A Phase II Gynecologic Oncology Group Trial of Ifosfamide and Mesna in Advanced or Recurrent Adenocarcinoma of the Endometrium

doi:10.1006/gyno.1996.0272

Gynecologic Oncology

Volume 63, Issue 1, October 1996, Pages 25-27

https://doi.org/10.1006/gyno.1996.0272 Get rights and content

Abstract

In other Gynecologic Oncology Group (GOG) studies, ifosfamide demonstrated antineoplastic activity against ovarian epithelial tumors, squamous carcinomas of the cervix, uterine sarcomas, and trophoblastic disease. Responses were also observed in 15% of patients with endometrial adenocarcinoma previously exposed to chemotherapy. This is a phase II trial of ifosfamide in patients with chemotherapy-naive advanced or recurrent endometrial adenocarcinoma. Thirty-seven patients with advanced adenocarcinoma of the endometrium recurrent after surgery and/or radiotherapy were treated with ifosfamide 1.2 g/m²intravenously daily for 5 days every 4 weeks and mesna 300 mg/m²intravenously every 4 hr for 3 doses daily for 5 days with each course. Three patients were ineligible—one due to a second primary, one did not have an endometrial primary, and the other because of wrong cell type. One patient was inevaluable for response; thus, 33 were evaluable for response. All patients had undergone hysterectomy and 24 had received radiotherapy before entering the trial. Eleven had GOG performance status of 0, 18 had a status of 1, and 4 had performance status of 2. Median age was 68 years (range, 41–86 years). Grade 3 or 4 neutropenia occurred in eight patients each and grade 3 thrombocytopenia was observed in one patient. One patient had a grade 4 neurotoxicity. Complete responses were observed in two patients (6.1%) and partial responses in six (18.2%) for an overall response rate of 24.3%. Ifosfamide in this dose and schedule is an active drug in the treatment of patients with advanced or recurrent adenocarcinoma of the endometrium.

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Cited by (39)

A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study
2017, Gynecologic Oncology
Citation Excerpt :
Patients with metastatic, recurrent, or persistent cervical cancers have limited treatment choices and poor prognosis. Previous GOG trials of chemotherapy agents showed response rates of < 30% and 6 month PFS of < 25% in this patient population [19–25]. Thus, options for treatment of recurrent and metastatic disease are limited and novel therapies are warranted.
Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients.
Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800 mg was administered orally every day (1 cycle = 28 days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) > 6 months and objective tumor response.
Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had > 2 cycles of brivanib with 4 (14%) receiving > 10 cycles (range: 1–20). Seven (25%) patients had PFS > 6 months (90% CI: 7.3%–33.9%). Two (7%) (90% CI: 1.3%–20.8%) patients had partial tumor response with duration of 8 and 22 months and 12 (43%) had stable disease. The median PFS was 3.2 months (90% CI: 2.1–4.4). The median overall survival was 7.9 months (90% CI: 6.1–11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension.
Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability.
A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: A study of the Princess Margaret, Chicago and California Consortia
2014, Gynecologic Oncology
Citation Excerpt :
In this subgroup of patients, the response rate was 16% and the prolonged disease control rate was 28%. These results compare favorably with other trials of second line chemotherapy in EC where cytotoxic agents including topotecan [9], liposomal doxorubicin [10] and ifosfamide [29] have reproducibly failed to achieve a response rate in excess of 10%. Moreover recent experience with the mTOR inhibitors reveals that although the level of activity of these drugs is encouraging in women with advanced EC [30–34], they have demonstrated reproducible antitumor activity across histology subtypes, predominantly stable disease and an objective response rate from 0 to 25%.
Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC.
We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50 mg daily administered on a 4 weeks on–2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate.
34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (30.3%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent. At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar–plantar erythrodysesthesia, diarrhea and hematologic.
Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.
Treatment options for advanced endometrial carcinoma
2010, Gynecologic Oncology
Citation Excerpt :
With more frequent use of cisplatin, carboplatin, doxorubicin, and paclitaxel in the adjuvant setting, women who have disease recurrence or develop metastastic disease face limited choices for additional treatment. The GOG has conducted numerous phase II trials of single-agent chemotherapy in the second-line treatment setting, but objective responses are seen in only a limited number of patients and typically last for only several months (Table 2) [34–40]. These observations underscore the unmet medical need for new and effective second-line therapies for endometrial adenocarcinoma.
Endometrial carcinoma is the most common malignancy of the female reproductive tract. Most cases are diagnosed at an early stage due to the appearance of symptoms such as postmenopausal bleeding. However, endometrial carcinoma carries a poor prognosis when it recurs after previous definitive treatment or when diagnosed at an advanced stage. Here, treatment options for advanced endometrial carcinoma are evaluated.
Literature review was performed to determine current therapy options, with a focus on the treatment landscape for women with recurrent, advanced, or metastatic disease.
Combination chemotherapy is being used more frequently as first-line treatment of advanced disease, consisting of cisplatin/doxorubicin/paclitaxel, if tolerated, or the doublet of carboplatin/paclitaxel. Options following disease progression after first-line treatment are extremely limited, particularly with the increasing use of active agents in the adjuvant setting. Fortunately, several new cytotoxic and biologic therapies appear promising for women who have progressed on first-line treatment.
Clinical trials are planned to further explore how to best incorporate novel agents into the current treatment algorithm with the aim to improve the options in both first- and second-line treatments for women with endometrial adenocarcinomas.
Absence of MGMT promoter methylation in endometrial cancer
2009, Gynecologic Oncology
Citation Excerpt :
This however, seems unlikely in the ovarian tumor specimen we investigated. Previous studies evaluating alkylating agents such as ifosfamide and cyclophosphamide in the treatment of advanced stage or progressive endometrial cancer showed lackluster responses to this class of cytotoxics [21–22]. MGMT activity in endometrial cancers could explain in part the limited response to alkylating agents.
O⁶-methylguanine-DNA methyltransferase (MGMT) acts to repair DNA damaged by alkylation of guanine residues. MGMT promoter methylation and gene silencing is seen in a variety of cancers and pre-cancerous changes [Ogino S, Meyerhardt JA, Kawasaki T, et al. CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma. Virchows Arch 2007;450:529–37; Rodriguez MJ, Acha A, Ruesga MT, Rodriguez C, Rivera JM, Aguirre JM. Loss of expression of DNA repair enzyme MGMT in oral leukoplakia and early oral squamous cell carcinoma. A prognostic tool? Cancer Lett 2007;245:263–8; Ishii T, Murakami J, Notohara K, et al. Oesophageal squamous cell carcinoma may develop within a background of accumulating DNA methylation in normal and dysplastic mucosa. Gut 2007;56:13–9]. The loss of MGMT activity and promoter methylation is associated with increased sensitivity to alkylating agents and is a favorable prognostic indicator in gliomas [Weaver KD, Grossman SA, Herman JG. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma. Cancer Invest 2006;24:35–40; Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000;343:1350–4; Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997–1003]. We sought to determine if MGMT promoter methylation plays a role in endometrial cancer.
One hundred and twenty primary endometrial cancers were analyzed for MGMT promoter methylation by combined bisulfite restriction analysis (COBRA). The cohort included 77 endometrioid endometrial cancers, 43 endometrial tumors of adverse histologic type, and 6 endometrial cancer cell lines. Twenty-one endometrioid and mixed endometrioid ovarian cancers were also analyzed. A subset of the primary tumors was analyzed for MGMT expression by immunohistochemistry.
No MGMT promoter methylation was seen in the 120 endometrial cancers evaluated or the 6 endometrial cancer cell lines. One of the 21 endometrioid ovarian cancers showed methylation. Immunohistochemistry revealed moderate to high level expression of MGMT in the primary endometrial tumors.
MGMT promoter methylation is an infrequent event in endometrial cancer. MGMT expression and the ability to repair damaged alkylguanine residues could in part explain the limited response of endometrial tumors to alkylating chemotherapy.
Phase II study of weekly docetaxel in patients with recurrent or metastatic endometrial cancer: AGO Uterus-4
2007, Gynecologic Oncology
The aim of this phase II multicenter study was to evaluate the safety, toxicity and efficacy of docetaxel administered weekly as first line chemotherapy in patients with recurrent or metastatic endometrial cancer.
Thirty five patients with recurrent or metastatic endometrial cancer without previous chemotherapy were enrolled to receive three 6-week cycles of docetaxel 35 mg/m²/week with 2-week breaks between the cycles. Therapy response was evaluated after every 6-week cycle, and therapy was continued in case of at least stable disease. Final therapy response was evaluated after three 6-week cycles of docetaxel.
Thirty five patients with a median age of 65 years (range, 37–80 years) were evaluable for toxicity assessment, one patient presented with severe anaphylactic reaction during the second application of docetaxel and therapy was discontinued. Subsequently, this patient received doxorubicin–cisplatin combination chemotherapy. Another patient was initially documented with uterine papillary serous cancer but secondarily confirmed as uterine carcinosarcoma. Thus, 33 patients were assessable for response. Overall response rate was 21% (3 PR and 4 CR). Three patients showed stable disease. Median TTP and OAS were 12 weeks and 43 weeks, respectively. Therapy with weekly docetaxel was well tolerated; in particular, no grade 3 or 4 hematological toxicities occurred.
Docetaxel weekly has a favorable toxicity profile, is well tolerated and shows encouraging activity in patients with advanced endometrial cancer.
Old and new perspectives in the pharmacological treatment of advanced or recurrent endometrial cancer: Hormonal therapy, chemotherapy and molecularly targeted therapies
2006, Critical Reviews in Oncology/Hematology
Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. Progesterone therapy obtains overall response rates ranging from 11% to 25% in patients with endometrioid-type tumours, and oral medroxyprogesterone acetate 200 mg daily appears to be a reasonable therapeutic option for those lesions that are well differentiated and/or have a high progesterone receptor (PgR) content. However, the activity of progestins is often compromised by the down-regulation of PgR within the target tissues, and therefore therapeutic strategies designed to enhance PgR expression are warranted. Little data are currently available about the new aromatase inhibitors and selective estrogen receptor modulators. As for chemotherapy, the combination of doxorubicin [DOX] + cisplatin [CDDP] achieves overall response rates ranging from 34% to 60%, and the addition of paclitaxel (TAX) seems to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. A phase III study is currently comparing TAX + DOX + CDDP versus the less toxic combination of TAX + carboplatin. Chemotherapy is active against both endometrioid-type carcinoma and uterine serous papillary carcinoma. However, this latter endometrial malignancy is less chemosensitive than the histologically similar high-grade serous ovarian carcinoma. Interesting fields of research are represented by investigational agents directed against specific intracellular signal transduction pathways involved in the proliferation, invasiveness and metastatic spread of endometrial cancer. Mammalian target of the rapamycin (mTOR) inhibitors, epidermal growth factor receptor inhibitors (gefitinib, erlotinib, lapatinib, the monoclonal antibody cetuximab), imatinib, the monoclonal antibody trastuzumab, and the Clostridium perfrigens enterotoxin are currently under evaluation as molecularly targeted therapies for endometrial cancer. Further investigations addressed to better understand the signal transduction pathways that are disregulated in endometrial carcinogenesis could identify novel biological targets suitable for tailored therapies.

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^☆: Address reprint requests to GOG Administrative Office, Suite 1945, 1234 Market Street, Philadelphia, PA 19107.

^☆☆: Presented at the 27th Annual Meeting of the Society of Gynecologic Oncologists, New Orleans, LA, February 10–14, 1996.

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Regular ArticleA Phase II Gynecologic Oncology Group Trial of Ifosfamide and Mesna in Advanced or Recurrent Adenocarcinoma of the Endometrium☆,☆☆

Abstract

Regular Article
A Phase II Gynecologic Oncology Group Trial of Ifosfamide and Mesna in Advanced or Recurrent Adenocarcinoma of the Endometrium☆,☆☆