Doxorubicin and ifosfamide-mesna in advanced and recurrent uterine sarcomas

PURPOSE OF INVESTIGATION: To report the experience of a single institution in the south of Israel with doxorubicin and ifosfamide-mesna in patients with advanced/recurrent uterine sarcomas. METHODS: The hospital records of five patients with advanced/recurrent uterine sarcomas who had combination chemotherapy with doxorubicin and ifosfamide-mesna were retrospectively reviewed. Doxorubicin 30 mg/m2 was given on days 1 and 2 and ifosfamide 2000 mg/m2 (+ mesna, W/W 60%) was given on days 1, 2 and 3 of every 21 days. Dose intensity, relative dose intensity and average relative dose intensity (ARDI) of chemotherapy were calculated. Response was determined using clinical evaluation and radiological reports. Toxicity was graded using the National Cancer Institute (NCI) criteria. RESULTS: The median ARDI of the combination of doxorubicin and ifosfamide received by the patients was 0.68 (range, 0.53-0.74). One (20%) patient had disease complete response lasting three months and four (80%) patients had progressive disease. Toxicity was mainly hematological with grade 3 or 4 leukopenia--four (80%) patients, neutropenia--four (80%), thrombocytopenia--one (20%) and anemia--one (20%). Non-hematological toxicity was negligible. At follow-up, four (80%) patients had died of disease and one (20%) was alive with disease. CONCLUSION: Although the combination of doxorubicin and ifosfamide has certain activity in advanced/recurrent uterine sarcomas, the toxicity is of much concern and the results of treatment in terms of response duration and survival are poor.     

A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study

OBJECTIVE: The aims of this study were to substantiate the previously reported activity of ifosfamide in patients with advanced, persistent, or recurrent carcinosarcoma (mixed mesodermal sarcoma) of the uterus, and to determine whether the addition of cisplatin results in an improved response or survival. Secondarily, we sought to determine the toxicity of ifosfamide-cisplatin in this patient population. METHODS: Patients were randomized to receive ifosfamide (1.5 g/m(2)/day) times 5 days every 3 weeks for eight courses with mesna uroprotection, with or without cisplatin (20 mg/m(2)/day) times 5 days. No patient had received previous chemotherapy. RESULTS: Of 224 patients entered on this study, 30 were ineligible for a variety of reasons, leaving 194 evaluable patients. Early in the study, the dose of the combination regimen was reduced by 20% (1 day) because of toxicity. The investigational arms were balanced for age, grade, and Gynecologic Oncology Group performance status. Percentages of adverse effects reported in 191 patients receiving chemotherapy included (ifosfamide/cisplatin-ifosfamide) grade 3 or 4 granulocytopenia (36/60), grade 3 or 4 anemia (8/17), grade 3 or 4 central nervous system toxicity (19/14), and grade 3 or 4 peripheral neuropathy (1/12). Treatment may have contributed to the deaths of 6 patients treated with full doses of ifosfamide and cisplatin for 5 days. The proportion of patients responding to ifosfamide alone versus ifosfamide-cisplatin therapy was (0.36 versus 0.54) overall, 0.47 versus 0.61 for pelvic, 0.21 versus 0.54 for lung, and 0.33 versus 0.40 for "other" metastatic sites of measurable disease. The relative odds ratio of response adjusted for measurable sites of disease was 1.82 (P = 0.03, one-tailed test; 95% lower confidence limit, 1.06). Progression-free survival (PFS) and survival data suggest that the combination offers a slight prolongation of PFS (relative risk, 0.73; 95% upper confidence limit, 0.94; P = 0.02, one-tailed test), but no significant survival benefit (relative risk, 0.80, 95% upper confidence limit, 1.03; P = 0.071, one-tailed test). CONCLUSION: The addition of cisplatin to ifosfamide appears to offer a small improvement in progression-free survival over ifosfamide alone in the management of advanced carcinosarcoma of the uterus; the added toxicity may not justify the use of this combination.     

Solid malignant uterine tumours

Uterine sarcomas are a rare group of uterine tumours. The majority consist of leiomyosarcomas, endometrial stromal and mixed mesodermal sarcomas. The most important treatment for this tumour group is removal of the uterus. Radiotherapy is of use in reducing the incidence of local relapse but its effect on the 5-year survival is not proven. Trials are currently evaluating chemotherapy for advanced or recurrent disease the most active agents being ifosfamide and doxirubicin.     

Chemotherapy of endometrial cancer revisited]

The current status and future directions of chemotherapy in the management of endometrial cancer are reviewed. For patients with advanced or recurrent endometrial carcinoma the most active single drugs are doxorubicin, epirubicin, cisplatin, carboplatin, paclitaxel, ifosfamide, 5-fluorouracil and vincristine with response rates ranging from 18 to 36%. Data at the present time support the conclusion that if chemotherapy is indicated a combination of doxorubicin + cisplatin is the standard chemotherapy for patients with advanced or recurrent endometrial carcinoma and yields a response rate of 47-60%. A first trial using a combination of these drugs with paclitaxel promises an increase in response rate to 73%, but data regarding prolongation of survival are not yet available. Up to now the benefit of neither chemotherapy nor endocrine therapy could be established in the adjuvant setting.     

Systematic review of systemic therapy for advanced or recurrent endometrial cancer

OBJECTIVE: To evaluate the chemotherapeutic options for women with advanced or recurrent endometrial cancer. METHODS: The MEDLINE, CANCERLIT and the Cochrane Library databases were searched from 1984 to March 2005 for randomized controlled trials (RCTs) comparing chemotherapy regimens in patients with advanced or recurrent endometrial cancer. Studies were included only if patients had measurable or evaluable disease, and/or response rates were reported. RESULTS: Seventeen RCTs compared regimens involving chemotherapy and/or hormonal therapies. Three chemotherapy trials demonstrated a statistically significant difference in response rates between treatment arms, but only one of these trials showed a modest survival advantage. The addition of cisplatin to doxorubicin in two RCTs significantly improved response rates (1.7- to 2.5-fold higher) but did not impact on survival. In two other RCTs using cisplatin and doxorubicin as standard therapy, the addition of paclitaxel improved response rates (57% versus 34%) and median survival (15.3 versus 12.3 months) when combined with cisplatin and doxorubicin but not when combined with doxorubicin only. Toxicity was increased with the three-drug combination. Quality of life was assessed in one trial, which is currently only in abstract form. Medroxyprogesterone acetate (200 mg/day) was effective in one RCT, particularly in patients with well-differentiated, receptor-positive tumors. CONCLUSIONS: Combination chemotherapy with doxorubicin and cisplatin results in higher response rates than doxorubicin alone. The addition of paclitaxel to either of these regimens resulted in a small survival advantage in one trial using all three drugs. In light of the limited survival advantage associated with this regimen, the use of less toxic combinations of taxanes with carboplatin requires further study. Medroxyprogesterone acetate is useful in selected patients.     

Diagnosis and therapy of uterine sarcoma

Radical surgery in stage I and II uterine sarcoma removing all tumor manifestations is the only curative therapy option for early stage disease. Larger tumors (> 4 cm) and the presence of lymph node metastasis correlate with a high local recurrence rate. For these tumors adjuvant radiation and/or adjuvant chemotherapy may be recommended after surgical therapy. Adjuvant therapy however, should preferably be considered for uterine stromal sarcomas and mixed mesodermal tumors. The toxicity of radiation and/or chemotherapy is greater than any possible benefit for patients with leiomysarcomas as these tumors rarely respond to radiation or chemotherapy. For advanced (> stage I and II) and recurrent disease, curative therapy options are not available and palliative therapy for these patients has to take into consideration the negative side effects and weigh up quality of life against an often very limited possible benefit of such therapy.     

Safety and efficacy of adjuvant single-agent ifosfamide in uterine sarcoma

PURPOSE: The role of adjuvant therapy for completely resected uterine sarcoma continues to be debated. Previous chemotherapy trials have shown little, if any, advantage over surgery alone, with significant added toxicity. To our knowledge, the current study is the first to evaluate adjuvant ifosfamide in completely resected uterine sarcomas. METHODS: Between 1992 and 1999, 13 consecutive patients with completely resected moderate- to high-grade uterine sarcoma received three cycles of adjuvant ifosfamide (1.5 g/m(2)/day x 3 days, repeated every 28 days). Mesna was given 30 min prior to infusion. Postinfusion mesna was administered to 10 of the patients in the outpatient setting utilizing a subcutaneous infusion pump. The remaining 3 patients received traditional intravenous mesna at 4 and 8 h after infusion. RESULTS: The median follow-up of the patient population was 26 months. For early-stage patients (n = 10), the 2-year progression-free survival was 60%, with a median of 26 months. The 2-year overall survival was 100%, dropping to 67% at 3 years. Early-stage patients showed an advantage in both progression-free and overall survival. Early-stage patients with mixed müllerian tumor (MMT) had a significantly longer time to progression that those with leiomyosarcoma (LMS) (2-year progression-free survival of 100% versus 33%; P = 0.019). Three patients required dose reduction secondary to grade 2-3 toxicities (neutropenia x2, nausea and vomiting x1). All significant toxicity was eliminated with dose reduction. CONCLUSIONS: Adjuvant ifosfamide appears to be safe and well tolerated in patients with completely resected uterine sarcoma. It can easily be given in the outpatient setting if mesna is administered via a subcutaneous pump. Our data, consistent with previous studies in advanced sarcoma, suggest a potentially greater role for ifosfamide in MMT than in LMS.     

Leiomyosarcomas have a poorer prognosis than mixed mesodermal tumours when adjusting for known prognostic factors: the result of a retrospective study of 423 cases of uterine sarcoma.

OBJECTIVE: To determine the survival data for the various tumour types of uterine sarcoma and determine the influence of various prognostic factors on survival. DESIGN: Retrospective analysis of all uterine sarcoma cases registered in the 15 year period 1967-1981. SETTING: West Midlands Regional Cancer Registry, serving a catchment area of 2.6 million women. SUBJECTS: 423 women registered as having a uterine sarcoma; 367 of these were associated with the two main histological types, leiomyosarcomas (LMS) and mixed mesodermal tumours (MMT). MAIN OUTCOME MEASURES: Duration of survival was taken as the primary endpoint. RESULTS: The overall 5-year survival for uterine sarcomas in this series was 31%, with the major prognostic indicator being tumour stage. Survival for mixed mesodermal tumours is similar to other sarcomas despite a tendency towards less differentiation, wider dissemination and a greater age of the patient at diagnosis. Multivariate analysis shows that for cases with similar stage, age and grade, mixed mesodermal tumours have a better prognosis than leiomyosarcomas. CONCLUSIONS: These results demonstrate the danger of considering each variable in isolation when the relation between variables can lead to spurious significance or lack of significance because of the imbalances in the numbers between groups of prognostic importance. This study underlines the need for an adequate inspection of the intra-abdominal contents at the time of hysterectomy for uterine fibroids.     

Treatment of advanced uterine sarcoma with adriamycin

Between 1971 and 1979, 39 patients with clearly measurable metastatic or advanced recurrent sarcoma of uterine origin were treated with Adriamycin, either alone or in combination with other chemotherapeutic drugs. The median survival was 7.2 months. No patient lived beyond 32 months from the start of chemotherapy. The response rate was 10.3% (10.3% partial responses and no complete responses). The median duration of a partial response was 4 months. There was no difference between the median survival of the responders and nonresponders.     

Adjuvant chemotherapy in early stage uterine sarcomas: an open question.

Uterine sarcomas are aggressive gynecological cancers even at early stage of disease. The most common histological types are represented by leiomyosarcoma, endometrial stromal sarcoma, and carcinosarcoma. The mainstay of treatment of stage I-II disease is total hysterectomy with bilateral salpingo-oophorectomy. Adjuvant radiotherapy may decrease local recurrence rates without any significant impact on survival. Adjuvant chemotherapy is a logical approach, since distant recurrences are more frequent than local failures. The chemotherapy regimens commonly used in advanced uterine sarcomas are similar to the ones for advanced soft tissue sarcomas, with anthracyclines and ifosfamide as the most active drugs. However, carcinosarcomas respond better to cisplatin-based regimens. It is advisable to design international cooperative randomized trials with the aim of defining the role of adjuvant chemotherapy in the treatment of early stage uterine sarcomas.     

Is there any place for cytotoxic chemotherapy in endometrial cancer?

Cytotoxic chemotherapy has an established role in the treatment of many solid tumours that are considered to be incurable with any modern treatment method. Such treatment may result in an improvement in quality of life without influencing overall survival. In this chapter the evidence to support the use of chemotherapy in patients with advanced or recurrent endometrial adenocarcinoma is reviewed. The most effective single agent and combination treatments are outlined. Although evidence from randomized trials is limited, combination chemotherapy can lead to response rates of over 40% in patients with advanced disease. The role of chemotherapy as adjuvant treatment in patients with early-stage disease is less well defined and this treatment is not recommended outside a clinical trial. The role of chemotherapy for treatment of the aggressive histological variant, uterine papillary serous carcinoma is also discussed.     

复发性子宫肉瘤的诊治

子宫肉瘤是罕见的女性生殖道恶性肿瘤,从组织学类型可分为子宫平滑肌肉瘤、子宫内膜间质肉瘤和恶性混合性中胚叶瘤。复发率高,治疗以手术、化疗等综合治疗为主,放疗效果不确切,可以协助控制局部复发,抗雌激素治疗也有一定效果。影响预后的因素很多,主要是临床期别和肿瘤大小。     

Paclitaxel in the treatment of carcinosarcoma of the uterus: a gynecologic oncology group study

OBJECTIVE: The goal of this study was to estimate the clinical activity of paclitaxel in patients with persistent or recurrent carcinosarcoma of the uterus who have failed other treatments. METHODS: The Gynecologic Oncology Group (GOG) conducted a phase II study of paclitaxel 170 mg/m(2) (135 mg/m(2) in those with prior irradiation) intravenously every 3 weeks in patients with histologic confirmation of carcinoma and measurable disease who had failed appropriate local therapy. RESULTS: A total of 53 patients were entered into the study between September 1994 and January 1997; 44 patients were evaluable for response. The median age of the patients treated was 65 years (range: 38-79). Twenty-six patients had heterologous mixed mesodermal tumors (MMTs) and 18 patients had homologous tumors. A median of three courses were administered (range: 1-18). Fifteen patients had previous radiation therapy and 33 patients had failed prior chemotherapy. Eight patients (18.2%) had a response to paclitaxel: four patients had a complete response and four had a partial response. Neutropenia was the most common toxic effect. CONCLUSIONS: Paclitaxel had moderate activity in patients with carcinosarcoma of the uterus. The GOG is currently studying the combination of paclitaxel and ifosfamide versus ifosfamide alone for patients with advanced or recurrent carcinosarcoma of the uterus.     

Mesna, doxorubicin, ifosfamide and dacarbazine chemotherapy for uterine leiomyosarcoma: a report of two cases

The prognosis of uterine leiomyosarcoma (LMS) is notoriously poor and a standard chemotherapy for patients with uterine LMS has not yet been established. Here, we describe two patients with recurrent LMS of the uterus who were treated with mesna, doxorubicin, ifosfamide and dacarbazine chemotherapy; one achieved complete and the other partial remission.     

Systematic review of first-line chemotherapy for newly diagnosed postoperative patients with stage II, III, or IV epithelial ovarian cancer

OBJECTIVE: The aim of this study was to determine the optimal postoperative chemotherapy regimen for women with newly diagnosed stage II, III (micro or macro), or IV epithelial ovarian cancer. METHODS: A systematic search was conducted to find randomized controlled trials and meta-analyses published between 1980 and April 2001. RESULTS: A published meta-analysis found that, compared with non-platinum-based regimens, platinum, alone or in combination with other agents, improved survival when used as first-line chemotherapy for ovarian cancer. The meta-analysis did not detect a difference in efficacy between cisplatin and carboplatin. A published randomized trial of cisplatin plus paclitaxel versus carboplatin plus paclitaxel did not detect a significant difference in survival between these regimens. In two randomized trials, treatment with paclitaxel plus cisplatin resulted in improved survival compared with cyclophosphamide plus cisplatin. A randomized trial of paclitaxel plus cisplatin versus paclitaxel alone versus cisplatin alone detected no differences in survival among the three treatment groups. While hematologic adverse effects were more frequent with carboplatin than with cisplatin, nonhematologic adverse effects were less frequent with carboplatin. The addition of paclitaxel to cisplatin did not appear to increase the incidence of serious adverse effects. CONCLUSIONS: Intravenous carboplatin plus paclitaxel is the recommended postoperative chemotherapy regimen for newly diagnosed stage II-IV epithelial ovarian cancer. Intravenous cisplatin plus paclitaxel may also be considered a treatment option. Intravenous carboplatin as a single agent may be considered a treatment option in patients for whom paclitaxel is contraindicated or in patients who are unwilling to accept the adverse effects of paclitaxel chemotherapy.     

Excellent progression-free survival with liposomal doxorubicin for a patient with recurrent ovarian malignant mixed müllerian tumor: case report and literature review

INTRODUCTION: Ovarian malignant mixed müllerian tumor (MMMT) is a rare, highly aggressive, fatal disease. Patients have a median survival of 18 months and a 5-year survival rate of only 8%. Optimal cytoreduction surgery plus platinum-based combination chemotherapy are associated with better outcomes. CASE REPORT: A 65-year-old patient of stage IIIc ovarian MMMT having obtained a 41-month remission after four courses of aggressive surgical debulking procedures, platinum-containing chemotherapy, and intraoperative radiotherapy suffered from multi-focal recurrences and obtained another 22-month progression-free survival after treatment with monthly liposomal doxorubicin (Lipo-Dox) for 14 courses and Lipo-Dox/carboplatin for subsequent 6 courses without obvious toxicity. DISCUSSION: Liposomal doxorubicin might be useful as salvage chemotherapy for heavily pretreated, recurrent ovarian MMMT. A prospective trial is needed for more proof.     

Chemotherapy for recurrent epithelial ovarian cancer previously treated with platinum--a systematic review of the evidence from randomized trials

PURPOSE: To evaluate the chemotherapeutic options for women with recurrent epithelial ovarian cancer who have received platinum-based chemotherapy. METHODS: A systematic search of the Medline, CancerLit and Cochrane Library databases was performed for the period from 1984 to June 2001 to find randomized trials comparing second- or higher-line chemotherapy regimens in patients with recurrent platinum-pretreated epithelial ovarian cancer. RESULTS: Seven randomized trials have failed to demonstrate the clear superiority of any one chemotherapy regimen in terms of improvements in long-term survival, quality of life or response rate. One trial detected a statistically significant difference between treatments in progression-free survival, which was longer with cyclophosphamide/doxorubicin/cisplatin than with paclitaxel in women with platinum-sensitive ovarian cancer. Another trial did not show a difference between liposomal doxorubicin and topotecan overall in women with recurrent ovarian cancer but a subgroup analysis detected a significant survival advantage for liposomal doxorubicin over topotecan in women with platinum-sensitive disease. CONCLUSION: The evidence available does not support firm conclusions about the preferred chemotherapy regimen for recurrent ovarian cancer. Randomized trials that compare new drugs with current standard treatments are needed.     

Role of chemotherapy and biomolecular therapy in the treatment of uterine sarcomas

Uterine sarcomas are rare, high-risk malignancies. Expert histologic review is important for accurate diagnosis. For high-grade leiomyosarcomas, the risk of recurrence is high after complete resection of uterus-limited disease; however, no adjuvant therapy has been proven to improve survival. Chemotherapy regimens with efficacy in treating advanced uterine leiomyosarcoma include gemcitabine-docetaxel, doxorubicin and ifosfamide. Uterine carcinosarcomas also carry a high risk of recurrence. Adjuvant chemotherapy is a standard approach for completely resected and metastatic carcinosarcoma. Active agents include carboplatin, cisplatin, ifosfamide and paclitaxel.     

Hormonal therapy and chemotherapy of endometrial cancer

Endometrial cancer is usually diagnosed at an early stage where surgery alone is the adequate therapy. Chemotherapy and hormonal treatment are therefore almost exclusively performed in palliative situations. Hormonal treatment with progestogens (medroxyprogesterone acetate and megestrol acetate) should be the therapy of choice primarily as these drugs are very well tolerated. Tamoxifen and GnRH analogs are further options but are seldom used. The response rates to hormonal treatment are relatively low (max. 25 %) with short remissions in most cases. - So far neither hormonal treatment nor cytotoxic chemotherapy has been shown to have substantial benefits in the adjuvant setting. In some selected high risk cases (serous papillary carcinomas, extra uterine manifestation) adjuvant chemotherapy may be an option following surgery, before or after radiotherapy. Age, general condition and morbidity of the patients need to be considered as limiting factors for chemotherapy. Crucial for the prognosis of all endometrial cancer patients however, is the stage adapted surgery. - Cytotoxic chemotherapy has failed to bring a break through in the therapy of advanced endometrial cancer. Cisplatin plus doxorubicin is the standard combination to date, with anthracyclines being the more important component. In a mono-therapy setting, doxorubicin and epirubicin are well tolerated and convenient in their efficacy. For recurrent and metastatic disease, docetaxel is being evaluated for efficacy and side effects in a multicenter phase II trial.     

Adjuvant chemotherapy with cisplatin, ifosfamide, and doxorubicin followed by radiotherapy in localized uterine sarcomas: results of a case-control study with radiotherapy alone

Uterine sarcoma is a poor prognosis disease, with a high risk of metastatic relapse. We conducted a study of adjuvant chemotherapy with cisplatin, ifosfamide, and doxorubicin followed by radiotherapy (n=18). The results were then compared in a matched case-controlled study to radiotherapy alone (n=16) or no therapy at all (n=2). Chemotherapy consisted in three cycles of adriamyein-platinum-ifosfamide (API) (doxorubicin 60 mg /m2 on day 1; cisplatin 100 mg /m2 on day 2; ifosfamide 5 g /m2 on day 1+mesna 5 g /m2 on day 1+granulocyte colony-stimulating factor; q 3 weeks). Drug doses were reduced (20% for ifosfamide and cisplatin) four times (four patients) due to hematologic toxicity. Compared to a case-control study of adjuvant radiotherapy alone, results were not decreased by the addition of a toxic chemotherapy. CONCLUSION: Adjuvant API chemotherapy followed by radiotherapy is a feasible protocol; a multicenter phase III study comparing radiotherapy alone versus API chemotherapy followed by radiotherapy just began in France.