In this study, we showed that the combination therapy of THP + IFO + VP-16 was effective for patients with soft tissue sarcomas, with an overall response rate of 36%, which was relatively higher than the response rate found with ADR + IFO combination and other combinations. (Table 3) In addition, this regimen might have better cardiac tolerance as compared to ADR-based combinations.
Table 3. The comparison of first-line treatments for patients with soft tissue sarcoma
Chemotherapy regimen
|
Overall response
(CR + PR)
|
Adverse events
(> Grade3)
|
Doxorubicin monotherapy (10)
|
14%
|
LP = 18%, FN = 13%,
AN = 4%, TP = 0.4%
|
Doxorubicin + ifosfamide (10)
|
26%
|
LP = 43%, FN = 46%,
AN = 35%, TP = 33%
|
Gemcitabine + docetaxel (19)
|
20%
|
LP = 7%, FN = 12%,
AN = 6%, TP = 0%
|
Current protocol
|
36%
|
LP = 96%, FN = 68%,
AN = 68%, TP = 48%
|
CR = complete response, PR = partial response, LP = leukopenia, FN = febrile neutropenia, AN = anemia, TP = thrombocytopenia
To date, ADR monotherapy is considered the standard first-line treatment for advanced soft tissue sarcoma (9). This is based on a randomized controlled phase III trial of ADR monotherapy versus ADR + IFO combination therapy for the first-line treatment of patients with this disease (10). Although the response rate and progression-free survival (PFS) were significantly improved in the combination group, adverse events were more frequent and there was no significant difference in overall survival (OS) between the 2 groups (10). Therefore, ADR monotherapy has been recommended for delaying tumor progression or alleviating tumor-related symptoms with acceptable adverse events. On the other hand, ADR + IFO combination therapy is recommended when tumor shrinkage is expected to be beneficial, such as in patients experiencing severe symptoms caused by tumors compressing adjacent essential organs, or in those intending to convert to resectable status for their primary or metastatic lesions.
From the mathematical model (Goldie-Coldman hypothesis) about the proliferation of tumor and acquisition of cancer resistance (11), further multi-combination therapies were expected to increase the efficacy of anti-tumor agent. Thus, the VP-16 was added to the combination of THP + IFO therapy and expected to be superior to conventional chemotherapies in terms of efficacy. Although in this study, patients with grade 3 or higher hematological toxicities were obviously increased than other regimen (Table 3), the contribution of this multi-combination therapy to oncological outcomes should be validated by future study.
A similar combination regimen comprising VP-16 (125 mg/m2) + IFO (1500 mg/m2) + ADR (50 mg/m2) (i.e., an “EIA regimen”) with the addition of G-CSF to treat any perioperative conditions was reported by Schmitt et al. in 2010 (12). Although it was almost difficult to compare to current protocol, according to their data, the response to this regimen was CR, PR, SD, and PD in 6%, 24%, 62%, and 8% of their patients, respectively. When it comes to cardiac toxicity, grade 2 cardiac toxicity occurred in 4% of their patients, contrarily, no cardiac adverse event was observed in the current study, which might be one of the merits of substitution of ADR by THP in the combination. Moreover, EIA regimen was also reported by Issels et al. in a phase III trial that also included regional hyperthermia (13). Although that study showed promising results in terms of combining hyperthermia with EIA, secondary leukemias were also reported in 5 patients, and 3 patient deaths were attributed to the treatment. Therefore, the investigators concluded that the EIA regimen should be discontinued in further studies due to the risk of leukemia owing to VP-16 administration. Despite no secondary leukemia occurring among our own patients, the administration of VP-16 should be considered in a prudent manner. In our hospital, for the fear of the risk of secondary cancers, we did not include children under 15 years of age into this regimen.
The fact that the tolerated dose limit is approximately twice that of ADR is an advantage of THP chemotherapy. However, THP has not been approved for soft tissue sarcoma in Japan, and its off-label use was permitted as a substitute for the first-line drug ADR by our hospital. A Phase II trial on the efficacy of THP monotherapy in various types of tumor; metastatic renal cancer, colon cancer, melanoma, and soft tissue sarcoma, reported that the responses after the median cumulative dose of 165 mg/m2 (range: 55–630) were: 3 patients with PR and 18 patients with SD, out of a total of 80 patients (14). Therefore, THP is not approved in the US and Europe, and there is no IND application with the FDA. However, because most patients with soft tissue sarcoma were pretreated with other chemotherapies, including anthracyclines, the definite evaluation in soft tissue sarcoma was suspended (14). Since then, there have been various case reports or case series analysis that indicated preferable outcomes with THP-based combination chemotherapy (15,16,17,18). Thus, a randomized controlled trial for the usage of THP-based chemotherapy will be needed to gain future approval for soft tissue sarcoma.
This study had several limitations. First, it was performed at a single institution and had a small sample size, which may have biased the results. Also, because of the versatile histology of soft tissue sarcoma, the responses to chemotherapy can vary considerably among patients; hence, our results should be interpreted with caution. Moreover, although we showed that our regimen was superior to ADR monotherapy in terms of response, it was difficult to compare the result directly.