The Dynamic Effects on Bone Mass of Chemotherapy and Surgery in Lung Cancer Patients

doi:10.21203/rs.3.rs-2353936/v1

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The Dynamic Effects on Bone Mass of Chemotherapy and Surgery in Lung Cancer Patients

https://doi.org/10.21203/rs.3.rs-2353936/v1

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Background The aim of this study was to evaluate the dynamic effects on bone mass of chemotherapy and surgery in lung cancer patients by computed tomography (CT).

Methods This was a retrospective study, 147 patients with lung cancer from June to December 2021 in our hospital were finally selected. Data consisted of cycle of chemotherapy and surgery. CT scans before chemotherapy and cycle 1-6 after chemotherapy were performed.The CT values of the T11-L1 vertebral body were recorded and compared.

Results The mean CT values of T11-L1 vertebral body in cycle 1, 5and 6 were lower than that in pre-chemotherapy (P=0.007＜0.05，P=0.038＜0.05，P=0.048＜0.05). There was no significant difference among the rest groups (all P＞0.05）. The CT value of T11 was higher than those of L1 in pre-chemotherapy and cycle 1, 2 after chemotherapy (P＜0.001，P=0.042< 0.05，P=0.015< 0.05). There was no statistically significant difference in CT values among the T11,T12 and L1 in cycle 3, 4, 5 and 6 (all P＞0.05). There was no statistical significant difference in the mean CT values of the T11-L1 vertebral body between operation group and non-operation group in pre-chemotherapy and same cycle after chemotherapy (all P＞0.05).

Conclusions Osteodeficiency exacerbated by ongoing chemotherapy and unaffected by operation in lung cancer patients indicates the need for the development of antiosteoporosis treatment and osteoporosis prophylaxis for lung cancer patients.

Lung cancer

Bone mass

Chemotherapy

Surgery

Tomography

X-ray computed

Lung cancer is one of the most common malignant tumors, and non-small cell lung cancer (NSCLC) is the commonest form of lung cancer. In recent years,its incidence and mortality rate have gradually increased and it has become the fastest growing malignant tumor in China [1]. Most patients with lung cancer have progressed to the middle and late stages when they are diagnosed. Chemotherapy is the main treatment modality for patients with intermediate to advanced lung cancer, which can greatly improve the survival rate of patients [2]. Yet, studies revealed patients with malignant cancer treated with chemotherapy and patients with gastric cancer after gastrectomy had a lower bone mineral density (BMD) and were confronted with a higher risk of osteoporosis [3–6].In our knowledge,no studies about the effect on bone mass of surgery in lung cancer patients were reported. Osteoporosis is a skeletal disorder,that is defined as low bone mass and micro-architectural deterioration of bone tissue [7]. It has been reported that the CT values can be used to evaluate BMD and can serve as a diagnostic tool for osteoporosis [8]. In addition to this,information on vertebral bone mineral density can be obtained in a one-stop manner while undergoing chest CT scans,and thus another test is obviated.Therefore, it is worth to measure vertebral HU on conventional chest CT images to evaluate bone mass in lung cancer patients.

In this study, we retrospectively analyzed the changes in CT values of T11-L1 vertebral body in 147 lung cancer patients in pre-chemotherapy and cycle 1–6 of chemotherapy to investigating the dynamic effects on bone mass of chemotherapy and surgery in lung cancer patients.

Participants:This investigation was conducted as a retrospective study including 147 patients with lung cancer, who received chemotherapy at the Second Affiliated Hospital of Shandong First Medical University from June to December 2021.Data on age, weight, type of chemotherapy, number of chemotherapy cycle, pathological type and whether to perform an operation were obtained from the patient's medical record. Patients with the following conditions were excluded from the study: ①:T11-L1 vertebral body fracture; ②:T11-L1 vertebral body with bone metastases or other tumors;③:T11-L1 vertebral body with severe hyperostosis;④:a history of spinal surgery or having metal in the body, such as surgical materials for fractures; ⑤:combined metabolic and endocrine diseases, as well as liver and kidney dysfunction;⑥:with a long-term history of hormonal therapy.Because of the retrospective nature of this study, patients’ informed consent was also exempted by the institute.

CT examination: All chest CT examinations were performed on multislice spiral CT scanners (GE Light Speed VCT, PHILIPS Brilliance ICT and GE Revolution CT). Transverse (axial) images were acquired with thin collimation at 120 kVp. Images were reconstructed with a 5mm section thickness with an interval of 5 mm using a standard soft tissue algorithm. Sagittal reconstructions are routinely obtained with 5mm thickness with an interval of 5 mm. The axial and sagittal CT images were assessed on a clinical picture archiving and communication system (PACS) workstation by two radiologists,and bone windows were used to view the images. CT attenuation was assessed by the primary reader placing a single click-and-drag ROI in the anterior trabecular bone space of the T11-L1 vertebral body on the middle slice of axial images. We avoided placing the ROI(300-400mm²) over areas of attenuation heterogeneity, such as the posterior venous plexus, spinal hemangiomas, spinal hardware, and compression fractures in order to avoid distortion of attenuation measurements.The middle slice of axial images of vertebral body was located by sagittal CT image.(Figure 1, 2)

Statistical analyses: SPSS statistical software (version 26.0) was used for statistical processing.The CT values were expressed as mean ± standard deviation. Categorical data were described with frequency and percentage. Values of P<0.05 were considered as statistically significant.

1.Patient characteristics.

The final analysis included 147 patients.Patient characteristics are outlined in Table 1. There were 116 male and 31 female cases; The mean age is 64.48(range, 35–82 years old).Among them, 37 cases (25.2%) were squamous carcinoma, 67 cases (45.6%) were adenocarcinoma, 42 cases (28.6%) were small cell lung cancer,and 1 cases(0.6%)were large cell lung carcinoma. The chemotherapy regimen consisted of various combinations: pemetrexed combined with a platinum-based chemotherapy regimen (57 cases), etoposide combined with a platinum-based chemotherapy regimen (42 cases),docetaxel combined with a platinum-based chemotherapy regimen (29 cases),gemcitabine combined with a platinum-based chemotherapy regimen (5 cases), paclitaxel combined with a platinum-based chemotherapy regimen (7 cases), and pemetrexed as single-agent therapy (3 cases),platinum as single-agent therapy (2 cases),gemcitabine as single-agent therapy (1cases), docetaxel as single-agent therapy (1 cases).A total of 357 vertebrae (T11 127, T12 125, L1 105) were included in the data analysis.

Table 1. Characteristics of the study population.

2.1 Comparison of mean CT values of T11-L1 vertebral body among pre-chemotherapy and cycle 1–6 after chemotherapy[Table 2]

The data are shown as the mean CT values of T11-L1 vertebral body. The mean CT values are expressed as the mean ± standard deviation and were compared with analysis of variance (ANOVA). we found that the mean CT values of T11-L1 vertebral body in cycle 1, 5and 6 were lower than that in pre-chemotherapy (P = 0.007<0.05, P = 0.038<0.05, P = 0.048<0.05) (Fig. 3).The remaining pairwise comparisons were not statistically significant(all P>0.05).

Table 2 The mean CT values of T11-L1 vertebral body in pre-chemotherapy and cycle 1-6 of chemotherapy (HU, x±s）

2.2 Comparison of CT values of vertebral body among T11,T12 and L1 within pre-chemotherapy and each chemotherapy cycle.[Table 3]

The CT values are expressed as medians and interquartile range, median (Q1,Q3).The CT value of T11 was higher than those of L1 in pre-chemotherapy and cycle 1, 2 after chemotherapy(P<0.001, P = 0.042 < 0.05, P = 0.015 < 0.05).There was no statistically significant differences in CT values between T11 and T12 in pre-chemotherapy and cycle 1, 2 after chemotherapy, and no statistically significant difference was found between T12 and T1(all P>0.05).No statistically significant difference was found in CT values among the T11,T12 and L1 in cycle 3, 4, 5 and 6(all P>0.05).(Fig. 4)

Table 3 Comparison of CT values of vertebral body among T11,T12 and L1 within

pre-chemotherapy and each chemotherapy cycle

2.3 The impact of operation on mean CT values of T11-L1 vertebral body is summarized in Table 4 .

The mean CT values are expressed as medians and interquartile range, median (Q1,Q3).By comparing the mean CT values of T11-L1 vertebral body between operation group and non-operation group in pretherapy and the same cycle, no statistical significant difference was found(all P>0.05). (Fig. 5)

Table 4

The impact of operation on mean CT values of T11-L1 vertebral body
	Operation median (Q1,Q3)	Non-Operation median (Q1,Q3)	P-value
Pre-chemotherapy	140.72(144.20,175.82)	129.66(112.85,165.24)	0.401
the 1st cycle	114.58(90.92,144.31)	111.80(91.08,141.99)	0.799
the 2nd cycle	129.47(106.13,169.16)	134.23(102.93,166.05)	0.723
the 3rd cycle	139.68(103.13,177.42)	114.03(89.10,171.50)	0.405
the 4th cycle	132.24(106.17,166.79)	126.90(100.64,158.17)	0.577
the 5th cycle	102.23(90.19, 127.97)	115.85(102.69,195.31)	0.248

Lung cancer is the most common neoplasm worldwide, it has the characteristics of high mortality and morbidity, and non-small-cell lung cancer (NSCLC) accounts for 80–85% of all lung cancer [9]. Most of the patients are already in the middle or advanced stage once diagnosed [10]. Chemotherapy plays an important role in lung cancer, which is an effective means to improve the quality of life and prolong the survival time.Currently,cisplatin or cisplatin-based chemotherapy regimens are standard first-line treatment of lung cancer.Yet, some studies showed that patients with malignant cancer treated with chemotherapy had a lower bone mineral density (BMD) and were confronted with a higher risk of osteoporosis [3–5]. H J Oh et al.found that BMD decreased significantly after gastrectomy in patients with gastric cancer[6].

At present, Dual energy x-ray absorptiometry (DXA) is the criterion standard for the evaluation of BMD [11]. However,it has some limitations. It is possibly prone to falsifying factors, such as vascular calcification in elderly patients,degenerative changes or vertebral compression fractures, which may affect the BMD value [12]. Beyond that,DXA is not universally available and may result in additional healthcare costs. Computed Tomography (CT) scans measure tissue attenuation coefficients in response to X-ray exposure.The CT values(Hounsfield Units–HU) expresses the structural characteristics of the local tissues and is not affected by human factors [13]. Alawi et al.confirmed that there was a positive correlation between the HU and BMD calculated from the DXA [14].

Some studies demonstrated that chest and abdominal CT could be used for initial evaluations of BMD [15, 16]. Chest CT scans play a key role in the screening for lung cancer [17], and patients with lung cancer routinely require chest CT scans before and after treatment [18]. Bone mass can also be assessed in patients undergoing chest and abdominal CT.This strategy might also be useful in reducing patients radiation exposure and financial burden. As lung cancer screening is being implemented, osteoporosis screening may gain a role in this setting ,which enhances the cost-effectiveness of chest screening by chest CT [19]. In this study, we investigated the dynamic changes of BMD before and after treatment in lung cancer patients using routine chest CT scans.The number of L2 vertebral body was small and therefore not included in this study.

Our results revealed that BMD of patients with lung cancer after chemotherapy was lower than that before chemotherapy,which indicated that chemotherapy could produce adverse effect on bone.Patients with lung cancer are at an increased risk of osteopenia and osteoporosis。The possible underlying mechanism for the BMD reduced by chemotherapy in patients with lung cancer might be as follows:A)Chemotherapy has a cytotoxic effect on osteoblasts,which disrupts the process of bone formation.Markedly increased bone resorption leads to a reduction in BMD in the patients with lung cancer [20, 21]. B)The cytotoxic effects of chemotherapeutic drugs can result in hypogonadism and oestrogen levels dropping quickly,which might indirectly affect bone metabolism. Estrogens are known to inhibit the formation of osteoclasts and to induce osteoclast apoptosis.Accordingly, the estrogen levels decrease rapidly and so too does the BMD [22]. C)Chemotherapeutic agents cause direct damage to the liver and kidney,and influence the activity of vitamin D. Vitamin D can maintain the BMD by increasing the absorption and transportation of calcium and phosphate in the human gut. Patients with lung cancer have vitamin D deficiency and lower BMD, and are more likely to have osteoporosis [23]. And some studies showed that chemotherapy could cause severe damage to renal tubules.Reabsorption of calcium in the distal renal tubule is reduced [24]. D)In addition, chemotherapy may cause gastrointestinal symptom such as nausea and vomiting,which can affect the uptake of protein and trace elements.

The results of the present study showed that the mean CT values of T11-L1 vertebral body decreased in cycle 1, 5and 6 of chemotherapy compared to pre-chemotherapy,which indicates that chemotherapy may produce undesirable effects on the bone quality of the vertebral body.The number of vertebral body included in cycle 1 and 6 was relatively small, and thus statistical analyses of cycle 1 and 6 were limited relatively.The results indicate the need for clinicians to pay timely attention to bone changes after 5 cycle of chemotherapy, and necessary interventions could be carried out as early as possible.The CT value of T11 was higher than those of L1 in pre-chemotherapy and cycle 1, 2 after chemotherapy,but no statistically significant difference was found in CT values among the T11,T12 and L1 in cycle 3, 4, 5 and 6.The results revealed the bone mass of the T11 vertebral body declined faster compared with those of T12 and L1.

H J Oh et al.found that BMD decreased significantly after gastrectomy in patients with gastric cancer,this could be due to the fact that Vitamin D deficiency and secondary hyperparathyroidism result in decreased BMD [6]. But we did not retrieve papers about the effect of surgery on BMD in lung cancer patients.Our study showed that there was no significant difference in BMD between surgical group and non-surgical group.This indicates that the surgical resection do not influence bone mass of patients with lung cancer.We hypothesized it might be related to no Vitamin D deficiency and secondary hyperparathyroidism after tumorectomy in patients with lung cancer.

There are still some limitations in this study.First, the number of subjects were relatively small.Secondly, this study did not take the time interval of CT examination after chemotherapy into account.In the further study, we will expand the sample size to further refine grouping,and future studies are needed to further investigate.

In summary, routine chest CT can be used to evaluate bone mass,osteodeficiency is exacerbated by ongoing chemotherapy and unaffected by operation in lung cancer patients. It indicate that clinicians should pay close attention to these indicators and identify high-risk patients as early as possible.And it is suggested to develop antiosteoporosis treatment and osteoporosis prophylaxis for lung cancer patients.It is of great significance to improve the quality of life and prolong the survival time of patients.

computed tomography

NSCLC

non-small cell lung cancer

BMD

bone mineral density

PACS

picture archiving and communication system

DXA

Dual energy x-ray absorptiometry

Hounsfield Units

Ethics approval and consent to participate

The study was performed in accordance with the Declaration of Helsinki and approved by the ethics review committee of the second affiliated hospital of shandong first medical university. Informed written consent was obtained from each participant.

Consent to publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Funding

This study was funded by the Shandong First Medical University Academic Improvement Plan (No.2019QL017); the Shandong Province Medicine and Health Science and Technology Development Plan (No.2015WS0114).

Authors and Affiliations

Department of Imageology ,The Second Affiliated Hospital of Shandong First Medical University , Taian, Shandong , China

Guoqing Wang ,Tianyu Li,,Jicong Cong,Jian Qin, Changqin Li, Jianzhong Zhu & Shenjiang Li

Department of Radiology, the Tai’an Eighty-eighth Military Hospital, Tai’an, Shandong Province, 271000, P.R. China

Le Zhang

Medical imaging department,Taian City Central Hospital,Taian, Shandong ,China

Changcheng Li

Department of Imageology ,Taian Disabled Soldiers’ Hospital of Shandong Province, Taian, Shandong , China

Jinglei Li

Authors’ information

Guoqing Wang is the first author.

Corresponding author

Shenjiang Li

Authors' contributions

GW wrote the first draft of the manuscript; TL,LZ and JC were responsible for revising the manuscript; CL ,JL and JQ supplied the CT image information; CL and JZ participated in writing of the manuscript; SLwas responsible for the final draft, analysis and proofreading.All authors read and approved the final manuscript.

Acknowledgments

We thank all the individuals who have helped us in this study.We acknowledge the valuable work of the many investigators whose published articles we were unable to cite owing to space limitations.

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No competing interests reported.

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The Dynamic Effects on Bone Mass of Chemotherapy and Surgery in Lung Cancer Patients

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