Contribution of collegial support meetings (CSM) in the management of complex situations of patients with advanced cancer.

PURPOSE: Collegial support meetings (CSM) have been set up in the Gustave Roussy Cancer Center for inpatients whose complex care requires a multi-professional approach involving many participants: oncologists but also health-caregivers, a member of the palliative care team, an intensivist, and a psychologist. This study is aimed at describing the role of this newly multidisciplinary meeting implemented in a French Comprehensive Cancer Center. METHODS: Each week, the health-caregivers decide which situations should be examined, depending on the difficulty of a case. The discussion goes on to include the goal of treatment, the intensity of care, ethical and psychosocial issues, and the patient's life plan. Finally, to obtain feedback from the teams, a survey has been distributed to assess the interest in the CSM. RESULTS: In 2020, 114 inpatients were involved, and 91% were in an advanced palliative situation. During the CSMs, 55% of the discussions focused on whether to continue specific cancer treatment-29% about whether to continue invasive medical care-50% about optimizing supportive care. We estimate that between 65 and 75% of CSMs influenced further decisions. Death occurred during the hospitalization for 35% of the patients that were discussed. The lapse of time between last chemotherapy and death was 24 days (IQR, 28.5). CSMs were well received, since 80% of the teams find these meetings useful. CONCLUSIONS: CSMs reach conclusions for medical and nursing staff involved, in order to improve the management of inpatients with cancer in advanced palliative situation and to define the better goals of care.

[Implementation of a multimodal strategy for information and collection of advance directives in a comprehensive cancer center]. / Mise en place d'une stratégie multimodale d'information et de recueil des directives anticipées dans un Centre de lutte contre le cancer (CLCC).

INTRODUCTION: In France, advance directives (AD) remain unknown and underused by healthcare users and professionals. This is particularly true in oncology. This work was carried out with patients and caregivers of a Comprehensive Cancer Center to improve their appropriation and information. METHODS: The project, built by the Ethics Committee, the Patients Committee and the Palliative Care Team, made it possible to develop over 6 months a training program, an information procedure and several original documents. RESULTS: A total of 34 one-hour training courses for all professionals were organized. A procedure for making information available, including the right to draft ADs, has been implemented. This procedure is personalized, gradual and multi-professional. When a patient wishes to write his AD, he is accompanied by a dedicated team and benefits from a specific form, which enlighten values and preferences before addressing the desired level of therapeutic commitment. Communication elements were diffused, and a specific training on "anticipated discussions" was created. A dedicated space in the computerized chart makes it possible to locate the existence of ADs and to display them instantaneously. DISCUSSION - CONCLUSION: Based on the observation of the obstacles to the use of ADs, the strategy we implemented aims to provide information that is both efficient and ethically respectful for both patients and caregivers. ADs are only one element facilitating autonomy and anticipation, and must be associated with a shared continuous definition of the project and of the goals of care.

Bevacizumab in real-life patients with recurrent glioblastoma: benefit or futility?

PURPOSE: Angiogenesis plays a key role in glioblastoma, but most anti-angiogenic therapy trials have failed to change the poor outcome of this disease. Despite this, and because bevacizumab is known to alleviate symptoms, it is used in daily practice. We aimed to assess the real-life benefit in terms of overall survival, time to treatment failure, objective response, and clinical benefit in patients with recurrent glioblastoma treated with bevacizumab. METHODS: This was a monocentric, retrospective study including patients treated between 2006 and 2016 in our institution. RESULTS: 202 patients were included. The median duration of bevacizumab treatment was 6 months. Median time to treatment failure was 6.8 months (95%CI 5.3-8.2) and median overall survival was 23.7 months (95%CI 20.6-26.8). Fifty percent of patients had a radiological response at first MRI evaluation, and 56% experienced symptom amelioration. Grade 1/2 hypertension (n = 34, 17%) and grade one proteinuria (n = 20, 10%) were the most common side effects. CONCLUSIONS: This study reports a clinical benefit and an acceptable toxicity profile in patients with recurrent glioblastoma treated with bevacizumab. As the panel of therapies is still very limited for these tumors, this work supports the use of bevacizumab as a therapeutic option.

Digital remote monitoring plus usual care versus usual care in patients treated with oral anticancer agents: the randomized phase 3 CAPRI trial.

Strategies that individualize the care of cancer patients receiving oral anticancer agents offer opportunities to improve treatment adherence and patient care. However, the impact of digital remote monitoring systems in this setting has not been evaluated. Here, we report the results of a phase 3 trial (CAPRI, NCT02828462) to assess the impact of a nurse navigator-led program on treatment delivery for patients with metastatic cancer. Patients receiving approved oral anticancer agents were randomized (1:1) to an intervention combining a nurse navigator-led follow-up system and a web portal-smartphone application on top of usual care, or to usual symptom monitoring at the discretion of the treating oncologist, for a duration of 6 months. The primary objective included optimization of the treatment dose. Secondary objectives were grade ≥3 toxicities, patient experience, rates and duration of hospitalization, response and survival, and quality of life. In 559 evaluable patients the relative dose intensity was higher in the experimental arm (93.4% versus 89.4%, P = 0.04). The intervention improved the patient experience (Patient Assessment of Chronic Illness Care score, 2.94 versus 2.67, P = 0.01), reduced the days of hospitalization (2.82 versus 4.44 days, P = 0.02), and decreased treatment-related grade ≥3 toxicities (27.6% versus 36.9%, P = 0.02). These findings show that patient-centered care through remote monitoring of symptoms and treatment may improve patient outcomes and experience.

Genome-driven medicine for patients with recurrent glioma enrolled in early phase trials.

BACKGROUND: Recent studies showed that patients with glioma can safely participate in early phase clinical trials; however, clinical benefits in this population were limited. We aimed to evaluate the benefit of molecular profiling to guide enrolment in early phase trials for patients with recurrent glioma. METHODS: Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2018 were reviewed for clinico-pathological characteristics, toxicity, response, progression-free survival and overall survival (OS). The primary objective was to evaluate response rates in molecularly-oriented versus non-molecularly-oriented patients. RESULTS: Eighty-eight patients were enrolled, of whom 45 (51.1%) patients were molecularly-oriented. Targets included IDH1/2 (n = 15), BRAF (n = 11), and FGFR1 (n = 3) mutations, FGFR2-3 fusions (n = 9), and mismatch repair deficiency (n = 7). Among patients with high-grade glioma (n = 74), the rate of stable disease ≥6 months and partial or complete response was 25.7% in molecularly-oriented versus 5.1% in non-molecularly-oriented patients (p = 0.02). Upon multivariable adjustment, baseline steroid use ≥20 mg prednisone equivalent per day was associated with shorter OS (OR 3.15 [95% CI 1.62-6.13], p = 0.0008), while molecular enrichment strategy was associated with longer OS (OR 0.40 [95% CI 0.22-0.73], p = 0.003). Nine (10.2%) patients experienced grade 3-4 toxicity and no dose limiting toxicity (DLT) occurred in both cohorts. CONCLUSION: The use of molecular profiling to guide enrolment in early phase trials is feasible and might provide benefits to selected patients with glioma. Further studies are warranted to confirm these results in larger randomised settings and identify the patients most likely to benefit from this approach.

Ethical issues related to the COVID-19 pandemic in patients with cancer: experience and organisations in a French comprehensive cancer centre.

BACKGROUND: The COVID-19 pandemic has aggressively reached the most vulnerable, not only the elderly but also patients with chronic conditions such as cancer. In this study, we present the outlines of ethical thinking and the measures implemented to try to respect our basic values of care, in the specific environment of an oncology hospital. METHODS: Our ethics committee created an ethical watch system based on 24/7 shifts to assist practitioners in their daily decisions. We discuss the challenges faced by patients with cancer during the pandemic, such as access to critical care and ethical dilemmas in the context of resource scarcity, as well as the issue of isolation of patients. We also debate the restrictions in access to oncology care in a health context strongly 'prioritised' against COVID-19. RESULTS: In all areas of an ethical dilemma, either for sorting out access to critical care or for the dramatic consequences of prolonged isolation of patients, our common thread was our attempt to protect, whenever possible, the principles of deontological ethics by strictly resisting utilitarian pressure. Respecting democratic health decision-making processes is a cornerstone of ethically relevant decisions, including in the context of a sanitary crisis. CONCLUSION: The role of an ethics committee related to real-life situations includes not only a reflexive perspective in respect of fundamental principles, but also the help to enlighten and resolve ethical dilemmas in complex clinical situations. This ethical watch team assists physicians in decision-making, promoting the supportive and palliative dimension of care with a holistic approach.

Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG).

BACKGROUND: No systemic treatment has been established for meningioma progressing after local therapies. METHODS: This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. RESULTS: Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. CONCLUSIONS: Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.

A Predictive Clinical-Radiomics Nomogram for Survival Prediction of Glioblastoma Using MRI.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adult patients with a median survival of around one year. Prediction of survival outcomes in GBM patients could represent a huge step in treatment personalization. The objective of this study was to develop machine learning (ML) algorithms for survival prediction of GBM patient. We identified a radiomic signature on a training-set composed of data from the 2019 BraTS challenge (210 patients) from MRI retrieved at diagnosis. Then, using this signature along with the age of the patients for training classification models, we obtained on test-sets AUCs of 0.85, 0.74 and 0.58 (0.92, 0.88 and 0.75 on the training-sets) for survival at 9-, 12- and 15-months, respectively. This signature was then validated on an independent cohort of 116 GBM patients with confirmed disease relapse for the prediction of patients surviving less or more than the median OS of 22 months. Our model insured an AUC of 0.71 (0.65 on train). The Kaplan-Meier method showed significant OS difference between groups (log-rank p = 0.05). These results suggest that radiomic signatures may improve survival outcome predictions in GBM thus creating a solid clinical tool for tailoring therapy in this population.

Beyond the Driver Mutation: Immunotherapies in Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are a subtype of soft tissue sarcoma (STS), and have become a concept of oncogenic addiction and targeted therapies.The large majority of these tumors develop after a mutation in KIT or platelet derived growth factor receptor α (PDGFRα), resulting in uncontrolled proliferation. GISTs are highly sensitive to imatinib. GISTs are immune infiltrated tumors with a predominance of tumor-associated macrophages (TAMs) and T-cells, including many CD8+ T-cells, whose numbers are prognostic. The genomic expression profile is that of an inhibited Th1 response and the presence of tertiary lymphoid structures and B cell signatures, which are known as predictive to response to ICI. However, the microtumoral environment has immunosuppressive attributes, with immunosuppressive M2 macrophages, overexpression of indoleamine 2,3-dioxygenase (IDO) or PD-L1, and loss of major histocompatibility complex type 1. In addition to inhibiting the KIT oncogene, imatinib appears to act by promoting cytotoxic T-cell activity, interacting with natural killer cells, and inhibiting the expression of PD-L1. Paradoxically, imatinib also appears to induce M2 polarization of macrophages. There have been few immunotherapy trials with anti-CTLA-4 or anti-PD-L1drugs and available clinical data are not very promising. Based on this comprehensive analysis of TME, we believe three immunotherapeutic strategies must be underlined in GIST. First, patients included in clinical trials must be better selected, based on the identified driver mutation (such as PDGFRα D842V mutation), the presence of tertiary lymphoid structures (TLS) or PD-L1 expression. Moreover, innovative immunotherapeutic agents also provide great interest in GIST, and there is a strong rationale for exploring IDO targeting after disease progression during imatinib therapy. Finally and most importantly, there is a strong rationale to combine of c-kit inhibition with immune checkpoint inhibitors.

Machine-Learning-Based Radiomics MRI Model for Survival Prediction of Recurrent Glioblastomas Treated with Bevacizumab.

Anti-angiogenic therapy with bevacizumab is a widely used therapeutic option for recurrent glioblastoma (GBM). Nevertheless, the therapeutic response remains highly heterogeneous among GBM patients with discordant outcomes. Recent data have shown that radiomics, an advanced recent imaging analysis method, can help to predict both prognosis and therapy in a multitude of solid tumours. The objective of this study was to identify novel biomarkers, extracted from MRI and clinical data, which could predict overall survival (OS) and progression-free survival (PFS) in GBM patients treated with bevacizumab using machine-learning algorithms. In a cohort of 194 recurrent GBM patients (age range 18-80), radiomics data from pre-treatment T2 FLAIR and gadolinium-injected MRI images along with clinical features were analysed. Binary classification models for OS at 9, 12, and 15 months were evaluated. Our classification models successfully stratified the OS. The AUCs were equal to 0.78, 0.85, and 0.76 on the test sets (0.79, 0.82, and 0.87 on the training sets) for the 9-, 12-, and 15-month endpoints, respectively. Regressions yielded a C-index of 0.64 (0.74) for OS and 0.57 (0.69) for PFS. These results suggest that radiomics could assist in the elaboration of a predictive model for treatment selection in recurrent GBM patients.

TP53 Mutation as a Prognostic and Predictive Marker in Sarcoma: Pooled Analysis of MOSCATO and ProfiLER Precision Medicine Trials.

(1) Background: locally resected high-grade sarcomas relapse in 40% of cases. There is no prognostic or predictive genomic marker for response to peri-operative chemotherapy. (2) Methods: MOSCATO and ProfiLER are pan-tumor prospective precision medicine trials for advanced tumors. Molecular analysis in both trials comprised targeted next-generation sequencing and comparative genomic hybridization array. We investigated if molecular alterations identified in these trials in sarcomas were associated with disease-free survival (DFS) and response to anthracyclines. (3) Results: this analysis included 215 sarcomas, amongst which 53 leiomyosarcomas, 27 rhabdomyosarcomas, 20 undifferentiated pleomorphic sarcomas, and 17 liposarcomas. The most frequently altered gene was TP53 (46 mutations and eight deletions). There were 149 surgically resected localized sarcomas. Median DFS in TP53 wild type (WT), deleted, and mutated sarcomas was 16, 10, and 10 months, respectively (p = 0.028; deletions: HR = 1.55; 95% CI = 0.75-3.19; mutations: HR = 1.70; 95%CI = 1.13-2.64). In multivariate analysis, TP53 mutations remained associated with shorter DFS (p = 0.027; HR = 2.30; 95%CI = 1.10-4.82). There were 161 localized and advanced sarcomas evaluable for response to anthracyclines. Objective response rates were 35% and 55% in TP53 WT and mutated sarcomas, respectively (OR = 2.24; 95%CI = 1.01-5.03; p = 0.05). In multivariate analysis, TP53 mutations remained associated with increased response (OR = 3.24; 95%CI = 1.30-8.45; p = 0.01). (4) Conclusions: TP53 mutations are associated with shorter DFS and increased response to anthracyclines. Post-validation, these findings could assist in decision-making for peri-operative treatments.

[Preoperative versus postoperative radiotherapy in soft tissue sarcomas: State of the art and perspectives]. / Radiothérapie préopératoire versus postopératoire dans les sarcomes des tissus mous : état des lieux et perspectives.

Radiation therapy is a standard treatment for limbs soft tissue sarcomas. Preoperative versus postoperative radiotherapy has been a controversial topic for years. With preoperative irradiation, the treatment volume is more limited, the delivered dose possibly lower and the tumor volume easier to delimit. Only one randomized trial compared these two irradiation sequences. The results in terms of local control and survival were equivalent but the risk of acute postoperative complications was higher if irradiation was administered before surgery. However, in the latest update of this trial, patients who received adjuvant irradiation exhibited more severe late toxicity than those treated preoperatively. In addition, with modern irradiation techniques such as conformal with image-guided intensity modulated radiotherapy and flap coverage techniques, the incidence of complications after preoperative irradiation were lower than historically published rates. Locally advanced proximal sarcomas and the failure of other neoadjuvant treatments are nowadays classical indications for preoperative irradiation. As with other neoadjuvant treatments, induction radiotherapy must be personalized according to the histological subtype, the tumor site and the benefit/risk ratio, which is best appreciated by a multidisciplinary surgical and oncological team in a specialized center in the management of soft-tissue sarcomas.

Prospective evaluation of intensity-modulated radiotherapy toxicity in extremity soft tissue sarcomas patients: A role for irradiated healthy soft tissue volume?

AIM: To prospectively assess toxicities of curative-intent intensity-modulated conformal radiotherapy (IMRT) in patients with extremity soft tissue sarcomas (ESTS). METHODS: Data from 59 consecutive patients with ESTS between 2014 and 2019 were both retrospectively and prospectively analysed. Toxicity data were collected both by confidential mailed survey (39% completed) and medical charts, and graded according to CTCAE v5.0. Normal tissues dosimetric data (healthy soft tissue segment, joint and bone) were included. The healthy soft tissue segment was created by adding 5 cm on either side of the PTV on CT axial slices, the PTV and bone (and articulation if present) were then removed from the generated volume. RESULTS: IMRT was delivered post-operatively for nearly half of patients (n = 24, 41%), preoperatively for 18 (31%) and exclusively for 17 (28%; salvage: 13% or immediately inoperable: 15%). The median total dose delivered to the planned target volume (PTV) was 50.4 Gy (36-68 Gy) and 13 patients (22%) received a boost. With a median follow-up of 27 months (6-94 months), a total of 87 late effects were identified in 44/59 (75%) patients: 89% G1-2, and 11% G3-4. The main G1-2 toxicities were: functional limitation (36%), oedema (29%), gait disorders (20%), neurological disorders (20%) and chronic pain (32%). G3-4 toxicities were pain (n = 2), arterial stricture (n = 1) and a chronic wound requiring skin graft (n = 2). No bone fracture was observed. Quality of life was rated as good or very good in 70% patients who completed the survey. Larger (>3500 cm3) healthy soft tissue segment volume was associated with decreased late toxicities (p = 0.02). No other predictive factor of toxicity was identified. The 2-year rates of local control, overall survival and recurrence-free survival were 90%, 90% and 64%, respectively. CONCLUSION: Healthy soft tissue segment volume influenced toxicity. Long-term prospective monitoring in a homogeneous population remains critical to assess the impact of IMRT induced chronic toxicity in ESTS patients. This should ideally lead to a validated normal tissue dose constraint (e.g.: healthy soft tissue segment volume > 3500 cm3) to recommend for practitioners to help reduce the late toxicity risk.

Surgical management of soft tissue tumors of the abdominal wall: A retrospective study in a high-volume sarcoma center.

BACKGROUND: The aim of the study is to evaluate functional and oncological outcomes of patients undergoing abdominal wall soft tissue tumors (AWSTT) surgery. METHODS: All consecutive patients that underwent surgery for malignant and intermediate AWSTT from 1999 to 2019 were retrospectively analyzed. RESULTS: Ninety-two patients were identified, 20 (22%) operated on for a desmoid tumor and 72 (78%) for a soft tissue sarcoma (STS). Fifty-two patients (57%) had in toto resection of the abdominal wall (from the skin to the peritoneum) and 9 (10%) required simultaneous visceral resection. The closure was direct in 28 patients (30%) and requiring a mesh, a flap or a combination of the two in respectively 42, 16, and 6 patients (47%, 17%, 6%). The postoperative complications rate was 26%. Thirteen patients (14%) developed an incisional hernia after a median delay of 27 months. After a median follow-up of 40 months, out of the 72 patients operated on for STS, 7 (10%) developed local recurrence and 11 (15%) distant recurrence. The median recurrence-free and overall survivals were 61 and 116, months respectively. CONCLUSIONS: Management of AWSTT requires extensive surgery but allows good local control with an acceptable rate of incisional hernia.

Systematic review of phase-I/II trials enrolling refractory and recurrent Ewing sarcoma: Actual knowledge and future directions to optimize the research.

BACKGROUND: Optimal Phase-II design to evaluate new therapies in refractory/relapsed Ewing sarcomas (ES) remains imperfectly defined. OBJECTIVES: Recurrent/refractory ES phase-I/II trials analysis to improve trials design. METHODS: Comprehensive review of therapeutic trials registered on five databases (who.int/trialsearch, clinicaltrials.gov, clinicaltrialsregister.eu, e-cancer.fr, and umin.ac.jp) and/or published in PubMed/ASCO/ESMO websites, between 2005 and 2018, using the criterion: (Ewing sarcoma OR bone sarcoma OR sarcoma) AND (Phase-I or Phase-II). RESULTS: The 146 trials identified (77 phase-I/II, 67 phase-II, and 2 phase-II/III) tested targeted (34%), chemo- (23%), immune therapies (19%), or combined therapies (24%). Twenty-three trials were ES specific and 48 had a specific ES stratum. Usually multicentric (88%), few trials were international (30%). Inclusion criteria cover the recurrent ES age range for only 12% of trials and allowed only accrual of measurable diseases (RECIST criteria). Single-arm design was the most frequent (88%) testing mainly single drugs (61%), only 5% were randomized. Primary efficacy outcome was response rate (RR=CR+PR; Complete+Partial response) (n = 116/146; 79%), rarely progression-free or overall survival (16% PFS and 3% OS). H0 and H1 hypotheses were variable (3%-25% and 20%-50%, respectively). The 62 published trials enrolled 827 ES patients. RR was poor (10%; 15 CR=1.7%, 68 PR=8.3%). Stable disease was the best response for 186 patients (25%). Median PFS/OS was of 1.9 (range 1.3-14.7) and 7.6 months (5-30), respectively. Eleven (18%) published trials were considered positive, with median RR/PFS/OS of 15% (7%-30%), 4.5 (1.3-10), and 16.6 months (6.9-30), respectively. CONCLUSION: This review supports the need to develop the international randomized phase-II trials across all age ranges with PFS as primary endpoint.

EWSR1-PATZ1 fusion sarcoma - A new case report and review of the literature / Sarcome avec transcrit de fusion EWSR1-PATZ1 - Une nouvelle observation avec revue de la littérature.

Sarcoma with EWSR1-PATZ1 gene fusion is an exceedingly rare and newly described Ewing-like sarcoma harboring EWSR1 rearrangements involving fusion partners other than ETS family genes. The clinical, histopathologic and immunophenotypic features of cases reported in literature are fairly diverse and not specific. We report a new case report posing real challenges for histological and molecular diagnosis.

Postoperative Outcome of Surgery with Pancreatic Resection for Retroperitoneal Soft Tissue Sarcoma: Results of a Retrospective Bicentric Analysis on 50 Consecutive Patients.

BACKGROUNDS: Multivisceral resection is the standard treatment for retroperitoneal sarcoma (RPS) during which pancreas resection may be necessary. METHODS: All consecutive patients operated for RPS with pancreatectomy in 2 expert centers between 1993 and 2018 were retrospectively analyzed. RESULTS: Fifty patients (median age: 57 years, IQR: [46-65]) with a primary (n = 33) or recurrent (n = 17) RPS underwent surgery requiring pancreas resection (distal pancreatectomy (DP) (n = 43), pancreaticoduodenectomy (PD) (n = 5), central pancreatectomy (n = 1), and atypical resection (n = 1)). Severe postoperative morbidity (Clavien-Dindo III-IV) was observed in 14 patients (28%), and 7 of them (14%) required reoperation for anastomotic bowel leakage (n = 5), gastric volvulus (n = 1), or hemorrhage (n = 1). Pancreas-related complications occurred in 25 patients (50%): 10 postoperative pancreatic fistulas (POPF) (grade A (n = 12), grade B (n = 6), grade C (n = 1)), 13 delayed gastric emptying (grade A (n = 8), grade B (n = 4), grade C (n = 1)), 1 hemorrhage (grade C). Postoperative mortality was 4% (n = 2), all following PD, caused by a massive intraoperative air embolism and by a multiple organ failure after anastomotic leakage. Pathological analysis confirmed pancreatic involvement in 17 (34%) specimens. Microscopically complete resection (R0) was achieved in 22 (44%) patients. After a follow-up of 60 months, 36 patients (75%) were still alive, among whom 27 without recurrence (56%). CONCLUSION: Pancreatic resection during RPS surgery is associated with significant postoperative morbidity and mortality. PD should be avoided whenever possible while other procedures seemed achievable without excessive morbidity and with long-term survival.

Efficacy and safety of oral metronomic etoposide in adult patients with metastatic osteosarcoma.

Therapeutic options in patients with metastatic osteosarcoma are limited and effective systemic treatments are needed in this setting. The aim of this case series was to assess the efficacy and toxicity of oral metronomic etoposide in adult patients with progressive metastatic osteosarcoma. We retrospectively reviewed the electronic records of patients treated with oral metronomic etoposide (25 mg thrice daily, 3 weeks out of 4) from December 2002 to December 2018 at Gustave Roussy (Villejuif, France). The primary endpoint was progression-free rate (PFR) at 4 months; secondary endpoints were: best response (according to RECIST v1.1), progression-free survival (PFS), overall survival (OS) and safety. With a median follow-up of 9.8 months, 37 patients were eligible for this analysis: 68% males, median age 42 (range: 21-75), 19% with synchronous metastases, 92% with lung metastases, median PS: 1 (range: 0-3). Median number of previous treatment lines in the metastatic setting was 1 (range: 0-4). Progression-free rate at 4 months was 40.3% (95% CI: 24.5-56.2). Best response was partial response in 11% and stable disease in 35% of patients (disease control rate: 46%). Median PFS was 3.1 months (95% CI: 2.5-4.7) and median OS was 9.8 months (95% CI: 5.1-12.3). Toxicity profile was acceptable, with 13% grade 3 haematological toxicities (anaemia and neutropenia), without any grade 3-4 non-haematological toxicity. In our experience, oral metronomic etoposide demonstrated effective palliation along with acceptable toxicity in patients with progressive metastatic osteosarcoma.

Outcomes of patients with metastatic gastrointestinal stromal tumors (GIST) treated with multi-kinase inhibitors other than imatinib as first-line treatment.

BACKGROUND: Imatinib is the standard first-line therapy in metastatic gastrointestinal stromal tumours (GIST). Investigational multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result either in increased survival or in early emergence of resistance to approved MKIs. METHODS: To assess whether using MKIs other than imatinib in first line decreases imatinib efficacy in second line for patients with GIST, a retrospective chart review was performed from 2005 to 2011 in two French tertiary centres of patients with GIST who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by imatinib as second line. RESULTS: Of 46 patients, (55% women, median age 55 years (range 24-81)), 22 (47%) had a KIT exon 11 mutation, 1 a KIT exon 9 mutation (2%), 1 a PDGFRA D842V mutation (2%). Out of 46 patients, 21 (46%) received masitinib, 17 (37%) received dasatinib and 8 (17%) received nilotinib as first-line treatment with a median progression-free survival of 18.0 months (95% CI: 8.5 to 25.5). Median time to imatinib failure was 19.7 months (95% CI: 13.5 to 29.0). Median time to second relapse was 48.7 months (95% CI: 31.2 to 72.0). Median overall survival from time of initial metastasis diagnosis was 5.7 years (95% CI: 4.5 to 7.4). CONCLUSIONS: Patients with GIST who received investigational MKIs as first-line treatment and imatinib as second line had a time to second relapse longer than that observed historically with imatinib in first line, suggesting that using MKIs other than imatinib in first line does not decrease the efficacy of subsequent treatment lines.