FIT leads to a decrease in CRC incidence and to detection at an earlier stage. However, approximately twenty percent of patients with CRC without metastases at initial diagnosis still develop metachronous metastases. We investigated the association between detection mode of the primary tumor and overall survival (OS) after metachronous metastasis in patients with CRC. METHODS: Nationwide registry-based data was obtained of 794 patients who developed metachronous metastases after being diagnosed with stage I-III CRC between January and June 2015. With multivariable Cox PH regression modelling, we analyzed the (causal) association between detection mode of the primary tumor (FIT screen-detected versus non-screen-detected) and OS after metachronous metastasis while adjusting for potential confounders. RESULTS: Median OS and five-year OS after metachronous metastasis were significantly higher for patients with screen-detected (n = 152) vs. non-screen-detected primary tumors (n = 642): 38.3 vs. 19.2 months, and 35.4% vs. 18.8%, respectively, p < 0.0001). After adjustment for potential confounders, the association between detection mode and OS after metachronous metastasis remained significant (HR 0.70 [95% CI 0.56-0.89]). CONCLUSIONS: Screen-detection of the primary tumor was independently associated with longer OS after metachronous metastasis. This may support the clinical utility of the population screening program and it shows the prognostic value of detection mode of the primary tumor once metachronous metastasis is diagnosed.

External Validation of the Colon Life Nomogram for Predicting 12-Week Mortality in Dutch Metastatic Colorectal Cancer Patients Treated with Trifluridine/Tipiracil in Daily Practice.

BACKGROUND: Predicting prognosis in refractory metastatic colorectal cancer (mCRC) patients is needed to guide decision making. The Colon Life nomogram was developed to predict 12-week mortality in refractory mCRC patients. The aim of this study is to validate the Colon Life nomogram in last line/refractory patients receiving trifluridine/tipiracil (FTD/TPI) in daily practice. METHODS: The validation cohort consists of 150 QUALITAS study patients, an observational substudy of the Prospective Dutch CRC cohort, who were treated with FTD/TPI between 2016 and 2019. Model performance was assessed on discrimination, calibration, and clinical usefulness. The additional prognostic value of baseline quality of life (QoL) and thymidine kinase (TK1) expression in tissue was explored. RESULTS: Of the 150 patients, 25 (16.7%) died within 12 weeks of starting FTD/TPI treatment. The C-statistic was 0.63 (95% C.I. 0.56-0.70). The observed/expected ratio was 0.52 (0.37-0.73). The calibration intercept and slope were -1.06 (-1.53 to -0.58) and 0.41 (0.01-0.81), respectively, which indicated overestimation of 12-week mortality by the nomogram. Decision curve analysis showed the nomogram did not yield a positive net benefit at clinically meaningful thresholds for predicted 12-week mortality. Addition of QoL to the nomogram improved the C-statistic to 0.85 (0.81-0.89). TK1 expression was associated with progression-free survival but not with overall survival. CONCLUSION: We demonstrated evident miscalibration of the Colon Life nomogram upon external validation, which hampers its use in clinical practice. We recommend conducting a study with a sufficiently large sample size to update the Colon Life nomogram or to develop a new model including QoL.

Quality of Life and Survival of Metastatic Colorectal Cancer Patients Treated With Trifluridine-Tipiracil (QUALITAS).

INTRODUCTION: The RECOURSE trial demonstrated a modest benefit in overall survival (OS) for trifluridine/tipiracil (FTD/TPI) versus placebo in pretreated metastatic colorectal cancer (mCRC) patients. Unfortunately, quality of life (QoL) was not assessed. We evaluated QoL and survival of patients treated with FTD/TPI in daily practice. PATIENTS AND METHODS: QUALITAS is a substudy of the Prospective Dutch CRC cohort (PLCRC). From 150 mCRC patients treated with FTD/TPI, QoL (EORTC QLQ-C30 and QLQ-CR29) was assessed monthly from study entry, and linked to clinical data of the Netherlands Cancer Registry. Joint models were constructed combining mixed effects models with Cox PH models. Primary endpoint was difference in QoL over time (which was deemed clinically relevant if ≥10 points). Secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF), and OS. We analyzed the association between QLQ-C30 Summary Score (QoL-SS) at FTD/TPI initiation (baseline) and survival. RESULTS: There was no clinically relevant change in QoL-SS from baseline to 10 months post-baseline (i.e. the cut-off point after which 90% of patients had discontinued FTD/TPI treatment): -5.3 [95% CI -8.7;-1.5]. Patients who were treated with FTD/TPI for ≥ 3 months (n = 85) reported 6.3 [1.6;11.1] points higher baseline QoL, compared to patients treated < 3 months (n = 65, "poor responders"). In the latter, time to a clinically relevant QoL deterioration was < 2 months. Median PFS, TTF and OS were 2.9 [2.7;3.1], 3.1 [2.9;3.2] and 7.7 [6.6;8.8] months, respectively. Worse baseline QoL-SS was independently associated with shorter OS (HR 0.45 [0.32;0.63]), PFS (0.63 [0.48;0.83]), and TTF (0.64 [0.47;0.86]). CONCLUSION: The maintenance of QoL during FTD/TPI treatment in daily practice supports its use. The QoL deterioration in "poor responders" is likely due to disease progression. The strong association between worse baseline QoL and shorter survival suggests that clinicians should take QoL into account when determining prognosis and treatment strategy for individual patients.

External validation of the MSKCC nomogram to estimate five-year overall survival after surgery for stage I-III colon cancer in a Dutch population.

INTRODUCTION: The Memorial Sloan Kettering Cancer Centre (MSKCC) nomogram has been developed to estimate five-year overall survival (OS) after curative-intent surgery of colon cancer based on age, sex, T stage, differentiation grade, number of positive and examined regional lymph nodes. This is the first evaluation of the performance of the MSKCC model in a European population regarding prediction of OS. MATERIAL AND METHODS: Population-based data from patients with stage I-III colon cancer diagnosed between 2010 and 2016 were obtained from the Netherlands Cancer Registry (NCR) for external validation of the MSKCC prediction model. Five-year survival probabilities were estimated for all patients in our dataset by using the MSKCC prediction equation. Histogram density plots were created to depict the distribution of the estimated probability and prognostic index. The performance of the model was evaluated in terms of its overall performance, discrimination, and calibration. RESULTS: A total of 39,805 patients were included. Five-year OS was 71.9% (95% CI 71.5; 72.3) (11,051 events) with a median follow up of 5.6 years (IQR 4.1; 7.7). The Brier score was 0.10 (95% CI 0.10; 0.10). The C-index was 0.75 (95% CI 0.75; 0.76). The calibration measures and plot indicated that the model slightly overestimated observed mortality (observed/expected ratio = 0.86 [95% CI 0.86; 0.87], calibration intercept = -0.14 [95% CI -0.16; -0.11], and slope 1.07 [95% CI 1.05; 1.09], ICI = 0.04, E50 = 0.04, and E90 = 0.05). CONCLUSIONS: The external validation of the MSKCC prediction nomogram in a large Dutch cohort supports the use of this practical tool in the European patient population. These personalised estimated survival probabilities may support clinicians when informing patients about prognosis. Adding potential relevant prognostic factors to the model, such as primary tumour location, might further improve the model.

Survival of patients with deficient mismatch repair metastatic colorectal cancer in the pre-immunotherapy era.

BACKGROUND: Metastatic colorectal cancer patients with deficient mismatch repair (dMMR mCRC) benefit from immunotherapy. Interpretation of the single-arm immunotherapy trials is complicated by insignificant survival data during systemic non-immunotherapy. We present survival data on a large, comprehensive cohort of dMMR mCRC patients, treated with or without systemic non-immunotherapy. METHODS: Two hundred and eighty-one dMMR mCRC patients (n = 54 from three prospective Phase 3 CAIRO trials; n = 227 from the Netherlands Cancer Registry). Overall survival was analysed from diagnosis of mCRC (OS), from initiation of first-line (OS1) and second-line (OS2) systemic treatment. Cox regression analysis examined prognostic factors. As comparison for OS 2746 MMR proficient mCRC patients were identified. RESULTS: Of 281 dMMR patients, 62% received first-line and 26% second-line treatment. Median OS was 16.0 months (13.8-19.6) with antitumour therapy and 2.5 months (1.8-3.5) in untreated patients. OS1 was 12.8 months (10.7-15.2) and OS2 6.2 months (5.4-8.9) in treated dMMR patients. Treated dMMR patients had a 7.6-month shorter median OS than pMMR patients. CONCLUSION: Available data from immunotherapy trials lack a control arm with standard systemic treatment. Given the poor outcome compared to the immunotherapy results, our data strongly suggest a survival benefit of immunotherapy in dMMR mCRC patients.

Informing metastatic colorectal cancer patients by quantifying multiple scenarios for survival time based on real-life data.

Reported median overall survival (mOS) in metastatic colorectal cancer (mCRC) patients participating in systemic therapy trials has increased to over 30 months. It is uncertain whether trial results translate to real-life populations. Moreover, patients prefer presentation of multiple survival scenarios. Population-based data of all stage IV CRC patients diagnosed between 2008 and 2016 were obtained from the Netherlands Cancer Registry, which has a case ascertainment completeness surpassing 95%. We calculated the following percentiles (scenarios) of OS per year of diagnosis for the total population, and for treatment subgroups: 10th (best-case), 25th (upper-typical), 50th (median), 75th (lower-typical) and 90th (worst-case). Twenty-five percent of patients did not receive any antitumor treatment. From 2008 to 2016, mOS of the total population (n = 27275) remained unchanged at approximately 12 months. OS improved only for the upper-typical and best-case patients; by 4.2 to 29.1 months (P < .001), and by 6 to 62 months (P < .001), respectively. No clinically relevant change was observed among patients who received systemic therapy, with mOS close to 15 months and best-case scenario approximately 40 months. A clinically relevant improvement in survival over time was observed in patients who initially received metastasectomy and/or HIPEC only. In contrast to the wide belief based on trial data that mOS of mCRC patients receiving systemic therapy has improved substantially, improvement could not be demonstrated in our real-life population. Clinicians should consider quoting multiple survival scenarios based on real-life data instead of point estimates from clinical trials, when informing patients about their life expectancy.

An ICU patient with spots and a peculiar pneumonia.

This is the first report of varicella zoster virus (VZV) pneumonia in an adult patient treated with rituximab because of autoimmune haemolytic anaemia and it illustrates that a VZV infection should be considered when an immunocompromised patient develops pulmonary symptoms, even in the absence of cutaneous lesions. It also depicts the importance of performing varicella serology in patients receiving multiple immunosuppressive agents.