Background & Aims Postoperative ileus is characterized by delayed gastrointestinal (GI) transit and is a major determinant of recovery after colorectal surgery. Both laparoscopic surgery and ...fast-track multimodal perioperative care have been reported to improve clinical recovery. However, objective measures supporting faster GI recovery are lacking. Therefore, GI transit was measured following open and laparoscopic colorectal surgery with or without fast-track care. Methods Patients (n = 93) requiring elective colonic surgery were randomized to laparoscopic or conventional surgery with fast-track multimodal management or standard care, resulting in 4 treatment arms. Gastric emptying and colonic transit were scintigraphically assessed from days 1 to 3 in 78 patients and compared with clinical parameters such as time to tolerance of solid food and/or bowel movement and time until (ready for) discharge. Results A total of 71 patients without mechanical bowel obstructions or surgical complications requiring intervention were available for analysis. No differences in gastric emptying 24 hours after surgery between the different groups were observed ( P = .61). However, the median colonic transit of patients undergoing laparoscopic/fast-track care was significantly faster compared with the laparoscopic/standard, open/fast-track, and open/standard care groups. Multiple linear regression analysis showed that both laparoscopic surgery and fast-track care were significant independent predictive factors of improved colonic transit. Both were associated with significantly faster clinical recovery and shorter time until tolerance of solid food and first bowel movement. Conclusions Colonic transit recovers significantly faster after laparoscopic surgery and the fast-track program; laparoscopy and fast-track care lead to faster recovery of GI motility and improve clinical recovery.
Objective:
To present short-term outcomes of liver surgery in patients with initially unresectable colorectal liver metastases (CRLM) downsized by chemotherapy plus targeted agents.
Background:
The ...increase of complex hepatic resections of CRLM, technical innovations pushing boundaries of respectability, and use of intensified induction systemic regimens warrant for safety data in a homogeneous multicenter prospective cohort.
Methods:
Patients with initially unresectable CRLM, who underwent complete resection after induction systemic regimens with doublet or triplet chemotherapy, both plus targeted therapy, were selected from the ongoing phase III CAIRO5 study (NCT02162563). Short-term outcomes and risk factors for severe postoperative morbidity (Clavien Dindo grade ≥ 3) were analyzed using logistic regression analysis.
Results:
A total of 173 patients underwent resection of CRLM after induction systemic therapy. The median number of metastases was 9 and 161 (93%) patients had bilobar disease. Thirty-six (20.8%) 2-stage resections and 88 (51%) major resections (>3 liver segments) were performed. Severe postoperative morbidity and 90-day mortality was 15.6% and 2.9%, respectively. After multivariable analysis, blood transfusion (odds ratio OR 2.9 95% confidence interval (CI) 1.1–6.4,
P =
0.03), major resection (OR 2.9 95% CI 1.1–7.5,
P =
0.03), and triplet chemotherapy (OR 2.6 95% CI 1.1–7.5,
P =
0.03) were independently correlated with severe postoperative complications. No association was found between number of cycles of systemic therapy and severe complications (
r
= −0.038
, P
= 0.31).
Conclusion:
In patients with initially unresectable CRLM undergoing modern induction systemic therapy and extensive liver surgery, severe postoperative morbidity and 90-day mortality were 15.6% and 2.7%, respectively. Triplet chemotherapy, blood transfusion, and major resections were associated with severe postoperative morbidity.
Recurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Postoperative circulating tumour DNA (ctDNA) is a promising prognostic ...biomarker. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS).
Twenty-three patients were selected from an ongoing phase-3 trial who underwent resection of RAS-mutant CRLM after induction systemic treatment. CtDNA analysis was performed by droplet digital PCR using blood samples collected at baseline, before and after resection. Pathologic response of CRLM was determined via the Tumour Regression Grading system.
With a median follow-up of 19.6 months, the median RFS for patients with detectable (N = 6, 26%) and undetectable (N = 17, 74%) postoperative ctDNA was 4.8 versus 12.1 months, respectively. Among 21 patients with available tumour tissue, pathologic response in patients with detectable compared to undetectable postoperative ctDNA was found in one of six (17%) and 15 of 15 (100%) patients, respectively (p < 0.001). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1–9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4–15, p = 0.01) were associated with poorer RFS and were strongly correlated (r = 0.88, p < 0.001). After adjusting for clinical characteristics in pairwise multivariable analyses, postoperative ctDNA status remained associated with RFS.
The detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response.
None
Optimized surgical techniques and systemic therapy have increased the number of patients with colorectal liver metastases (CRLM) eligible for local treatment. To increase postoperative survival, we ...need to stratify patients to customize therapy. Most clinical risk scores (CRSs) which predict prognosis after CRLM resection were based on the outcome of studies in specialized centers, and this may hamper the generalizability of these CRSs in unselected populations and underrepresented subgroups. We aimed to externally validate two CRSs in a population-based cohort of patients with CRLM. A total of 1105 patients with local treatment of CRLM, diagnosed in 2015/2016, were included from a nationwide population-based database. Survival outcomes were analyzed. The Fong and more recently developed GAME CRS were externally validated, including in pre-specified subgroups (≤70/>70 years and with/without perioperative systemic therapy). The three-year DFS was 22.8%, and the median OS in the GAME risk groups (high/moderate/low) was 32.4, 46.7, and 68.1 months, respectively (p < 0.005). The median OS for patients with versus without perioperative therapy was 47.6 (95%CI 39.8, 56.2) and 54.9 months (95%CI 48.8, 63.7), respectively (p = 0.152), and for below/above 70 years, it was 54.9 (95%CI 49.3−64.1) and 44.2 months (95%CI 37.1−54.3), respectively (p < 0.005). The discriminative ability for OS of Fong CRS was 0.577 (95%CI 0.554, 0.601), and for GAME, it was 0.596 (95%CI 0.572, 0.621), and was comparable in the subgroups. In conclusion, both CRSs showed predictive ability in a population-based cohort and in predefined subgroups. However, the limited discriminative ability of these CRSs results in insufficient preoperative risk stratification for clinical decision-making.
Tumor‐derived cell‐free DNA (cfDNA) is an emerging biomarker for guiding the personalized treatment of patients with metastatic colorectal cancer (CRC). While patients with CRC liver metastases ...(CRC‐LM) have relatively high levels of plasma cfDNA, little is known about patients with CRC peritoneal metastases (CRC‐PM). This study evaluated the presence of tumor‐derived cfDNA in plasma and peritoneal fluid (i.e. ascites or peritoneal washing) in 20 patients with isolated CRC‐PM and in the plasma of 100 patients with isolated CRC‐LM. Among tumor tissue KRAS/BRAF mutation carriers, tumor‐derived cfDNA was detected by droplet digital polymerase chain reaction (ddPCR) in plasma of 93% of CRC‐LM and 20% of CRC‐PM patients and in peritoneal fluid in all CRC‐PM patients. Mutant allele fraction (MAF) and mutant copies per ml (MTc/ml) were lower in CRC‐PM plasma than in CRC‐LM plasma (median MAF = 0.28 versus 18.9%, p < 0.0001; median MTc/ml = 21 versus 1,758, p < 0.0001). Within patients with CRC‐PM, higher cfDNA levels were observed in peritoneal fluid than in plasma (median MAF = 16.4 versus 0.28%, p = 0.0019; median MTc/ml = 305 versus 21, p = 0.0034). These data imply that tumor‐derived cfDNA in plasma is a poor biomarker to monitor CRC‐PM. Instead, cfDNA detection in peritoneal fluid may offer an alternative to guide CRC‐PM treatment decisions.
To describe a case of bilateral diffuse uveal melanocytic proliferation (BDUMP) that was mistaken for nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome.
We present the case of a ...58-year-old white man with metastatic renal clear cell carcinoma for which he was palliatively treated with IV nivolumab immunotherapy. The patient developed subacute onset of blurry vision and gray spots in the visual fields of both eyes, macular subretinal fluid, thickening of the retinal pigment epithelium, and swollen optic nerve heads. Differential diagnosis included nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome, and the patient was initially treated with steroids, which gave no improvement. Investigation showed the development of dark-gray patches in the peripheral retina of both eyes and cataract, which prompted reevaluation of the diagnosis, deeming BDUMP most likely. The patient was successfully treated with plasmapheresis.
The initial presentation of the case was incorrectly diagnosed as nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome. On repeat studies of the patients' symptoms and imaging, we concluded we had missed signs of BDUMP.
The diagnosis BDUMP was missed in the first evaluation. We present this case to discuss the similarities and differences between this disease and nivolumab-induced Vogt-Koyanagi-Harada disease-like syndrome. More importantly, we want to highlight that reevaluation of the diagnosis on worsening of a disease was key in this unusual case.
There is no consensus on the optimal systemic conversion therapy in patients with unresectable colorectal cancer liver-only metastases (CRLM) to achieve a complete resection. Interpretation of trials ...is complicated by heterogeneity of patients caused by emerging prognostic and predictive characteristics, such as RAS/BRAF mutation status, lack of consensus on unresectability criteria and lack of data on clinical outcome of secondary resections. A systematic review was performed of characteristics of study populations and methodology of trials regarding patients with initially unresectable colorectal cancer liver-only metastases.
Phase II/III randomised trials, published after 2008, regarding first-line systemic conversion therapy in patients or subgroups of patients with CRLM were included. Data on secondary resection outcomes were collected.
Overall, 20 trials were included for analysis: seven prospective trials in patients with unresectable CRLM and 13 trials in the overall population of unresectable metastatic colorectal cancer (mCRC) with retrospective subgroup analysis of CRLM patients. Fourteen trials did not provide unresectability criteria at baseline, and criteria differed among the remaining studies. Trials and study populations were heterogeneous in prognostic/predictive factors, use of primary end-points, and reporting on long-term clinical outcomes. R0-resection rates in CRLM patients varied between CRLM studies and mCRC studies, with rates of 22–57% and 11–38%, respectively.
Cross-study comparison of (subgroups of) studies regarding first-line systemic treatment in patients with unresectable CRLM is hampered by heterogeneity in study populations, trial designs, use of (K)RAS/BRAF mutational tumour status, and differences/absence of unresectability criteria. No optimal conversion systemic regimen can be selected from available data. Prospective studies with well-defined criteria of these issues are warranted.
•Cross-study comparison of systemic conversion therapies in CRLM patients is complicated.•Study populations and resection rates vary considerably between CRLM studies.•No preferential systemic regimen for conversion therapy can be given.•Transparent baseline (un)resectability criteria for CRLM are needed.•Long-term survival outcomes after resection were not reported in the majority of studies.
Circulating tumor DNA (ctDNA) has the potential to guide therapy selection and monitor treatment response in patients with metastatic cancer. However, germline and clonal hematopoiesis-associated ...alterations can confound identification of tumor-specific mutations in cell-free DNA (cfDNA), often requiring additional sequencing of tumor tissue. The current study assessed whether ctDNA-based treatment response monitoring could be performed in a tumor tissue-independent manner by combining ultra-deep targeted sequencing analyses of cfDNA with patient-matched white blood cell (WBC)-derived DNA.
In total, 183 cfDNA and 49 WBC samples, along with 28 tissue samples, from 52 patients with metastatic colorectal cancer participating in the prospective phase III CAIRO5 clinical trial were analyzed using an ultra-deep targeted sequencing liquid biopsy assay.
The combined cfDNA and WBC analysis prevented false-positives due to germline or hematopoietic variants in 40% of patients. Patient-matched tumor tissue sequencing did not provide additional information. Longitudinal analyses of ctDNA were more predictive of overall survival than standard-of-care radiological response evaluation. ctDNA mutations related to primary or acquired resistance to panitumumab were identified in 42% of patients.
Accurate calling of ctDNA mutations for treatment response monitoring is feasible in a tumor tissue-independent manner by combined cfDNA and patient-matched WBC genomic DNA analysis. This tissue biopsy-independent approach simplifies sample logistics and facilitates the application of liquid biopsy ctDNA testing for evaluation of emerging therapy resistance, opening new avenues for early adaptation of treatment regimens.
Background
It is unclear whether curative-intent local therapy of metastases is of similar benefit for the biological distinct subgroup of patients with deficient mismatch repair (dMMR) metastatic ...colorectal cancer (mCRC) compared with proficient mismatch repair (pMMR) mCRC.
Patients and Methods
In this nationwide study, recurrence-free (RFS) and overall survival (OS) were analyzed in patients with dMMR versus pMMR mCRC who underwent curative-intent local treatment of metastases between 2015 and 2018. Subgroup analyses were performed for resection of colorectal liver metastases (CRLM) and cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy (CRS ± HIPEC). Multivariable regression was conducted.
Results
Median RFS was 11.1 months 95% confidence interval (CI) 8.5–41.1 months for patients with dMMR tumors compared with 8.9 months (95% CI 8.1–9.8 months) for pMMR tumors. Two-year RFS was higher in patients with dMMR versus pMMR (43% vs. 21%). Results were similar within subgroups of local treatment (CRLM and CRS ± HIPEC). Characteristics differed significantly between patients with dMMR and pMMR mCRC; however, multivariable analysis continued to demonstrate dMMR as independent factor for improved RFS hazard ratio (HR): 0.57, 95% CI 0.38–0.87. Median OS was 33.3 months for dMMR mCRC compared with 43.5 months for pMMR mCRC, mainly due to poor survival of patients with dMMR in cases of recurrence in the preimmunotherapy era.
Conclusion
Patients with dMMR eligible for curative-intent local treatment of metastases showed a comparable to more favorable RFS compared with patients with pMMR, with a clinically relevant proportion of patients remaining free of recurrence. This supports local treatment as a valuable treatment option in patients with dMMR mCRC and can aid in shared decision-making regarding upfront local therapy versus immunotherapy.
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