Circulating Tumour DNA as Biomarker for Colorectal Liver Metastases:A Systematic Review and Meta-Analysis

Circulating tumour DNA (ctDNA) is a potential biomarker that could contribute to more judicious patient selection for personalised treatment. This review and meta-analysis gives an overview of the current knowledge in the literature investigating the value of ctDNA in patients with colorectal liver metastases (CRLM). A systematic search was conducted in electronic databases for studies published prior to the 26th of May 2023. Studies investigating the association between ctDNA and oncological outcomes in patients undergoing curative-intent local therapy for CRLM were included. Meta-analyses were performed to pool hazard ratios (HR) for the recurrence-free survival (RFS) and overall survival (OS). A total of eleven studies were included and nine were eligible for meta-analyses. Patients with detectable ctDNA after surgery experienced a significantly higher chance of recurrence (HR 3.12, 95% CI 2.27–4.28, p &lt; 0.000010) and shorter OS (HR 5.04, 95% CI 2.53–10.04, p &lt; 0.00001) compared to patients without detectable ctDNA. A similar association for recurrence was found in patients with detectable ctDNA after the completion of adjuvant therapy (HR 6.39, 95% CI 2.13–19.17, p &lt; 0.0009). The meta-analyses revealed no association between detectable ctDNA before surgery and the RFS and OS. These meta-analyses demonstrate the strong association between detectable ctDNA after treatment and oncological outcomes in CRLM patients.</p

Isolated Limb Perfusion with Melphalan and TNF-α in the Treatment of Extremity Sarcoma

Isolated limb perfusion (ILP) with chemotherapy alone has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor necrosis factor-alpha (TNF-α) to this treatment approach contributed to a major step forward in the treatment of locally advanced extremity soft tissue sarcoma (STS). High response rates and limb salvage rates have been reported in multicenter trials, which combined ILP with TNF-α plus melphalan, which resulted in the approval of TNF-α for this indication in Europe in 1998. Subsequently a series of confirmatory single institution reports on the efficacy of the procedure have now been published. TNF-α has an early and a late effect; it enhances tumor-selective drug uptake during the perfusion and plays an essential role in the subsequent selective destruction of the tumor vasculature. These effects result in a high response rate in high-grade soft tissue sarcomas. This induction therapy thus allows for resection of tumor remnants some 3 months after ILP and thus avoidance of limb amputation. TNF-α-based ILP is a well-established treatment to avoid amputations. It represents an important example of tumor vasculatory-modulating combination therapy and should be offered in large volume tertiary referral centers

Experiences of resuming life after immunotherapy and associated survivorship care needs:A qualitative study among patients with metastatic melanoma

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved the overall survival of patients with metastatic melanoma. It is unclear how the growing group of metastatic melanoma survivors resume their lives after treatment, and which needs they have regarding survivorship care (SSC). OBJECTIVES: To gain an in-depth understanding of metastatic melanoma survivors' experiences of resuming life after ICIs and their associated SSC needs. METHODS: A qualitative study was conducted among 20 patients with metastatic melanoma in whom ICIs had been discontinued after ongoing tumour response. One focus group (n = 9) was held, which was complemented by 11 individual interviews. Purposive sampling was used to select a variable sample in terms of sex, age, time since discontinuation of ICIs, and perceived impact of the disease. A topic guide was used to structure the (group) interviews, which were transcribed verbatim and analysed in a thematic content analysis, using several phases of coding. RESULTS: In resuming life after ICIs, the prognosis switch often caused mixed feelings among patients, mainly because of the uncertainty about the future. Demands and expectations from self and others, persistent complaints and new problems in different life domains often make it challenging to proceed with life as it was prior to metastatic cancer. Patients indicated they needed to find a new balance, which included learning to cope with uncertainty and a changed perspective on life and close relationships. In terms of SSC needs, patients particularly stressed the need for more tailored patient information, available at one location. In addition, they emphasized the need to know who to turn to in case of questions and indicated the need for psychosocial support, also for their close relatives. CONCLUSIONS: Metastatic melanoma survivors face various challenges in resuming life after ICIs and are left with several unmet SSC needs. Efforts should be focused on offering psychosocial supportive care in addition to medical care, from diagnosis onwards, taking into account the patient's close relatives. A single point of contact and personalized survivorship care plan (SCP) could be of added value in guiding them through the patient journey, which is, given its multidisciplinary nature, particularly important in melanoma care. What is already known about this topic? Since the introduction of immune checkpoint inhibitors (ICIs) the overall survival of patients with metastatic melanoma has improved significantly, leading to a growing group of melanoma survivors. Melanoma survivors may face various problems and challenges in resuming life after treatment, which may be associated with unmet survivorship care (SSC) needs. An in-depth understanding of their experiences with resuming life and the associated SSC needs is currently lacking. What does this study add? Metastatic melanoma survivors experience various challenges after immunotherapy, from the uncertain prognosis switch to the struggle of finding a new balance in life. Besides negative aspects, such as complaints in different life domains, the patient journey is often accompanied by positive outcomes, for example a changed perspective on life. They stress the need for tailored patient information and broader supportive care, also for their close relatives. What are the clinical implications of this work? In addition to medical care, efforts should be focused on offering psychosocial supportive care, including return-to-work issues, from diagnosis onwards, ideally taking into account the patient's close relatives. To guide them through the patient journey, a single point of contact and a personalized survivorship care plan (SCP) could be of added value. The latter is particularly important in melanoma care, given its multidisciplinary nature

Clinical evaluation of the clinicopathologic and gene expression profile (CP-GEP) in patients with melanoma eligible for sentinel lymph node biopsy:A multicenter prospective Dutch study

Sentinel lymph node biopsy (SLNB) is recommended for patients with &gt;pT1b cutaneous melanoma, and should be considered and discussed with patients diagnosed with pT1b cutaneous melanoma for the purpose of staging, prognostication and determining eligibility for adjuvant therapy. Previously, the clinicopathologic and gene expression profile (CP-GEP, Merlin Assay®) model was developed to identify patients who can forgo SLNB because of a low risk for sentinel node metastasis. The aim of this study was to evaluate the clinical use and implementation of the CP-GEP model in a prospective multicenter study in the Netherlands. Both test performance and feasibility for clinical implementation were assessed in 260 patients with T1-T4 melanoma. The CP-GEP model demonstrated an overall negative predictive value of 96.7% and positive predictive value of 23.7%, with a potential SLNB reduction rate of 42.2% in patients with T1-T3 melanoma. With a median time of 16 days from initiation to return of test results, there was sufficient time left before the SLNB was performed. Based on these outcomes, the model may support clinical decision-making to identify patients who can forgo SLNB in clinical practice.</p

Postoperative Radiotherapy in Stage I-III Merkel Cell Carcinoma

BACKGROUND: Postoperative radiotherapy (PORT) is currently recommended for the treatment of Merkel cell carcinoma. Nevertheless, deviations occur frequently due to the generally elderly and frail patient population. We aimed to evaluate the influence of PORT on survival in stage I-III MCC patients treated in the Netherlands. METHODS: Patients were included retrospectively between 2013 and 2018. Fine-Gray method was used for cumulative incidence of recurrence and MCC-related survival, cox regression was performed for overall survival (OS). Analyses were performed in patients with clinical (sentinel node biopsy [SN] not performed) stage I/II (c-I/II-MCC), pathologic (SN negative) stage I/II (p-I/II-MCC) and stage III MCC (III-MCC), separately. Propensity score matching (PSM) was performed to assess confounding by indication. RESULTS: In total 182 patients were included, 35 had p-I/II-MCC, 69 had c-I/II-MCC and 78 had III-MCC. Median follow up time was 53.5 (IQR 33.4-67.4), 30.5 (13.0-43.6) and 29.3 (19.3-51.0) months, respectively. Multivariable analysis showed PORT to be associated with less recurrences and improved OS, but not with MCC-related survival. In stage III-MCC, extracapsular extension (sub-distribution hazard [SDH] 4.09, p=0.012) and PORT (SDH 0.45, p=0.044) were associated with recurrence, and ≥4 positive lymph nodes (SDH 3.24, p=0.024) were associated with MCC-related survival. CONCLUSIONS: PORT was associated with less recurrences and improved OS in patients with stage I-III MCC, but not with improved MCC-related survival. Trends in OS benefit are likely to be caused by selection bias suggesting further refinement of criteria for PORT is warranted, for instance by taking life expectancy into account

Multimodality treatment of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) in the elderly

Introduction: This subgroup analysis of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) from the PERSARC collaborative group aimed to achieve a more personalized multimodality treatment approach for primary eUPS in elderly patients. Material and methods: A multicenter retrospective study including primary high-grade eUPS surgically treated with curative intent between 2000 and 2016. Overall survival (OS), local recurrence (LR) and distant metastasis (DM) curves were calculated by Kaplan Meier analysis. Cox proportional hazard models were used to determine the effect of radiotherapy. Results: From a total of 2511 patients with extremity soft tissue sarcoma (eSTS) of the PERSARC study collaborative; 703 patients with eUPS were included in this study. In elderly patients with eUPS 5-year OS, LR and DM were 35.4 (95%CI 29.3–42.8), 17.7 (95%CI 12.7–22.6) and 24.6 (95%CI 19.1–30.1). eUPS was significantly less treated with radiotherapy compared with other eSTS, especially in elderly patients. Patients with R1-R2 margins treated with radiotherapy had about half the risk of developing LR compared with patients treated without radiotherapy (HR = 0.454, p = 0.033). Conclusion: Elderly patients with eUPS were less often treated with radiotherapy and showed higher LR. Nowadays, given an increasing life expectancy in elderly patients, multimodality treatment should be considered

Gastrointestinal Stromal Tumours (GIST) in Young Adult (18-40 Years) Patients:A Report from the Dutch GIST Registry

Gastrointestinal stromal tumour (GIST) is a disease of older adults and is dominated by KIT/PDGFR mutations. In children, GIST is rare, predominantly occurs in girls, has a stomach location and generally lacks KIT/PDGFR mutations. For young adults (YA), aged 18 to 40 years, the typical phenotypic and genotypic patterns are unknown. We therefore aimed to describe the clinical, pathological and molecular characteristics of GIST in in YA. YA GIST patients registered in the Dutch GIST Registry (DGR) were included, and data were compared to those of older adults (OA). From 1010 patients in the DGR, 52 patients were YA (54% male). Main tumour locations were stomach (46%) and small intestine (46%). GIST genetic profiles were mutations in KIT (69%), PDGFRA (6%), SDH deficient (8%), NF1 associated (4%), ETV6-NTRK3 gene fusion (2%) or wildtype (10%). Statistically significant differences were found between the OA and YA patients (localisation, syndromic and mutational status). YA presented more often than OA in an emergency setting (18% vs. 9%). The overall five-year survival rate was 85%. In conclusion, YA GISTs are not similar to typical adult GISTs and also differ from paediatric GISTs, as described in the literature. In this series, we found a relatively high percentage of small intestine GIST, emergency presentation, 25% non-KIT/PDGFRA mutations and a relatively good survival

The EORTC-DeCOG nomogram adequately predicts outcomes of patients with sentinel node-positive melanoma without the need for completion lymph node dissection

Purpose: Based on recent advances in the management of patients with sentinel node (SN)–positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM). Methods: The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation. Results: The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of <25% and an overall 5-year recurrence rate of 13%. A model including information on completion lymph node dissection (CLND) showed only marginal improvement in model performance. Conclusions: The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making

Outcomes After Major Surgical Procedures in Octogenarians:A Nationwide Cohort Study

Introduction: Aging of the worldwide population has been observed, and postoperative outcomes could be worse in elderly patients. This nationwide study assessed trends in number of surgical resections in octogenarians regarding various major surgical procedures and associated postoperative outcomes. Methods: All patients who underwent surgery between 2014 and 2018 were included from Dutch nationwide quality registries regarding esophageal, stomach, pancreas, colorectal liver metastases, colorectal cancer, lung cancer and abdominal aortic aneurysms (AAA). For each quality registry, the number of patients who were 80 years or older (octogenarians) was calculated per year. Postoperative outcomes were length of stay (LOS), 30 day major morbidity and 30 day mortality between octogenarians and younger patients. Results: No increase in absolute number and proportion of octogenarians that underwent surgery was observed. Median LOS was higher in octogenarians who underwent surgery for colorectal cancer, colorectal liver metastases, lung cancer, pancreatic disease and esophageal cancer. 30 day major morbidity was higher in octogenarians who underwent surgery for colon cancer, esophageal cancer and elective AAA-repair. 30 day mortality was higher in octogenarians who underwent surgery for colorectal cancer, lung cancer, stomach cancer, pancreatic disease, esophageal cancer and elective AAA-repair. Median LOS decreased between 2014 and 2018 in octogenarians who underwent surgery for stomach cancer and colorectal cancer. 30 day major morbidity decreased between 2014 and 2018 in octogenarians who underwent surgery for colon cancer. No trends were observed in octogenarians regarding 30 day mortality between 2014 and 2018. Conclusion: No increase over time in absolute number and proportion of octogenarians that underwent major surgery was observed in the Netherlands. Postoperative outcomes were worse in octogenarians