Curr. Oncol., Volume 19, Issue s1 (June 2012) – 21 articles

The number of prostate cancer survivors is rapidly growing in the Western world. As a result of better oncologic outcomes, more patients are living longer with the adverse effects of treatment, which can be both functional and psychological. Clinicians, in an era of shared decision-making, must not only cure the cancer, but also ensure that, after treatment, their patients experience the best quality of life and minimal post-treatment decisional regret. To participate in the decision-making process, men and their involved partners and family need to fully understand the relative benefits and harms of prostate cancer treatments. Patient preference studies indicate that men with prostate cancer are not well informed. Decision- making aids are a positive treatment adjunct both to convey information and to allow patients to explore their own beliefs and values during the decision-making process. The evidence suggests that decision-making aids better prepare patients for involvement in treatment decisions, but further studies are required to investigate the relationship between the use of decision-making aids and post-treatment decisional regret in prostate cancer. Full article

Treatment options for castration-resistant prostate cancer (CRPC) have evolved since the start of the 2000s, with most of the new effective therapies appearing since 2010. In 2004, docetaxel was the first chemotherapeutic agent to improve survival in CRPC, but little else was available once patients recurred. Since 2010, four new options have been shown to improve survival in patients with refractory or recurring disease after docetaxel. In the management of bone metastases, two bone-targeted therapies have been shown to reduce the risk of bone complications, and they are part of the overall management strategy in CRPC patients. Therapeutic options before chemotherapy have shown promising results and may soon become available in Canada. The present article reviews the treatment options that have shown to be effective in CRPC and also some of the ongoing work in the field. Full article

Since the year 2000, tremendous progress has been made in the understanding of castration-resistant prostate cancer (CRPC), a disease state now recognized to retain androgen receptor (AR)—dependency in most cases. That understanding led to the rational design of novel therapeutic agents targeting hormonal pathways in metastatic crpc. Two new drugs—the CYP17 inhibitor abiraterone acetate and the potent AR antagonist enzalutamide—were recently shown to prolong overall survival after chemotherapy treatment in patients with metastatic disease, with the former agent also demonstrating impressive activity in the pre-chemotherapy setting. Other new drugs targeting the AR—as well as drugs targeting heat shock proteins that protect cytoplasmic AR from degradation—are currently undergoing clinical development. This review brief ly describes the molecular mechanisms underlying castration resistance and hormonal dependence in prostate tumours and summarizes the current ongoing and completed clinical trials that are targeting hormonal pathways in metastatic crpc. Potential mechanisms of resistance to these novel hormonal agents are reviewed. Finally, future research directions, including questions about drug sequencing and combination, are discussed. Full article

Purpose: Intermittent androgen deprivation is increasingly used as an alternative to continuous life-long androgen deprivation therapy for men with advanced or recurrent prostate cancer. Recent Findings: Two recent phase III trials have clarified the benefits of intermittent therapy. The Canadian-led pr.7 trial in men with nonmetastatic disease and prostate-specific antigen recurrence after definitive local therapy showed that intermittent therapy resulted in survival equivalent to that with continuous therapy, with significant improvements in quality of life. Patients on intermittent therapy experienced improved bone health, fewer metabolic and hematologic disturbances, fewer hot flashes, and improved sexual function. In men with metastatic disease, the data are less clear. The long-awaited results of the Southwest Oncology Group 9346 trial, comparing intermittent with continuous therapy in metastatic disease, showed no difference in overall survival. Post hoc stratification analysis showed a worse outcome in patients with “minimal” metastatic disease, and no difference in those with widespread bone metastases. The significance of that observation is in dispute. The present review also addresses practical issues in the use of intermittent therapy, including patient selection, follow-up, and therapy cycling. Summary: The recent results of randomized clinical trials now establish that intermittent androgen deprivation therapy is an approach that should be considered the standard of care in most patients with nonmetastatic prostate cancer requiring hormonal therapy and in selected patients with metastatic disease. Key Points: (1) Level I evidence supports the oncologic equivalence of intermittent compared with continuous androgen blockade in men with biochemical failure. (2) Compared with continuous androgen deprivation, intermittent therapy demonstrates improved quality of life and fewer side effects. (3) Patient selection for intermittent therapy is important to maintain good oncologic results. (4) Monitoring of prostate-specific androgen response and duration of off-treatment intervals allow for stratification of patients by risk of progression. Full article

Prostate cancer is a common malignancy worldwide, and in Canada, it is the most frequently diagnosed cancer in men. The stratification of prostate cancer into risk categories has allowed for improved counselling of patients and provides guidance for treatment selection. However, the exact definition of high-risk prostate cancer remains controversial, and that lack of consensus remains a barrier to assessing available data from various institutions and from clinical trials. The proportion of patients with locally advanced high-risk disease has fallen in the last 20 years largely because of screening for prostate-specific antigen, but management in this population continues to be an important clinical problem. A factor that has emerged in recent years is the importance of local disease control, with data from multiple randomized trials suggesting that local therapy improves progression-free survival, diseasefree survival, and overall survival. Further research in this population is necessary to improve outcomes. Full article

It was with a great deal of pride that I accepted to be the guest editor of this Current Oncology supplement dedicated to prostate cancer. It is especially exciting to realize that the whole supplement was able to be based on data that has only recently been published or that is still unpublished. [...] Full article

PE vte Objective: We aimed to determine which combination of physical examination (PE), mammography (MAM), and ultrasonography (US) would optimize breast cancer detection in China. Methods: We conducted a trial of screening with pe, mam, and us among Chinese women 25 years of age and older. All initial screenings using the three modalities were completed within 30 days of each other, and subjects were followed approximately 1 year later. The performances of the three screening methods used alone, in parallel, or in series were compared. Data were analyzed using exact confidence intervals (CIS) and the McNemar test. Results: Between March 2009 and July 2011, 3028 eligible women completed all study examinations. At a mean follow-up of 1.3 years, 33 breast cancers were identified in the study population. Mammography detected 28 cancers; US, 24 cancers; and PE, 22 cancers. During the follow-up period, 2 false-negative cases occurred clinically. The highest sensitivity for breast cancer screening (93.9%) was achieved by paralleling MAM with US, but came at the cost of a higher recall rate (12.15%). Using us alone at the first stage, followed by mam when indicated, offered high specificity (99.4%) and the lowest recall rate (1.82%), which were not reached at the expense of sensitivity (84.8%). Used in series, us and mam achieved a sensitivity similar to that for the same modalities used in parallel (McNemar p > 0.05). Conclusions: Taking limited health resources into consideration, the strategy of screening with US alone at the first stage, followed by mam when indicated, may optimize breast cancer detection in most regions of China. Full article

Background and Objectives: The present study evaluated the potential role of lysophosphatidic acid receptors (LPARS) in processes leading to local invasiveness and metastasis in Chinese pancreatic carcinoma. Methods: Real-time reverse-transcriptase polymerase chain reaction and Western blot analysis were used to detect expression of LPARS in tumour and adjacent non-tumour tissues from patients with surgically resected pancreatic carcinoma. Surgical specimens from 50 patients were examined for relative expression of each receptor’s messenger RNA (mRNA) and protein. Findings were analyzed for correlations with tumour size, pathologic classification, clinical stage, and infiltration of capsule and lymphonodi. Results: Increased levels of mrna of LPARS (LPAR1 ≈ LPAR3 < LPAR2) were found in the pancreatic cancer tissues examined. Low levels of transcripts for LPAR1, LPAR2, and LPAR3 receptors were detectable in adjacent non-tumour tissues. The difference in LPAR1 protein expression between tumour and adjacent non-tumour tissues does not seem significant, but the signals of LPAR2 expression in pancreatic cancer tumour tissues were significantly amplified compared with those in adjacent non-tumour tissues. Tumour and adjacent non-tumour tissues both weakly expressed LPAR3 protein with no statistical difference. However, expression of LPAR1, LPAR2, and LPAR3 showed an obvious correlation with infiltration of capsule cells, surrounding lymphonodi, and specific histopathologic features. Conclusions: Lysophosphatidic acid receptor is a promising indicator for pancreatic cancer, and our findings suggested that LPAR2 might be a potential target for clinical treatment of pancreatic cancer. Full article

Background: Patients with malignant ascites (MA) usually experience poor quality of life, and treatment of this symptom remains a challenge. Oxidative stress, which can cause oxidative damage to DNA, plays a pivotal role in carcinogenesis; however, the relationship between oxidative stress and DNA damage to tumour-associated lymphocytes (TALS) in MA is unclear. Methods: We measured the total antioxidant capacity (TAC) of plasma and MA supernatant in 31 cancer patients with MA, and we used a comet assay to assess DNA damage to both peripheral blood mononuclear cells (PBMCS) and TALS. Measurements in age- and sex-matched healthy volunteers were used as controls. Results: The TAC of plasma was remarkably lower in cancer patients (9.73 ± 1.96 U/mL) than in healthy control subjects (11.31 ± 1.50 U/mL, p < 0.001). The TAC of MA supernatant (6.34 ± 1.57 U/mL) was significantly lower than that of plasma in cancer patients (7.42 ± 1.36 U/mL, p < 0.001). The comet percentage of PBMCS was higher in cancer patients (17.26% ± 6.04%) than in healthy control subjects (9.44% ± 4.47%, p < 0.01). In cancer patients, the comet percentage of TALS (36.14% ± 17.85%) was significantly higher than that of PBMCS (17.26% ± 6.04%, p < 0.001). In cancer patients with MA, negative correlations were observed between plasma TAC and DNA damage to PBMCS (r = −0.505, p = 0.004) and between the TAC of ma supernatant and the comet percentage of TALS (r = −0.588, p = 0.001). Conclusions: Results indicate the presence of significant oxidative damage to the DNA of lymphocytes in peripheral blood and ascites from patients with MA, being especially higher in the cells from ascites. The lower TAC of MA supernatant may be related to a higher degree of DNA damage to TALS. The present study suggests that an oxidant–antioxidant imbalance may be one of the mechanisms leading to the DNA damage detected in peripheral blood and local TALS in patients with MA, which may provide a novel approach to the treatment of MA. Full article

Objective: Many scientific studies have shown that Asparagus officinalis has an antitumour effect and enhances human immunity, but the active components and the antitumour mechanisms are unclear. We investigated the effects of saponins isolated from Asparagus on proliferation and apoptosis in the human hepatoma cell line HepG2. Methods: HepG2 cells were treated with varying concentrations of Asparagus saponins at various times. Using mtt and flow cytometry assays, we evaluated the effects of Asparagus saponins on the growth and apoptosis of HepG2 cells. Transmission electron microscopy was used to observe the morphology of cell apoptosis. Confocal laser scanning microscopy was used to analyze intracellular calcium ion concentration, mitochondrial permeability transition pore (MPTP), and mitochondrial membrane potential (MMP). Spectrophotometry was applied to quantify the activity of caspase-9 and caspase-3. Flow cytometry was used to investigate the levels of reactive oxygen species (ROS) and pH, and the expressions of Bcl2, Bax, CytC, and caspase-3, in HepG2 cells. Results: Asparagus saponins inhibited the growth of HepG2 cells in a dose-dependent manner. The median inhibitory concentration (IC₅₀) was 101.15 mg/L at 72 hours. The apoptosis morphology at 72 hours of treatment was obvious, showing cell protuberance, concentrated cytoplasm, and apoptotic bodies. The apoptotic rates at 72 hours were 30.9%, 51.7%, and 62.1% (for saponin concentrations of 50 mg/L, 100 mg/L, 200 mg/L). Treatment with Asparagus saponins for 24 hours increased the intracellular level of ROS and Ca²⁺, lowered the pH, activated intracellular MPTP, and decreased MMP in a dose-dependent manner. Treatment also increased the activity of caspase-9 and caspase-3, downregulated the expression of Bcl2, upregulated the expression of Bax, and induced release of CytC and activation of caspase-3. Conclusions: Asparagus saponins induce apoptosis in HepG2 cells through a mitochondrial-mediated and caspase-dependent pathway, suggesting that they may be a potent agent for the treatment of hepatocellular carcinoma. Full article

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death globally, with most patients presenting with non-curable disease. Platinum-based doublet chemotherapy has been the cornerstone of treatment for patients with advanced-stage disease and has resulted in a modest increase in overall survival (on the order of an incremental 2 months increased survival per decade) and quality of life. Improved knowledge of the molecular signalling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics, thus changing the treatment paradigm for many NSCLC patients. In this review, we present a summary of many of the currently investigated NSCLC targets, discuss their current clinical trial status, and provide commentary as to the likelihood of their success making a positive impact for NSCLC patients. Full article

Lung cancer has become a leading cause of cancer-related death in the world. Patient survival has improved with the introduction of new chemotherapy regimens and targeted drugs, but still, because of tumour progression or deterioration in performance status, a high percentage of patients do not receive more than one line of treatment. Given this situation, studies of maintenance therapies have begun, with results that have led to the clinical use of various drugs in a maintenance scenario. Additionally, results obtained in various clinical trials have raised the question of personalized approaches based on the clinical, pathologic, and molecular features of the cancer—not only in the initial approach, but also in the context of maintenance. Overall, the survival benefit seen with maintenance treatment has introduced a new therapy option that should be considered and discussed with patients, and (given the controversies that currently remain) chosen based on the preferences of patients and physicians. Full article

Targeting of the epidermal growth factor receptor (EGFR) pathway has become routine practice in the treatment of lung carcinoma. As more health authorities approve targeted compounds in a variety of treatment lines, use of this approach is expected only to increase. Gefitinib, an oral tyrosine kinase inhibitor (TKI), is approved by Health Canada in the first-line setting of advanced non-small-cell lung carcinoma (NSCLC) for tumours that harbour the EGFR gene mutation. Erlotinib, another TKI, is currently approved in advanced NSCLC in the second- and third-line settings. The side-effect profile of this class of drugs is unique. Hematologic toxicity is seldom seen. The most frequent side effects are rash and diarrhea. Although no randomized trials have addressed treatment of the side effects of this class of drugs, some basic principles of management have been agreed on and can likely improve patient compliance and decrease inappropriate dose reduction. The prognostic and predictive implications of side effects are also evolving. Finally, the ALK fusion mutation is being recognized as a mutation driver. The use of crizotinib (again, a TKI) in this setting awaits approval. The side-effect profile of crizotinib is interesting and is also reviewed here. Full article

Metastatic non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality in Canada. Although treatment outcomes in advanced disease remain modest, with paradigm shifts in the approach to treatment, they are steadily improving. Customizing treatment based on histology and molecular typing has become the standard of care. EGFR genotyping and pathology subtyping should be considered routine in new diagnoses of metastatic NSCLC. Treatment options for those with somatic EGFR activating mutations include gefitinib until progression, followed by standard chemotherapy. For patients with wild-type EGFR, or in patients whose EGFR genotype is unknown, platinum-based chemotherapy remains the first-line standard, with single-agent chemotherapy as an option for older patients and those who are unfit for platinum-doublet therapy. Patients with nonsquamous histology may receive treatment regimens incorporating pemetrexed or bevacizumab. In patients with squamous cell carcinoma, the latter agents should be avoided because of concerns about enhanced toxicity or decreased efficacy. Second-line chemotherapy is offered to a selected subgroup of patients upon progression and may include pemetrexed in non-squamous histology and docetaxel or erlotinib (or both) in all histologies. Currently, only erlotinib is offered as a third-line option in unselected NSCLC patients after failure of first- and second-line chemotherapy. Maintenance therapy is emerging as a new option for patients, as are targeted therapies for particular molecular subtypes of NSCLC, such as crizotinib in tumours harbouring the EML4–ALK gene rearrangement. Full article

Non-small-cell lung cancer (NSCLC) constitutes about 85% of all lung cancers. Approximately 50% of patients diagnosed with NSCLC present with advanced disease (stage III or IV) that is not amenable to curative treatment. The number of patients with stage IIIB or IV disease who are alive at 1 year after diagnosis has increased from 10% in the untreated population in the early 1980s to 50% in patients with a good performance status receiving treatment today. However, those statistics remain dismal, and the two dominant reasons are the large number of patients diagnosed with advanced-stage disease and the observed primary or secondary resistance to current therapies. The present article addresses the question of drug resistance in lung cancer, focusing on subjects that are currently topical and under intense scrutiny. Full article

New drugs such as pemetrexed, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, and the Alk inhibitor crizotinib have recently enabled progress in the management of advanced non-small-cell lung cancer (NSCLC). More drugs, especially Met inhibitors, will follow. However, the benefits of these agents are not uniform across the spectrum of NSCLC, and optimizing their utility requires some degree of subgrouping of NSCLC by the presence or absence of certain biomarkers. The biomarkers of current or imminent value are EGFR and KRAS mutational status, ALK rearrangements, and MET immunohistochemistry. As a predictor of benefit for anti-EGFR monoclonal antibodies, EGFR immunohistochemistry is also of potential interest. Some of the foregoing biomarkers (EGFR, ALK, MET) are direct drivers of the malignant phenotype. As such, they are, quite rationally, the direct targets of inhibitory drugs. However, KRAS, while definitely a driver, has resisted attempts at direct pharmacologic manipulation, and its main value might lie in its role as part of an efficient testing algorithm, because KRAS mutations appear to exclude EGFR and ALK mutations. The indirect value of KRAS in determining sensitivity to other targeted agents or to pemetrexed remains controversial. The other biomarkers (EGFR, ALK, MET) may also have indirect value as predictors of sensitivity to chemotherapy in general, to pemetrexed specifically, and to radiotherapy and molecularly targeted agents. These biomarkers have all enabled the codevelopment of new drugs with companion diagnostics, and they illustrate the paradigm that will govern progress in oncology in the immediate future. However, in NSCLC, the acquisition of sufficient biopsy material remains a stubborn obstacle to the evolution of novel targeted therapies. Full article

In recent years, better understanding of the molecular biology of non-small-cell lung carcinoma (NSCLC) has led to a revolution in the work-up of these neoplasms. As a pathology diagnosis, “NSCLC” without further attempt at subclassification is no longer accepted as a standard of care; separating squamous cell carcinoma from adenocarcinoma and large-cell carcinoma carries implications for prognosis and treatment decisions. Currently, detection of the presence in NSCLC of mutations involving the epidermal growth factor receptor (EGFR) gene and fusion of the N-terminal portion of the protein encoded by EML4 (echinoderm microtubule-associated protein-like 4 gene) with the intracellular signaling portion of the receptor tyrosine kinase encoded by ALK (anaplastic lymphoma kinase gene)—that is, EML4–ALK—and variants has become routine in many centres because patients having tumours harbouring such alterations might benefit from tyrosine kinase inhibitors as part of their treatment regimen. The purpose of the present review is to highlight important aspects of the screening for molecular derangements in NSCLC and to briefly discuss the emergence of possible future biomarkers. Full article

Advances in molecular biology are improving the understanding of lung cancer and changing the approach to treatment. A satisfactory biopsy that allows for histologic characterization and mutation analysis is becoming increasingly important. Most patients with lung cancer are diagnosed at an advanced stage, and diagnosis is often based on a small biopsy or cytology specimen. Here, we review the techniques available for making a diagnosis of lung cancer, including bronchoscopy, ultrasound-guided bronchoscopy, mediastinoscopy, transthoracic needle aspiration, thoracentesis, and medical thoracoscopy. We also discuss the indications, complications, and tissue yields of those techniques, especially as they pertain to testing for molecular markers. Full article

Historically, a simple approach to the treatment of non-small-cell lung cancer (NSCLC) was applicable to nearly all patients. Recently, a more complex treatment algorithm has emerged, driven by both pathologic and molecular phenotype. This increasing complexity underscores the importance of a multidisciplinary team approach to the diagnosis, treatment, and supportive care of patients with NSCLC. A team approach to management is important at all points: from diagnosis, through treatment, to end-of-life care. It also needs to be patient-centred and must involve the patient in decision-making concerning treatment. Multidisciplinary case conferencing is becoming an integral part of care. Early integration of palliative care into the team approach appears to contribute significantly to quality of life and potentially extends overall survival for these patients. Supportive approaches, including psychosocial and nutrition support, should be routinely incorporated into the team approach. Challenges to the implementation of multidisciplinary care require institutional commitment and support. Full article