This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van Glabbeke, M. Articles by Tursz, T. Search for Related Content PubMed PubMed Citation Articles by Van Glabbeke, M. Articles by Tursz, T. Social Bookmarking                            What's this?

Prognostic Factors for the Outcome of Chemotherapy in Advanced Soft Tissue Sarcoma: An Analysis of 2,185 Patients Treated With Anthracycline-Containing First-Line Regimens—A European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study

From the European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium; Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium; Rotterdam Cancer Institute, Rotterdam, the Netherlands; Righospitalet, Copenhagen, Denmark; Christie Hospital, Manchester, United Kingdom; Antoni van Leeuwenhoekhuis, Amsterdam, the Netherlands; Istituto Tumori, Milan, Italy; Hospital General de Asturias, Oviedo, Spain; and Institut Gustave Roussy, Villejuif, France.

Address reprint requests to Martine Van Glabbeke, EORTC Data Center, avenue Mounier 83, bte 11, 1200 Bruxelles, Belgium; Email mvg{at}eortc.be

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: A total of 2,185 patients with advanced soft tissue sarcomas who had been treated in seven clinical trials investigating the use of doxorubicin- or epirubicin-containing regimens as first-line chemotherapy were studied in this prognostic-factor analysis.

PATIENTS AND METHODS: Overall survival time (median, 51 weeks) and response to chemotherapy (26% complete response or partial response) were the two end points. The cofactors were sex; age; performance status; prior therapies; the presence of locoregional or recurrent disease; lung, liver, and bone metastases at the time of entry onto the trial; long time period between the initial diagnosis of sarcoma and entry onto the study; and histologic type and grade.

RESULTS: Univariate analyses showed (a) a significant, favorable influence of good performance status, young age, and absence of liver metastases on both survival time and response rate, (b) a significant, favorable influence of low histopathologic disease grade on survival time, despite a significantly lower response rate, (c) increased survival time for patients with a long time period between the initial diagnosis of sarcoma and entry onto the study, despite equivalent response rates, and (d) increased survival time with liposarcoma or synovial sarcoma, a decreased survival time with malignant fibrous histiocytoma, a lower response rate with leiomyosarcoma, and a higher response rate with liposarcoma (P < .05 for all log-rank and ² tests). The Cox model selected good performance status (P < .0001), absence of liver metastases (P = .0001), low histopathologic grade (P = .0002), long time lapse since initial diagnosis (P = .0004), and young age (P = .0045) as favorable prognostic factors of survival time. The logistic model selected absence of liver metastases (P < .0001), young age (P = .0024), high histopathologic grade (P = .0051), and liposarcoma (P = .0065) as favorable prognostic factors of response rate.

CONCLUSION: This analysis demonstrates that for advanced soft tissue sarcoma, response to chemotherapy is not predicted by the same factors as is overall survival time. This needs to be taken into account in the interpretation of trials assessing the value of new agents for this disease on the basis of response to treatment.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
FOR MORE THAN 20 YEARS, the Soft Tissue and Bone Sarcoma Group (STBSG) of the European Organization for Research and Treatment of Cancer (EORTC) has been investigating different chemotherapy regimens for advanced and metastatic soft tissue sarcomas. In chemotherapy-naive patients with advanced disease (who had either relapsed after primary tumor surgery and/or radiotherapy or presented with inoperable or metastatic disease), successive clinical trials were performed that investigated a series of doxorubicin- or epirubicin-containing regimens (Table 1). None of the randomized trials has demonstrated the superiority of any of the investigated regimens, either in terms of response to chemotherapy or in terms of survival.^1-7 The data from all trials have been managed at the EORTC Data Center, resulting in the accumulation of an homogeneous database for more than 2,000 prospectively recruited patients. This accumulation presented a unique opportunity to conduct a retrospective analysis of prognostic factors influencing response to chemotherapy and overall survival time. Although the prognosis of patients with primary disease, as well as that of patients amenable to metastasectomy, had previously been studied, no data are currently available from large series to predict the duration of survival and probability of response to chemotherapy of patients with advanced disease.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Patients who had been treated in seven studies investigating doxorubicin- or epirubicin-containing regimens as a mode of first-line chemotherapy were included in this prognostic-factor analysis. The therapeutic regimens are described in Table 1.

End Points of the Analysis
The two end points of our study were response to chemotherapy and overall survival time. The aim of the study was to determine whether the factors that influenced response to chemotherapy were the same as the factors that influenced survival time and to build a set of independent prognostic factors for each end point.

Survival time was computed from the date of randomization (in the randomized trials) or from the date of prospective registration (in the nonrandomized trials) to the date of death. Patients who were alive at the last follow-up date were censored.

Response to chemotherapy was evaluated according to World Health Organization (WHO) criteria⁸ in all trials. Complete responses and partial responses were externally reviewed and validated on the basis of source documents. Response to therapy was analyzed as a binary variable: patients who achieved a complete or partial response were considered "responders," and patients with stable disease or progression were considered "failures."

Sample Size
A total of 2,233 patients were registered in the seven trials. Patients were included in the analysis presented here regardless of their eligibility status for each particular trial. For 48 patients, no follow-up data were available. Consequently, a total of 2,185 patients was included in the survival time analysis, and 446 patients were still alive at the time of their last follow-up. The analysis of response to chemotherapy included 1,922 cases. The 263 remaining patients were not assessable for this end point.

Investigated Cofactors
The factors routinely recorded as baseline data in the different trials were investigated as potential prognostic factors (demographic data, history of sarcoma, extent of disease at the time of trial inclusion, and histology). The demographic variables included age, sex, and performance status before the start of chemotherapy. Age was recoded into four categories (< 40, 40 to 50, 50 to 60, and > 60 years). Performance status was measured on the WHO scale except for two trials in which it was retrospectively converted from the Karnofsky scale to the WHO scale. Variables related to the history of sarcoma included prior surgery and prior radiotherapy, as well as the time since the first diagnosis of sarcoma. This last variable was recoded into six categories (< 3, 3 to 6, 6 to 12, 12 to 24, 24 to 60, and > 60 months). Prior chemotherapy was an exclusion criterion in all trials.

Data on the extent and localization of the disease included the presence of locoregional disease or local recurrence, as well as lung, liver, and bone metastases. Chest radiography, bone scans, and liver scans were mandatory at the time of entry onto all trials. Histologic subtype and histopathologic grade, as assessed by a panel of reference pathologists, were preferred over the use of local diagnosis, to ensure the consistency and homogeneity of the data. For practical reasons, only 70% of the cases could be reviewed. Analyses including these factors are therefore based on the subset of reviewed cases. Histologic subtypes were recoded as multiple binary variables.

Statistical Methods
All cofactors were first investigated as potential prognostic factors of survival and of response by univariate techniques. For survival time, the proportion of survivors was estimated by the Kaplan-Meier method,⁹ and the log-rank test was used for th e comparisons.¹⁰ For ordered categorical variables (age group, performance status, histopathologic grade, time since initial diagnosis), the log-rank test for trend was used. The proportion of responders was estimated in contingency tables, and the categories were compared using the ² test. For ordered categorical variables, the ² test for trend was used.¹¹ Two multivariate models were built: a Cox model¹² for overall survival time, and a logistic model¹³ for response to chemotherapy. All factors that presented with a significant or borderline prognostic value in the univariate analyses were initially included in the models. Nonsignificant factors were subsequently removed according to a backward selection procedure.

The results presented in this article are based on unadjusted analyses of categorical variables. The final multivariate models were later adjusted by therapeutic regimen and by study, which did not change any conclusion. Replacement of categorized variables by original continuous variables (age, time lapse since diagnosis) also did not change any conclusion.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In the series of 2,185 patients with follow-up data, the median survival time was 51 weeks. The overall survival time for all patients is shown in Fig 1. Survival curves for the therapeutic arms of the different studies were all superimposable. Comparison of the therapeutic arms in all randomized trials showed no significant differences (Table 2).

View larger version (9K): [in this window] [in a new window]   Fig 1. Overall survival. O, observed failures; N, total number of cases.

In the series of 1,922 patients who were assessable for response, an overall response rate of 26% was observed. This response rate varied largely from one study to the other, but, with the exception of one study, no statistically significant difference was observed between the randomized therapeutic arms in any of the studies (Table 2). These findings are in agreement with the individual study results from the original publications, which were based on eligible patients.^1-7

Univariate Analysis of Survival Time
The univariate analysis of survival time (Table 3) demonstrated a highly significant favorable prognostic value of young age, good performance status, absence of liver and bone metastases, low histopathologic grade, and long time lapse since the initial diagnosis of sarcoma. Patients with liposarcoma and those with synovial sarcoma had a significantly better survival time, whereas patients with malignant fibrous histiocytoma had a significantly worse survival time. The other investigated cofactors did not affect survival time.

Multivariate Analysis of Survival Time
The final Cox model for overall survival time is described in Table 4. According to this model, good performance status (P < .0001), absence of liver metastases (P < .0001), low histopathologic grade (P = .0002), long time lapse since the first diagnosis of sarcoma (long disease-free interval) (P = .0004), and young age (P = .0045) were the only independent favorable prognostic factors of survival time.

The impact of each factor may be quantified by the increase in the "hazard ratio" (immediate risk of death) of two successive patient categories (ie, in performance status, PS 1 compared with PS 0). According to the final Cox model, this risk increased by 51.5% for performance status categories, 46.1% for liver involvement, 24% for histopathologic grade categories, and 10.7% for age categories and decreased by 7.9% for elapsed time categories.

The liposarcoma and malignant fibrous histiocytoma categories dropped out of the multivariate models when tumor grade was included. Indeed, these factors are correlated. The overall series included 13% of grade 1 tumors, 34% of grade 2 tumors, and 53% of grade 3 tumors. For liposarcoma, these figures were 39%, 34%, and 28%, respectively. For malignant fibrous histiocytoma, these figures were 8%, 24%, and 68%, respectively.

The synovial sarcoma category included only 1% of patients with liver involvement (v 19% in other histologic categories and 14% if the leiomyosarcoma category is excluded), as well as a high proportion (58%) of patients under 40 years of age (v 25% in other histologic categories). This factor dropped out of the final model, which included age and liver involvement. The overall survival for all independent prognostic subgroups is shown in Figs 2 through 7.

View larger version (16K): [in this window] [in a new window]   Fig 2. Overall survival, by age group. O, observed failures; N, total number of cases.

View larger version (17K): [in this window] [in a new window]   Fig 3. Overall survival, by performance status. O, observed failures; N, total number of cases.

View larger version (12K): [in this window] [in a new window]   Fig 4. Overall survival, by liver metastases. O, observed failures; N, total number of cases.

View larger version (16K): [in this window] [in a new window]   Fig 5. Overall survival, by histopathologic grade. O, observed failures; N, total number of cases.

View larger version (19K): [in this window] [in a new window]   Fig 6. Overall survival, by histologic cell type. O, observed failures; N, total number of cases; Leio, leiomyosarcoma; MFH, malignant fibrous histiocytoma; Synov, synovial sarcoma; Lipo, liposarcoma; Fibro, fibrosarcoma; Other, other cell types.

View larger version (20K): [in this window] [in a new window]   Fig 7. Overall survival, by time elapsed since initial diagnosis of sarcoma. O, observed failures; N, total number of cases.

Univariate Analysis of Response Rate
The results of the univariate analysis of response rate (Table 5) demonstrated a highly significant favorable prognostic value for the absence of liver metastases, young age, and good performance status. The response rates were also significantly higher for high-grade tumors and lower for leiomyosarcoma. The higher response rate of patients with lung metastases and those with liposarcoma is of borderline significance.

Multivariate Analysis of Response Rate
The final logistic model for response to chemotherapy is described in Table 6. According to this model, absence of liver lesions (P < .0001), young age (P = .0024), high histopathologic grade (P = .0051), and liposarcoma (P = .065) were the only independent favorable prognostic factors of response. The leiomyosarcoma category dropped out of the logistic model when liver involvement was included. In patients with liver lesions, leiomyosarcoma accounted for 62% of the cases; 11% of responses were observed versus 20% for other histologic categories. In patients without liver lesions, leiomyosarcoma only represented 29% of the cases, with a response rate of 29%, compared with 32% in other histologies. Performance status also dropped out of the final model.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Identification of prognostic factors in soft tissue sarcoma has been a field of extensive research in this rare group of malignant diseases, but it was primarily limited to the definition of staging systems for patients presenting for the first time with this disease.^14-26 The staging systems used in these analyses were usually based on a combination of clinical and histopathologic factors. Universally agreed-upon clinical prognostic factors include tumor size and quality of surgery (which obviously depends on tumor localization), whereas proposed histopathologic grading systems are usually based on mitotic count, tumor necrosis, and degree of differentiation.¹⁴ In most of the studies, histopathologic grade was the most important prognostic factor, but Gaynor et al²⁰ also demonstrated that the prognostic value of this factor disappeared beyond 18 months. On behalf of the EORTC–Soft Tissue and Bone Sarcoma Group, van Unnik et al¹⁴ have proposed a prognostic index, which is based on tumor size, mitotic count, and necrosis.

The prognostic factors for patients presenting with inoperable or metastatic disease and for patients developing metastases after surgery and/or radiotherapy may be different. So far, the prognostic factors for advanced and recurring cases have only been studied in the highly select population of patients amenable to metastasectomy.^27-30 In patients with advanced sarcomas who were not candidates for surgery, some data are available from studies that investigated specific chemotherapy regimens,^1,31-33 but no large-scale analysis has been conducted so far. Our unique series of over 2,000 patients has been used to provide a model that predicts the probability of response to chemotherapy and the overall survival time in this population.

Despite the fact that age and performance status are generally not reported as prognostic factors for patients with primary disease, it is not surprising that these factors correlate with survival time in patients with advanced disease. This was also reported by Borden et al.³¹ In our study, we have also demonstrated that age is highly predictive for response to first-line chemotherapy, but performance status does not add predictive information to the model. The absence of significant prognostic value for factors related to the nature and extent of previous therapy suggests that once a patient presents with inoperable advanced soft tissue sarcoma, prior modes of therapy do not have any further impact on the outcome.

Liver metastases had a very significant adverse predictive value for both response and survival. This might be explained by two hypotheses: (1) liver metastases are a sign of advanced disease, which explains the poor prognosis of those patients, or (2) the presence of liver metastases in itself is a poor prognostic factor, regardless of the degree of advancement of the disease, because liver metastases are apparently less chemosensitive than other lesions.³³ Both hypotheses need to be explored further.

Patients with a long time lapse since the first diagnosis of sarcoma had a better survival time than did patients recently diagnosed. This has also been reported with regard to other types of tumors, for which a long previous "disease-free survival" predicts a long survival time when patients relapse. Patients with a high histopathologic grade of disease had a significantly worse survival time than did the others, despite a significantly higher response rate. This is compatible with the recognition that high-grade tumors are more chemosensitive, but responses tend to be of short duration in these patients and are often followed by rapid progression.

The univariate analysis demonstrated the prognostic importance of histologic subtype. Patients with liposarcoma and synovial sarcoma had a significantly better survival time than did patients with other cell types, whereas patients with malignant fibrous histiocytoma had a worse survival time. Liposarcoma patients had a higher response rate, and leiomyosarcoma patients had a lower response rate. According to our analysis, liposarcoma appears in the form of chemosensitive tumors with a good prognosis of survival. The distribution of tumor grades in this histologic subtype explains the favorable survival time but is in contrast with the high response rate. Other histopathologic variables dropped out of the multivariate models, but the analysis presented here clarifies these findings on the basis of their correlation with other prognostic factors.

The lower probability of response to chemotherapy in leiomyosarcoma patients, which is in contrast with previously reported data,^31,33 is linked to the increased frequency of liver metastases in these patients. Correlation of these two factors could be a result of the high proportion of abdominal leiomyosarcoma cases in our series, which have a greater propensity for liver metastases. Because our data are up to 20 years old, the histologic entity of "gastrointestinal stromal sarcoma" had not been identified at the time of diagnosis of most of these patients, and these cases are probably included as leiomyosarcomas in our series. Unfortunately, we have not systematically recorded the site of origin of sarcoma in all trials and therefore cannot confirm this hypothesis. More recent data will enable us to study this issue further.

The decreased survival time in cases of malignant fibrous histiocytoma is obviously linked to the distribution of the histopathologic grades of these tumors. Synovial sarcoma usually involves young patients without liver metastases, which explains their good survival time. Finally, the overall survival time curve shows that a small proportion of patients is still surviving after 5 years and suggests that some of these patients may have been cured by chemotherapy.

In conclusion, this analysis demonstrates that for advanced soft tissue sarcomas, the probability of achieving response to chemotherapy is not predicted by the same factors as in overall survival time. While young age and the absence of liver metastases significantly affect both end points in a favorable way, low histopathologic grade has a favorable impact on survival time and an adverse impact on response rate. This should be taken into account in the interpretation of trials of new therapeutic agents in which the activity results are based on response.

The study also demonstrates the prognostic value of histologic subtypes of sarcoma. So far, we have been unable to confirm whether these factors add independent prognostic information to the described models, except for cases of liposarcoma, but we could demonstrate why they affected overall survival time and response to chemotherapy. Further investigations of the correlation between the histologic subtype, the site of origin of the disease, and the sites of the metastases should provide a better understanding of the behavior of the different histologic subtypes.

	NOTES

 
The studies that form the basis of this work were supported by the Prix Pierre Bardoux.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Pinedo H, Bramwell VHC, Mouridsen HT, et al: CYVADIC in advanced soft tissue sarcoma: A randomized study comparing two schedules. Cancer 53:1825-1832, 1984[Medline]

2. Mouridsen HT, Batshold L, Somers R, et al: Adriamycin versus epirubicin in advanced soft tissue sarcoma: A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol 23:1477-1483, 1987[Medline]

3. Schütte J, Mouridsen HT, Stewart W, et al: For the EORTC Soft Tissue and Bone Sarcoma Group: Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma. Eur J Cancer 26:558-561, 1990

4. Santoro A, Tursz T, Mouridsen H, et al: Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: A randomized study of the EORTC Soft Tissue and Bone Sarcoma Group. J Clin Oncol 13:1537-1545, 1995[Abstract/Free Full Text]

5. Dombernowsky P, Mouridsen H, Nielsen OS, et al: A phase III study comparing adriamycin vs. two schedules of high dose epirubicin in advanced soft tissue sarcoma. Proc Am Soc Clin Oncol 14:237, 1995 (abstr 1688)

6. Steward WP, Verweij J, Somers R, et al: Granulocyte-macrophage colony-stimulating factor (GM-CSF) allows safe escalation of dose intensity of chemotherapy in metastatic adult soft tissue sarcoma: A study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 11:15-21, 1993[Abstract]

7. Tursz T, Verweij J, Judson I, et al: Is high-dose chemotherapy of interest in advanced soft tissue sarcomas (ASTS)? An EORTC randomized phase III trial. Proc Am Soc Clin Oncol 15:337, 1996 (abstr 973)

8. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, WHO, WHO Offset Publication 48, 1979

9. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

10. Mantel L: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline]

11. Sylvester R: On the analysis of response rates in studies of advanced disease. Eur J Cancer Suppl 1:5-7, 1980

12. Cox DR: Regression models and life tables. [with discussion]. J R Stat Soc B 34:187-220, 1972

13. Cox DR: The Analysis of Binary Data. London, United Kingdom, Methuen, 1970

14. van Unnik JAM, Coindre JM, Contesso C, et al: Grading of soft tissue sarcomas: Experience of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 29A:2089-2093, 1993

15. Peabody TD, Monson D, Montag A, et al: A comparison of the prognoses for deep and subcutaneous sarcomas of the extremities. J Bone Joint Surg Am 76:1167-1173, 1994[Abstract/Free Full Text]

16. Gustafson P: Soft tissue sarcoma: Epidemiology and prognosis in 508 patients. Acta Orthop Scand Suppl 259:1-31, 1994[Medline]

17. Tomita Y, Kuratsu S, Naka N, et al: A staging system for soft-tissue sarcoma and its evaluation in relation to treatment. Int J Cancer 58:168-173, 1994[Medline]

18. Singer S, Corson JM, Gonin R, et al: Prognostic factors predictive of survival and local recurrence for extremity soft tissue sarcoma. Ann Surg 219:165-173, 1994[Medline]

19. LeVay J, O'Sullivan B Catton C, et al: Outcome and prognostic factors in soft tissue sarcoma in the adult. Int J Radiat Oncol Biol Phys 27:1091-1099, 1993[Medline]

20. Gaynor JJ, Tan CC, Casper ES, et al: Refinement of clinicopathologic staging for localized soft tissue sarcoma of the extremity: A study of 423 adults. J Clin Oncol 10:1317-1329, 1992[Abstract/Free Full Text]

21. Saddegh MK, Lindholm J, Lundberg A, et al: Staging of soft-tissue sarcomas: Prognostic analysis of clinical and pathological features. J Bone Joint Surg Br 74:495-500, 1992

22. Baldursson G, Agnarsson BA, Benediktsdottir KR, et al: Soft tissue sarcomas in Iceland 1955-1988: Analysis of survival and prognostic factors. Acta Oncol 30:563-568, 1991[Medline]

23. Choong PF, Gustafson P, Willen H, et al: Prognosis following locally recurrent soft-tissue sarcoma: A staging system based on primary and recurrent tumour characteristics. Int J Cancer 60:33-37, 1995[Medline]

24. Bauer HC, Kreicbergs A, Tribukait B: DNA content prognostic in soft tissue sarcoma: 102 patients followed for 1-10 years. Acta Orthop Scand 62:187-194, 1991[Medline]

25. Jensen OM, Hogh J, Ostgaard SE, et al: Histopathological grading of soft tissue tumours: Prognostic significance in a prospective study of 278 consecutive cases. J Pathol 163:19-24, 1991[Medline]

26. Coindre Jean-Michel Terrier Philippe Binh Bui Nguyenet al: Prognostic factors in adult patients with locally controlled soft tissue sarcoma: A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 14:869-877, 1996[Abstract/Free Full Text]

27. van Geel AN, van Coevorden F, Blankensteijn JD, et al: Surgical treatment of pulmonary metastases from soft tissue sarcomas: A retrospective study in the Netherlands. J Surg Oncol 56:172-177, 1994[Medline]

28. Girard P, Baldeyrou P, Le Chevalier T, et al: Surgical resection of pulmonary metastases: Up to what number? Am J Respir Crit Care Med 149:469-476, 1994[Abstract]

29. Ueda T, Uchida A, Kodama K, et al: Aggressive pulmonary metastasectomy for soft tissue sarcomas. Cancer 72:1919-1925, 1993 (see comments)[Medline]

30. Verazin GT, Warneke JA, Driscoll DL, et al: Resection of lung metastases from soft-tissue sarcomas: A multivariate analysis. Arch Surg 127:1407-1411, 1992[Abstract/Free Full Text]

31. Borden EC, Amato DA, Rosenbaum CH, et al: Randomized comparison of three adriamycin regiments for metastastic soft tissue sarcomas. J Clin Oncol 5:840-850, 1987[Abstract/Free Full Text]

32. Omura GA, Major FJ, Blessing JA, et al: A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer 52:626-632, 1983[Medline]

33. Yap BS, Baker LH, Sinkovics JG, et al: Cyclophosphamide, vincristine, adriamycin and DTIC (CYVADIC) combination chemotherapy for the treatment of advanced sarcomas. Cancer Treat Rep 64:93-98, 1980[Medline]

Submitted October 22, 1996; accepted September 14, 1998.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				N. Penel, A. Italiano, N. Isambert, E. Bompas, G. Bousquet, F. Duffaud, and on behalf of the French Sarcoma Group (Groupe Sarc Factors affecting the outcome of patients with metastatic leiomyosarcoma treated with doxorubicin-containing chemotherapy Ann. Onc., October 30, 2009; (2009) mdp485v1. [Abstract] [Full Text] [PDF]

				J.-Y. Blay and A. Le Cesne Adjuvant Chemotherapy in Localized Soft Tissue Sarcomas: Still Not Proven Oncologist, October 1, 2009; 14(10): 1013 - 1020. [Abstract] [Full Text] [PDF]

				A. Le Cesne, M. Van Glabbeke, J. Verweij, P. G. Casali, M. Findlay, P. Reichardt, R. Issels, I. Judson, P. Schoffski, S. Leyvraz, et al. Absence of Progression As Assessed by Response Evaluation Criteria in Solid Tumors Predicts Survival in Advanced GI Stromal Tumors Treated With Imatinib Mesylate: The Intergroup EORTC-ISG-AGITG Phase III Trial J. Clin. Oncol., August 20, 2009; 27(24): 3969 - 3974. [Abstract] [Full Text] [PDF]

				A. LASHKARI, W. A. CHOW, F. VALDES, L. LEONG, V. PHAN, P. TWARDOWSKI, N. KAPOOR, A. MOLINA, Z. AL-KADHIMI, P. FRANKEL, et al. Tandem High-dose Chemotherapy Followed by Autologous Transplantation in Patients with Locally Advanced or Metastatic Sarcoma Anticancer Res, August 1, 2009; 29(8): 3281 - 3288. [Abstract] [Full Text] [PDF]

				J. Verweij Soft Tissue Sarcoma Trials: One Size No Longer Fits All J. Clin. Oncol., July 1, 2009; 27(19): 3085 - 3087. [Full Text] [PDF]

				I. Ray-Coquard, C. Cropet, M. Van Glabbeke, C. Sebban, A. Le Cesne, I. Judson, O. Tredan, J. Verweij, P. Biron, I. Labidi, et al. Lymphopenia as a Prognostic Factor for Overall Survival in Advanced Carcinomas, Sarcomas, and Lymphomas Cancer Res., July 1, 2009; 69(13): 5383 - 5391. [Abstract] [Full Text] [PDF]

				J. Maurel, A. Lopez-Pousa, R. de las Penas, J. Fra, J. Martin, J. Cruz, A. Casado, A. Poveda, J. Martinez-Trufero, C. Balana, et al. Efficacy of Sequential High-Dose Doxorubicin and Ifosfamide Compared With Standard-Dose Doxorubicin in Patients With Advanced Soft Tissue Sarcoma: An Open-Label Randomized Phase II Study of the Spanish Group for Research on Sarcomas J. Clin. Oncol., April 10, 2009; 27(11): 1893 - 1898. [Abstract] [Full Text] [PDF]

				N. Penel, B. N. Bui, J.-O. Bay, D. Cupissol, I. Ray-Coquard, S. Piperno-Neumann, P. Kerbrat, C. Fournier, S. Taieb, M. Jimenez, et al. Phase II Trial of Weekly Paclitaxel for Unresectable Angiosarcoma: The ANGIOTAX Study J. Clin. Oncol., November 10, 2008; 26(32): 5269 - 5274. [Abstract] [Full Text] [PDF]

				I. Ray-Coquard, A. Le Cesne, J. S. Whelan, P. Schoffski, B. N. Bui, J. Verweij, S. Marreaud, M. van Glabbeke, P. Hogendoorn, and J.-Y. Blay A Phase II Study of Gefitinib for Patients with Advanced HER-1 Expressing Synovial Sarcoma Refractory to Doxorubicin-Containing Regimens Oncologist, April 1, 2008; 13(4): 467 - 473. [Abstract] [Full Text] [PDF]

				A. Hajitou, D. C. Lev, J. A. F. Hannay, B. Korchin, F. I. Staquicini, S. Soghomonyan, M. M. Alauddin, R. S. Benjamin, R. E. Pollock, J. G. Gelovani, et al. A preclinical model for predicting drug response in soft-tissue sarcoma with targeted AAVP molecular imaging PNAS, March 18, 2008; 105(11): 4471 - 4476. [Abstract] [Full Text] [PDF]

				J. Fayette, E. Martin, S. Piperno-Neumann, A. Le Cesne, C. Robert, S. Bonvalot, D. Ranchere, P. Pouillart, J. M. Coindre, and J. Y. Blay Angiosarcomas, a heterogeneous group of sarcomas with specific behavior depending on primary site: a retrospective study of 161 cases Ann. Onc., December 1, 2007; 18(12): 2030 - 2036. [Abstract] [Full Text] [PDF]

				M. Tascilar, W. J. Loos, C. Seynaeve, J. Verweij, and S. Sleijfer The Pharmacologic Basis of Ifosfamide Use in Adult Patients with Advanced Soft Tissue Sarcomas Oncologist, November 1, 2007; 12(11): 1351 - 1360. [Abstract] [Full Text] [PDF]

				R. G. Maki, J. K. Wathen, S. R. Patel, D. A. Priebat, S. H. Okuno, B. Samuels, M. Fanucchi, D. C. Harmon, S. M. Schuetze, D. Reinke, et al. Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Alliance for Research Through Collaboration Study 002 J. Clin. Oncol., July 1, 2007; 25(19): 2755 - 2763. [Abstract] [Full Text] [PDF]

				T. M. Pawlik, J.-N. Vauthey, E. K. Abdalla, R. E. Pollock, L. M. Ellis, and S. A. Curley Results of a Single-Center Experience With Resection and Ablation for Sarcoma Metastatic to the Liver Arch Surg, June 1, 2006; 141(6): 537 - 544. [Abstract] [Full Text] [PDF]

				N. Theou, S. Gil, A. Devocelle, C. Julie, A. Lavergne-Slove, A. Beauchet, P. Callard, R. Farinotti, A. Le Cesne, A. Lemoine, et al. Multidrug Resistance Proteins in Gastrointestinal Stromal Tumors: Site-Dependent Expression and Initial Response to Imatinib Clin. Cancer Res., November 1, 2005; 11(21): 7593 - 7598. [Abstract] [Full Text] [PDF]

				S. Sleijfer, C. Seynaeve, and J. Verweij Using Single-Agent Therapy in Adult Patients with Advanced Soft Tissue Sarcoma Can Still Be Considered Standard Care Oncologist, November 1, 2005; 10(10): 833 - 841. [Abstract] [Full Text] [PDF]

				R. Garcia-Carbonero, J.G. Supko, R.G. Maki, J. Manola, D.P. Ryan, D. Harmon, T.A. Puchalski, G. Goss, M.V. Seiden, A. Waxman, et al. Ecteinascidin-743 (ET-743) for Chemotherapy-Naive Patients With Advanced Soft Tissue Sarcomas: Multicenter Phase II and Pharmacokinetic Study J. Clin. Oncol., August 20, 2005; 23(24): 5484 - 5492. [Abstract] [Full Text] [PDF]

				M. A. Clark, C. Fisher, I. Judson, and J. M. Thomas Soft-Tissue Sarcomas in Adults N. Engl. J. Med., August 18, 2005; 353(7): 701 - 711. [Full Text] [PDF]

				A. S. Pappo, M. Devidas, J. Jenkins, B. Rao, R. Marcus, P. Thomas, M. Gebhardt, C. Pratt, and H. E. Grier Phase II Trial of Neoadjuvant Vincristine, Ifosfamide, and Doxorubicin With Granulocyte Colony-Stimulating Factor Support in Children and Adolescents With Advanced-Stage Nonrhabdomyosarcomatous Soft Tissue Sarcomas: A Pediatric Oncology Group Study J. Clin. Oncol., June 20, 2005; 23(18): 4031 - 4038. [Abstract] [Full Text] [PDF]

				L. H. Baker Medical and Pediatric Oncology, Not Adult and Pediatric Oncology J. Clin. Oncol., June 20, 2005; 23(18): 4003 - 4005. [Full Text] [PDF]

				E. L. Spurrell, C. Fisher, J. M. Thomas, and I. R. Judson Prognostic factors in advanced synovial sarcoma: an analysis of 104 patients treated at the Royal Marsden Hospital Ann. Onc., March 1, 2005; 16(3): 437 - 444. [Abstract] [Full Text] [PDF]

				A. Le Cesne, J.Y. Blay, I. Judson, A. Van Oosterom, J. Verweij, J. Radford, P. Lorigan, S. Rodenhuis, I. Ray-Coquard, S. Bonvalot, et al. Phase II Study of ET-743 in Advanced Soft Tissue Sarcomas: A European Organisation for the Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group Trial J. Clin. Oncol., January 20, 2005; 23(3): 576 - 584. [Abstract] [Full Text] [PDF]

				C. S. P. van Rijswijk, M. J. A. Geirnaerdt, P. C. W. Hogendoorn, A. H. M. Taminiau, F. van Coevorden, A. H. Zwinderman, T. L. Pope, and J. L. Bloem Soft-Tissue Tumors: Value of Static and Dynamic Gadopentetate Dimeglumine-enhanced MR Imaging in Prediction of Malignancy Radiology, November 1, 2004; 233(2): 493 - 502. [Abstract] [Full Text] [PDF]

				J. V. Heymach, J. Desai, J. Manola, D. W. Davis, D. J. McConkey, D. Harmon, D. P. Ryan, G. Goss, T. Quigley, A. D. Van den Abbeele, et al. Phase II Study of the Antiangiogenic Agent SU5416 in Patients with Advanced Soft Tissue Sarcomas Clin. Cancer Res., September 1, 2004; 10(17): 5732 - 5740. [Abstract] [Full Text] [PDF]

				G. A. Porter, S. B. Cantor, G. L. Walsh, V. W. Rusch, D. H. Leung, A. Y. DeJesus, R. E. Pollock, M. F. Brennan, and P. W. T. Pisters Cost-effectiveness of pulmonary resection and systemic chemotherapy in the management of metastatic soft tissue sarcoma: A combined analysis from the University of Texas M. D. Anderson and Memorial Sloan-Kettering Cancer Centers J. Thorac. Cardiovasc. Surg., May 1, 2004; 127(5): 1366 - 1372. [Abstract] [Full Text] [PDF]

				R. Garcia-Carbonero, J.G. Supko, J. Manola, M.V. Seiden, D. Harmon, D.P. Ryan, M.T. Quigley, P. Merriam, J. Canniff, G. Goss, et al. Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients With Progressive Sarcomas of Soft Tissues Refractory to Chemotherapy J. Clin. Oncol., April 15, 2004; 22(8): 1480 - 1490. [Abstract] [Full Text] [PDF]

				A. Yovine, M. Riofrio, J.Y. Blay, E. Brain, J. Alexandre, C. Kahatt, A. Taamma, J. Jimeno, C. Martin, Y. Salhi, et al. Phase II Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma Patients J. Clin. Oncol., March 1, 2004; 22(5): 890 - 899. [Abstract] [Full Text] [PDF]

				J. N. Cormier and R. E. Pollock Soft Tissue Sarcomas CA Cancer J Clin, March 1, 2004; 54(2): 94 - 109. [Abstract] [Full Text] [PDF]

				A. S. Colwell, J. D'Cunha, S. O. Vargas, B. Parker, P. D. Cin, and M. A. Maddaus Synovial sarcoma of the pleura: A clinical and pathologic study of three cases J. Thorac. Cardiovasc. Surg., October 1, 2002; 124(4): 828 - 832. [Abstract] [Full Text] [PDF]

				S. L. Spunt, D. A. Hill, A. M. Motosue, C. A. Billups, A. M. Cain, B. N. Rao, C. B. Pratt, T. E. Merchant, and A. S. Pappo Clinical Features and Outcome of Initially Unresected Nonmetastatic Pediatric Nonrhabdomyosarcoma Soft Tissue Sarcoma J. Clin. Oncol., August 1, 2002; 20(15): 3225 - 3235. [Abstract] [Full Text] [PDF]

				M. Lopez, P. Vici, L. Di Lauro, and S. Carpano Increasing Single Epirubicin Doses in Advanced Soft Tissue Sarcomas J. Clin. Oncol., March 1, 2002; 20(5): 1329 - 1334. [Abstract] [Full Text] [PDF]

				V. H. C. Bramwell, D. Morris, D. S. Ernst, I. Hings, M. Blackstein, P. M. Venner, E. I. Ette, M. W. Harding, A. Waxman, and G. D. Demetri Safety and Efficacy of the Multidrug-Resistance Inhibitor Biricodar (VX-710) with Concurrent Doxorubicin in Patients with Anthracycline-resistant Advanced Soft Tissue Sarcoma Clin. Cancer Res., February 1, 2002; 8(2): 383 - 393. [Abstract] [Full Text] [PDF]

				S. Delaloge, A. Yovine, A. Taamma, M. Riofrio, E. Brain, E. Raymond, P. Cottu, F. Goldwasser, J. Jimeno, J. L. Misset, et al. Ecteinascidin-743: A Marine-Derived Compound in Advanced, Pretreated Sarcoma Patients--Preliminary Evidence of Activity J. Clin. Oncol., March 1, 2001; 19(5): 1248 - 1255. [Abstract] [Full Text] [PDF]

				A. J. Spillane, R. A'Hern, I. R. Judson, C. Fisher, and J. M. Thomas Synovial Sarcoma: A Clinicopathologic, Staging, and Prognostic Assessment J. Clin. Oncol., November 15, 2000; 18(22): 3794 - 3803. [Abstract] [Full Text] [PDF]

				J-Y. Blay, D. Bouhour, I. Ray-Coquard, C. Dumontet, T. Philip, and P. Biron High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Transplantation for Advanced Soft Tissue Sarcoma in Adults J. Clin. Oncol., November 1, 2000; 18(21): 3643 - 3650. [Abstract] [Full Text] [PDF]

				B. E. C. Plaat, H. Hollema, W. M. Molenaar, G. H. T. Broers, J. Pijpe, M. F. Mastik, H. J. Hoekstra, E. van den Berg, R. J. Scheper, and W. T. A. van der Graaf Soft Tissue Leiomyosarcomas and Malignant Gastrointestinal Stromal Tumors: Differences in Clinical Outcome and Expression of Multidrug Resistance Proteins J. Clin. Oncol., September 18, 2000; 18(18): 3211 - 3220. [Abstract] [Full Text] [PDF]

				A. Le Cesne, I. Judson, D. Crowther, S. Rodenhuis, H. J. Keizer, Q. Van Hoesel, J. Y. Blay, J. Frisch, M. Van Glabbeke, C. Hermans, et al. Randomized Phase III Study Comparing Conventional-Dose Doxorubicin Plus Ifosfamide Versus High-Dose Doxorubicin Plus Ifosfamide Plus Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor in Advanced Soft Tissue Sarcomas: A Trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group J. Clin. Oncol., July 14, 2000; 18(14): 2676 - 2684. [Abstract] [Full Text] [PDF]

				J. Verweij, S. M. Lee, W. Ruka, J. Buesa, R. Coleman, R. van Hoessel, C. Seynaeve, E. D. di Paola, M. van Glabbeke, D. Tonelli, et al. Randomized Phase II Study of Docetaxel Versus Doxorubicin in First- and Second-Line Chemotherapy for Locally Advanced or Metastatic Soft Tissue Sarcomas in Adults: A Study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group J. Clin. Oncol., May 10, 2000; 18(10): 2081 - 2086. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van Glabbeke, M. Articles by Tursz, T. Search for Related Content PubMed PubMed Citation Articles by Van Glabbeke, M. Articles by Tursz, T. Social Bookmarking                            What's this?