Access to innovative medicines for metastatic melanoma worldwide: Melanoma World Society and European Association of Dermato-oncology survey in 34 countries.

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found.

Prognostic factors in patients with advanced hypopharyngeal squamous cell carcinoma treated with concurrent chemoradiotherapy.

PURPOSE: The aim of this study was to evaluate different prognostic factors affecting response to treatment, locoregional control (LRC) and survival in patients with advanced hypopharyngeal squamous cell carcinoma (HPSCC). METHODS: A retrospective analysis of 41 patients with advanced HPSCC who had undergone definitive concurrent chemoradiation treatment between January 2006 and October 2009 was performed. RESULTS: Complete composite response (CCR) was achieved in 27 patients (65.9)). Significant prognostic factors for CCR were T stage, technique of radiation, and gross tumor volume (GTV). Unfavorable prognostic factors for CCR in multivariate analysis were higher T stage and radiation technique with electron-photon fields. The 2-year LRC rate was 51.3%. The 2-year disease-free survival (DFS) and overall survival (OS) rates were 29.3% and 32.8%, respectively. Significant prognostic factors for LRC, DFS, and OS in univariate analysis were T stage, overall stage, and GTV. OS was also significantly influenced by N stage. In multivariate analysis T stage was found to be the only significant independent prognostic factor for LRC (p=0.003), DFS (p=0.01), and OS (p=0.005). CONCLUSION: Revealing the significant prognostic value of T stage for CCR, LRC, DFS, and OS in the multivariate analysis, we consider that the implementation of intensity modulated radiotherapy (IMRT) and the adoption of intensified concurrent chemoradiotherapy (CCRT), sequential therapy, and targeted therapy should be strongly advocated in order to improve outcome in patients with locally advanced HPSCC.

Radical radiotherapy for squamous cell carcinoma of the larynx--comparison of three-dimensional conformal radiotherapy with cobalt-60 teletherapy.

The aim of the study was to report the results of radical radiotherapy performed by three-dimensional conformal radiotherapy (3DCRT) for squamous cell carcinoma of the larynx and to compare these data with those obtained with two-dimensional radiotherapy (2DRT) realized with cobalt-60 teletherapy i.e. telecobalt therapy (TCT). Eighty patients with previously untreated laryngeal cancer were irradiated with curative intent at the University of Radiotherapy and Oncology Clinic (UCRO) in Skopje between February 1999 and December 2008. Radical radiotherapy with the TCT unit was performed on 38 patients between February 1999 and May 2005. From June 2005 to December 2008, 42 patients were treated with a linear accelerator using 3DCRT. Complete response rates three months after completion of radiotherapy were 84.2% (32 of 38) and 92.6% (39 of 42) in the group irradiated with TCT unit and in the group treated with 3DCRT, respectively. No statistically significant differences were observed either in locoregional control (LRC) or overall survival (OS) between the patients treated with two different radiotherapy techniques. The grade of acute reactions of the skin and the larynx differed significantly between the accomplished radiotherapy techniques (Nonparametric Mann-Whitney U Test; U=577.0; Z=-2.129; p=0.012, and U=497.0; Z=-2.90; p=0.001, respectively). There were statistically significant differences observed in the grade of late effects in the skin and in the subcutaneous tissue between the radiotherapy techniques used (Nonparametric Mann-Whitney U Test; U=425.0; Z=-3.593; p=0.001 and U=637.0; Z=-1.551; p=0.035, respectively). According to the confirmed advantage of 3DCRT in terms of reduced treatment toxicity observed in our study, we consider conformal techniques being a basis in definitive radiotherapy of squamous cell carcinoma of the larynx until the new revolutionary techniques will be clinically available.

Factors influencing the development of distant metastases in patients with head and neck squamous cell carcinoma.

PURPOSE: the aim of this retrospective study was to evaluate the frequency of distant metastases (DM) and to define factors that influence DM free survival (DMFS) in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: the charts of 201 patients with oral cavity, pharyngeal, or laryngeal carcinoma, treated with postoperative radiotherapy (RT) or definitive RT between 1999 and 2004 and achieved locoregional control were analyzed. RESULTS: DM occurred in 26 of 201 (12.9%) patients. The mean time of DM diagnosis was 16.5 months (range 5-35). The median time to death after diagnosis of DM was 5 months (range 1-13). The DMFS rate at 5 years was 84.8%. Univariate analysis demonstrated that the risk of DM was significantly influenced by age (p=0.047), cigarette smoking (p=0.024), ECOG performance status (PS) (p=0.008), location of the primary site (p=0.003), N stage (p<0.0001), overall stage (p<0.0001), histological differentiation (p<0.0001), levels of nodal involvement (p<0.0001), treatment modality (p<0.0002), presence of locoregional recurrence (LRR) (p<0.0001), and time to LRR (p<0.0001). In multivariate analysis nodal involvement (N1: p=0.007; N2: p=0.036; N3: p=0.043), and the time to LRR ≤ 6 months (p=0.037) were proven as independent factors that significantly influenced DMFS. CONCLUSION: development of DM in patients with HNSCC was significantly influenced by the presence of positive nodal status and the presence of LRR whose appearance was within 6 months of RT.

Prognostic factors in patients with recurrent head and neck cancer treated with reirradiation.

PURPOSE: The aim of this study was to determine the prognostic factors concerning overall survival (OS) and progression- free survival (PFS) following reirradiation in patients with recurrent squamous cell head and neck cancer (HNC). PATIENTS AND METHODS: We performed a retrospective analysis on 65 recurrent HNC patients treated with reirradiation for local/locoregional recurrence between 1999 and 2004 at the Institute of Radiotherapy and Oncology in Skopje. The initial treatment of their HNC consisted of radiotherapy following surgery, radiotherapy alone, or concurrent chemoradiotherapy. RESULTS: The median reirradiation dose was 39.8 Gy (range 24-58). Clinically complete response (CR) was observed in 9 (13.9%) patients. The median OS and PFS was 8 months (range 1-22) and 4.9 months (range 0-18), respectively. The univariate analysis of prognostic factors identified Karnofsky performance status (KPS), response to reirradiation, dose to recurrent site, and disease-free interval (DFI) as strongly associated with both OS and PFS. Initial tumor site and cumulative dose had a significant influence only on OS. Multivariate analysis revealed that response to reirradiation and the radiation dose to the recurrent site were two independent variables significantly influencing OS (p<0.0001 and p=0.049, respectively). The only significant independent prognostic factor for PFS was response to reirradiation (p=0.0008). CONCLUSION: The necessity of improvement of patients' outcome allows us to consider concurrent chemoradiotherapy as a more efficient treatment strategy that has a potential to increase the response to reirradiation of unresectable recurrent HNC. Using higher radiation doses is also expected to enhance the response rates and consequently to positively influence OS and PFS.

Concurrent chemoradiotherapy in locally and/or regionally advanced nasopharyngeal carcinoma.

The aim of the study was to investigate the efficacy of concurrent chemoradiotherapy (CCRT) in patients with locally and/or regionally advanced nasopharyngeal carcinoma (NPC). Between February 2005 and November 2007, 27 patients with advanced NPC were included in a prospective study of CCRT at the Radiotherapy and Oncology Institute in Skopje. Radiotherapy was performed using a sophisticated three-dimensional conformal technique. A dose of 69.4-71.4 Gy (median, 69.4 Gy) was delivered to the primary tumour and to the positive neck nodes. Chemotherapy consisted of cisplatin 30 mg/m(2) given concomitantly with radiation on a weekly basis. The median age was 49 years and 51.2% had stage IV disease. Eighty-eight percent received >or= 5 cycles of concurrent cisplatin. Complete response rates three months after chemoradiotherapy completion were 81.5% (22 of 27) and 91.3% (21 of 23) at the primary site and in the neck, respectively. Only one patient had a locoregional relapse and four patients developed distant metastases. The most prevalent grade 3 acute effect was mucositis present in 63.0% of patients. The 2-year disease-free survival (DFS) rate was 42.6%, the 2-year locoregional relapse-free survival (LR-RFS) rate was 76.9%, and the 2-year distant metastases relapse-free survival (DM-RFS) rate was 63.6%. Considering the preliminary results of our study which do not indicate that the therapeutic effects of CCRT evaluated are comparable with the results from the randomised phase III studies, we recommend an effort for the routine use of the new radiotherapy technique, intensity-modulated radiation therapy (IMRT), as well as an initiation of a phase III trial addressing the definition of the precise role of sequential chemotherapy in the management of patients with locally advanced NPC.

Chemotherapy in locoregionally advanced nasopharyngeal carcinoma-a review.

Locoregionally advanced nasopharyngeal carcinoma (NPC), when traditionally treated with radiotherapy (RT) alone, has been associated with low overall survival (OS). Efforts to improve the efficacy of treatment for locoregionally advanced NPC have led to the use of multimodality approach with combination of RT and chemotherapy (CT). Analyzing the historical progress of the incorporation of CT as an integral part of the management of advanced NPC, we reviewed 12 randomized controlled trials on induction, concurrent, and adjuvant therapy, or a combination of these approaches. Four meta-analyses on this subject have been also reviewed. Evidence that concurrent chemoradiotherapy (CCRT) provides significant improvement in OS in patients with locoregionally advanced NPC is based on the results of 2 meta-analyses and several randomized studies on the administration of CT concomitantly with RT. The revealed survival benefits with CCRT compared with RT alone resulted in confirmation of CCRT as the currently recommended treatment for patients with advanced-stage NPC. The recognition of the development of distant metastatic disease as more frequent pattern of failure when concurrent CT is utilized has led to the assumption that the use of both induction chemotherapy (ICT) and CCRT in a sequential manner may provide improvement in overall treatment outcome in this patient category. The definition of the precise role of sequential CT in the management of patients with locally advanced NPC is to be revealed from the results of future phase III trials addressing this issue.