Refining the optimal chemotherapy regimen for good-risk metastatic nonseminomatous germ-cell tumors: a randomized trial of the Genito-Urinary Group of the French Federation of Cancer Centers (GETUG T93BP).

BACKGROUND: High cure rates are expected in good-risk metastatic nonseminomatous germ-cell tumor (NSGCT) patients with bleomycin, etoposide and cisplatin. PATIENTS AND METHODS: Patients received either three cycles of BE500P or four cycles of E500P every 3 weeks. Disease was defined according to the Institut Gustave Roussy prognostic model. Patients were retrospectively assigned into the International Germ Cell Cancer Collaborative Group (IGCCCG) classification. A sample size of 250 patients was necessary for an expected favorable response rate (primary end point) of 90% and not more than a 10% difference between the two arms. RESULTS: Among 257 assessable patients, 124 and 122 patients achieved a favorable response in the 3BE500P and 4E500P arms, respectively (P = 0.34). Median follow-up was 53 months. The 4-year event-free survival rates were 91% and 86%, respectively (P = 0.135). The 4-year overall survival rates were not significantly different [five deaths versus 12 deaths, respectively (P = 0.096)]. Similar nonsignificant trends were observed in good IGCCCG prognosis patients. CONCLUSIONS: Both regimens produced similar results in terms of favorable response rates. As the trial was underpowered for survival analyses, conclusive data would require a larger randomized trial. Unless such a study is done, 3BE500P is the treatment of choice for metastatic NSGCT patients.

Prognostic factors in localized primary synovial sarcoma: a multicenter study of 128 adult patients.

PURPOSE: To identify most significant and therapeutically relevant prognostic factors in adults with localized primary synovial sarcomas (SS) and to confirm the usefulness of the French Federation of Cancer Centers (FNCLCC) grading system, the prognostic impact of which has been already proven in soft tissue sarcomas. PATIENTS AND METHODS: Data on 128 patients with nonmetastatic SS collected from a cooperative database by the FNCLCC Sarcoma Group between 1980 and 1994 were studied retrospectively. Immunohistochemistry was performed at diagnosis in 77 cases (61%). The tumors were classified as biphasic (n = 45), monophasic fibrous (n = 72), and poorly differentiated (n = 10) subtypes. Histologic grade was determined according to the FNCLCC method, and vascular invasion was assessed in every case. RESULTS: The 5-year disease-specific survival (DSS) rate for this series of patients with localized SS was 62.9% (+/- 9.6% [SD]) with a median follow-up time of 37 months (range, 8 to 141 months). In multivariate analysis, the adverse risk factors associated with decreased DSS were International Union Against Cancer/American Joint Committee on Cancer stage III/IVA disease, male sex, and truncal tumor locations. For metastasis-free survival (MFS), disease stage III/IVA, tumor necrosis, and monophasic subtypes were the major factors associated with a less favorable prognosis. Separately, when not using disease stage, tumor necrosis, and mitotic activity, histologic grade became the most significant prognostic factor for both DSS and MFS. In addition, larger tumors and older patients become associated with a significantly worse prognosis. Independent adverse risk factors for local recurrence-free survival included histologic grade 3 and truncal tumor location. CONCLUSION: These data confirm that not all SS present the same severe outcome. High-risk patients identified on the basis of these parameters may qualify for an aggressive treatment approach.

[Chemotherapy of soft tissue sarcoma in the adult]. / Chimioradiothérapie [correction of Chimiothérapie] des sarcomes des tissus mous de l'adulte.

The goal of postoperative treatment in adult soft tissue sarcoma is local control, and in high-risk patients prevention of distant failures. Radiation therapy is essential after non-radical surgery. The role of adjuvant chemotherapy on improvement of overall survival remains to be evidenced; however, recent meta-analysis data have confirmed its impact on both local and metastatic evolution of the disease. Because for both radiotherapy and chemotherapy, delay of treatment may be crucial for efficacy following tumor excision, concomitant radiochemotherapy should be considered. Review of the literature as well as personal results showed the feasibility of postoperative radiochemotherapy in adult soft tissue sarcoma, even when the chemotherapeutic associations used included an anthracycline. Prospective study of radiochemotherapy should be performed in order to assess its real impact in terms of efficacy and toxicity.

Prognostic factors for patients with localized primary malignant fibrous histiocytoma: a multicenter study of 216 patients with multivariate analysis.

BACKGROUND: The purpose of this study was to determine the independent prognostic variables in a well documented subset of 216 patients with localized primary malignant fibrous histiocytomas (MFH). METHODS: Between the years 1980 and 1989, 216 patients with localized, primary (International Union Against Cancer [UICC]/American Joint Committee on Cancer [AJCC] Stage I-IVA) MFH were evaluated and treated in 10 participating centers of the sarcoma group of the French Federation of Cancer Centers (FNCLCC). Clinicopathologic factors were collected retrospectively and entered into a cooperative database. Tissue slides of all cases were jointly reviewed microscopically by the pathology subcommittee. Surgical treatment was performed on all but 6 (3%) patients. One hundred ninety-five patients (90%) were free of gross disease, with complete local control at the end of the initial treatment. The adjuvant treatment was radiotherapy in 78 patients (36%), chemotherapy in 19 patients (9%), and both in 61 patients (28%). RESULTS: The median follow-up was 3.5 years (range, 45 days to 12 years). Five-year actuarial rates of disease specific (DSS), metastasis free (MFS), and local recurrence free (LRFS) survival were 70%, 63.3%, and 62.7%, respectively. Multivariate analyses showed that the adverse prognostic factors independently associated with decreased disease specific survival were UICC/AJC Stage III + IVA (P < 0.00001; relative risk [RR], 3.27; 95% confidence interval [CI], 1.6-6.58), residual macroscopic disease following primary local therapy (P = 0.00024; RR, 3.99, CI, 2.04-7.82), deep tumor location (P = 0.0045; RR, 3.37; CI, 1.21-9.38), non-myxoid histology (P = 0.0056; RR, 9.28; CI, 1.03-83.41), and age older than 50 years (P = 0.037; RR, 2.19; CI, 1.04-4.61). Two factors were significantly related to MFS in the patients with the poorest prognosis: histopathologic Grade 3 (P < 0.0001, RR, 3.46; CI, 2.02-5.91) and tumor size greater than 8 cm in largest dimension (P = 0.0012; RR, 2.78; CI, 1.36-3.66). With regard to LRFS, patients who did not undergo radiotherapy had reduced local control (P = 0.0043; RR, 2.36; CI, 1.46-3.83). CONCLUSIONS: Resection of all macroscopic disease was independently associated with improved disease specific survival and adjuvant radiotherapy significantly decreased the local relapse risk. Histopathologic grade was the most important prognostic factor for DSS and MFS.

[Locally developed sarcoma of the thoracic wall]. / Sarcome localement évolué de la paroi thoracique.

Important advances have been obtained in the care of soft tissue sarcoma in adults, mainly in the field of locoregional treatment. Surgery or combination of surgery and radiotherapy allow adequate tumor control with preservation of function for the majority of patients. However, the management of locally advanced primaries remains problematic. Moreover, although patients survival mainly depends on the metastatic risk of the disease, controversies remain in definition of pronostic factors as well as in the evaluation of the role of chemotherapy in curative therapeutical strategies. The case reported here allows a discussion of the different modalities of treatment for adults with soft tissue sarcomas and stresses the necessity of a multimodal approach in these patients.

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.

PURPOSE: To define the prognostic factors in adult patients with locally controlled soft tissue sarcoma (STS) and to determine which patients should be considered for adjuvant treatment. PATIENTS AND METHODS: Five hundred forty-six patients with a nonmetastatic and locally controlled STS, collected in a cooperative data base by the French Federation of Cancer Centers (FNCLCC) Sarcoma Group from 1980 and 1989, were studied. Histologic slides of all patients were collegially reviewed. Initial treatment consisted of complete tumor resection with amputation in only 4% of the patients. Adjuvant radiotherapy was administered to 57.9% and adjuvant chemotherapy to 31%. Relationships between tumor characteristics were analyzed, and univariate and multivariate analyses were performed using Cox models for the hazards rate of tumor mortality, development of distant metastasis, and strictly local recurrence. RESULTS: Unfavorable characteristics with an independent prognostic value for tumor mortality were: grade 3 (P = 3 x 10(-10)), male sex (P = 1.5 x 10(-5)), no adjuvant chemotherapy (P = 5.4 x 10(-5)), tumor size > or = 5 cm (P = 3.8 x 10(-3)), and deep location (P = 4.6 x 10(-3)). Unfavorable characteristics for the development of distant metastasis were: grade 3 (P = 4 x 10(-12)), no adjuvant chemotherapy (P = 6.4 x 10(-4)), tumor size > or = 10 cm (P = 9.8 x 10(-4)), and deep location (P = 1.3 x 10(-3)). For the development of local recurrence, the unfavorable characteristics were: no adjuvant radiotherapy (P = 3.6 x 10(-6)), poor surgery (local excision) (P = 2 x 10(-4)), grade 3 (P = 7.6 x 10(-4)), and deep location (P = 10(-2)). Grade, depth, and tumor size were used to define groups of patients according to the metastatic risk. Adjuvant chemotherapy was beneficial in terms of overall survival and metastasis-free survival in grade 3 tumor patients only. Despite worse characteristics concerning tumor depth, tumor-node-metastasis (TNM) and American Joint Committee (AJC)/International Union Against Cancer (UICC) classifications and grade in patients with adjuvant radiotherapy, the latter experienced significantly fewer local recurrences than patients with no radiotherapy. CONCLUSION: Grade, tumor depth, and tumor size could be used to select patients with a high metastatic risk, for which adjuvant chemotherapy could be beneficial.

Prognostic variables for the selection of patients with operable soft tissue sarcomas to be considered in adjuvant chemotherapy trials.

From 1975 to 1988, 144 patients naive of treatment, with non-metastatic soft tissue sarcoma were treated at Fondation Bergonié by surgery, followed by radiotherapy and without chemotherapy. An analysis of prognostic variables was done on this population to determine patients for whom an adjuvant chemotherapy would be relevant. Prognostic variables in overall survival (OS), metastasis-free survival (MFS), disease-free and local free recurrence survivals were analysed by univariate and multivariate analysis. In multivariate analysis using Cox's model, only tumour depth and tumour grade were significant with the MFS end point, while tumour depth, tumour grade and tumour site were significant when considering OS. A predictive stratification for patients is proposed: a favourable prognostic group with grade 1 tumour or superficial, grade 2 tumour (5-year OS: 97.8%; 5-year MFS: 100%); an intermediate prognostic group with deep, grade 2 tumour or superficial, grade 3 tumour (5-year OS: 58.8%; 5-year MFS: 48.1%); and finally a poor prognostic group with deep, grade 3 tumour (5-year OS: 31.7%; 5-year MFS: 34.1%). Patients in the intermediate and poor prognostic groups who present a high metastatic risk are to be considered for adjuvant chemotherapy trials.

Pharmacokinetics and metabolism of epirubicin administered as i.v. bolus and 48-h infusion in patients with advanced soft-tissue sarcoma.

We have studied the pharmacokinetics of epirubicin after its administration in sarcoma patients either as an i.v. bolus or as a 48-h infusion (5 courses each; 9 patients in total). Bolus injection was followed by a three exponential decay in plasma, with half-lives of 2.43 min, 1.95 h and 21.7 h; 48-h infusions were characterized by the very rapid establishment of a plasma plateau concentration followed by a biexponential decay after stopping the infusion. Pharmacokinetic parameters such as total plasma clearance, total volume of distribution, mean residence time and elimination half-life were similar, irrespective of the duration of the administration. In contrast, the relative amounts of the metabolites of epirubicin were reduced when the drug was administered over 48 h; in particular, the plasma levels of epirubicin glucuronide never exceeded those of epirubicin, which always occur after bolus injection. This may result from a lower availability of epirubicin for metabolism. These results now require validation in a larger group of patients using a cross-over design.

[Neoadjuvant chemotherapy and combined conservative treatment of soft tissue sarcoma in the adult]. / Chimiothérapie d'induction et traitement combiné conservateur des sarcomes des tissus mous de l'adulte.

Between 1980 and 1990, 64 adults with a locally advanced soft tissue sarcoma, but without metastasis, were treated with neoadjuvant chemotherapy before conservative local treatment. Tumour localizations were limbs in 26 patients (40.6%) and other parts of the body in 38 patients (59.4%). Moreover, 27 patients had bone and/or vasculo-nervous axis involvement. Response to chemotherapy was > or = 50% for 23 patients (37.7%) with 3 complete remissions, < 50% for 36 patients and only 2 tumours progressed during chemotherapy. Conservative surgery was thus carried out for 51 patients (79.7%), 11 received external radiotherapy only. At the end of treatment, 49 patients (76.5%) were in complete remission. With a median follow-up of 76 months (range: 25 to 147), 25 patients are alive with no evolutive disease. For the whole population, the actuarial 5-year overall survival is 33.8%. Among the patients who were in complete remission at the end of therapy, 15 developed local recurrences (with metastasis for 7 patients) and 10 became metastatic. Actuarial 5-year overall survival for this subset of patients is 44.8%.

[Dedifferentiated liposarcoma. A clinico-pathologic study of 6 cases]. / Liposarcome dédifférencié. Etude anatomoclinique de 6 cas.

During a period of 15 years, 6 cases of dedifferentiated liposarcomas were found among 542 cases of adult soft tissue sarcomas, 77 of which were liposarcomas. They were huge tumors of the retroperitoneum, containing distinct areas of well-differentiated liposarcoma most often of sclerosing type and malignant fibrous histiocytoma or undifferentiated sarcoma most often of high grade malignancy. Immunohistochemistry on the dedifferentiated component showed a positivity with anti-vimentin and alpha-1-antichymotrypsin in 5 cases and with anti-alpha smooth muscular actin in 4 cases. Three patients developed local recurrence and a fourth one quickly died with bone metastasis. Other types of dedifferentiated sarcomas, the process of dedifferentiation and links between malignant fibrous histiocytoma and dedifferentiated sarcomas are discussed.

[Postoperative radiotherapy in soft tissue sarcomas of the limbs. Analysis of irradiation volumes and doses in a series of 31 cases]. / Radiothérapie postopératoire des sarcomes des parties molles des membres. Analyse des volumes et des doses d'irradiation sur une série de 31 cas.

From October 1985 to October 1988, 31 patients with a soft tissue sarcoma of extremities were treated in our institute by conservative resection and post-operative radiation therapy. The initial target volume encompasses the entire musculoskeletal area occupied by the tumor. The compartmental definition of this initial target volume is based on clinical, radiographic, histopathologic and operative findings. We analyzed the irradiated volume in terms of the anatomical definition and feasibility. We then evaluated the distribution of the dose in the irradiated volume. The variation of the dose is always less than 10%. Accordingly, the range of dose in the irradiated volume varies from 45 to 50 Gy in the compartmental volume after a complete resection, and from 55 to 60 Gy in the tumor bed after a marginal or incomplete resection. For this series, the median follow-up is 27 months. We observed 3 distant metastases and 1 progressive disease in the irradiated volume. No locoregional recurrence appeared in the margins or outside the irradiated volume. These preliminary results validate the compartmental definition of the initial target volume. Furthermore, they point out the lack of opportunity to encompass tendinous insertions in the irradiated volume and to boost the scar. Finally, the definition of optimal dose for the control of microscopic residual tumor is discussed.

[Fatal myocardiopathy due to adriamycin in spite of a reportedly non-dangerous cumulative dose]. / A propos d'une myocardiopathie mortelle à l'adriamycine malgré une dose cumulative réputée non dangereuse.

We report a case that illustrates the risk of major, irreversible heart failure despite theoretically safe cumulative doses of adriamycin. We discuss risk factors for cardiotoxicity, predictive methods among which echocardiography is the most useful, and preventive measures. Data are still lacking concerning long term consequences on cardiac function. Until less cardiotoxic adriamycin derivatives become available, modifications in the treatment regimen can be proposed, including a tolerance test, lower doses approximating 20 mg per week instead of 60 mg every three weeks, and administration by continuous infusion through a deep catheter or a pump as cardiotoxicity seems more dependent on drug level peaks than on total dose. These measures should reduce the hazards of adriamycin, a drug that also has potent antimitotic properties.

[Cytologic diagnosis of breast angiosarcoma]. / Diagnostic cytologique d'angiosarcome mammaire.

Angiosarcomas of the breast are exceedingly rare tumors that are only infrequently seen by pathologists examining fine-needle biopsy specimens. We report two cases in two women aged 52 and 57 years. Cytologic features are analyzed and differential diagnosis is discussed.

[Sarcomas of soft tissue in the adult. Therapeutical indications]. / Sarcomes des tissus mous de l'adulte. Indications therapeutiques.

Treatment of soft-tissue sarcomas has to deal simultaneously with three goals: 1) to obtain the control of the primary tumor, 2) to preserve the function, and 3) to treat the micrometastatic disease. For local control, surgery remains the most efficient treatment, but the extent of the resection of macroscopically non-involved tissue, and as consequence, resulting dysfunction, can be reduced by properly planned postoperative radiotherapy and chemotherapy. Moreover, surgery may be easier, following preoperative radiotherapy or chemotherapy, which may also allow secondary excision of a primarily inoperable tumor. For the treatment of the micrometastatic disease, the efficacy of adjuvant chemotherapy has to be confirmed by further studies; some results published to date are encouraging. Thus, treatment of soft-tissue sarcomas remains difficult, but important advances are to be expected in the next few years. A multidisciplinary approach is necessary, involving not only surgeons, radiotherapists and medical oncologists, but also radiologists and pathologists.

Pharmacokinetics of doxorubicin in sarcoma patients.

The pharmacokinetics of doxorubicin has been studied in 26 sarcoma patients receiving polychemotherapy. Mean elimination half-life was 34.7 +/- 16.6 h and the total plasma clearance was 29.5 +/- 9.31 X h-1 X m-2. No relationship was found between the pharmacokinetic parameters and the response to treatment, or its toxicity. Special attention was paid to the early-phase kinetics of the drug (3-20 min after injection). A correlation between the early clearance and the ages of the patients was observed. The early clearance was clearly correlated with the total plasma clearance measured over 48 h after injection, indicating the importance of the distribution phase in the overall kinetics of the drug.

Reproducibility of a histopathologic grading system for adult soft tissue sarcoma.

Tumor grade has been proposed as an essential factor in the staging of patients with soft tissue sarcomas. In a previous study, a histopathologic grading system using the evaluation of tumor differentiation, mitosis count, and tumor necrosis was described. The current study was conducted to test its reproducibility. The pathologic sections of 25 soft tissue sarcomas were submitted to a study group composed of 15 pathologists who had not been involved in the development of the grading system. The results were compared with those of a panel group. The crude proportion in agreement observed between the study group and the panel group was 81% for the evaluation of tumor necrosis, 74% for tumor differentiation, and 73% for the mitosis count. The crude proportion in agreement for the tumor grade was 75%, which was significantly better than the crude agreement rate of 61% for the diagnosis of histologic type (P = 0.001). A kappa statistical analysis, to check the possibility of chance-related concordance, showed a proportion in agreement of 68%. A two-way variance analysis showed that the homogeneity of the evaluation of tumor grade is impaired by tumor-related and observer-related factors. However, an improvement may be obtained by better training of pathologists. We conclude that the tumor grading system developed inside the French Federation of Cancer Centers, although perfectible, already provides reliable prognostic information and its use in prospective clinical studies may provide more information about its clinical usefulness.