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.     

The role of neoadjuvant chemotherapy in ovarian cancer

Introduction: Ovarian cancer is mostly diagnosed at advanced stage. Better survival is achieved through complete debulking surgery and chemotherapy. Historically, neoadjuvant chemotherapy (NAC) has been introduced for unresectable disease to decrease tumor load and perform a unique complete surgery. Four randomized control trials have compared primary debulking surgery to NAC, but there is still controversy about the use of neoadjuvant chemotherapy and questions about its modalities.

Areas covered: We made a review of knowledge on benefits of NAC compared to primary debulking chemotherapy, in terms of survival and morbidity, methods of administration, new drugs in early and late phase trials, the selection of patients. Similar survival was observed after NAC and interval debulking surgery or primary debulking surgery. Morbidity of surgery was decreased after interval debulking compared primary debulking surgery. Conventional drugs are carboplatin and paclitaxel. Safety of bevacizumab was evaluated in phase 2 trials associated with conventional drugs. Immunotherapy trials are enrolling patients in phase 1 study.

Expert commentary: NAC followed by debulking surgery is the best treatment for patients with advanced ovarian cancer.     

How to use neoadjuvant medical treatment to maximize surgery in melanoma

Introduction: The aim of this work is to discuss the role of neoadjuvant therapy in melanoma patients, namely the potential to improve control and surgical resectability of locoregional disease. Moreover, potential survival benefits for high-risk stage III and IV melanoma patients will be addressed.

Areas covered: In this review, the different available neoadjuvant treatments including chemotherapy, bio-chemotherapy, targeted therapy, immunotherapy and local therapy will be presented and discussed. The PubMed published articles were identified and searched using the following terms located in the publication title: neoadjuvant therapy and melanoma. Studies investigating targeted therapy, immunotherapy and local melanoma treatments were included. Clinicaltrial.gov was also used as a source for recruiting or ongoing but not recruiting neoadjuvant clinical trials, for which no published results are available.

Expert commentary: Targeted therapy and immunotherapy in a neoadjuvant setting are still under investigation and not yet approved, however several neoadjuvant trials are ongoing. Shortly, results from these trials will answer the question whether neoadjuvant treatment translates into survival benefit and improves local disease control in stage III and IV melanoma patients. Immunotherapy and targeted therapy will play as relevant a role as in the metastatic setting, whereas chemotherapy will be used seldom.     

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.     

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.     

Fulvestrant for the treatment of advanced breast cancer

Introduction: The current issues with endocrine therapy for treatment of advanced breast cancer include balance of efficacy of therapy versus tolerability as well as hormone resistance. The efficacy of fulvestrant, a selective oestrogen receptor degrader (SERD), has been demonstrated in hormone receptor positive patients previously untreated or treated with hormonal therapy.

Areas covered: This article discusses the journey of fulvestrant licensing, its efficacy in combination with other endocrine therapies and the future role it may have within breast cancer treatment.

Expert commentary: Within phase III trials, fulvestrant has demonstrated equivalent or improved clinical efficacy when compared with established endocrine agents. In the recent decade, fulvestrant has achieved licensing as a second line agent in non-operative advanced breast cancer at initially 250mg, increasing to 500mg. Presently, fulvestrant is licensed globally as first line endocrine management for advanced breast cancer in post-menopausal women. Early combination trials of fulvestrant and cyclin dependent kinase 4/6 inhibitors have demonstrated good clinical efficacy with improved progression free survival when compared to fulvestrant alone.     

LncRNA PTCSC3 affects drug resistance of anaplastic thyroid cancer through STAT3/INO80 pathway

Background: LncRNA PTCSC3 is a tumor suppressor in thyroid cancer, and its role in drug resistance of anaplastic thyroid cancer (ATC) to chemotherapy drug doxorubicin was investigated in this study.

Methods: Expression of RNA and protein was analyzed by qRT-PCR and western blot, respectively. Flow cytometry was used to analyze the expression rate of CD133⁺ cells. The endogenous expression of related genes was modulated by recombinant plasmids and cell transfection. Combination condition and interaction between PTCSC3 and STAT3 were determined by RIP and RNA pull-down assay, respectively. MTT assay was performed to detect cytotoxicity. Chromatin immunoprecipitation was conducted to identify interactions between STAT3 and DNA promoter of INO80.

Results: LncRNA PTCSC3 was low-expressed in ATC tissues and cells. Over-expressed PTCSC3 inhibited the drug resistance of ATC to doxorubicin. PTCSC3 negatively regulated STAT3, and STAT3 promoted expression of INO80. PTCSC3 regulated INO80 through STAT3. PTCSC3 suppressed stem cells properties and drug resistance of ATC to doxorubicin.

Conclusion: LncRNA PTCSC3 inhibits INO80 expression by negatively regulating STAT3, and thereby attenuating drug resistance of ATC to chemotherapy drug doxorubicin.     

Pembrolizumab for the treatment of bladder cancer

Introduction: Until recently, patients with locally advanced or metastatic urothelial carcinoma after progression on cisplatin-containing chemotherapy had limited systemic treatment options with no significant survival benefit and poor tolerability. Advances in the field of immunotherapy with the introduction of checkpoint inhibitors have led to paradigm shifts in the treatment of various malignancies.

Areas covered: The current review will summarize the clinical evidence of checkpoint inhibitors in bladder cancer, with a focus on pembrolizumab.

Expert commentary: Category 1 evidence indicates that the checkpoint inhibitor pembrolizumab improves overall survival in patients with locally advanced or metastatic urothelial carcinoma who progressed after or during cisplatin-containing therapy as compared to current standard of care chemotherapy. Phase 1 and 2 evidence also indicates that checkpoint inhibitors are active in first line in patients who are ineligible for cisplatin-containing chemotherapy.     

Treatment of advanced breast cancer with a metronomic schedule of oral vinorelbine: what is the opinion of Italian oncologists?

Background: The aim of this study was to record the opinions of Italian oncologists about the use of oral vinorelbine administered metronomically in patients with advanced breast cancer.

Methods: A series of meetings were held throughout Italy, and participants were asked how much they agreed with each of the several statements.

Results: The majority of oncologists agreed that the concept of the minimum biologically effective dose should be used for drugs administered metronomically. Over 50% agreed that metronomic vinorelbine is an option in first-line chemotherapy for patients with advanced breast cancer, including those with a terminal illness and the elderly, as well as in young and fit patients. Just over one-third of experts agreed that a combination of two chemotherapy agents instead of one is not desirable in metastatic breast cancer because of increased toxicity. Most experts agreed that the main aim of a first-line therapy is to control the disease over time and to preserve quality of life.

Conclusion: Metronomically administered oral vinorelbine, either as monotherapy or in combination with other drugs, is effective in the long-term treatment of patients with advanced breast cancer. The clinical profiles of patients should be carefully considered to determine the appropriate treatment strategy.     

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.     

Results of concurrent chemotherapy and hyperthermia in patients with recurrent cervical cancer after previous chemoradiation

Background: Concomitant hyperthermia has been shown to improve response rate after cisplatin in recurrent cervical cancer in previously irradiated patients. It is unclear whether similar response rates can be obtained in patients with a recurrence after previous platinum-containing chemoradiation.

Objective: This study aimed to evaluate the outcome of cisplatin-based chemotherapy with concurrent hyperthermia in patients with recurrent cervical cancer after radiotherapy and cisplatin.

Methods: Patients with recurrent cervical cancer after cisplatin-based chemoradiation or neoadjuvant chemotherapy followed by surgery and radiotherapy who were treated with concurrent platinum-based chemotherapy and hyperthermia were eligible for this retrospective analysis. All patients received six or eight weekly platinum-based chemotherapy cycles in combination with six or eight weekly hyperthermia sessions. The time-to-event variables were estimated using Kaplan-Meier analysis. P-values less than 0.05 were considered significant.

Results: All 38 evaluable patients were selected from the hyperthermia database in the Academic Medical Centre (Amsterdam) and the Erasmus Medical Centre (Rotterdam). Mean age at relapse was 45.7 years (range 27–74). Median time to recurrence after first-line treatment was 15 months. A total of 27 patients had a local and/or regional recurrence; 11 had disease beyond the pelvis. All planned courses of cisplatin chemotherapy and hyperthermia were administered in 17/38 patients. Median follow-up was 6.5 months. One patient died during treatment; response rate was 4/37 (14%), with one complete response. Overall survival was 23% at 12 months and 4% at 24 months. The incidence of grade 3–4 haematological complications did not exceed 10%.

Conclusion: In this retrospective study, concurrent cisplatin and hyperthermia after first-line cisplatin-containing chemoradiation showed poor response and survival. We do not recommend this treatment for recurrence of locally advanced cervical 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.     

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.     

First-line chemotherapy with pemetrexed plus cisplatin for malignant peritoneal mesothelioma

Background: Mesothelioma of peritoneal origin has wider variation in treatment outcomes than mesothelioma of pleural origin, likely because peritoneal mesothelioma comprises borderline malignant variants and aggressive malignant peritoneal mesothelioma (MPeM). This study retrospectively evaluates the efficacy of first-line systemic pemetrexed and cisplatin chemotherapy in MPeM.

Research design and methods: Twenty-four patients with histologically proven MPeM were treated with pemetrexed plus cisplatin as a first-line systemic chemotherapy. The response was evaluated radiologically according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Twenty-two patients underwent ¹⁸F-fluorodeoxyglucose positron emission tomography/(FDG-PET)/computed tomography(CT) at baseline, and 13 were eligible for metabolic assessment.

Results: Two complete responses and 9 partial responses were achieved. Overall response rate and disease control rate were 45.8% and 91.7%, respectively. Median progression-free survival and median overall survival were 11.0 months and 15.8 months, respectively. Wet- type MPeM had significantly longer survival (40.9 months median) than other clinical types (15.5 months) (P = 0.045). The baseline maximum standardized uptake value in 22 patients was 8.93 (range, 2.5–16.77).

Conclusions: Systemic pemetrexed plus cisplatin is active for MPeM. Disparity with the outcome of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) needs to receive more emphasis, since peritoneal mesothelioma has a 5-year survival rate of 50%.     

Prognostic factors for uterine adenosarcoma: a review

Introduction: Uterine adenosarcoma is a rare tumor with both epithelial and stromal components. Standard treatment is total abdominal hysterectomy and bilateral salpingo-oophorectomy. There is no defined role for adjuvant or neoadjuvant chemotherapy or radiation. There is a misconception that this is an indolent, low-grade sarcoma. In fact, at least 50% of patients will develop disease recurrence. Establishing prognostic factors is of paramount importance.

Areas covered: This article reviews the current literature regarding adenosarcoma prognostic factors from case reports, case series, and retrospective series. An extensive review of the literature was undertaken via PubMed and Medline searches, relevant articles are included in this review.

Expert commentary: The most important prognostic factors of uterine adenosarcoma are age, presence of sarcomatous overgrowth, presence of myometrial invasion, presence of lymphovascular invasion, and lymph node involvement. These factors can be used to accurately prognosticate for uterine adenosarcoma patients. Patients at low risk of disease recurrence can be identified. These patients require observation alone. Patients at high risk of disease recurrence can be identified and are candidates for aggressive therapy with adjuvant chemotherapy to reduce the risk of disease recurrence.     

Total pathological complete response versus breast pathological complete response in clinical trials of reference and biosimilar trastuzumab in the neoadjuvant treatment of breast cancer

Introduction: Trastuzumab is a key drug in the neoadjuvant treatment of breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2). Pathological complete response (pCR) is commonly used as an endpoint in neoadjuvant clinical trials of trastuzumab as evidence suggests it may be a surrogate for long-term survival. Several biosimilar candidates of originator or ‘reference’ trastuzumab are in development and have used pCR as a primary endpoint to assess therapeutic equivalence between treatments. The exact definition of pCR has varied across studies.

Areas covered: Here we look at the clinical relevance of pCR and compare rates of total pCR (defined as ypT0/is ypN0) and breast pCR (defined as ypT0/is) in clinical trials of reference and biosimilar trastuzumab.

Expert commentary: In order to evaluate the efficacy of neoadjuvant systemic therapies in a uniform way, standardization of trial endpoints is necessary. Future studies in HER2-positive breast cancer should include full assessment of the breast and lymph node basin before and after neoadjuvant systemic therapy, and the use of total pCR as the primary outcome.     

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.