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Bisphosphonates
No full textBisphosphonates are potent inhibitors of osteoclast mediated bone resorption. These compounds are stable analogues of the inorganic pyrophosphate (PPi), which is an endogenous regulator of bone mineralization.
Characteristics
Bisphosphonates were developed in the nineteenth century for industrial use, in particular as “water softeners.” The first clinical use of bisphosphonates in humans was in the 1960s for the treatment of Paget disease, a focal disorder of bone remodeling due to abnormally increased osteoclast-mediated bone resorption. So far, bisphosphonates have been successfully studied in several clinical disorders characterized by an alteration in bone resorption, such as metastatic and osteolytic bone diseases, hypercalcemia of malignancy and osteoporosis.
All bisphosphonates share a common structure which consists of two phosphate groups attached to a single carbon atom (P-C-P).
The P-C-P group is responsible for the affinity of these drugs for the bone, since it is essential for binding to hydroxyapatite or hydroxylapatite. The substitution in the R1 and R2 side chains give rise to a variety of compounds with different potency and biological effects. For instance, the presence of a hydroxyl group in the R1 side chain confers a higher affinity for the bone mineral. The R2 side chains directly influence the potency of bisphosphonates for inhibiting osteoclast-mediated bone resorption. In particular, the bisphosphonates containing a basic primary nitrogen atom in an alkyl chain (such as pamidronate and alendronate) are 10–100 times more potent than non nitrogen bisphosphonates. Indeed, the higher antiresorptive potency is obtained when the R2 side chain contains a nitrogen atom within a heterocyclic ring (as in risendronate and zoledronate)
Lapatinib plus letrozole for postmenopausal patients with advanced HER2(+)/HR(+) breast cancer.
No full textLapatinib is an oral, small-molecule dual inhibitor of human EGF receptor 1 (EGFR/erbB1) and 2 (HER2/erbB2). Lapatinib has recently been approved, in combination with capecitabine, for the treatment of HER2-positive metastatic breast cancer patients failing trastuzumab therapy. Data from clinical trials are consistently showing the key role of this agent in the management of HER2-positive disease. Moreover, interesting data are suggesting a key role of lapatinib in enhancing endocrine responsiveness and/or restoring endocrine sensitivity in hormone receptor-positive disease. The present article will summarize the main data leading to the clinical development of the combination of lapatinib and the aromatase inhibitor letrozole
Bone health: new horizons in the prevention of cancer-treatment induced bone loss and management of bone metastases.
No full textBisphosphonates (BPs) provide meaningful clinical benefit in cancer patients by significantly reducing the onset of skeletal complications. Apart from their established role in the treatment of hypercalcaemia of malignancy and bone metastases, these agents have also been explored in earlier stages of disease. In particular, BPs have shown the promise of a role in the adjuvant setting, to prevent bone metastatisation, and to prevent loss in bone density related to cancer therapies. This review will briefly summarise the current evidence in these particular settings, and will examine new potential approaches to metastatic bone disease, including new agents, new formulations and new schedules for BPs. Most available data are focused on breast cancer and prostate cancer; this is because of: their prevalence worldwide, the likelihood of bone metastatisation caused by these diseases, and the loss in bone density being a major clinical concern in these patients as a consequence of both aging and cancer therapies
Clinical utility of measuring circulating tumor cells in metastatic breast cancer
No full textDespite significant improvements in screening, early diagnosis, and adjuvant treatment of breast cancer, some women still develop metastatic disease.1 Metastatic breast cancer (MBC) remains an incurable condition, and its treatment is considered palliative; nevertheless, the selection of appropriate treatments is generally associated with survival prolongation.2,3 Moreover, our increasing knowledge of the biology of the disease and the availability of targeted therapies have improved significantly the prognosis of some subsets of patients, such as women with amplification of the erbb2 oncogene.4The use of novel technologies to accurately assess disease status can theoretically provide the possibility of better prognostic stratification for patients with MBC, which should also contribute to better treatment outcomes in this condition. However, measurement of serum tumour marker levels and extensive radiological monitoring of women with a history of primary breast cancer have failed to detect early recurrences and have not provided any survival benefit when tested in large prospective studies.5,6The detection of circulating tumour cells (CTCs) in MBC has been shown to be reliable, sensitive, reproducible, and predictive of prognosis and early treatment response.7 A multicenter prospective trial demonstrated that the level of CTCs in patients with MBC who have measurable disease is a powerful predictor of progression-free and overall survival. In that trial patients with > 5 CTCs per 7.5 ml of blood (a prospectively identified cut-off level) had significantly shorter progression-free and overall survival durations compared to those with < 5 CTCs per 7.5 ml of blood. The continue monitoring of CTCs predicted for disease outcome as early as 3 weeks, therefore indicating the benefit of treatments. Furthermore, in a multivariate analysis, the level of CTCs had a predictive value independent of the line and type of therapy, time to metastasis, site of recurrence (visceral vs. nonvisceral), and hormone receptor statu
The curability of breast cancer and the treatment of advanced disease
No full textBreast cancer represents a major health problem, with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade, in spite of an increasing incidence, breast cancer mortality has been declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments. Better knowledge of breast cancer biology now allows the cosmetic, physical and psychological consequences of radical mastectomy to be spared in the majority of breast cancer patients. Use of the sentinel node technique is rapidly expanding and this will further reduce the extent and the consequences of surgery. Several clinico-pathological factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse. Nodal status, tumour size, tumour grade and age are accepted universally as important factors to define risk categories. Newer factors such as uPA/PAI-1, HERer2-neu, proliferative indices and gene expression profile are promising and will allow better discrimination between patients at different risk. Endocrine manipulation with tamoxifen, ovarian ablation or both is the preferred option in the case of endocrine-responsive tumours. Tamoxifen administered for 5 years is the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen, with a different safety profile. At present, anastrozole can be used in the adjuvant setting in cases of tamoxifen intolerance or toxicity. Chemotherapy is the treatment of choice for steroid receptor-negative tumours. Polychemotherapy is superior to single agents and anthracycline-containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four of CMF are the recommended regimens. New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. The taxanes have been approved for adjuvant therapy in the USA, while European approval is pending. Combined endocrine-chemotherapy is the standard adjuvant treatment in high-risk patients with endocrine-responsive tumours. Endocrine manipulation is usually administered after completion of the chemotherapy programme. For HER2-neu overexpressing tumours, several rapidly accruing trials are exploring the potential additive effect of trastuzumab, a monoclonal antibody directed against the extramembrane portion of the HER2 receptor. Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer, with increased rates of breast-conserving surgery. A proportion of patients achieve a pathological complete response and these patients have significantly better long-term outcomes. Twenty-five to forty percent of breast cancer patients develop distant metastases. At this stage the disease is incurable; however, treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In the case of hormone receptor positivity and in the absence of visceral, life-threatening disease, endocrine manipulation is the treatment of choice. Active treatments include tamoxifen, ovarian ablation, aromatase inhibitors, pure anti-oestrogens and progestins. Aromatase inhibitors are the most active agents, but the choice and the sequence of endocrine therapies are also dictated by prior adjuvant treatment. Chemotherapy has to be preferred in cases of receptor-negative tumours, acquired resistance to hormones and aggressive visceral disease. Combination regimens are usually associated with higher response rates and sometimes survival prolongation, and this approach should be recommended in young patients with good performance status and visceral disease. On the other hand, single agents have a better tolerability profile and should be tand should be the treatment of choice when a careful balance between activity and tolerability is needed. For HER2-neu positive tumours, the combination of trastuzumab and chemotherapy is significantly superior to chemotherapy alone in terms of both response rates and survival. Other useful palliative treatments include bisphosphonates for the control of metastatic bone disease and radiotherapy for painful bone lesions or local relapses
Safety of intravenous and oral bisphosphonates and compliance with dosing regimens
No full textPatients with advanced cancers--particularly breast and prostate cancers--are at high risk for bone metastasis, leading to accelerated bone resorption and clinically significant skeletal morbidity. Bisphosphonates are effective inhibitors of bone resorption and reduce the risk of skeletal complications in patients with bone metastases. The standard routes of administration for bisphosphonates used in clinical practice are either oral or i.v. infusion. Oral administration of bisphosphonates is complicated by poor bioavailability (generally <5%) and poor gastrointestinal tolerability. First-generation bisphosphonates, such as clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), must be administered at high oral doses (1,600-3,200 mg/day) to achieve therapeutic effects, which leads to poor tolerability and compliance with oral dosing regimens. Infusion of bisphosphonates is associated with dose- and infusion-rate-dependent effects on renal function. In particular, high bisphosphonate doses (e.g., 1,500 mg clodronate) can cause severe renal toxicity unless infused slowly over many hours. In contrast, the newer, more potent bisphosphonates effectively inhibit bone resorption at micromolar concentrations, and the small doses required can be administered via relatively short i.v. infusions without adversely affecting renal function. Zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ) is a new generation bisphosphonate, and the recommended dose of 4 mg can be safely infused over 15 minutes. The 90-mg dose of pamidronate (Aredia; Novartis Pharmaceuticals Corp.) and the 6-mg dose of ibandronate (Bondronat; Hoffmann-La Roche Inc.; Nutley, NJ) require 1- to 4-hour infusions. Intravenous bisphosphonates require less frequent dosing (once a month) and are generally well tolerated with long-term use in patients with bone metastases. Zoledronic acid has demonstrated the broadest clinical activity in patients with bone metastases
In response to Body letter to the editor regarding "Safety of intravenous and oral Bisphosphonates and compliance with dosing regimens"
No full textCorrespondenc
Triple-negative breast cancer: current management and future options.
Full text linkAbstract: Triple-negative breast cancer is a particularly difficult to treat and biologically aggressive disease with limited treatment options. However, a subset of patients with triple-negative tumours may respond to chemotherapy. Therefore, optimisation of chemotherapy regimens may be key in treating triple-negative breast cancer. Emerging treatment approaches include novel chemotherapeutic agents such as the epothilones. The epothilones are a group of novel microtubule-stabilising agents with demonstrated activity in anthracycline-/taxane-resistant triple-negative breast cancer, and ongoing trials are evaluating the combination of epothilones with targeted agents or inclusion of epothilones in novel combination regimens. Other interesting new treatment options include the PARP inhibitors, which are currently in clinical trials for triple-negative breast cancer. © 2009 Elsevier Ltd. All rights reserved
Metastatic breast cancer: therapeutic options according to molecular subtypes and prior adjuvant therapy.
No full textAbstract
In spite of advances in treatment strategies, about 25%-40% of patients with breast cancer still eventually develop metastatic disease that is largely incurable. Treatment goals vary from symptom control to lengthening survival, mainly on the basis of patient age and performance status, tumor biology, site and extent of disease, and prior therapies. In particular, breast cancer molecular characterization allows for the identification of breast cancer subtypes with distinct biological features, a distinct clinical course, and distinct treatment sensitivity. Endocrine manipulation is the cornerstone of therapy in hormone receptor-positive tumors; anti-human epidermal growth factor receptor (HER)-2 agents are essential in the management of HER-2(+) tumors; and chemotherapy is the only available option so far for the triple-negative subtype. In each of these subtypes, the more efficacious agents have been progressively incorporated into adjuvant treatment. As a consequence, the choice of the optimal therapeutic strategy for patients with metastatic disease is largely influenced by prior exposure to adjuvant therapies. This review contextualizes the data from clinical trials into different clinical scenarios of metastatic disease, taking into account the molecular subtype and prior adjuvant treatments
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