Salvatore Alfieri

Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients

Background:Ipilimumab improves the survival of metastatic melanoma patients. Despite documented, durable objective responses, a significant number of patients fails to benefit from treatment. The aim of this study was to identify an upfront marker for treatment benefit.Methods:A total of 187 metastatic melanoma patients treated in three Italian Institutions with 3 mg kg−1 ipilimumab, and 27 patients treated with 10 mg kg−1 ipilimumab, were evaluated. Neutrophil-to-lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts. Progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan–Meier method, and multivariate Cox models were applied, adjusting for confounders and other prognostic factors.Results:In the training cohort of 69 patients treated at European Institute of Oncology, pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in multivariate analyses. Patients with baseline NLR<5 had a significantly improved PFS (HR=0.38; 95% CI: 0.22–0.66; P=0.0006) and OS (HR=0.24; 95% CI: 0.13–0.46; P<0.0001) compared with those with a NLR⩾5. Associations of low NLR with improved survival were confirmed in three validation cohorts of patients.Conclusion:Our findings show that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve to identify patients most likely to benefit from this therapy.

Does a multidisciplinary team approach in a tertiary referral centre impact on the initial management of head and neck cancer

OBJECTIVES A multi-disciplinary team (MDT) is essential in the management of cancer. Head and neck cancer (HNC) is a rare, complex and heterogeneous group of malignancies for which different treatment options are available. However, the potential impact of MDT on the management of HNC has been only poorly evaluated to date. This study evaluates the impact of MDT on the management of HNC in a tertiary centre. METHODS We retrospectively analysed records of HNC patients referred to a MDT evaluation at the Istituto Nazionale Tumori of Milan, Italy, from May 2007 to January 2012. All cases were reviewed by a MDT consisting of a head and neck surgeon, a radiation oncologist, and a medical oncologist. RESULTS Data from 781 HNC patients were analysed. Approximately 70% of patients were referred to our Institution for a second opinion consultation. Following MDT evaluation, new staging examinations were requested in 49% of patients, and treatment plan was modified in 10%. CONCLUSIONS A MDT approach in a tertiary referral hospital leads to staging refinement of disease or changes in treatment plan in about 60% of patients.

Temporal course and predictive factors of analgesic opioid requirement for chemoradiation-induced oral mucositis in oropharyngeal cancer

Oral mucositis (OM)‐related pain affects most patients with head and neck cancer during treatments, but its management is not standardized.

Investigational drugs for head and neck cancer

ABSTRACT Introduction: In the treatment of advanced/metastatic head and neck cancer (HNC), resistance to chemotherapy and to anti-EGFR agents remains a major issue, and new molecular drugs are eagerly awaited. Over the last decade, knowledge of the genetic landscape of HNC has rapidly grown. However, no tailored therapeutic intervention targeting HNC molecular abnormalities is currently available outside from clinical trials. Areas covered: In this review, the authors analyze new drugs in the HNC setting which have been investigated in recently published trials or are currently being investigated. The article excludes strategies directed towards the EGFR pathway and antivascular agents. Expert opinion: Agents acting on the PI3K axis have a strong biological rationale and show the preliminary signs of activity, in particular when combined with other agents. There is limited clinical data of the other discussed pathways; the CMET/HGF pathway as a possible modulator of anti-EGFR drug sensitivity and agents directed towards MEK, WEE-1, NOTCH represent new interesting approaches to HNC. It is of the utmost importance to try and incorporate the molecular dissection of the tumor profiles in clinical trials with such agents. Moreover, the mutational status of other cross-talking pathways should be assessed, since potential resistance mechanisms can be recognized and possibly overcome by a careful selection of patients and combination regimens. Immunotherapy represents a growing field in HNC and its wider application will impact on future therapeutic strategies, including the association with chemotherapy, targeted agents and radiation.

The Benefit of a Multidisciplinary Approach to the Patient Treated with (Chemo) Radiation for Head and Neck Cancer

Opinion statementIn the past two decades, multidisciplinary care has emerged as new way to manage cancer given the need to gather together specific areas of expertise and to discuss the variety of treatment approaches available for each patient. Of all the cancer subtypes, head and neck cancer might be considered one of the most valid areas, from an oncological point of view, for a multidisciplinary approach to be applied. Head and Neck Cancer is a complex disease area due to its varied histology and subsites, its numerous feasible treatments, its multiple typical comorbidities, and its treatment-induced toxicities whose management requires the simultaneous involvement of several professionals as part of the same health care team. However, the benefits of a multidisciplinary team approach in this particular area have not yet been properly documented in terms of survival outcomes. Moreover, there are some concerns and the limitations of a multidisciplinary team approach for Head and Neck Cancer patients are still open to question: cost-efficiency, the implications from a medical law perspective, the level of expertise required and the timing of each intervention (fixed or as required; before, during or after oncological treatment), and the role of the leader with other interested specialists to optimize all multidisciplinary care mechanisms.

In situ hybridization detection methods for HPV16 E6/E7 mRNA in identifying transcriptionally active HPV infection of oropharyngeal carcinoma: an updating

The aim of this study is to compare 2 in situ hybridization (ISH) detection methods for human papilloma virus (HPV) 16 E6/E7 mRNA, that is, the RNAscope 2.0 High Definition (HD) and the upgraded RNAscope 2.5 HD version. The RNAscope 2.5 HD has recently replaced the RNAscope 2.0 HD detection kit. Therefore, this investigation starts from the need to analytically validate the new mRNA ISH assay and, possibly, to refine the current algorithm for HPV detection in oropharyngeal squamous cell carcinoma with the final goal of applying it to daily laboratory practice. The study was based on HPV status and on generated data, interpreted by a scoring algorithm. The results highlighted that the compared RNAscope HPV tests had a good level of interchangeability and enabled to identify oropharyngeal squamous cell carcinoma that are truly driven by high-risk HPV infection. This was also supported by the comparison of the RNAscope HPV test with HPV E6/E7 mRNA real-time reverse-transcription polymerase chain reaction in a fraction of cases where material for HPV E6/E7 mRNA real-time reverse-transcription polymerase chain reaction was available. Furthermore, the algorithm that associates p16 immunohistochemistry with the identification of HPV mRNA by RNAscope was more effective than the one that associated p16 immunohistochemistry with the identification of HPV DNA by ISH.

Outcome of recurrent and metastatic head and neck squamous cell cancer patients after first line platinum and cetuximab therapy

OBJECTIVES Second-line chemotherapy in recurrent and/or metastatic head and neck cancer (r/mHNSCC) patients showed dismal results with limited tumor response and reduced life expectancy. Outside of clinical trials, data on efficacy of second line treatment after first line anti-EGFR-AB combination therapy are not available. MATERIAL AND METHODS Data regarding r/mHNSCC consecutive pts treated with cetuximab and platinum from 2009 to 2014 at our center were retrospectively collected. The analyses of response, Progression-Free Survival (PFS) and Overall Survival (OS), each evaluated starting from first and second-line treatment, were performed. Survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. RESULTS We identified 117 patients treated with first-line platinum and cetuximab-based therapy. Sixty-four (55%) patients did not receive second-line treatment due to worsening in performance status, 2 were not assessable for response thus 51 patients were included for analysis. Fifty-six percent were smokers/former smokers and 78% were male. Primary tumor sites were oropharynx (39%), oral cavity (31%), larynx/hypopharynx (24%) and others (6%). Regimens used in second-line were mostly monotherapies. Twenty-one % of the patients were treated within a clinical trial. Response rate (PR, CR) was 6% with 45% showing SD as best response. Median PFS was 2.2months (95%CI:1.5-2.8months) and OS 6.1months (95%CI:3.7-7.2months). CONCLUSIONS Within our single center experience only half of the patients with r/mHNSCC were able to receive second-line treatment. Response rate was unsatisfactory, but median OS seems higher than previously reported in an anti-EGFR-AB naïve population (Leon 2005).

The Case Volume Issue in Head and Neck Oncology

Opinion statementIn the past few years, several evidences reported better outcomes, in terms of reduced toxicities and longer survival, for head and neck cancer (HNC) patients when “regionalized,” namely if they are managed at “high-volume” cancer referral centers (CRC). The benefit of case volume has been demonstrated in HNC patients primarily treated with surgery and in those receiving curative radiotherapy and chemotherapy. Many factors could explain these positive results: organization, facilities, processes of care, quality assurance programs, professional expertise, technology, and patient referral bias. In other words, the “high volume” could be linked both to all hospital-related volume and to the expertise of each involved professional figure (e.g., surgeon, radiation oncologist, medical oncologist, etc.). In this context, it is still debatable whether there is a need to understand which one of these factors is more able to influence the final outcomes of HNC patients. Considering the complexity and heterogeneity of HNC, all of these aspects are likely to impact and plot each other. However, there is no consensus regarding the criteria and the cut-off used to define as “high” the case volume. Moreover, some limitations or biases of the regionalization process have to be highlighted: (1) personal and financial discomfort of patients, their caregivers, and families; (2) a frequent referral of the healthiest or youngest patients to CRC could change the survival outcomes; (3) potential higher difficulties for colleagues working outside of CRC in the emergency. Nevertheless, the case volume represents one of the factors impacting on the quality of the treatment itself, in terms of reduced toxicity and better treatment outcome. Therefore, it should be considered as a stratifying factor in randomized controlled trials for HNC patients.

Prognostic role of PIK3CA and TP53 in human papillomavirus–negative oropharyngeal cancers:

Background: Human papilloma virus (HPV)–negative oropharyngeal squamous cell carcinomas (OPCs) have a poorer prognosis and best management is an unmet need. We studied the prognostic role of epidermal growth factor receptor (EGFR) and PIK3CA amplifications and TP53 functional status. Methods: Between 1992 and 2000, 90 consecutive patients with OPCs were treated with surgery, followed by radiotherapy in case of high-risk pathologic features. Of those, 73 cases were HPV-negative and therefore were selected for molecular analysis (PIK3CA and EGFR fluorescent in situ hybridization [FISH] analysis and TP53 mutation analysis). Results: FISH analyses of EGFR and PIK3CA were successfully conducted on 69 and 63 of 73 tumor samples, respectively. EGFR alterations were detected in 43% of patients but just 7% showed amplification. Seven cases (11%) carried PIK3CA amplification and 18 (29%) gene gain or high polysomy. TP53 was detected as nonfunctional in 24 of 67 (36%) successfully analyzed cases. Both univariable and multivariable analysis showed statistically significantly worse disease-free survival (DFS) for patients with PIK3CA disomy compared to those with gene gain or high polysomy. No differences in overall survival or DFS for EGFR and TP53 alteration were evident. The combined evaluation of PIK3CA and TP53 showed that PIK3CA gene copy number gain separated a population with better outcome, defining an overall worse prognosis population (disomy) now clearly further divided according to TP53 functional status. Conclusion: PIK3CA gene copy number increase is associated with a favorable clinical outcome in HPV-negative OPCs treated with surgery ± postoperative radiotherapy. In patients without PIK3CA alteration, TP53 nonfunctional mutations are associated with poor prognosis.

Lenvatinib-induced renal failure : two first-time case reports and review of literature

ABSTRACT Introduction: Lenvatinib (LEN) is a multi-kinase anti-angiogenic drug recently approved in several cancers. LEN is not easily manageable due to its complex safety profile. Proteinuria and renal failure (RF) were reported among the most frequent LEN-induced adverse events (AEs), often leading to discontinuations or dose modifications. Understanding the pathogenesis of these AEs could ameliorate the management of LEN-induced renal toxicity. Areas covered: We present two cases of LEN-induced renal failure (LIRF) with different pathogenesis. 1) LIRF with severe proteinuria in a man treated for a metastatic papillary thyroid carcinoma. Kidney biopsy showed a glomerular damage secondary to LEN, having excluded other causes of RF. 2) LIRF without proteinuria in a woman with metastatic adenoid cystic carcinoma of minor salivary gland. A tubulointerstitial nephropathy was supposed by clinical evaluation and laboratory tests. Effective management was obtained by oral steroids without interrupting LEN. Expert opinion: The case 1 presented for the first time the histological picture of LIRF with a classical glomerular damage leading to secondary proteinuria and tubular failure. Case 2 showed an alternative LIRF pattern of likely tubulointerstitial injury without proteinuria. These reports reflect two sides of the same coin, both to be considered in case of LIRF.