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.     

Efficacy of ibandronate for the treatment of skeletal events in patients with metastatic breast cancer

Patients with breast carcinoma often develop bone metastases that carry a high risk of complications. A randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of ibandronate in patients with metastatic bone disease following breast cancer. The primary efficacy end point of the study was the proportion of patients who developed skeletal-related events (SREs, defined as pathologic fracture, spinal cord compression, radiation therapy to bone, change in anti-neoplastic therapy and surgery to bone). Secondary end points included time to first skeletal event, skeletal morbidity rate (events/year) and time to progression of bone lesions. In 150 patients (148♀/2♂) with breast carcinoma and bone metastases, treatment with intravenous ibandronate 6 mg over 15 min every 4 weeks for 24 months significantly reduced the proportion of patients who experienced an SRE compared with placebo (36% vs. 48%; P  = 0.027). Time to first SRE was also delayed significantly (median 457 vs. 304 days; P  = 0.007). Multiple event analysis showed that ibandronate reduced the risk of developing an SRE by 32% (hazard ratio = 0.69; 95% confidence interval 0.42–0.79; P  = 0.003). In general, ibandronate was well tolerated with very rare grade 3 or 4 toxicity. In this study, ibandronate was shown to be significantly more effective than placebo as a treatment for metastatic bone disease from breast cancer using multiple end points.     

Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease

Background: Bisphosphonates are an important component of the treatment of metastatic bone disease but more potent, oral formulations are required to improve the effectiveness and convenience of treatment. An oral formulation of the new bisphosphonate, ibandronate (BM 21.0955) has recently been developed.Patients and methods: One hundred ten patients with bone metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were recruited from a single institution to this double blind placebo-controlled evaluation of four oral dose levels (5, 10, 20 and 50 mg) of ibandronate. No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. After an initial four-week tolerability phase, patients could continue on treatment for a futher three months without unblinding; patients initially allocated to placebo received ibandronate 50 mg. The primary endpoint was urinary calcium excretion (UCCR). Bone resorption was also assessed by measurement of pyridinoline (Pyr), deoxypyridinoline (Dpd), and the N-terminal (NTX) and C-terminal (Crosslaps) portions of the collagen crosslinking molecules.Results: Two patients did not receive any trial medication thus, 108 patients were evaluable for safety. Ninety-two patients were evaluable for efficacy. A dose dependent reduction was observed in both UCCR and collagen crosslink excretion. At the 50 mg dose level, the percentage reductions from baseline in UCCR, Pyr, Dpd, Crosslaps and NTX were 71%, 28%, 39% 80% and 74% respectively.One or more gastrointestinal (GI) adverse events occurring in the first month of treatment were reported by six (30%), seven (33%), nine (39%), nine (41%) and eleven (50%) patients at the placebo, 5, 10, 20 and 50 mg dose levels respectively. One patient (20 mg dose) developed radiographically confirmed oesophageal ulceration. GI tolerability may have been adversely affected by concommitant administration of non-steroidal anti-inflammatory agents. Nine (8%) patients stopped treatment within the first month due to GI intolerability but these patients were evenly distributed across the five treatment groups. There was no difference in non-GI adverse events between groups.Conclusions: Oral ibandronate has potent effects on the rate of bone resorption at doses which are generally well tolerated. Further development is appropriate to evaluate the effects of long-term administration in the prevention of metastatic bone disease and the management of established skeletal metastases.     

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.     

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.     

Ibandronate: its pharmacology and clinical efficacy in the management of tumor-induced hypercalcemia and metastatic bone disease

It is well accepted that tumor cells in the bone, especially from breast cancer, prostate cancer and multiple myeloma, can stimulate osteoclast formation and activity. Bisphosphonates are potent inhibitors of osteoclast-mediated normal and pathologic bone resorption. Besides their apoptotic and antiproliferative activity on osteoclasts, bisphosphonates can also exert similar effects on macrophages and tumor cells. Currently, it is unknown if this effect can be translated into clinical practice with regard to an effective adjuvant therapeutic regimen for high-risk patients with systemic recurrences following primary treatment of a given cancer. There are several new aspects that might extend the clinical use of ibandronate, a bisphosphate, in oncology: prevention of hypogonadal osteoporosis in men, palliative management of painful osseous metastases and adjuvant therapy of high-risk prostate cancer patients. Safety and tolerability are excellent for the oral and intravenous formulations, and ibandronate can even be safely applied in pre-existing renal insufficiency. The purpose of this review is to critically reflect the pharmacology and clinical efficacy of ibandronate in the management of tumor-induced hypercalcemia, osteoporosis and metastatic bone disease.     

伊班膦酸钠治疗肺癌骨转移的临床研究

背景与目的: 骨骼是肺痛最常见的转移部位.骨转移的并发症如疼痛、功能障碍不仅会降低患者的生活质量,甚至会加快患者的死亡.基于上述情况,本文探讨伊班膦酸钠联合化疗治疗肺痛骨转移的临床作用.方法: 2006年6月-2007年6月共收治肿痛骨转移患者64例,随机分为两组:伊班膦酸钠联合化疗组和单纯化疗对照组.对比两组的疼痛缓解率、血清AKP、Ca2 和Scr的变化.结果: 研究组骨骼疼痛较对照组有明显缓解(有效率71.1%比42.3%)(P=0.006):研究组治疗后血清AKP和Ca<'2 >较治疗前有明显下降(P＜0.05);两组患者血清肌苷在治疗前后无明显改变(P＞0.05).结论: 伊班膦酸钠是安全、低毒性药物,其联合化疗有缓解肺癌骨转移疼痛和抑制骨转移的作用.     

Efficacy of YM-175, a new bisphosphonate,in the treatment of metastatic bone tumor from breast cancer and its effect on scintigraphy

Background Bisphosphonates are powerful inhibitors of osteoclast-mediated bone resorption. They are effective in the treatment of Paget's disease of the bone, tumor-associated hypercalcemia, and osteoporosis. They are also used to treat metastatic bone disease. YM-175 is a new highly potent bisphosphonate. Bisphosphonates are also used as radiopharmaceuticals in bone scintigraphy. The data remain unclear as to whether or not the administration of large amounts of bisphosphonate interferes with the bone scintigraphy process. Methods We have treated 8 patients with bone metastases from breast cancer with 10 mg IV, once a week for 5 weeks. The monitoring of bone pain, laboratory analysis with bone metabolic markers, and bone imaging including x-ray and bone scintigraphy, was performed for 8 weeks. A quantitative method was employed to evaluate serial bone scintigraphy. Results Bone pain improved in 5 out of 8 cases at 2 and 4 weeks post-treatment without serious adverse effects, but the duration of pain relief was short. Markers of osteoclast activity were decreased significantly to a minimum at 2 weeks. No significant changes were shown in markers of osteoblast activity or in serum calcium levels. Intact parathyroid hormone (PTH) was elevated at 2 and 4 weeks. It appears that YM-175 suppressed osteoclast activity, however, its effect was negated by a PTH elevation response. No changes were detected in either x-ray findings or serial bone scintigraphy by use of visual images and quantitative methods. Conclusion YM-175, a new bisphosphonate, was a safe and promising drug for the treatment of metastatic bone pain from breast cancer. Osteoclast activity was suppressed by bisphosphonate treatment, but, the PTH response negated the osteoclast suppression. Furthermore, YM-175 treatment did not alter bone scintigraphic images.     

伊班膦酸治疗肺癌骨转移痛疗效及安全性分析

目的:对比分析首剂负荷剂量及常规剂量伊班膦酸钠(ibandronate)治疗肺癌转移性骨痛的疗效和安全性。方法:选择2008年1月-2013年1月我院确诊的非小细胞肺癌骨转移患者40例,随机分为A组(首剂负荷剂量组)和B组(首剂常规剂量组)各20例。A组首剂给予负荷剂量,即伊班膦酸钠6mg+0.9%氯化钠100ml静滴15min以上,每天1次,连用3天,以后每4周重复给予1次维持剂量6mg。B组首剂给予常规剂量,即第1天给予伊班膦酸钠6mg+0.9%氯化钠100ml静滴15min以上,第2天及第3天只给予0.9%氯化钠100ml静滴15min以上作为对照,以后剂量及用法同A组。对比分析2组患者的止痛起效时间、止痛维持时间、用药3个周期后的总有效率及不良反应之间的差异。结果:止痛起效时间:A组平均(2.4±1.09)天,B组平均(7.7±1.86)天,差异有统计学意义(P<0.05)。止痛疗效维持时间:A组平均(22.9±8.27)天,B组平均(16.3±3.52)天,差异有统计学意义(P<0.05)。总有效率:A组85%,B组55%,差异有统计学意义(P<0.05)。2组在不良反应发生情况上无统计学差异(P>0.05)。结论:伊班膦酸钠首剂负荷剂量给药止痛起效快,维持时间长,无严重毒副作用,耐受性良好,可明显改善患者转移性骨痛,提高生活质量,是非小细胞肺癌转移性骨痛治疗的一个新选择。     

伊班膦酸钠对人乳腺癌细胞系MDA-MB-231、MDA-MB-453的体外生长抑制作用

目的：研究伊班膦酸钠（IBN）对体外培养的人乳腺癌细胞MDA—MB-231、MDA—MB-453细胞生长增殖的影响及其潜在的作用机制。方法：采用MTT法检测不同浓度的IBN、及相同浓度不同作用时间的IBN对MDA—MB-231、MDA—MB-453两类不同的人乳腺癌细胞系生长增殖的影响；应用流式细胞仪检测不同浓度IBN作用下，MDA—MB-231、MDA—MB-453细胞细胞周期的变化。结果：在（10～100）μg／ml的浓度范围内，IBN对MDA—MB-231、MDA—MB-453细胞生长增殖均有抑制作用（P〈0．01），抑制效果与IBN浓度呈剂量依赖性，与其作用时间呈时间依赖性；IBN可使细胞明显阻滞于S期，G2／M期细胞比例则明显减少，且呈剂量依赖趋势。结论：在（10～100）μg／ml的浓度范围内，IBN对体外生长的人乳腺癌细胞MDA—MB-231、MDA—MB-453产生剂量、时间依赖性的抑制作用，其机制可能与其将细胞阻滞在DNA合成的S期，阻碍肿瘤细胞分裂增殖有关。     

Ibandronate is effective in preventing skeletal events in patients with bone metastases from colorectal cancer

Patients with metastatic colorectal carcinoma (CRC) often develop bone metastases with a high risk of complications. Ibandronate is a novel single-nitrogen bisphosphonate that has been shown to be effective for treating bone metastases from breast cancer. A randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of ibandronate in patients with bone metastases from CRC. The primary efficacy end point was the proportion of patients with skeletal-related events (defined as pathologic fracture, spinal cord compression, radiation therapy to bone, change in antineoplastic therapy or surgery to bone). Secondary end points included time to first skeletal event, skeletal morbidity rate (events/year) and time to progression of bone lesions. In 73 patients with CRC, treatment with intravenous ibandronate 6 mg administered via a 15-min infusion significantly reduced the proportion of patients with skeletal events (39% vs. 78% with placebo; P = 0.019) and prolonged the time to first event by at least 6 months (median >279 vs. 93 days with placebo; P = 0.009). Ibandronate also significantly reduced the skeletal morbidity rate (mean 2.36 vs. 3.14 with placebo; P = 0.018) and prolonged time to progression of bone lesions (214 days vs. 81 days with placebo; P = 0.018). Ibandronate was well tolerated with very rare grade 3 or 4 toxicity. Furthermore, the incidence of renal adverse events was comparable with placebo and there were no clinically relevant changes in serum creatinine. Ibandronate provided significant clinical benefits for patients with bone metastases secondary to CRC. These results indicate that ibandronate may be an effective treatment for patients with metastatic bone disease following CRC. Larger studies are required for further assessment.     

Salvage chemotherapy for metastatic breast cancer: results of a phase II study with bendamustine.

BACKGROUND: Bendamustine, a bifunctional alkylating agent with anticipated purin-like properties is active in metastatic breast cancer (MBC) patients. This multicenter phase II trial defines the toxicity and activity of bendamustine in heavily pretreated patients. PATIENTS AND METHODS: Fifty-one patients were included. Patients had a median number of 2 prior chemotherapeutic regimens for MBC (range 0-7) consisting of anthracyclines and taxanes: 26 patients (51%); anthracyclines: nine patients (17.6%); taxanes: seven patients (13.7%); others: five patients (9.8%). Bendamustine was administered four weekly at a dose of 120 mg/m(2) on days 1 and 2. RESULTS: Fifty patients were assessable. Of total, 200 courses were administered. We observed no complete response (CR); 10 patients [20%; 95% confidence interval (CI): 10.0% to 33.7%] achieved a partial response (PR), 14 patients (28%) remained stable for at least 6 months resulting in a clinical benefit rate (CR + PR + stable disease) of 48% (95% CI: 33.7%to 52.6%). Median time to progression was 3.4 months (range 1-51.1). The median duration of remission was 6.6 months (range 1.8-48.7). The treatment was well tolerated with mainly hematologic toxic effects. CONCLUSION: Single-agent bendamustine is an active treatment in patients with MBC independent of the previous treatment. The low toxicity profile favors its use as a single agent.     

Oral medroxyprogesterone acetate in the treatment of metastatic breast cancer

Summary Thirty-nine evaluable, postmenopausal patients with metastatic breast carcinoma were treated with medroxyprogesterone acetate administered orally at daily doses of 800 mg/day in 29 patients and 400 mg/day in 10 patients. One patient experienced a complete remission and 16 had partial remissions for an objective remission rate of 44%. There was no apparent difference in response between the two dose levels. Median remission duration was 8 months, and median survival for the whole group is expected to exceed 18 months. Increased appetite (66%) and weight gain (97%) were the most common side effects, followed by fluid retention, muscle cramps, and increased blood pressure. Performance status improved and white blood cell and platelet counts increased in the majority of patients. Medroxyprogesterone acetate is an effective hormonal agent in the treatment of metastatic breast cancer.     

Vinorelbine, methotrexate and fluorouracil (VMF) as first-line therapy in metastatic breast cancer: a randomized phase II trial.

BACKGROUND: The purpose of this study was to determine the best tolerated and efficacious dose of vinorelbine given once or twice in 3-week cycles in combination with methotrexate and fluorouracil (VMF). PATIENTS AND METHODS: Vinorelbine 40 mg/m(2) was given as follows: 20 mg/m(2) on days 1 and 8 (group 1); 30 mg/m(2) on day 1 and 10 mg/m(2) on day 8 (group 2); or 40 mg/m(2) on day 1 (not exeeding 60 mg/m(2)) (group 3). The methotrexate dose was 40 mg/m(2) on day 1 and the fluorouracil dose 600 mg/m(2) on days 1 and 8. Thirty patients with evaluable metastases were randomly allocated to the groups (first step). The second step was to exclude the worst tolerated regimen and then to expand the study to 60 patients. Thus, group 1 had 26 patients, group 2 had 24 patients and group 3 had 10 patients. RESULTS: World Health Organization (WHO) grade 3 hematological toxicity occurred in 23%, 36% and 50% of patients and grade 4 in 39%, 32% and 50% of patients in groups 1, 2 and 3, respectively; grade 3 infections were observed in 15%, 9% and 10% of patients in groups 1, 2 and 3, and grade 4 infections in 5% and 10% of patients in groups 2 and 3, respectively. Nonhematological toxicity included a mild to moderate neurotoxicity manifesting as constipation, abdominal colics and myalgia in the majority of patients. One patient in group 3 had serious convulsions after vinorelbine administration; she also developed neutropenic sepsis; all symptoms were reversible. No patient died from side-effects. The objective response rates were 50%, 55% and 44% for groups 1, 2 and 3, respectively. Median time to progression was 7, 10 and 8 months and median survival time was 26, 23 and 16 months in groups 1, 2 and 3, respectively. CONCLUSION: VMF regimens where the vinorelbine dose (40 mg/m(2)) is divided (20 + 20 mg/m(2) and 30 + 10 mg/m(2)) between days 1 and 8 of a 3-week cycle are equally well tolerated and the efficacy is comparable to other modern first line regimens used in the treatment of metastatic breast cancer.     

Oral ibandronate is as active as intravenous zoledronic acid for reducing bone turnover markers in women with breast cancer and bone metastases.

BACKGROUND: Phase III study comparing the effect of oral ibandronate and intravenous zoledronic acid on bone markers. PATIENTS AND METHODS: Breast cancer patients with bone metastases received ibandronate 50 mg/day (n = 137) or zoledronic acid 4 mg every 4 weeks (n = 138) for 12 weeks. The primary end point was mean percentage change in serum levels of cross-linked C-terminal telopeptide of type I collagen (S-CTX) at week 12. Urinary CTX (U-CTX), bone alkaline phosphatase (ALP), amino-terminal procollagen propeptide of type I collagen (PINP) and osteocalcin (OC) were also measured and bone pain and safety assessed. RESULTS: Both bisphosphonates significantly reduced S-CTX (mean ibandronate 76% +/- 29 (SD) versus mean zoledronic acid 73% +/- 47; P < 0.001 for both versus baseline) and U-CTX (ibandronate 78% +/- 50 versus zoledronic acid 86% +/- 17; P < 0.001). The difference in S-CTX between treatments was 0.6% (confidence interval -1.7% to 3.0%), which was within the prespecified noninferiority margin. Bone ALP, PINP and OC decreased by 26%-47% compared with baseline with both bisphosphonates. Compared with zoledronic acid, ibandronate patients reported fewer adverse events overall (65.0% versus 75.9%), and on days 1-3 (8.0% versus 47.5%), including less pyrexia (overall incidence 0% versus 16.8%) and bone pain (5.8% versus 12.4%). CONCLUSIONS: Oral ibandronate was well tolerated and statistically noninferior to zoledronic acid for percentage change in the bone resorption marker, S-CTX.     

Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study

The combination of intravenous (i.v.) vinorelbine and epirubicin is highly active in the treatment of metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated a regimen alternating i.v. and oral vinorelbine in combination with epirubicin as first-line chemotherapy of patients with MBC. In all, 49 patients with MBC received, as first-line treatment, a combination regimen consisting of i.v. vinorelbine 25 mg m(-2) plus epirubicin 90 mg m(-2) given on day 1, and oral vinorelbine 60 mg m(-2) on day 8 (or day 15 if neutrophils <1500 mm(-3)) every 3 weeks, in an open-label, multicentre phase II study. Treatment was to be repeated for a maximum of six cycles. The study population had a median age of 55 years, half of the patients had received prior adjuvant chemotherapy and 86% presented a visceral involvement. In all, 25 responses were documented and validated by an independent panel review, yielding response rates of 51% (95% CI: 36-66) in the 49 enrolled patients and 54.5% (95% CI: 39-70) in the 44 evaluable patients. Median durations of progression-free survival and survival were 8 and 20 months, respectively. Neutropenia was the main dose-limiting toxicity, but complications were uncommon, four patients having experienced febrile neutropenia and six having developed neutropenic infection. Other frequently reported adverse events included stomatitis, nausea and vomiting, which were rarely severe. No toxic death was reported. Among patients who received six cycles, global score of quality of life remained stable. This regimen alternating oral and i.v. vinorelbine in combination with epirubicin is effective and safe. Oral vinorelbine on day 8 offers greater convenience to the patient, and decreases the need for i.v. injection and reduces time spent in hospital. Therefore, oral vinorelbine is a convenient alternative to the i.v. form in combination regimens commonly used to treat MBC.     

Predictive factors for skeletal complications in hormone-refractory prostate cancer patients with metastatic bone disease

Factors predictive of skeletal-related events (SREs) in bone metastatic prostate cancer patients with hormone-refractory disease were investigated. We evaluated the frequency of SREs in 200 hormone-refractory patients consecutively observed at our Institution and followed until death or the last follow-up. Baseline parameters were evaluated in univariate and multivariate analysis as potential predictive factors of SREs. Skeletal-related events were observed in 86 patients (43.0%), 10 of which (5.0%) occurred before the onset of hormone-refractory disease. In univariate analysis, patient performance status (P=0.002), disease extent (DE) in bone (P=0.0001), bone pain (P=0.0001), serum alkaline phosphatase (P=0.0001) and urinary N-telopeptide of type one collagen (P=0.0001) directly correlated with a greater risk to develop SREs, whereas Gleason score at diagnosis, serum PSA, Hb, serum albumin, serum calcium, types of bone lesions and duration of androgen deprivation therapy did not. Both DE in bone (hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.07-1.25, P=0.000) and pain score (HR: 1.13, 95% CI: 1.06-1.20, P=0.000) were independent variables predicting for the onset of SREs in multivariate analysis. In patients with heavy tumour load in bone and great bone pain, the percentage of SREs was almost twice as high as (26 vs 52%, P<0.02) and occurred significantly earlier (P=0.000) than SREs in patients with limited DE in bone and low pain. Bone pain and DE in bone independently predict the occurrence of SREs in bone metastatic prostate cancer patients with hormone-refractory disease. These findings could help physicians in tailoring the skeletal follow-up most appropriate to individual patients and may prove useful for stratifying patients enrolled in bisphosphonate clinical trials.     

Oral vinorelbine in metastatic breast cancer: a review of current clinical trial results

Background

Oral chemotherapy is one of the options for the treatment of endocrine non-responsive metastatic breast cancer.

Patients and methods

A search of the online PubMed database was undertaken to identify clinical trials evaluating oral vinorelbine in metastatic breast cancer. All the clinically relevant data have been analysed in this article.

Results

A total of 31 studies including more than 1000 patients have been included into this analysis. Oral vinorelbine either as a single-agent or in combination has shown consistent efficacy results (response rates between 27% and 85% in first-line). The all-oral combination of oral vinorelbine and capecitabine has shown comparable efficacy to a taxane-based combination in a randomised phase II study. Importantly, activity has also been observed in the subset of patients previously treated with anthracyclines and taxanes. For HER2-positive patients, oral vinorelbine in combination with trastuzumab is among the most active options. Oral vinorelbine presents a manageable tolerance profile. Neutropenia is the most common adverse event and alopecia is not frequently observed. Anti-emetic prophylaxis is recommended.

Conclusion

Taken together, these data indicate that oral vinorelbine is a highly effective and well tolerated agent which can be used in first-line and subsequent metastatic breast cancer settings. Moreover, this compound may offer the specific advantages of oral chemotherapy, as fewer and shorter hospital visits, delayed use of central venous access devices and maintained social activities.     

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

Background:

HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients'' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies.

Methods:

In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab.

Results:

For HER2-positive tumours (n=100), objective response rate was 19.0% (95% confidence interval (CI): 11.8–28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9–34.7). One out of 22 HER2-negative tumour was documented as complete response (n=22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P=0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib.

Conclusion:

Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.     

The effect of the bisphosphonate ibandronate on breast cancer metastasis to visceral organs

Bisphosphonate (BPs), specific inhibitors of osteoclastic bone resorption, are widely used therapeutic agents for bone metastases in breast cancer patients. Nevertheless, the effects of BPs on visceral metastases are controversial. Here we specifically studied the effects of the BP ibandronate on visceral metastases of breast cancer using two animal models. In the first set of experiments, we examined the effects of ibandronate on lung metastasis using 4T1 mouse mammary tumor that developed pulmonary and bone metastases following orthotopic inoculation in syngeneic female Balb/c mice. In the second set of experiments, we examined the effects of ibandronate on adrenal metastasis using a clone of the MDA-MB-231 (MDA-231) human breast cancer (MDA-231AD cells) that developed adrenal and bone metastases following intracardiac inoculation in female nude mice. These breast cancer cells were stably transfected with a firefly luciferase cDNA to facilitate quantification of the metastatic tumor burden in visceral organs. Ibandronate (4 µg/day, sc, daily) was given either after metastases were established (therapeutic administration) or at the time of tumor cell inoculation (preventative administration). In both models with each protocol, ibandronate reproducibly reduced bone metastases, establishing that BPs are effective pharmacological agents for the treatment of bone metastases in breast cancer. In the 4T1 model, neither the preventative nor therapeutic administration of ibandronate caused any effects on lung metastases. In the MDA-231 model, the preventative administration of ibandronate significantly increased adrenal metastases. However, no increase in the adrenal metastases was observed when an anti-cancer agent doxorubicin was co-administered. Therapeutic administration of ibandronate showed no effects on the adrenal metastases. Our results suggest that BPs cause no adverse effects on visceral metastases when administered in the manners that breast cancer patients usually receive.