Metastatic Bone Disease

While bisphosphonates remain the backbone of treatment for metastatic bone disease, recent research has uncovered several potential targets for drug therapy to treat, and possibly even prevent, bone metastases. “We are beginning to elucidate the mechanisms by which bones fall apart in patients with cancer,” said James R. Berenson, MD, Director of the Multiple Myeloma and Bone Metastasis Programs at Cedars-Sinai Medical Center and Professor at the UCLA School of Medicine. But equally important, he said, “we are also getting the attention of the National Institutes of Health. The NIH is beginning to offer grants specifically focused on treatment and prevention of metastatic bone disease.” The focus of recent research has been finding specific targets in the pathways leading to bone-tumor development that can be attacked with targeted therapies. Dr. Berenson said several new targeted therapies for bony metastases are beginning early clinical trials, but nothing is as far along in treatment of bone metastases as the bisphosphonates. “Bisphosphonate therapy is going to be the mainstay for some years,” said Gregory R. Mundy, MD, Professor in the Department of Cellular and Structural Biology and Assistant Dean for Clinical Research at the University of Texas Health Science Center at San Antonio. It is evident from both preclinical and most clinical studies that bisphosphonates cause a decrease in tumor burden in bone metastatic sites, Dr. Mundy said. They may possibly have additional effects in vivo at non-bone sites, but that has still not been satisfactorily proven, he added. “My sense is that bisphosphonates do not have a have a direct cytotoxic effect on tumors, but rather change the bone environment so that tumors growing in bone do not thrive well there,” he said. “It's the old ‘seed and soil’ hypothesis revisited.”Figure: James R. Berenson, MD: “We are beginning to elucidate the mechanisms by which bones fall apart in cancer. But equally important, we are also getting the attention of the NIH, which is beginning to offer grants specifically focused on treatment and prevention of metastatic bone disease.”Bone Loss, Bone Growth Most of the research in metastatic bone disease has been directed against inhibiting bone loss rather than increasing bone density, but recently some researchers have begun looking at both sides of the problem. This is how bisphosphonates, developed to treat bone loss from osteoporosis, came to be used in treating malignant bone growth. “If you lose bone you want to rebuild bone at the same time,” Dr. Berenson said. ''And if you measure bone density in people who get bisphosphonates and other anti bone-resorptive therapy, it actually gets better. “Somehow, bisphosphonate treatment not only prevents further bone loss but also increases bone density as measured on bone densitometry scans.” He said metastatic prostate cancer is a disease that refutes the conventional wisdom of just a few years ago, when it was thought that bone involvement in prostate cancer was osteoblastic. “People thought prostate cancer metastases caused too much bone formation, but in fact the amount of bone loss in men with advanced prostate cancer is very high,” Dr. Berenson said. “On x-ray they may appear to have too much bone formation, but if you measure overall bone loss it is very high.” In fact, he said, when a prostate-cancer tumor is put into an immunodeficient mouse, “the first thing you see is holes in the bone.” ‘Zometa Betta’? Two bisphosphonates featured in recent Phase III trials are clodronate (Aredia) and zolendronate (Zometa). Zolendronate is the “new kid on the block,” Dr. Berenson said, positioned to replace clodronate. Its manufacturer's representatives are fond of saying “Zometa is betta,” he said. “In the 1990s we had data that clearly showed clodronate reduced skeletal complications in breast cancer and myeloma with osteolytic bone disease," Dr. Berenson said,” and now zolendronate has clearly shown activity in all bone mets. “So regardless of whether you have a lesion that comes from the liver, the colon, breast, or lung, your chances of having a skeletal complication are lessened with zolendronate.” In multiple myeloma, he said, research has shown an equivalence of zolendronate to clodronate, although not increased efficacy. But he added that the dose of zolendronate used in those trials was only 4 mg versus 90 mg of clodronate, so there is a clear potential to increase the zolendronate dose in myeloma. “The advantage of zolendronate is that it is a 15-minute drug, while clodronate takes several hours to infuse, though we don't have head-to-head data showing Zometa to be any better than Aredia at the present 4 mg dose,” Dr. Berenson said last month. “But we are planning to start a trial in the next few weeks with a higher zolendronate dose.” Zolendronate doses of 8 mg have caused renal dysfunction in some trials, and Dr. Berenson said this next trial will administer it more slowly to protect the kidneys. Osteoblast-Osteoclast Crosstalk Crosstalk between the bone and the cancer in the bone plays a far more important role than researchers previously believed. It is now thought that if a therapy can affect one it might also affect the other, or that interfering with signaling between a bone and the metastatic tumor in the bone might cause the tumor to regress. Some of the newer molecules that are antitumor turn out to be anti bone-resorptive as well, irrespective of their ability to cross the circuitry between the two, Dr. Berenson noted. Imatinib (Gleevec) may be an example of just such a molecule, he said. Research has begun on the use of imatinib in treating multiple myeloma and bone metastasis. But Dr. Berenson said there are other agents that may be better than imatinib in treating bone metastasis—specifically inhibitors of the new transcription factor nuclear factor kappa-B. NF-kappa-B is a member of the tumor necrosis factor receptor family, an important factor in the crosstalk between osteoclasts and osteoblasts in the bone microenvironment. Inhibiting NF-kappa-B interferes with the crosstalk and thwarts the development of osteoclasts. OPG: Promising Inhibitor A promising inhibitor is the protein osteoprotegerin (OPG), a naturally occurring “decoy” receptor present in the circulation. OPG maintains a natural balance between bone formation and bone resorption by preventing osteoclastogenesis, acting as a rheostat that determines how much or how little bone is resorbed. Animals lacking OPG show profound osteoporosis, Dr. Berenson said. Amgen has cloned OPG, first as an analog and now as an antibody, he noted, and OPG is now being tested in clinical trials in myeloma and breast cancer patients with bone metastases. PS-341 is another recently developed inhibitor of NF-kappa-B now entering early clinical trials as an antitumor agent. And there are recent data that interferon-beta may be a possible treatment for bone cancer and osteoporosis in general, Dr. Berenson said. He said interferon-beta appears to autoregulate osteoclastogenesis and prevent too many osteoclasts from being made. "Inteferon-beta has been administered into animals with ovaries removed, and they don't get osteoporosis,” Dr. Berenson said. The future might also see these novel bone-met treatments combined with a bisphosphonate as the drug carrier, since in the laboratory anticancer agents such as OPG, ibritumomab (Zevalin), and rituximab can already be piggybacked onto bisphosphonate molecules directly. Statins in Bone Therapy Those statin drugs taken by millions of Americans to control their cholesterol level may also have a medical application as treatment for bone metastases. Statins have recently been shown to increase bone formation in vitro and in in-vivo animal models, possibly through their ability to induce apoptosis of osteoclasts. “We're very hopeful that statins will have major use for the treatment of bone diseases,” Dr. Mundy said. ''The statins as they are currently used may or may not be effective, since they have been selected to target the liver, and very small amounts get to the periphery, namely bone. “However, we do know that when statins get to bone, they have a powerful stimulatory effect on bone formation. We're working currently on better methods of delivery so we can bypass the liver.” Dermal application may be the secret to more effective use of statins here, as suggested by preclinical animal studies, Dr. Mundy said. Clinical Trials Imatinib's effect on metastatic bone tumors might have to do with its antiangiogenic activity, according to researchers at The University of Texas M.D. Anderson Cancer Center, who are completing a Phase I trial of the agent in combination with docetaxel in men with androgen-independent prostate cancer. The clinical trial follows animal research there by Dr. Sun Jin Kim in the laboratory of Isaiah J. Fidler, PhD, DVM. Injecting prostate cancer cells into tibia of a nude mouse, Dr. Kim found that the platelet-derived growth factor receptor (PDGFR), a tyrosine kinase transmembrane protein, is overexpressed in prostatic epithelial cells adjacent to bone. Imatinib in combination with paclitaxel prevented skeletal morbidity in a mouse prostate-cancer model and reduced tumor size compared with either drug used alone. The combination was apparently specific to bone, as the researchers observed that it induced endothelial cell apoptosis in the vasculature of the bone tumors but not in the vasculature of tumors in adjacent muscle. The principal investigator of the Phase I trial, Paul Mathew, MD, Assistant Professor in the Department of Genitourinary Medical Oncology, said that imatinib with docetaxel is a rational combination since docetaxel is one of the most commonly used single-agent chemotherapy drugs for advanced prostate cancer. In the Phase I study, 22 men with androgen-independent prostate cancer with bone metastases have been receiving oral imatinib at 600 mg/day, plus escalating doses of weekly docetaxel starting at 30 mg/m2. Once the maximally tolerated dose has been determined, a Phase II trial will begin, Dr. Mathew said. Dr. Mathew said that in preclinical studies the combination appears to have activity in both lytic as well as blastic tumors, so it might have use in treating bone metastases from cancers other than prostate cancer. Bisphosphonates in Prostate Cancer Reports from a much anticipated Phase III trial in prostate cancer show that zolendronate reduced the incidence of skeletal-related events by approximately 25% in men with advanced, androgen-independent disease. In the randomized trial, men taking zolendronate had a 33% rate of skeletal-related events compared with 44% for men taking placebo, said principal investigator Fred Saad, MD, Associate Professor of Urology and Director of Urologic Oncology at Montreal Cancer Institute. In a presentation at this year's American Urological Association annual meeting, Dr. Saad reported on 214 patients taking 4 mg of zolendronate and 208 patients taking placebo. Not included in the data were 155 subjects in an 8-mg zolendronate trial arm, which was discontinued due to early reports of renal dysfunction. The 15-month data showed that the rate of subsequent skeletal-related events was reduced by 36% in the zolendronate arm. Dr. Saad noted that this is a substantial decrease considering that men who develop a first clinically detectable bone tumor typically develop further tumors quite rapidly. There was also a trend toward increased survival with the 4 mg dose, with a median survival of 563 days with zolendronate versus 469 days with placebo. “This improvement in survival, while only a trend, is surprising in a group of men with advanced disease for whom life expectancy is usually not much more than a year,” Dr. Saad said. All men in the trial had failed to respond to hormone therapy for their disease. Dr. Saad said the most common skeletal-related event in both trial groups was a need for radiation to control pain. There were only two cases of hypercalcemia. The bisphosphonate apparently had no effect on the prostate-specific antigen (PSA) level, as there was no difference between the two trial arms at the study's conclusion. But patients with a rising PSA will eventually develop bone metastases, Dr. Saad said, “and it is possible that early administration of zolendronate will prevent or at least delay their development.” Adjuvant Bisphosphonates in Breast Cancer Preventing the development of bone metastases was the object of another important trial just completed. Dr. Trevor Powles and colleagues examined the potential of clodronate as adjuvant therapy for primary breast cancer in the largest clinical study published so far on this topic (J Clin Oncol 2002;20:, 3219-3224) The data showed there were fewer bone metastases in women treated with clodronate, and that clodronate treatment provided a likely survival advantage. The randomized study of 1,069 women with primary operable breast cancer treated 530 with clodronate at 1,600 mg/day and 539 with placebo, for two years, following primary treatment. With a median follow-up of 2,007 days, the study showed that the occurrence of bone metastases was significantly reduced in the treatment patients, with an incidence of 2.3% vs 5.2% with placebo. The effect was not maintained once treatment was discontinued. Actuarial bone metastases-free survival rates at two years were 96.2% for clodronate vs 93.3% for placebo; at five years the rates were 88.9% and 89.8%, respectively. Benefits Outside Bone Debated In an accompanying editorial, Dr. Mundy wrote that there was no apparent deleterious effect of clodronate in soft tissue metastases (J Clin Oncol 2002;20:3191–3192) But he also noted that the Powles report did not answer the question of whether bisphosphonates have a beneficial effect in cancer other than their well-known and well-, documented effect of reducing bone lesions. “Bisphosphonates' effect on non-osseous metastases is one of the hotly debated and still unresolved issues in the bone metastasis field,” Dr. Mundy said. “It does appear from the study of Powles et al that bisphosphonates can likely be used safely in breast cancer in the adjuvant setting, although their benefits as far as long-term effects on visceral metastases are concerned remain unclear.” Pancreatic Cancer Action Network Starts New Patient Service The Pancreatic Cancer Action Network (PanCAN) has launched a new program called Patient and Liaison Services (PALS). The service is dedicated to informing patients, families, and physicians about pancreatic cancer clinical trials, as well as providing one-on-one information, decision-making tools, and follow-up for patients and their families over the telephone or via e-mail or direct mail. The program is in the process of compiling a comprehensive database of all the pancreatic cancer clinical trials that will provide patients with all their clinical trial options. This information system is being developed in conjunction with the Coalition of National Cancer Cooperative Groups and the Clinical Trials Information Project. “We are ecstatic that we can add such a great resource and continue to provide the very best services to the pancreatic cancer community,” said Paula Kim, PanCAN's Founding CEO and Chairman of the Board. The toll free phone line can be reached Monday through Friday, from 9 am to 5 pm PST by dialing 877-2-PANCAN (877-272-6226). Further information can also be obtained online at the organization's Web site, www.pancan.org.

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