Salvage chemotherapy for advanced sarcoma patients: a single-institution experience survey.

There is no standard salvage chemotherapy for patients with recurrent sarcoma following a first-line chemotherapy. A few therapeutic options are available and of limited efficacy. The objective of this study was to determine the activity and toxicity of salvage therapies in advanced sarcoma patients in our experience. A retrospective analysis of 41 case records of patients with recurrent sarcoma treated at our division between May 1995 and October 2000 was conducted. Several different therapy regimens were employed: dacarbazine (DTIC) in 16 patients; carboplatin (CBDCA) plus gemcitabine (GEM) in 9 patients; ifosfamide (IFO) in 10 patients; other regimens in 6 patients. A total of 153 cycles of chemotherapy were delivered (median, 3 cycles). Among 38 evaluable patients, seven partial responses were obtained (RR 18.4%). Treatment-related responses were: 2/15 in DTIC group; 1/8 in CBDCA/GEM group; 3/9 in IFO group; 1/6 in other regimens. Stable disease was obtained in 10 patients. Median time to treatment failure and median survival time were 5 months and 4.5 months, respectively. The main treatment-related toxicities were hematologic and gastrointestinal. Most of salvage chemotherapies for recurrent sarcoma patients have an unacceptably high treatment failure rate and do not appear to offer any quality of life advantages. Future clinical trials with high dose ifosfamide seem appropriate even if the use of investigational new drugs and novel strategies in these patients should be considered.

High frequency ultrasound in the preoperative staging of primary melanoma: a statistical analysis.

High frequency sonography has been shown to be a useful tool in the preoperative staging of malignant melanoma. In the present study sonometric and histometric data concerning tumour thickness were compared, using appropriate statistical methods, in order to assess the accuracy of ultrasonography. From December 1997 all pigmented lesions suspected of being melanoma were preoperatively assessed by a 20 MHz ultrasound B scan. The results of these ultrasound examinations were compared with histometric data. Pearson's correlation coefficient and absolute and relative differences were used for statistical analysis. Of the 261 examined lesions, 193 were malignant melanoma. A high correlation between sonometry and histometry was computed (r = 0.95), with an absolute difference of 0.32 +/- 0.03 mm (mean +/- SEM) and a mean relative difference of 27.2% (95% confidence interval 23-31.4%). The highest correlation was found in melanoma > or = 1.51 mm thick and the lowest correlation in melanoma < or = 0.75 mm. In conclusion, the high accuracy of this technique in the preoperative staging of malignant melanoma would offer a basis for defining the surgical margins of > or = 0.76 mm thick lesions. The limited accuracy of sonometry in the preoperative staging of thin melanoma < or = 0.75 mm has emerged by applying adequate statistical methods.

Ifosfamide and epirubicin combination in untreated sarcomas: two treatment schedules.

BACKGROUND: The Epirubicin (EPI) and ifosfamide (IFO) combination has been widely tested in soft tissue sarcomas, even though the optimal schedule of drug administration has still to be defined. In this article, we reviewed the activity and the toxicity of two EPI- and IFO-based schedules in newly diagnosed sarcomas. MATERIAL AND METHODS: 22 patients (group A) received a 'concurrent' schedule of short-infusion IFO at total dose of 7.5-9 g/m(2) over 5 days plus iv bolus EPI at 90-120 mg/m(2)/cycle, repeated every 3 weeks. The other 22 patients (group B) received a 'sequential' schedule of dose-intense, continuous infusion IFO at a total dose of 14-18 g/m(2) for 2 cycles followed by bimonthly EPI at 120-160 mg/m(2)/cycle. Application of growth factors was planned for each course of treatment. RESULTS: Since 1994, 44 consecutive patients have been treated. The overall response rate was 35% with no significant differences between the two treatment groups in terms of response rate (group A: 33%, group B: 37%), time to progression (group A: 7 months, group B: 8 months), and overall survival (group A: 12 months, group B: 15 months). General tolerance to treatment was better in group A. Gastrointestinal symptoms occurred significantly more often with the sequential regimen. Severe hematologic toxicity was common but no toxic deaths were observed. CONCLUSIONS: Based on this limited experience, a concurrent schedule of EPI and IFO seems to be an appropriate management strategy in the front-line therapy of advanced sarcomas. Nevertheless, a randomized trial is warranted to define the optimal dosages to be used for further clinical trials.

A phase II study of dose-intense ifosfamide plus epirubicin with hematopoietic growth factors for the treatment of patients with advanced soft tissue sarcomas; a novel sequential schedule.

PURPOSE: The efficacy and feasibility of a novel sequential schedule of high-dose ifosfamide (HD-IFO) and full-dose epirubicin (EPI) with granulocyte colony-stimulating factor (G-CSF) was evaluated in adult patients with soft tissue sarcomas (STS). METHODS: Since November 1995, 22 chemotherapy-naive patients have been treated. HD-IFO was given as a continuous infusion at a total dose of 14-18 g/m2 per cycle, with mesna, over 6 to 8 days, q 3 weeks, twice. EPI was administered subsequently as an i.v. bolus at a total dose of 120-160 mg/m2, on days 1-2, q 2 weeks, twice. G-CSF was planned for each course of treatment as a daily subcutaneous injection for 7 days, starting 24 h after the end of the treatment. After the first four cycles, patients were evaluated for surgery and patients with locally inoperable or metastatic disease received further chemotherapy up to a maximum of eight cycles. RESULTS: The response of 19 patients could be assessed. One complete response (CR) and six partial responses (PRs) were achieved for an overall response rate of 37% (95% confidence interval, 15-59%). Noteworthy is that two of the six leiomyosarcoma patients responded to the HD-IFO treatment. The median survival period was 15 months. Most common toxicities included myelosuppression, nausea and vomiting, and stomatitis. Six patients were hospitalized for complicated nadir fever. No severe renal and CNS toxicities were seen. Transient gross hematuria occurred in six patients and affected treatment in only one case. There were no treatment-related deaths. CONCLUSIONS: By the protraction of continuous infusion of HD-IFO over 6 to 8 days, ifosfamide-induced acute renal toxicity is avoided, while G-CSF support allows the delivery of the planned dose intensity in most of the patients. Although manageable in an oncology setting, the hematologic toxicity of such a regimen remains substantial. Moreover, in terms of efficacy and median survival, this regimen showed no benefits over a conventional-dose anthracycline-ifosfamide schema. Further evaluations of this novel ifosfamide-epirubicin schedule are not warranted, even if the HD-IFO regimen could be taken forward specifically for leiomyosarcomas in a phase II trial.

Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview.

Dacarbazine (DTIC) is the only single-agent approved by the Food and Drug Administration for treating metastatic melanoma. With DTIC as single agent, an approximately 20% objective response rate can be achieved with median response duration of 5 to 6 months and complete response rates of 5%. Current status of DTIC single agent and DTIC-based combination chemotherapy has been extensively reviewed in this article. Moreover, future directions including new combination chemotherapies and/or new therapeutical approaches have been considered. The addition to DTIC of agents such as cisplatin, nitrosoureas and tubular toxins has been reported to yield high response rates, up to 40%, in single-institution phase II trials. Historically, promising combination regimens like BOLD (bleomycin, vincristine, lomustine and DTIC) and CVD (cisplatin, vinblastine and DTIC) have induced responses on metastatic lesions to the liver, bone and brain, commonly unresponsive to DTIC alone, even though have failed to produce impact on patient survival. Several other studies have suggested a significant enhancement of antitumor effect associated with the addition of tamoxifen to various cytotoxic regimens. The four-drug combination CBDT (cisplatin, carmustine, DTIC and tamoxifen) or "Dartmouth regimen" has yielded high response rates, up to 55%, with continuous, maintained, complete responses, up to 82 months, in a subset of patients, that is considerably longer than observed with other combinations. Some authors recommend CBDT as reference therapy, even though recently presented results of a randomized phase III trial of CBDT versus DTIC alone, show no statistical difference in survival between the two groups. While a survival benefit from DTIC-based chemotherapy or DTIC alone has never been shown in metastatic melanoma patients and, therefore, the survival has remained unchanged over the past 30 years, some long term survivors have been reported with the "Dartmouth regimen" and/or with high dose interleukin-2 (IL-2) based regimens whose role is going to be defined in prospective randomized phase III trials. On the other hand, the better understanding of the mechanisms responsible for melanoma chemoresistance and the development of new therapeutical strategies could change the scenario in the next future.

The chemoresistance of human malignant melanoma: an update.

Malignant melanoma is considered to be a chemotherapy-refractory tumour and the commonly used anticancer drugs do not seem to modify the prognosis of metastatic disease. The cellular resistance mechanisms involved in melanoma chemoresistance have not yet been elucidated. Melanoma-derived cell lines are often markedly chemoresistant. Using the in vitro soft agar culture system to predict tumour cell sensitivity in well-established human melanoma cell lines, a high degree of resistance against all the cytostatic agents studied has been reported, suggesting the presence of intrinsic cellular resistance mechanisms. The relevance of the well-defined resistance mechanisms mediated by P-glycoprotein, multidrug resistance-associated protein (MRP), the glutathione/glutathione S-transferase system and topoisomerase II enzyme are reviewed. Mutated N-Ras oncogene has recently been implicated in melanoma resistance to cisplatin, both in vitro and in vivo, and the role of two other oncogenes, Bcl-2 and p53, which are already involved in the chemoresistance of haematological and solid malignancies, is beginning to be better elucidated. The finding that many chemotherapeutic agents can kill susceptible cells through the apoptosis pathway provides new molecular insight into chemoresistance mechanisms and suggests that apoptosis and/or resistance to apoptosis of melanoma cells should be investigated to better clarify the mechanism of melanoma chemoresistance.

13-cis retinoic acid and interferon alfa-2a in the treatment of metastatic renal cell carcinoma.

Eleven patients, pre-treated with chemotherapy and immunotherapy, with renal cell carcinoma were given 13-cis-retinoic acid (CRA) in association with interferon alfa-2a (IFN 2a). 13-ci retinoic acid was administered at the dose of 1 mg/Kg/die while interferon alfa-2a at the dose of 3X10 U.I./die s.c. All patients had been previously treated with chemotherapy in association with immunotherapy. Therapy was not discontinued until neoplastic progression occurred. Clinical results were as follows: partial responses (PR) were observed in two patients, disease stabilization (SD) in 5 and progression (PD), with 8-month median treatment duration, in 4. Side effects were mild.