Olfa Derbel

Results of combined treatment of anaplastic thyroid carcinoma (ATC)

BackgroundAnaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies. It is associated with a high rate of local recurrence and with poor prognosis.MethodsWe retrospectively reviewed 44 consecutive patients treated between 1996 and 2010 at Leon Berard Cancer Centre, Lyon, France. The combined treatment strategy derived from the one developed at the Institut Gustave Roussy included total thyroidectomy and cervical lymph-node dissection, when feasible, combined with 2 cycles of doxorubicin (60 mg/m2) and cisplatin (100 mg/m2) Q3W, hyperfractionated (1.2 Gy twice daily) radiation to the neck and upper mediastinum (46-50 Gy), and then four cycles of doxorubicin-cisplatin.ResultsThirty-five patients received the three-phase combined treatment. Complete response after treatment was achieved in 14/44 patients (31.8%). Eight patients had a partial response (18.2%). Twenty-two (50%) had progressive disease. All patients with metastases at diagnosis died shortly afterwards. Thirteen patients are still alive. The median survival of the entire population was 8 months.ConclusionDespite the ultimately dismal prognosis of ATC, multimodality treatment significantly improves local control and appears to afford long-term survival in some patients. There is active ongoing research, and results obtained with new targeted systemic treatment appear encouraging.

Long-term outcome and effect of maintenance therapy in patients with advanced sarcoma treated with trabectedin: an analysis of 181 patients of the French ATU compassionate use program

BackgroundThe long term outcome of advanced sarcoma patients treated with trabectedin outside of clinical trials and the utility of maintenance treatment has not been reported.MethodsBetween 2003 and 2008, patients with advanced sarcoma failing doxorubicin could be treated within a compassionate use program (ATU, Temporary Use Authorization) of trabectedin in France using the standard 3-weekly regimen. Data from 181 patients (55%) were collected from 11 centres and analyzed.ResultsTrabectedin was given in first, second, third or fourth line in metastatic phase in 6%, 37%, 33% and 23% of patients respectively. With a median follow-up of 6 years, median PFS and OS were 3.6 months and 16.1 months respectively. The median number of cycles was 3 (range 1–19). Best response were partial response (PR, n = 18, 10%), stable disease (SD, n = 69, 39%) and progressive disease (PD, n = 83, 46%), non evaluable (NE, n = 9, 5%). Thirty patients (17%) had to be hospitalized for treatment- related side effects. Independent prognostic factors in multivariate analysis (Cox model) were myxoid LPS and line of trabectedin for PFS, and myxoid LPS and retroperitoneal sarcomas for OS. Patients in PR or SD after 6 cycles continuing treatment had a better PFS (median 5.3 vs 10.5 months, p = 0.001) and OS (median 13.9 vs 33.4 months, p = 0.009) as compared to patients who stopped after 6 cycles.ConclusionsIn this compassionate use program, trabectedin yielded similar or better PFS and OS than in clinical trials. Maintenance treatment beyond 6 cycles was associated with an improved survival.

Outcome of patients with advanced solitary fibrous tumors: the Centre Léon Bérard experience

BackgroundSolitary Fibrous Tumor is a rare type of soft tissue tumor of intermediate malignant potential which may recur or metastasize in 15-20% of cases. Data on the management of patients with advanced SFT is scarce: chemotherapy has been described as ineffective, while recent data suggests that anti-angiogenic therapies may be more efficient.MethodsWe conducted a retrospective study on patients treated for advanced SFT at a single institution: from January 1994 to December 2011, 30 patients were treated in the Centre Léon Bérard for an advanced SFT.ResultsTwenty-three patients received cytotoxic chemotherapy as first-line therapy. Best responses were 2 (9%) partial responses, 13 (57%) stable diseases (SD) and 8 (35%) progressive diseases (PD). Median Progression Free Survival (PFS) was 5.2 (95% CI: 3.2-7.1) months and 9 patients were free of progression at 6 months. Ten patients received an anti-angiogenic treatment (sunitinib or pazopanib) as a 2nd, 3rd or 4th line. Best responses were 5 SD and 5 PD; median PFS was 5.1 months (95% CI 0.7-9.6). Four patients (36%) were progression-free for more than 6 months. Two patients receiving pazopanib were without progression at 6 and 8 months and two patients receiving sunitinib were free of progression at 30 months.ConclusionResponse rate with standard chemotherapy was low and PFS appear similar between cytotoxic chemotherapy and anti-angiogenic agents.

An Unusual Giant Cell Tumor of the Thyroid: Case Report and Review of the Literature

CONTEXT Bone giant cell tumors (GCTs) are among the most common benign bone tumors and affect mostly young patients. They represent a rare etiology of head and neck cancer. OBJECTIVE We report the case of a 38-yr-old male with a GCT of the thyroid cartilage, initially treated as a thyroid cancer. CASE ILLUSTRATION The patient had incomplete initial surgery, and a substantial tumor residue was observed at postoperative morphological evaluation. Given the potential risks associated with complete definitive surgery and recent data supporting the use of the receptor activator of nuclear factor κB ligand inhibitor, we proposed treatment with denosumab. Three months after initiating denosumab, computed tomography scan imaging showed a significant modification of the lesion with several calcifications. The patient underwent partial laryngectomy, and examination of the surgical specimen revealed a complete histological response. RESULTS A review of the literature was conducted to identify previous studies pertaining to GCTs, focusing on reports related to their management. CONCLUSION Denosumab emerges as a new treatment for patients with GCTs. Additional clinical trial data are needed to establish the real efficacy and long-term safety of this treatment for the management of GCT.

Survival impact of centralization and clinical guidelines for soft tissue sarcoma (A prospective and exhaustive population-based cohort)

Purpose The outcome of sarcoma has been suggested in retrospective and non-exhaustive studies to be better through management by a multidisciplinary team of experts and adherence to clinical practice guidelines (CPGs). The aim of this prospective and exhaustive population based study was to confirm the impact of adherence to CPGs on survival in patients with localized sarcoma. Experimental design Between 2005 and 2007, all evaluable adult patients with a newly diagnosis of localized sarcoma located in Rhone Alpes region (n = 634), including 472 cases of soft-tissue sarcoma (STS), were enrolled. The prognostic impact of adherence to CPGs on progression-free survival (PFS) and overall survival (OS) was assessed by multivariate Cox model in this cohort. Results The median age was 61 years (range 16–92). The most common subtypes were liposarcoma (n = 133, 28%), unclassified sarcoma (n = 98, 20.7%) and leiomyosarcoma (n = 69, 14.6%). In the initial management phase, from diagnosis to adjuvant treatment, the adherence to CPGs for patients with localized STS was 36% overall, corresponding to 56%, 85%, 96% and 84% for initial surgery, radiation therapy, chemotherapy and follow-up, respectively. Adherence to CPGs for surgery was the strongest independent prognostic factor of PFS, along with age, gender, grade, and tumor size. For OS, multivariate analysis adherence to CPGs for surgery was a strong independent prognostic factor, with an important interaction with a management in the regional expert centers. Conclusions This study demonstrates impact of CPGs and treatment within an expert center on survival for STS patients in a whole population-based cohort.

Pazopanib for the treatment of soft-tissue sarcoma.

Pazopanib is a multikinase inhibitor which potently inhibits the activity of major receptor tyrosine kinases, including vascular endothelial growth factor receptor-1, vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, platelet-derived growth factor receptor-a, platelet-derived growth factor receptor-a, and c-Kit. Approved by the Food and Drug Administration in 2009 in the United States for the treatment of metastatic renal cell carcinoma, pazopanib has been tested in advanced or metastatic soft-tissue sarcoma. Unlike other tyrosine kinase inhibitors, a statistically significant efficacy in phase II but also in randomized phase III studies has been shown. In comparison with sunitinib or sorafenib, pazopanib has a similar toxicity profile and is generally well tolerated. This review details the development of this new therapeutic class in the treatment of metastatic soft-tissue sarcomas.

Impact of KRAS, BRAF and PI3KCA mutations in rectal carcinomas treated with neoadjuvant radiochemotherapy and surgery.

BackgroundConventional treatment for locally advanced rectal cancer usually combines neoadjuvant radiochemotherapy and surgery. Until recently, there have been limited predictive factors (clinical or biological) for rectal tumor response to conventional treatment. KRAS, BRAF and PIK3CA mutations are commonly found in colon cancers. In this study, we aimed to determine the mutation frequencies of KRAS, BRAF and PIK3CA and to establish whether such mutations may be used as prognostic and/or predictive factors in rectal cancer patients.MethodsWe retrospectively reviewed the clinical and biological data of 98 consecutive operated patients between May 2006 and September 2009. We focused in patients who received surgery in our center after radiochemotherapy and in which tumor samples were available.ResultsIn the 98 patients with a rectal cancer, the median follow-up time was 28.3 months (4–74). Eight out of ninety-eight patients experienced a local recurrence (8%) and 17/98 developed distant metastasis (17%). KRAS, BRAF and PIK3CA were identified respectively in 23 (23.5%), 2 (2%) and 4 (4%) patients. As described in previous studies, mutations in KRAS and BRAF were mutually exclusive. No patient with local recurrence exhibited KRAS or PIK3CA mutation and one harbored BRAF mutation (12.5%). Of the seventeen patients with distant metastasis (17%), 5 were presenting KRAS mutation (29%), one BRAF (5%) and one PIK3CA mutation (5%). No relationship was seen between PIK3CA, KRAS or BRAF mutation and local or distant recurrences.ConclusionThe frequencies of KRAS, BRAF and PIK3CA mutations in our study were lower than the average frequencies reported in colorectal cancers and no significant correlation was found between local/distant recurrences and KRAS, BRAF or PIK3CA mutations. Future studies with greater number of patients, longer follow-up time and greater power to predict associations are necessary to fully understand this relationship.

The clinician’s perspective on sarcoma pathology reporting: impact on treatment decisions?

Summary The current refinement of nosological classification of sarcoma which integrates molecular typing with a growing number of subtypes contrasts with the one-size-fits-all approach proposed in clinical practice guidelines for both local treatment and systemic treatment in the past. However, there is a growing proportion of sarcomas in which specific treatment strategies are proposed as standard. As a consequence, central review by expert sarcoma pathologists should be organised to ensure the optimal management of all patients. The key parameters in the pathology report influencing treatment decisions are therefore rapidly evolving. First a diagnostic biopsy, ideally an imaged guided microbiopsy performed by an experienced team, is a recommended practice. On the resection specimen, the size, histological grade, location, depth, surgical margins and tumour fragmentation are essential parameters to guide the treating physician. Molecular characterisation of the driving genomic event is becoming increasingly important for treatment decision making, in routine practice and in clinical trials. Molecular grade is a research tool with potentially high utility, and requires further evaluation and validation in prospective clinical trials.

Concomitant occurrence of pulmonary invasive aspergillosis and Pneumocystis pneumonia during FOLFIRINOX chemotherapy for pancreatic carcinoma.

trointestinal system. Sinclair et al published a case series of 11 children with valproic acidYinduced pancreatitis. Other data in children are limited. Storer reported a case of an adult with probable carbamazepineinduced pancreatitis. A study conducted by eHealthMe.com based on 110 reports from the Food and Drug Administration and user community showed, by January 2012, a prevalence of 0.91% of pancreatitis among the patients that reported any source of adverse effect when taking Keppra. Of these cases, 44.44% occurred in the first month of the drug use, as related in our case. Of these, 20.26% occurred in the pediatric population (0Y19 years old). The Naranjo Algorithm is a tool that can be applied to assess the likelihood that a change in the clinical status is the result of an adverse drug reaction (ADR) rather than the result of other factors, and the scores (from 0 to 9) determine if the ADR is doubtful, possible, probable, or highly probable. Our patient had a final score of 7, meaning that an ADR is probable (Table 1). The positive scores were related to previous conclusive reports of pancreatitis with levetiracetam use: that the adverse event appeared after the suspect drug was administered, that the adverse reaction improved when the drug was discontinued, and that other alternate causes for the pancreatitis were excluded. We did not do a challenge with re-administration of the drug, administration of placebo, or increasing in dose to support evidences of ADR, owing to the risk of severe complications of pancreatitis. It is important to note that the pancreatitis occurred even in the presence of subtherapeutic levels of the drug.

Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer

Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene affects the clinical outcome of ovarian cancer patients. Experimental Design: A study cohort of 353 women with ovarian cancer who underwent genetic germline testing for BRCA1 and BRCA2 genes was identified. Progression-free survival (PFS), platinum-free interval (PFI), and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of ovarian cancer (n = 316) was used as a validation cohort. Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2. After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS [58%; adjusted HR, 0.36; 95% confidence interval (CI), 0.20–0.64; P = 0.001] and prolonged PFI (29.7 vs. 15.5 months, P = 0.011), compared with noncarriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42–1.07; P = 0.094) or PFI (19 vs. 15.5 months, P = 0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13–0.68; P = 0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02–0.38; P = 0.001). Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged PFS, PFI, and OS. Clin Cancer Res; 24(2); 326–33. ©2017 AACR.