Background
Patients with peritoneal metastases from colorectal cancer have a poor prognosis. If the intraperitoneal tumour load is limited, patients may be eligible for cytoreductive surgery followed ...by hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment has improved overall survival, but recurrence rates are high. The aim of this study was to create a preclinical platform for the development of more effective intraperitoneal chemotherapy strategies.
Methods
Using organoid technology, five tumour cultures were generated from malignant ascites and resected peritoneal metastases. These were used in an in vitro HIPEC model to assess sensitivity to mitomycin C (MMC) and oxaliplatin, the drugs used most commonly in HIPEC. The model was also used to test a rational combination treatment involving MMC and inhibitors of the checkpoint kinase ATR.
Results
MMC was more effective in eliminating peritoneal metastasis‐derived organoids than oxaliplatin at clinically relevant concentrations. However, the drug concentrations required to eliminate 50 per cent of the tumour cells (IC50) were higher than the median clinical dose in two of five organoid lines for MMC, and all five lines for oxaliplatin, indicating a general resistance to monotherapy. ATR inhibition increased the sensitivity of all peritoneal metastasis‐derived organoids to MMC, as the IC50 decreased 2·6–12·4‐fold to well below concentrations commonly attained in clinical practice. Live‐cell imaging and flow cytometric analysis showed that ATR inhibition did not release cells from MMC‐induced cell cycle arrest, but caused increased replication stress and accelerated cell death.
Conclusion
Peritoneal metastasis‐derived organoids can be used to evaluate existing HIPEC regimens on an individual‐patient level and for development of more effective treatment strategies.
Surgical relevance
Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has improved prognosis of patients with peritoneal metastases from colorectal cancer, but disease recurrence is common. More effective and personalized HIPEC is urgently needed. Organoid technology is frequently used for drug screens, as patient‐derived organoids can accurately predict clinical therapeutic response in vitro.
A panel of organoids was established from peritoneal metastases from colorectal cancer and used to develop a model for testing HIPEC regimens in vitro. Patient‐derived organoids differed in sensitivity to commonly used chemotherapeutics, in line with variable clinical outcomes following cytoreductive surgery–HIPEC. Combining MMC with an ATR inhibitor improved the efficacy of MMC.
Peritoneal metastasis‐derived organoids can be used as a platform to test novel (combination) strategies that increase HIPEC efficacy. In the future, organoids could be used to select patent‐tailored HIPEC regimens.
Antecedentes
Los pacientes con metástasis peritoneales (peritoneal metastasis, PM) de cáncer colorrectal tienen un mal pronóstico. Si la carga tumoral intraperitoneal es reducida, los pacientes pueden ser candidatos a cirugía citorreductora seguida de quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC). Este tratamiento ha mejorado la supervivencia global, pero las tasas de recidiva son altas. El objetivo de este estudio fue crear una plataforma preclínica para el desarrollo de las estrategias de quimioterapia intraperitoneal más efectivas.
Métodos
Mediante la utilización de la tecnología de organoides, se generaron cinco cultivos tumorales a partir de ascitis maligna y PM resecadas. Se utilizó un modelo de HIPEC in vitro para evaluar la sensibilidad a la mitomicina C (mitomycin C, MMC) y al oxaliplatino, los fármacos más utilizados en la HIPEC. El modelo también se usó para probar un tratamiento combinado de MMC e inhibidores de control inmunitario de la quinasa ATR.
Resultados
A concentraciones clínicamente relevantes, la MMC fue más efectiva que el oxaliplatino para eliminar los organoides derivados de PM. Sin embargo, las concentraciones de fármaco necesarias para eliminar el 50% de las células tumorales (IC50) fueron más elevadas que la mediana de la dosis clínica en 2/5 (MMC) o 5/5 (oxaliplatino) de las líneas de organoides, lo que indica una resistencia general a la monoterapia. La inhibición de ATR aumentó la sensibilidad a MMC de todos los organoides derivados de PM, ya que la IC50 disminuyó (2,6‐12,4 veces) a concentraciones muy por debajo de las que se alcanzan comúnmente en la práctica clínica. Los análisis de viabilidad celular y de citometría de flujo (FACS) mostraron que la inhibición de ATR no liberaba células tras la detención del ciclo celular inducida por la MMC, sino que causaba un aumento en el estrés replicativo y muerte celular acelerada.
Conclusión
Se pueden usar los organoides derivados de PM para evaluar los regímenes HIPEC existentes a nivel del paciente individual y para desarrollar estrategias terapéuticas más efectivas.
Organoid technology was used to create a preclinical model for evaluation of hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases from colorectal cancer. Current HIPEC regimens were tested and a novel rational treatment combination of mitomycin C with inhibitors of ATR was investigated. This combination improved HIPEC efficacy and has potential for clinical implementation.
Exciting advances
It is estimated that around 15-30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from ...chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy. It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs.
In this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3-4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8-10 Dutch hospitals. The first patient was included in February 2020.
Patient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated.
This study has been registered in the Netherlands Trial Register (NL8177) at 11-26-2019, https://www.trialregister.nl/trial/8177 . The study has been approved by the medical ethics committee Utrecht (MEC18/712).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Pathological complete response (pCR) following neoadjuvant treatment for locally advanced rectal cancer (LARC) is associated with better survival, less local recurrence, and less distant ...failure. Furthermore, pCR indicates that the rectum may have been preserved. This meta-analysis gives an overview of available neoadjuvant treatment strategies for LARC and analyzes how these perform in achieving pCR as compared with the standard of care.
Methods
Pubmed, Embase, and Cochrane Central bibliographic databases were searched. Randomized controlled trials in which patients received neoadjuvant treatment for MRI-staged nonmetastatic resectable LARC were included. The primary outcome was pCR, defined as ypT0N0. A meta-analysis of studies comparing an intervention with standard fluoropyrimidine-based chemoradiation (CRT) was performed.
Results
Of the 17 articles included in the systematic review, 11 were used for the meta-analysis. Addition of oxaliplatin to fluoropyrimidine-based CRT resulted in significantly more pCR compared with fluoropyrimidine-based CRT only (OR 1.46), but at the expense of more ≥ grade 3 toxicity. Other treatment strategies, including consolidation/induction chemotherapy and short-course radiotherapy (SCRT), did not improve pCR rates. None of the included trials reported a benefit in local control or OS. Five-year DFS was significantly worse after SCRT-delay compared with CRT (59% vs. 75.1%, HR 1.93).
Conclusions
All included trials fail to deliver high-level evidence to show an improvement in pCR compared with standard fluoropyrimidine-based CRT. The addition of oxaliplatin might result in more pCR but at the expense of more toxicity. Furthermore, this benefit does not translate into less local recurrence or improved survival.
Background
Patients with colorectal peritoneal carcinomatosis have a very poor prognosis. The recently developed consensus molecular subtype (CMS) classification of primary colorectal cancer ...categorizes tumours into four robust subtypes, which could guide subtype‐targeted therapy. CMS4, also known as the mesenchymal subtype, has the greatest propensity to form distant metastases. CMS4 status and histopathological features of colorectal peritoneal carcinomatosis were investigated in this study.
Methods
Fresh‐frozen tissue samples from primary colorectal cancer and paired peritoneal metastases from patients who underwent cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy were collected. Histopathological features were analysed, and a reverse transcriptase–quantitative PCR test was used to assess CMS4 status of all collected lesions.
Results
Colorectal peritoneal carcinomatosis was associated with adverse histopathological characteristics, including a high percentage of stroma in both primary tumours and metastases, and poor differentiation grade and high‐grade tumour budding in primary tumours. Furthermore, CMS4 was significantly enriched in primary tumours with peritoneal metastases, compared with unselected stage I–IV tumours (60 per cent (12 of 20) versus 23 per cent; P = 0.002). The majority of peritoneal metastases (75 per cent, 21 of 28) were also classified as CMS4. Considerable intrapatient subtype heterogeneity was observed. Notably, 15 of 16 patients with paired tumours had at least one CMS4‐positive tumour location.
Conclusion
Significant enrichment for CMS4 was observed in colorectal peritoneal carcinomatosis.
Surgical relevance
Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS‐HIPEC) improves survival of selected patients with colorectal peritoneal carcinomatosis, but recurrence is common. Histopathological and molecular analysis of colorectal peritoneal carcinomatosis could provide clues for development of novel therapies.
In this study, colorectal peritoneal carcinomatosis was found to be enriched for tumours with high stromal content and CMS4‐positive status.
To further improve prognosis for patients with colorectal peritoneal carcinomatosis, therapies that target tumour–stroma interaction could be added to CRS‐HIPEC.
Mesenchymal subtype predominates
Aim
A prolonged interval (>4 weeks) between short‐course radiotherapy (25 Gy in five fractions) (SCRT‐delay) and total mesorectal excision for rectal cancer has been associated with a decreased ...postoperative complication rate and offers the possibility of organ preservation in the case of a complete tumour response. This prospective cohort study systematically evaluated patient‐reported bowel dysfunction and physician‐reported radiation‐induced toxicity for 8 weeks following SCRT‐delay.
Method
Patients who were referred for SCRT‐delay for intermediate risk, oligometastatic or locally advanced rectal cancer were included. Repeated measurements were done for patient‐reported bowel dysfunction (measured by the low anterior resection syndrome LARS questionnaire and categorized as no, minor or major LARS) and physician‐reported radiation‐induced toxicity (according to Common Terminology Criteria for Adverse Events version 4.0) before start of treatment (baseline), at completion of SCRT and 1, 2, 3, 4, 6 and 8 weeks thereafter.
Results
Fifty‐one patients were included; 31 (61%) were men and the median age was 67 years (range 44–91). Patient‐reported bowel dysfunction and physician‐reported radiation‐induced toxicity peaked at weeks 1–2 after completion of SCRT and gradually declined thereafter. Major LARS was reported by 44 patients (92%) at some time during SCRT‐delay. Grade 3 radiation‐induced toxicity was reported in 17 patients (33%) and concerned predominantly diarrhoea. No Grade 4–5 radiation‐induced toxicity occurred.
Conclusion
During SCRT‐delay, almost every patient experiences temporary mild–moderate radiation‐induced toxicity and major LARS, but life‐threatening toxicity is rare. SCRT‐delay is a safe alternative to SCRT‐direct surgery that should be proposed when counselling rectal cancer patients on neoadjuvant strategies.
IMPORTANCE: Despite ongoing advances in the field of colorectal surgery, the quality of surgical treatment is still variable. As an intrinsic part of surgical quality, the technical information ...regarding the surgical procedure is reflected only by the narrative operative report (NR), which has been found to be subjective and regularly omits important information. OBJECTIVE: To investigate systematic video recording (SVR) as a potential improvement in quality and safety with regard to important information in colorectal cancer surgery. DESIGN, SETTING, AND PARTICIPANTS: The Imaging for Quality Control Trial was a prospective, observational cohort study conducted between January 12, 2016, and October 30, 2017, at 3 centers in the Netherlands. The study group consisted of 113 patients 18 years or older undergoing elective laparoscopic surgery for colorectal cancer. These patients were case matched and compared with cases from a historical cohort that received only an NR. INTERVENTIONS: Among study cases, participating surgeons were requested to systematically capture predefined key steps of the surgical procedure intraoperatively on video in short clips. MAIN OUTCOMES AND MEASURES: The SVRs and NRs were analyzed for adequacy with respect to the availability of important information regarding the predefined key steps. Adequacy of the reported information was defined as the proportion of key steps with available and sufficient information in the report. Adequacy of the SVR and NR was compared between the study and control groups, with the SVR alone and as an adjunct to the NR in the study group vs NR alone in the control group. RESULTS: Of the 113 study patients, 69 women (61.1%) were included; mean (SD) age was 66.3 (9.8) years. In the control group, a mean (SD) of 52.5% (18.3%) of 631 steps were adequately described in the NR. In the study group, the adequacy of both the SVR (78.5% 16.5%, P < .001) and a combination of the SVR with NR (85.1% 14.6%, P < .001) was significantly superior to NR alone. The only significant difference between the study and historical control groups regarding postoperative and pathologic outcomes was a shorter postoperative mean (SD) length of stay in favor of the study group (8.0 7.7 vs 8.6 6.8 days; P = .03). CONCLUSIONS AND RELEVANCE: Use of SVR in laparoscopic colorectal cancer surgery as an adjunct to the NR might be superior in documenting important steps of the operation compared with NR alone, adding to the overall availability of necessary intraoperative information and contributing to quality control and objectivity.
Background
Before 2016, patients with isolated synchronous colorectal peritoneal metastases (PMCRC) diagnosed in expert centers had a higher odds of undergoing cytoreductive surgery with hyperthermic ...intraperitoneal chemotherapy (CRS-HIPEC) and better overall survival (OS) than those diagnosed in referring centers. Nationwide efforts were initiated to increase awareness and improve referral networks.
Methods
This nationwide study aimed to evaluate whether the between-center differences in odds of undergoing CRS-HIPEC and OS have reduced since these national efforts were initiated. All patients with isolated synchronous PMCRC diagnosed between 2009 and 2021 were identified from the Netherlands Cancer Registry. Associations between hospital of diagnosis and the odds of undergoing CRS-HIPEC, as well as OS, were assessed using multilevel multivariable regression analyses for two periods (2009–2015 and 2016–2021).
Results
In total, 3948 patients were included. The percentage of patients undergoing CRS-HIPEC increased from 17.2% in 2009–2015 (25.4% in expert centers, 16.5% in referring centers), to 23.4% in 2016–2021 (30.2% in expert centers, 22.6% in referring centers). In 2009–2015, compared with diagnosis in a referring center, diagnosis in a HIPEC center showed a higher odds of undergoing CRS-HIPEC (odds ratio OR 1.64, 95% confidence interval CI 1.02–2.67) and better survival (hazard ratio HR 0.80, 95% CI 0.66–0.96). In 2016–2021, there were no differences in the odds of undergoing CRS-HIPEC between patients diagnosed in HIPEC centers versus referring centers (OR 1.27, 95% CI 0.76–2.13) and survival (HR 1.00, 95% CI 0.76–1.32).
Conclusion
Previously observed differences in odds of undergoing CRS-HIPEC were no longer present. Increased awareness and the harmonization of treatment for PMCRC may have contributed to equal access to care and a similar chance of survival at a national level.
The identification of four Consensus Molecular Subtypes (CMS1-4) of colorectal cancer forms a new paradigm for the design and evaluation of subtype-directed therapeutic strategies. The most ...aggressive subtype - CMS4 - has the highest chance of disease recurrence. Novel adjuvant therapies for patients with CMS4 tumours are therefore urgently needed. CMS4 tumours are characterized by expression of mesenchymal and stem-like genes. Previous pre-clinical work has shown that targeting Platelet-Derived Growth Factor Receptors (PDGFRs) and the related KIT receptor with imatinib is potentially effective against mesenchymal-type colon cancer. In the present study we aim to provide proof for the concept that imatinib can reduce the aggressive phenotype of primary CMS4 colon cancer.
Tumour biopsies from patients with newly diagnosed stage I-III colon cancer will be analysed with a novel RT-qPCR test to pre-select patients with CMS4 tumours. Selected patients (n = 27) will receive treatment with imatinib (400 mg per day) starting two weeks prior to planned tumour resection. To assess treatment-induced changes in the aggressive CMS4 phenotype, RNA sequencing will be performed on pre- and post-treatment tissue samples.
The development of effective adjuvant therapy for primary colon cancer is hindered by multiple factors. First, new drugs that may have value in the prevention of (early) distant recurrence are almost always first tested in patients with heavily pre-treated metastatic disease. Second, measuring on-target drug effects and biological consequences in tumour tissue is not commonly a part of the study design. Third, due to the lack of patient selection tools, clinical trials in the adjuvant setting require large patient populations. Finally, the evaluation of recurrence-prevention requires a long-term follow-up. In the ImPACCT trial these issues are addressed by including newly diagnosed pre-selected patients with CMS4 tumours prior to primary tumour resection, rather than non-selected patients with late-stage disease. By making use of the pre-operative window period, the biological effect of imatinib treatment on CMS4 tumours can be rapidly assessed. Delivering proof-of-concept for drug action in early stage disease should form the basis for the design of future trials with subtype-targeted therapies in colon cancer patients.
ClinicalTrials.gov: NCT02685046 . Registration date: February 9, 2016.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: The nationwide fecal immunochemical test–based screening program has influenced surgical care for patients with colorectal cancer (CRC) in the Netherlands, although these implications ...have not been studied in much detail so far. OBJECTIVE: To compare surgical outcomes of patients diagnosed as having CRC through the fecal immunochemical test–based screening program (screen detected) and patients with non–screen-detected CRC. DESIGN, SETTING, AND PARTICIPANTS: This was a population-based comparative cohort study using the Dutch ColoRectal Audit and analyzed all Dutch hospitals performing CRC resections. Patients who underwent elective resection for CRC between January 2011 to December 2016 were included. INTERVENTIONS: Colorectal cancer surgery. MAIN OUTCOMES AND MEASURES: Postoperative nonsurgical complications, postoperative surgical complications, postoperative 30-day or in-hospital mortality, and complicated course (postoperative complication resulting in a hospital stay >14 days and/or a reintervention and/or mortality). A risk-stratified comparison was made for different postoperative outcomes based on screening status (screen detected vs not screen detected), cancer stage (I-IV), and for cancer stage I to III also on age (aged ≤70 years and >70 years) and American Society of Anesthesiologists score (I-II and III-IV). To determine any residual case-mix–corrected differences in outcomes between patients with screen-detected and non–screen-detected cancer, univariable and multivariable logistic regression analyses were performed. RESULTS: In total, 36 242 patients with colon cancer and 17 416 patients with rectal cancer were included for analysis. Compared with patients with non–screen-detected CRC, screen-detected patients were younger (mean SD age, 68 5 vs 70 11 years), more often men (3777 60% vs 13 506 57%), and had lower American Society of Anesthesiologists score (American Society of Anesthesiologists score III+: 838 13% vs 5529 23%). Patients with stage I to III colon cancer who were screen detected had a significantly lower mortality and complicated course rate compared with non–screen-detected patients. For patients with rectal cancer, only a significant difference was found in mortality rate in patients with a cancer stage IV disease, which was higher in the screen-detected group. Compared with non–screen-detected colon cancer, an independent association was found for screen-detected colon cancer on nonsurgical complications (adjusted odds ratio, 0.81; 95% CI, 0.73-0.91), surgical complications (adjusted odds ratio, 0.80; 95% CI, 0.72-0.89), and complicated course (adjusted odds ratio, 0.80; 95% CI, 0.71-0.90). Screen-detected rectal cancer had significantly higher odds on mortality. CONCLUSIONS AND RELEVANCE: Postoperative outcomes were significantly better for patients with colon cancer referred through the fecal immunochemical test–based screening program compared with non–screen-detected patients. These differences were not found in patients with rectal cancer. The outcomes of patients with screen-detected colon cancer were still better after an extensive case-mix correction, implying additional underlying factors favoring patients referred for surgery through the screening program.
Aim
Anastomotic leakage (AL) is one of the most feared complications after rectal resection. This study aimed to assess a combination of biomarkers for early detection of AL after rectal cancer ...resection.
Method
This study was an international multicentre prospective cohort study. All patients received a pelvic drain after rectal cancer resection. On the first three postoperative days drain fluid was collected daily and C‐reactive protein (CRP) was measured. Matrix metalloproteinase‐2 (MMP2), MMP9, glucose, lactate, interleukin 1‐beta (IL1β), IL6, IL10, tumour necrosis factor alpha (TNFα), Escherichia coli, Enterococcus faecalis, lipopolysaccharide‐binding protein and amylase were measured in the drain fluid. Prediction models for AL were built for each postoperative day using multivariate penalized logistic regression. Model performance was estimated by the c‐index for discrimination. The model with the best performance was visualized with a nomogram and calibration was plotted.
Results
A total of 292 patients were analysed; 38 (13.0%) patients suffered from AL, with a median interval to diagnosis of 6.0 (interquartile ratio 4.0–14.8) days. AL occurred less often after partial than after total mesorectal excision (4.9% vs 15.2%, P = 0.035). Of all patients with AL, 26 (68.4%) required reoperation. AL was more often treated by reoperation in patients without a diverting ileostomy (18/20 vs 8/18, P = 0.03). The prediction model for postoperative day 1 included MMP9, TNFα, diverting ileostomy and surgical technique (c‐index = 0.71). The prediction model for postoperative day 2 only included CRP (c‐index = 0.69). The prediction model for postoperative day 3 included CRP and MMP9 and obtained the best model performance (c‐index = 0.78).
Conclusion
The combination of serum CRP and peritoneal MMP9 may be useful for earlier prediction of AL after rectal cancer resection. In clinical practice, this combination of biomarkers should be interpreted in the clinical context as with any other diagnostic tool.
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