Outcomes from second-line therapy in long-term responders to first-line tyrosine kinase inhibitor in clear-cell metastatic renal cell carcinoma.

BACKGROUND: Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1). PATIENTS AND METHODS: Retrospective multicenter study (2004-2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). END POINTS: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM). RESULTS: Sequence effect in the overall cohort was in favor of the TKI-TKI sequence over the TKI-mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI-TKI superiority was attributed in large part to the 11-22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9-12.2) versus 3.9 (3.0-5.5), P = 0.003; TTF(months): 8.0 (5.5-11.0) versus 3.6 (3.0-4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI. CONCLUSIONS: m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.

Clinical prognostic factors in locally advanced nasopharyngeal carcinoma in Moroccan population.

BACKGROUND: Nasopharyngeal carcinoma is a distinct cancer of head and neck by its pathology, etiology, epidemiology and clinical behavior. Morocco is considered an endemic region with intermediate incidence. The aim of our report is to underline some clinical determinants of survival in locally advanced disease. PATIENTS AND METHODS: We conducted a retrospective study from January 2003 to December 2005. All patients with undifferentiated nasopharyngeal carcinoma treated in the National Institute of Oncology of Rabat, Morocco were recorded. Classified stage II to IVB disease according to TNM classification adopted by the AJCC (American Joint Committee of Cancer) 6th edition. RESULTS: The study included 339 patients, 122 women and 217 men (sex-ratio: 1.7). Mean age was 43 years old (range: 6-91years). Median duration to diagnosis was 6 months (range: 1-72) presenting symptoms at diagnosis were predominantly cervical lymph node in 79%. Forty- two patients have T1 tumors, 159 = T2 tumors, 64 = T3 tumors and 69 = T4 tumors. Sixty-five patients do not have lymph-node involvement, 49 have N1, 128 have N2 and 95 have N3. Three patients were at stage IIA, 57 patients were at stage IIB, 40 patients were at stage III, and 57 patients were at stage IVA and the remaining 96 patients were at stage IVB. Eighty-seven percent of patients underwent sequential chemoradiation and 17% underwent concurrent chemo-radiation (CTR). Response to induction chemotherapy was assessed in 235 patients. There were 31 patients with complete response and 59 patients have partial response. Complete response to radiotherapy was reached in 235 patients. Mean overall survival (OS) was 66.2%. Gender was a prognostic factor of OS (p=0.045) and DFS favoring women. Age wasn't a prognostic factors determining the outcome with no difference between patients aged more than 40 years old and patients younger. Tumor size was not a determinant of survival with a non-significant p in OS and DFS (0.27 and 0.46 respectively) but T4 stage patients appear to have a worse prognosis. Lymph node involvement was significantly determining the outcome either in OS and DFS (p=0.001 and 0.009 respectively). TNM stage was also a significant prognostic factor in OS but not in DFS favoring those with early stage (p= 0, 004 and p= 0, 13 respectively). The treatment strategy was not a significant prognostic factor with no difference between patients who underwent sequential or concurrent chemoradiation (OS p= 0, 48 and DFS p= 0, 9). In multivariate analysis, lymph-node involvement is the most significant factor. CONCLUSION: Our findings were mostly concordant with the literature data in endemic areas for TNM staging; however we are limited by the bias of retrospective studies. Prospective studies would be more accurate to define those prognostic factors in our population. KEYWORDS: UCNT, prognostic factors, endemic areas, lymph node involvement.

Pancreatic adenocarcinoma in young adults in a moroccan population.

INTRODUCTION: Pancreatic adenocarcinoma (PAC) is diagnosed generally in patients older than 60 years old of age. It is rarely diagnosed in young adults. There is a dearth of data in younger population of patients with pancreatic ductal adenocarcinoma regarding epidemiology, prognosis, and outcome. The aim of our study of young PAC patients was to characterize the clinical features of this distinct young population who were treated in the National Institute of Oncology of Rabat. We selected the age of 45 years and under as the cutoff point in defining our patient population of interest. MATERIALS AND METHODS: A retrospective analysis of patients referred to the national institute of oncology of Rabat with PAC, who were ≤45 years at the date of histological diagnosis, between January 2005 and February 2010, was performed. Epidemiological, clinical, and pathological staging and therapeutic and follow-up data were extracted. RESULTS: The study included 32 cases of PAC. Male:female ratio was 2:1. It represents 17% of the entire population (N = 176) of PAC referred to the National Institute of Oncology over the time of study period. Mean age was 44-years-old (range: 28-45). Age range distribution was 1, 5, and 26 patients in age subgroups 20-29, 30-39, 40-45 years, respectively. Four patients (12.5%) had a smoking history and two patients (6%) had diabetes. None of the patients had a positive familial history of PAC or chronic pancreatitis. Tumor was located in head of pancreas in 75%, body in 12.5 %, and tail in 12,5%. Six patients (18.7%) had localized resectable disease and underwent resection with curative intent. Seven (21.8%) presented with locally advanced, inoperable disease. Two of them received only concurrent chemoradiation. Nineteen patients (59.3%) presented as AJCC Stage IV. Four (12.5%) of the six patients with resected tumors underwent adjuvant chemoradiation. Median overall survival was 50% at median follow-up of 6.8 months. CONCLUSION: This is the first reported study in our patient population of young patients with PAC. The data suggested that patients with younger age seem to have the same poor prognosis as the typical (older) patient population with PAC. No risk factors have been identified. However, this study is retrospective and more larger studies are needed in this young population.

[Protein tyrosine kinase inhibitors in cancer therapy]. / Bilan des inhibiteurs de protéine tyrosine kinase dans le traitement des cancers.

The tyrosine kinase inhibitors (TKI) are small molecules of low molecular weight that inhibit tyrosine kinases, enzymes responsible for the activation of signal transduction cascades. Currently, a number of TKI received approval in various cancers, while others are in clinical development process: TKI are specifically clinically active when they target a tyrosine kinase (TK) with constitutional activity subsequent to a mutation, being then a master-gene driving transformation and tumour progression. Already, this drug-family provides a major therapeutic weapon against cancer.