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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 26

Effect and clinical significance of zoledronic acid combined with radiotherapy in the treatment of bone pain caused by bone metastasis in non-small cell lung cancer patients


Department of Cancer Center, Daping Hospital, Army Medical University, Chongqing, China

Date of Submission22-Mar-2022
Date of Decision13-Jun-2022
Date of Acceptance24-Jun-2022
Date of Web Publication09-Nov-2022

Correspondence Address:
Minying Geng
Department of Cancer Center, Daping Hospital, Army Medical University, No. 10 Changjiang Zhilu, Yuzhong District, Chongqing 400042
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/digm.digm_10_22

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  Abstract 


Objective: To investigate the effect of zoledronic acid on the remission of bone pain in patients with non-small cell lung cancer (NSCLC) during and after radiotherapy. Materials and Methods: A total of 197 NSCLC patients who received radiotherapy for osteopathy with complete recorded visual analog scale (VAS) scores were enrolled. Of these, 79 patients were treated with radiotherapy alone (radiotherapy group), and 118 patients were treated with radiotherapy combined with zoledronic acid (zoledronic acid group). The differences in VAS scores between the two groups were compared. Logistic regression was used to determine the odds ratio (OR) of the complete response rate for osteodynia between the zoledronic acid group and the radiotherapy group. Univariate and multivariate Cox regression analyses were used to evaluate the independent prognostic factors for overall survival (OS). Results: The complete response rate in patients in the zoledronic acid group was significantly higher than that in patients in the radiotherapy group (odds ratio [OR] = 3.201, 95% confidence interval [CI]: 1.559–6.575, P = 0.002). Except for the baseline VAS score, all VAS scores in the zoledronic acid group at different time points during radiotherapy, at the end of radiotherapy, and 1 month after radiotherapy were significantly lower than those in the radiotherapy group (all P < 0.01). Grade 3 constipation was observed in only one patient in the zoledronic acid group. There were no other Grade 3 adverse events. Multivariate Cox regression analysis showed that only the treatment group (zoledronic acid group vs. radiotherapy group, hazard ratio [HR] = 0.720, 95% CI: 0.530–0.978, P = 0.036) and manner of bone destruction (mixture vs. osteolytic, HR = 0.596, 95% CI: 0.424–0.837, P = 0.003) were independent prognostic factors for OS. Conclusion: Zoledronic acid combined with radiotherapy can not only accelerate bone pain control but also prolong survival in NSCLC patients with bone metastases.

Keywords: Bone metastases, Non-small cell lung cancer, Radiotherapy, Visual analog scale, Zoledronic acid


How to cite this article:
Li J, He R, Xiao H, Zhou P, Geng M. Effect and clinical significance of zoledronic acid combined with radiotherapy in the treatment of bone pain caused by bone metastasis in non-small cell lung cancer patients. Digit Med 2022;8:26

How to cite this URL:
Li J, He R, Xiao H, Zhou P, Geng M. Effect and clinical significance of zoledronic acid combined with radiotherapy in the treatment of bone pain caused by bone metastasis in non-small cell lung cancer patients. Digit Med [serial online] 2022 [cited 2022 Dec 2];8:26. Available from: http://www.digitmedicine.com/text.asp?2022/8/1/26/360637




  Introduction Top


There were 2.1 million newly diagnosed lung cancer cases and 1.8 million deaths in 2018 worldwide, and lung cancer has the highest incidence rate and mortality rate among carcinogenesis.[1] Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers.[2] Bone is the most frequent metastasis site in NSCLC patients.[3] Bone metastasis usually leads to osteodynia and skeletal-related events (SREs), which seriously impair the quality of life in advanced lung cancer patients.[4],[5] Approximately 30% of lung cancer patients with bone metastasis can develop refractory pain. Many studies have focused on efficient strategies to alleviate osteodynia caused by bone metastasis in advanced NSCLC patients.[6]

It has been well established that opioid therapy (morphine consumption >30 mg) is used for the treatment of osteodynia in NSCLC patients with bone metastases with a visual analog scale (VAS) score >4. Radiotherapy is one of the common and effective methods for such patients. Given the advancements in medicine, especially third-generation bisphosphonates, which are becoming widely used in clinical practice, the incidence of SREs and symptoms of osteodynia has dramatically decreased in many patients with malignant tumors and bone metastasis. Therefore, zoledronic acid is recommended as a commonly used drug to control bone metastasis and bone pain in NSCLC patients. Many studies have confirmed that the combination of zoledronic acid and radiotherapy can improve the rate of bone pain relief and the quality of life in patients with various malignant tumors after radiotherapy.[7–12] In addition, many studies have also demonstrated that zoledronic acid combined with radiotherapy is more effective than radiotherapy alone in the treatment of bone metastasis in patients with malignant tumors.[13],[14] However, whether zoledronic acid can accelerate pain relief during radiotherapy and whether cooperative treatment increases the adverse effects of radiotherapy are still questions that need to be elucidated. In the present study, we evaluated the treatment effect in patients who received radiotherapy combined with zoledronic acid and compared it with those who received radiotherapy alone with the purpose of identifying the optimal strategy to overcome osteodynia in NSCLC patients.


  Materials and Methods Top


General information

From January 2008 to January 2016, pathologically confirmed NSCLC patients with bone metastases and poor bone pain control who received radiation therapy for bone pain in our institute were enrolled. The inclusion criteria were as follows: (1) bone pain for more than 1 week after daily morphine dosage more than 30 mg, (2) having the most severe pain every day, (3) VAS score >4 points, and (4) complete VAS score records during radiotherapy. A total of 197 patients met these criteria. Among them, 79 patients were treated with radiotherapy alone (radiotherapy group), and 118 patients were treated with the combination therapy of radiotherapy and zoledronic acid (zoledronic acid group). This was a retrospective study and was approved by our hospital's ethics committee. Patient's written informed consent was waived.

Treatment

Radiotherapy and three-dimensional conformal radiation therapy (3D-CRT) were used in all patients after the patients were fixed by the thermoplastic body cover and simulated positioning. The position was carried out with Philips 16-slice computed tomography (CT), and the positioning image was transmitted to the MOSAIQ XIO planning system to sketch the target area. According to the International Commission on Radiation Units and Measurements Report No. 50, the definition of the tumor volume included: gross target volume (GTV), clinical target volume (CTV), and plan target volume (PTV). For spinal irradiation, the CTV range included half of the diseased upper and lower vertebrae and the diseased vertebrae. The PTV range is 5 mm of the CTV, and 6 MV X-ray irradiation was given. For other parts of the bone lesions, the GTV is the tumor site, the CTV is 5 mm of the GTV, and the PTV is 5 mm of the CTV.

Zoledronic acid: Before the 1st day of radiotherapy, the patients were treated with zoledronic acid: 100 mL 0.9% sodium chloride + 4 mg zoledronic acid in an intravenous drip, once every 28 days.

Efficacy evaluation criteria

Patient pain score

the doctor scored the patient's pain through the VAS score. One side of the scale faces the doctor, and the other side of the scale faces the patient; the scale has a patient's face that corresponds to a scale of 0–10, in which 0 represents no pain and 10 represents unbearable severe pain. The doctor will evaluate each part of the patient that is in pain by moving the scale. The VAS pain score at the time of most pain was recorded.

The daily dose of morphine was recorded during the treatment.

Assessment of bone pain relief

complete relief

After treatment, the patient has no pain and stops using morphine; partial relief: daily morphine dosage decreases by more than 25%, and VAS score remains the same or decreases; or the VAS score decreases by more than 2 points (or below 3 points), and the daily morphine dosage remains the same or decreases. Progress: In the course of radiotherapy, if the daily dose of morphine does not change, the VAS pain score increases by more than 2 points or the daily dose of morphine increases by more than 25%, the pain is stable. If the patient's efficacy evaluation does not meet the criteria of complete remission, partial remission, and progress, the patient's efficacy evaluation is stable. Among them, complete and partial remission is called remission, and stable and progress are called no remission. This study evaluated only the pain of patients, not the imaging evaluation.

Follow-up

During the treatment, the diagnosis time of bone metastasis, the VAS score of the most severe bone pain every day during the radiotherapy, the relief of bone pain every day during the radiotherapy, the relief of bone pain in the patient 1 month after the radiotherapy, and the follow-up results of bone pain relief in the patient 1 month after the treatment were recorded in detail. All patients were followed up for survival, and the last survival follow-up was November 20, 2019.

Statistical analysis

The Chi-square test or Fisher's exact probability test, if necessary, was used to evaluate associations between the treatment groups and clinicopathological characteristics. The nonparametric Kruskal-Wallis test was used to determine differences in the VAS scores between the two treatment groups at various time points. Univariate and multivariate Cox regression analyses were used to evaluate the independent prognostic factors for overall survival (OS). P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS software (version 16.0; SPSS Inc., Chicago, IL, USA).


  Results Top


All baseline clinicopathological characteristics, histology, T stage, epidermal growth factor receptor (EGFR) mutation status, and adverse events were significantly different between the radiotherapy group and the zoledronic acid group [Table 1]. A lower incidence of squamous cell histology, a lower tumor burden, a higher prevalence of EGFR-sensitive mutations, and a higher prevalence of adverse events occurred in the zoledronic acid group than in the radiotherapy group [Table 1].
Table 1: Comparison of baseline clinicopathological characteristics between the radiation alone group and the zoledronic acid group

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Regarding the treatment effect of the combination of zoledronic acid and radiation, the complete response rate in the patients in the zoledronic acid group was significantly higher than that in the patients in the radiotherapy group (odds ratio [OR] = 3.201, 95% confidence interval [CI]: 1.559–6.575, P = 0.002) [Table 2]. Except for the baseline VAS score, all VAS scores in the zoledronic acid group at different time points during radiotherapy, at the end of radiotherapy, and 1 month after radiotherapy were significantly lower than those in the radiation alone group [Table 2] and [Figure 1]. Among all adverse events that occurred, only the incidence of anemia was significantly different between the two groups (P = 0.010) [Table 3]. Grade 3 constipation was observed in only one patient in the zoledronic acid group. There were no other Grade 3 adverse events. However, all adverse events in this cohort were tolerable and manageable.
Figure 1: Box plot showing a summary of VAS scores between the radiotherapy group and zoledronic acid group at different time points during and after radiotherapy. IR and Zole represent the radiotherapy group and zoledronic acid group, respectively. EIR and OM indicate end of radiotherapy and 1 month after completion of radiotherapy, respectively. VAS: Visual analog scale, **P<0.001.

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Table 2: Evaluation of response and VAS

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Table 3: Adverse events and comparison between the radiation alone group and the zoledronic acid group

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Regarding OS, univariate Cox regression analysis revealed that zoledronic acid, EGFR-sensitive mutation status, tyrosine kinase inhibitor treatment, osteogenesis, and no change in osseous morphology significantly decreased the risk of death, whereas patients with T3-T4 had a significantly higher risk of death [Table 3]. Using clinicopathological characteristics significantly associated with OS in univariate Cox regression analyses as independent variates, multivariate Cox regression analysis showed that only zoledronic acid and manner of bone destruction remained significantly associated with OS [Table 3]. In particular, patients treated with the combination of radiotherapy and zoledronic acid had a significantly decreased risk of death by 28% compared with patients who underwent radiotherapy alone (hazard ratio [HR] = 0.720, 95% CI: 0.530–0.978, P = 0.036).

Analysis of subgroups of patients who died within 6 months

All clinicopathological characteristics, except for EGFR mutation and response rate, were not significantly different between the zoledronic acid group and radiotherapy group. The percentages of wild type, mutations, and unknown mutation status were 38.1%, 9.5%, and 52.4%, respectively, in the zoledronic acid group and 7.7%, 7.7%, and 84.6%, respectively, in the radiotherapy group (χ2 = 9.891, P = 0.005). In addition, the response rate was significantly higher in the zoledronic acid group than in the radiotherapy group (100% vs. 76.9%, Fisher's exact P = 0.026). In line with the results from the entire population, except for the baseline VAS score, all VAS scores in the zoledronic acid group at different time points during radiotherapy, at the end of radiotherapy, and 1 month after irradiation were also significantly lower than those in the radiotherapy group.


  Discussion Top


Bone pain is the most common symptom of NSCLC patients with bone metastasis. [10,15–17] Patients with bone metastasis often suffer from both physical and psychological pain. Their quality of life is significantly reduced. The purpose of this study was to determine how to relieve bone pain quickly and whether zoledronic acid combined with radiotherapy can result in rapid remission of bone pain and radiosensitization in NSCLC patients with bone metastasis.

At present, there are no large-scale clinical studies to evaluate the treatment effect of radiotherapy combined with zoledronic acid with regard to remission of bone pain for NSCLC patients with bone metastasis. Previous studies have shown that the main causes of bone pain caused by bone metastasis are as follows: first, the nerves of adjacent organs are compressed, and the pressure of the bone marrow cavity increases with the increased volume of metastatic tumor. Second, the periosteum is destroyed due to the invasion of metastatic tumors. Third, the cytokines secreted by the tumor itself can increase the pain of patients and promote the activity of osteoclasts to aggravate the destructive effect of osteoclasts on the bone. Radiotherapy can directly kill tumor cells by radiation. The decreased tumor mass reduces the compression symptoms, and the pressure of the bone marrow cavity reduces bone pain. The decrease in the number of tumor cells and their activity can indirectly reduce the release of inflammatory factors and in turn reduce the pain caused by inflammatory effects. The progress of radiotherapy technology has reduced the occurrence of side effects of radiotherapy. The pain relief rate of patients after radiotherapy has also significantly improved. In our study, patients were treated with 3D-CRT, and the pain relief rate was more than 80% in the patients treated with radiotherapy alone when evaluated 1 month after radiotherapy. Zoledronic acid has diverse biological effects, including interrupting the process of isoprene in osteoclasts, interfering with RAS signal transduction, and impairing the bone absorption function of osteoclasts.[18] Moreover, zoledronic acid is able to block the transformation of tumor cells from the G2 and M phases to the S phase and prolongs the period of radiotherapy sensitivity. Finally, zoledronic acid has anti-angiogenesis effects. Previous basic studies have shown that zoledronic acid can inhibit the growth of lung cancer cells, which provides a more favorable theoretical basis for the combination of zoledronic acid with radiotherapy in the treatment of NSCLC bone metastasis.[19],[20] In many domestic studies, the combined treatment of zoledronic acid and radiotherapy is shown to be better than the radiotherapy alone for bone pain, and the side effects of the combined treatment are tolerable, which is in line with the preliminary results of our study.
Table 4: Univariate and multivariate Cox regression for OS

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The main endpoint of most studies evaluating the beneficial effect of zoledronic acid combined with radiotherapy for the treatment of bone metastases in NSCLC patients is pain relief and improvement in quality of life 1 month after radiotherapy.[10–12,21] Few studies have focused on bone pain relief during radiotherapy. For patients with NSCLC with bone metastasis, survival is limited. The observation of bone pain relief during and after radiotherapy is equally important and should be used as the research content of pain relief. We compared the changes in the VAS score and daily morphine dosage of zoledronic acid combined with radiotherapy and radiotherapy alone in NSCLC patients with bone metastasis during and after radiotherapy. The results showed that zoledronic acid combined with radiotherapy undoubtedly improved the pain relief of patients 1 month after radiotherapy. For the first time, we observed that the patients who received zoledronic acid combined with radiotherapy exhibited greater bone pain relief on the 3rd day of radiotherapy than that in the patients treated with radiotherapy alone. The survival of patients treated with zoledronic acid was also better than that of patients treated with radiotherapy alone. It seems that zoledronic acid combined with radiotherapy can not only improve the degree of bone pain relief during and after radiotherapy but also reduce the incidence of SREs or inhibit the growth of tumor cells. It has been reported that zoledronic acid can benefit the survival of patients with stage III or even more advanced stage lung cancer.[22] However, whether zoledronic acid can prolong OS in NSCLC patients with bone metastasis is still worth exploring. The results obtained in the present study need to be further verified in large-scale clinical research or real-world research.

It is difficult to evaluate the therapeutic effect of one treatment for bone metastasis. The bone lesions of patients with bone metastasis are unmeasurable lesions, except for patients with clear soft tissue shadows. In clinical practice, most bone lesions have limited regression after radiotherapy. It is not accurate to evaluate the curative effect of bone metastasis only using the Response Evaluation Criteria in Solid Tumours (RECIST) standard. The evaluation of patients' symptom relief is more effective and reliable than tumor regression evaluated by the RECIST standard. All patients enrolled in this study were patients with more than 1 week of bone pain whose daily dosage of morphine was more than 30 mg and whose VAS score for the daily most severe pain was more than 4. Most of the studies worldwide usually use the VAS score or verbal response scale pain rating combined with the change in the dosage of painkillers to evaluate the grade of bone pain relief.[10],[11],[16],[23] Therefore, in this study, we utilized the VAS score combined with daily morphine consumption instead of radiographic imaging as a standard for the evaluation of relief of bone pain symptoms. Most of the studies of bisphosphonates combined with radiotherapy or chemotherapy in China evaluate only the pain relief of patients and do not take into consideration the concept of daily morphine dose.[24–26] It is not clear whether patients can benefit from radiotherapy; otherwise, the morphine dose should be increased. Most other studies consider only a decrease in the VAS score of more than 2 points as the indicator of pain relief. However, in clinical practice, for cancer patients with bone pain and refractory bone pain caused by bone metastases, most patients with a VAS score of <3 points do not need painkiller intervention. Therefore, a VAS score of ≤3 points was added to the pain relief index in this study. This is also the reason why the pain relief rate of patients is higher in this study regardless of the combined therapy or radiotherapy alone. However, this method is more objective to reflect the actual situation of patients in a clinical setting.

In this retrospective study, the VAS score records for the most severe bone pain during radiotherapy for almost all patients were complete (some of the VAS score records were missing). The preliminary results showed, for the first time, that the VAS scores declined faster in the zoledronic acid group than in the radiotherapy group and that the side effects were still manageable. Combined therapy may be a better strategy for patients with bone metastasis to relieve bone pain quickly. However, the sample size in this study was limited. A prospective study with a large sample size is needed to further verify the present results.

Zoledronic acid can improve the treatment of osteolytic lesions by several mechanisms, including inhibiting the proliferation of osteoclasts, reducing the activity of osteoclasts, and promoting new bone formation.[18] In a basic study, it was suggested that zoledronic acid can inhibit the proliferation of prostate cancer (CaP) cells and play a therapeutic role in osteogenic lesions.[27] Several preclinical studies have shown that the activation of osteoclasts is the basis of the pathogenesis of osteolytic metastasis and osteoclasts. The treatment of osteogenic metastasis can benefit from zoledronic acid through the decrease in osteoclast activation. In this retrospective study, regarding osteolytic pain relief, the results showed that patients can benefit from radiotherapy alone or radiotherapy combined with zoledronic acid. Multivariate Cox regression analysis revealed that NSCLC patients with osteogenic lesions found on CT images can benefit more from pain relief than osteolytic patients in terms of OS, which is consistent with the results of many previous in vitro studies. It seems likely that zoledronic acid may be efficient for both osteolytic and osteogenic lesions.

Unlike bone metastasis involved in breast cancer, prostate cancer, and renal cancer, the survival of patients with NSCLC is greatly limited once bone metastasis occurs. How to quickly relieve the pain of patients without increasing the side effects of radiotherapy and chemotherapy is a common concern for both clinicians and patients. In our retrospective study, we conducted a subgroup analysis of patients who died within 6 months after radiotherapy to explore whether the treatment of zoledronic acid combined with radiotherapy can yield rapid analgesic effects in these patients both during and after radiotherapy.

Previous studies have shown that the relief rate of bone pain after multiple fractionated low-dose radiotherapy is similar to that of single high-dose radiotherapy,[28] but the pain recurrence rate in patients who underwent single high-dose radiotherapy is 2–2.5 times higher than that of multiple low-dose radiotherapies. The results of our study showed that zoledronic acid can enhance the analgesic effect of radiotherapy. However, it remains to be elucidated whether zoledronic acid can be used as a sensitizer to increase radiosensitivity; therefore, the conventional radiation dose of patients can be reduced accordingly but without a significant increase in the incidence of pain recurrence. Previous studies have found that in the treatment of bone metastasis in patients with breast cancer and renal cancer,[14],[29] zoledronic acid has been proven to provide the short-term analgesic effect equivalent to the radiotherapy dose segmentation of 30 Gy/10 F after 15 Gy/5 F radiotherapy without increasing the local recurrence rate. In this study, zoledronic acid combined with radiotherapy improved the pain relief of patients on the 3rd, 5th, 8th, and 10th days better than radiotherapy alone, and the VAS score of the most painful day in the majority of patients on the 5th day was <3. Based on the results of this study, a prospective clinical trial has been planned to evaluate whether the treatment effect of 15 Gy/5 fractions (F) radiotherapy combined with zoledronic acid is noninferior to 30 Gy/10 F radiotherapy with regard to the control rate and recurrence rate of bone pain in patients at 1 month, 3 months, and 6 months after radiotherapy to obtain better therapeutic effects and theoretical guidance for lung cancer patients with bone metastasis and bone pain.


  Conclusion Top


Although zoledronic acid has become the standard treatment for bone metastasis in patients with lung cancer, we found in the present study that it not only relieves patients' bone pain after radiotherapy but also improves the radiotherapy effect on controlling the bone pain of NSCLC patients. Zoledronic acid has a synergistic effect with radiotherapy to relieve bone pain in NSCLC patients with bone metastasis during radiotherapy. Therefore, zoledronic acid treatment during radiotherapy can yield more benefits for NSCLC patients with bone metastasis, which is worth being verified in further clinical observations. However, whether zoledronic acid can be used for the radiosensitivity of bone metastases remains to be further investigated.

Financial support and sponsorship

This work was supported by the National Key Research and Development Project (2018YFC0114402).

Conflicts of interest

There are no conflicts of interest.



 
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