A real-world experience of using denosumab in treating lung cancer patients with bone metastasis
Lung cancer is the leading cause of cancer-related deaths worldwide with 2.09 million cases annually.1 In Hong Kong, lung cancer was responsible for 27.1% of all cancer deaths in 2017.2 Among all lung cancers, non-small cell lung cancer (NSCLC) accounts for about 80%, and small cell lung cancer (SCLC) accounts for 20%. The most common and the earliest site of metastases from lung cancer is bone, which can have a debilitating effect on a patient’s life.3 In a recent interview with Omnihealth Practice, Dr. Lee, Ho-Fun Victor, Clinical Associate Professor, Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, shared his insights on the management of bone metastases in lung cancer patients in Hong Kong.
Burden of bone metastases and skeletal complications in lung cancer
About 30-70% of bone metastases are associated with lung cancer and 20%-30% of patients with lung cancer show evidence of bone metastases at initial visits.3 In Hong Kong, the prevalence of bone metastases due to lung cancer is around 30%-50%. Bone metastases can cause SREs, such as bone pain, pathological fracture, spinal instability, spinal cord compression, hypercalcemia and increased alkaline phosphatase levels, and usually occurs at an advanced stage of the disease, significantly impacting the patient’s quality of life.3 The bone scan index (BSI), which indicates the number and extent of bone metastases, has been associated with activities of daily living (ADL) in patients with advanced NSCLC, with a higher BSI being an independent predictor of poor ADL in patients with NSCLC.4
Bone metastases of lung cancer are associated with many factors, such as age, sex, pathologic type, number of primary lesions, treatment regimens, and serum markers.3 Patients may have better treatment outcomes if these risk factors are identified early. Early treatment may help lower the incidence of complications and medical expenses.5 Recently, additional predictors of bone metastases have been identified: Lung cancer patients with T4 category, N3 category stage and positive bone sialoprotein expression.5 Furthermore, being a previous smoker and having multiple bone metastases are significantly associated with an increased risk of SREs.5 According to recent findings presented at European Society of Medical Oncology (ESMO) 2019 meetings, the use of bone targeting agents (BTAs) in Hong Kong has been increased from 2012 to 2017 indicating the progressive burden of bone metastases.6 The use of BTAs in lung cancer patients in Hong Kong was reportedly 41% and the most commonly used BTAs are zoledronic acid, pamidronate and denosumab (Figure 1).6
Personalized management approach for bone metastases
Treatment for bone metastases depends on the patient’s characteristics, tumor behavior and dynamics of metastasis. Thus, it is imperative to identify the extent of bone metastases in different locations, and the kinetics and histology of the tumor.7 Assessments of each individual bone metastasis for pain, chronology of signs (acute or chronic), neurological consequences (e.g. paresthesia and weakness), impact on adjacent critical organs (e.g. spinal cord and nerve roots) and fracture risk should also be carried out.7 Once the patient’s baseline tumor and metastatic characteristics have been evaluated, a personalized treatment schedule for each patient should be devised.7 If the patient’s performance status is good and asymptomatic, no immediate treatment is necessary. However, if the patient experiences debilitating or critical symptoms such as cord compression with high serum calcium and alkaline phosphatase (ALP) levels, he/she should receive treatment urgently.
Bone targeting agents in the treatment of bone metastases
Bone metastases disrupt the finely controlled balance between bone resorption and formation, resulting in net bone breakdown. With increased understanding of the pathogenesis of bone metastases, a number of BTAs have been developed, including inhibitors of osteoclastogenesis and osteoclast activation such as bisphosphonates, and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors like denosumab.
ESMO and National Comprehensive Cancer Network (NCCN) recommend BTAs in the management of bone metastases in lung cancer.8,9 ESMO recommends zoledronic acid or denosumab in selected patients with advanced lung cancer and bone metastases with a life expectancy of >3 months and who are considered at high risk of SREs.8 NCCN guidelines recommend the use of denosumab or bisphosphonates in bone metastasis to reduce SREs.9 It is also important to discuss the different treatment options and their cost-effectiveness with patients before initiating treatments to ensure patients are well informed of their management plan. In Hong Kong, there are currently no official guidelines or recommendations regarding the use of BTAs when patients have high serum calcium and ALP levels with multiple bone metastases and symptoms. If the bone metastasis is only a single lesion without any symptoms, the patient could be kept under review until the symptoms develop.
Denosumab in preventing skeletal related events and improving overall survival
Denosumab binds to RANKL, thus preventing the activation of RANK on osteoclasts and osteoclast precursors. This leads to the inhibition of osteoclast differentiation and osteoclast-mediated bone reabsorption. In a meta-analysis evaluating denosumab and zoledronic acid in preventing SREs, 4,050 patients with bone metastases from solid tumors showed that denosumab could significantly reduce SREs (OR=0.84; 95% CI: 0.74-0.95; p=0.008).10 These osteoclast inhibitors tended to prolong the short-term survival of ES‑SCLC patients with bone metastasis.11 Moreover, in non-squamous NSCLC patients with bone metastasis, denosumab improved the OS (p<0.01).12
As shown in Figure 2, Scagliotti et al. found denosumab to be associated with improved median OS over zoledronic acid in 702 patients with NSCLC (9.5 vs. 8.0 months), and in 811 patients with any lung cancer (8.9 vs. 7.7 months).13 Similar OS was evident in spite of visceral metastases.13 Incidence of overall AEs was balanced between treatment groups; 66.0% of denosumab-treated patients and 72.9% of zoledronic acid-treated patients experienced AEs.13 Furthermore, cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab vs. 0.8% zoledronic acid).13
The longer survival of patients with denosumab treatment occurred through both direct and indirect effects on tumor cells.14 There is a symbiotic relationship between tumor cells and the bone marrow microenvironment, whereby tumor growth is promoted with progressive bone damage.14 By inhibiting bone damage, tumor growth is inadvertently reduced. Simultaneously, tumor cells secrete various factors that stimulate the production of RANKL which leads to increased formation, activation, and survival of osteoclasts, resulting in osteolytic lesions.14 By inhibiting osteoclasts, denosumab has a direct inhibitory effect on osteolysis.14
However, denosumab is usually administered in combination with systemic chemotherapy or targeted therapy. Therefore, these therapies also play an effect on OS. Nevertheless, the risk of SREs with denosumab are much less, which concurrently contributes to enhanced OS.
The baseline variables analyzed by the Scagliotti et al., such as age and Eastern Cooperative Oncology Group status, did not influence OS in denosumab-treated patients.13 Moreover, other characteristics of the study population may have played a role in survival, such as bone turnover markers, which can provide insight into the aggressiveness and biological aspects of metastases.13 N-telopeptide of type I collagen (NTX) is a sensitive marker of osteolysis. High baseline NTX levels were correlated with increased SRE risk in patients with NSCLC and bone metastases.13 As denosumab is a more potent inhibitor of bone osteolysis, its effects could be more beneficial in patients with high baseline NTX.13
A case sharing of a lung cancer patient with bone metastases in Hong Kong stabilized with denosumab
Dr. Lee shared a case of an 85-year-old patient who presented with lung cancer and numerous bone metastatic lesions in the cervical, thoracic and lumbar spine and other long bones 7 years ago. The primary tumor was 2.5cm, and metastases were also observed in the mediastinal lymph nodes. A tissue biopsy showed that adenocarcinoma and further testing found no oncogenic mutations. Initial treatment consisted of palliative radiotherapy to the thoracic spinal metastases followed by systemic chemotherapy with pemetrexed and carboplatin. However, due to the patient’s advanced age and impaired creatinine clearance, the carboplatin dose was reduced. After 4 cycles of therapy, maintenance therapy with pemetrexed and denosumab was initiated. Denosumab was selected due to sub-optimal renal function, and zoledronic acid or bisphosphonates could lead to further deterioration. The patient tolerated the regimen well, and after 4 cycles, PET scans showed shrinkage of the original tumor and a significant reduction in metabolic activities of the bone metastases. He continued to receive the pemetrexed and denosumab maintenance regimen. After 2 ½ years, the patient complained of an abscess in the submandibular region. Folliculitis was initially suspected, and local antibiotics were administered. After 3 weeks, the abscess reappeared, and systemic antibiotics were prescribed. The abscess healed, but 2 months later, the submandibular swelling and abscess reappeared. An X-ray detected mild changes in the bone structure of the mandible and despite another course of systemic antibiotics, the abscess relapsed. Osteonecrosis of the mandible was suspected, and the patient discontinued denosumab treatment. The osteonecrosis was mild (grade 1) and did not affect the patient’s performance status or daily life; discontinuation was purely a clinical decision due to the repeated swelling and abscess. In fact, denosumab therapy could have been continued for longer if the patient tolerated the treatment without any AEs. To date, this patient was still receiving pemetrexed maintenance therapy and free from any SREs.
Long-term denosumab therapy in the treatment of bone metastases
In the presented case, we could observe that the patient received denosumab therapy for 2 ½ years. The patient has tolerated the therapy well except mild grade 1 osteonecrosis. In Hong Kong, the mean duration of BTA use was 252.4 days and denosumab use was longer than average use of BTAs (315.9 days) (Figure 3).6 In fact, in this particular case, the duration of denosumab use is higher than the previously reported denosumab use in Hong Kong. Therefore, continuation of denosumab therapy depends on the development of adverse events (AEs) and the severity of these AEs. If patients do not develop any AEs, continuation of denosumab therapy for longer durations is desired.
Bone metastases are common in lung cancer and treatment with BTAs could prevent the progression of debilitating complications, including pain and skeletal defects. Denosumab has been shown to reduce the risk of SREs in patients with bone metastases from solid tumors, including lung cancer, and to be superior to zoledronic acid in improving the OS in lung cancer patients. Denosumab can be administered with other cancer therapies, such as chemotherapy or targeted therapy, which has no effect on renal function and is well tolerated. Symptomatic patients with bone metastases, increased serum calcium and ALP levels may be particularly suitable for denosumab therapy as shown by the case presented. Treatment with denosumab can be also continued for an extended duration if AEs, such as osteonecrosis, are not observed, allowing increased benefits for lung cancer patients with bone metastases.
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