Bisphosphonate therapy for bone metastases from Breast Cancer: Clinical results and a new therapeutic approach

BACKGROUND: We evaluated the usefulness of bisphosphonate (BIS) monotherapy, the safety of rapid infusion of BIS and the efficacy of BIS-sequential therapy for bone metastases from breast cancer. PATIENTS AND METHODS: Twenty-nine patients with bone metastasis or invasion were treated with BIS monotherapy. Each BIS (pamidronate 30 mg, alendronate 10 mg, or incadronate 10 mg) was infused over 30 minutes every two weeks a median of 12 times. RESULTS: With BIS therapy, five patients (17%) showed partial response of the bone lesions, and eighteen patients (64%) had pain relief. Of the nine patients treated with BIS-sequential therapy, one (11%) showed a partial response of the bone metastases, three (33%) had pain relief, and one (11%) showed a decrease in the serum tumor marker level. CONCLUSION: BIS therapy is effective against bone metastases from breast cancer, and rapid infusion of BIS is both safe and convenient for patients. BIS-sequential therapy can be a unique therapeutic option in some cases.     

Breast cancer with osteoblastic bone metastasis treated successfully with bisphosphonate: a case report]

A 52-year-old woman with painful osteoblastic bone metastasis received pamidronate therapy which resulted in marked pain relief with a normalization of elevated tumor marker levels. However, the patient complained of increased pain after the 26th pamidronate infusion. Although a change from pamidronate to alendronate therapy did not relieve bone pain, a second change from alendronate to incadronate therapy resulted in pain relief with a decrease in re-elevated tumor marker levels. These findings suggest that bisphosphonate therapy is effective against osteoblastic bone metastasis in breast cancer, and that sequential therapy with bisphosphonates may be effective against bone metastasis in some cases.     

The bisphosphonate incadronate for bone metastases of breast cancer

Background. Bisphosphonates are bone resorption inhibitors which are effective in the treatment of diseases of increased bone turnover, such as hypercalcemia of malignancy and osteolytic bone metastasis. The safety and efficacy of incadronate, a third-generation bisphosphonate, were evaluated in breast cancer patients with bone metastases. Methods. Fifteen breast cancer patients with bone metastasis were enrolled. Incadronate's safety, its effectiveness in relieving bone pain, and its effects on bone metabolic markers and a tumor marker were assessed in 8 patients treated with a 10-mg IV infusion once a week for 5 weeks (10 mg × 5), 3 patients treated with a single 20-mg IV infusion (20 mg × 1), and 4 patients treated with a 20-mg IV infusion once a week for 5 weeks (20 mg × 5). Pain assessment was performed only in the patients with the repeated infusion regimens. Results. All incadronate treatment regimens were administered without any serious adverse reactions. Minimal fever was noted in 6 patients, but it subsided without any treatment. Incadronate relieved bone pain in 10 of the 12 patients who received repeated infusions. Levels of bone resorption markers dropped transiently, but the decreases in the individual markers of bone resorption varied. Levels of bone formation markers did not change significantly. Levels of a tumor marker specific to breast cancer, carbohydrate antigen (CA)15-3 decreased in patients whose metastases were limited to bone. Conclusion. The third-generation bisphosphonate, incadronate, was administered safely at dosages of up to 20 mg once a week for 5 weeks. Incadronate reduced bone pain, bone resorption marker levels, and CA15-3 tumor marker levels in breast cancer patients with bone metastases. Received: November 9, 1999 / Accepted: March 6, 2000     

A case of effective bisphosphonate therapy of sequential pamidronate and incadronate for bone metastases from breast cancer

A 55-year-old woman complained of neck pain ten years after undergoing surgery. She was diagnosed as having bone metastases and treated using pamidronate therapy with doxifluridine, tamoxifen and fadrozole, which was assessed as effective. She complained of neck pain 32 months after pamidronate infusion. CT revealed that the sclerosis had continued but new lytic lesions were detected in the cervical vertebra. Thus, we attempted incadronate and medroxyprogesterone acetate (MPA) administration. After 2 months, incadronate therapy with MPA relieved her neck pain. CT revealed lytic lesions of cervical vertebra showing sclerosis 3 months after this treatment and the sclerosis has continued. Bisphosphonate therapy of sequential pamidronate and incadronate with MPA administration is a useful treatment for bone metastasis from breast cancer.     

Pain relief with alendronate therapy in a breast cancer patient with bone metastasis

A 66-year-old woman developed a bone metastasis from breast cancer to the sternum in September, 1997. She received alendronate therapy, consisting of biweekly intravenous administrations of 10 mg-alendronate 6 times and monthly 20 mg-alendronate infusions 15 times. The first alendronate administration markedly alleviated her bone pain. She obtained complete pain relief after the 4th alendronate infusion. However, an elevation of tumor marker levels in serum without any pain increase forced us to treat her with medroxyprogesterone acetate and doxifluridine in addition to the alendronate therapy. With these therapies, she has shown an objective response (PR) of the bone metastasis for 8 months. In conclusion, alendronate therapy was effective against bone pain due to metastasis of breast cancer.     

A study of the safety of rapid infusion of alendronate

To investigate the safety of rapid infusion of alendronate, we used alendronate therapy for 11 breast cancer patients with bone metastasis. Of the 11 patients, only 1 had hypercalcemia and the remaining 10 normocalcemia. Rapid infusion of alendronate consisted of an administration of alendronate 10 mg diluted in 100 ml saline in 30 minutes, and was repeated every two weeks. Each patient underwent 1 to 9 alendronate treatments. During alendronate therapy, only one patient complained of general fatigue, and the remaining 10 showed no alendronate-induced clinical symptoms. Rapid infusion of alendronate caused an increase in BUN level in two patients receiving intravenous hyperalimentation (IVH), a mild increase of GOT level in one, and a decrease of serum phosphorus level in two receiving IVH. However, no increase was found in serum creatinine and GOT levels. In addition, no patients showed alendronate-induced hypocalcemia. In conclusion, rapid infusion of alendronate brings about no major adverse effects, and makes it easier for many patients with bone metastasis to receive alendronate therapy on an outpatient basis.     

白细胞介素-11结缔组织生长因子对乳腺癌骨转移的诊断价值分析

目的:研究白细胞介素-11（IL- 11）和结缔组织生长因子（CTGF）对乳腺癌的诊断价值,探索新的乳腺癌早期诊断的标志物。方法:对180 例经病理证实的乳腺癌及45例其他癌骨转移患者的外周血标本进行研究,以20例健康女性外周血标本作对照,应用酶联免疫法定量检测血中IL- 11与CTGF的含量。结果:IL- 11在乳腺癌骨转移组、未发生骨转移组与正常对照组之间差异均有统计学意义（P<0.05）,在乳腺癌骨转移组明显升高,而CTGF在各组间比较差异无统计学意义（P>0.05）。 两两进行比较发现IL- 11在乳腺癌骨转移组明显升高（P<0.05）,但在乳腺癌未发生骨转移组与健康对照组比较差异无统计学意义（P>0.05）。IL- 11在乳腺癌骨转移中的水平与其他肿瘤骨转移的表达水平相比差异有统计学意义（P<0.05）。 IL- 11与乳腺癌骨转移患者的年龄、骨痛程度及骨转移程度密切相关（P<0.05）。 结论:IL- 11的定量检测有助于乳腺癌骨转移的诊断,有望成为乳腺癌骨转移的血清标志物。      

A case report of bone metastasis diagnosed by MRI and effectively treated with UFT after breast conserving therapy for breast cancer]

A 66-year-old woman with left breast cancer (medullary carcinoma; T1cN1M0; Stage II A) was treated with breast conserving therapy combined with lumpectomy, radiotherapy, chemotherapy and endocrine therapy beginning in March, 1990. She complained of back pain and was diagnosed as having bone metastasis to the lower thoracic spine by bone scintigram and MRI examination in September, 1990. Oral administration of UFT (300 mg/day) was started, and 5 months later, back pain disappeared; nineteen months later, no definite findings of bone metastasis were observed on bone scintigram and MRI. It was concluded that long-term oral administration of UFT is an effective remedy for bone metastasis after breast conserving therapy for breast cancer.     

89SrCl2治疗转移性骨肿瘤的临床应用

目的探讨^89SrCl2治疗转移性骨肿瘤的临床应用价值和特点。方法504例有不同程度骨痛、伴或不伴活动受限的广泛转移性骨肿瘤患者,静脉注射^89SrCl21．48～2．22MBq／kg体重。随访时间最短3个月,最长4．5年。结果^89SrCl2治疗后无效（疼痛无明显变化,活动能力无改善）97例,占19．2％;有效（疼痛明显减轻,活动能力有改善）298例,占59．1％;显效（疼痛基本消失,活动能力明显恢复）109例,占21．6％。总有效率为80、8％。疗效发生在鹕SrCl2治疗后1～46d（大多在14d内）,疗效维持56d至13个月以上（大多数为4～10个月）。部分患者复查骨显像显示,原异常浓聚影明显缩小、减少和（或）消失。80．0％患者住接受^89SrCl2治疗后的4～6周白细胞和血小板计数有轻、中度下降,55.0％曾下降至正常水平以下。经对症处理后,大多数患者在3～6个月内,1／3患者在7～9个月内,个别患者在1年左右恢复到治疗前水平。血象的变化与疗效无明显相关性。结论^89SrCl2可以安全、有效地缓解骨转移癌所致疼痛,大多数患者的生活质量有所改善,部分患者病灶缩小或消失。     

Bisphosphonate treatment and radiotherapy in metastatic breast cancer

Patients with advanced breast cancer frequently develop metastasis to bone. Bone metastasis results in intractable pain and high risk of pathologic fractures due to osteolysis. The treatment of breast cancer patients with bone metastases requires a multidisciplinary approach. Radiotherapy is an established treatment for metastatic bone pain. It may be delivered either as a localized low dose treatment for localized bone pain or systemically for more widespread symptoms. Bisphosphonates have been shown to reduce morbidity and bone pain from bone metastases when given to patients with metastatic bone disease. In vivo studies indicate that early bisphosphonates administration in combination with radiotherapy improves remineralization and restabilization of osteolytic bone metastases in animal tumor models. This review focused on a brief discussion about biology of bone metastases, the effects of radiotherapy and bisphosphonate therapy, and possible mechanisms of combination therapy in metastatic breast cancer patients.     

Bone metastases in breast cancer

Opinion statement Patients with advanced breast cancer who develop bone metastases suffer from longterm skeletal morbidity. Complications of bone metastases include pain, pathologic fractures, and spinal cord compression, which have a significant impact on the quality of life of patients. Treatment options for patients with bone metastases include surgery, radiation, and analgesics to reduce bone pain and to prevent or repair fractures. Intravenous bisphosphonates can delay the onset of bone metastasis and reduce the percentage of patients who experience skeletal complications of bone metastasis, thus reducing skeletal morbidity. For the past 6 years, pamidronate disodium (90 mg administered by 2-hour intravenous infusion) has been the treatment of choice for the prevention of skeletal complications of bone metastases in patients with breast cancer. However, a more potent bisphosphonate, zoledronic acid (4 mg administered by 15-minute intravenous infusion), was approved for use and has improved efficacy in patients with bone metastases. Because of the increased efficacy and more convenient infusion time, zoledronic acid may become the new standard of care for the treatment and prevention of skeletal complications secondary to bone metastases in patients with breast cancer. Phase III clinical trials have shown that patients with an existing skeletal complication are more likely to develop subsequent complications compared with patients who have not experienced a complication. Therefore, zoledronic acid therapy should be initiated when the patient is diagnosed with bone metastasis.     

Retrospective evaluation of the safety of pamidronate administration at the dose of 90 mg/day/month in Japanese breast cancer patients with bone metastasis

The Japanese Ministry of Health, Labor and Welfare approved the use of pamidronate in November 2004 at a dose of 90 mg/day/month especially for Japanese breast cancer patients with lytic bone metastasis. But no safety data have been shown for these Japanese patients thus far. Therefore, we evaluated the safety of pamidronate treatment for breast cancer patients with bone metastasis at the dose of 90 mg/day/month since July 1, 2004 until Dec 31, 2004, retrospectively, in our institute, the Shikoku Cancer Center. No definite severe side effects were detected in these patients, including renal dysfunction and thrombocytopenia. In addition, there were no definite alternations in hemoglobin titers, platelet counts, BUN, serum creatinine and potassium levels in one month and 3 months after beginning the treatment except for significant alternations in RBC counts in one month and in the serum calcium level 3 months later (p=0.03). Improvements of clinical symptoms or data due to bone metastases, i.e., bone pain or elevation of tumor markers, were obtained in 91% of patients. As a conclusion, pamidronate administration at the dose of 90 mg/day/month was safe for Japanese breast cancer patients with bone metastasis.     

Alpha CTX as a biomarker of skeletal invasion of breast cancer: immunolocalization and the load dependency of urinary excretion.

We recently showed that increased urinary excretion of the cross-linked, nonisomerized form of the C-telopeptide of collagen type I (alphaalphaCTX) could be a sensitive indicator of the presence of bone metastases in breast cancer patients. The present study was sought to investigate (a) the localization of alphaCTX epitopes in the proximity of a bone metastasis and (b) the relationship between number of metastases and the urinary excretion of alphaalphaCTX. Adjacent bone sections from breast cancer patients were stained for the presence of tumor cells (anti-cytokeratin antibody), osteoclasts (TRAcP activity), and alphaCTX (anti-alphaCTX antibody). The association between the extent of metastatic bone disease and urinary excretion of alphaalphaCTX measured with ELISA was assessed in 90 breast cancer patients (45 with bone metastasis and 45 without bone metastasis). Immunohistochemistry revealed accumulation of TRAcP-positive osteoclasts and intense staining for alphaCTX epitopes in the proximity of cytokeratin-positive bone metastasis. Areas of alphaCTX staining showed unstructured bone tissue under polarized light. In addition, there was a significant linear association between the number of bone metastases and the urinary levels of alphaalphaCTX in breast cancer patients with metastatic bone disease, independent of age and body mass index (r = 0.56, P < 0.001). The estimated relative increases in alphaalphaCTX associated with the presence of one, two, or three metastases are 38%, 57%, and 81%, respectively. Taken into account the 17% intraindividual variation of the assay, alphaalphaCTX could be a sensitive biochemical marker for the close monitoring of cancer patients aiming the facilitation of early metastasis detection.     

New treatment strategy for bone metastases from breast cancer

Breast cancer patients frequently develop bone metastasis. Parathyroid hormone-related protein, an osteoclast activating factor, might be necessary for tumorto erode bone and grow at skeletal site. Bisphosphonates have an affinity for bone and are potent inhibitors of osteoclastic bone resorption. In light of this,53 patients with bone metastasis from breast cancer were treated with chemoendocrine(mainly high-dose medroxyprogesterone acetate as the endocrine therapy) therapy + bisphosphonate (pamidronate, Aredia (R)). During the previous 6 years (median 27 months), 53 breast cancer patients with bone metastasis were treated with pamidronate + chemoendocrine therapy. The regimen consisting of pamidronate + chemoendocrine agent was administered to 27 patients as a post relapse first-line regimen and to the remaining 26 cases, which failed first- or second-line treatment as a second or third line regimen. As a result of the combination therapy, sclerotic changes were observed in the osteolytic lesions in 31 of the 53 patients (59%). The effect on the osteolytic lesions did not correlate with the duration of disease free interval, estrogen receptor (ER) status, presence/absence of previous therapy or number of " hot spot(s) ] on bone scintigraphy. Lessening of pain from the bone metastasis was achieved in 83% of the patients after 3 months of pamidronate administration. Pamidronate + chemoendocrine therapy seems highly promising.     

国产因卡膦酸二钠治疗骨转移癌疼痛的Ⅱ期临床试验

目的 :观察评价国产因卡膦酸二钠治疗恶性肿瘤骨转移疼痛的有效性和安全性。方法 :自 2 0 0 1年 1 2月至2 0 0 2年 1 0月 ,收治恶性肿瘤骨转移患者 4 3例 ,随机分配至试验组和对照组 ,分别给予国产因卡膦酸二钠 1 0mg与帕米膦酸二钠 90mg静滴 ,观察其疗效和毒副作用。结果 :试验组 2 3例止痛有效率 5 2 2 % ,生活质量改善有效率为 4 3 5 % ,与对照组 2 0例相比无显著性差异 (P >0 0 5 ) ,但毒副反应少见。结论 :国产因卡膦酸二钠治疗恶性肿瘤骨转移疼痛疗效显著 ,安全可靠 ,值得临床上推广使用     

Increased rate of brain metastasis with trastuzumab therapy not associated with impaired survival

Trastuzumab is important for treatment of metastatic breast cancer patients with tumors that overexpress HER2/neu, but its penetration to the brain is poor. The aims of this study are to determine the prevalence of bone and brain metastasis during therapy, to compare the survival of breast cancer patients with brain metastasis who received trastuzumab to those patients not receiving trastuzumab, and to assess the impact of brain metastasis on the overall survival of trastuzumab patients. Of 103 patients treated with trastuzumab, 16 had brain metastasis and 43 had bone metastasis at the beginning of trastuzumab. The control group consisted of 196 patients with metastatic breast cancer who had never received trastuzumab. Six had brain metastasis and 75 had bone metastasis at the beginning of therapy. During therapy, only 9 of 60 trastuzumab patients (15%) developed bone metastasis, while 170 of 186 control patients (91%; c2 = 129.8, P < 0.0001) developed bone metastasis. In addition, 22 of 87 trastuzumab patients (25%) and 58 of 190 control patients (31%) subsequently developed brain metastasis. Control patients without brain metastasis experienced significantly better survival (median survival = 928 days) than those with brain metastasis (median survival = 639 days, c2 = 8.34, P < 0.005). There was no difference in survival for trastuzumab-treated patients if they acquired brain metastasis (median survival = 1400 days) or no brain metastasis (median survival > 2000 days, c2 = 0.12, P > 0.05). Patients receiving trastuzumab were unlikely to develop new bone metastasis but were as likely as control patients to develop brain metastasis. However, patients who developed brain metastasis experienced better survival compared with those patients with brain metastasis who never received trastuzumab.     

Baseline serum NTx levels are prognostic in metastatic breast cancer patients with bone-only metastasis.

BACKGROUND: There is significant heterogeneity in survival of patients with metastatic breast cancer who have bone-only metastasis. We studied the correlation of serum N-telopeptide (NTx), a marker of bone resorption, and its correlation with clinical outcomes in patients with metastatic breast cancer with bone-only or bone plus soft tissue metastasis. PATIENTS AND METHODS: Serum was taken from 250 metastatic breast cancer patients with bone-only or bone plus soft tissue metastasis who participated in two similar randomized studies of second-line hormone therapy. An enzyme-linked immunosorbent assay specific for NTx of type I bone collagen was used to detect serum levels. RESULTS: Sixty patients (24%) had elevated serum NTx levels, using the mean + 2 standard deviations (26 nanomoles Bone Collagen Equivalents per liter) of healthy women as a cut-off. The median duration of clinical benefit was significantly shorter in the group with elevated serum NTx levels compared with the group that had normal serum NTx levels (P=0.0004). Time to progression (TTP) was also significantly shorter in the patients with elevated serum NTx at 139 days compared with 220 days (P=0.0006). Median survival was also significantly shorter in patients with elevated baseline serum NTx levels at 663 days compared with 941 days (P<0.0001). CONCLUSION: In this study, breast cancer patients with bone-only or bone plus soft tissue metastasis and elevated serum NTx levels have a shorter duration of clinical benefit, TTP and overall survival.     

Loco-regional cancer therapy for hepatic metastasis

We undertook a clinical evaluation of chemotherapy for hepatic metastasis of gastric, colorectal and breast cancer. Between 1980 and 1989, chemotherapy for hepatic metastasis of gastric cancer was performed in 96 cases. Between 1973 and 1989, chemotherapy for hepatic metastasis of colorectal cancer and breast cancer was performed in 40 and 14 cases. Results: (1) In hepatic metastasis of gastric cancer, the 50% survival period was 149 days in local injection therapy, 132 days in arterial infusion therapy and 117 days with no chemotherapy. There was no significant difference in the survival period in gastric cancer. (2) In hepatic metastasis of colorectal cancer, the 50% survival period was 445 days in arterial infusion therapy, 206 days in local injection therapy and 96 days with no chemotherapy. The survival period with hepatic metastasis of colorectal cancer that had undergone chemotherapy was longer than for no chemotherapy. (3) In hepatic metastasis of breast cancer, arterial infusion therapy was more effective, and the survival period was prolonged significantly.     

Two cases of stage IV breast cancer with severe hypercalcemia

Case 1: A 34-year-old woman,who had a right breast cancer with axillary lymph node metastasis and multiple bone metastases, was referred to our clinic. She developed paralysis of lower extremities and disorder of the bladder and rectum due to metastasis to the thoracic vertebra, and also had renal dysfunction due to severe hypercalcemia and hemorrhagic cystitis. Correcting the serum calcium level with intravenous infusion, elcatonin, pamidronate and betamethasone, she underwent radiation therapy for the vertebral metastasis. The first hormonal therapy (leuprorelin/exemestane) had been effective for about 4 months, however the second hormonal therapy (leuprorelin/tamoxifen) was not effective. Chemotherapy with paclitaxel (80 mg/m(2), day 1, 8, 15, every 4 weeks) brought about a stable general condition and a normal level of serum calcium with zoledronate in the ninth month of treatment. Case 2: A 32-year-old woman, who had a right breast cancer with multiple bone metastases and axillary and hilar lymph node metastases, came to our clinic, complaining of nausea due to severe hypercalcemia. After successful correction of hypercalcemia by the intravenous infusion and administration of elcatonin, pamidronate and dexamethasone, the hormonal therapy(goserelin/tamoxifen) caused rapid re-elevation of serum calcium and tumor marker, so that a tumor flare was suspected. After 3 cycles of EC therapy (EPI 90 mg/m(2), CPM 600 mg/m(2), every 3 weeks), 2 cycles of paclitaxel therapy (80 mg/m(2), day 1, 8, 15, every 4 weeks) brought about tumor reduction and the normal level of serum calcium. After 7 cycles of paclitaxel therapy,the hormonal therapy (goserelin/tamoxifen) proved effective for several months. To achieve tumor reduction and stabilize the serum calcium level, we need to start immediately the treatment of breast cancer with severe hypercalcemia, considering the general condition of the patient.     

355例恶性肿瘤骨转移的临床分析

目的 分析恶性肿瘤骨转移的临床特征,提高肿瘤骨转移的诊治水平.方法 对355例恶性肿瘤骨转移患者的发病特点、临床特征及生存期等进行回顾性分析.结果 恶性肿瘤骨转移男性多见,原发肿瘤以肺癌(44.5%)、乳腺癌(11.0%)多见.转移部位以胸椎(51.0%)、肋骨(43.1%)、腰椎(42.3%)、骨盆(26.8%)等多见.骨转移灶多发常见(83.4%).75.2%的患者表现为不同程度的疼痛,少数以局部肿块、功能障碍、病理性骨折甚至截瘫为主要临床表现,78例(22.0%)患者无症状.影像学表现以溶骨性破坏为主(82.2%).采用化疗、内分泌治疗、生物治疗、放疗、姑息性手术、双膦酸盐类药物及止痛等综合治疗.骨痛治疗临床获益率为98.5%,影像学有效率为72.2%.中位生存期为13.9个月,其中前列腺癌骨转移为34.9个月,肝癌骨转移为4.6个月.未合并其他部位或脏器转移者生存期长,中位生存期可达14.7个月,骨转移灶单发与多发者生存期无明显差异.结论 恶性肿瘤骨转移应争取早期诊断,其治疗应以提高患者生存质量、延长生存期为目标,以姑息治疗为主,采取综合治疗.