Objectives: Concurrent chemoradiotherapy is the standard treatment for patients with unresectable, locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN); induction chemotherapy (ICT) may provide survival benefits in some patients. This study aimed to demonstrate the noninferiority of concomitant cetuximab plus radiotherapy (cet+RT) vs cisplatin plus radiotherapy (cis+RT) in patients with unresectable LA-SCCHN who were responsive to ICT.Materials and methods: This randomized, open-label, phase 3 trial studied patients with unresectable LA-SCCHN who received 3 cycles of ICT (docetaxel, cisplatin, and 5-fluorouracil; TPF) followed by cis+RT (standard arm) or cet+RT (experimental arm). The primary endpoint was noninferiority of the experimental arm vs the standard arm in terms of overall survival (OS), based on a hazard ratio (HR) of < 1.3. Secondary endpoints included progression-free survival, overall response, safety, and quality of life (QOL).Results: Between July 15, 2008, and July 5, 2013, 519 patients were recruited and started ICT; 407 patients received post-ICT treatment (cis+RT, n = 205; cet+RT, n = 202). At a median follow-up of 43.9 (cis+RT) and 41.1 (cet+RT) months, median OS was 63.6 and 42.9 months with cis+RT and cet+RT, respectively (HR [90% CI] = 1.106 [0.888-1.378], P =.4492). There were no differences in progression-free survival, overall response rates, or adverse event rates between groups. There was greater late neurotoxicity with cis+RT than cet+RT (P =.0058). Several QOL dimensions improved with cet+RT vs cis+RT (physical functioning, P=.0287; appetite loss, P=.0248; social contact, P=.0153).Conclusion: Noninferiority of cet+RT over cis+RT was not demonstrated.

BACKGROUND AND PURPOSE:The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS:Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS:For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). CONCLUSION:The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.

Our previous phase-3 study (TTCC 2503) failed to show overall survival advantage of 2 induction chemotherapy (IC) regimens followed by standard concurrent chemoradiotherapy (CRT) over CRT alone in patients with unresectable locally advanced head and neck squamous-cell carcinoma (LAHNSCC). This study described the long-term survival of those patients. Long-term follow-up study of patients with untreated LAHNSCC assigned to IC (three cycles), with either docetaxel, cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CRT, or CRT alone, included in the previous TTCC 2503 trial. In the intention-to-treat population (n = 439), the median OS times were 25.4 (95% CI, 16.8–34.4), 26.2 (95% CI, 18.2–36.6) and 25.4 months (95% CI, 17.4–36.0) in the TPF-CRT, PF-CRT and CRT arms, respectively (log-rank p = 0.51). In the per-protocol population (n = 355), patients with larynx–hypopharynx primary tumors treated with IC (TPF or PF) followed by CRT had a longer median PFS than those who received CRT alone. Moreover, patients with ECOG 0 treated with IC (TPF or PF) followed by CRT had a better TTF than those with CRT alone. There were no statistically significant differences in terms of OS, PFS or TTF, according to the tumor load or affected nodes. After a long follow-up, the TTCC 2503 trial failed to show the benefit of IC-CRT in unresectable LAHNSCC regarding the primary end point. However, fit patients with ECOG 0 and primary larynx–hypopharyngeal tumors may benefit from the use of IC if administered by an experienced team. ClinicalTrials.gov identifier NCT00261703

El Cancer de Origen Desconocido (COD) es un cancer metastasico con histologia confirmada del cual se desconoce el origen primario despues de realizar un estudio diagnostico inicial mediante el estudio clinico patologico, el estudio analitico y de imagen. El estudio diagnostico incluye la obtencion precoz de material de biopsia de calidad. Incluye su analisis histologico e inmunohistoquimico: un estudio para determinar la estirpe tumoral, analisis de citoqueratinas y una bateria amplia de anticuerpos para confirmar el origen especifico. El desarrollo de plataformas moleculares ha mejorado su diagnostico, incrementando el numero de pacientes que se benefician del tratamiento con terapia especifica, aumentando su supervivencia y reduciendo la toxicidad. Sin embargo, las guias actualizadas (NICE, ESMO, NCCN) destacan que el impacto en el beneficio clinico del tratamiento especifico segun los resultados de las plataformas moleculares es todavia controvertido.

El Cancer de Origen Desconocido (COD) es un cancer metastasico con histologia confirmada del cual se desconoce el origen primario despues de realizar un estudio diagnostico inicial mediante el estudio clinico patologico, el estudio analitico y de imagen. El estudio diagnostico incluye la obtencion precoz de material de biopsia de calidad. Incluye su analisis histologico e inmunohistoquimico: un estudio para determinar la estirpe tumoral, analisis de citoqueratinas y una bateria amplia de anticuerpos para confirmar el origen especifico. El desarrollo de plataformas moleculares ha mejorado su diagnostico, incrementando el numero de pacientes que se benefician del tratamiento con terapia especifica, aumentando su supervivencia y reduciendo la toxicidad. Sin embargo, las guias actualizadas (NICE, ESMO, NCCN) destacan que el impacto en el beneficio clinico del tratamiento especifico segun los resultados de las plataformas moleculares es todavia controvertido.

BackgroundThe value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet cisplatin and fluorouracil. We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens.DesignWe nonsystematically reviewed published phase III clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017.ResultsTPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (i.e. cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further.ConclusionsTPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

Surgery and radiotherapy are the standard treatment options for patients with squamous cell carcinoma of the head and neck (SCCHN). Chemoradiotherapy is an alternative for patients with locally advanced disease. In recurrent/metastatic disease and after progression to platin-based regimens, no standard treatments other than best supportive care are currently available. Most SCCHN tumours overexpress the epidermal growth factor receptor (EGFR). This receptor is a tyrosine-kinase membrane receptor that has been implicated in angiogenesis, tumour progression and resistance to different cancer treatments. In this review, we analysed the different drugs and pathways under development to treat SCCHN, especially recurrent/metastatic disease. Until now, the EGFR signalling pathway has been considered the most important target with respect to new drugs; however, new drugs, such as immunotherapies, are currently under study. As new treatments for SCCHN are developed, the influence of therapies with respect to overall survival, progression free survival and quality of life in patients with this disease is changing.

C l i n M e d International Library Citation: Rodriguez VA, Moreira P, Camara M, Rondon P, Garrido M, et al. (2016) Malignant Peritoneal Mesothelioma in a Clerk: A Diagnostic Dilemma. Clin Med Rev Case Rep 3:127 Received: July 23, 2016: Accepted: September 02, 2016: Published: September 05, 2016 Copyright: © 2016 Rodriguez VA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Volume 3 | Issue 9

The management of locally advanced head and neck cancer has seen the emergence of different combined modality therapies in recent years, and new treatment types, such as chemoradiation, new induction chemotherapy schemes, and salvage surgery.

Our previous meta-analysis showed that concomitant chemotherapy (CT) improved overall survival (OS) in patients with non-metastatic head and neck squamous cell carcinoma (HNSCC). The study purpose was to update patient follow up, gather data on toxicity and include randomized trials conducted up to 2010. This individual patient data meta-analysis included trials comparing loco-regional treatment (LRT) to LRT + CT or induction CT + radiotherapy (RT) to RT + concomitant (or alternating) CT in non-metastatic HNSCC patients and conducted between 1965 and 2010. A fixed effect model was used. The log-rank test, stratified by trial, was used to compare treatments. OS was the primary endpoint. 15 new trials (2,574 patients) were included. Updated data were obtained for 11 additional trials. For the comparison of LRT vs. LRT + CT, 94 trials (18,394 patients) with median follow-up of 6.7 years were analyzed. The most frequent tumor site was oropharynx (35%). Stage III and IV tumors represented 29% and 63% of patients. The addition of CT improved OS with a hazard ratio (HR) [95% confidence interval] of 0.89 [0.86; 0.92], p < 0.0001. There was a significant interaction between treatment effect and the timing of CT, the benefit being limited to concomitant CT (p < 0.0001), with a HR of 0.83 [0.79; 0.87], translating into a 5-(10-)year absolute survival benefit of 6.5 (3.4)%. The addition of induction CT did not increase OS, with a HR of 0.97 [0.91; 1.03]. Interaction test performed in recent concomitant trials revealed a trend toward decreased efficacy with increasing age (p for trend = 0.06; HR of 1.00 [0.81; 1.23] for age ≥ 70) or performance status (p for trend = 0.07, HR of 0.93 [0.73; 1.19] for PS ≥ 2). The analysis of 8 trials (1,214 patients) comparing induction CT + RT to RT + concomitant CT confirmed the superiority of concomitant CT on OS (HR of 0.84 [0.74; 0.95], p = 0.007) and progression-free survival (HR of 0.85 [0.75; 0.96], p = 0.008). This update of the MACH-NC meta-analysis confirms the superiority of concomitant CT for locally advanced HNSCC with longer follow-up, when compared to induction treatment. Study of patterns of relapse and toxicity is ongoing.

6001Background: CetRT has not been compared with CRT after ICT in phase III. Objective: To compare the impact on overall survival of CRT vs. CetRT after ICT in a Phase III randomized controlled cli...

Background: Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy.Patients and methods: An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m(2)/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR).Results: A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade = 3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab.Conclusion: Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.

6021^ Background: The EXTREME trial demonstrated that patients with R/M-SCCHN benefit significantly from the addition of cetuximab to first-line platinum-based CT in relation to overall survival, progression-free survival (PFS) and response rate. We report the 5-year follow-up data. Methods: The intent-to-treat (ITT) population comprised patients (pts) randomized to receive either platinum-based CT plus cetuximab (n=222) or CT alone (n=220) for 18 weeks (6 x 3-week cycles). Results: A total of 100 pts in the cetuximab arm who had at least stable disease received cetuximab monotherapy until disease progression or unacceptable toxicity, with a median treatment duration of 29.9 weeks. For 77% of these pts, the relative dose intensity (RDI) of cetuximab was ≥90% during this maintenance period. Thirty-one (14%) pts in the cetuximab arm and 25 (11%) in the CT arm of the ITT population were deemed long-term survivors (>2 years). Of these, 6 (22%) and 5 (23%) pts were p16+ and 11 (35%) and 10 (40%) pts had oropharyngeal tumors, in both arms respectively. At 5-years, 6 pts treated with CT plus cetuximab and 2 pts treated with CT alone were still in the study and known to be alive. In pts in the cetuximab arm, the frequency of severe (grade 3-4) adverse events (AEs) decreased from 81% to 49% during the cetuximab maintenance period compared with the previous treatment period with CT plus cetuximab. Grade 3 skin toxicity decreased from 9% when combined with CT to 5% during cetuximab maintenance and no grade 4 skin toxicity was observed.Twelve pts (5%) in the cetuximab arm of the ITT population were long-term responders (PFS>12 months) compared with 3 pts (1%) in the CT arm, with a median treatment duration of 67.7 weeks. The RDI of cetuximab was ≥90% for all long-term responders. Conclusions: The addition of cetuximab to first-line platinum-based CT significantly improves outcome for patients with R/M-SCCHN. Although there are notable differences in long-term responders favoring cetuximab, the 5-year survival figures are still extremely low for both arms of the study. Cetuximab maintenance therapy proved to be feasible with manageable skin reactions. Clinical trial information: NCT00122460.

Background: ICT with taxanes regimens has been demonstrate increase overall survival (OS) in the recent metaanalysis (Blanchard JCO 2013) in patients (pts) with LAHNC. However CRTP or RTCx hasńt be compared as consolidation treatment. This randomized phase III trial (TTCC-2007-01, NCT00716391) compared OS and not inferiority of RTCx respect to CRTP. Now, we report preliminary results of toxicity in both regimen.

Aim: MEHD, a novel dual-action humanized IgG1 antibody that blocks ligand binding to EGFR and HER3, inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody dependent cell mediated cytotoxicity. MEHD is active in multiple tumor models, including models resistant to anti-EGFR or anti-HER3. Preclinical and early clinical data suggest that high expression of neuregulin 1 (NRG1) in tumors may enhance sensitivity to MEHD.

PURPOSE Cisplatin plus fluorouracil (PF) induction chemotherapy has been compared with taxane (docetaxel or paclitaxel), cisplatin, and fluorouracil (Tax-PF) in randomized trials in locoregionally advanced head and neck cancers (LAHNCs). The aim of this meta-analysis was to study the efficacy and toxicity of Tax-PF and PF and identify differences in outcomes in subsets of patients. METHODS Five randomized trials representing 1,772 patients were identified. Updated individual patient data (IPD) were retrieved for all trials. The log-rank test, stratified by trial, was used for comparison. Interaction or trend tests were used to study the interaction between covariates and treatment. Results Median follow-up was 4.9 years. The hazard ratio (HR) of death was 0.79 (95% CI, 0.70 to 0.89; P < .001; absolute benefit at 5 years: 7.4%) in favor of Tax-PF. Heterogeneity was significant (P = .08, I(2) = 51%) and related to one trial. There was no more heterogeneity after exclusion of this trial (P = .99, I(2) = 0%), and HR of death was 0.72 (95% CI, 0.63 to 0.83) in favor of Tax-PF. There was no interaction between treatment effect and the following patient covariates: age, sex, performance status, tumor stage, or site. Tax-PF was associated with significant reductions of progression, locoregional failure, and distant failure compared with PF, with HRs of 0.78 (95% CI, 0.69 to 0.87; P < .001), 0.79 (95% CI, 0.66 to 0.94; P = .007), and 0.63 (95% CI, 0.45 to 0.89; P = .009) respectively. CONCLUSION This IPD meta-analysis shows the superiority of Tax-PF over PF as induction chemotherapy. Its precise role in the management of LAHNC remains to be determined.