J Genin

High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas.

PURPOSE The study was designed to assess the toxicity and activity of high-dose ifosfamide (HDI) administered by continuous infusion at a dose of 4 g/m2/d over 3 days every 4 weeks in adult patients with advanced soft tissue sarcomas (ASTS) pretreated with doxorubicin and/or a standard-dose ifosfamide (SDI)-containing regimen. PATIENTS AND METHODS Between January 1991 and November 1993, 40 patients with progressive ASTS were entered onto the study. Twenty-eight patients had been pretreated with a multidrug regimen that contained SDI and were classified as follows: SDI-refractory (n = 21), SDI-resistant (n = 2), and indeterminate SDI-sensitive (n = 5). Patients were treated until progression or major toxicity. RESULTS One hundred forty-seven cycles of HDI were administered. Neutropenia was dose-limiting, with 100% of patients experiencing grade 3 to 4 toxicity and 12 admissions for febrile neutropenia (30% of patients). Neurotoxicity (17% of patients) was significantly associated with acute renal failure (n = 4) (P < .001), grade 4 thrombocytopenia (P < .01) and febrile neutropenia (P = .048). Chronic renal toxicity (n = 4) was significantly associated with retroperitoneal masses and/or prior nephrectomy (P = .008). Partial responses (PRs) were observed in 12 of 36 assessable patients (33%) and eight patients (22%) experienced disease stabilization. All but one response occurred in patients pretreated with SDI, with five PRs among SDI-refractory patients. Leiomyosarcomas appear resistant to HDI. The median response duration was 8 months (range, 6 to 13+) and the median overall survival time was 12 months. CONCLUSION The activity of HDI in these pretreated ASTS patients and the apparent circumvention of SDI resistance suggest a real dose-response relationship for ifosfamide and deserve further evaluation. Although toxic, this treatment appears feasible and manageable using routine clinical support. Since prophylaxis of ifosfamide-induced renal damage remains unknown, frequent monitoring of renal and tubular functions during therapy is highly recommended.

Twenty years experience of interstitial iridium brachytherapy in the management of soft tissue sarcomas

From February 1968 to February 1988, 50 patients above 10 years of age with a soft tissue sarcoma were treated with interstitial brachytherapy, combined with a wide excision. After pathologic review, 48 were included in the final analysis. A pathological grading was made possible in 41, which showed a majority of high grades (2 + 3 = 86%). Patients presented mainly with small (less than 5 cm: 36) or mid-size lesions (greater than 5 cm: 12). The tumor was located in the limbs (32), trunk (9), and head and neck (7). Four patients had metastases at the time of treatment. Brachytherapy was part of the initial treatment in 22 cases, and of a salvage procedure after previous excision(s) combined or not with another form of treatment in 26. A uniform technique of iridium 192 wires after-loaded in plastic tubing was used. Sixty Gy median doses were delivered with brachytherapy alone (44) or combined with external beam (4). Sixteen patients also received an adjuvant chemotherapy. Follow up ranged from 16 months to 20 years (median 82 months). At the time of analysis, two patients (4%) only had failed in the irradiated volume, but the marginal failures rate (14:31%) was unexpectedly high. Seven of the patients who failed (43%) were salvaged by a second similar procedure. The 5-year survival was 62% in non-previously treated patients and 56.5% in previously treated ones (pNS). By multivariate analysis, only the tumor location appeared predictive of LF (p less than 0.01), which in turn was strongly correlated with the metastatic outcome (p less than 0.01). Necroses were observed in 17 cases (35%) and associated with a benign course in most of them. High dose brachytherapy combined with conservative surgery is highly effective in small and mid-size soft tissue sarcomas located in the extremities and head and neck, whereas in trunk and in recurrent tumors, the adjunction of large fields external radiotherapy and/or possibly polychemotherapy appears necessary.

Does malignant small round cell tumor of the thoracopulmonary region (Askin tumor) constitute a clinicopathologic entity? An analysis of 30 cases with immunohistochemical and electron-microscopic support treated at the Institute Gustave Roussy.

The morphology and clinical outcome of 30 patients with malignant small round cell tumors located in the thoracopulmonary region (Ask in tumor) are reported. Histologically, all tumors had similar patterns, with small round‐to‐oval cells and a lobulated stroma. Immunohistochemical analysis always resulted in positive staining for one or several neural markers. No significant differences were found compared with the immunomarkers in 26 typical Ewings sarcomas located outside the thoracic wall. In three specimens, electron microscopy confirmed the presence of membrane‐bound neurosecretory granules. It was confirmed that there is a remarkable similarity among all malignant small round cell tumors, including Ask in tumor and Ewings sarcoma. Overall survival was poor with a 2‐year rate of 38% and a 6‐year rate of 14%. Cancer 1992; 69:1012–1020.

Preoperative induction chemotherapy in the treatment of locally advanced soft tissue sarcomas

Evidence that supports the use of systemic, presurgical induction chemotherapy to render soft tissue sarcomas resectable or to minimize the extent of surgical excision is presented. Induction chemotherapy was administered in 34 cases of nonmetastatic soft tissue sarcomas. All patients had large tumors for which only mutilating surgery, if any, was possible. In 21 patients, a combination of Adriamycin (doxorubicin), cyclophosphamide, cisplatin, vindesine, and DTIC (DCPAV) produced two complete remissions (CR) and 6 partial remissions (PR). A combination of cyclophosphamide, vincristine, Adriamycin, and DTIC (CYVADIC) produced three PR in eight patients, and a combination of Adriamycin and ifosfamide (AI) produced two PR in five patients. After two to seven cycles of chemotherapy, 24 patients underwent surgery. In 19, gross tumor excision was performed; 12 proved to be microscopically fully resected. Disease in two patients entered CR with chemotherapy alone, but surgery was performed in both patients as well. Irradiation was administered in ten patients to produce or insure CR (eight cases of residual disease postoperatively), and in two patients with unresectable disease. Four patients with disease in CR after surgery also received radiation due to the initial massive tumor size. The Kaplan‐Meier survival curves at 2 years showed 18% total survival in the patients in whom CR of disease was not achieved, and 80% survival in patients with disease in CR. Of the 22 patients with disease in CR (by all means), disease‐free survival was 1 to 44 months (mean, 13.7). Disease currently remains in CR in ten patients with a mean follow‐up of 13.6 months (3 to 34 months from end of therapy). Ten patients had a local recurrence following a CR after 3 to 44 months (mean, 15.3 months).

Postoperative radiotherapy in the management of adult soft tissue sarcoma of the extremities: results with two different total dose, fractionation, and overall treatment time schedules.

PURPOSE This retrospective study was performed to evaluate two postoperative radiotherapy schedules in terms of dose, fractionation, and overall treatment time in soft tissue sarcoma (STS) of the extremities. METHODS AND MATERIALS Between January 1984 and December 1993, 62 patients with newly diagnosed localized STS of the extremities were treated with maximal conservative surgery and postoperative radiotherapy (RT). Forty-five patients received 50 Gy with conventional fractionation plus a boost dose (5 to 20 Gy). Seventeen patients had hyperfractionated accelerated radiotherapy (HFART) up to a dose of 45 Gy in 3 weeks. RESULTS With a median follow-up of 72 months, the 5-year local failure rate was 25%, the 5-year disease-free and overall survival rates were respectively 42% and 62%. The 3-year local relapse, disease-free, and overall survival rates were respectively 16%, 44%, and 70% in the conventional radiotherapy group, and 36%, 47%, and 82% in the HFART group (NS). No factor significantly influenced local control with a trend, however, in favor of conventional RT (p = 0.10). CONCLUSION HFART at the dose of 45 Gy does not seem to be superior to the standard RT schedule, neither in terms of local control, survival, nor in terms of long-term side effects. However this dose could be considered too low as well as the power of comparison between the two groups to draw definitive conclusions.

Problems and pitfalls in the use of computed tomography for the local evaluation of long bone osteosarcoma: Report on 30 cases

Forty-eight, computed tomography (CT) examinations undertaken in 30 patients with osteosarcoma of long bones were studied in detail, their diagnostic information being compared with that obtained from corresponding plain films. The latter were of more value in assessing peripheral bony involvement, by cortical extension and periosteal reaction, while the former, in general, permitted more accurate observation of extensions into adjacent soft tissues. Recognition of such extensions, however, was vitiated when they arose in relation to the proximal ends of the tibia, fibula, and humerus and when a haematoma had developed as a result of a biopsy. Plain films were also of more value in appreciation of response to chemotherapy. On the other hand CT is the only examination which permits a satisfactory study of intramedullary extensions of the tumour and in consequence is invaluable in determining the exact sites required for local resection. No cases of skip metastases were observed in our series, although similar appearances due to nutrient vessels or bony ridges, remote from the primary tumour, were noted on several occasions. Differentiation of these densities proved to be easy, particularly in the case of nutrient vessels when examination of the contralateral bone showed them to be symmetrical. Several authors have described the role of CT in the evaluation of local extensions. This paper reports the difficulties and errors encountered by us.