Locoregional recurrence negatively impacts both long‐term survival and quality of life for several malignancies. For appropriate‐risk patients with an isolated, resectable, local recurrence, surgery ...represents the only potentially curative therapy. However, oncologic outcomes remain inferior for patients with locally recurrent disease even after macroscopically complete resection. Unfortunately, these operations are often extensive, with significant perioperative morbidity and mortality. This review highlights selected malignancies (mesothelioma, sarcoma, lung cancer, breast cancer, rectal cancer, and peritoneal surface malignancies) in which surgical resection is a key treatment modality and local recurrence plays a significant role in overall oncologic outcome with regard to survival and quality of life. For each type of cancer, the current, state‐of‐the‐art treatment strategies and their outcomes are assessed. The need for additional therapeutic options is presented given the limitations of the current standard therapies. New and emerging treatment modalities, including polymer films and nanoparticles, are highlighted as potential future solutions for both prevention and treatment of locally recurrent cancers. Finally, the authors identify additional clinical and research opportunities and propose future research strategies based on the various patterns of local recurrence among the different cancers.
Desmoid tumors (DTs) are a rare disease of intermediate malignancy characterized histologically by a locally aggressive, monoclonal, fibroblastic proliferation and clinically by a variable and often ...unpredictable course. For decades, surgical resection has been the standard initial treatment approach; however, more recently, a paradigm shift toward a more conservative treatment strategy has been introduced. More than 5 years ago, The Desmoid Tumor Working Group started a consensus initiative in Europe with the aim of harmonizing the strategy among clinicians and setting up treatment recommendations for patients with DTs. This review summarizes the latest joint, global, evidence‐based guideline approach to DT management. Moreover, a number of gray areas in the treatment recommendations are discussed, and possible future perspectives on the treatment armamentarium for patients with DTs are presented.
The current review of desmoid tumors summarizes the recommendations for management and treatment strategies for this disease from the joint, global, evidence‐based, consensus guideline approach of The Desmoid Tumor Working Group and highlights future perspectives for these patients.
Tumor rupture is an important risk factor predictive of recurrence after macroscopically complete resection of gastrointestinal stromal tumors (GISTs), and an indication for defined interval or even ...lifelong adjuvant therapy with imatinib according to guidelines. However, there is no consensus or universally accepted definition of the term ‘tumor rupture’, and, consequently, its incidence varies greatly across reported series. Without predefined criteria, the clinical significance of rupture has also been difficult to assess on multivariate analysis of retrospective data. We reviewed the relevant literature and international guidelines, and, based on the Oslo criteria, proposed the following six definitions for ‘tumor rupture’: (1) tumor fracture or spillage; (2) blood-stained ascites; (3) gastrointestinal perforation at the tumor site; (4) microscopic infiltration of an adjacent organ; (5) intralesional dissection or piecemeal resection; or (6) incisional biopsy. Not all minor defects of tumor integrity should not be classified as rupture, i.e. mucosal defects or spillage contained within the gastrointestinal lumen, microscopic tumor penetration of the peritoneum or iatrogenic damage only to the peritoneal lining, uncomplicated transperitoneal needle biopsy, and R1 resection. This broad definition identifies GIST patients at particularly high risk of recurrence in population-based cohorts; however, its applicability in other sarcomas has not been investigated. As the proposed definition of tumor rupture in GIST has limited evidence based on the small number of patients with rupture in each retrospective study, we recommend validating the proposed definition of tumor rupture in GIST in prospective studies and considering it in clinical practice.
Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery ...versus surgery alone on abdominal recurrence-free survival.
EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov, NCT01344018.
Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8–59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71–1·44; log rank p=0·95). The most common grade 3–4 adverse events were lymphopenia (98 77% of 127 patients in the radiotherapy plus surgery group vs one 1% of 128 patients in the surgery alone group), anaemia (15 12% vs ten 8%), and hypoalbuminaemia (15 12% vs five 4%). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events.
Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma.
European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.
Despite rare cancers accounting for 25% of adult tumors
, they are difficult to study due to the low disease incidence and geographically dispersed patient populations, which has resulted in ...significant unmet clinical needs for patients with rare cancers. We assessed whether a patient-partnered research approach using online engagement can overcome these challenges, focusing on angiosarcoma, a sarcoma with an annual incidence of 300 cases in the United States. Here we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling US and Canadian patients to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 patients registered for the ASCproject, which comprises a large proportion of all patients with angiosarcoma. Whole-exome sequencing (WES) of 47 tumors revealed recurrently mutated genes that included KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, which suggested a therapeutic rationale. Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature, which suggested that for the subset of patients with angiosarcoma of HNFS, ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. Medical record review revealed that two patients with HNFS angiosarcoma had received off-label therapeutic use of antibody to the programmed death-1 protein (anti-PD-1) and had experienced exceptional responses, which highlights immune checkpoint inhibition as a therapeutic avenue for HNFS angiosarcoma. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for patients with angiosarcoma. Collectively, this proof-of-concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and can enable discoveries.
Epigenetic aberrations are widespread in cancer, yet the underlying mechanisms and causality remain poorly understood
. A subset of gastrointestinal stromal tumours (GISTs) lack canonical kinase ...mutations but instead have succinate dehydrogenase (SDH) deficiency and global DNA hyper-methylation
. Here, we associate this hyper-methylation with changes in genome topology that activate oncogenic programs. To investigate epigenetic alterations systematically, we mapped DNA methylation, CTCF insulators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes shared similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on a disrupted insulator that normally partitions a core GIST super-enhancer from the FGF4 oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancer and oncogene. CRISPR-mediated excision of the corresponding CTCF motifs in an SDH-intact GIST model disrupted the boundary between enhancer and oncogene, and strongly upregulated FGF4 expression. We also identified a second recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-deficient GISTs. Finally, we established a patient-derived xenograft (PDX) from an SDH-deficient GIST that faithfully maintains the epigenetics of the parental tumour, including hypermethylation and insulator defects. This PDX model is highly sensitive to FGF receptor (FGFR) inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance of the underlying epigenetic lesions. Our study reveals how epigenetic alterations can drive oncogenic programs in the absence of canonical kinase mutations, with implications for mechanistic targeting of aberrant pathways in cancers.
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