The role of surgery in recurrent endometrial cancer

Introduction: Endometrial cancer is a common gynecologic malignancy in the United States, and the recurrence rate depends on the disease stage at diagnosis. Recurrence can affect several areas and follow different patterns.

Areas covered: The role of surgery at the time of recurrence is not clearly defined. In this review, we fully describe the current evidence available. In particular, we describe how surgical treatment might be recommended for 1) vaginal or pelvic recurrences; 2) retroperitoneal or localized intra-abdominal recurrence, when a maximal cytoreductive effort is more likely to be successful; or 3) isolated distant recurrences when microscopically tumor-free margins can be achieved.

Expert commentary: Cases should be evaluated individually, considering factors such as comorbidities, risks of intervention, and impact of treatment on quality of life.     

The safety and efficacy of bevacizumab in the treatment of patients with recurrent or metastatic cervical cancer

Introduction: Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF). (Avastin; Genetech, Inc, San Francisco, CA) Angiogenesis is blocked by the binding of bevacizumab to VEGF, inhibiting the binding of this ligand to the VEGF receptor. On 14 August 2014 the Food and Drug Administration (FDA) approved use of bevacizumab in persistent, recurrent, or metastatic cervical cancer.

Areas covered: Herein we review pharmacodynamics and kinetics, clinical data and treatment-related toxicities of bevacizumab in the treatment of metastatic, recurrent or persistent cervical cancer. Additionally, future areas of development are reviewed.

Expert commentary: Anti-angiogenesis therapy with bevacizumab is central to metastatic, persistent, and recurrent cervical cancer treatment. Additional anti-angiogenesis drugs are in development. Future studies will need to establish if the addition of multiple anti-angiogenesis agents or anti-angiogenesis in combination with immunotherapy is more effective than bevacizumab with chemotherapy.     

Understanding dendritic cell immunotherapy in ovarian cancer

Introduction: Approximately eighty percent of patients with ovarian cancer are diagnosed with advanced disease. Even with cutting edge surgical techniques and the best regimens of standard therapies most patients relapse and die of drug resistant disease within five years of diagnosis. Dendritic cell (DC) immunotherapy can induce anti-tumor T cell immunity in patients and holds great potential in the era of modern anti-cancer treatment.

Areas Covered: This review outlines critical factors regulating the outcome of DC immunotherapy in ovarian cancer, summarizes the important findings in ovarian cancer DC clinical trials, and discusses new directions which may improve the effectiveness of DC immunotherapy.

Expert Commentary: Administration of DC vaccines with other forms of immunotherapy may enhance the efficacy of these treatments, ultimately increasing cures for this disease.     

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.     

Optimizing treatment in recurrent epithelial ovarian cancer

Introduction: Optimal management of recurrent ovarian cancer (ROC) remains an area of uncertainty. An estimated 85% of patients with epithelial ovarian cancer who achieve a full remission following first-line therapy will develop recurrent disease and median survival for these patients’ ranges from 12 months to 24 months. Many patients receive several lines of treatment following recurrence and, although each subsequent line of therapy is characterized by shorter disease-free intervals, decisions about the most appropriate treatment is complex.

Areas covered: This review focuses on chemotherapy, surgery and emerging biologic agents that present a therapeutic option for patients with ROC.

Expert commentary: Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrence treated with a platinum-based agent. For patients whose cancer progresses after platinum retreatment and for those with platinum-resistant disease, numerous other non-platinum combination and targeted therapies have been shown to be effective in palliating cancer-related symptoms and extending life.     

Therapeutic approaches for refractory germ cell cancer

Introduction: Most germ cell cancer patients with metastatic disease are cured by cisplatin-based combination chemotherapy. 30% of metastatic patients will develop relapse or progress despite adequate first-line treatment and will require salvage therapy, with about 10% of metastasized patients ultimately developing platinum-resistant and fatal disease.

Areas covered: Based on a comprehensive literature search of MEDLINE, EMBASE and conference proceedings of ESMO, ASCO and EAU meetings, this review provides an overview on current and potential future treatment options for platinum-refractory germ cell cancer patients including cytostatics and molecularly targeted therapies.

Expert commentary: Treatment of platinum-refractory disease remains challenging and long-term survival is rarely achieved despite multimodal treatment approaches. Targeted treatment approaches do not yet play a role in the treatment of platinum-refractory disease due to lacking efficacy in small, unselected clinical trials. Inclusion of patients into clinical trials is strongly recommended.     

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.     

Further insight into prognostic factors in endometrial cancer: the new serum biomarker HE4

Introduction: Endometrial cancer (EC) is one of the most common gynecological cancer worldwide. To date, no good markers are routinely used in clinical practice for prognosis and monitoring.

Areas covered: During the last years, an increasing interest in literature has been growing on HE4 (Human epididimis 4). Therefore, we aimed to gather all the evidence reported in literature analysing the potential prognostic value of HE4, compared to the well know tumor’s features (histological type and grade, stage of disease, depth of myometrial invasion, lymphovascular space involvement and cervical involvement).

Expert commentary: The analysis of data suggests that HE4 seems to have a good performance in prognosis and monitoring of the disease, helping to schedule the appropriste timing of imaging and surgery in a more individualized fashion. However, these findings surely require a validation in a larger cohorts of patients. Probably, in the next five years, prospective randomized trials will be performed to confirm the prognostic role of HE4 in EC and to find a tailored EC management strategy.     

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.     

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.     

The role of alectinib in the treatment of advanced ALK-rearranged non-small-cell lung cancer

Introduction: The identification of anaplastic lymphoma kinase (ALK) gene rearrangements in subsets of non-small cell lung cancer patients has provided with unparalleled opportunities to hinder the progression of this disease through targeting the activity of these specific molecules. Unfortunately most patients develop disease progression in less than a year of treatment with crizotinib, the first-generation ALK-inhibitor.

Areas covered: We review the resistance mechanisms to ALK inhibitors as well as an overview of the clinical activity of the alectinib, a second generation ALK inhibitor.

Expert commentary: Second generation ALK inhibitors as alectinib and ceritinib can overcome crizotinib-resistant mutations and improve central nervous system control. Novel third-generation inhibitors and combination of agents give hope of achieving an even longer disease control in the next decade.     

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.     

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.     

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.     

Chemoprevention of colorectal cancer in inflammatory bowel disease

Introduction: Patients with inflammatory bowel disease are at an increased risk of colorectal cancer when compared to the general population. Chronic inflammation is thought to be the underlying cause, and medications that reduce inflammation have the potential to reduce the risk of colorectal cancer.

Areas covered: After conducting a PubMed search for relevant literature, we examined several classes of medications that have been studied as potential chemopreventive agents. These include 5-aminosalicylates, thiopurines, tumor necrosis factor antagonists, ursodeoxycholic acid, NSAIDs, and statins.

Expert commentary: While each class of medications has some data to support its use in chemoprevention, the majority of the evidence in each case argues against the routine use of these medications solely for a chemopreventive benefit.     

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.     

Risk of cardiac death among cancer survivors in the United States: a SEER database analysis

Background: Population-based data on the risk of cardiac death among cancer survivors are needed. This scenario was evaluated in cancer survivors (>5 years) registered within the Surveillance, Epidemiology and End Results (SEER) database.

Methods: The SEER database was queried using SEER*Stat to determine the frequency of cardiac death compared to other causes of death; and to determine heart disease-specific and cancer-specific survival rates in survivors of each of the 10 most common cancers in men and women in the SEER database.

Results: For cancer-specific survival rate, the highest rates were related to thyroid cancer survivors; while the lowest rates were related to lung cancer survivors. For heart disease-specific survival rate, the highest rates were related to thyroid cancer survivors; while the lowest rates were related to both lung cancer survivors and urinary bladder cancer survivors. The following factors were associated with a higher likelihood of cardiac death: male gender, old age at diagnosis, black race and local treatment with radiotherapy rather than surgery (P < 0.0001 for all parameters).

Conclusion: Among cancer survivors (>5 years), cardiac death is a significant cause of death and there is a wide variability among different cancers in the relative importance of cardiac death vs. cancer-related death.     

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.     

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.     

Tackling non-metastatic castration-resistant prostate cancer: special considerations in treatment

Introduction: Prostate cancer (PCa) is currently the second most common cancer affecting men worldwide. Metastatic castration-resistant prostate cancer (mCRPC) is the incurable form of PCa, carrying the poorest prognosis, and can develop from non-metastatic CRPC (M0 CRPC). CRPC is defined as progression of the disease with castrate level testosterone levels, achieved with primary androgen deprivation therapy (ADT). M0 CRPC is a highly heterogeneous disease process lacking clear standard of care therapies.

Areas covered: In this review, a broad literature search was undertaken to explore data available for therapeutic options and guidelines in the management of M0 CRPC.

Expert commentary: While there are compelling data for various therapeutics for the treatment of M0 CRPC, no clear standard of care is apparent at this time. Furthermore, technological advances in imaging may have a significant impact on this future of this disease state.