Should the Denosumab Metastasis Prevention Trial Change Practice for Men with Nonmetastatic Prostate Cancer?

Presentation of the Case

A 68-year-old man presents for management of prostate-specific antigen (PSA)-recurrent prostate cancer. His PSA level had become undetectable after prostatectomy for a high-risk localized tumor but began to rise 8 months later. This later led to the initiation of androgen deprivation therapy (ADT), which he has received for the last 3.5 years. After initially falling in response to ADT, his PSA level again trended steadily upward and is now 13.2. Restaging with an abdominal and pelvic computed tomography scan and a bone scan reveals no evidence of metastases. Is this man likely to benefit from denosumab?Bone is the most common site of metastasis for advanced prostate cancer. Bone metastases can cause considerable morbidity in the form of pain, pathologic fractures, and even spinal cord compression. Two bone-targeted therapies (zoledronic acid and denosumab) have been shown to reduce the risk for skeletal events (SREs) among men with bone metastases and a rising PSA level despite a testosterone level <50 ng/dL (castration-resistant prostate cancer [CRPC]). Until recently, no therapy had been shown to reduce the risk for developing bone metastases for the first time. Denosumab 147 was a randomized, placebo-controlled, phase III trial that enrolled 1,432 men with CRPC, no bone metastases, and at least one feature consistent with a high risk for the development of bone metastases (PSA ≥8 ng/mL or PSA doubling time ≤10 months). Participants were treated every 4 weeks with s.c. denosumab (120 mg) or placebo.The trial was positive because denosumab led to a 4.2-month significantly longer bone-metastasis-free survival time relative to placebo (median, 29.5 months versus 25.2 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73–0.98; p = .028) [1]. The time to first bone metastasis and risk for symptomatic bone metastasis were also significantly better with denosumab treatment. Dror Michaelson and Philip Saylor discuss the potential implications of this trial.

• Oncologist. 2012 Feb; 17(2): 288–290.
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2012 Feb; 17(2): 288–290. Published online 2012 Jan 20. doi: 10.1634/theoncologist.2011-0433

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Copyright and License information DisclaimerCopyright notice By M. Dror MichaelsonMassachusetts General HospitalOpen in a separate windowM. Dror MichaelsonThe pivotal trial of denosumab in men with nonmetastatic CRPC reported a significant benefit in preventing the development of metastasis [1]. Bone-targeted therapy in prostate cancer has a well established role, because the majority of morbidity and mortality attributable to prostate cancer is a function of the skeletal metastases that characterize this disease. In contrast to hormone therapy and cytotoxic chemotherapy, which focus on antineoplastic effects, bone-targeted therapies such as denosumab and zoledronic acid focus on impacting the bone milieu to produce benefit [2].A randomized, phase III study of zoledronic acid in men with metastatic CRPC demonstrated a significant benefit in preventing SREs, a composite outcome that combines symptomatic and asymptomatic pathologic fractures, the need for radiation therapy or surgery to treat bone metastases, spinal cord compression, and change in antineoplastic therapy to treat bone pain [3]. On the basis of this study, zoledronic acid became the accepted standard of care for bone-targeted therapy in men with metastatic CRPC.More recently, a double-blind, multicenter trial treated 734 men receiving androgen ablative therapy for nonmetastatic prostate cancer with either denosumab or placebo [4]. Significant improvements in bone mineral density were seen in the denosumab-treated men, along with a lower incidence of vertebral fractures (1.5% at 36 months, versus 3.9% in the placebo group; relative risk, 0.38; p = .006). Another important trial, published in 2011, compared denosumab with zoledronic acid among 1,900 men with metastatic CRPC [5]. The investigators found that the time to first SRE was 3.6 months longer in men treated with denosumab than in those treated with zoledronic acid (HR, 0.82; p = .008.). There was greater suppression of bone turnover markers in men treated with denosumab, whereas the overall adverse event rates were comparable in the two treatment arms. These studies further established a role for bone-targeted therapy, and in particular for denosumab, in men with advanced prostate cancer.The current landmark trial in men with nonmetastatic CRPC extended these findings by demonstrating that bone metastases can be prevented or delayed with bone-targeted therapy. In men with high-risk features for the development of bone metastases, the median time to initial metastasis was 25.2 months in the placebo group and 29.5 months in the denosumab group. Considering the clinical impact of bone metastases on men with prostate cancer, a median delay of 4.2 months in their development is a meaningful observation with immediate treatment implications. Moreover, treatment with bone-targeted therapy should continue for men with advanced prostate cancer even after the development of bone metastases, because both zoledronic acid and denosumab have shown benefit in preventing SREs after the development of metastases.Though the majority of bone metastases detected in the Denosumab 147 study were not symptomatic, the study design required that men be immediately withdrawn from the investigational study drug upon detection of initial metastasis. One implication of this design was that the ability to establish when metastases became symptomatic was limited. A second implication was that bone-targeted treatment was discontinued sooner than would be done in standard practice. The impact of denosumab on the development of symptomatic metastases is therefore not yet established, and conceivably the true benefit of ongoing bone-targeted therapy would be greater than represented in this study.In balancing the risk–benefit ratio of treatment, the main toxicity to consider is the development of osteonecrosis of the jaw (ONJ), a difficult but fortunately rare complication with denosumab [5–7]. The incidence of ONJ was 5% in this study and it resolved in 39% of observed cases with conservative management. It is important to emphasize to all practitioners the critical role for universal dental examinations as bone-targeted therapies are used in more patients and for longer durations. The more widespread recognition of ONJ risk, and adoption of preventative measures, will hopefully result in a diminished incidence in the future.At the current time, because skeletal-related complications are the main source of morbidity in men with prostate cancer, the significantly longer time before the appearance of skeletal metastases is an important benefit that establishes denosumab as the standard of care for men with CRPC and a high risk for development of bone metastases.     

Intake Water for Prevention of Cancer: an Enzymological Lesson?

Extensive studies have so far been principally made using hydrophobic carcinogens in the field of chemicalcarcinogenesis. However, the species of glutathione S-transferases (GSTP1-1) linked to neoplasia of rat and humanwere recently shown to be selective for hydrophilic carcinogens such as acrolein and hydroxyalkenals (Satoh, 1998;Satoh et al., 1999) in accord with the finding of a water-network in the active site of the human GSTP1-1 by X-rayanalysis (Hu et al.; Ji et al., 1997). These results indicate that water-soluble carcinogens may be more significant thantheir hydrophobic counterparts in vivo. Of note, half-times for excretion of hydrophilic compounds are as short asseveral hrs, while those for hydrophobic ones are as long as several months or years. These available enzymologicaldata suggest on importance of consuming water to prevent cancer.     

Cancer Prevention and Control: A Role for Medical Assistants?

This study aimed to assess medical assistants' willingness to engage in patient education and counseling about cancer prevention and control. A questionnaire was mailed to 402 medical assistants living in Maryland in June 2006 to assess attitudes and practices about counseling and educating patients on cancer prevention and control topics. Findings reveal that medical assistants are engaging patients in discussions about cancer prevention, with diet/nutrition and exercise being most often discussed. Medical assistants are willing to counsel and educate patients on cancer prevention and control topics.     

Should women under 50 be screened for breast cancer?

Despite some controversy in recent years, the majority of experts agree on the evidence for effectiveness of breast screening by mammography for women aged 50 years and above, but for those under 50 years, the picture is much less clear. However, the issue remains of importance both to policy makers and to individual women; although the incidence of breast cancer is lower at younger ages, the life years lost due to cancers diagnosed below 50 years amount to a third of all those lost due to the disease.     

Should there be a standard therapy for mantle cell lymphoma?

Mantle cell lymphoma (MCL) is an uncommon subtype of B-cell lymphoma that is characterized by monoclonal B cells that express CD5 on their surface, but not CD23, and harbor the t(11:14) chromosomal translocation that leads to dysregulated expression of cyclin D1. MCL is a biologically and clinically heterogeneous disease. It has the unfavorable characteristics of both aggressive and indolent lymphoma in that MCL is not curable with current standard therapy, yet patients have a shorter survival compared with other indolent histology. MCL is incurable, yet more intensive therapy does lead to longer disease-free intervals; therefore, treatment must be designed to optimize survival while maintaining quality of life. Thus, therapy should be individualized based on both the clinical behavior of the lymphoma and the patient's status. While there is no clear standard therapy that can be recommended for all patients, there may be an optimal choice for each patient. Knowledge of the expected clinical benefits and toxicities of various approaches will allow the physician and patient to appropriately select the therapy.     

Aspirin and Colorectal Cancer Prevention and Treatment: Is It for Everyone?

There is now a considerable body of data supporting the hypothesis that aspirin could be effective in the prevention and treatment of colorectal cancer, and a number of phase III randomised controlled trials designed to evaluate the role of aspirin in the treatment of colorectal cancer are ongoing. Although generally well tolerated, aspirin can have adverse effects, including dyspepsia and, infrequently, bleeding. To ensure a favourable balance of benefits and risks from aspirin, a more personalised assessment of the advantages and disadvantages is required. Emerging data suggest that tumour PIK3CA mutation status, expression of cyclo-oxygenase-2 and human leukocyte antigen class I, along with certain germline polymorphisms, might all help to identify individuals who stand to gain most. We review both the underpinning evidence and current data, on clinical, molecular and genetic biomarkers for aspirin use in the prevention and treatment of colorectal cancer, and discuss the opportunities for further biomarker research provided by ongoing trials.     

Secondary Prevention of Colorectal Cancer: Is There an Optimal Follow-up for Patients with Colorectal Cancer?

Secondary prevention of colorectal cancer, as opposed to primary prevention, indicates that a person has already had the disease and there are steps being taken to prevent cancer recurrence, usually as metachronous tumors. This generally involves annual surveillance with colonoscopy after surgical removal of the initial cancer if some aspect of the colon remains. However, some familial cases may involve other modalities, such as cyclooxygenase inhibitors, as an adjunct after the initial operation. Genetic testing in suspected familial cases may identify candidates for secondary prevention. The timing for secondary prevention is critical to prevent recurrent advanced disease, which is detrimental to patient survival. Recommendations are often empiric, but some cases are based on the biological behavior of the tumor. Close follow-up with a competent health care provider, such as a gastroenterologist, is necessary to help prevent recurrence.     

Is Male Breast Cancer Similar or Different than Female Breast Cancer?

OBJECTIVE. To determine if male breast carcinogenesis was similar to its more common female counterpart, we compared incidence patterns among men and women with breast cancer. METHODS. Breast cancer records were obtained from the SEER database. Women were stratified by age < 50 and > or = 50 years to simulate premenopausal and postmenopausal breast cancer. RESULTS. Age-adjusted incidence trends were stable among men but increased among women. Male to female breast cancer ratio was higher for blacks than for whites. Favorable prognostic factors reflective of tumor biology (nuclear grade and hormone receptor expression) were more common for men and postmenopausal women than for premenopausal women. For example, low nuclear grade, estrogen and progesterone receptor-positive expression were more common among men and postmenopausal women than among premenopausal women. The age-specific incidence rate curve for men increased steadily for all ages with a constant slope. On the other hand, age-specific rates for women increased rapidly until age 50 years then rose at a slower rate for postmenopausal women. Age-frequency distribution for male breast cancer was unimodal, with peak incidence at age 71 years. Age-frequency distribution for women was bimodal with early-onset and late-onset incidence at 52 and 71 years, respectively. CONCLUSIONS. Gender-specific incidence trends differed, most likely reflective of female-related changes in surveillance and/or reproductive risk factors. On the other hand, similar prognostic factor profiles reflective of tumor biology, age-specific incidence rate patterns, and age-frequency distributions suggested that male breast cancer was more like postmenopausal than premenopausal female breast cancer.     

Surgery for Relapsed Ovarian Cancer: When Should it Be Offered?

Whilst cytoreductive surgery is the mainstay treatment for primary ovarian cancer, its role in relapse is still unclear. Surgery in platinum-sensitive recurrent ovarian cancer might be beneficial if it results in complete resection of the disease. Clinical scores could help to identify suitable patients. Level I evidence is still missing; however, two randomized trials (DESKTOP III and GOG 213) are ongoing.