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.

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.

Analysis of a series of sixty soft tissue sarcomas in adults treated with a cyclophosphamide-vincristine-adriamycin-dacarbazine (CYVADIC) combination.

From 1976 to 1983, a group of 60 adult patients presenting with metastatic and/or locally advanced soft tissue sarcomas was treated with combination chemotherapy consisting in cyclophosphamide, vincristine, adriamycin, and DTIC (CYVADIC). A tumor response was obtained for 29 patients (48.3%), with 4 (6.7%) cases of complete regression. The median duration of the response was 10 months. Responses were noted in 14/22 patients receiving induction chemotherapy for advanced, and previously nonirradiated, primary tumors; among the patients with metastatic disease tumor regression was recorded in 17/32 patients with pulmonary metastases, but in none of the patients with metastases at other sites. Moreover, the attainment of a response was found to correlated with the patient's general condition, while response duration depended on the histoprognostic grade of the tumors.

[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.

[Treatment of locally extensive soft tissue sarcomas. Value of intra-arterial chemotherapy (author's transl)]. / Traitement des sarcomes des tissus mous localement évolués. Intérêt de la chimiothérapie d'induction par voie intra-artérielle.

Between 1964 and 1978, 21 patients with locally extensive soft tissue sarcoma received intal-arterial regional chemotherapy (IAC), combined with radiotherapy. Some patients were also submitted to conservative surgery. Although there were three serious accidents, one of which was lethal, the tolerance was considered acceptable. Tumor regression of more than 50 per cent was observed in 9 of the 21 patients after chemotherapy. Overall, the addition of IAC to radiation therapy gave satisfactory local control. Recurrent local disease occurred in only four patients. On the basis of these results IAC can be considered as an important element of combined treatment methods to achieve local control in locally extensive soft tissue sarcomas, which are generally not very responsive to systemic chemotherapy.

[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%.

[Metastatic cancer of the prostate: phase II study of spirogermanium (NSC 192965)]. / Cancer de la prostate métastatique: étude de phase II du spirogermanium (NSC 192965).

A phase II study of spirogermanium was conducted in a series of 15 patients with metastatic prostatic carcinoma. All the patients have previously received multiple hormonal therapies. The drug was administered at the dose of 200 mg/m2 by a continuous infusion for five days, and 120 mg/m2, three times a week subsequently. The side effects were mainly neurological toxicity and phlebitis at the injection points which were dose and schedule dependent. Only one partial response for two months was noted in this series. Thus, spirogermanium seems to have a limited value in patients with prostatic cancer.

[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.

[High dose metoclopramide during cancer chemotherapy. Phase II study in 80 consecutive patients]. / Métoclopramide a forte dose au cours de chimiothérapies anticancéreuses lourdes. Etude de phase II chez 80 malades consécutifs.

From november 1981 to january 1982, 80 consecutive patients received high dose metoclopramide, adjoined to different cancer chemotherapy regimens containing cisplatine, dacarbazine, actinomycin D or mithramycin. Nineteen of them (23,75%) had no chemotherapy induced nausea or vomiting, 30 (37,5%) had nausea alone or vomited only once, and 17 (21,3%) had 3 to 5 episodes of vomiting. The overall efficacy of high-dose metoclopramide was 83,7 per cent. It has been seen whatever the chemotherapeutic agents used, and was inchanged for the following courses in 33 of 37 patients who received 2 to 4 courses. In 25 out of 33 patients who had already received the same chemotherapy without high dose metoclopramide, the digestive tolerance have been improved by the antiemetic treatment. Toxicity of high dose metoclopramide had been encountered in 17 (21,5%) of the patients and necessited this treatment to be stopped in 10. There were mainly extrapyramidal syndroms, diarrhea and drownsiness. The toxicity of high dose metoclopramide was of concern mainly in patients younger than 30, and/or when dosage escalation have been attempted.

[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.

[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.

[Echography and computed x-ray tomography in the diagnosis and surveillance of hepatoblastoma. Apropos of 5 cases]. / Apport de l'échographie et de la tomodensitométrie dans le diagnostic et la surveillance des hépatoblastomes. A propos de cinq observations.

Ultrasound imaging and CT scans were performed in a homogeneous group of five patients with hepatoblastoma. Effectiveness in determining characteristics of the tumor mass and its location and possible vascular extension were compared for the two exploratory methods. Findings suggest that these two examinations are useful and complementary for the diagnosis and follow up of hepatoblastoma.

[Uterine sarcoma. Retrospective analysis of a series of 22 cases]. / Sarcomes de l'utérus. Analyse rétrospective d'une série de 22 cas.

37 uterine tumors originally diagnosed as uterine sarcomas at Fondation Bergonié between 1970 and 1982 were histologically reclassified. 15 patients were excluded from this study because of inadequate data or not confirmed initial diagnosis. The 22 remaining cases were classified as leiomyosarcomas 13, endometrial stromal sarcomas 7 and mixed mesodermal sarcomas 2. The mean age of the patients was 56. The cases were classified according to the FIGO staging system. 5 patients had previously undergone (between 1 and 8 years) a subtotal hysterectomy for uterine leiomyoma. 5 patients had stage 1 sarcoma, 13 patients stage III and 2 patients stage IV. 13 patients are dead, 7 are alive without evidence of disease, 2 are alive with evidence of disease. The 5 year actuarial survival rate was 30%. Tumor extent at diagnosis was not correlated with survival. Analysis of failures revealed : 4 metastatic, 5 metastatic and pelvic and 6 isolated pelvic failures. Prognosis was not significantly different between leiomyosarcomas and endometrial stromal sarcomas. There was no pelvic failure in patients with stage I sarcoma (treated by surgery plus radiotherapy). Survival was not found to be correlated with histopathological grade as described in soft tissue sarcomas. Nevertheless a correlation (non significant) was found between survival and mitosis count. Chemotherapy (Cyvadic) was administered in 8 advanced tumors with partial response (always below 50% of the initial tumor) in 5 patients.

[Conservative loco-regional treatment of soft tissue sarcoma in adults after induction chemotherapy]. / Traitement loco-régional conservateur des sarcomes des tissus mous chez l'adulte après chimiothérapie d'induction.

Between June, 1979 and December, 1983, 23 adult patients with non-metastatic soft tissue sarcoma were treated with induction chemotherapy since local spread precluded primary conservative surgery. Eighteen patients received a combined cyclophosphamide, vincristine, adriamycin and dacarbazine treatment and 5, a combined adriamycin, cis-platinum and vindesine treatment. Both drug combinations exhibited toxic effects, notably on blood and digestive tract. However, tumoral volume was reduced by 50 p. cent or more in 14/23 patients, including 2 complete remissions; the course of the disease remained unchanged under treatment in only 3 cases. Chemotherapy facilitated surgical excision in 14 patients, and subsequent radiotherapy resulted in complete remission in 13 of these. None of the 13 patients relapsed during a mean follow-up period of 12 months (range: 3 to 48 months). Among the 9 patients who could not be operated upon, 5 benefited from radiotherapy with satisfactory local control, but only one still remains in complete remission. Thus, induction chemotherapy made it possible to achieve local control in two-thirds of patients with locally advanced sarcoma. However, a more prolonged follow-up is necessary to confirm that these results are long-lasting and to determine the effects of chemotherapy, if any, on the metastatic potential of these tumours.

[Role of chemotherapy in the treatment of soft tissue sarcoma in adults]. / Place de la chimiothérapie dans le traitement des sarcomes des tissus mous de l'adulte.

Soft tissue sarcomas of adults represent an heterogeneous group of rare malignant tumors, for which clinical and histopathological prognostic factors are now well defined. The GTNM classification recommended by the UICC is effectively predictive for the metastatic potential of these diseases. Although chemotherapy still have limits in advanced sarcomas, the efficacy level reached allows to consider its use with a curative intend, in multidisciplinary therapeutic program. A critical analysis of the studies already published shows that adjuvant chemotherapy can reduce the distant metastases rate in patients presenting an operable primary tumor. Furthermore, the preliminary results of a study indicate that neoadjuvant (induction) chemotherapy may be of value for primarily inoperable patients. All these encouraging results remain to be confirmed by further studies with a long-term follow up of the patients.

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.

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.