Comprehensive geriatric assessment and decision-making in older men with incurable but manageable (chronic) cancer.

PURPOSE: In older cancer patients, treatment decision-making is often complex. A comprehensive geriatric assessment (CGA) is an established tool used in geriatric medicine to identify unmet need requiring intervention. This study aimed to assess whether using a CGA in older male cancer patients with incurable but manageable disease provides information that would alter a cancer clinician's intended management plan. Acceptability and feasibility were secondary aims. METHODS: Elderly men with incurable but manageable malignancies (advanced prostate cancer and multiple myeloma) who had previously received at least one line of treatment were recruited from hospital outpatient clinics. A CGA was undertaken. Additional parameters measuring pain, fatigue and disease-specific concerns were also recorded, at the recommendation of patient involvement groups. Results were made available to clinicians. Patient and clinician acceptability and changes in subsequent management were recorded. RESULTS: Forty-eight patients completed the study. The median ages were 70.8 years and 74 years for myeloma and prostate respectively. Most identified concerns are related to disease-specific concerns (93%), pain (91%), frailty (57%) and nutrition (52%). Results altered the clinician's oncological management plan in nine cases only. Patients found the format and content of CGA acceptable. CONCLUSIONS: Many unmet needs were identified in this population of elderly men with manageable but non curable cancer which led to supportive care referrals and interventions. The CGA, however, did not result in significant changes in clinical oncology treatment plans for the majority of patients. The application of the CGA and other assessments was viewed positively by participants and can feasibly be undertaken in the outpatient oncology setting.

Associations Between Serum Bone Biomarkers in Early Breast Cancer and Development of Bone Metastasis: Results From the AZURE (BIG01/04) Trial.

Background: Adjuvant therapies can prevent/delay bone metastasis development in breast cancer. We investigated whether serum bone turnover markers in early disease have clinical utility in identifying patients with a high risk of developing bone metastasis. Methods: Markers of bone formation (N-terminal propeptide of type-1 collagen [P1NP]) and bone resorption (C-telopeptide of type-1 collagen [CTX], pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen [1-CTP]) were measured in baseline (pretreatment blood samples from 872 patients from a large randomized trial of adjuvant zoledronic acid (AZURE-ISRCTN79831382) in early breast cancer. Cox proportional hazards regression and cumulative incidence functions (adjusted for factors having a statistically significant effect on outcome) were used to investigate prognostic and predictive associations between recurrence events, bone marker levels, and clinical variables. All statistical tests were two-sided. Results: When considered as continuous variables (log transformed), P1NP, CTX, and 1-CTP were each prognostic for future bone recurrence at any time (P = .006, P = .009, P = .008, respectively). Harrell's c-indices were a P1NP of 0.57 (95% confidence interval [CI] = 0.51 to 0.63), CTX of 0.57 (95% CI = 0.51 to 0.62), and 1-CTP of 0.57 (95% CI = 0.52 to 0.63). In categorical analyses based on the normal range, high baseline P1NP (>70 ng/mL) and CTX (>0.299 ng/mL), but not 1-CTP (>4.2 ng/mL), were also prognostic for future bone recurrence (P = .03, P = .03, P = .10, respectively). None of the markers were prognostic for overall distant recurrence; that is, they were bone metastasis specific, and none of the markers were predictive of treatment benefit from zoledronic acid. Conclusions: Serum P1NP, CTX, and 1-CTP are clinically useful, easily measured markers that show good prognostic ability (though low-to-moderate discrimination) for bone-specific recurrence and are worthy of further study.

Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial.

BACKGROUND: The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer. METHODS: In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age ≥18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3-4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66-93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov, NCT00072020. FINDINGS: 3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio [HR] 0·94, 95% CI 0·82-1·06; p=0·30). IDFS (HR 0·93, 95% CI 0·82-1·05; p=0·22), overall survival (0·93, 0·81-1·08; p=0·37), and distant recurrences (0·93, 0·81-1·07; p=0·29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0·78, 95% CI 0·63-0·96; p=0·020) and at any time during follow-up (0·81, 0·68-0·97; p=0·022). The effects of zoledronic acid on DFS were not affected by oestrogen-receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n=1041; HR 0·77, 95% CI 0·63-0·96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n=2318; HR 1·03, 95% CI 0·89-1·20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1·7%, 95% CI 1·0-2·4). INTERPRETATION: These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes. FUNDING: Novartis Global and NIHR Cancer Research Network.

Breast-cancer adjuvant therapy with zoledronic acid.

BACKGROUND: Data suggest that the adjuvant use of bisphosphonates reduces rates of recurrence and death in patients with early-stage breast cancer. We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients. METHODS: In this open-label phase 3 study, we randomly assigned 3360 patients to receive standard adjuvant systemic therapy either with or without zoledronic acid. The zoledronic acid was administered every 3 to 4 weeks for 6 doses and then every 3 to 6 months to complete 5 years of treatment. The primary end point of the study was disease-free survival. A second interim analysis revealed that a prespecified boundary for lack of benefit had been crossed. RESULTS: At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P=0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths--243 in the zoledronic acid group and 276 in the control group--were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P=0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P<0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups. CONCLUSIONS: These findings do not support the routine use of zoledronic acid in the adjuvant management of breast cancer. (Funded by Novartis Pharmaceuticals and the National Cancer Research Network; AZURE Current Controlled Trials number, ISRCTN79831382.).

Zoledronic acid.

IMPORTANCE OF THE FIELD: Both bone metastases and fragility fractures due to bone loss result in considerable morbidity affecting quality of life and independence as well as placing complex demands on healthcare resources. Zoledronic acid is a widely used intravenous bisphosphonate that reduces this skeletal morbidity in both benign and malignant conditions. AREA COVERED IN THIS REVIEW: The incidence, clinical importance and prevention strategies to minimize side effects associated with the use of zoledronic acid are discussed with a particular focus on use in oncology where intensive monthly scheduling is required. This potentially increases the risk for adverse events over the 6-12 monthly administration used to treat benign bone diseases. WHAT THE READER WILL GAIN: A detailed understanding of the generally favorable safety profile of zoledronic acid, but particularly the potential for renal dysfunction and osteonecrosis of the jaw. TAKE HOME MESSAGE: When compared to many other therapies, especially in the cancer setting, the severity of adverse events related to zoledronic acid is generally mild and, with the exception of the acute phase response causing transient fever, myalgia and bone pain, side effects are infrequent. Thus, the benefits of treatment with zoledronic acid within its licensed indications almost always outweigh the risks.

Bisphosphonates as adjuvant therapy for breast cancer.

Great strides have been made over the last 20 years in the treatment of breast cancer and despite an increasing incidence, the number of deaths has fallen sharply since the late 1980s. The advent of new therapies, including taxanes and aromatase inhibitors, and exciting results announced recently using trastuzumab in the adjuvant treatment of HER2-positive patients should decrease this even further. However, although most patients present with disease that appears to be localized to the breast, a significant proportion of women will eventually develop metastatic breast cancer. Therefore, the detection and treatment of micrometastatic disease represents perhaps the most important remaining challenge in breast cancer management, and is the focus of extensive ongoing research. Bone is the most frequent site of distant relapse, accounting for approximately 40% of all first recurrences. In addition to the well recognized release of bone cell-activating factors from the tumor, it is now appreciated that the release of bone-derived growth factors and cytokines from resorbing bone can attract cancer cells to the bone surface and facilitate their growth and proliferation. Bisphosphonates are potent inhibitors of bone osteolysis and the inhibition of bone resorption could therefore have an effect on the development and progression of metastatic bone disease. They could represent an adjuvant therapeutic strategy of potential importance. Clinical trial results with the early bisphosphonate, clodronate, have proved inconclusive. A large, randomized, controlled trial has recently completed accrual and should provide the definitive answer to the question of the role of clodronate in this setting. More potent second- and third-generation bisphosphonates have also shown enhanced antitumor effects in preclinical evaluation and further studies are required to determine whether this antitumor potential of bisphosphonates translates to the clinical setting. Adjuvant bisphosphonates are, therefore, currently only recommended in the research setting and clinical trials evaluating the adjuvant use of these newer compounds are currently recruiting or being established. This article will review in more detail the rationale for the adjuvant use of bisphosphonates, the results of early trials, the progress of the later trials and the potential future role of bisphosphonates in the adjuvant treatment of breast cancer. In addition, it is increasingly acknowledged that many cancer treatments have detrimental effects on bone and can increase the risk of fracture. The increasing use of aromatase inhibitors, in particular, will become a major cause of treatment-induced bone loss. This bone loss can be prevented with bisphosphonate treatment and this will also be discussed.

Mucosal immune responses to capsular pneumococcal polysaccharides in immunized preschool children and controls with similar nasal pneumococcal colonization rates.

BACKGROUND: Immunization with conjugate pneumococcal vaccines induces significant primary and memory IgG anti-polysaccharide (PS) responses in serum. It can also induce mucosal responses in infants especially after a polysaccharide booster. However, it is unclear whether it can prime for mucosal memory responses on nasal exposure to pneumococcus, which may be important in protection against pneumococcal invasion and/or carriage. METHOD: IgA and IgG to serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (conjugate vaccine serotypes), 1 and 3 (nonvaccine serotypes) capsular PS were measured by immunoassay in saliva from 2- to 5-year-old children previously given three doses of 7-valent pneumococcal conjugate vaccine in infancy, followed by 23-valent PS vaccine at 13 months and from unvaccinated controls of similar age and sex. Salivary antibody responses were analyzed in relation to carriage of pneumococci assessed by bacterial culture of nasopharyngeal swab samples collected in the summer and winter of the year 2000. RESULTS: Rates of detectable IgG antibodies to all vaccine serotypes except 23F were higher in subjects than in controls. No such differences were observed for IgA antibodies except for serotype 6B. Nasal colonization rates were similar, and in both groups mucosal IgA responses were more common and larger than IgG responses. CONCLUSIONS: The mucosal anti-capsular IgA responses observed could develop in response to colonization in preschool children, regardless of vaccination status, and contribute to the falling carriage rates observed with increasing age.

Prior meningococcal A/C polysaccharide vaccine does not reduce immune responses to conjugate vaccine in young adults.

The immune responses induced in young adults by a meningococcal A/C polysaccharide-diphtheria toxoid conjugate vaccine (Mcj) and a meningococcal A/C plain polysaccharide vaccine (Mps) were evaluated in unvaccinated subjects and those who had received either vaccine previously. 195 subjects aged 17-30 years received either Mps or Mcj. After 12 months, they were randomised again to receive a second dose of either vaccine. Serogroup specific serum bactericidal assay (SBA) titers and IgG antibody responses were assayed before and 4-8 weeks after primary and booster immunisation. Both vaccines were immunogenic in previously unvaccinated subjects. Administration of a dose of Mps after previous Mps or Mcj induced lower bactericidal titers to group C Neisseria meningitidis than those seen after a single dose of Mps. Bactericidal antibody responses to Mcj were not reduced in subjects who had previously received Mps.

Mucosal immune responses to meningococcal conjugate polysaccharide vaccines in infants.

BACKGROUND: Serogroup C meningococcal conjugate polysaccharide vaccines have been reported to induce significant serum IgG antibodies and immunologic memory in infants. Because meningococcus is a mucosal pathogen colonizing the nasopharynx, local mucosal immune responses may play an important role in host defense against infection and carriage. We have investigated the mucosal IgA and IgG antibody responses to two meningococcal C conjugate vaccines in the saliva of healthy infants. METHODS: Specific salivary IgA and IgG antibodies to two meningococcal C polysaccharide conjugate vaccines (Menjugate from Chiron Corp., n = 46; and Meningitec from Wyeth Lederle, n = 54) were investigated by immunoassay in infants after parenteral vaccinations at the ages of 2, 3 and 4 months. Unstimulated saliva samples were collected immediately before the first immunization and 1 month after the third immunizations. Forty healthy infants receiving the same routine vaccines but no meningococcal C vaccine were recruited as controls. RESULTS: There were significant increases in meningococcal C polysaccharide-specific IgG antibody concentrations postvaccination compared with prevaccination concentrations in both vaccinated groups (both P < 0.001), but no change in the control group. There were no significant increases in specific IgA postvaccination geometric mean concentrations in either the vaccine or the control groups. The number of IgA positives postvaccination increased slightly in the Wyeth vaccine group vs. controls (P < 0.05). CONCLUSIONS: Significant salivary IgG antibodies to meningococcal C polysaccharide were observed after parenteral immunization with two meningococcal C conjugate vaccines, whereas there was no significant increase in specific IgA antibody levels for these two vaccines.