Overview: Most patients with bone metastases from lung cancer develop bone-related events (SREs), and the number of patients who develop SREs may increase further as patient survival is prolonged with advances in initial therapy. Zoledronic acid (ZA) has been shown to delay the onset and reduce the risk of SERs in patients with NSCLC while maintaining quality of life and functional independence. An exploratory analysis of phase III clinical trials in patients with bone metastases from lung cancer or other solid tumors has shown that ZA also normalizes biochemical markers of bone metastases and has the potential to prolong survival in specific patient populations. Ongoing studies are evaluating the role of ZA in preventing bone metastases in patients with early-stage tumors. Recent data from a phase III clinical trial study comparing ZA and denosumab in lung cancer or other solid tumors demonstrated that denosumab was non-inferior to ZA in preventing SREs and that patient survival was consistent between the two treatments. Huijuan Wang, Department of Internal Medicine, Henan Cancer Hospital
Key points.
1. bone-related events gradually disrupt functional independence, worsen physical status, and degrade quality of life.
2. Early diagnosis and continuous application of zoledronic acid treatment are necessary to delay the occurrence of SREs and reduce the risk of SREs.
3. Zoledronic acid increases the N-terminal peptide level of standardized type I collagen and prolongs survival in a subgroup of NSCLC patients.
4. Because of the significant prolongation of progression-free survival in breast cancer, studies have now begun to evaluate whether the same effect will be seen in early-stage lung cancer.
5. Denosumab has been shown to be non-inferior to ZA for the prevention of SREs in randomized phase III clinical trials in NSCLC and other solid tumors, and survival was similar in both groups; subgroup analysis in NSCLC is pending.
Treatment targeting bone metastases is considered a necessary component of treatment for patients with metastatic NSCLC. Approximately 30-40% of patients with metastatic NSCLC have both bone metastases at the time of diagnosis. Most patients with NSCLC bone metastases will present with SREs, including pathologic fractures, spinal cord compression, hypercalcemia of the malignancy, and the need for orthopedic surgery or bone radiotherapy. And as initial treatment progresses and patient survival increases, this subset of patients will further increase. However, because early bone metastases may be asymptomatic and often difficult to diagnose, resulting in delays in the initial treatment to prevent SREs. Prevention of SREs may help maintain patients’ quality of life and functional independence and prevent pain, depression, and worsening of physical status.
Currently, bone scans are only recommended for NSCLC patients with symptoms (e.g., bone pain) or abnormal laboratory findings (e.g., high alkaline phosphate levels). Errors in bone metastasis findings in these patients may lead to incorrect tumor staging and treatment decisions. In addition, because approximately 50% of patients with bone metastases from NSCLC develop SREs during the course of their disease, especially in the first two months after bone metastases are diagnosed, failure to diagnose bone metastases in a timely manner will likely result in a lost opportunity to delay the onset of SREs.
A recent retrospective evaluation of patients with bone metastases from lung cancer showed that although there was no difference in survival for bone metastases compared with metastases from other sites, patients who developed SREs had approximately 50% shorter survival compared with patients with bone metastases without SREs. However, patients with bone metastases from NSCLC who survive longer will eventually develop SREs, and preventing or delaying SREs may help protect functional independence throughout disease progression, stop PS from deteriorating, and maintain a better quality of life.
Novel therapeutic agents against bone metastases have emerged, and their use may reduce the incidence of SREs and prolong survival in this subgroup of patients. Bisphosphonates are inhibitors of osteoclast-mediated bone resorption. By reducing osteoclast-mediated osteolysis, bisphosphonates may reduce the incidence of SREs and delay the onset of pathological fractures in patients with bone metastases.
Several bisphosphonate drugs, including clodronate, pamidronate disodium, ibandronate, and zoledronic acid, have been shown to be effective in the treatment of breast cancer bone metastases and multiple myeloma. However, clodronate and disodium pamidronate have shown limited or even conflicting effects in preventing SREs in multiple small clinical trials (which included patients with bone metastases from lung cancer). In a study of 94 patients with painful bone metastases who received palliative radiotherapy for breast cancer or NSCLC, there was no significant difference in pain exacerbation between those treated with clodronate (4/12) and those with NSCLC who did not receive clodronate (18/31). However, another independent study including 66 patients found that clodronate reduced analgesic use compared with placebo in anti-bone metastasis treatment in patients with tumors that were poorly responsive to treatment, including NSCLC (p=0.042). Evidence for the palliative effect of pamidronate disodium in the treatment of bone metastases in NSCLC is currently limited to case reports.
The important objective clinical benefit of ZA compared to clodronate and pamidronate disodium has been demonstrated in a phase III clinical trial in aggressive solid tumors. Patients (773) with bone metastases from lung cancer and other solid tumors were enrolled in a placebo-controlled phase III clinical trial of ZA (4 mg IV drip/15 minutes, repeated every 3 weeks). In this trial, approximately 50% of patients had NSCLC and 8% had SCLC; the remaining 42% had other solid tumors (excluding breast and prostate cancer). 21 months later, the ZA group significantly reduced the odds of patients developing SREs compared with the placebo group (including malignant hypercalcemia [HCM]: 39% vs. 48%, respectively; p=0.039). It reduced the mean annual incidence of SREs by 36% (1.74 vs. 2.71 per year, p=0.012) and delayed the median time to first SRE by more than two months (236 vs. 155 days, respectively; p=0.009; Fig. 1). Multi-event analysis showed that ZA reduced the risk of developing SREs by 31% (relative risk ratio 0.693; p=0.003). These results, establish ZA as the standard of care for bone metastases from lung cancer in many countries.
Failure of initial anti-bone resorption therapy prior to the onset of SREs does not mean that anti-bone metastasis therapy will no longer be beneficial. For example, in an exploratory analysis of a phase III clinical trial of ZA, it was found that patients who had developed SREs before the start of the trial had a 41% increased risk of developing SREs over the course of the study compared with patients who did not have SREs before the trial. In these patients, ZA reduced their risk of developing SRE during the trial by 31% compared to the placebo group (p=0.009) and significantly reduced the mean annual incidence of SRE (p=0.03). An exploratory analysis of 378 NSCLC patients enrolled in this phase III clinical trial showed that ZA reduced the cumulative mean incidence of SREs by 34% during the first 6 months of treatment compared to placebo. In addition, there was a trend for ZA to prolong the median time to first presentation of SREs compared to placebo (171 vs 151 days, p=0.104). Patients who entered the study presenting with SRE continued to be given study treatment, with the exception of patients with hypercalcemia, who were required to receive bisphosphonate therapy (a violation of trial design). It was particularly important for patients who had developed SRE before or after the start of ZA treatment to receive treatment to prevent the recurrence of SRE. These results suggest a clinical benefit from continued ZA therapy, and consistent with these data —- the current international panel of experts recommends that bisphosphonate therapy be continued as tolerated by the patient and not discontinued until the patient shows a significant reduction in PS score.
ZA is generally well tolerated, with similar adverse event data between ZA and placebo, except for symptoms associated with acute phase (during infusion) reactions. Influenza-like symptoms can occur after the first infusion of nitrogen-containing bisphosphonates, but rarely occur in subsequent infusions. All bisphosphonates requiring intravenous infusion have dose-dependent and infusion frequency-dependent effects on renal function. Therefore, serum creatinine should be monitored before each infusion and the dose of ZA should not exceed 4 mg with an infusion time of not less than 15 minutes. In the phase III clinical trial, after doing all these measures to prevent renal impairment, there was no significant difference in the time to first creatinine elevation in the ZA group compared to the placebo group. The principles of dose adjustment for patients with concomitant impaired serum creatinine clearance are quite well established. In addition, patients should take 500 mg of calcium and 400 IU of vitamin D orally daily to minimize the risk of hypocalcemia. Osteonecrosis of the jaw (ONJ) is an oral pathological process in which the exposed bone in the oral cavity fails to heal despite at least 6 weeks of adequate dental treatment (in the absence of malignancy and radiological osteonecrosis of the jaw). 4019 patients in a retrospective analysis reported ONJ as an uncommon event in patients with advanced cancer. Prospective data on the occurrence of ONJ in patients receiving ZA or the investigational anti-bone resorption drug denosumab have been recently published (discussed below). In a 21-month clinical observation of patients with bone metastases from solid tumors or multiple myeloma, ONJ was also an uncommon event in patients treated with ZA (incidence of 1.3%, including patients with myeloma), but the risk of ONJ was higher in patients with myeloma compared to patients with solid tumors. Immediately following this, research is ongoing to address the prevention, management and treatment of ONJ.
In addition to bisphosphonates, a new class of anti-bone resorption agents is being investigated, and efficacy data from phase III trials have recently been reported for denosumab, a fully humanized IgG2 immunoglobulin isotype monoclonal antibody that targets the receptor activator of nuclear factor-kappaB (RANK-L) ligand and acts via subcutaneous injection. Denosumab has high affinity and specificity for human RANK-L, which is required for osteoclast formation, action, and survival. In the randomized, double-blind phase III clinical trial of Denosumab versus ZA for the treatment of bone metastases, a total of 1776 patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma were enrolled, 886 patients were randomized to receive Denosumab subcutaneously at 120 mg once every 4 weeks and placebo administered intravenously, and 890 patients received intravenous administration of 4 mg ZA and placebo administered subcutaneously, and the two groups were compared. Thirty-nine percent of patients in each group had NSCLC (345 and 343 patients, respectively), and 50% had previously developed SREs. the time to first presentation of SREs in the study (non-inferiority), the primary study endpoint, was achieved. the median time to first presentation of SREs was 20.6 months in the denosumab group and 16.3 months in the ZA group (HR=0.84; non-inferiority p = 0.0007; p-value advantage of 0.06 for Denosumab compared with ZA). The difference in time to first and subsequent SRE (multiple event analysis) between the two groups in the trial was also not statistically significant, and there was no significant advantage in the Denosumab group compared with the two groups (HR = 0.9; p = 0.14). There were no significant differences in overall survival and time to disease progression between the two groups. The incidence of acute phase reactions was 14.5% and 6.9% in the ZA and Denosumab groups, respectively, and nephrotoxicity was 10.9% and 8.3%, respectively. the incidence of ONJ was also not statistically different between the groups (1.3% in the ZA group and 1.1% in the Denosumab group). Results of subgroup analyses in patients with NSCLC are not yet available.
Recent studies have found that the Src protein tyrosine kinase inhibitor dasatinib inhibits the activity of osteoclasts and therefore may prevent harmful bone destruction. A phase II clinical trial of dasatinib is underway in patients with advanced NSCLC who have previously undergone surgery and/or radiation therapy but developed recurrence and are treated with dasatinib 70 mg twice daily. Tumor remission rates, progression-free survival and overall survival, and 2-year bone marker analysis will be evaluated in these patients.
Bone marker analysis for ZA treatment in patients with lung cancer and other solid tumors
The pathophysiological alterations addressed below are commonly used for bone metastases in all cancers. For all tumors, the underlying cause of SREs is bone destruction due to the malignant osteolytic effect of the tumor. Biochemical markers of bone metabolism can be used to dynamically monitor the level of bone formation and resorption, reflecting the interaction between tumor and bone. Elevated levels of the N-terminal peptide of type I collagen (NTX) is a marker of bone resorption in patients with bone metastases and is associated with an increased risk of SREs and death.
Early studies of biochemical markers of bone metabolism provided a rationale for exploring their prognostic and predictive value in patients with lung cancer and other solid tumors in a phase III clinical study of ZA. In the placebo group of 238 patients, the risk of first SRE (relative risk 1.76; p=0.029) and mortality (relative risk 3.03; p<0.001) were increased in patients with high baseline NTX levels (≥100 nmol/mmol creatinine) compared to those with low baseline NTX levels (<100 nmol/mmol creatinine).ZA treatment was effective normalizing NTX levels in close to 80% of patients with NSCLC and other solid tumors at 3 months. Exploratory analysis of a subgroup of NSCLC patients with high baseline NTX levels showed that the extensive benefit of ZA treatment controlled the occurrence of SREs. In this subset of patients, ZA resulted in a significant 35% reduction in the risk of death compared to placebo (Fig2; HR=0.650; p=0.024) and prolonged survival by approximately 6 months. These results suggest that for patients with high baseline NTX levels, appropriate bone health treatment may prolong survival and that biochemical markers of bone metabolism are useful prognostic and efficacy predictors.
The anti-tumor activity of ZA has been demonstrated, which may benefit even patients who have not yet developed bone metastases. For example, ZA has dose- and time-dependent cytotoxicity, apoptotic precursor protein activity, and synergistic antitumor activity with some chemotherapeutic agents. In preclinical models, ZA attenuated cancer cell invasion and adhesion to the base, inhibited tumor-associated angiogenesis and activated anti-tumor subsets of immune cells (γδ T cells). Preclinical studies have laid the groundwork for the theory that ZA may halt disease progression, particularly in patients with bone metastases.2419 The study is an international, randomized, open-label, active control, parallel study comparing the use of ZA with or without ZA in patients with IIIA or IIIBNSCLC (446 patients). The study will assess the efficacy of ZA in terms of time to disease progression, risk of SREs at 12 and 24 months, time to first SRE, and survival at 12 and 24 months.
Conclusion
A meta-analysis of all clinical studies of ZA in patients with solid tumor bone metastases, placebo-controlled, showed that ZA reduced the risk of death by 17% in all patients with baseline NTX ≤ 64 nmol/mmol creatinine. The benefit was greater in patients with baseline NTX greater than 100 nmol/mmol creatinine.
Improvements in treatment prolonged the survival of lung cancer patients. Early and continuous application of ZA is currently recommended to delay the onset of SREs and reduce the risk of developing SREs. In the era of treating NSCLC according to prognostic and predictive markers, standardizing the detection of bone biochemical markers can guide future anti-bone metastasis treatment decisions aimed at prolonging the survival of NSCLC patients. Studies in early stage lung cancer are ongoing to evaluate whether the application of anti-resorptive therapy such as ZA prolongs disease-free survival or overall survival.
The role of ZA and other new drugs for bone metastases (e.g. denosumab) will continue to be expanded. This treatment not only improves the quality of life and functional independence of patients with bone metastases from lung cancer, but is gradually moving beyond its role as a supportive treatment only. We eagerly await the results of ongoing studies.
Translated by Huijuan Wang, Lung Cancer Treatment Center, Henan Province, China Yanyan Mu