Ipilimumab in melanoma

Introduction: The treatment of melanoma is evolving rapidly over the past few years. Patients with BRAFv600 mutations can be treated with a combination of a BRAF-inhibitor and an MEK-inhibitor. Patients with BRAF wild-type tumors and BRAFv600 mutated tumors can be treated with immunotherapy i.e. check point inhibitors.

Areas covered: We conducted a comprehensive review of the literature on the efficacy and predictive markers, safety, and pharmacoeconomics of ipilimumab in melanoma

Expert commentary: Ipilimumab was the first check point inhibitor reaching the clinic, gaining FDA and EMA approval for metastatic melanoma in 2011. Ipilimumab was also approved by FDA in the adjuvant setting for patients with high risk, stage III melanoma. The anti-PD1 directed antibodies pembrolizumab and nivolumab are superior to single agent ipilimumab, which is no longer considered the standard first line treatment in metastatic melanoma.

The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of a steep increase in grade 3–4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients potentially requiring the combination and its pharmacoeconomic implications are to be elucidated.     

The safety and efficacy of nivolumab in advanced (metastatic) non-small cell lung cancer

Introduction: Advanced non-small cell lung cancer (NSCLC) is a challenging oncological problem. Following standard initial therapy, disease progression will typically develop. Patients with relapsed or refractory disease are left with limited treatment options. The advent of nivolumab, a monoclonal antibody against Program Death-1 (PD-1), has substantially changed the outlook for such patients.

Area covered: Nivolumab is the first checkpoint immunotherapeutic agent to gain regulatory approval for NSCLC. By enabling host immune-mediated cytotoxic activity against tumor cells, nivolumab induces a partial or complete tumor response in 15–20% of patients, regardless of number of previous lines of anti-cancer therapy. Nivolumab-related adverse effects are generally milder and less frequent than those observed with conventional cytotoxic chemotherapy. Although immune-related adverse events such as fatal pneumonitis have been reported with nivolumab therapy, most adverse events are reversible with a prompt immunosuppression. Studies investigating nivolumab in combination with other agents are ongoing.

Expert commentary: Nivolumab represents a significant breakthrough in the treatment of advanced NSCLC. Its therapeutic role for NSCLC may soon expand to include consolidation or maintenance setting. Furthermore, several clinical trials investigating the combination of nivolumab with other immunologic or non-immunologic treatments are ongoing and these will likely result in additional roles of nivolumab in NSCLC.     

Nivolumab for the treatment of colorectal cancer

Introduction: Despite a variety of therapies for advanced metastatic colorectal cancer being available, the outcomes in this malignancy remain suboptimal. Immunotherapy has been slow to impact the management of this patient group. Checkpoint inhibitors, such as nivolumab, have had disappointing results when used broadly. However, for the subset of patients with microsatellite unstable colorectal cancer, the use of checkpoint inhibitors such as nivolumab appears to be transformative, and will provide a new therapeutic option for patient with advanced disease.

Areas covered: Nivolumab gained regulatory approval for the treatment of dMMR/MSI-H metastatic colorectal cancer in mid 2017. The current review will summarize the clinical evidence of checkpoint inhibitors in metastatic colorectal cancer, with a focus on nivolumab.

Expert commentary: For patients with dMMR/MSI-H mCRC, the use of nivolumab has now been shown to have objective and sustained clinical responses in a pivotal phase II trial. While additional data are limited, the therapeutic role for augmenting an immune response in metastatic colorectal cancer is likely to continue to expand. Further combination trials of nivolumab with immunologic and non-immunologic agents are ongoing.     

Nivolumab in squamous cell carcinoma of the head and neck

Introduction: The prognosis of recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (HNSCC) after failure of first line chemotherapy is dismal. Until the publication of the results of CheckMate 141, not a single agent provided any survival benefit as a second line treatment for R/M HNSCC.

Areas covered: A comprehensive review of the literature was conducted on the role of nivolumab in HNSCC.

Expert commentary: Nivolumab is approved by the Food and Drug Administration for the treatment of patients based on the results of CheckMate 141 showing an overall survival benefit as compared to standard care (single agent docetaxel, methotrexate, or cetuximab). Of particular interest are immune-related adverse events which should be managed according to published guidelines.     

Nivolumab for the treatment of urothelial cancers

Introduction: Advanced urothelial cancer patients had limited therapeutic options following failure of platinum-based chemotherapy. The recognition that anti-PD1/PDL1 immune checkpoint inhibitors lead to dramatic and durable responses in a subset of patients has transformed the therapeutic landscape of these cancers. Since May 2016, five agents targeting this pathway have been approved by the US FDA, including the PD-1 inhibitor nivolumab.

Areas covered: The purpose of this paper was to review the safety, activity and efficacy of nivolumab, an anti-PD1 checkpoint inhibitor for the treatment of locally-advanced or metastatic urothelial cancers. Future therapeutic perspectives were also discussed.

Expert commentary: Nivolumab is one of five anti-PD1/PDL1 checkpoint inhibitors approved for treatment of advanced urothelial cancers. While durable responses can be observed, only 15 – 24% of patients are likely to respond. To date, there are no validated biomarkers, including PDL1 expression, which might accurately identify patients who are likely to respond. Many different biomarkers are currently under active investigation. Future direction for therapeutic development is likely to involve combination therapies with PD1/PDL1 agent as the therapeutic backbone.     

Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review

Introduction: Immune-related ocular toxicities are uncommon but serious adverse events that may be associated with the use of immune checkpoint inhibitors. The objective of this review is to assess the incidence and risk of ocular toxicities which are potentially immune-related and occur with immune checkpoint treatment of solid tumors.

Areas covered: PubMed database has been searched till June 2016. Prospective clinical trials reporting the occurrence of immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors were included. Eleven trials with 4965 participants were included. These studies included one study for ipilimumab and tremelimumab, three studies for nivolumab, five studies for pembrolizumab and one study comparing pembrolizumab to ipilimumab. No atezolizumab studies were included. The most common ocular toxicities reported with these agents included uveitis and dry eyes. Pooled analysis for odds ratio of all-grade immune-related ocular toxicities is 3.40 [95% CI: 1.32–8.71; P = 0.01].

Expert commentary: Despite being uncommon, immune-related ocular toxicities (particularly uveitis and dry eyes) occur with a higher frequency in cancer patients treated immune checkpoint inhibitors compared to those treated with control regimens.     

The safety and efficacy of nivolumab for the treatment of advanced renal cell carcinoma

Introduction: Despite a variety of therapies for advanced advanced renal cell carcinoma (RCC) including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors, outcomes for these patients are still not optimal. Immunotherapy with checkpoint inhibitors such as nivolumab, a fully human immunoglobulin (Ig) G4 PD-1 inhibitor antibody, is a promising development in RCC and provides a new therapeutic option for patients with advanced disease.

Areas Covered: This article reviews safety and efficacy data from the phase I, II, and III clinical trials that have led to the approval of nivolumab for the treatment of patients with advanced RCC who have previously been treated with VEGF-directed therapy.

Expert Commentary: Given the overall survival advantage with nivolumab compared to previously approved therapy, nivolumab is a new standard of care in the second-line setting for patients with advanced RCC. Additional studies are underway to answer important questions including the identification of biomarkes and the use of nivolumab in treatment-naïve patients.     

Current and future immunotherapies for thyroid cancer

Introduction: Cancer immunotherapies were approved in recent years, including immune checkpoint inhibitors. Experience with ipilimumab (CTLA-4 antagonist), nivolumab and pembrolizumab (PD-1 antagonists), and atezolizumab (PD-L1 antagonist) has shown that the impact on overall survival in cancer patients is paramount. Immune checkpoint inhibitors target the immune system and they can be applied across multiple cancers; the response rate is ranging from 20 to 40%. Many studies have shown that thyroid cancer (TC) cells produce cytokines and chemokines, inducing several tumor-promoting effects. Targeting and/or lowering cytokines and chemokines concentrations within the tumor microenvironment would produce a therapeutic benefit. In TC, increased Treg and PD-1⁺ T cell frequencies are indicative of aggressive disease and PD-L1 expression correlates with a greater risk of recurrence.

Area covered: After performing a literature search, a few pioneering studies have evaluated immunotherapy in thyroid cancer. More recently a case has been described involving anaplastic thyroid cancer treated with vemurafenib and nivolumab, with substantial regression and complete radiographic and clinical remission.

Expert commentary: The use of immune checkpoint inhibitors in aggressive TC has not yet been extensively investigated and further studies in a large number of TC patients are urgently needed.     

Risk factors for acute kidney injury associated with the treatment of bacterial endocarditis at a tertiary academic medical center*

Background: Acute kidney injury (AKI) is a common complication of endocarditis.

Objective: To determine risk factors for the development of AKI in patients treated for endocarditis.

Methods: This single centre, retrospective univariate and multivariate analysis to determine risk factors for the development of AKI included patients diagnosed with endocarditis between January 2009 and October 2013.

Results: Of 211 included patients, a total of 84 (39.8%) patients developed AKI. We identified multiple independent variables associated with the development of AKI, including: age ≥ 65 years, presence of hardware, chronic kidney disease, AKI on admission, infection with Staphylococcus spp, receipt of nafcillin or oxacillin or aminoglycoside and nafcillin or oxacillin or aminoglycoside and vancomycin, vancomycin trough level ≥ 20.0 mcg/ml, aminoglycoside total daily dose reduction, duration of vancomycin exceeding three days, receipt of loop diuretic or more than three concomitant nephrotoxins and duration of loop diuretic or non-steroidal anti-inflammatory drug therapy exceeding seven days.

Conclusions: In patients treated for endocarditis, multiple risk factors for AKI were identified. Prospective studies are needed to evaluate these variables for causation of AKI in patients treated for endocarditis.     

Optimizing treatments for recurrent or metastatic head and neck squamous cell carcinoma

Introduction: The majority of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) will recur. The treatment of patients with recurrent/metastatic (R/M HNSCC) is rapidly evolving.

Areas covered: This article will comprehensively review the current systemic treatment of R/M HNSCC.

Expert commentary: For the time being, the EXTREME regimen (cetuximab in combination with platinum and 5-fluorouracil) still remains standard of care in previously untreated R/M HNSCC patients who are candidates for combination chemotherapy. Single agents with well documented activity in HNSCC include methotrexate, cisplatin, 5-FU, docetaxel, and paclitaxel. The anti-PD-1 monoclonal antibody nivolumab can be considered the current standard of care in patients with R/M HNSCC progressing after platinum-based therapy based on the results of CheckMate 141 showing a survival benefit over standard of care drugs, such as single agent weekly cetuximab, methotrexate, or docetaxel.

Multiple randomized phase III trials comparing anti-PD(L)-antibodies either as single agent or in combination with chemotherapy or an anti-CTLA-4 with the EXTREME as fist line treatment are ongoing or planned. The outcome of these trials might change the current treatment paradigm in previously untreated R/M HNSCC. Immunotherapeutic agents under active investigation include Toll-like receptor 8 agonists and inhibitors of IDO1.     

EGFR expression in circulating tumor cells from high-grade metastatic soft tissue sarcomas

Introduction: Soft tissue Sarcomas (STS) are rare malignances, with high mortality rates. Half of patients develop metastasis. The presence of isolated Circulating Tumor Cells (CTCs) and Circulating Tumor Microemboli (CTM) in the blood may be early markers of tumor invasion. Epidermal Growth Factor (EGF) family receptors can also influence this process.

Objectives: to quantify CTCs and identify CTM as well as the EGF Receptor (EGFR) protein expression in these cells and correlate with clinical outcome in metastatic STS.

Materials and methods: Approximately 8mL of blood was prospectively collected from patients with different types of high-grade STS, before the beginning of chemotherapy. The samples were processed and filtered by ISET (Rarecells, France) for the isolation and quantification of CTCs and CTMs. EGFR expression was analyzed by immunocytochemistry (ICC) on CTCs/ CTMs.

Results: We analyzed 18 patients with median age of 49 years (18-77 y). The positivity for EGFR protein expression in CTCs was observed in 93.75% of the patients. This result shows that targeting EGFR positive CTCs from STS origen can be translated in clinical benefit for some patients. In addition, if target therapy is chosen, the EGFR expression in CTCs can be used in follow-up to measure treatment effectiveness.

Conclusions: This is the first study to demonstrate the expression of EGFR protein in CTCs from sarcoma patients. It may open an area for future investigations. The next step is to characterize CTCs in a larger cohort of patients to better understand the role of EGFR in sustaining tumor metastasis in sarcomas.     

Application of microwave ablation in the emergent control of intraoperative life-threatening tumor hemorrhage during hepatic surgeries

Purpose: This study was designed to evaluate the efficacy and safety of microwave ablation (MWA) in the treatment of intraoperative life-threatening tumour haemorrhage during hepatic surgeries.

Methods: Three cases of MWA application in the emergent control of life-threatening hepatic tumour haemorrhage were analysed and reported.

Results: Satisfactory hemostasis for hepatic tumour rupture was achieved by MWA in all three cases. No major complications, such as post-operative haemorrhage, bile duct injury, liver abscess, colon perforation, skin burns, tumour seeding or renal dysfunction, were identified.

Conclusions: MWA may be a feasible, effective and simple strategy for the emergent control of intraoperative hepatic tumour bleeding. To the best of our knowledge, this study represents the first reported cases of this novel application of MWA.     

CT-guided radiofrequency ablation of spinal osteoblastoma: treatment and long-term follow-up

Objective: Osteoblastoma (OB) is a painful, rare, benign bone tumour usually observed in young populations, and this condition involves the spine in up to one-third of cases. We sought to focus on the minimally invasive treatment of spinal OB with radiofrequency ablation (RFA) under computed tomography (CT) guidance. When performed near the spinal cord, surgery can lead to instability of the spine, sometimes requiring additional interventions to stabilise the segments involved, and can cause the precocious onset of arthrosis or other degenerative diseases.

The results were evaluated both clinically and with the aid of diagnostic imaging techniques during a 5-year follow-up study.

Materials and methods: Eleven patients affected by spinal OB were treated in a single session with biopsy and CT-guided RFA. Pre- and post-evaluations of the patients were performed both clinically and with CT and magnetic resonance imaging (MRI).

Results: Complete success in terms of pain relief was achieved in all patients. Additional treatments were not required in any patients. There were no complications. During follow-up, neither complications nor pathological findings related to the treatment were observed.

Conclusions: Our experience demonstrates that RFA for spinal OB is safe and effective. One of the main advantages of this technique is represented by its lower grade of invasiveness compared with that for potentially hazardous surgical manoeuvres.     

Therapeutic strategies for organ-confined and non-organ-confined bladder cancer after radical cystectomy

Introduction: In patients with muscle invasive or Bacillus Calmette-Guérin refractory urothelial carcinoma of the urinary bladder (UCUB) radical cystectomy represents the standard of care. However, a proportion of patients experience disease progression, local recurrence and/or metastatic disease.

Areas covered: This review provides an overview of available therapeutic strategies after radical cystectomy and examines ongoing clinical trials including cytotoxic chemotherapy and immunotherapy.

Expert commentary: Cytotoxic chemotherapy offers limited benefit in UCUB patients. However, the recent introduction of immunotherapy provides new hope for durable responses or possibly complete cures.     

Evaluating the addition of oxaliplatin to single agent fluoropyrimidine in the treatment of locally advanced rectal cancer: a systematic review and meta-analysis

Introduction: Multimodality treatment of patients with locally advanced rectal cancer (LARC) has significantly improved local disease control, however the unaltered overall survival (OS) implicates an inability to further control micrometastases, providing rationale for intensified systemic treatment.

A systematic review was conducted to evaluate the efficacy and toxicity of adding oxaliplatin to a fluoropyrimidine (intervention) compared with fluoropyrimidine alone (control) in the treatment of LARC.

Methods: We searched CENTRAL, Medline Ovid, PubMed and EMBASE databases. Randomised trials comparing the intervention and control delivered either pre- or post-operatively were included.

Results: Seven trials involving 4444 patients were identified; five studies evaluated the intervention vs control preoperatively; one study peri-operatively; and one, post-operatively. There was no significant difference in OS with oxaliplatin addition, HR 0.89, 95% CI, 0.75 to 1.06. There was however an improvement in disease free survival, 3-year local and distant recurrence rates (RR) favouring oxaliplatin. Preoperative oxaliplatin improved pathological complete response (pCR), but with a greater toxicity and reduced compliance with radiation.

Conclusion: There is no OS benefit with oxaliplatin, despite improved pCR, local and distant RR. Before drawing definitive conclusions, longer follow-up in included trials and availability of published data from other eligible studies, including the induction setting, are needed.     

Opportunities and challenges of long term anti-estrogenic adjuvant therapy: treatment forever or intermittently?

Introduction: Extended adjuvant (5–10 years) therapy targeted to the estrogen receptor (ER) has

significantly decreased mortality from breast cancer (BC).

Areas covered: Translational research advanced clinical testing of extended adjuvant therapy with tamoxifen or aromatase inhibitors (AIs). Short term therapy or non-compliance increase

recurrence, but surprisingly recurrence and death does not increase dramatically after 5 years of adjuvant therapy stops.

Expert commentary: Compliance ensures optimal benefit from extended antihormone adjuvant therapy.Retarding acquired resistance using CDK4/6 or mTOR inhibitors is discussed. Preventing acquired resistance from mutations of ER could be achieved with Selective ER Downregulators (SERDs), eg fulvestrant. Fulvestrant is a depot injectable so oral SERDs are sought for extended use. In reality, a ‘super SERD’ which destroys ER but improves women’s health like a Selective ER Modulator (SERM), would aid compliance to prevent recurrence and death. Estrogen-induced apoptosis occurs in 30% of BC with antihormone resistance. The ‘one in three’ rule that dictates that one in three unselected patients respond to either hormonal or antihormonal therapy in BC occurs with estrogen or antiestrogen therapy and must be improved. The goal is to maintain patients for their natural lives by blocking cancer cell survival through precision medicine using short cycles of estrogen apoptotic salvage therapy, and further extended antihormone maintenance.     

Female cancer patients' perceptions of the fertility preservation decision-making process: An exploratory prospective study

Purpose: To assess female cancer patients' perceptions of the fertility preservation decision-making process and to examine the effect of clinicians' support on the decision quality.

Methods: A total of 71 patients participated in this longitudinal study with two assessment time points (before cancer therapy, after cancer therapy). Self-report measures assessed the decision-making process, the decision quality and the clinicians' support.

Results: A less positive experience in the decision-making process was associated with higher decisional regret and lower decisional satisfaction. In the group that decided not to pursue FP, participants who perceived higher oncologist's support reported higher decisional satisfaction.

Conclusions: A higher quality decision is positively associated with a better experience in the decision-making process. The oncologist's support is crucial for the decisional satisfaction of patients who decide not to pursue FP.

Implications for psychosocial providers: Psychologists may be important in helping patients to adequately cope with the FP decision so that they can make a high-quality decision.     

The safety and efficacy of sonidegib for the treatment of locally advanced basal cell carcinoma

Introduction: Basal cell carcinomas (BCCs) are the commonest malignancy in the Western world. Locally advanced BCCs (laBCCs) represent tumours that have developed in difficult-to-treat facial sites, aggressively recurrent tumours, large neglected tumours and those in which current treatment options are excluded by clinical or patient-driven criteria. It is estimated laBCCs represent 1% of BCCs.

Areas covered: Sonidegib is an oral hedgehog pathway inhibitor with a novel structure. It has recently been licensed for the treatment of laBCC.

This article provides a comprehensive review of the literature regarding sonidegib, detailing the pharmacology of the compound, clinical trial data, competitor compounds and a future perspective.

Expert commentary: Sonidegib is a novel smoothened (SMO) inhibitor with comparable efficacy to vismodegib, with patient response rates of 44% (sonidegib) and 43% (vismodegib). The adverse effect profile of these two treatments is similar with the main effects being considered to be class effects of SMO inhibitors.     

The safety and efficacy of olaparib therapy in patients with relapsed ovarian cancer

Introduction: PARP inhibition is an exciting new anticancer strategy. Olaparib has recently obtained a first in class license in Europe and the USA for the treatment of relapsed BRCA-mutant ovarian cancer.

Areas covered: We review the key preclinical and clinical data surrounding its use in the maintenance setting.

Expert commentary: We also consider the market profile, regulatory issues surrounding the agent and offer a five year speculative viewpoint of its future development in ovarian cancer.     

Use of specific immunoglobulins and vaccines for the management of accidental needlestick injury in the child: a practical review in the anti-vaccination movement era

Introduction: Accidental needle injury is a common but still discussed problem.

Objective: We discuss possible options to optimize the management of injured children in light of the available literature findings.

Results: The risk of viral infection is low. However, blood investigations are mandatory, as well as appropriate counselling. Anti-HBV immunoglobulins are recommended in all unvaccinated subjects exposed to a HBsAg-positive source; however, there is no agreement regarding their administration in unvaccinated children. Use of anti-tetanus immunoglobulins in unvaccinated child with minor and clean wound is well defined; however, wound type classification in the event of needlestick injury may be difficult and subjective. There is no agreement on the routine use of antiretroviral prophylaxis.

Conclusion: From a practical point of view, several unsolved issues have emerged regarding the management of the children with needlestick injury, which appear particularly relevant in the anti-vaccination movement era. International guidelines should be encouraged at this regard.