Feasibility of chemosensitivity testing in soft tissue sarcomas
© Lehnhardt et al; licensee BioMed Central Ltd. 2005
Received: 28 December 2004
Accepted: 18 April 2005
Published: 18 April 2005
Soft tissue sarcomas comprise less than 1% of all solid malignancies. The presentation and behavior of these tumors differs depending on location and histological characteristics. Standard therapy consists of complete surgical resection in combination with adjuvant radiotherapy. The role of chemotherapy is not clearly defined and is largely restricted to clinical trials. Only a limited number of agents have proved to be effective in soft tissue sarcomas. The use of doxorubicin, epirubicin and ifosfamide allowed response rates of more than 20%. In addition, recent chemotherapy trials did not demonstrate any significant differences in efficacy for various histological subtypes.
The objective of this study was to gain additional information about the chemosensitivity of soft tissue sarcomas to seven 7 different chemotherapy agents as single drugs and 4 combinations. Therefore we used an established ATP based in-vitro testing system and examined 50 soft tissue sarcomas. Chemosensitivity was assessed using a luciferin-luciferase-based luminescence assay providing individual chemosensitivity indices for each agent tested.
The sensitivity varied widely according to the histological subtypes. The tumors state of cellular dedifferentiation played a crucial role for the efficiency of the chemotherapeutic agents. The sensitivity also depended on the presentation of the sarcoma as a primary or recurrent tumor. The highest sensitivity was demonstrated for actinomycin D as a single agent, with 74% of the tumor samples exhibiting a high-grade sensitivity (20% low sensitivity, no resistance). The combination of actinomycin D and ifosfamide yielded a high sensitivity in 76% (2% resistance). Doxorubicin as a mono-therapy or in combination with ifosfamide achieved high sensitivity in 70% and 72%, respectively, and resistance in 6% of the samples.
Chemosensitivity testing is feasible in soft tissue sarcomas. It can be used to create sensitivity and resistance profiles of established and new cytotoxic agents and their combinations in soft tissue sarcomas. Our data demonstrate measurable discrepancies of the drug efficiency in soft tissue sarcomas, sarcoma subtypes and tumor recurrencies. However, current therapeutic regime does not take this in consideration, yet.
Soft tissue sarcomas account for less than 1% of malignant neoplasms. Approximately 140 different histological types of sarcomas have been described . Sarcomas arise in tissues of mesenchymal or ectodermal origin and may thus occur anywhere in the body The surgical treatment of choice is the wide surgical excision of the tumor in combination with radiotherapy [2, 3]. Currently, about 30–50% of all patients die within 5 years of primary diagnosis. This overall poor prognosis is mainly due to metastatic disease at the time of diagnosis. Approximately 40% of patients with high-grade sarcomas develop pulmonary metastases in spite of local tumor control . The median duration of survival with apparent metastases is presently 8–12 months [2, 4].
Soft tissue sarcomas are notoriously resistant against most chemotherapeutic agents . As first line treatment, only doxorubicin (adriamycin), epirubicin and ifosfamide have achieved a single-agent activity of more than 15% resulting in response rates of 18%-29% [6, 7]. The combination of anthracyclines and ifosfamide resulted in response rates of 40%-50%, with 10% of patients in complete remission . ite the reported association between remission and prolonged survival, an overall superiority of combination chemotherapy over the administration of single-agent doxorubicin has not been established yet. Ifosfamide can play a major role as a second-line treatment with response rates of up to 30%-50% following the failure of anthracylin [2, 7].
Recently, new strategies have been pursued to improve treatment options for well defined subgroups of sarcomas. One example is the successful use of imatinib hydrolasis, a specific tyrosine kinase inhibitor, in gastrointestinal stromal tumors [10, 11].
Several new drugs such as exatecan, TZT 1027, trofosfamid and topotecan are under investigation [12–15]. Another promising agent for the treatment of soft tissue sarcomas is ET-743. Several clinical trials have shown response rates of up to 20% in untreated and 10% in pretreated sarcoma patients. Approximately 50% of patients in these series have shown long-lasting stabilization of disease [4, 9, 16, 17].
Patients and Methods
Basic data of patients with soft tissue sarcomas (n = 50)
Cytotoxic drugs used in the ATP-TCA
100% TDC* (μg/ml)
Classification of ATP-TCA chemosensitivity testing results
Tumor growth inhibition at 200% TDC*
Tumor growth inhibition at 25% TDC*
The statistical significance of differences between sub entities of soft tissue sarcomas, tumor grading and the comparison between primary and recurrent tumors was calculated by the Mann-Whitney-U-test and the Chi squared test. P < 0.05 was considered statistically significant.
Chemosensitivity testing in 50 soft tissue sarcoma patients
Mean Sensitivity Index*
Doxorucicin + Ifosfamide
Actinomycin D + Ifosfamide
The cytotoxic treatment with actinomycin D resulted in significantly divergent profiles of chemosensitivity depending on the histological type of soft tissue sarcoma (Fig. 4). Rhabdomyosarcomas were especially chemoresistant against actinomycin D (p < 0.05).
This is in contrast to the response pattern of other types of sarcomas to this particular chemotherapy. There was no difference in chemosensitivity between rhabdomyosarcomas and other tumor types for the remaining cytotoxic drugs used.
In view of the limited number of effective chemotherapeutic drugs with response rates of less than 20%, the need for more detailed information about the tumor specific chemoresistance seems obvious [4, 5, 28]. A testing system would have to produce repeatable and comparable results of the chemosensitivity of various tumor types. Chemosensitivity testing with ATP-TCA proved a success in acquiring resistance profiles for different chemotherapeutic agents in metastasizing carcinoma of the breast  and recurrent tumors of the ovaries . In these tumors, the intra- and inter-assay variability was less than 15%, which demonstrated a high sensitivity and linearity . In the present study, the ATP-TCA test was practicable in 94% of all cases and thus represented a feasible method in soft tissue sarcomas.
Only a limited number of cytotoxic drugs, such as doxorubicin, epirubicin and ifosfamide, have been reported to produce response rates of more than 15% in the treatment of sarcomas, either as single agents or as part of drug combinations. There are no clinical trials providing evidence of prolonged survival rates after either adjuvant or neoadjuvant chemotherapy [30–32]. Currently, the EORTC is not conducting any clinical trials on the efficacy of chemotherapy in soft tissue sarcomas due to the lack of a prospected benefit. Chemotherapy is presently used in metastasized disease only which may account for the low acceptance of this therapeutic option in adult soft tissue sarcoma [30, 33–36].
Further limiting factors regarding the feasibility of large-scale trials are the low incidence of sarcomas and the enormous heterogeneity of the types of tumors. At the moment, pathologists know more than 140 entities that may explain some problems of classification. The application of chemotherapy is thus not differentiated according to the histological type of tumor, yet.
Doxorubicin has been reported to achieve response rates of 20% to 26% and represents the most effective chemotherapeutic agent among the available first line single drug therapies . In our study, the ATP-TCA testing of doxorubicin showed that 70% of tumors reacted highly sensitive. However, among all cytotoxic agents tested, doxorubicin proved to be only a second rate treatment regimen. The overall highest sensitivity of all single therapeutic agents was demonstrated for actinomycin D. This is in contrast to the poor clinical response rates of approximately 17% rendered by this drug [15, 38]. Especially actinomycin D is in common use as single agent and combination chemotherapy for treatment of rhabdomyosarcomas in childhood and hyperthermia/isolated limb perfusion [15, 39–41].
Ifosfamide serves as a prime drug in first line treatments under clinical conditions and as a high-dose cytotoxic agent in second line applications with response rates of more than 25% [7, 42–45]. Yet, the ATP-TCA chemosensitivity testing found it to be significantly inferior to actinomycin D and doxorubicin.
The analysis of respective histological entities showed, that specific types of tumors respond in different ways. Rhabdomyosarcomas were significantly more resistant against actinomycin D than any of the other tumors tested (Fig. 4). Another example of sub-entity-dependant resistance was found in the chemosensitivity of extraskeletal chondrosarcomas on doxorubicin. The ATP-TCA testing showed a considerable chemoresistance of these tumors against doxorubicin, when compared to other types of soft tissue sarcomas (Fig. 5).
Different test results were also found depending on grading and whether the sarcoma presented as a primary or a recurrent tumor.
The results outlined in Fig. 7 show that the chemoresistance of primary tumors was considerably higher than the resistance of recurrent tumors. These results correspond to the regularly higher differentiation and the lower turn over time of primary tumors compared to recurrent tumors. The superior chemosensitivity of recurrent tumors is in sharp contrast to the worse prognosis of recurrencies [47–51].
GII tumors (n = 17) exhibited a significantly higher chemoresistance when compared to GIII tumors (n = 33) (Fig. 6). This could be due to the higher mitotic activity of tumor cells in the GIII group. The test results stress the importance of the state of cellular differentiation as a crucial parameter for the responsiveness of soft tissue sarcomas to cytotoxic therapies [32, 36].
The results indicate that protocols for chemotherapy should be designed based on tumor specificity, sub entity specificity and according to the tumors grading to improve the response rates of soft tissue sarcomas.
The pre-therapeutic chemosensitivity testing of cytotoxics with ATP-TCA offers the opportunity of improving the hitherto moderate success rates of conventional chemotherapy in soft tissue sarcomas. Sarcomas usually are of sufficient size to gain enough tissue for the testing procedure, a problem often encountered with small carcinomas of the breast. The test poses no risk or disadvantage for the patient and should be performed in cooperation with the oncologist.
To create an individualized chemotherapy protocol, evaluation of ATP-TCA chemosensitivity testing correlated with clinical data and in-vitro results are required. Due to the limited course of time of this study, the results were not yet associated with data of clinical responses in long-term follow-up observations. Future trials on any positive correlations of this kind should prove the validity of the testing method.
This work was supported by FoRUM-grant, Ruhr-University-Bochum, Germany
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