Background
Guidelines recommend that retroperitoneal sarcoma (RPS) be managed in a reference sarcoma center (RSC), but the benefit remains to be demonstrated. This study investigated the impact of ...initial surgery performed within the NetSarc network on overall survival (OS).
Methods
NetSarc is a network of 26 RSCs with specialized multidisciplinary tumor boards (MDTs) that is funded by the French NCI. Since 2010, presentation to an MDT and second pathological review are mandatory for sarcoma patients, and data have been collected in a nationwide database. We extracted data for all patients who received surgery in or outside the network and who presented at a NetSarc center (NSC) for primary nonmetastatic RPS between 2010 and 2017.
Results
A total of 2945 patients were included: 1078 (36.6%) underwent the first surgery in an NSC, and 1867 (63.4%) in an out-of-network center. The median number of operations at an NSC during the study period was 23 (range: 3–209), and the corresponding median was 1 (range: 1–2) at out-of-network centers. The diagnostic procedures followed significantly more clinical practice guidelines within NetSarc, where there were significantly more first R0 resections 452 (41.9%) vs. 230 (12.3%). The OS was significantly superior for patients treated within NetSarc, with a 2-year OS of 87% vs. 70% (
p
< 0.001). In the multivariate analysis, surgery within an NSC was an independent predictor of OS, with a twofold lower odds ratio of death.
Conclusions
In this national study, surgery for primary RPS within an NSC was associated with a better OS.
Abstract Background Malignant peripheral nerve sheath tumors (MPNST) are a rare subtype of soft tissue sarcoma. They can arise in irradiated fields, in patients with type 1 neurofibromatosis (NF1), ...or sporadically. MPNST exhibit an aggressive behaviour, and their optimal management remains controversial. An unsolved issue is whether NF1-related and sporadic forms of MPNST have a different prognosis, and should be managed differently. Material and methods Adult and paediatric patients with histologically confirmed MPNST treated between 1990 and 2013 in French cancer centres of the GSF/GETO network, were included in this retrospective study. Results A total of 353 patients (37% with NF1 and 59% with sporadic tumours) were analysed. Median age at diagnosis was 42 years (range 1–94). The majority of tumours developed in the limbs, were deep-seated and of high grade. Two hundreds and ninety four patients underwent a curative intent surgery. Among them, 60 patients (21%) had neoadjuvant treatment (mainly chemotherapy), and 173 (59%) had adjuvant treatment (mainly radiotherapy). For operated patients, median progression free and overall survival (OS) were 26.3 months and 95.8 months, respectively. In multivariate analysis, poor-prognosis factors for OS were high grade, deep location, locally advanced stage at diagnosis, and macroscopically incomplete resection (R2). NF1 status was not negatively prognostic, except in the recurrence or metastatic setting, where NF1-related MPNST patients treated with palliative chemotherapy showed worse survival than patients with sporadic forms. Conclusion To our knowledge, our series is the largest study of patients with MPNST reported to date. For operated patients, we showed a worse prognosis for NF1-related MPNST, due to different clinical features at diagnosis, more than NF1 status itself. The French sarcoma group is now conducting correlative analyses on these patients, using the latest molecular tools.
Aggressive fibromatosis (AF) is a monoclonal proliferative disease but does not metastasize and does not dedifferentiate to a high-grade malignancy in case of recurrence. Biopsy is usually necessary ...to confirm the diagnosis. A hallmark is its apparent unpredictable clinical course producing a large heterogeneity even with an indistinguishable morphology. Additional studies of the molecular determinants of desmoid behavior are needed to guide selection of the various therapeutic modalities. During the last 10 years, the treatment of AF has evolved and the role of routine, aggressive first-line treatment (radiotherapy and surgery) is now debated. If a wait-and-see policy is used at initial presentation, it is observed that >50% of patients will have relatively indolent disease. Aggressive treatments that take their indications from retrospective studies should be re-evaluated in the light of new data. The objective of this article is to propose an algorithm that commences with more conservative approaches before treatments that have associated long-term morbidity, the more aggressive therapies being reserved only for those who really need it.
There are some lines of evidence suggesting a potential role of immunotherapy for treating patients with osteosarcomas.
This was an open-label, multicentre, phase 2 study of pembrolizumab in ...combination with metronomic cyclophosphamide in patients with advanced osteosarcomas. All patients received 50 mg b.i.d. of cyclophosphamide one week on and one week off and 200 mg of intravenous pembrolizumab (every 3 weeks). There was a dual primary end-point, encompassing both the non-progression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. An objective response rate of 20% and/or a 6-month non-progression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from the patients' tumour samples.
Between October 13 2015 and July 3 2017, 17 patients were included. Fifty were assessable for the efficacy end-point. Four patients experienced tumour shrinkage, resulting in a partial response (PR) in one patient (6.7%). The 6-month non-progression rate was 13.3% (95% confidence interval CI: 1.7–40.5). The most frequent adverse events were grade I or II nausea, anaemia, anorexia and fatigue. programmed death-ligand 1 (PD-L1) expression rate was low, observed in only 2 cases of 14 with available tumour material. The only patient who experienced PR had a PD-L1–negative tumour.
Programmed cell death 1 (PD-1) inhibition has limited activity in osteosarcomas. Further studies investigating PD-1 inhibitor in combination with agents modulating the microenvironment are warranted.
This study is registered with ClinicalTrials.gov, number NCT02406781.
•We report here the results of PD-1 targeting in patients with advanced osteosarcomas.•This therapeutic strategy has only modest activity.•Further studies should explore combination strategies reprogramming the microenvironment.
In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) ...patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study.
This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used.
Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, HR = 0.71, 95% CI (0.57; 0.89), P = 0.002; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years HR = 0.88, 95% CI (0.65; 1.21), P = 0.43. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively.
With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.
•Adjuvant imatinib for 2 years significantly improved RFS, with a trend towards a better imatinib failure free survival.
Retroperitoneal sarcomas (RPS) are heterogeneous. No previous study has investigated the impact of specialized surgery, evaluated locoregional relapse (LRR), abdominal sarcomatosis and distant ...metastatic relapse as separate events, or considered histological subtypes separately. This study addresses these specific points in a homogeneous cohort of patients with completely resected primary RPS.
We conducted a retrospective analysis of adult patients diagnosed with a RPS between 1 January 1988 and 31 December 2008 and eventually referred to one of 12 centers of the French Sarcoma Group. All cases were centrally reviewed by an expert pathologist.
Five hundred eighty-six patients were included. Median follow-up was 6.5 years 95% confidence interval (CI) 5.9–7.1. Five hundred thirty-seven patients had localized disease and 389 patients (76%) had macroscopically complete resection of the tumor. In this latter group, the 5-year LRR-free survival rate was 46% 41–52 and the 5-year overall survival (OS) rate was 66% 61–71. In multivariate analysis, gender, adjacent organ involvement, specialization of the surgeon, piecemeal resection and perioperative radiotherapy were independently associated with LRR. Specialization of the surgeon and piecemeal resection were independently associated with abdominal sarcomatosis whereas histology and adjacent organ involvement were independently associated with distant metastasis. Age, gender, grade, adjacent organ involvement and piecemeal resection were significantly associated with OS. Prognostic factors for LRR and OS were analyzed in well-differentiated and dedifferentiated liposarcomas and leiomyosarcomas. Grade 3 was an independent prognostic factor for OS of dedifferentiated liposarcomas.
This study underlines the crucial role of pretherapeutic assessment and meticulous histological examination of RPS as well as the need to consider histological subtypes separately. Surgery in a specialized center and avoidance of piecemeal resection stand out as the two most important prognostic factors for RPS and highlight the importance of treating these patients in specialized centers.
Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation of myofibroblasts lacking metastatic capacity. It may be observed in nearly every part of the body. Considering ...the variable clinical presentations, anatomic locations, and biologic behaviors, an individualized treatment approach is required. The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/&bgr;-catenin pathway. No established and evidence-based approach for the treatment of this neoplasm is available as of today. Considering the unpredictable behavior and the heterogeneity of this disease, we propose a treatment algorithm approved by the French and the Italian Sarcoma Group, based on a front-line wait and see approach and subsequent therapy in the case of progression. A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis.
Data regarding the role of systemic therapy in patients with advanced well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) are limited.
From 2000 to 2010, 208 patients with advanced ...WDLPS/DDLPS received chemotherapy in 11 participating institutions. Clinical and pathological data were collected by reviewing medical records.
Median age was 63 years (range 32–84). Combination chemotherapy was delivered in 85 cases (41%) and single agent in 123 cases (59%), respectively. One hundred and seventy-one patients (82%) received an anthracycline-containing regimen. Using RECIST, objective response was observed in 21 patients (12%), all treated with anthracyclines. Median progression-free survival (PFS) was 4.6 months 95% confidence interval (CI) 3.3–5.9. On multivariate analysis, age and performance status (PS) were the sole factors significantly associated with poor PFS. Median overall survival (OS) was 15.2 months (95% CI 11.8 –18.7). On multivariate analysis, grade and PS were the sole factors significantly associated with OS.
Chemotherapy was associated with clinical benefit in 46% of patients with advanced WDLPS/DDLPS. OS remains poor, even though visceral metastatic disease is less frequent than in other sarcomas.
Despite being associated with a very poor prognosis, long-term survivors across all series of Desmoplastic Small Round Cell Tumor (DSRCT) have been reported.
To analyze patients ‘characteristics ...associated with a prolonged survival after DSRCT diagnosis.
All consecutive patients treated for DSRCT in nine French expert centers between 1991 and 2018 were retrospectively analyzed. Patients with a follow-up of less than 2 years were excluded and cure defined as being disease-free at least 5 years.
100 pts were identified (median age 25 years, 89% male). 27 had distant metastases at diagnosis and 80 pts underwent upfront chemotherapy (CT). 71 pts were operated, 20 pts without prior CT). Surgery was macroscopically complete (CC0/1) in 50 pts. Hyperthermic intraperitoneal Chemotherapy (HIPEC) was administered during surgery in 15 pts 54 pts had postoperative CT and 26 pts had postoperative whole abdomino-pelvic RT (WAP-RT). After a median follow-up of 103 months (range 23–311), the median overall survival (OS) was 25 months. The 1- year, 3-year and 5-year OS rates were 90%, 35% and 4% respectively. 5 patients were considered cured after a median disease-free interval of 100 months (range 22–139). Predictive factors of cure were female sex (HR = 0.49, p = 0.014), median PCI<12 (HR = 0.32, p = 0.0004), MD Anderson stage I (HR = 0.25, p < 0.0001), CC0/1 (HR = 0.34, p < 0.0001), and WAP-RT (HR = 0.36, p = 0.00013). HIPEC did not statistically improve survival.
Cure in DSRCT is possible in 5% of patients and is best achieved combining systemic chemotherapy, complete cytoreductive surgery and WAP-RT. Despite aggressive treatment, recurrence is common and targeted therapies are urgently needed.
PDF
