Current Treatment for Metastatic Disease
Diagnosis
Bone metastases are often found in multiple sites at the time of diagnosis. Principal sites include the vertebrae, pelvis, femur, ribs, humerus and skull. Several procedures may be used to detect bone metastases. In patients with a diagnosed primary cancer, bone pain is highly indicative of bone metastasis, though not all patients report pain. A bone fracture in a patient with primary disease should also be investigated for possible metastasis. A radionuclide bone scan is usually the first method of checking for bone metastasis, as it is the most cost-effective and available whole-body screening test. Bone scans are not appropriate for patients with myeloma, since they underestimate the extent of disease.15 Radiography is the standard for characterizing lesions once they have been identified. Combined analysis improves diagnosis and assessment of response to therapy. The use of magnetic resonance imaging (MRI) or position emission tomography (PET) scans, which have improved diagnostic sensitivity, depends on their availability, patient throughput and cost. MRI commonly costs 2- 3 times more than a bone scan, and PET often 8 times as much.
Bisphosphonate Therapy
Bisphosphonates are the principal therapeutic option currently available to treat skeletal-related events associated with bone metastasis. Over the past decade, successive generations of ever more potent nitrogen-containing bisphosphonates with higher therapeutic indices have been developed. In the late 1990’s, the second-generation bisphosphonate pamidronate (Aredia®, Novartis Oncology, East Hanover) received international regulatory approval and became a standard treatment for preventing SREs in patients with breast cancer or multiple myeloma. In 2002 zoledronic acid (Zometa®, Novartis Oncology, East Hanover) was approved to treat skeletal morbidity associated with bone metastasis from breast cancer and multiple myeloma, as well as bone metastasis secondary to any solid tumor, including prostate, lung and renal cell cancers. It is now considered the standard of care for the SREs associated with bone metastasis. Three other bisphosphonates have now received regulatory approval for use in the oncology setting outside the US, including ibandronic acid (Boniva®, GlaxoSmithKline and Roche Laboratories), risedronate (Actonel®, Proctor and Gamble Pharmaceuticals, Cincinnati) and clodronate (Bonefos®, Schering AG, Berlin).
Consensus Guidelines recommend that all patients with multiple myeloma and radiologically confirmed bone metastases from breast cancer should start on bisphosphonates from the time of diagnosis and continue for at least two years.16,17 Once on therapy, the development of a skeletal complication is not a sign of treatment failure or a signal to stop treatment, and evidence is now available to confirm that bisphosphonates delay second and subsequent complications, not just the first event.
Switching to a more potent agent like zoledronic acid may be an appropriate option for patients in whom a less potent agent like pamidronate or clodronate therapy proves unsatisfactory. Bisphosphonate treatment, specifically zoledronic acid, is also appropriate for patients with endocrine-resistant metastatic bone disease from prostate cancer and a broad range of other solid tumors. Patients with symptomatic metastasis to bone should be considered for treatment with zoledronic acid, especially if bone is the dominant site of metastasis and/or the prognosis is more than three to six months. Patients with renal cell cancer particularly appear to benefit from treatment.18
Pamidronate
Pamidronate (90 mg infused over 2-4 hours) was demonstrated to significantly reduce the incidence and delay the onset of skeletal complications in patients with osteolytic lesions from multiple myeloma or metastatic breast cancer in three randomized, placebo-controlled trials. In patients with multiple myeloma, pamidronate significantly decreased the percentage of patients who experienced a skeletal complication and significantly reduced the mean annual incidence of skeletal complications.19 In patients with breast cancer, pamidronate significantly reduced the percentage of patients who experienced a skeletal complication and extended the median time to the onset of skeletal complications by almost 6 months.18
Zoledronic Acid
Zoledronic acid is the most potent bisphosphonate currently available. It was first demonstrated to be superior to pamidronate in the treatment of hypercalcemia of malignancy.20 The phase III testing program of zoledronic acid was conducted in over 3,000 patients with bone lesions from multiple myeloma or bone metastases secondary to breast, prostate, lung cancer and a variety of other solid tumors. Zoledronic acid (4 mg via 15-minute infusion) is currently the only bisphosphonate approved around the world for use in treating bone lesions from all malignancies.
In the largest single trial of bisphosphonates (n=1,648), zoledronic acid was compared with pamidronate in patients with bone lesions from breast cancer or multiple myeloma.21 Patients were treated with zoledronic acid every 3-4 weeks for up to 2 years. In the final 25-month analysis of these patients, zoledronic acid was equivalent to pamidronate and reduced the overall risk of developing skeletal complications (including hypercalcemia of malignancy) by an additional 16% relative to pamidronate as assessed by multiple event analysis.22 In patients with breast cancer, zoledronic acid reduced the risk of SREs by an additional 20% compared with pamidronate.
Zoledronic acid is the only bisphosphonate to demonstrate long-term efficacy in men with advanced prostate cancer. In a 24-month randomized trial in men with hormone refractory metastatic prostate cancer, zoledronic acid significantly reduced the percentage of patients with a skeletal complication by 25% compared with placebo, reduced the percentage of patients who experienced each type of skeletal complication and reduced the mean skeletal morbidity (0.77 vs. 1.47 SREs/year) compared with placebo. In addition, zoledronic acid delayed the median time to the first SRE by more than 5 months. Patients treated with zoledronic acid had a 36% lower risk of developing an SRE by multiple event analysis and pain scores were reduced relative to the placebo group at every time point.23
Zoledronic acid has also demonstrated significant benefits in patients with bone metastases from solid tumors other than breast or prostate cancer. Zoledronic acid significantly delayed the median time to the first skeletal complication by more than 2 months and significantly delayed the median time to the first pathologic fracture. Multiple event analysis revealed a 27% reduction in the overall risk of developing a skeletal complication among patients treated with 4 mg zoledronic acid.The benefits to the overall population are especially profound given the poor prognosis of the overall patient population (median survival was only 6 months).24 In a retrospective subset analysis of patients with renal cell cancer, zoledronic acid reduced the risk of developing an SRE by 61% and significantly prolonged the time to first SRE and time until bone lesion progression.25
For patients in whom a less potent bisphosphonate, such as pamidronate or clodronate, proves unsatisfactory, switching to a more potent agent like zoledronic acid may be an appropriate option. Clemons et al. conducted a phase II clinical trial involving 31 patients with breast cancer who had experienced progression in bone or a skeletal complication while on pamidronate or clodronate therapy.Thirteen of 31 (42%) subjects who were switched to monthly zoledronic acid reported a reduction in pain (P<.001) and showed significant reductions in urinary markers of bone turnover (P=.008).26
Bisphosphonate Safety
The safety profile of zoledronic acid is well defined from the large database of phase III clinical trials. The most common adverse events include bone pain, myalgia, nausea, fatigue, pyrexia and emesis. These events are among those that characterize an initial infusion (acute-phase) reaction. Approximately 33% of patients receiving an intravenous bisphosphonate experience an infusion reaction.27 Acutephase reactions are typically self-limiting, resolve within 24-48 hours, and occur less frequently after subsequent infusions. Supportive care, such as nonsteroidal anti-inflammatory drugs, acetaminophen, and adequate hydration, are often sufficient management of the acute-phase reaction.
Intravenous bisphosphonates are excreted primarily by the kidneys and may cause an increase in serum creatinine levels. Intravenous bisphosphonates are associated with dose and infusion rate dependent effects on renal function. In the clinical trials evaluating zoledronic acid, 8 mg treatment arms were discontinued due to renal toxicity. The infusion of 4 mg was increased from 5 to 15 minutes because of renal toxicity. Based on these observations, the modifications in package inserts for both pamidronate and zoledronic acid require testing of patients for renal sufficiency before dosing.
Osteonecrosis of the jaw (ONJ) is the presence of exposed bone in the mandible or maxilla for a period of 8 weeks or longer with proper dental care in the absence of infection or tumor in the jaw. Osteonecrosis has been reported in patients receiving bisphosphonate therapy, both oral and IV. The frequency of ONJ has previously been reported in patients receiving cytotoxic chemotherapy, corticosteroids, and stem cell transplant. The frequency of ONJ has been estimated in a number of retrospective studies. An MD Anderson chart review of 3,994 patients with metastatic bone disease receiving cancer therapies, which included bisphosphonate treatment, estimated the overall frequency at 0.73%.28 The incidence appears to be higher in patients with multiple myeloma ranging from 2-10%.29 The frequency of ONJ is difficult to estimate, and relies extensively on retrospective review. The variation in the reported frequency of ONJ may be, in part, because until recently there was no consensus definition for ONJ.
Practice guidelines for the prevention, diagnosis and management of ONJ in cancer patients were recently published.30 Before starting bisphosphonate therapy, patients should be encouraged to have a routine dental examination. If the patient requires a surgical dental procedure, then it is recommended that it be completed before initiation of bisphosphonate therapy when possible. While on therapy, patients should maintain excellent oral hygiene and avoid invasive dental procedures, if possible. A conservative approach is recommended to treat ONJ. This includes antibiotics, oral rinses, pain control and limited debridement.
Trials represented: National Surgical Adjuvant Breast and Bowel Project (NSABP), Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE), South Western Oncology Group (SWOG) Bisphosphonates in Preventing Bone Metastasis
Bisphosphonates in Preventing Bone Metastasis
Because bisphosphonates are potent inhibitors of bone osteolysis, their use in early cancer could be an adjuvant therapeutic strategy of potential importance.31 Bisphosphonates may also have direct effects on tumor cells in the bone marrow microenvironment.32 Although clinical trial results with the early bisphosphonate clodronate have proved inconclusive in metastasis prevention,33 several large phase III clinical trials with clodronate and zoledronic acid now underway to assess the ability of bisphosphonates to prevent bone metastasis: NSABP, AZURE and S0307, with results expected in 2008/2009 (Table 3). Results of these studies are eagerly awaited.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34 trial of adjuvant clodronate has randomized over 3000 women with stage I-III breast cancer to daily oral clodronate or placebo in addition to standard adjuvant treatment( s).34 Accrual was completed more than 3 years ago but, due to the low event rate, efficacy results are not anticipated until 2008/2009.
The Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial has finished accrual of 3,360 relatively high-risk patients with stage II or III breast cancer.35 The trial tested the hypothesis that zoledronic acid may have beneficial effects, not only through the inhibition of bone resorption and reduction in growth factors and cytokines in the bone marrow microenvironment that appear to promote the development of a metastasis, but also through direct effects on tumor cells in the bone marrow and possible synergy with adjuvant chemotherapy.The AZURE study will assess disease-free survival and time to bone and distant metastasis in patients treated with standard anticancer therapy alone, compared to those treated with standard therapy plus zoledronic acid (4 mg) administered initially monthly for 6 doses, and then every 3-6 months to complete 5 years of treatment. Recruitment was completed in early 2006. Initial results indicate that zoledronic acid given with neoadjuvant chemotherapy caused a significant proportion of women with no detectable DTC at baseline to continue to be DTC-free at 3 months. Reports of the first full efficacy data are expected in 2008/2009.36 A third trial, the South Western Oncology Group study S0307, is ongoing and is planned to recruit 4500 women with stage I-III breast cancer. Following completion of adjuvant chemotherapy, patients are randomized to zoledronic acid 4 mg monthly for 6 months then 3 monthly, oral ibandronate 50mg daily or oral clodronate 1600mg daily.37