Outpatient palliative care and thoracic medical oncology: Referral criteria and clinical care pathways.

OBJECTIVES: Recent evidences show that early integration of palliative care (PC) with oncology has a positive impact on patients' quality of life, quality of care and costs. However, there is no consensus on outpatient referral criteria. Based on real world data, the aim of this study was to identify timing and factors associated to PC referral in patients with thoracic malignancies, and to describe their clinical care pathway. MATERIAL AND METHODS: This observational retrospective study included consecutive patients with thoracic cancer, seen for the first time at the Thoracic Medical Oncology outpatient Clinic (TMOC) of our institution, between Jan.01-Dec.31 2014. Patients were followed-up till death or Dec.31 2015. Clinical and demographic data were collected from the electronic patient records. Cox regression models were used to evaluate the association between time to Palliative care Outpatient Clinic (POC) referral and performance status (PS), disease stage and symptoms at inclusion. RESULTS: 229 patients were eligible. 98 of them (43%; 95%IC 36%-49%) were referred to the POC within a median of 30 days (IQR 4-188). 80/98 patients received simultaneous anticancer therapy and PC. Univariable analysis showed that the hazard ratio (HR) of being referred to POC was significantly higher for patients with worse PS (HR = 4.5), more advanced disease stage (HR = 3.1), pain (HR = 4.9), dyspnea (HR = 2.5) and cough (HR = 2.2). The multivariable model confirmed independent prognostic value for PS, disease stage and pain. On Dec.31, 2015, 25/98 patients were still alive, 8 were lost at follow up and 65 had died. Among the latter, 61% died with hospice or home care, and, in the last 30 days of life, 16% received chemotherapy and 29% were admitted to hospital. CONCLUSIONS: Our results suggest considering symptom burden, PS and disease stage as screening criteria for referral to PC in patients with thoracic malignancies.

Italian Cohort of the Nivolumab EAP in Squamous NSCLC: Efficacy and Safety in Patients With CNS Metastases.

BACKGROUND/AIM: Brain metastases are an additional challenge in patients with non-small-cell lung cancer (NSCLC) because most chemotherapy agents cannot cross the blood-brain barrier. Nivolumab has demonstrated efficacy in patients with advanced squamous NSCLC, but because patients with central nervous system (CNS) metastases are typically excluded from registration trials, 'field-practice' data are needed. PATIENTS AND METHODS: Patients in the Italian cohort of the Expanded Access Program (EAP) who had CNS metastases at baseline were analyzed. RESULTS: Thirty-seven patients with CNS metastases received a median of six doses of nivolumab. Three patients (8%) had grade 3-4 adverse events and one patient discontinued due to an adverse event. The objective response rate was 19%. Median overall survival was 5.8 (95% confidence interval=1.9-9.8) months and median progression-free survival was 4.9 (95% confidence interval=2.7-7.1) months. CONCLUSION: The safety and efficacy of nivolumab in patients with CNS metastases appear to be similar to those seen in the overall EAP cohort in Italy.

Association between antibiotic-immunotherapy exposure ratio and outcome in metastatic non small cell lung cancer.

OBJECTIVES: Immunotherapy (IO) is effective in metastatic Non Small Cell Lung Cancer (NSCLC). Gut microbiota has an impact on immunity and its imbalance due to antibiotics may impair the efficacy of IO. We investigated this topic in a case series of NSCLC patients treated with IO. MATERIALS AND METHODS: Data about all metastatic NSCLC patients treated with IO between 04/2013 and 01/2018 were collected. Patients were stratified according to antibiotic use during the Early IO Period (EIOP), and according to the Antibiotic-Immunotherapy Exposure Ratio (AIER) defined as "days of antibiotic/days of IO" during the Whole IO Period (WIOP). Survival was estimated using the Kaplan-Meier method. Log-rank test was used to compare the curves. Multivariate analyses were performed with the Cox model. RESULTS: We analyzed 157 patients. Forty-six patients received antibiotics during the WIOP, 27 patients during the EIOP. No differences in either Progression-Free Survival (PFS) or Overall Survival (OS) were observed according to antibiotic use during the EIOP (p = 0.1772 and p = 0.2492, respectively). Considering the WIOP, median AIER was 4.2%. The patients with a higher AIER had worse PFS (p < 0.0001) and OS (p = 0.0004) than the others. Results were significant also after correction for the IO line (p = 0.0018 for PFS) and performance status (p < 0.0001 for PFS, p = 0.0052 for OS). CONCLUSION: Although no difference in outcome were observed with antibiotic use in the EIOP, a detrimental effect became evident for patients with a higher AIER in the WIOP. If its relevance is confirmed, AIER may become an innovative variable for estimating the impact of antibiotics on IO efficacy.

Low Baseline Serum Sodium Concentration Is Associated with Poor Clinical Outcomes in Metastatic Non-Small Cell Lung Cancer Patients Treated with Immunotherapy.

BACKGROUND: A consistent percentage of patients with metastatic non-small cell lung cancer (NSCLC) derives no or only marginal benefit from immunotherapy (IO). OBJECTIVE: Since serum sodium has been linked to both prognosis in NSCLC and modulation of immune cells activity, we aimed to assess the association between low baseline serum sodium concentration (≤ 135 mEq/L) and clinical outcomes of patients with metastatic NSCLC treated with IO. PATIENTS AND METHODS: We included metastatic NSCLC patients treated with checkpoint inhibitors in our department from April 2013 to April 2018 with available baseline serum sodium concentration. Demographics, clinical and pathological characteristics were collected. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional-hazards model. RESULTS: Of 197 patients included, 26 (13%) presented low baseline serum sodium concentration. Patients in the low sodium cohort experienced a poorer disease control rate (OR 0.36; 95% CI, 0.15-0.86; Wald test P = .02), median overall survival (OS) (2.8 vs. 11.6 months; HR 3.00; 95% CI, 1.80-4.80; P < .001) and progression-free survival (PFS) (1.8 vs. 3.3 months; HR 2.60; 95% CI, 1.70-3.90; P < .001) compared to patients in the control cohort. At multivariate analyses, low baseline serum sodium concentration was independently associated with disease control and OS, but not with PFS. CONCLUSIONS: Our study showed for the first time that low baseline serum sodium concentration is associated with impaired clinical outcomes in patients with metastatic NSCLC treated with IO. The role of serum sodium concentration in this setting warrants further pre-clinical and clinical investigation.

Best practices for the management of thymic epithelial tumors: A position paper by the Italian collaborative group for ThYmic MalignanciEs (TYME).

Thymic epithelial tumors (TETs) are a heterogenous group of rare tumors, with a complex histopatological classification. Furthermore, the recent introduction of the first TNM staging system, that is scheduled to replace the Masaoka-Koga system, may create further difficulties in TET management, that remains challenging. Several guidelines for treatment of TETs are available and provide recommendations based mainly on non randomized trials and retrospective or limited series. Often the lack of evidence leads to formulation of indications based on expert opinions. As for other rare cancers it is crucial to create networks to coordinate the work among centres involved in treatment of these diseases in order to offer the best diagnostic and therapeutic tools. For this purpose, in 2014 a network named TYME (ThYmic MalignanciEs), was founded in Italy with the aim of improving care and research in TETs. In September 2017 a panel of multidisciplinary experts from TYME network and from other Italian centres strongly involved in TET diagnosis and treatment convened a first Italian Expert meeting together with representatives of association for patients affected by rare thoracic cancers Tu.To.R, to explore how these tumors are managed in the different centres of Italy compared to ESMO guidelines. In this paper we summarize the issues discussed during that meeting and we propose recommandations based on Masaoka Koga and the new TNM staging system.

Immunotherapy in non-small-cell lung cancer: a bridge between research and clinical practice.

Lung cancer has been historically considered a poorly immunogenic disease because of the few evidence of immune responses in affected patients and the limited efficacy of immunomodulating strategies. Recent understanding of the molecular mechanisms leading to cancer immune evasion has allowed the development of a new class of drugs called immune checkpoint inhibitors, which reactivate host responses with outstanding clinical benefits in a portion of patients with non-small-cell lung cancer. In this review, we briefly summarize the basis of immunogenicity and immune escape of cancer, with specific focus on non-small-cell lung cancer, mechanisms underlying immune checkpoint inhibitors efficacy and the most updated results on potential biomarkers, with the final aim of defining current unmet needs of immunotherapy in clinical practice.

RELEVENT Trial: Phase II Trial of Ramucirumab, Carboplatin, and Paclitaxel in Previously Untreated Thymic Carcinoma/B3 Thymoma With Area of Carcinoma.

Thymic epithelial tumors are rare malignancies. Thymic carcinoma represents about 20% of all thymic epithelial tumors and has aggressive behavior, with a greater tendency to metastatic spread. Thymic carcinoma is often diagnosed in advanced stages for which systemic treatment is the main therapeutic option. The association of chemotherapy and antiangiogenic agents in the first-line setting has never been investigated in this very rare cancer. However, preclinical and clinical evidence has suggested that inhibition of angiogenesis could be beneficial. The RELEVENT trial is a multicenter, open-label, single-arm, phase II study aimed at investigating the activity and safety of ramucirumab combined with paclitaxel and carboplatin in chemotherapy-naive patients affected by thymic carcinoma or B3 thymoma with area of carcinoma. The primary endpoint of the trial is the overall response rate. Progression-free survival, overall survival, and safety are secondary endpoints. Patient-reported outcomes will be collected at each visit. The mutational status of a subset of genes, polymorphisms, and selected micro-RNA expression will be evaluated.

Uncommon mutations in epidermal growth factor receptor and response to first and second generation tyrosine kinase inhibitors: A case series and literature review.

Epidermal growth factor receptor (EGFR) is the most common driver gene involved in non small cell lung cancer (NSCLC) growth, being found in approximately 10-15% of Caucasian and 40% of Asian patients. A wide variety of pathogenic mutations, deletions, insertions and duplications have been described in EGFR exons 18-21. The presence of the most common among them (e.g. exon 21 L851R and exon 19 deletions) is associated to response to first and second generation EGFR tyrosine kinase inhibitors (TKIs), which have demonstrated clear superiority over chemotherapy in terms of both progression free survival (PFS) and overall survival (OS) in all treatment lines. However, scarcity of data exists in literature about the response of rarer EGFR alterations to first and second generation TKIs, most works consisting in sporadic case reports and small case series. In this review we aim to discuss the available evidence about this topic, in order to derive suggestions for clinical practice. Furthermore, we report seven cases of patients with lung tumors harboring uncommon EGFR mutations, treated in our Institution with first or second generation TKIs.

Cognitive impairment and chemotherapy: a brief overview.

Patients with cancer are experiencing long-term survival following chemotherapy, but the treatment may also be associated with short and long-term toxicity, including the possibility of cognitive dysfunction. A literature overview indicated a significant association between chemotherapy and cognitive impairment but prospective longitudinal research is warranted to examine the degree and persisting nature of this decline. Although chemotherapeutic agents are unlikely to cross the blood-brain barrier, it has been alleged that the occurrence of neurotoxicity is linked to the pro-inflammatory cytokine pathways. Moreover in most cases many other factors could play an ancillary and concomitant role. The contribution of hormone therapy as well as emotional, social, behavioural and genetic factors should always be considered. Especially physical activity and cognitive training appear promising in the management of cognitive impairment but additional studies are required to establish their efficacy.

Concomitant EML4-ALK rearrangement and EGFR mutation in non-small cell lung cancer patients: a literature review of 100 cases.

The discovery of EGFR mutations and EML4-ALK gene rearrangements has radically changed the therapeutic scenario for patients with advanced non-small cell lung cancer. ALK and EGFR tyrosine-kinase inhibitors showed better activity and efficacy than standard chemotherapy in the first and second line treatment settings, leading to a clear advantage in overall survival of advanced non-small cell lung cancer patients harboring these genetic alterations. Historically the coexistence of EGFR mutations and EML4-ALK rearrangements in the same tumor has been described as virtually impossible. Nevertheless many recent observations seem to show that it is not true in all cases. In this review we will discuss the available literature data regarding this rare group of patients in order to give some suggestions useful for their clinical management. Furthermore we report here two cases of concomitant presence of both alterations that will help us in the development of discussion.

Small-Cell Lung Cancer: Clinical Management and Unmet Needs New Perspectives for an Old Problem.

Small cell lung cancer is a highly aggressive, difficult to treat neoplasm. Among all lung tumors, small cell lung cancers account for about 20%. Patients typically include heavy smokers in 70s age group, presenting with symptoms such as intrathoracic tumors growth, distant spread or paraneoplastic syndromes at the time of diagnosis. A useful and functional classification divides small cell lung cancers into limited disease and extensive disease. Concurrent chemo-radiotherapy is the standard treatment for limited disease, with improved survival when combined with prophylactic cranial irradiation. Platinum compounds (cisplatin/carboplatin) plus etoposide remain the cornerstone for extensive disease. Nevertheless, despite high chemo- and radio-sensitivity of this cancer, nearly all patients relapse within the first two years and the prognosis is extremely poor. A deeper understanding about small cell lung cancer carcinogenesis led to develop and test a considerable number of new and targeted agents but the results are currently weak or insufficient. To date, small cell lung cancer is still a challenge for researchers. In this review, key aspects of small cell lung cancer management and controversial points of standard and new treatments will be discussed.

Peptide receptor radionuclide therapy: focus on bronchial neuroendocrine tumors.

Well-differentiated bronchial neuroendocrine tumors (B-NETs) are rare. They represent 1-5 % of all lung cancers. The incidence of these neoplasms has risen over the past 30 years and, especially for advanced or metastatic disease, management is complex and requires a multidisciplinary approach. Treatment with somatostatin analogs (SSAs) is the most important first-line therapy, in particular in well-differentiated NETs with high somatostatin type receptor (SSTR) expression. In these tumors, the role of mammalian target of rapamycin (m-TOR) inhibitors and the potential utility of other target therapies remain unclear while chemotherapy represents the gold standard treatment only for aggressive forms with low SSTR expression. Peptide receptor radionuclide therapy (PRRT) is an emerging treatment modality for advanced NETs. There are many cumulative evidences about the effectiveness and tolerability of this therapeutic approach, especially in gastro-entero-pancreatic (GEP)-NETs. For B-NETs, scientific research is moving more slowly. Here, we performed a review in order to evaluate the efficacy and toxicity of PRRT with a focus on patients with inoperable or metastatic well-differentiated B-NETs.

Treatment of lung large cell neuroendocrine carcinoma.

Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I-II-III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L-LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues.

Diagnosis and management of typical and atypical lung carcinoids.

An estimated 20% to 30% of all neuroendocrine tumours originate in the bronchial tree and lungs. According to the 2015 World Health Organization categorization, these tumours are separated into four subtypes characterized by increasing biological aggressiveness: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma and small-cell carcinoma. Although typical and atypical lung carcinoids account for less than 1-5% of all pulmonary malignancies, the incidence of these neoplasms has risen significantly in recent decades. Surgery is the treatment of choice for loco-regional disease but for advanced lung carcinoids there is no recognized standard of care and successful management requires a multidisciplinary approach. The aim of this review is to provide a useful guide for the clinical management of lung carcinoids.

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future.

Lung cancer is one of the major causes of cancer related mortality worldwide. Brain metastases (BM) complicate clinical evolution of non-small cell lung cancer (NSCLC) in approximately 25-40% of cases, adversely influencing quality of life (QoL) and overall survival (OS). Systemic therapy remains the standard strategy for metastatic disease. Nevertheless, the blood-brain barrier (BBB) makes central nervous system (CNS) a sanctuary site. To date, the combination of chemotherapy with whole brain radiation therapy (WBRT), surgery and/or stereotactic radiosurgery (SRS) represents the most used treatment for patients (pts) with intracranial involvement. However, due to their clinical conditions, many pts are not able to undergo local treatments. Targeted therapies directed against epidermal growth factor receptor (EGFR), such as gefitinib, erlotinib and afatinib, achieved important improvements in EGFR mutated NSCLC with favorable toxicity profile. Although their role is not well defined, the reported objective response rate (ORR) and the good tolerance make EGFR-tyrosine kinase inhibitors (TKIs) an interesting valid alternative for NSCLC pts with BM, especially for those harboring EGFR mutations. Furthermore, new-generation TKIs, such as osimertinib and rociletinib, have already shown important activity on intracranial disease and several trials are still ongoing to evaluate their efficacy. In this review we want to highlight literature data about the use and the effectiveness of EGFR-TKIs in pts with BM from NSCLC.

Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy?

Malignant pleural mesothelioma is a rare cancer with a cause-effect relationship to asbestos exposure. The prognosis is poor and chemotherapy seems the best treatment option. In the last two decades a deeper understanding of mesothelioma carcinogenesis and invasiveness mechanisms has prompted research efforts to test new agents in patients with malignant pleural mesothelioma, but the results have been modest. Attractive preclinical data disappointed in subsequent experimental phases. Other promising agents failed to improve patient outcomes due to high toxicity. Interesting suggestions have come from preliminary data on immunotherapy. Several trials are ongoing and the results are eagerly awaited. The aim of this review is to discuss the most recent news on systemic therapy for advanced malignant pleural mesothelioma.

Hyponatremia in cancer patients.

Hyponatremia is the most frequent electrolyte disorder in hospitalized patients but also a well known poor prognostic factor in cancer patients. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is often misdiagnosed by oncologist because of difficulties in the interpretation of laboratory tests. Etiology is heterogeneous but the predominant cause is represented by the unbalance between excessive presence of water and serum sodium deficiency. Ectopic production of arginine vasopressin (AVP) develops more frequently in small cell lung cancer but it is not so rare in other malignancies. Neurological impairment may range from subclinical to life-threating symptoms depending by the rate of serum sodium deficiency. Appropriate diagnosis is essential to set a proper therapy. When hyponatremia is caused by SIADH, hypertonic saline infusion is indicated for acute presentation whereas fluid restriction is preferred in case of chronic asymptomatic evolution. Other options include vaptans, vasopressin receptor antagonists, targeted specifically for the correction of euvolemic hyponatremia. The aim of this brief report is to provide concise and specific informations for the management of SIADH in oncology clinical practice.

Emerging toxicities in the treatment of non-small cell lung cancer: ocular disorders.

The treatment of advanced disease (stage IIIb and IV) of non-small cell lung cancer (NSCLC) is based on systemic treatment with platinum-based chemotherapy or biological compounds depending on the disease molecular profile. In the last few years, intensive investigational efforts in anticancer therapy have led to the registration of new active chemotherapeutic agents, combination regimens, and biological drugs, expanding choices for customizing individual treatment. However, the introduction of new drugs in the clinical setting has led to several new toxicities, creating some difficulties in daily management. Among these, ocular toxicity is generally overlooked as more common toxicities such as myelosuppression, stomatitis, diarrhea, vomiting, "hand-foot syndrome", and neurological alterations attract greater attention. Ophthalmic complications from cytotoxic chemotherapeutics are rare, transient, and of mild/moderate intensity but irreversible acute disorders are possible. The best way to prevent potential irreversible visual complications is an awareness of the potential for ocular toxicity because dose reductions or early drug cessation can prevent serious ocular complications in the majority of cases. However, given the novelty of many therapeutic agents and the complexity of ocular pathology, oncologists may be unfamiliar with these adverse effects of anticancer therapy. Although toxicities from chemotherapy are generally intense but short lasting, toxicities related to targeted drugs are often milder but longer lasting and can persist throughout treatment. Here we review the principal clinical presentations of ocular toxicity arising from chemotherapy [1-3], target therapies [4], and newly developed drugs and provide some recommendations for monitoring and management of ocular toxicity.

Clinical retrospective analysis of erlotinib in the treatment of elderly patients with advanced non-small cell lung cancer.

In order to evaluate the clinical efficacy and the safety profile of molecularly targeted therapies as a palliative approach in elderly populations affected by advanced thoracic neoplasms, we retrospectively studied, in terms of effectiveness and toxicities, a group of pretreated elderly metastatic non-small cell lung cancer (NSCLC) patients admitted to our institution and treated with erlotinib at standard daily/dose. Forty-three patients aged 70 years or older who had previously failed on chemotherapy or radiotherapy were treated with oral Eerlotinib (150 mg/d) until disease progression or unacceptable toxicity. Clinical data, pathological types, potential prognostic factors, efficacy and toxicity of erlotinib were included in this analysis. In our series we observed: objective responses in six patients (14%) and stable disease in 15 (35%). Skin rash was the most common side effect (67%). Grade 3-4 adverse events were observed in 16 cases (37%). The median overall survival and the median progression-free survival were 8.4 months (CI 95%: 0.7-43.6) and 3 months (CI 95%: 0.4-28.4), respectively. Patients with adenocarcinoma achieved the best disease control rate (p = 0.027), while not/former smokers showed a better response (p = 0.069). In our experience the use of erlotinib after chemotherapy failure in an unselected elderly population affected by NSCLC showed moderate efficacy and a moderate safety profile. However, erlotinib represents a valid option in this setting, but other factors such as biological information, comorbidities and concomitant medications need to be carefully take into consideration in this particular subset of cancer patients.

An unusually large pleural mesothelioma with an outstanding clinical response and long lasting survival: a case report and literature review.

Malignant pleural mesothelioma is a neoplasm characterized by an increasing incidence and poor prognosis. When surgical treatment cannot be performed, systemic chemotherapy remains the main therapeutic option. Here we report the case of a 41-year-old female patient with epithelioid malignant pleural mesothelioma who was treated with carboplatin and pemetrexed despite her critical condition. She showed an impressive response to this first-line chemotherapy and, after disease progression, to further chemotherapy with gemcitabine and vinorelbine. She is still alive, with unexpectedly long-lasting survival.