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Clinical Approaches to Osseous Metastases in Prostate Cancer

Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Medical College of Cornell University, New York, New York, USA

Correspondence: Michael J. Morris, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 444, New York, New York 10021, USA. Telephone: 646-422-4469; Fax: 212-988-0701; e-mail: morrism{at}mskcc.org

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
After completing this course, the reader will be able to:

1. Recognize the biology underlying metastatic prostate cancer to bone.
   
2. Identify the clinical risks that osseous metastases pose to prostate cancer patients.
   
3. Explain the clinical management of osseous disease in prostate cancer patients.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
Background. Prostate cancer is unique among solid tumors in its proclivity to metastasize primarily to bone. Osseous metastases pose a formidable health threat to patients with metastatic disease, putting them at risk for pain, marrow crowding, fracture, and other sequelae. Treatments directed against bone disease have the potential both to palliate pain and to increase survival.

Conclusions. A number of agents exist that have the potential to palliate the effects of osseous metastases and should be routinely applied in the clinical care of the patient with advanced prostate cancer. These include hormones, bone-seeking radiopharmaceuticals, chemotherapy, and bisphosphonates. Strategies under investigation aim to eradicate bone disease, and not merely palliate symptoms. These approaches combine those listed above with tumor-directed targeting of osseous disease and manipulation of the biology that underlies the cancer’s relationship to bone.

Key Words. Prostate cancer • Osseous metastases • Bisphosphonates • Radiopharmaceuticals • Bone disease

	INTRODUCTION

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
Prostate cancer is unique among solid tumors in that the greatest threat to a patient’s survival and quality of life is posed by bone metastases rather than visceral involvement. Indeed, nearly all treatments of patients with metastases are directed toward eradicating or limiting osseous disease or palliating its side effects. Untreated, patients face an array of sequelae that includes bone pain, fracture, hematologic consequences of packed marrow, and neurologic impairment resulting from base-of-skull disease or cord compression. Treated, these effects can be effectively palliated, and patients may also derive a survival benefit. However, despite a wealth of treatments available to ameliorate the consequences of bone disease, complete durable responses to existing treatments remain elusive.

Although previous efforts to treat osseous disease have focused on palliation, there is increasing recognition that targeting tumors in the marrow will be necessary to achieve curative outcomes. This report reviews these evolving strategies.

	OSSEOUS DISEASE: WHEN DOES A PATIENT HAVE BONE DISEASE?

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
Clinical investigators are increasingly employing unifying models that describe the clinical risks, appropriate treatment strategies, and tumoral biology of a patient, throughout the natural history of the disease. Unlike the standard tumor/node/metastasis staging system, these models describe the patient not only at the time of diagnosis, but as he progresses through the untreated and treated history of the disease. In the Memorial Sloan-Kettering Cancer Center (MSKCC) model, seen in Figure 1, the natural history of the disease is defined by several discrete clinical states: localized disease, rising prostate-specific antigen (PSA), noncastrate metastatic, and castrate metastatic. Patients transition from one state to another as they progress. Hence, a patient enters the state of rising PSA as he biochemically relapses following definitive local therapy such as radiation therapy or prostatectomy. Patients enter the noncastrate metastatic state when diagnosed with radiographically evident metastases in the setting of noncastrate testosterone levels, and generally respond to castration; patients in the castrate metastatic state have progressive disease despite castrate levels of testosterone. Patients face a variety of risks that are state dependent, including the risk of increasing morbidity from progressive disease (state-to-state transitions), death from prostate cancer, or death from other causes [1].

View larger version (16K): [in this window] [in a new window]   Figure 1. A clinical states model is used to describe the natural history of prostate cancer, to define treatment aims appropriate to a given phase of the disease, and to design clinical trials. Reprinted with permission from Urology 2000;55:323–327 and Surg Oncol 2002;11:13–23.

	RADIOGRAPHIC IMAGING OF OSSEOUS METASTASES

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
By convention, patients are thought to have formally made the transition to having metastatic disease when bone scintigraphy is positive or, less commonly, when nodal or visceral metastases emerge. It is widely recognized, however, that changes in PSA levels usually antedate changes on bone scans by several months. During that time, micrometastatic disease is likely proliferating, but bone turnover is as yet insufficient to manifest scintigraphically. The marrow phase of the disease can be seen using imaging studies that visualize tumors directly, which bone scans unfortunately do not. Such modalities can visualize tumors on the basis of metabolism, surface proteins, or disruption of normal marrow. For example, positron emission tomography (PET) scans visualize tumors by detecting alterations in normal metabolism. The usual tracer is fluorinated deoxyglucose (FDG). Most investigators have reported mixed results using PET to detect prostate cancer [8–11]. However, these studies examined patients at various phases of the disease and at various points in treatment. Contemporary clinical trials in prostate cancer require that such heterogeneity be minimized [12]. When PET scanning is studied on a state-by-state basis, using patients carefully controlled for progressive metastatic disease, PET can, indeed, not only detect active disease seen on bone scans well, but can detect FDG-avid disease in bone months before it is scintigraphically evident. PET can also identify areas of uptake on bone scans that represent inactive tumor, arthritis, or trauma, which ultimately are quiescent, nonprogressive, and pose no clinical threat to the patient [13].

	HORMONAL THERAPY AND BONE DISEASE: WHEN TO TREAT?

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
The historic view that prostate cancer is an indolent disease that requires treatment only in its later stages is changing. A number of prospective randomized clinical trials have demonstrated that early hormonal therapy benefits patients by delaying progressive bone disease and increasing survival. These studies have shown that hormones started at the diagnosis of locally advanced disease [14], as adjuvant therapy following radiation [15], and following the detection of nodal disease can confer a survival benefit [16]. In a trial randomizing 415 patients to either adjuvant hormones or observation following radiation therapy, 78% of the patients who received hormones were alive at 5 years compared with 62% of those who did not (p = 0.0001) [17]. Critics have noted that the applicability of this study might be limited to the management of poor-risk cases, as patients in the control arm of the trial did more poorly than one would expect historically [18]. In a study that accrued 98 patients (despite a target accrual of 220) with early nodal disease randomized to start hormones either at diagnosis or at the onset of radiographic metastases, the patients who received early hormones enjoyed a clear survival benefit (85% versus 65%, p = 0.02) at a median follow-up of 7.1 years [16]. Finally, in a British trial, 938 patients were randomized to either hormones at diagnosis or at progression (as determined by the local physician). Three hundred sixty-one patients died in the deferred arm compared with 328 in the immediate arm (p = 0.02, two-tailed) [14]. This difference was most pronounced in patients with localized disease, although the fact that 5% of patients in the study died from prostate cancer having never received any hormonal therapy has raised questions as to whether some patients on the control arm received adequate monitoring. All of these studies have flaws, and no single trial, therefore, has set a standard that all prostate patients should receive early hormonal therapy. In aggregate, however, these studies form a legitimate basis for concluding that at least selected subsets of patients will derive an overall survival benefit when metastatic bone disease is treated, even before it is radiographically evident.

The trend toward treating patients with hormones earlier in the disease course is further driven by the Early Prostate Cancer program in which 8,113 men with localized prostate cancer were treated with 150 mg of bicalutamide or placebo as primary therapy or as an adjuvant following surgery or radiation. Patients who received the bicalutamide derived a 42% relative risk reduction of developing clinical metastases [19]. However, clinical metastases occurred in only 14% of the patients, with an absolute difference of only 5% between the two treatment groups. Treatment was associated with either gynecomastia or breast pain or both in 83% of the patients who received bicalutamide [19].

Castrating hormonal therapy itself induces bone wasting, which must also be considered in the decision of whether to treat patients earlier in the natural history. Prostate cancer patients treated with castrating hormones experience a 6%–18% loss in bone mineral density relative to eugonadal men and have greater bone turnover rates [20–22]. Clinically, this results in a fivefold greater risk of fracture relative to age-matched controls, which is proportional to the duration of treatment [23]. These risks should give pause to the clinician who is faced with the dilemma of wanting to intervene early and aggressively without inducing debilitating treatment-related side effects that compete with disease-related morbidity. At the root of this balance is the inadequacy of present hormonal therapy: it is not curative, its antitumor effects are not durable, and its side effects as a chronic strategy mitigate its benefits. Hence, the trend to treat patients for bone disease earlier should advance lockstep with an effort to develop treatments more effective and less toxic than hormones.

There is no current established standard that defines the clinical state in which it is most appropriate to initiate systemic hormonal treatment. For some patients, starting therapy immediately after definitive local therapy is too early, yet deferring therapy until the tumor induces bone pain and threatens bone structural integrity is too late. Methods of assessing the risk of developing bone disease must be used to predict accurately which patients require a systemic intervention. For patients with localized disease, a number of models exist to predict the likelihood of cure following definitive local therapy [24–27]. For example, the Kattan and Scardino nomogram can predict the likelihood of biochemical relapse at 5 years following surgery, external beam radiation therapy, or brachytherapy on the basis of the patient’s pretreatment PSA level, Gleason score, and clinical staging [24–26, 28]. By implication, such models identify patients who have micrometastatic disease at diagnosis and who might, therefore, benefit from an early systemic intervention.

For patients who have undergone a prostatectomy and who have biochemically relapsed, Pound et al. have created a prognostic model predicting the likelihood of developing radiographically evident bone metastases [29]. In this model, Gleason score, the time interval in which the PSA level doubles, and the time to relapse are used to predict the likelihood of developing metastases at 3, 5, and 7 years. One limitation of this data set is that it is based on 1,997 patients, only 304 of whom developed a rising PSA level. Only 103 men ultimately developed metastases, so the model is based on relatively few events. Furthermore, the model is based on a select group of patients, all of whom underwent prostatectomies by a single surgeon. Models also exist for determining which men with advanced androgen-independent disease will die from their disease, using such factors as age, hemoglobin level, and lactate dehydrogenase level [30].

These prognostic models, though imperfect, are at least starting points for predicting the likelihood of developing micrometastases for patients with localized disease, radiographic metastases for patients with localized disease, and death for patients with clinical metastases. Systemic therapies can then be selected and matched to an appropriate treatment population.

	BISPHOSPHONATES: MITIGATING THE EFFECTS OF HORMONES AND TUMOR

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
Both hormonal therapy and bone metastases pose threats to prostate cancer patients; bisphosphonates likely have a role in countering both. Prostate cancer is uniquely characterized by a predominance of sclerotic, or blastic, lesions. The scientific rationale for using bisphosphonates in prostate cancer is compelling, despite the fact that bisphosphonates primarily act on osteoclasts. Notwithstanding the sclerotic nature of prostate cancer bone lesions, both blastic and lytic processes are active. Histomorphometric studies reveal that sclerotic prostate metastases involve both lytic and blastic processes, suggesting that the normal coupling between the two processes may be dysregulated, but is not entirely lost [31–33]. Factors such as transforming growth factor beta (TGF-ß) form a component of the proposed basis of such linkage. TGF-ß, which is produced by prostate cancer cell lines [34] and is elevated in prostate cancer pathology specimens [35, 36], activates both osteoblast bone deposition and osteoclastic bone resorption [37]. Furthermore, suppressing osteoclast activity results in a decrease in osteoblastic lesions. For example, in rat prostate cancer in vivo models, inhibition of osteoclast activity resulted in diminished growth of bone (though not soft tissue) tumors [38]. Bisphosphonates also appear to have direct antitumor effects in prostate cancer cell lines. For example, drugs such as zoledronate, clodronate, and alendronate diminish the adhesion and invasiveness of PC3 prostate cancer cells [39–41].

Regardless of the good rationale for the use of bisphosphonates in prostate cancer, proving a clinical benefit has been difficult. Initial studies were small and nonrandomized, used a variety of dosing schedules, and had dubious end points and variable outcomes, leaving clinicians with little convincing data, positive or negative, to guide practice.

In contrast to these small studies, a prospective randomized trial involving 643 patients with androgen-independent metastatic prostate cancer was performed in which patients received zoledronic acid 4 mg, zoledronic acid 8 mg, or placebo. The primary end point of the study was prevention of skeletal-related events (SREs), defined as fracture, cord compression, the need for surgery or radiation, or the need to change treatment due to bone pain. Pain relief was a secondary aim. The 8-mg arm was discontinued due to nephrotoxicity. Of the remaining 422 patients, 33% of the treated group sustained an SRE in contrast with 44% of the patients who received a placebo (p = 0.021). This represented a relative reduction of 25%. Pain scores were also significantly lower in the patients receiving zoledronic acid [42]. Zoledronic acid was approved for the treatment of metastatic prostate cancer in February of 2002 by the U.S. Food and Drug Administration (FDA).

Bisphosphonates also have a role in the management of the bone demineralization that results from hormonal therapy. In a randomized prospective trial of prostate cancer, patients on gonadotropin-releasing hormone (GnRH) analogues were treated with either pamidronate or the GnRH analogue only. The men who received only the GnRH analogue suffered bone mineral density losses of 3.3% in the lumbar spine, 8.5% in trabecular bone of the lumbar spine, 2.1% in the trochanter, and 1.8% in the hip. Those who received the pamidronate suffered no bone mineral density loss and had lower markers of bone turnover as well [43]. However, this trial was small (only 47 men were treated) and the end point was bone mineral density, rather than clinical events such as fracture. Prevention of osteoporosis in castrate men may not even require chronic treatment: in a study of postmenopausal women, a single 4-mg annual dose of zoledronate was as effective at preventing osteoporosis as treatment given every 3 months [44].

Whether to prevent the effects of hormones or the effects of tumors, the use of bisphosphonates for the treatment of castrate men with metastatic disease is of clear benefit. Whether men in other clinical states warrant treatment, whether these beneficial effects are seen with all bisphosphonates or only some, and what the optimal treatment schedule should be are all issues that are undergoing investigation.

	TARGETING BONE: RADIOPHARMACEUTICALS

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
Radiopharmaceuticals that localize to bone is an attractive strategy for patients with metastatic prostate cancer, as therapy is delivered directly to the primary reservoir of disease. Presently, a number of agents are available for clinical use. Their physical properties are compared in Table 1. Isotopes such as phosphorous-32 (³²P) and strontium-89 (⁸⁹Sr) have considerably longer half-lives (12 and 50 days, respectively) than samarium-153 (¹⁵³Sm) or rhenium-186 (¹⁸⁶Re), which have half-lives of 1.9 and 3.8 days, respectively. Drugs such as ³²P phosphate and yttrium-90 (⁹⁰Y) citrate have no gamma emission, and therefore, posttreatment imaging to define drug localization cannot be performed. Since the bone surrounding the tumor is the target and not the tumor itself, the dose delivered to disease varies depending on the dimensions of the cancer and the properties of the isotope. For example, metallic chelates tend to distribute to trabecular surfaces, while ³²P and ⁸⁹Sr do not have such well-defined localization. Tumor density and the ratio of trabecular to cortical bone sclerotic lesions are also sources of variability in dose and distribution [45].

Samarium-153 EDTMP is a combined gamma and beta emitter with a half-life of approximately 2 days. Its beta emission is one third the strength of that of ⁸⁹Sr, and it has lower tissue penetration as well. Sixty percent to 75% of patients treated had an improvement in pain, which was usually appreciated within the first month of therapy and lasted for approximately 2–4 months [51, 52]. The primary toxicity, like with ⁸⁹Sr, was hematologic.

Other radiopharmaceuticals that are not FDA approved have, nonetheless, a large body of data supporting their use. Phosphorous-32 has a long half-life and is a pure beta emitter. It can be taken orally, is inexpensive, and appears to be as effective as ⁸⁹Sr in palliating pain [52]. Another chelated agent is ¹⁸⁶Re hydroxyethylidene diphosphate (HEDP), which, like ¹⁵³Sm, has a short half-life and lower energy beta emission than ⁸⁹Sr. It is approved in Europe, but not in the U.S., for the palliation of bone metastases.

No trial of any one bone-seeking radiopharmaceutical alone has resulted in a significant overall survival benefit. Indeed, evidence of cell kill appears not to be a prerequisite for palliation of pain, as pain relief can be observed in the absence of a PSA level decline, or change in appearance of bone metastases on bone scintigraphy. Hence, although bone-seeking radiopharmaceuticals are useful tools for palliating pain, when used alone, they cannot consistently deliver radiation to achieve substantial cell kills. Nonetheless, the concept of delivering radiation directly to the site of metastatic disease is an appealing one. To optimize this strategy, one of two approaches might be taken: A) combine bone-seeking radiopharmaceuticals with cytotoxic treatments such as chemotherapy or B) target osseous metastases with drugs that do not localize to bone but to the tumor within the bone. These approaches are discussed below.

	THE ROLE OF CHEMOTHERAPY IN THE TREATMENT OF BONE DISEASE

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
Chemotherapy, long denigrated as ineffective for the treatment of prostate cancer, is now recognized as being active. Although chemotherapy for the treatment of androgen-independent disease has not yet been shown to confer a survival benefit, its role in the palliation of disease is indisputable. Trials comparing mitoxantrone and steroids with steroids alone for androgen-independent patients with bone pain showed that chemotherapy conferred a significant palliative benefit [53, 54]. For example, a Canadian study randomized 161 patients with symptomatic progressive metastatic disease to either mitoxantrone and prednisone or prednisone only. Pain and quality of life were primary end points. Patients who received chemotherapy enjoyed a 29% palliative response, whereas only 12% of patients who did not receive chemotherapy achieved this end point [53]. Based on data such as these, mitoxantrone has been approved by the FDA for the palliation of bone pain in prostate cancer.

Presently, treatments that target microtubular trafficking appear to be the most active agents for prostate cancer, at least on the basis of declines in PSA levels, regression of soft tissue disease, and stabilization of bone scans. In our trial using paclitaxel, estramustine, and carboplatin for the treatment of patients with castrate metastatic prostate cancer, 67% of patients achieved a PSA level decline of 50%, 45% of patients had a major regression of soft tissue disease, 52% had stabilization or improvement of bone scintigraphy, and 79% of the patients who reported significant pain at the start of therapy demonstrated relief of that pain and a reduction in opiate use while on chemotherapy [55]. These results are commensurate with those found in other nonrandomized studies that examine combination antimicrotubule therapy [55–59]. In a multicenter phase II study conducted by the Cancer and Leukemia Group B, 46 patients with progressive androgen-independent disease received docetaxel, estramustine, and low-dose hydrocortisone. Sixty-eight percent of the patients achieved a PSA level decline of >50%, and of the patients with measurable disease, 50% of the patients achieved either a partial or complete response [57].

The impact of antimicrotubule chemotherapy on survival has not been established. A phase III study examining the survival of patients treated with estramustine and vinblastine relative to those who received vinblastine alone revealed a 12.5-month survival in the combination arm and a 9.4-month survival in the monotherapy arm (p = 0.051) [60]. The survival benefits of more contemporary regimens, which are taxane based, are presently under study. The combination of docetaxel with estramustine is presently being compared with mitoxantrone and prednisone in a randomized phase III trial with survival as the primary end point; the palliative benefits of each regimen are being compared as secondary end points.

	CHEMOTHERAPY AND BONE-SEEKING RADIOPHARMACEUTICALS

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
Chemotherapy can induce significant antitumor responses as assessed by standard criteria; however it is not curative. The median duration of antimicrotubule chemotherapy is only 6 months, regardless of the regimen used, usually due to the persistence of resistant disease in bone. This pattern of relapse suggests that there may be a benefit to combining chemotherapy with bone-directed treatments. One study has shown the feasibility of coadministering bone-seeking radiopharmaceuticals with estramustine and vinblastine [61]. A small phase III trial was conducted in which patients were randomized to either ⁸⁹Sr and cisplatin or to ⁸⁹Sr alone. Only 35 patients were on each arm. Chemotherapy enhanced the palliative effects of ⁸⁹Sr (91% versus 63%, p < 0.01) and increased the duration (134 days versus 68 days, p = 0.002) of these effects. In addition, a lower proportion of patients receiving both therapies progressed in bone than in those who received samarium only (27% versus 64%, p = 0.01). However, significant alterations in PSA levels were not reported, and there was no significant difference in survival [62].

Combinations of contemporary chemotherapy with bone-seeking radiopharmaceuticals have had significantly more promising results. In a randomized phase II trial conducted at the M.D. Anderson Cancer Center, 103 patients received induction chemotherapy using ketoconazole and doxorubicin alternating with estramustine and vinblastine. Patients who did not progress following induction were randomized to either ⁸⁹Sr with doxorubicin or to doxorubicin only. Patients who received the bone-targeted therapy had a 14-month progression-free survival, compared with a 7-month progression-free survival for those patients who received chemotherapy alone. More important was the fact that patients treated with the ⁸⁹Sr achieved an overall survival of 27.7 months compared with 16.8 months for those who received chemotherapy alone [63]. Although the trial was not powered to make direct comparisons of the two arms, the data do suggest that combinations of chemotherapy and treatments directed at bone metastases should be pursued.

	TUMOR-DIRECTED THERAPY

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
The limitation of bone-seeking radiopharmaceuticals is that increases in dose result in increased hematologic toxicity. Yet significant antitumor responses cannot be achieved without higher doses of radiation. The limitation of chemotherapy is that it too cannot eradicate tumors in bone by itself. The combination of the two modalities, however, may confer a survival advantage, but it is also not curative. Tumor-specific antigens have the potential to address these limitations. Monoclonal antibodies raised against such antigens can be ligated to either radiation or chemotherapy. If used to deliver radiation, antibodies can deliver high doses of radiation to osseous metastases while sparing uninvolved bone. If used to deliver chemotherapy, such agents can deliver cytotoxic treatments directly to bone without systemic toxicity.

CC49 is an antibody that targets the tumor-associated glycoprotein TAG72. In early trials of murine iodine-131 labeled CC49, no antitumor responses were seen because the development of human anti-mouse antibody (HAMA) precluded repetitive dosing. Even had HAMA not been present, dose-liming marrow effects were observed, as the antibody localized to tumor in the marrow cavity [64]. In addition, we explored C225, a monoclonal antibody that targets the epidermal growth factor, ligated to doxorubicin. As part of a phase I study, antibody mass and dose of chemotherapy were escalated, revealing that such treatment was well tolerated and could induce significant PSA level declines, as well as regression in soft tissue disease [65]. These preliminary studies showed that monoclonal antibodies could be used to deliver a "payload" to tumors in bone using molecular targeting. However, to optimize therapeutic effects, repetitive dosing is required, and a radioactive ligand should have properties that allow for tumoricidal effects without prohibitive doses to neighboring marrow. A further means of improving the therapeutic index is to target an antigen than can be modulated, either to enrich or deplete the target on tumor cells, depending on the sensitivity of the surrounding tissues.

An example of such a target is prostate-specific membrane antigen (PSMA) [66, 67]. Not only is PSMA expressed across the spectrum of the disease, it is present both in the primary disease and in bone metastases, its expression can be modulated, and its expression is greater in androgen-independent disease [68].

Targeting PSMA for diagnostic purposes is FDA approved. The ProstaScint (Cytogen; Princeton, NJ) scan utilizes a monoclonal antibody that targets the internal domain of PSMA. Monoclonal antibodies that target the external domain of PSMA have also been developed [69]. These have been humanized as well, they localize to tumors regardless of site, and they can be repetitively administered. Preliminary studies using ⁹⁰Y and lutetium-177 radioconjugates demonstrated that PSA level declines in the range of 65%–85% are achievable. For patients who have soft tissue disease, reductions in size are commensurate with the PSA level declines [70]. These antitumor effects are dose related, as is myelosuppression. Although uptake of either the isotope or the conjugate is seen in the liver, no hepatotoxicity has been observed. A trial using repetitively dosed unlabeled cold and indium-111-labeled (at tracer doses) anti-PSMA antibody is ongoing at MSKCC to establish the impact of antibody mass on tumor localization, hepatic uptake, and normal organ dosimetry.

	BIOLOGIC THERAPY

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
Over the past several decades, the biology of prostate cancer has increasingly been defined. This has led to an increased understanding of the mechanisms that underlie the cancer’s tropism to bone and the mechanisms that facilitate growth despite a castrate environment. This understanding has led to the introduction of drugs that target these pathways.

As shown in Figure 2, the processes that underlie the bone tropism of prostate cancer, as well as its stimulation of bone growth, are multifold. First, the tumor itself appears to produce factors that stimulate new bone formation and bone growth. These are summarized in Table 2. For example, TGF-ß enhances osteoblastic differentiation, promotes matrix formation, and inhibits matrix degradation [71, 72]. Prostate cancer cell lines produce TGF-ß and latent TGF-ß1 [71, 72]. Higher levels of TGF-ß are found in prostate cancer pathology specimens than in normal specimens [36]. Similarly, prostate cancer cells further stimulate bone growth through the production of insulin-like growth factors (IGFs), which stimulate osteoblasts and reduce matrix degradation [73]. These actions are, in part, regulated by IGF-binding proteins (IGFBPs), which are also produced by the tumor [74]. Serum proteases, such as PSA, may play a role in the regulation of bone growth by cleaving IGFBPs as well as latent TGF-ß [75, 76].

View larger version (34K): [in this window] [in a new window]   Figure 2. Simplified illustration of the pathways that interconnect bone metabolism and the tumor cell. Abbreviations: FGF = fibroblast growth factor; BMP = bone morphogenetic protein.

The tumor may also be able to modulate osteoblast-osteoclast interactions directly. Receptor activator of nuclear factor (NF)-B (RANK) is a membrane-bound homologue of tumor necrosis factor receptor (TNFR). It is present on osteoclast precursors, can trigger osteoclast formation and signaling, and is activated when bound to its ligand (RANKL) [84–86]. RANKL is expressed by osteoblasts and induces osteoclastogenesis from hematopoietic precursors [87]. Osteoprotegerin (OPG) is a secreted receptor protein, also similar to TNFR, that binds to RANKL and thereby inhibits osteoclastogenesis and promotes osteoclast apoptosis [88]. Both OPG and RANKL are highly expressed on prostate cancer osseous metastases, in contrast with expression on the primary tumor or nonosseous sites of disease [89]. This finding suggests direct tumoral participation in bone remodeling.

Targeting these biologic relationships between tumor and bone is presently being explored in clinical trials. For example, endothelin-1 (ET-1) activates osteoblasts [90, 91] and is upregulated by factors such as TGF-ß and TNF- [92]. The endothelin receptors, particularly endothelin receptor A (ET_A), are highly expressed in patients with metastatic disease [93]. ABT-627 (Atrasentan; Abbott Laboratories; Abbott Park, IL) is an ET_A antagonist that is well tolerated, reduces bone pain, slows objective tumor progression, and reduces bone turnover, as shown in single-center phase I/II trials [94–96]. The agent is in phase III studies now. Other agents, such as the proteosome inhibitor PS-341, hold the promise of targeting multiple proteins implicated in metastatic growth, including NF-B, and are presently in clinical trials [97]. Such approaches ultimately seek to undermine the biologic interactions between the tumor and bone.

	NEW METHODS OF ASSESSING RESPONSES IN BONE

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
Investigators have long struggled with the lack of good measures of treatment effects in prostate cancer. Only a minority of patients has soft tissue disease. Consequently, most patients do not have, or cannot be categorized as having, complete or partial responses. Most patients have only osseous lesions, which are not measurable. Furthermore, bone scintigraphy lags behind both symptoms and PSA levels in reflecting either a response to treatment or progression of disease. Bone scintigraphy is further limited by pseudoprogression, which occurs when the bone scan worsens due to bone healing around the regressing tumor as a result of a vigorous antitumor response. Finally, there is no consensus on what represents a response on a bone scan. It might be a diminution of the intensity of all lesions, the resolution of lesions, or the lack of new lesions. Mixed responses further cloud the picture.

An attempt to address these issues and to minimize inter-reader variability, is the development of the bone scan index (BSI) [98, 99]. The BSI is an expression of the percentage of marrow actively involved by tumor, as represented by tracer uptake on the bone scan. In Figure 3, the application of the BSI is shown. In this patient, increasing lesions can be expressed with a single quantifiable number—the percentage of the total red marrow involved. In this manner, changes in bone scans can be plotted like any other quantifiable end point, such as changes in soft tissue disease or alterations in PSA levels.

View larger version (75K): [in this window] [in a new window]   Figure 3. Illustration of changes in the BSI with disease progression and response to therapy.

In addition, novel ways of imaging bone through magnetic resonance imaging (MRI) are being explored. For example, using animal xenograft models of metastatic prostate cancer to bone, MRI was used to quantify the totality of bone involvement in the skeleton. This technology offers the promise of overcoming the limitation of the immeasurability of bone metastases using standard imaging modalities. However, the method is far more effective for lytic than for blastic metastases. Therefore, further technical refinement of the technique is required [101].

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 
The prostate cancer patient faces a formidable range of dangers from metastatic disease: fracture, pain, and marrow compromise, among others. As summarized in Table 3, a number of treatment modalities now exist to address osseous metastases in patients with prostate cancer. Bisphosphonates can mitigate the osteopenic effects of hormones and delay skeletal related events due to tumor. Bone-seeking radioisotopes can palliate pain, but doses are insufficient to achieve major antitumor responses. Chemotherapy and hormones can induce significant responses, but are not curative because of the persistence of resistant clones harbored in bone. Although combinations of chemotherapy and bone-seeking radiopharmaceuticals show promise of improving the results of either modality alone, major changes in survival will likely require exploiting our knowledge of the biology of the disease. Antibodies directed against tumor-specific antigens will allow repetitively dosed tumor-directed radiation and chemotherapy to focus directly on osseous disease. Biologic therapy can target the mechanisms underlying the mutually supportive relationship between tumor and bone. These strategies are undergoing testing in present clinical trials.

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Top Learning Objectives Abstract Introduction Osseous Disease: When Does... Radiographic Imaging of Osseous... Hormonal Therapy and Bone... Bisphosphonates: Mitigating the... Targeting Bone:... The Role of Chemotherapy... Chemotherapy and Bone-Seeking... Tumor-Directed Therapy Biologic Therapy New Methods of Assessing... Conclusions References

 

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