Treatments for colorectal cancer (CRC) of all stages have evolved considerably over the past two decades, resulting in improved long-term outcomes. After curative treatment, however, 30% of patients ...with stage I-III and up to 65% of patients with stage IV CRC develop recurrent disease. Thus, patients are routinely offered surveillance in order to detect disease recurrence at an early, asymptomatic stage, with the intention of improving survival. Nevertheless, controversy continues to surround the optimal surveillance protocols. For patients with stage I-III CRC, more-intensive surveillance improves overall survival compared with less-intensive or no surveillance, probably owing to improved outcomes after cancer recurrence, as well as proactive treatment of other conditions detected opportunistically. The benefit of surveillance after curative treatment of stage IV CRC is more controversial, but might be justified because repeat resection can improve overall survival and 20% of these patients are eligible for such treatment with curative intent. No trials have assessed the optimal follow-up approach after curative resection of metastatic CRC, and similarly to surveillance of patients with stage I-III disease, most programmes are more intensive during the first 3 years than at later time points. Herein, we provide a comprehensive overview of surveillance strategies for patients with CRC, and discuss the future development of patient-centred programmes.
Background
In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The ...desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of patients with CRLM resected either with or without neoadjuvant chemotherapy.
Methods
All consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the interface between the tumour and surrounding liver.
Results
In total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort (
n
= 367), the dHGP was present in 19% (
n
= 68) and the non-dHGP was present in 81% (
n
= 299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39,
p
< 0.001) and progression-free survival (PFS) (HR: 0.54,
p
= 0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with 100% dHGP, regardless of the proportion of non-dHGP (all
p
values ≤ 0.001). In the neoadjuvantly treated patient cohort (
n
= 365), more patients were found to express dHGP (
n
= 109, 30%) (adjusted odds ratio: 2.71,
p
< 0.001). On univariable analysis, dHGP was associated with better OS (HR 0.66,
p
= 0.009) and PFS (HR 0.67,
p
= 0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92,
p
= 0.623) or PFS (HR 0.76,
p
= 0.065) was seen.
Conclusions
The current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of the clinical utility of HGPs in prospective clinical trials.
Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the ...distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.
Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.
Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).
The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.
Background
This study investigated the impact of perioperative systemic chemotherapy on the recurrence rate and pattern following resection of colorectal liver metastases.
Methods
A retrospective ...cohort study was conducted in two centers. Rates and patterns of recurrence and overall survival (OS) were compared between patients treated with and without perioperative systemic chemotherapy. The clinical risk score (CRS) was used to stratify patients in low risk (CRS 0–2) and high risk (CRS 3–5) of recurrence.
Results
A total of 2020 patients were included, of whom 1442 (71%) received perioperative systemic chemotherapy. The median follow-up was 88 months, and 1289 patients (64%) developed a recurrence. The recurrence pattern was independent of chemotherapy in low-risk patients: intrahepatic recurrences (30% vs. 30%,
p
= 0.97) and extrahepatic recurrences (38% vs. 39%,
p
= 0.52). In high-risk patients, no difference in intrahepatic recurrences was found (48% vs. 50%,
p
= 0.59). However, a lower rate of extrahepatic recurrences (43% vs. 55%,
p
= 0.007) was observed with perioperative systemic chemotherapy, mainly due to a reduction in pulmonary recurrences (25% vs. 35%,
p
= 0.007). In competing risk analysis, the cumulative incidence of extrahepatic recurrence was significantly lower with perioperative systemic chemotherapy in high-risk patients only (5-year cumulative incidence 44% vs. 59%,
p
< 0.001). Perioperative chemotherapy was associated with improved OS in high-risk patients (adjusted HR 0.73, 95% CI 0.57–0.94,
p
= 0.02), but not in low-risk patients (adjusted HR 0.99, 95% CI 0.82–1.19,
p
= 0.90).
Conclusions
Perioperative systemic chemotherapy had no association with intrahepatic recurrence, but was associated with fewer pulmonary recurrences and superior OS in high-risk patients only.
Adjuvant systemic chemotherapy (CTx) is widely administered in patients with colorectal liver metastases (CRLM). Histopathological growth patterns (HGPs) are an independent prognostic factor for ...survival after complete resection. This study evaluates whether HGPs can predict the effectiveness of adjuvant CTx in patients with resected CRLM. Two main types of HGPs can be distinguished; the desmoplastic type and the non-desmoplastic type. Uni- and multivariable analyses for overall survival (OS) and disease-free survival (DFS) were performed, in both patients treated with and without preoperative chemotherapy. A total of 1236 patients from two tertiary centers (Memorial Sloan Kettering Cancer Center, New York, USA; Erasmus MC Cancer Institute, Rotterdam, The Netherlands) were included (period 2000–2016). A total of 656 patients (53.1%) patients received preoperative chemotherapy. Adjuvant CTx was only associated with a superior OS in non-desmoplastic patients that had not been pretreated (adjusted hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.37–0.73, p < 0.001), and not in desmoplastic patients (adjusted HR 1.78, 95% CI 0.75–4.21, p = 0.19). In pretreated patients no significant effect of adjuvant CTx was observed, neither in the desmoplastic group (adjusted HR 0.83, 95% CI 0.49–1.42, p = 0.50) nor in the non-desmoplastic group (adjusted HR 0.96, 95% CI 0.71–1.29, p = 0.79). Similar results were found for DFS, with a superior DFS in non-desmoplastic patients treated with adjuvant CTx (HR 0.71, 95% CI 0.55–0.93, p < 0.001) that were not pretreated. Adjuvant CTx seems to improve OS and DFS after resection of non-desmoplastic CRLM. However, this effect was only observed in patients that were not treated with chemotherapy.
The majority of patients recur after resection of colorectal liver metastases (CRLM). Patients with CRLM displaying a desmoplastic histopathological growth pattern (dHGP) have a better prognosis and ...lower probability of recurrence than patients with non-dHGP CRLM. The current study evaluates the impact of HGP type on the pattern and treatment of recurrences after first resection of CRLM. A retrospective cohort study was performed, including patients with known HGP type after complete resection of CRLM. All patients were treated between 2000 and 2015. The HGP was determined on the CRLM resected at first partial hepatectomy. The prognostic value of HGPs, in terms of survival outcome, in the current patient cohort were previously published. In total 690 patients were included, of which 492 (71%) developed recurrent disease. CRLM displaying dHGP were observed in 103 patients (21%). Amongst patients with dHGP CRLM diagnosed with recurrent disease, more liver-limited recurrences were seen (43% vs. 31%, p = 0.030), whereas patients with non-dHGP more often recurred at multiple locations (34% vs. 19%, p = 0.005). Patients with dHGP CRLM were more likely to undergo curatively intended local treatment for recurrent disease (adjusted odds ratio: 2.37; 95% confidence interval (CI) 1.46–3.84; p < 0.001) compared to patients with non-dHGP. The present study demonstrates that liver-limited disease recurrence after complete resection of CRLM is more often seen in patients with dHGP, whereas patients with non-dHGP more frequently experience multi-organ recurrence. Recurrences in patients with dHGP at first CRLM resection are more likely to be salvageable by local treatment modalities, but no prognostic impact of HGPs after salvage therapy for recurrent disease was found.
Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin‐stained sections of resected colorectal liver ...metastases (CRLM). Assessment estimates the relative fraction of the tumour–liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo‐naïve versus 67% for preoperatively treated patients (p < 0.001). A significant association between chemotherapy and desmoplastic HGP was found on multivariable analysis (β 95% confidence interval, CI: 24.57 18.28–30.87, p < 0.001). In the validation cohort, the average presence of desmoplastic HGP was 40% for chemo‐naïve versus 63% for preoperatively treated patients (p < 0.001). This association remained on multivariable analysis (β 95% CI: 24.18 18.70–29.66, p < 0.001). In the EORTC 40983 trial, the average desmoplastic HGP presence was 33% in the resection arm versus 61% in the chemotherapy arm (p = 0.005). Chemotherapy was independently associated with an increase in desmoplastic HGP (β 95% CI: 23.29 1.78–44.79, p = 0.022). All three tumour regression gradings were significantly associated with the desmoplastic HGP in the chemotherapy arm (all p < 0.04). None were associated in the resection arm (all p > 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.
Abstract Objective To evaluate and compare the overall survival (OS) in case-matched patient groups treated either with systemic therapy or surgery for colorectal liver metastases (CRLM). Methods ...Patients with CRLM, without extra-hepatic disease, treated with chemotherapy with or without targeted therapy in two phase III studies ( n = 480) were selected and case-matched to patients who underwent liver resection ( n = 632). Matching criteria were sex, age, established prognostic factors for survival (clinical risk score). Available computed tomography (CT)-scans of patients treated with systemic therapies were reviewed by three independent liver surgeons for resectability. Survival was compared between patients with resectable CRLM (based on CT-scan review) who were treated with systemic therapy versus patients who underwent liver resection. Results A total of 96 patients treated with systemic therapy were included. Pre-treatment CT-scans of the liver were available for review in 56 of the systemically treated patients, and metastases were unanimously considered resectable in 36 patients (64.3%) (complex resectable: n = 25; 69%). These 36 patients were case-matched with 36 patients who underwent liver resection (wedge resection or segmentectomy: n = 26; 72%). Median OS in the patient group treated with systemic therapy was 26.5 months (range 0–81 months), which was significantly lower than that in case-matched patients who underwent liver resection (median OS 56 months; range 6–116) ( p = 0.027). Conclusions In this case-matched control study, surgery provided superior OS rates compared to systemic therapy for CRLM. Resection of CRLM should always be considered, preferably in a dedicated liver centre, since not all patients that qualify for resection are identified as such.
Introduction
Human pregnancy is considered term from 37+0/7 to 41+6/7 weeks. Within this range, both maternal, fetal and neonatal risks may vary considerably. This study investigates how gestational ...age per week is related to the components of perinatal mortality and parameters of adverse neonatal and maternal outcome at term.
Material and Methods
A registry‐based study was made of all singleton term pregnancies in the Netherlands from January 2014 to December 2017. Stillbirth and early neonatal mortality, as components of perinatal mortality, were defined as primary outcomes; adverse neonatal and maternal events as secondary outcomes. Neonatal adverse outcomes included birth trauma, 5‐minute Apgar score ≤3, asphyxia, respiratory insufficiency, neonatal intensive care unit admission and composite neonatal outcome. Maternal adverse outcomes included instrumental vaginal birth, emergency cesarean section, obstetric anal sphincter injury, postpartum hemorrhage, hypertensive disorders of pregnancy and composite maternal outcome. The primary outcomes were evaluated by comparing weekly prospective risks of stillbirth and neonatal death using a fetuses‐at‐risk approach. Secondly, odds ratios (OR) for perinatal mortality, adverse neonatal and maternal outcome using a births‐based approach were compared for each gestational week with all births occurring after that week.
Results
Data of 581 443 births were analyzed. At 37, 38, 39, 40, 41 and 42 weeks, the respective weekly prospective risks of stillbirth were 0.015%, 0.022%, 0.031%, 0.036%, 0.069% and 0.081%; the respective weekly prospective risks of early neonatal death were 0.051%, 0.047%, 0.032%, 0.031%, 0.039% and 0.035%. The OR for adverse neonatal outcomes were the lowest at 39 and 40 weeks. The OR for adverse maternal outcomes, including operative birth, continuously increased with each gestational week.
Conclusions
The prospective risk of early neonatal death for babies born at 39 weeks is lower than the risk of stillbirth in pregnancies continuing beyond 39+6/7 weeks. Birth at 39 weeks was associated with the best combined neonatal and maternal outcome, fewer operative births and fewer maternal and neonatal adverse outcomes compared with pregnancies continuing beyond 39 weeks. This information with appropriate perspectives should be included when counseling term pregnant women.
The risk of stillbirth increases with advancing gestation. We assessed the risk of adverse maternal and neonatal outcomes per gestational week in term singleton pregnancies. Birth at 39 weeks is associated with lower number of maternal and neonatal adverse outcomes.
Introduction
Local treatment of metastases is frequently performed in patients with multiorgan metastatic colorectal carcinoma (mCRC) analogous to selected patients with oligometastatic disease for ...whom this is standard of care. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival benefit from tumor debulking in addition to chemotherapy in patients with multiorgan mCRC. Here, we report the preplanned safety and feasibility evaluation after inclusion of the first 100 patients.
Methods
Patients were eligible if at least 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy. In case of clinical benefit after three or four cycles of respectively 5‐fluorouracil/leucovorin or capecitabine and oxaliplatin ± bevacizumab patients were randomized to tumor debulking followed by chemotherapy in the intervention arm, or standard treatment with chemotherapy.
Results
Twelve patients dropped out prior to randomization for various reasons. Eighty‐eight patients were randomized to the standard (n = 43) or intervention arm (n = 45). No patients withdrew after randomization. Debulking was performed in 82% (n = 37). Two patients had no lesions left to treat, five had progressive disease, and one patient died prior to local treatment. In 15 patients (40%) 21 serious adverse events related to debulking were reported. Postoperative mortality was 2.7% (n = 1). After debulking chemotherapy was resumed in 89% of patients.
Conclusion
Tumor debulking is feasible and does not prohibit administration of palliative chemotherapy in the majority of patients with multiorgan mCRC, despite the occurrence of serious adverse events related to local treatment.
Implications for Practice
This first prospective randomized trial on tumor debulking in addition to chemotherapy shows that local treatment of metastases is feasible in patients with multiorgan metastatic colorectal cancer and does not prohibit administration of palliative systemic therapy, despite the occurrence of serious adverse events related to local treatment. The trial continues accrual, and overall survival (OS) data and quality of life assessment are collected to determine whether the primary aim of >6 months OS benefit with preserved quality of life will be met. This will support evidence‐based decision making in multidisciplinary colorectal cancer care and can be readily implemented in daily practice.
The ORCHESTRA trial was designed to prospectively evaluate overall survival benefit from tumor debulking in addition to chemotherapy in patients with multi‐organ metastatic colorectal cancer. This article reports the preplanned safety and feasibility evaluation after inclusion of the first 100 patients.
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