Conventional IV adjuvant chemotherapy and neoadjuvant chemotherapy have been applied extensively in multimodal osteosarcoma treatment for over 45 years.(24) Though changes in drug combination, dosage, and administration duration were made to optimize the regimen, no significant improvement was achieved based on the approximately 50–70% 5-year OS and EFS rates in the past decade.(25–27) As a modified approach to augment the potential of chemotherapy drugs, the AI technique combined with MSCs has been studied for years.(13, 28, 29) In the present study, we attempted to investigate the therapeutic effect of the CAI + MSC + S protocol in osteosarcoma treatment. The 5-year OS and EFS rates were 57.8% and 52.5%, respectively.
The CAI regimen and its outcome measurements were first documented by Jaffe et al. in 1983.(30) Then, a series of studies concerning CAI-facilitated multidrug chemotherapy followed.(13, 29, 31–36) Information on all 9 studies, including the present study, is listed in Table 4.
Table 4
Synopsis of IA CDDP information reported in the literature
Authors
|
Type of study
|
No. of patients
|
Ages
(y)
|
Sites
|
Metastases
|
Preoperative CDDP courses No.
|
> 90% TN
|
OS
|
EFS
|
Winkler et al. and Fuchs et al.
|
Nonrandomized,
2 arms
|
50
|
< 40
|
All
|
Included
|
2
|
68%
|
67% at 10 y
|
63% at 10 y
|
Ferrari et al.
|
Single arm
|
164
|
< 40
|
Extremity
|
Excluded
|
2
|
NA
|
72% at 8 y
|
63% at 8 y
|
Ferrari et al.
|
Randomized, 2
arms
|
59
|
< 40
|
Extremity
|
Excluded
|
2
|
64%
|
61% at 8 y
|
54% at 8 y
|
Rha et al.
|
Single arm
|
37
|
8 ~ 41
|
Extremity
|
?
|
3
|
75%
|
78% at 3 y
|
55% at 3 y
|
Bacci et al.
|
Randomized, 2
arms
|
40
|
< 40
|
Extremity
|
Included
|
2
|
77%
|
NA
|
26% at 5 y
|
Bacci et al.
|
Randomized, 2
arms
|
72
|
< 40
|
Extremity
|
Included
|
2
|
80%
|
NA
|
61% at 5 y
|
Wilkins et al.
|
Single arm
|
47
|
< 21
|
Extremity
|
Excluded
|
3–5 (response
dependent)
|
87%
|
92% at 10 y
|
84% at 10 y
|
Wilkins et al.
|
Single arm
|
62
|
< 22
|
Extremity
|
Excluded
|
3–5 (response
dependent)
|
87%
|
93% at 10 y
|
86% at 10 y
|
Xie et al.
|
Nonrandomized,
2 arms
|
48
|
NA
|
Extremity
|
Included
|
3
|
63%
|
64% at 5 y
|
60% at 5 y
|
Hu et al.
|
Single arm
|
12
|
11 ~ 69
|
Pelvis
|
Excluded
|
2
|
66.7%
|
57.8% at 5 y
|
52.5% at 5 y
|
Among these 9 studies, 8 used CAI and systematic chemotherapy sequentially before surgery, and 5 studies scheduled a 2-course preoperative regimen. Six of 9 studies suggested a higher chemotherapy response rate and/or survival rate in the CAI group compared with the IV CDDP group; 2 of these investigations were 2-arm randomized cohort studies and reported a statistically significant improvement in the good-response ratio (21% and 31%, respectively). In the third randomized cohort study reported by Rha et al., the improvement was not statistically significant, probably because the limited sample size was insufficient to test the 9% difference between the two groups.(34) In the multicenter study reported by Winkler et al. and Fuchs et al. in the 1990s, no difference in chemotherapy response was observed between the intraarterial and IV CDDP groups.(29, 33) Similarly, Xie et al. also proved a superior histological response rate but similar survival in the CAI group versus the IV group in 2019.(13) However, the reliability of the conclusions in the 2 studies may be impaired by the nonrandomized grouping design conducted at the researchers’ discretion, which could be affected by the severity of disease. Although CAI may bring benefits to chemotherapy response augmentation and survival rates in limb osteosarcoma patients, how pelvic osteosarcoma reacts to CAI-facilitated multidrug chemotherapy remains elusive.
Pelvic tumor resection surgeries such as hemipelvectomy are notoriously known as one of the most destructive operations in modern orthopedic surgery.(37) Due to the adjacency of the vascular network, nerves and viscera in the pelvis, surgeons have to weigh tumor eradication against functional preservation in the determination of the extent of surgical excision. This dilemma makes the treatment more challenging. Patients with pelvic osteosarcoma have an approximately 30% lower survival rate compared with the extremity-morbidity population, which could be explained by the higher rate of not only failure of surgical remission but also advanced age, large tumor size, primary metastasis, prolonged latency periods and poor chemotherapy responses.(11, 38) Thus, it is critical to maximize the chemotherapy response and achieve better survival outcomes in pelvic osteosarcoma patients.
The combination of agents in our MSC protocol was determined according to NCCN guidelines for bone cancer. Although the agent numbers and categories differed, all of the above-reviewed studies and the present study deployed a multidrug protocol to treat tumor cells in different phases of the cell cycle. Unfortunately, insufficient data are available to appropriately compare the therapeutic effect of CAI alone or in various combinations with MTX, VCR, ADM and IFO because of great heterogeneity. In the present study, we used high-dose MTX at 10 g/m2 and CAI at 120 mg/m2 in 2 doses as routine treatment before surgery. For patients with tumors over 8 cm, we employed an enhanced dose of CAI at 160 mg/m2. Additionally, additional IFO courses were given to slow responders. This individualized regimen directly yielded a 66.7% prevalence of good histopathologic responders and contributed to the 5-year survival rate of 57.8% in pelvic osteosarcoma, both of which were superior to the corresponding produced by conventional systematic chemotherapy.(11)
The cumulative dosage of CDDP was 780 mg/m2 for a good responder with a tumor size ≤ 8 cm in the present study. Wilkins et al. reported the highest accumulated dose of CDDP at 960 mg/m2 and a single dose at 160 mg/m2 over 24 h as an enhanced regimen for patients with tumors over 10 cm versus 120 mg/m2 over 6 h as routine, which consequently yielded the highest 10-year OS and EFS rates (93% and 86%, respectively) among all reviewed studies. Notably, Ferrari et al. and Xie et al. investigated CDDP administration at similar doses to those in the present study but yielded significantly poorer survival outcomes.(13, 32) This may be because 120 mg/m2 CDDP was given intraarterially in 72 h in the first study, which is too long to achieve a high enough blood concentration; patients with tumor metastases at the initial diagnosis were included in the second study so that the survival rate would be reduced. We used relatively high-dose CDDP administered over 3 to 6 h combined with 4 other drugs, including etoposide, and made individualized adjustments to the protocol for patients with high-risk factors. This may have contributed to the 57.8% OS and 52.5% EFS rate at 5 years, which is favorable for pelvic osteosarcoma. Moreover, we discovered that the OS and EFS rates in the population with tumors ≤ or > 8 cm showed insignificant differences. This finding suggests that this protocol with adjustment in the drug dosage and combination could be beneficial to bridge the gap in survival rate between patients with large tumors and those with small tumors.
Only 4 poor responders were observed, 3 of whom developed tumor relapses. Two of the 3 patients died of metastasis during postoperative MSC; another showed no evidence of disease after receiving secondary amputation and resection for local recurrence. This protocol seemed to provide limited benefit to the poor responders. However, the present data are so limited that few tenable conclusions can be drawn from it to guide salvage treatment for poor responders.
Although the AI technique and additional courses were given in this protocol, no patients received an overdose of chemotherapy drugs compared with previous studies using similar drug combinations. No AI-relative grade 4 or 5 adverse events were observed. Although systematic adverse events, including nausea, vomiting, anemia and an increase in creatinine/aminotransferase levels, shared similar incidence rates and severities with the study reported by Xie et al., local skin hyperpigmentation and pelvic soft tissue necrosis in muscle occurred after only 3 and 1 of 24 CAI events (12.5% and 4.2%, respectively), which is more favorable than the situation reported in the most reviewed studies concerning extremity osteosarcoma.(13, 29, 32) This finding could be explained by the shorter local drug-retention time since the pelvis has a more sufficient blood supply and drainage.
In terms of the postoperative MSC regimen, we found it hard for patients to accept 12 cycles of second-line therapy in 3 years, as reported in the evidence provided in the guidelines in view of the high expenditure and physical discomfort. Therefore, the number of cycles was reduced to 6 for poor responders. During the postoperative MSC period, there was no early death. The reported cardiac irritation, increase in creatinine/aminotransferase, oral mucosa inflammation and hematologic system abnormality were acceptable. In summary, our chemotherapy regimen seems to be well tolerated.
To monitor the chemotherapy response, several methods have been reported in previous studies. In the studies reported by Winkler et al. and Fuch et al., plain X-ray, local CT and emission CT of bone were used to monitor the TNR before the surgery.(29, 33) Bacci et al., Wilkins et al. and Xie et al. deployed CT arterial angiography, which yielded sensitivity and specificity over 90% and 50%, respectively.(13, 31, 35, 36) Nevertheless, a repeated CT arterial angiography assessment is difficult to be accepted by patients because it requires multiple invasive operations and high expenditure. RECIST-1.1-based MRI remains one of the most commonly used approaches in tumor response evaluation.(39, 40) In the present study, we used CE-MRI to detect the tumor response and guide the adjustment of treatment for each patient. Although the results did not seem to suggest that this method is highly predictive of the histopathologic chemotherapy response, the similar survival rate between patients with large and small tumors may reflect the effectiveness of the individualized treatment.
There were several limitations in our investigation. First, the design was restricted to a small-sample-size single-arm clinical study due to the rarity of pelvis osteosarcoma morbidity, therefore reducing the reliability of the conclusions. Second, several previous studies reported that pathological subtypes of osteosarcoma, such as chondroblastic and telangiectatic osteosarcoma, respond differently to chemotherapy. However, the pathological subtype of each patient was not analyzed as an independent prognostic factor in our study.(38, 41) Heterogeneity of the osteosarcoma subtype constitution could distort survival outcomes. Third, we used CE-MRI per RECIST 1.1 to monitor the tumor response before surgery and guide the individualized adjustment of the treatment protocol. However, CE-MRI evaluation was not the gold standard for TNR prediction. Multiple innovative approaches for TNR prediction in osteosarcoma have been researched in the past 30 years, such as dynamic CE-MRI with sensitivity and specificity over 70% and 80%, respectively, according to previous studies.(42–44) We endeavor to deploy approaches with higher accuracy to evaluate viable tumors in hope of providing more precise guidance for individualized pelvic osteosarcoma treatment in further studies.