Real-World Safety and Effectiveness of a Bevacizumab Biosimilar (ABP 215) in Metastatic Colorectal Cancer Patients in Canada.

BACKGROUND: ABP 215 is a biosimilar to the reference product, bevacizumab, and was one of the first biosimilars approved by Health Canada for the first-line treatment of metastatic colorectal cancer (mCRC). This study aimed to address gaps in real-world evidence (RWE) including patient characteristics, treatment safety (primary objective), and effectiveness (secondary objective) for first-line ABP 215 therapy in Canadian patients with mCRC. MATERIALS AND METHODS: Retrospective data were collected in 2 waves, at least 1 year (Wave 1) or 2 years (Wave 2) after commercial availability of ABP 215 at each participating site. RESULTS: A total of 75 patients from Wave 1 and 164 patients from Wave 2 treated with a minimum of 1 cycle of ABP 215 were included. At least one safety event of interest (EOI) was recorded for 34.7% of Wave 1 and 42.7% of Wave 2 patients. The median progression free survival (PFS) for Wave 1 and 2 patients were 9.47 (95% confidence interval [CI]: 6.71, 11.90) and 21.38 (95% CI: 15.82, not estimable) months, respectively. Median overall survival was not estimable for Wave 1 and was 26.45 months for Wave 2. CONCLUSION: The safety and effectiveness of ABP 215 observed in this real-world study were comparable to clinical trial findings and to other RWE with longer PFS in the current study.

Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.

BACKGROUND: Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. METHODS: We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. RESULTS: Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). CONCLUSIONS: Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).

Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: the Princess Margaret IMPACT/COMPACT trial.

BACKGROUND: The clinical utility of molecular profiling of tumor tissue to guide treatment of patients with advanced solid tumors is unknown. Our objectives were to evaluate the frequency of genomic alterations, clinical "actionability" of somatic variants, enrollment in mutation-targeted or other clinical trials, and outcome of molecular profiling for advanced solid tumor patients at the Princess Margaret Cancer Centre (PM). METHODS: Patients with advanced solid tumors aged ≥18 years, good performance status, and archival tumor tissue available were prospectively consented. DNA from archival formalin-fixed paraffin-embedded tumor tissue was tested using a MALDI-TOF MS hotspot panel or a targeted next generation sequencing (NGS) panel. Somatic variants were classified according to clinical actionability and an annotated report included in the electronic medical record. Oncologists were provided with summary tables of their patients' molecular profiling results and available mutation-specific clinical trials. Enrolment in genotype-matched versus genotype-unmatched clinical trials following release of profiling results and response by RECIST v1.1 criteria were evaluated. RESULTS: From March 2012 to July 2014, 1893 patients were enrolled and 1640 tested. After a median follow-up of 18 months, 245 patients (15 %) who were tested were subsequently treated on 277 therapeutic clinical trials, including 84 patients (5 %) on 89 genotype-matched trials. The overall response rate was higher in patients treated on genotype-matched trials (19 %) compared with genotype-unmatched trials (9 %; p < 0.026). In a multi-variable model, trial matching by genotype (p = 0.021) and female gender (p = 0.034) were the only factors associated with increased likelihood of treatment response. CONCLUSIONS: Few advanced solid tumor patients enrolled in a prospective institutional molecular profiling trial were treated subsequently on genotype-matched therapeutic trials. In this non-randomized comparison, genotype-enrichment of early phase clinical trials was associated with an increased objective tumor response rate. TRIAL REGISTRATION: NCT01505400 (date of registration 4 January 2012).

Correlation of p16 status, hypoxic imaging using [18F]-misonidazole positron emission tomography and outcome in patients with loco-regionally advanced head and neck cancer.

INTRODUCTION: We investigated the relationship between hypoxia, human papillomavirus (HPV) status and outcome in head and neck squamous cell carcinoma. METHODS: Patients with stage III and IV head and neck squamous cell carcinoma treated on phase I and II chemoradiation trials with 70-Gy radiation combined with tirapazamine/cisplatin or cisplatin/fluorouracil (5FU), hypoxic imaging using [18F]-misonidazole positron emission tomography and known HPV status (by p16 immunohistochemistry) were included in this sub-study. Separate analyses were conducted to consider the impact of tirapazamine on HPV-negative tumours in the phase II trial. RESULTS: Both p16-positive oropharyngeal tumours and p16-negative head and neck squamous cell carcinoma tumours had a high prevalence of tumour hypoxia; 14/19 (74%) and 35/44 (80%), respectively. The distribution of hypoxia (primary, nodal) was similar. On phase II, trial patients with p16-negative hypoxic tumours had worse loco-regional control with cisplatin and 5FU compared with tirapazamine and cisplatin (P < 0.001) and worse failure-free survival (hazard ratio = 5.18; 95% confidence interval, 1.98-13.55; P = 0.001). Only 1 out of 14 p16-positive patients on the phase II trial experienced loco-regional failure. CONCLUSION: Hypoxia, as assessed by [18F]-misonidazole positron emission tomography, is frequently present in both p16-positive and negative head and neck cancer. Further research is required to determine whether hypoxic imaging can be used to predict benefit from hypoxia-targeting therapies in patients with p16-negative tumours.

Imaging of hypoxia with 18F-FAZA PET in patients with locally advanced non-small cell lung cancer treated with definitive chemoradiotherapy.

INTRODUCTION: For many cancers, tumour hypoxia is an adverse prognostic factor, and increases chemoradiation resistance; its importance in non-small cell lung cancer (NSCLC) is unproven. This study evaluated tumoural hypoxia using fluoroazomycin arabinoside ((18) F-FAZA) positron emission tomography (PET) scans among patients with locoregionally advanced NSCLC treated with definitive chemoradiation. METHODS: Patients with stage IIIA-IIIB NSCLC underwent (18) F-FAZA PET scans and (18) F-2-deoxyglucose (FDG)-PET scans within 4 weeks of commencing and 8 weeks following conventionally-fractionated concurrent platinum-based chemoradiation (60 Gy). Intra-lesional hypoxic volumes of the primary and nodal masses were compared with FDG-PET metabolic volumes. Baseline tumoural hypoxia was correlated with disease free survival (DFS). RESULTS: Seventeen patients underwent pre-treatment (18) F-FAZA PET and FDG-PET scans. Intra-lesional hypoxia was identified on 11 scans (65%). Baseline lesional hypoxic volumes were consistently smaller than FDG-PET volumes (P = 0.012). There was no statistical difference between the mean FDG-PET volumes in patients with or without baseline hypoxia (P = 0.38). Eight patients with baseline hypoxia had post treatment (18) F-FAZA scans and 6 of these (75%) had resolution of imageable hypoxia following chemoradiation. The DFS was not significantly different between the hypoxic or non-hypoxic groups (median 0.8 years and 1.3 years respectively, P = 0.42). CONCLUSIONS: Intra-lesional hypoxia, as detected by (18) F-FAZA PET, was present in 65% of patients with locally-advanced NSCLC and resolved in the majority of patients following chemoradiation. Larger studies are required to evaluate the prognostic significance of the presence and resolution of hypoxia assessed by PET in NSCLC.

Spirituality and use of complementary therapies for cure in advanced cancer.

OBJECTIVE: Complementary and alternative medicine (CAM) is frequently used by patients with advanced cancer, for a variety of reasons. We examined the use of CAM in this population, and associations of use for potential cure with spiritual faith and existential well-being. METHODS: Patients with advanced cancer on a palliative care unit completed a measure of spiritual well-being (existential well-being and faith), and a survey assessing complementary therapy use and reasons for such use. Information was also gathered on demographic data, previous cancer treatment, performance status, and symptom distress. Regression analyses assessed the association between the spirituality domains of existential well-being and faith, and the use of CAM for cure. RESULTS: Of 123 participants, 85% had used CAM, 42% with curative intent. More than 95% would consider future use of CAM, 48% for potential cure. Previous use for cure predicted current interest in using CAM for cure (p<0.0001). Spiritual faith was associated with previous (p<0.02) and interest in future use for cure (p<0.0001). Poor existential well-being was associated with interest in future use of CAM for cure (p=0.04). CONCLUSIONS: Interest in considering CAM for cure was relatively high in this group of inpatients on a palliative care unit, and was associated with increased spiritual faith and decreased existential well-being. Understanding factors associated with seeking CAM for cure may help health-care professionals to support and educate patients with advanced cancer.

Skeletal-related events (SREs) in breast cancer patients with bone metastases treated in the nontrial setting.

BACKGROUND: Clinical trials exploring bisphosphonate (BP) use in patients with bone metastases from breast cancer (BC) consistently state skeletal-related event (SRE) rates >50%. These trials predominantly include patients with bone only disease, and also frequently use screening radiology to detect asymptomatic fractures. Both these variables are likely to increase the incidence of SREs and thereby overestimate BP benefit. Little data exists regarding the natural history of SREs among patients treated with i.v. BPs in the nontrial setting. MATERIALS AND METHODS: Charts from two institutions (PMH and CVH) were reviewed to determine predictive risk factors for SRE development post i.v. pamidronate therapy in BC patients with bone metastases. RESULTS: Eighty-seven charts from 1999 to 2005 with complete outcome data were identified and reviewed. Pain was the most common presentation for bone metastases occurring in 49 women (56%). At diagnosis, 31 patients (35%) had bone only disease, and 57 (65%) had concomitant visceral metastases. Twenty-nine patients (33%) experienced an SRE prior to commencing BP treatment. Thirty-three women (38%) subsequently developed an SRE after a median of 5 BP treatments. SREs included radiation (79%), pathologic fractures (12%), and hypercalcemia (9%). On Cox regression, baseline history of osteoporosis (HR = 2.8; p = 0.045) and the presence of bone only disease (HR 3.0; p = 0.003) were predictive of SRE development. In patients with and without osteoporosis, median time to SRE was 305 and 866 days, respectively (p < 0.001). CONCLUSION: The frequency of SREs in this study was significantly lower than that reported in clinical trials of i.v. BP use. The lower incidence of SREs in this setting could affect sample size calculations for future event-driven BP trials. While the greatest risk of SREs despite BP therapy appears to be in patients with osteoporosis and with metastatic disease confined to the skeleton, further prospective study is merited to confirm and characterize the impact of these risk factors on SRE development.

Prevalence and severity of urogenital symptoms in postmenopausal women receiving endocrine therapy for breast cancer.

BACKGROUND: Data from randomized trials in postmenopausal women receiving endocrine therapy for breast cancer would suggest that the incidence of significant urogenital symptoms is around 40%. As there are inherent reporting biases associated with clinical trials, we sought to assess the prevalence, severity, and effect of urogenital side effects of endocrine therapy in the non-trial setting. PATIENTS AND METHODS: A cross-sectional survey study was undertaken and questionnaires used to assess vulvovaginal and urinary tract symptoms in a group of postmenopausal women receiving endocrine therapy for breast cancer. RESULTS: A total of 251 women were surveyed. Sixty-three percent (158) reported urogenital symptoms. Vaginal dryness was the most common vaginal symptom, occurring in 121 women (48%). This was rated as severe or very severe in 56 of 121 (46%). Thirty-one of 251 (12%) women experienced urinary symptoms. A total of 68 women (27%) had used some form of treatment for vaginal symptoms. Nine women (4%) had considered discontinuing treatment because of urogenital side effects. CONCLUSION: Urogenital side effects are common and often severe in women receiving endocrine therapy for breast cancer. The prevalence in this study was 63%, which is higher than that reported in the clinical trial literature. Less than one third of patients had used some form of treatment for these symptoms. This highlights the need for increased recognition and management of the urogenital side effects of estrogen deprivation therapy and raises the concern of the risk of non-compliance with potentially curative adjuvant therapy.

Examination of the mechanisms of osteolysis in patients with metastatic breast cancer.

The benefits of bisphosphonates (BPs) in reducing skeletal-related events (SREs) in patients with bone metastases has mainly been attributed to their potent osteoclast inhibiting effect. However, despite the use of modern systemic anticancer therapy including potent BPs, many patients with bone metastases continue to have SREs. An improved understanding of the fundamental mechanisms of bone destruction allows for further development of appropriate targeted treatments. In this study, archival paraffin-embedded bone metastases specimens from patients with metastatic breast cancer were examined for the presence of osteoclasts, expression of the receptor activator of nuclear factor kappaB (RANK), RANK Ligand (RANKL), osteoprotegerin (OPG) and vascular endothelial growth factor (VEGF). Histological specimens were available for primary breast cancer, lymph node metastases, normal breast and normal bone tissues for comparison. Bone metastasis specimens were available for 20 BP naïve patients and two BP-treated patients. Osteoclasts were significantly increased in the bone metastases of the BP naïve group compared to normal bone. No osteoclasts were detected in the BP-treated group. RANKL was predominantly expressed in osteoblasts and in the stromal elements of metastatic tissue. Conversely, RANK was present in osteoclasts of bone metastases and normal bone, as well as in tumor cells of metastatic lymph nodes and bone metastases. VEGF was strongly expressed in the control bone and bone metastases regardless of BP treatment. In summary, osteoclasts may not be the singular obligatory factor for osteolysis in bone metastases. An increased expression of RANKL in stromal tissue surrounding bone metastases, RANK in osteoclasts and VEGF may serve as future targeted therapies possibly in conjunction with bisphosphonates. The mechanisms for osteoclast expression and the expression of RANKL, RANK, OPG and VEGF merit further prospective analysis, particularly in the context of BP treatment and progressive bone metastases.

Should urogenital atrophy in breast cancer survivors be treated with topical estrogens?

Breast cancer survivors represent a unique patient population with a high prevalence of menopausal symptoms. Given the improved longevity of cancer patients, the consequences of menopause have become an increasingly important and challenging management issue. To date, considerable attention has been paid to the management of menopausal vasomotor symptoms and bone health among breast cancer patients. As a result, numerous nonhormonal treatment options have been developed for the management of these issues. The treatment of urogenital symptoms among this population is poorly understood and relatively understudied. Although systemic or topical estrogen replacement is the most effective method for treating hypoestrogenic urogenital symptoms, women with a prior diagnosis of breast cancer are cautioned from taking exogenous estrogens in order to avoid a potential contribution to recurrent breast cancer risk. This review focuses on the urogenital consequences of estrogen deprivation therapy in breast cancer patients and provides practitioners with a simple guide of current and future strategies for managing these symptoms.

Pharmacotherapy of bone metastases in breast cancer patients.

A diagnosis of bone metastases is often a devastating occurrence in breast cancer patients. Bone metastases are associated with increased morbidity as reflected through pain, reduced quality of life and skeletal-related events. This paper reviews the role of different pharmacotherapeutic agents in the treatment of bone metastases from breast cancer. Randomised controlled trials of osteoclast-inhibiting agents, that is the bisphosphonates, have shown significant patient benefit. The aims of bisphosphonates are to prevent and delay skeletal-related events, reduce bone pain and improve quality of life. However, there are some limitations with bisphosphonate treatment. Biochemical markers of bone turnover seem to be a promising tool in guiding bisphosphonate treatment and future research directions. Hopefully, patient management will be further improved as new agents become available such as denosumab, osteoprotegerin analogues and anti-angiogenic agents.