Multiple Lung Tumors Research Articles

Diagnosis of synchronous primary lung adenocarcinomas based on epidermal growth factor (EGFR) gene status: A case report

The diagnosis of multiple primary lung cancer is sometimes difficult when multiple lung tumors with the same histologic type are identified. We now present a case of synchronous double primary lung adenocarcinomas (one in the right upper lobe and another in the right middle lobe) diagnosed based on mutational analysis of the epidermal growth factor receptor (EGFR) gene, although clinico-pathological findings suggested the diagnosis of intrapulmonary metastasis. After complete resection, pathological sections revealed the similar pathological features of two adenocarcinomas and unexpected subcarinal nodal metastasis. As the L858R mutation within exon 21 of the EGFR gene was identified in the middle-lobe tumor and the subcarinal node but not in the upper-lobe tumor, we diagnosed as double primary cancers. Local mediastinal recurrence after operation has been well-controlled with administration of gefitinib, a EGFR-tyrosine kinase inhibitor, and mutational analysis of the EGFR gene provided important information not only in the diagnosis of double primary cancers but also in decision-making of selection of chemotherapeutic agent.

Transcriptional Pathway Signatures Predict MEK Addiction and Response to Selumetinib (AZD6244)

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.

Progesterone Receptor Membrane Component 1 (Pgrmc1): A Heme-1 Domain Protein That Promotes Tumorigenesis and Is Inhibited by a Small Molecule

Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and increase metabolism. Progesterone receptor membrane component 1 (Pgrmc1) is related to cytochrome b5, binds to heme, and is associated with DNA damage resistance and apoptotic suppression. Pgrmc1 is induced by carcinogens, including dioxin, and is up-regulated in multiple types of cancer. In the present study, we found that Pgrmc1 increased in vivo tumor growth, anchorage-independent growth, and migration. Pgrmc1 also promoted proliferation in the absence of serum in A549 non-small cell lung cancer cells but enhanced proliferation regardless of serum concentration in MDA-MB-468 breast cancer cells. Pgrmc1 promotes cholesterol synthesis and binds to Insig (insulin-induced gene), Scap (sterol regulatory element binding protein cleavage activating protein), and P450 proteins, but Pgrmc1 did not affect cholesterol synthesis in lung cancer cells. Pgrmc1 is also associated with progesterone signaling and plasminogen activator inhibitor (PAI1) RNA binding protein, but neither progesterone activity nor PAI1 transcript levels were altered in Pgrmc1-knockdown lung cancer cells. Pgrmc1 homologues bind to aryl ligands identified in an in silico screen, and we have found that a Pgrmc1 ligand induced cell death in a Pgrmc1-specific manner in multiple breast and lung tumor cell lines. Our data support a role for Pgrmc1 in promoting cancer-associated phenotypes and provide a therapeutic approach for targeting Pgrmc1 with a small molecule in lung and breast cancer.

Double primary adenocarcinomas of the jejunum and descending colon with lung metastases presenting rare immunohistochemical phenotypes: a case report

We report a male patient with double advanced tumors in the jejunum and descending colon and multiple lung tumors. The intestinal cancers were surgically resected. Immunoprofiling of the specimens revealed a rare phenotype: the jejunal cancer was positive for cytokeratin (CK) 7, partially positive for CK20, and Cdx-2-negative, whereas the colon cancer was CK7(+), CK20(-), and Cdx-2(-). Biopsied lung tumor was diagnosed as tubular adenocarcinoma, and CK7(+)/CK20(+)/Cdx-2(-). Together with clinical information, we deduced that the jejunal adenocarcinoma had presumably metastasized to the lung. Moreover, postoperative oxaliplatin, including chemotherapy, significantly reduced the lung metastases, suggesting that this regimen is a promising treatment option for advanced small bowel adenocarcinoma.

Five‐year lung cancer survival

The core strategy of American College of Chest Physicians lung cancer guidelines is identification of the earliest symptoms of lung cancer and the immediate initiation of diagnosis and treatment. In the absence of screening, most symptomatic lung cancer is discovered at advanced stages, with the goal of long-term survival entirely dependent on effective treatment of stage III and IV lung cancer. In a retrospective review, all patients diagnosed with stage IIIA, IIIB, and IV nonsmall cell lung cancer (NSCLC) between the years 1986 and 2001 at City of Hope National Medical Center who survived 5 years or longer were analyzed to identify parameters that might predict long-term survival. Of 846 patients presenting with stage III or IV disease, 56 (6.6%) survived 5 years or longer. Sixteen patients died of primary tumor progression beyond 5 years. Two 5-year survivors died of second tobacco-caused neoplasms, and 16 died from medical conditions potentially related to prior treatment. A substantial majority of survivors were from specific pathologic subsets including: 1) resectable N2 disease (n = 17, 30.4%), 2) multiple lung tumors (n = 7, 12.5%), 3) T3N0 (n = 5, 8.1%), and 4) single site distant metastasis (n = 8, 14.2%). Despite aggressive multimodality therapy, 5-year survival in patients with advanced stage NSCLC was very poor and limited to small pathological subsets. Patients with advanced stage NSCLC who did not belong to 1 of these subsets had a small chance of long-term survival.

Use of Epidermal Growth Factor Receptor/Kirsten Rat Sarcoma 2 Viral Oncogene Homolog Mutation Testing to Define Clonal Relationships Among Multiple Lung Adenocarcinomas: Comparison With Clinical Guidelines

The incidence of multiple lung adenocarcinomas is rising, making it difficult to determine the stage and assign treatment in an increasing number of patients following surgery. Clinical guidelines have been developed to distinguish independent non-small cell lung cancers from metastases, that is, criteria developed by Martini and Melamed and the American College of Chest Physicians (ACCP). However, these guidelines can be difficult to apply and may give conflicting results. Here, we report on seven patients in whom epidermal growth factor receptor (EGFR) and Kirsten-rat sarcoma 2 viral oncogene homolog (KRAS) tumor mutation status was used to determine clonal relationships among multiple lung lesions. We identified seven patients whose paired lung adenocarcinomas were found to harbor distinct EGFR or KRAS mutations. We assessed these patients' disease status using established clinical guidelines. We also explored the use of comprehensive histologic subtyping (CHS) of tumor sections to distinguish multiple primaries. According to the Martini-Melamed criteria, six of the seven patients had multiple primary lung tumors. By ACCP criteria, three patients had multiple primaries, and three patients had metastases. Classification of the seventh patient by ACCP criteria was indeterminate. Mutational testing suggested that all paired tumors were multiple primary adenocarcinomas, which was consistent with results from CHS. Assuming that independent tumor clones harbor distinct mutations, these seven cases highlight discrepancies between the existing clinical criteria used to distinguish independent tumor foci from metastases. EGFR/KRAS mutation testing of multiple lung adenocarcinomas can assist in differentiating multiple primary lung adenocarcinomas from metastatic lesions. Use of CHS in this setting should also be further explored.

Multiple lung tumors as the cause of death in a patient with subarachnoid hemorrhage: postmortem computed tomography study

A 77-year-old woman who had been in the hospital suffering from a subarachnoid hemorrhage suddenly died after undergoing a cerebral aneurysmal operation. Postmortem whole-body computed tomography (CT) demonstrated multiple lung tumors with abnormal masses in the bronchus with no evidence of complications in the cranium. The patient was estimated to have died from asphyxia caused by metastatic lung and endobronchial tumors. Although a traditional autopsy was not performed, postmortem CT provided strong evidence for detecting the cause of death. In this case, postmortem CT played an important role in hospital risk management.

Intratracheal Delivery of CX3CL1-Expressing Mesenchymal Stem Cells to Multiple Lung Tumors

The lung is one of the organs to which cancers from solid tumors frequently metastasize. Multiple tumors in the lung are usually treated by systemic chemotherapy because of the lack of efficient methods of targeting antitumor agents to the lung. Although intratracheal administration is an ideal route for targeting multiple lung tumors, antitumor agents are often harmful to the organ or induce inflammation. Mesenchymal stem cells (MSCs), nonhematopoietic stem cells capable of differentiating into various mesoderm-type cells, have a propensity to migrate to and proliferate in tumor tissues after systemic administration. We intratracheally injected MSCs expressing CX3CL1 (MSC/RGDFKN) into the lung of lung tumor-bearing mice with multiple metastases of C26 or Lewis lung carcinoma (LLC). Antitumor effects were evaluated by counting the number of lung metastases and survival. We demonstrated the tropism of mouse MSCs to lung tumor tissues after intratracheal administration of GFP-positive MSCs. Intratracheal injection of MSC/RGDFKN strongly inhibited growth of lung metastases of C26 or LLC, and thus prolonged survival. Intratracheal injection of MSC/RGDFKN did not induce an inflammatory reaction in the lung. These results suggest that MSCs expressing antitumor agents can be delivered intratracheally into multiple lung tumor tissues without causing inflammation.

Evidence for Common Clonal Origin of Multifocal Lung Cancers

Lung cancer is the most common cause of cancer death in the United States. Multiple anatomically separate but histologically similar lung tumors are often found in the same patient. The clonal origin of multiple lung tumors is uncertain. We analyzed 70 lung tumors from 30 patients (23 females and seven males) who underwent surgical resection for lung epithelial tumors, of whom 26 had non-small cell carcinomas and four had carcinoid/atypical carcinoid tumors. All patients had multiple tumors (two to five) involving one or both lungs. Genomic DNA was extracted from paraffin-embedded tissue sections using laser capture microdissection and analyzed for loss of heterozygosity, TP53 mutations, and X-chromosome inactivation status. The percentage (95% confidence interval [CI]) of patients in whom there were concordant patterns of genetic alteration was calculated. All 30 case subjects showed loss of heterozygosity (LOH) in at least one and at most four of the six polymorphic microsatellite markers. Completely concordant LOH patterns between synchronous and metachronous cancers in individual patients were seen in 26 (87%) of 30 informative patients (95% CI = 75% to 99%). Identical point mutations were present in eight of 10 patients who exhibited TP53 mutation by sequencing. Tumors in 18 (78%) of 23 female patients (95% CI = 67% to 98%) showed identical X-chromosome inactivation patterns. Combining the results of LOH studies, TP53 mutation screening analyses, and X-chromosome inactivation data, we demonstrated that the multiple separate tumors in 23 (77%) of 30 patients (95% CI = 62% to 92%) had identical genetic changes, consistent with monoclonal origin of the separate tumors. Our data indicate that the great majority of multifocal lung cancers have a common clonal origin and that multifocality in lung cancer represents local and regional intrapulmonary metastasis.

Benign Metastasizing Leiomyoma of the Lung: Potential Role of Low-Grade Malignancy

We report here 2 cases of multiple metastatic lung tumors after hysterectomy for leiomyoma. One patient was diagnosed as having a benign metastasizing leiomyoma (BML), while the other patient simultaneously developed a left pelvic tumor and multiple lung tumors, both of which were finally diagnosed as low-grade endometrial stromal sarcomas (ESSs). The metastatic potential of BML is not completely understood, but previously reported cases of BML may include low-grade ESS, which may play a significant role in the metastasis of benign uterine tumors.

Secondary Malignant Fibrous Histiocytoma Following Refractory Langerhans Cell Histiocytosis

We describe a rare case of secondary malignant fibrous histiocytoma (MFH) following Langerhans cell histiocytosis (LCH). A 23-year-old Japanese male exhibited systemic lymphadenopathy, multiple lung tumors, and osteolytic changes in bilateral iliac bones in 1989. A biopsy specimen from the left iliac bone revealed an infiltration of S-100 protein-positive histiocyte-like cells intermingled with eosinophils, which confirmed the diagnosis of eosinophilic granuloma, a type of LCH. Although the patient was treated with prednisolone initially, the disease did not respond well and progressed gradually over time. The patient subsequently received multiple courses of chemotherapy and immunosuppressive therapy with many kinds of anticancer agents for 6 years. He also received radiotherapy totaling 136.8 Gy for lung tumors and osteolytic lesions of the pelvis. In 1997, because of the LCH refractoriness, biopsy was performed again from the right inguinal lymph node. Microscopic examinations demonstrated a mixture of spindle-shaped cells and histiocyte-like cells, which appeared to be in a storiform pattern. The tumor cells were immunohistologically positive for CD68 and vimentin, but negative for CD1a and S-100 protein. Therefore, the patient was diagnosed with MFH. Although chemotherapy was continued, the patient died of pneumonia during the neutropenic period following chemotherapy. Autopsy revealed systemic invasion of MFH and dissemination of mucormycosis. LCH was not detected histologically in any tissues.

Gastric Metastasis of Breast Cancer in a Male Patient: Report of a Case

A 65-year-old male patient presented with epigastralgia. At 57 years of age, the patient was diagnosed as cancer of the right breast (T1cN0M0) and underwent a mastectomy and axillary dissection. ER and PgR were positive, and HER2 was 2+. At six years after surgery, multiple metastatic lung tumors were found to have developed, and the patient underwent a partial resection of the left lung. Supraclavicular and mediastinal lymph nodes and pleural metastasis also developed postoperatively and were treated with chemotherapy. The patient developed epigastralgia at 30 months after the lung surgery, and underwent upper gastrointestinal endoscopy. An elevated lesion with a bridging fold was detected in the middle body of the stomach, and the results of a biopsy showed adenocarcinoma. The immunohistochemical staining results were positive for cytokeratin (CK) 7 and negative for CK20, and the patient was diagnosed as breast cancer metastasis to the stomach. Although breast cancer metastasis to the stomach has been detected in a small percentage of cases based on autopsy findings, it is extremely rare that a diagnosis of this disease is made in the clinical setting. A case of breast cancer metastasis to the stomach in a male patient is even rarer. A search of the Japan Centra Revuo Medicina database revealed only one such case among previous reports in Japan. In conclusion, it is necessary to address the possibility of breast cancer metastasis to the stomach when searching for a gastric tumor in a patient with a past history of breast cancer.

Malignant Epithelioid Angiomyolipoma in the Kidney and Liver of a Patient with Pulmonary Lymphangioleiomyomatosis: Lack of Response to Sirolimus

A 26-year-old woman with lymphangioleiomyomatosis (LAM) was hospitalized for the surgical excision of a giant abdominal tumor of right kidney origin. The pathological diagnosis of the tumor was conventional angiomyolipoma (AML). After 8 months, 2 liver tumors appeared and grew rapidly. The tumors were resected, and the pathological finding of these tumors was epithelioid AML. Thereafter, metastatic multiple lung tumors appeared, and there was local recurrence of the liver tumors. Sirolimus, an mTOR protein inhibitor, was used to treat epithelioid AML. However, the drug did not inhibit the rapid growth of the tumor at all. This finding suggests that sirolimus might not be effective against epithelioid AML, and in such cases, complete surgical resection should be the treatment of choice.

Lymphoma and lung cancer in offspring born to pregnant mice dosed with dibenzo[ a,l]pyrene: The importance of in utero vs. lactational exposure

The fetus and neonate cannot be viewed as “little adults”; they are highly sensitive to toxicity from environmental chemicals. This phenomenon contributes to the fetal basis of adult disease. One example is transplacental carcinogenesis. Animal models demonstrate that environmental chemicals, to which pregnant women are daily exposed, can increase susceptibility of the offspring to cancer. It is uncertain to what degree in utero vs. lactational exposure contributes to cancer, especially for hydrophobic chemicals such as polyhalogenated biphenyls, ethers, dioxins, furans, etc., which can partition into breast milk. We developed a pregnant mouse model in which exposure to the polycyclic aromatic hydrocarbon (PAH), dibenzo[ a,l]pyrene (DBP), during late gestation, produces an aggressive T-cell lymphoma in offspring between 3 and 6 months of age. Survivors exhibit multiple lung and liver (males) tumors. Here, we adopt a cross-foster design with litters born to dams treated with DBP exchanged with those born to dams treated with vehicle. Exposure to DBP in utero (about 2 days) produced significantly greater mortality than residual DBP exposure only through breast milk (3 weeks of lactation). As previously observed pups in all groups with an ahr b-1/d (“responsive”) genotype were more susceptible to lymphoma mortality than ahr d/d (“non-responsive”) siblings. At termination of the study at 10 months, mice exposed in utero also had greater lung tumor multiplicity than mice exposed only during lactation. Our results demonstrate that short exposure to DBP during late gestation presents a greater risk to offspring than exposure to this very hydrophobic PAH following 3 weeks of nursing.

Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells

Most advanced solid tumors metastasize to different organs. However, no gene therapy effective for multiple tumors has yet been developed. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine whether MSCs could serve as a vehicle of gene therapy for targeting multiple tumors. First, we confirmed that mouse MSCs preferentially migrate to multiple tumors of the lung in the Colon-26 (C-26) lung metastasis model. Next, MSCs were efficiently transduced with NK4, an antagonist of hepatocyte growth factor (HGF), by an adenoviral vector with an RGD motif. MSCs expressing NK4 (NK4-MSCs) strongly inhibited development of lung metastases in the C-26 lung metastasis model after systemic administration via a tail vein. Treatment with NK4-MSCs significantly prolonged survival of the C-26-tumor-bearing mice by inhibiting tumor-associated angiogenesis and lymphangiogenesis and inducing apoptosis of the tumor cells. MSC-based gene therapy did not induce the severe adverse effects induced by conventional adenoviral vectors. These results indicate that MSCs can serve as a vehicle of gene therapy for targeting multiple lung metastatic tumors.

Targeted Delivery of CX3CL1 to Multiple Lung Tumors by Mesenchymal Stem Cells

MSCs are nonhematopoietic stem cells capable of differentiating into various mesoderm-type cells. MSCs have been considered to be a potential vehicle for cell-based gene therapy because MSCs are relatively easily expanded in vitro and have the propensity to migrate to and proliferate in the tumor tissue after systemic administration. Here, we demonstrated the tropism of mouse MSCs to tumor cells in vitro and multiple tumor tissues in the lung after i.v. injection of green fluorescent protein-positive MSCs in vivo. We transduced CX3CL1 (fractalkine), an immunostimulatory chemokine, to the mouse MSCs ex vivo using an adenoviral vector with the Arg-Gly-Asp-4C peptide in the fiber knob. Intravenous injection of CX3CL1-expressing MSCs to the mice bearing lung metastases of C26 and B16F10 cells strongly inhibited the development of lung metastases and thus prolonged the survival of these tumor-bearing mice. This antitumor effect depended on both innate and adaptive immunity. These results suggest that MSCs can be used as a vehicle for introducing biological agents into multiple lung tumor tissues. Disclosure of potential conflicts of interest is found at the end of this article.

Cardiac metastasis of renal pelvic cancer

A 66-year-old man was referred to our hospital with chest discomfort and shortness of breath. Seven months previously he had undergone a laparoscopic left nephroureterectomy for a left renal pelvic tumor and was given two cycles of adjuvant chemotherapy (methotrexate, epirubicin and cisplatin). Echocardiogram showed an 8-mm sized mass extending from the right atrium into the right ventricle. On computed tomography, multiple lung tumors, as well as the right atrial and ventricular mass, were seen. The patient died of acute heart failure caused by right ventricular outflow obstruction. On autopsy, a right atrial and ventricular metastasis of the initial transitional cell carcinoma was found. The patient's cause of death was acute heart failure as a result of cardiac metastasis of his initial renal pelvic carcinoma.

Genetic Heterogeneity in Patients with Multiple Neoplastic Lung Lesions: A Report of Three Cases

It is important to determine the relation among the various lesions in patients presenting with multiple malignant lung tumors to define the best treatment approach. A better understanding of the molecular alterations present in the different lesions may help in defining this relation. We performed a detailed molecular analysis of several tumor specimens obtained from three patients presenting with multiple lung lesions. Tumor specimens were analyzed for epidermal growth factor receptor (EGFR) and k-ras mutations by direct DNA sequencing. In addition, a genome-wide chromosomal copy number analysis was performed on DNA extracted from the various lesions using array-based comparative genomic hybridization. In one case, a deletion of 15 base pairs in exon 19 of EGFR was present in all tumor sites analyzed. Furthermore, a similar pattern of chromosomal aberrations was observed among the various lesions, suggesting that they share the same clonal origin. In the other two cases, in contrast, we identified distinct k-ras genotypes among the various lesions from the same patient. These lesions, moreover, showed different chromosomal aberration patterns, indicating that they may have different underlying pathways of tumorigenesis. Our results show that EGFR and k-ras mutation analysis, combined with chromosomal copy number profiling, can help in defining the relationship among different tumors in one patient.

ERBB Signaling Promotes BCR-Abl Expression and Modulates Multiple Signaling Pathways as Assessed by High-Throughput, Reverse Phase Protein Array.

ERBB family receptor tyrosine kinases, EGFR, Her-2, Her-3 and Her-4, are prognostic and therapeutic targets in multiple carcinomas, including breast, lung, and head and neck tumors. We previously reported aberrant expression and activation of Her-2 and Her-4 in a panel of Ph+ ALL cell lines: Z33, Z119, and Z181. Loss of cell viability and apoptotic DNA fragmentation were observed after treatment with the irreversible pan ERBB inhibitor, CI-1033, in vitro. In the present study, we define the mechanisms of cell death initiated by ERBB blockade. We examined the expression and Tyr1248 phosphorylation of Her-2 in Z119 and Z181 cell lines upon CI-1033 treatment and found a 4-fold decrease in Ph-Y1248 by Western blotting. We then assessed the impact upon downstream signaling pathways using reverse-phase protein microarray (RPPA) - a new high-throughput method to measure and profile the total expression and post-translational phosphorylation of signaling pathway components. Leukemia cells treated with CI-1033 assessed with RPPA using 34 different antibodies showed mTOR expression to be decreased by more than two-fold in Z119 and Z181. Concomitantly, we saw a more than three-fold decrease in phosphorylated S6-S240/244. This suggests that down-regulation of translational control caused by inhibition of activated ERBB-family receptors contributes to the reduced proliferation in these cells. We also observed a 3.5-fold decrease in phosphorylated glycogen synthase kinase (GSK)-3a/b 21/9 in Z119 and a 1.7-fold decrease in Z181. This suggests inactivation of GSK3, which is regulated by Akt/PKB signaling. We also observed a four-fold decrease in Bcr-Abl expression in Z181, identified as p190 by Western. This suggests that ERBB signaling helps maintain expression of Bcr-Abl protein, driving Ph+ lymphomagenesis, perhaps explaining why ERBB blockade induces apoptosis in Ph+ ALL. Elucidating the mechanism of this apoptosis, CI-1033 caused activation of caspase-3 in Z119 and Z181 as measured by DEVD-AMC cleavage, and caused PARP cleavage. Thus multiple, non-redundant signaling pathways downstream of ERBB can be downregulated with a small molecule inhibitor, CI-1033, causing reduced viability and increased apoptosis in ERBB+ Ph+ ALL cell lines. Our data suggest that inhibition of these signals may provide additional therapeutic efficacy to Ph+ ALL patients. [Display omitted]

Bisphosphonates for malignancy-related bone disease: current status, future developments

This review relates to the efficacy and safety of bisphosphonates in metastatic bone disease. It discusses practical recommendations and possible future indications for bisphosphonate therapy. The current aims of bisphosphonates for metastatic bone disease are to prevent skeletal-related events (SREs), reduce bone pain and improve quality of life. Phase III clinical trials of clodronate and pamidronate have established their efficacy against bone complications in patients with breast cancer and multiple myeloma, while randomized trials have shown SRE reductions with zoledronic acid in patients with breast cancer and multiple myeloma, prostate cancer, and lung and other solid tumors. These bisphosphonates also have some effect on metastatic bone pain. Ibandronate is a new aminobisphosphonate, available in more than 40 countries outside of the US as intravenous and oral formulations for the prevention of skeletal events in patients with breast cancer and bone metastases. Phase III studies have shown that both intravenously and orally administered ibandronate have efficacy for the prevention of skeletal events and for the reduction of metastatic bone pain. In addition to efficacy, the long-term tolerability of bisphosphonates in metastatic bone disease influences drug selection. Besides their use in patients with established bone metastases, recent and ongoing research suggests that bisphosphonates also have clinical benefit in the adjuvant setting, and for the treatment of cancer-treatment-induced bone loss. Such interesting new developments may underpin a new era of bisphosphonate use sometime in the near future.