Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases.

BACKGROUND: Osteonecrosis of the jaw (ONJ) has been reported in patients receiving bisphosphonates for metastatic bone disease. ONJ incidence, risk factors, and outcomes were evaluated in a combined analysis of three phase III trials in patients with metastatic bone disease receiving antiresorptive therapies. PATIENTS AND METHODS: Patients with bone metastases secondary to solid tumors or myeloma were randomly assigned to receive either s.c. denosumab (120 mg) or i.v. zoledronic acid (4 mg) every 4 weeks. On-study oral examinations were conducted by investigators at baseline and every 6 months. Oral adverse events were adjudicated by an independent blinded committee of dental experts. RESULTS: Of 5723 patients enrolled, 89 (1.6%) patients were determined to have ONJ: 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab (P = 0.13). Tooth extraction was reported for 61.8% of patients with ONJ. ONJ treatment was conservative in >95% of patients. As of October 2010, ONJ resolved in 36.0% of patients (29.7% for zoledronic acid and 40.4% for denosumab). CONCLUSIONS: In this combined analysis of three prospective trials, ONJ was infrequent, management was mostly conservative, and healing occurred in over one-third of the patients. Educating physicians about oral health before and during bone-targeted therapy may help reduce ONJ incidence and improve outcomes.

Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up.

BACKGROUND: Adding oral clodronate to postoperative adjuvant breast cancer therapy significantly improves disease-free survival (DFS) and overall survival (OS). Long-term follow-up data from the prospective, randomized, controlled study are reported. PATIENTS AND METHODS: Patients with primary breast cancer received clodronate 1600 mg/day for 2 years or no treatment along with standard adjuvant breast cancer treatment. RESULTS: Analysis of 290 of 302 patients demonstrated that a significant improvement in OS was maintained in the clodronate group at a median follow-up of 103 +/- 12 months; 20.4% of patients in the clodronate group versus 40.7% of control group patients (P = 0.04) died during the 8.5 years following primary surgical therapy. Significant reductions in the incidence of bony and visceral metastases and improvement in duration of DFS at 36- and 55-month follow-up periods were no longer seen with clodronate. CONCLUSION: These long-term survival data extend the survival advantage reported in previous studies with oral clodronate in breast cancer.

Intravenous ibandronate does not affect time to renal function deterioration in patients with skeletal metastases from breast cancer: phase III trial results.

As patients with metastatic bone disease typically receive long-term treatment with bisphosphonates, and often antineoplastic compounds, drug-related safety is of considerable importance. Clinical trial data for intravenous (i.v.) ibandronate suggest that its nephrotoxic potential is comparable with placebo. We conducted a post hoc Kaplan-Meier analysis of time to serum creatinine increase with i.v. ibandronate throughout 2 years of treatment. After 96 weeks, 12% of patients in the placebo group and 6% in the ibandronate 6 mg group (ns, P = 0.22) had defined serum creatinine increases. After 12 treatment months (48 weeks), 4% of patients receiving placebo and 2% of patients receiving ibandronate 6 mg showed increased serum creatinine. These results suggest that there is no clinically relevant change in serum creatinine levels with i.v. ibandronate 6 mg infused every 3-4 weeks for 2 years. Comparative trials to examine the renal safety of ibandronate and other i.v. bisphosphonates are warranted.

Rapid administration of ibandronate does not affect renal functioning: evidence from clinical studies in metastatic bone disease and hypercalcaemia of malignancy.

Ibandronate is a third-generation aminobisphosphonate that has an excellent safety record in hypercalcaemia of malignancy, and has recently been approved for the prevention of skeletal events from metastatic breast cancer. This paper reviews the safety data from clinical studies of intravenous ibandronate by infusion or injection, focusing on renal adverse events (AEs). In clinical trials of patients with hypercalcaemia of malignancy, 2-h infusions of ibandronate at doses of up to 6 mg had a low potential for renal events. In a phase III trial of patients with metastatic bone disease from breast cancer, 6 mg ibandronate infused over 1-2 h had a renal safety profile comparable to that of placebo. In pilot studies, repeated daily infusions of ibandronate (4 mg infused over 2 h for four consecutive days, or 6 mg infused over 1 h for three consecutive days) for severe metastatic bone pain were not associated with any renal AEs. The safety of single 15-min infusions of 6 mg ibandronate has been demonstrated in healthy volunteers and patients with metastatic bone disease from breast cancer or multiple myeloma. Furthermore, single and rapid bolus injections of 2 or 3 mg ibandronate did not increase the risk of renal dysfunction in patients with skeletal metastases. Implications for the renal safety of ibandronate in the management of patients with metastatic bone disease are discussed.

Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer.

Bone metastases occur in most women with advanced breast cancer and can lead to considerable morbidity and a rapid deterioration in the patient's quality of life. It was the aim of the present study to assess changes in quality of life and bone pain due to intravenous (i.v.) ibandronate, a potent third-generation bisphosphonate. In a phase III randomised, double-blind, placebo-controlled trial in patients with bone metastases due to breast cancer, 466 women were randomised to receive placebo, 2 mg ibandronate or 6 mg ibandronate for up to 96 weeks. Treatment was administered i.v. at 3- or 4-weekly intervals. Clinical endpoints included the incidence of adverse events, quality of life (assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Scale - Core 30 questionnaire (QLQ-C30)), and bone pain (assessed on a 5-point scale from 0=none to 4=intolerable). Ibandronate was generally well tolerated. Compared with baseline measurements, the bone pain score was increased at the last assessment in both the placebo and 2 mg ibandronate groups, but was significantly reduced in the patients receiving 6 mg ibandronate (-0.28+/-1.11, P < 0.001). A significant improvement in quality of life was demonstrated for patients treated with ibandronate (P < 0.05) for all global health status. Overall, at the last assessment, the 6 mg ibandronate group showed significantly better functioning compared with placebo (P = 0.004), and had significantly better scores on the domains of physical, emotional, and social functioning, and in global health status (P < 0.05). Significant improvements in the symptoms of fatigue and pain were also observed in the 6 mg ibandronate group. I.v. ibandronate treatment leads to significant improvements in quality of life, and is an effective and well-tolerated palliative treatment in patients with bone metastases due to breast cancer.

Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies.

Although intravenous (i.v.) bisphosphonates are the standard of care for metastatic bone disease, they are less than ideal for many patients due to infusion-related adverse events (AEs), an increased risk of renal toxicity and the inconvenience of regular hospital visits. The use of oral bisphosphonate therapy is limited by concerns over efficacy and gastrointestinal (GI) side effects. There remains a clinical need for an oral bisphosphonate that offers equivalent efficacy to i.v. bisphosphonates, good tolerability and dosing convenience. Oral ibandronate, a highly potent, third-generation aminobisphosphonate, has been evaluated in phase III clinical trials of patients with bone metastases from breast cancer. In two pooled phase III studies, patients with breast cancer and bone metastases were randomised to receive oral ibandronate 50 mg (n=287) or placebo (n=277) once daily for up to 96 weeks. The primary end point was the skeletal morbidity period rate (SMPR), defined as the number of 12-week periods with new skeletal complications. Multivariate Poisson's regression analysis was used to assess the relative risk of skeletal-related events in each treatment group during the study period. Oral ibandronate 50 mg significantly reduced the mean SMPR compared with placebo (0.95 vs 1.18, P=0.004). There was a significant reduction in the mean number of events requiring radiotherapy (0.73 vs 0.98, P<0.001) and events requiring surgery (0.47 vs 0.53, P=0.037). Poisson's regression analysis confirmed that oral ibandronate significantly reduced the risk of a skeletal event compared with placebo (hazard ratio 0.62, 95% CI=0.48, 0.79; P=0.0001). The incidence of mild treatment-related upper GI AEs was slightly higher in the oral ibandronate 50 mg group compared with placebo, but very few serious drug-related AEs were reported. Oral ibandronate 50 mg is an effective, well-tolerated and convenient treatment for the prevention of skeletal complications of metastatic bone disease.

Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.

BACKGROUND: This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer. PATIENTS AND METHODS: A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 3-4 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly. Results SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated. CONCLUSIONS: These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cancer.

Time independence of the prognostic impact of tumor cell detection in the bone marrow of primary breast cancer patients.

PURPOSE: Tumor cell detection (TCD) in bone marrow is an outstanding prognostic factor in breast cancer. There is only one other study that has investigated more than 300 patients with a median follow-up of more than 5 years (J. L. Mansi et al., Lancet, 354:197-202, 1999). We report data from 727 patients with a median follow-up period of 6.5 years. EXPERIMENTAL DESIGN: In a prospective study, intraoperatively aspirated bone marrow was screened for micrometastatic cancer cells. We used an immunocytological method (monoclonal mucin antibody 2E11; the avidin-biotin complex method). RESULTS: Forty-three percent of the patients were TCD positive. Sixty percent of the patients with distant metastases were tumor cell positive (155 of 258 patients). Forty-nine percent of the patients with positive TCD developed distant metastases (155 of 315 patients). TCD was an independent prognostic factor for clinical outcome after a median follow-up time of 6.5 years. The prognostic impact of TCD and tumor size remains constant with the time, whereas the impact of grading and progesterone receptor on risk seems to decrease with longer follow-up time. CONCLUSIONS: TCD remains an independent prognostic factor The impact of TCD does not change with longer follow-up time. TCD is a reliable prognostic factor and provides important information about the process of metastasis.

Bisphosphonates in the prevention of bone metastases: current evidence.

The use of bisphosphonates is well established for the treatment of bone metastases to reduce skeletal complications in patients with breast and other cancers, to provide a better quality of life. More recently, however, there is evidence that these agents may also have antitumor effects. Therefore, the use of bisphosphonates is now being examined in improving overall survival, by potentially reducing metastatic bone disease in particular. To date, three randomized trials have been conducted in over 1,500 women with breast cancer using 1,600 mg clodronate as adjuvant medication. This article evaluates and presents the results of these studies, and reviews current evidence surrounding the prophylactic use of bisphosphonates for skeletal progression of breast cancer.

Bone marrow staging for breast cancer: is it better than axillary node dissection?

Numerous studies have shown tumor cells in bone marrow to be a new and independent prognostic factor in primary breast cancer. The presence of such cytokeratin-positive or mucin-positive cells reflects the biology and systemic character of breast cancer much better than lymph node status. Axillary lymphadenectomy is associated with a considerable number of complications and is completely unnecessary in about 50% of cases (in node-negative patients). Whether axillary node dissection contributes to improved survival is highly controversial. However, since nearly all patients with primary breast cancer now receive adjuvant systemic therapy, the value of the classic prognostic factors must be discussed and re-evaluated. Much information can now be determined from primary tumor (HER-2/neu, etc). Tumor cell detection in bone marrow is a simple method that can be performed on an outpatient basis and that can be repeated if necessary (for monitoring therapy). The main disadvantage of the technique is that it has not been possible to standardize the laboratory methods and to find the ideal antibody--one that is not only able to recognize an epithelial cell, but which can also describe its metastatic potential. Semin Oncol 28:236-244.

Prognostic factors for skeletal relapse in breast cancer.

Bone metastases and the strong interaction between osseous and metastatic cell populations require interdisciplinary thought and actions. If it were possible to interrupt the malignant dialogue between tumour and bone at an early stage, this might not only reduce the amount of bone destruction, but could also reduce the incidence of osseous metastases and remove the source of secondary metastases to other organs. Studies into the preventive effects of bisphosphonates are currently running or are planned. Most of these studies are in breast cancer patients with involvement of the axillary lymph nodes. The prognostic factors of lymph node status, tumour size and grading are better than none, but do not select patients at a high risk of skeletal metastasis. This would be much better done by using immunohistochemical methods to investigate the primary tumour for bone sialoprotein and parathyroid hormone-related protein (PTHrP). However, these methods are complicated, have not been validated in large numbers of patients and are not standardized. Serum tests for bone sialoprotein, PTHrP and collagen fragments are currently still under development and cannot be recommended generally. The clinical importance of tumour cells in the bone marrow has been demonstrated but is still only used at a few centres.

Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients.

Previous studies with animal tumors showed that bone marrow (BM) is a privileged site where potentially lethal tumor cells are controlled in a dormant state by the immune system. Here, we investigated BM of breast cancer patients with respect to tumor cell content, immune activation status and memory T-cell content. BM-derived cells from primary operated breast cancer patients (n = 90) were compared with those from healthy donors (n = 10) and also with cells from respective blood samples. Cytokeratin 19-positive tumor cells were detected by nested polymerase chain reaction. Three-color flow cytometry was used to identify numbers and activation state of T cells, natural killer (NK) cells, monocytes/macrophages and subsets by a panel of monoclonal antibodies (mAbs). The proportion of memory T cells among the CD4 and CD8 T cells was much higher in BM of cancer patients than in healthy donors (p < 0.001). The extent of memory T-cell increase was related to the size of the primary tumor. Patient-derived BM memory CD8 T cells could be shown to contain specific HLA-A2/Her-2/neu(369-377) tetramer binding cells. Patients with disseminated tumor cells in their BM had more memory CD4 T cells and more CD56(+) CD8(+) cells than patients with tumor cell-negative BM. Only some of the immunological changes seen in BM samples of cancer patients were also detectable in peripheral blood samples. Our hypothesis that BM is a special compartment for immunological memory and tumor dormancy is supported by the above findings. The overall results reveal that BM is a valuable additional compartment for immune diagnosis in pathological conditions and possibly for follow-up treatment strategies.

Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow.

In an analysis of 84 primary-operated breast cancer patients and 11 healthy donors, we found that the bone marrow of most patients contained memory T cells with specificity for tumor-associated antigens. Patients' bone marrow and peripheral blood contained CD8+ T cells that specifically bound HLA/peptide tetramers. In short-term culture with autologous dendritic cells pre-pulsed with tumor lysates, patients' memory T cells from bone marrow (but not peripheral blood) could be specifically reactivated to interferon-gamma-producing and cytotoxic effector cells. A single transfer of restimulated bone-marrow T cells into NOD/SCID mice caused regression of autologous tumor xenotransplants associated with infiltration by human T cells and tumor-cell apoptosis and necrosis. T cells from peripheral blood showed much lower anti-tumor reactivity. Our findings reveal an innate, specific recognition of breast cancer antigens and point to a possible novel cancer therapy using patients' bone-marrow-derived memory T cells.

Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma.

To test the potential of immunoreactive BSP, a non-collagenous bone matrix component, as a clinical guide in patients with plasma cell dyscrasias, serum BSP concentrations were measured in 62 patients with newly diagnosed multiple myeloma (MM) followed over a period of 4 years, in 46 patients with monoclonal gammopathy of undetermined significance (MGUS), in 71 patients with untreated benign vertebral osteoporosis (OPO), and in 139 healthy adults. Results were compared with clinical and laboratory data, including serum osteocalcin (OC), and urinary pyridinoline (PYD) and deoxypyridinoline (DPD) as markers of bone turnover. In MM, serum BSP, and urinary PYD and DPD were higher than in healthy controls and in MGUS or OPO (P< 0.001). BSP levels correlated with the bone marrow plasma cell content (r = 0.40, P< 0.001), and serum beta2-microglobulin (r = 0.31, P < 0.01). The differentiation of MM from healthy controls and from MGUS or OPO was highest for BSP. After chemotherapy, BSP reflected the response to treatment and correlated with the change in monoclonal protein (r = 0.55, P< 0.001). MM patients with normal baseline BSP levels survived longer than patients with initially elevated BSP values (P< 0.001, log rank test). Only serum monoclonal protein and BSP were independent predictors of survival. We conclude that in MM, BSP levels are associated with skeletal involvement and tumour cell burden. The quantification of serum BSP may be a non-invasive method for the diagnosis and follow-up, and may improve the prognostic value of conventional staging in MM.

[Therapeutic value of aredia in treatment of breast carcinoma]. / Der therapeutische Wert von Aredia in der Behandlung des Mammakarzinoms.

BACKGROUND: Like other metastases, bone metastases in breast cancer patients are not only a sign of the incurable nature of the underlying disease, but are also associated with specific complications. In particular, bone pain and pathological fractures impair the quality of life of those affected. Any treatment concept must therefore place the highest priority on preventing or reducing skeletal complications. THERAPY: There are 2 treatment options--local and systemic. Local therapy includes radiotherapy as well as surgical and orthopedic measures. The 4 pillars of systemic treatment are hormone therapy and chemotherapy, antiresorptive therapy with bisphosphonates and treatment with centrally and/or peripherally acting analgesics. A precondition for successful treatment is close cooperation between gynecologists, medical/clinical oncologists, radiotherapists, surgeons/orthopedists, pain specialists and endocrinologists (in the presence of a hypercalcemic syndrome). CONCLUSION: Patients with breast cancer associated solely with osseous metastasis may survive for a number of years. It is therefore all the more important to start appropriate therapeutic measures in good time. Bisphosphonates play a particularly valuable role, since their main effect lies in the prevention of skeletal complications. Rather than replacing antineoplastic therapy, this class of substances supplements other treatments. Once started, bisphosphonate therapy should be given life-long, even in the event of osseous progression.

[Micrometastatic cells in the bone marrow of patients with breast carcinoma]. / Mikrometastatische Zellen im Knochenmark von Patientinnen mit Mammakarzinom.

BACKGROUND: The immunocytological detection of disseminated epithelial cells in bone marrow in patients with breast cancer has been performed at many hospitals and institutes since the early 1980s. Despite numerous publications in this field, it has not been possible to standardize the method and establish the ideal antibody, either nationally or internationally. Molecular biological methods using PCR technology could extend the diagnostic spectrum. However, one of the major problems in breast cancer is the lack of a disease-specific marker gene. As a result, immunocytology is still the standard procedure for tumour cell detection. METHODS: The detection of disseminated single cells in bone marrow in primary breast cancer (also known as minimal residual disease) is a new prognostic factor for disease-free and overall survival. This has been demonstrated in three large (N > 300) groups and several small to medium groups (N = 50-300). As a marker of dissemination in a target organ for metastasis this prognostic factor corresponds much more closely to the tendency of breast cancer to early haematogenic spread. Tumour cell detection may predict the course of the disease better than the axillary lymph node status. Bone marrow aspiration and detection of disseminated cells might replace lymph node dissection, at least in those patients with small tumours and no clinical signs of lymph node involvement. This strategy will soon be investigated in appropriate studies. Another possible clinical use might be deciding on whether or not to give adjuvant systemic therapy to node-negative patients. Patients with positive tumour cell detection are at a higher risk of subsequent metastasis, even if the axillary nodes are histologically normal. APPLICATION OF METHODS: The immunohistological or molecular biological detection of tumour cells in axillary lymph nodes might also be very useful, now that is has been shown that a considerable subset of patients determined to be node-negative by means of conventional methods, are positive according to these new techniques. These methods could be a useful supplement to sentinel node biopsy. A further potential use of this method is in monitoring therapy with new treatment modalities such as gene therapy and immunotherapy. Repeated bone marrow aspiration can provide information on the success of therapy in minimal residual disease (cytoreduction). Immunocytochemical investigation of individual cells may be useful in studying the pathogenesis of metastasis, in particular in the skeleton. Phenotyping of cells might allow statements to be made in the metastatic potential of cells and the question of cell dormancy. It remains to be hoped that this aspect of minimal residual disease will be granted more attention in future.

Reliable and sensitive analysis of occult bone marrow metastases using automated cellular imaging.

The presence of occult bone marrow metastases (OM) has been reported to represent an important prognostic indicator for patients with operable breast cancer and other malignancies. Assaying for OM most commonly involves labor-intensive manual microscopic analysis. The present report examines the performance of a recently developed automated cellular image analysis system (ACIS; ChromaVision Medical Systems, Inc.) for identifying and enumerating OM in human breast cancer specimens. OM analysis was performed after immunocytochemical staining. Specimens used in this study consisted of normal bone marrow (n = 10), bone marrow spiked with carcinoma cells (n = 20), and bone marrow obtained from breast cancer patients (n = 39). The reproducibility of ACIS-assisted analysis for tumor cell detection was examined by having a pathologist evaluate montage images generated from multiple ACIS runs of five specimens. Independent ACIS-assisted analysis resulted in the detection of an identical number of tumor cells for each specimen in all instrument runs. Additional studies were performed to analyze OM from 39 breast cancer patients with two pathologists performing parallel analysis using either manual microscopy or ACIS-assisted analysis. In 17 of the 39 cases (44%), specimens were classified by the pathologist as positive for tumor cells after ACIS-assisted analysis, whereas the same pathologist failed to identify tumor cells on the same slides after analysis by manual microscopy. These studies indicate that the ACIS-assisted analysis provides excellent sensitivity and reproducibility for OM detection, relative to manual microscopy. Such performance may enable an improved approach for disease staging and stratifying patients for therapeutic intervention.

Bisphosphonates and the prevention of metastasis: first evidences from preclinical and clinical studies.

BACKGROUND: Bisphosphonates have been used successfully for many years in the treatment of hypercalcemia and to reduce skeletal-related complications of metastases. In the first years of bisphosphonate use, the efficacy of these substances was thought to lie purely in the inhibition of osteoclasts. However, there is recent evidence to suggest that an antitumor effect also may play a role. As well as having an apoptotic and antiproliferative effect on osteoclasts, bisphosphonates may exert a similar influence on macrophages and tumor cells. METHODS: The current investigation summarizes all results published to date that deal with the potential antitumor properties of the bisphosphonates. On the one hand, these include results from basic research into the action mechanism and preventative models in animals. In addition, the results of initial clinical experience with metastasis prophylaxis with bisphosphonates in breast carcinoma patients are presented and interpreted. RESULTS: Improvements in the survival time of certain subpopulations have been found in many Phase III studies with bisphosphonates to date, both in the setting of metastatic breast carcinoma and in multiple myeloma. Some preclinical studies showed that down-regulation of bone metabolism by bisphosphonates is associated with a lower incidence of bone metastases and destruction in animals, whereas activation is correlated with a higher number of metastases. However, varying results were found in animal experiments with regard to the effect of bisphosphonates on the incidence and growth pattern of nonosseous metastases. The results of three randomized studies in patients with primary breast carcinoma in which patients received 1600 mg clodronate orally have now been evaluated and presented. All three studies arrived at different results. Because the dose was identical in all three studies, the differing results can only be either random or methodologic (inclusion criteria, sample size, etc.). CONCLUSIONS: Overall, the results are very promising but need confirmation in further studies. At the moment, we have more open than answered questions. First, it is unclear whether this type of adjuvant therapy with bisphosphonates should be given continually by the oral route, or whether an intravenous interval therapy could produce the same results. It is also uncertain whether the doses used in a palliative setting are optimal or whether lower doses might also suffice. The optimum period of adjuvant treatment is also subject to debate. What is clear, however, is that confirmation of the initial clinical results will open a new chapter in the treatment of malignant tumors.

Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis.

Although metastasis is a frequent event in breast cancer patients, insight into the clinical course, prognosis and therapy with respect to the site of the first metastases has been poor and contradictory in former investigations. Follow-up data from 648 patients with metastatic breast cancer were statistically analyzed. Patients with bone metastases at first relapse had better overall survival (median 71 vs. 48 months; p < 0.001) and survival after first metastases (median 24 vs 12 months; p < 0.001) than patients with visceral metastases at first relapse. Bone was the site of first metastasis in 46%, and 71% of patients with metastatic breast cancer developed bone metastases. The localization of the second metastatic site was of prognostic relevance in patients with first visceral metastases, but not in patients with first bone metastases. The presence of osseous metastases correlated significantly with estrogen and progesterone receptor positivity, tumor grading I/II and S-phase fraction <5%. The better prognosis of patients with bone metastases is not determined exclusively by hormone receptor status. The disease is significantly more stable in patients with first bone metastases than in those with first visceral metastases.

Antitumour effects of bisphosphonates: first evidence and possible mechanisms.

Bisphosphonates have been used successfully for many years in the treatment of hypercalcaemia and to reduce skeletal complications of metastases. In the first years of bisphosphonate use the efficacy of these substances was thought to lie purely in the inhibition of osteoclasts. However, there is recent evidence to suggest that an antitumour effect may also play a role. As well as having an apoptotic and antiproliferative effect on osteoclasts, bisphosphonates may exert a similar influence on macrophages and tumour cells. Whether this effect (at low doses) also plays a role in vivo remains unclear and requires further investigation. Improvements in the survival time of certain subpopulations have been found in many phase III studies with bisphosphonates to date, both in the setting of metastatic breast cancer and in multiple myeloma. However, because survival time in subgroups of patients was neither a primary nor a secondary objective in these studies, these advantages could only be seen as important pointers for future studies. Some preclinical studies have shown that down-regulation of bone metabolism by bisphosphonates is associated with a lower incidence of bone metastases and destruction in animals, whereas activation is correlated with a higher number of metastases. However, varying results were found in animal experiments with regard to the effect of bisphosphonates on the incidence and growth pattern of non-osseous metastases. The results of 3 randomised studies in patients with primary breast cancer who received clodronate 1600 mg/day orally have now been evaluated and presented. All 3 studies arrived at different results. In the Heidelberg study there was a reduction in both osseous and non-osseous metastases, whereas in a much larger study performed in Great Britain, Canada and Scandinavia there was a reduction only in the incidence of skeletal metastases. A third study from Finland found no effect on bone metastases, but an increase in the number of visceral metastases and a deterioration in overall survival. Because the dosage was identical in all 3 studies, the differing results can only be either random or methodological (for example inclusion criteria or sample size). Overall, the results are very promising, but there is a need for further studies.