Predicting chemosensitivity based on mini patient-derived xenografts in osteosarcoma patients: A retrospective study : Journal of Cancer Research and Therapeutics

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Predicting chemosensitivity based on mini patient-derived xenografts in osteosarcoma patients: A retrospective study

Long, Zuoyao1,4,*; Lu, Yajie1,2,*; Li, Minghui1; Ji, Chuanlei3; Chen, Guojing1; Li, Jing1; Xiang, Liangbi4; Yu, Hailong4; Wang, Qi4; Wang, Zhen1,

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Journal of Cancer Research and Therapeutics 19(1):p 71-77, March 2023. | DOI: 10.4103/jcrt.jcrt_825_22
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Osteosarcoma, the most common primary malignant bone tumor, has a bimodal incidence, peaking at adolescence and older age. It is characterized by its high heterogeneity and dismal prognosis.[1] The milestone of osteosarcoma treatment was the application of chemotherapy in the 1970s, which remarkably prolonged the five-year event-free survival from <20% to 60%-70%.[2] The current standard strategy of osteosarcoma is complete surgical resection combined with systemic neoadjuvant and adjuvant chemotherapy using first-line drugs, including high-dose methotrexate (HD-MTX), ifosfamide (IFO), cisplatin (CDP), and doxorubicin (ADM). Unfortunately, the survival of patients diagnosed with osteosarcoma has not improved in the past three decades, which was mostly caused by the low chemotherapy response rate despite the many therapeutic agents and strategies developed in clinical trials.[3] Therefore, it is necessary to filter patients sensitive to chemotherapy and optimize the therapeutic strategy for others.

Patient-derived xenograft (PDX) models are cancer models where donor tumors are implanted into immunodeficient mice. It has been widely used in preclinical drug assessment and personalized clinical decisions because of its high consistency of heterogeneity and similar molecular and histopathologic signatures with primary parent tumors; thus, a better model than cell lines or genetically engineered mouse models.[4] However, the unduly lengthy process and low engraftment rate (usually four to eight months with a success rate of <50%) prevent the widespread application of PDX in the individual treatment of malignant tumors.[5] Mini patient-derived xenograft (mini-PDX), invented by LIDE Biotech, is an in vivo assay of patient-derived tumor cells with a special culture system that only takes seven days to complete drug sensitivity tests and guides personalized regimens. It can improve the limitations of the PDX test and maintain the high sensitivity and specificity compared with PDX.[6]

In this study, we established 14 mini-PDX models using primary tumor cells from surgically resected osteosarcoma. Different regimens consisting of first- and second-line drugs, which included MTX, IFO, epirubicin, and etoposide, were examined for each patient. Based on the mini-PDX results, we treated 14 patients with the first-line drugs or combined with second-line drugs. This study aimed to explore the feasibility of mini-PDX in guiding the personalized treatment for patients with osteosarcoma.


Patients and study design

From January 1, 2018, to June 30, 2019, 14 patients with osteosarcoma were enrolled and underwent mini-PDX assay in our hospital. The inclusion criteria were defined as follows: (1) aged between 4 and 30 years old; (2) histologically confirmed osteosarcoma; (3) did not undergo other antitumor therapies except for chemotherapy before mini-PDX assay.

Additionally, this study was approved by the Ethics Committee of Xijing Hospital and complied with the Declaration of Helsinki. All participants provided written informed consent.

Mini-PDX models and drug sensitivity assays

Mini-PDX models were established using fresh osteosarcoma tissues from 14 patients using modified microencapsulation and hollow fiber culture system to implant in immunodeficient mice (OncoVee® Mini-PDX, LIDE Biotech). Tumor tissue with a volume of more than 500 mm3 and a necrotic area of <30% was briefly washed with Hanks balanced salt solution (HBSS) to remove nontumor and necrotic tumor tissues within 24 h after resection. Tissues were digested with collagenase at 37°C for 1–4 h after morcellation. Subsequently, cells were washed with HBSS and filled into OncoVee® capsules after pelleting by centrifugation at 600 g for five minutes and removing blood cells and fibroblasts. Four-week-old BALB/c nude mice were used for subcutaneous implanting of capsules via a small skin incision with three capsules per mouse [Figure 1]. Drugs were administered for seven days.[7]

Figure 1:
A brief introduction to the mini-PDX model. Tumor cells, digested from fresh tissue, were loaded into three capsules and subcutaneously implanted in 4-week-old BALB/c nude mice. Seven days after IP or oral administration of drug or placebo, capsules were harvested to evaluate drug sensitivity via cell viability test. According to the results of mini-PDX, the optimal regimens were selected for personalized chemotherapy

Evaluation of therapeutic responses

Strategies of mini-PDX included three to five drugs per patient. The equivalent doses in the administration of mice were: MTX, 3 g/kg, intraperitoneal (IP) injection, once weekly[8]; IFO, 150 mg/kg, IP, every two days[9]; epirubicin, 5 mg/kg, IP, every four days[10]; etoposide, 20 mg/kg, IP, every four days[11]; lobaplatin, 10 mg/kg, IP, every four days[12]; docetaxel, 20 mg/kg, IP, every four days[13]; apatinib, per os (PO), every seven days[14]; gemcitabine, 60 mg/kg, IP, every four days[15]; topotecan, 4 mg/kg, IP, every five days [Table 1].[16] Because ADM and DDP are included in all strategies of osteosarcoma chemotherapy, we did not test the sensitivity of these two drugs in our study.

Table 1:
Dosage, schedule, and route of drug administration in mini-PDX

Responses of mini-PDXs are represented using the tumor relative proliferation rate (TRPR). TRPR is the percentage of relative proliferation between the administration group and the control group. It can reveal the inhibition of drugs on tumor cells, which is proportional to drug sensitivity. TRPR was calculated based on the relative fluorescence units, using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega), by the following formula: TRPR (%) = ((RFUd7-RFUd0) drug/(RFUd7-RFUd0) placebo) x 100%. A positive response to the drug was considered present if TRPR was <55% (P < 0.05). In contrast, TRPR of ≥55% was considered a negative response to the drug.[6] Generally, lower TRPR levels refer to increased sensitivity to drugs. The clinical response status of patients was evaluated using CT or MRI images according to the RECIST 1.1 guidelines.

Statistical analysis

Progression-free survival (PFS) was calculated from the date of acquiring specimens until tumor progression or recurrence. The difference between the TRPRs of all agents was analyzed using a paired t-test. Kaplan-Meier method and log-rank test were used to analyze PFS. Data were censored for patients who refused to receive chemotherapy or were lost to follow-up. The SPSS 18.0 software (SPSS Inc.) was used for all statistical analyses. We considered P < 0.05 to be statistically significant.


The baseline characteristics of the patients

In this study, all patients were willing to undergo the mini-PDX test. The demographic and baseline characteristics of patients are presented in Table 2. A total of 14 patients were enrolled, with a median age of 13.5 years old. All patients were diagnosed with osteosarcoma without pulmonary metastasis; four were newly diagnosed, and ten had undergone neoadjuvant chemotherapy. Most of the pathology subtypes were common osteosarcoma except for two cases of small-cell osteosarcoma.

Table 2:
Patient demographic and baseline characteristics

The mean TRPR of each agent was MTX 80.7% for 13 patients, IFO 43.4% for 11, etoposide 82.8% for seven, epirubicin 69.8% for six, lobaplatin 94.3% for four, docetaxel 48.5% for three, apatinib 108.5% for two, gemcitabine 89% for one, and topotecan 82% for one [Figure 2a]. By comparing the TRPR using a paired t-test, we found that patients were potentially more sensitive to IFO than MTX with significantly lower TRPR levels (38.3% vs. 84.3%, P = 0.031), and the difference between MTX with etoposide and epirubicin was not significant (P = 0.414 and P = 0.336, respectively) [Figure 2b-d].

Figure 2:
Results of mini-PDX models. a) Scatter diagram presenting the tumor relative proliferation rate of all drugs in the mini-PDX models from 14 patients with osteosarcoma. b) IFO was more sensitive than MTX in the same patient (P = 0.031, n = 8). c) The sensitivity of MTX and Eto differed insignificantly (P = 0.414, n = 6). d) The sensitivity of MTX and Epi differed insignificantly (P = 0.366, n = 6).

Clinical treatment of patients

All patients received API (IFO 12 g/m2, alternating with the combination of ADM 60 mg/m2 and CDP 100 mg/m2) regimen as neoadjuvant chemotherapy and had R0 resection after two chemotherapy cycles. No progressive disease had occurred before surgery. Because the result of mini-PDX showed that IFO could inhibit tumor cells, alternating IFO with AP was recommended as an adjuvant chemotherapy regimen for these patients. Doxorubicin or etoposide were the alternatives to be combined with IFO if the TRPR was <55%. If the TRPR values under MTX treatment were better than those under IFO treatment, we recommended replacing IFO with MTX. Three patients who relapsed did not receive adjuvant chemotherapy.

The survival outcomes of patients and the relationship with mini-PDX models.

The results of our study showed that the six-month PFS of all patients was 36.36%, and that mini-PDX can be used as a prognosis predictor [Figure 3a]. Kaplan–Meier analysis revealed that these patients who had TRPR <40% for more than one drug had significantly longer mean PFS (9.4 months, 95% CI: 1.7–17.1 months) than other patients (3.7 months, 95% CI: 1.6–5.7 months) (P = 0.0324; hazard ratio (HR) = 3.39; 95% CI: 1.45–21.62). Thus, we speculated that a patient with any TRPR of <40% was sensitive to chemotherapy and had a better prognosis [Figure 3b].

Figure 3:
Survival analysis of patients who received chemotherapy using log-rank test and Kaplan–Meier test. a) The six-month PFS of all 11 patients was 36.36%. b) Patients with lower TRPR than 40% in more than one drug had a significantly longer mean PFS than other patients (9.4 months vs. 3.7 months, P = 0.0324, HR = 3.39, 95% CI: 1.45–21.62). c) There is no significant difference but with a tendency for better prognosis of guided patients compared with conventional patients (7.5 months vs. 4.8 months, P = 0.2323, HR = 0.49, 95%CI: 0.11–1.57)

Additionally, we compared the PFS between the six patients guided by mini-PDX and five patients who used the same regimen as neoadjuvant chemotherapy. PFS was defined as the duration from operation to progressive disease. Until the last follow-up, the six-month PFS rate was 50.00% (3/6) in the guided group and 20.00% (1/5) in the conventional group. There was no significant difference between the PFS of the guided group (12.67 months, 95% CI: 3.94–21.39) and the conventional group (4.0 months, 95% CI: 1.03–6.97), but there was a tendency for a better prognosis in the guided patients (P = 0.0835, HR = 0.37, 95% CI: 0.06–1.03) [Figure 3c].


Osteosarcoma, the most common primary malignant bone tumor, usually occurs at the metaphysis of long bones, including the distal femur, proximal tibia, and proximal humerus.[17] Many prospective and retrospective clinical trials have confirmed that the percentage of tumor necrosis was ≥90% (as evaluated by Huvos criteria) in half of the patients with good pathologic response rates. This condition can be expected in neoadjuvant chemotherapy as an independent factor of good prognosis.[18,19] Ferrari et al. compared the survival rate of nonmetastatic osteosarcoma having different pathological responses with neoadjuvant chemotherapy and revealed that patients who had a good response had similar five-year event-free survival as patients who had a poor response (47% vs. 56%, P = 0.6) but had better overall survival (88% vs. 73%, P = 0.02).[20] Additionally, both recurrence and distal metastasis are related to poor prognosis.[21,22] Therefore, increasing the chemosensitivity to improve the overall survival of patients with osteosarcoma is important. In this study, we attempted to utilize a mini-PDX assay to explore the optimal strategy for individualized treatment to prevent recurrence and distal metastasis. Results of the follow-up demonstrated that mini-PDX could be a predictor to identify patients sensitive to more than one drug, i.e., those who have a longer PFS (P = 0.0324) [Figure 4a-e].

Figure 4:
Clinical response and mini-PDX results of a patient with osteosarcoma located in the right proximal humerus. a) X-ray before chemotherapy. b) X-ray after two cycles of neoadjuvant chemotherapy (IFO alternating with the epirubicin + cisplatin) revealed that the tumor border was much clearer. c) Complete resection was performed after chemotherapy, followed by the same regimen as preoperation. d) Mini-PDX results showed that the patient was highly sensitive to IFO and epirubicin. e) Relative body weight (RBW) revealed that the toxicities of all regiments were tolerable and safe

Reflect the tumor characteristics of patients.[23–25] But a lengthy test period and unsatisfactory engraftment rate prevent its wide application in some high-grade malignant tumors, especially in osteosarcoma. Mini-PDX is a rapid, systematic in vivo assay for measuring the drug sensitivity of tumor cells, and it only takes seven days. As Zhang et al.[6] reported, mini-PDX can overcome the limitations of PDX and retain the accuracy and efficiency, compared with PDX models, with 92% positive value, 81% negative value, 80% sensitivity, and 90% specificity. Zhan et al.[26] used mini-PDX to guide the selection of chemotherapeutic regimens in patients with gallbladder carcinoma who had significantly longer median PFS (17.6 months vs. 12.0 months, P = 0.014) and overall survival (18.6 months vs. 13.9 months, P = 0.030) than patients with conventional chemotherapy. In another case reported by Zhao et al.,[5] personalized treatment based on mini-PDX and whole-exome sequencing in a patient with metastatic duodenal adenocarcinoma demonstrated that this combination could rapidly assess drug sensitivity and reveal important genetic alterations. In our study, individual chemotherapy based on mini-PDX tended to prolong the PFS of patients; however, it was not statistically significant (7.5 vs. 4.8 months, P = 0.2323) because of the small number of samples.

The regimens of MAP/MAPI (MTX, CDP, ADM, or plus IFO) are the standard strategy of chemotherapy in patients with osteosarcoma.[27] The administration of high-dose MTX requires admission, blood concentration monitoring, and leucovorin rescue because of the related toxicity.[28] The most common adverse events included gastrointestinal reaction, mucosal injury, myelosuppression, and a 2% mortality risk.[29] Regarding the problems mentioned before, non-MTX strategies have been attempted.[30] A retrospective study by Xu et al.[31] using 36 patients suggested that the API regimen produces an EFS rate and survival outcomes comparable with those attained with MTX-containing regimens, with fewer adverse events. Bajpai et al.[32] prospectively treated 237 nonmetastatic patients with osteosarcoma having eight sequential doublets of API, four courses each in the neoadjuvant and adjuvant settings. Fifty-eight percent of patients in the control group demonstrated good histological response and the same five-year EFS and overall survival compared with patients in the per-protocol analysis. Before surgery, 106 patients with osteosarcoma were treated with API-AI (three kinds of ADM-IFO-CDP and two ADM-IFO). Postoperative chemotherapy was assigned by the risk group: patients with localized tumors with a good pathological response received two AI and two PI courses, while others received five cycles of etoposide-IFO. Thirty-six patients responded well and had manageable toxicity. The five-year event-free survival and overall survival rates were 46% and 57%, respectively.[33] Our results showed that MTX was insensitive in patients with osteosarcoma compared with IFO in the mini-PDX group (TRPR 80.69% vs. 43.4%, P = 0.031), supporting the notion that non-MTX regimens produced comparable outcomes to the standard strategy. Mini-PDX could be an appropriate technique to identify patients who are sensitive to MAP or API regimen.

We recognize the following limitations of this study. Firstly, because of the low incidence of osteosarcoma, the sample size we included in this study was limited, which may compromise the reliability of the conclusions. Secondly, because of the insufficient follow-up time, it is unclear how an individual regimen designed using mini-PDX affects the overall survival of patients with osteosarcoma. Finally, the timing of the mini-PDX assay, whether to be performed before or after neoadjuvant chemotherapy, needs to be discussed. In our experience, we recommend performing a mini-PDX assay at the same time as tumor resection because it is necessary to use three or four first-line drugs after primary diagnosis. Therefore, the conclusions of this study need to be further verified in a randomized controlled clinical trial with a larger sample size. Nevertheless, as a preliminary case series, our study provides a meaningful and exploratory basis for the precise treatment of osteosarcoma and even other solid tumors in the future.


Mini-PDX showed a comparable outcome in guiding personalized chemotherapy with PDX, having a shorter time and a higher engraftment rate. Our results demonstrated that chemotherapy based on mini-PDX can significantly improve the survival of patients with osteosarcoma whose TRPR was <40% and that IFO was not inferior to MTX, indicating that API is an alternative regimen for neoadjuvant chemotherapy of osteosarcoma. Mini-PDX models have the potential to be used in treating other aggressive tumors. However, further investigation with a larger sample size is necessary to verify the results of this study.

Ethics approval

This study was been approved by the Ethics Committee of Xijing Hospital (KY20192050-F-2).

Financial support and sponsorship

This research was funded by National Natural Science Foundation, grant number 81572699” and “The Booster Project of Xijing Hospital (XJZT18MDT18)”.

Conflicts of interest

There are no conflicts of interest.


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Chemosensitivity; mini-PDX; osteosarcoma; prognosis

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